Antimicrobial compounds

Abstract

The present invention relates to the compound [Formula 1] TIFF2022548247000183.tif34170 wherein the integers are as defined herein, the compounds may be useful as pharmaceutical agents, for example for use in the treatment of tuberculosis.

Description

[Technical field]

[0001] The present invention relates to novel chemical compounds. The present invention also relates to such compounds for use as medicines and further for use in the treatment of bacterial diseases, such as diseases caused by pathogenic mycobacteria, e.g., Mycobacterium tuberculosis. Such compounds may act by interfering with ATP synthase in M. tuberculosis, with the main mechanism of action being the inhibition of cytochrome bc 1 Therefore, primarily, such compounds are anti-tuberculous drugs. [Background technology]

[0002] Mycobacterium tuberculosis is the causative agent of tuberculosis (TB), a serious and potentially fatal infectious disease distributed worldwide. The World Health Organization estimates that over 8 million people develop TB each year, and 2 million die from it annually. In the last decade, TB cases have increased by 20% worldwide, with the highest burden in the poorest regions. If these trends continue, TB incidence will increase by 41% in the next 20 years. 50 years after the introduction of effective chemotherapy, TB remains the second leading cause of infectious deaths in adults worldwide after AIDS. The spread of TB is driven by the increasing emergence of multidrug-resistant strains and a highly harmful symbiosis with HIV. HIV-positive TB-infected people are more than 30 times more likely to develop active TB than HIV-negative people, and TB accounts for one in three deaths from HIV / AIDS worldwide.

[0003] All existing approaches to tuberculosis treatment involve the combination of multiple drugs. For example, the regimen recommended by the US Public Health Service is a combination of isoniazid, rifampicin, and pyrazinamide for two months, followed by an additional four months of isoniazid and rifampicin alone. These drugs are continued for an additional seven months in patients infected with HIV. In patients infected with multidrug-resistant strains of M. tuberculosis, drugs such as ethambutol, streptomycin, kanamycin, amikacin, capreomycin, ethionamide, cycloserine, ciprofoxacin, and ofloxacin are added to the combination therapy. There is no single drug effective in the clinical treatment of tuberculosis, nor is there a combination of drugs that allows treatment for less than six months.

[0004] There is a high medical need for new agents that would improve current treatments by allowing for regimens that facilitate patient and provider compliance. A shorter regimen and one that requires less administration is the best way to achieve this. Most of the benefit of treatment is obtained during the intensive or sterilizing phase within the first 2 months, when the four combination drugs are given and the bacterial load is greatly reduced and the patient is no longer infectious. A continuation or sterilizing phase of 4-6 months is required to eliminate any remaining bacteria and minimize the risk of relapse. An effective sterilizing agent that would shorten treatment to 2 months or less would be extremely beneficial. Agents that facilitate compliance by reducing the need for intensive administration are also needed. Clearly, the greatest benefit would be achieved by a compound that reduces both the overall duration of treatment and the frequency of drug administration.

[0005] Contributing to the spread of TB is the increasing occurrence of multi-drug resistant strains, or MDR-TB. Up to 4 percent of all cases worldwide are considered MDR-TB, strains resistant to the four most effective standard drugs, isoniazid and rifampin. MDR-TB is fatal if untreated and cannot be adequately treated with standard therapies, requiring "second-line" drugs for up to two years. These drugs are often toxic, expensive, and only marginally effective. In the absence of effective treatments, infectious MDR-TB patients continue to spread the disease, generating new infections with MDR-TB strains. There is a high medical need for new drugs with novel mechanisms of action that may show activity against drug-resistant strains, especially MDR strains.

[0006] The term "drug resistance" as used herein above or below is a term well understood by those skilled in the art of microbiology. A drug-resistant Mycobacterium is a Mycobacterium that is no longer sensitive to at least one previously effective drug and has developed the ability to withstand antibacterial attack by at least one previously effective drug. Drug-resistant strains can pass this resistance on to their progeny. The resistance can be due to random genetic mutations in bacterial cells that alter their susceptibility to a single drug or to a variety of drugs.

[0007] MDR tuberculosis is a specific form of drug-resistant tuberculosis due to bacterial resistance to at least isoniazid and rifampicin, currently the two most powerful anti-TB drugs, with or without resistance to other drugs. Thus, wherever used herein above or hereinafter, "drug resistance" includes multiple drug resistance.

[0008] Another factor in controlling the spread of TB is the problem of latent TB. Despite decades of tuberculosis (TB) control programs, approximately 2 billion people are asymptomatically infected with Mycobacterium tuberculosis (M. tuberculosis). Approximately 10% of these individuals are at risk of developing active TB during their lifetime. The global spread of TB is fueled by TB infection in HIV patients and the rise in multidrug-resistant TB strains (MDR-TB). Reactivation of latent TB is a high risk factor for disease development and accounts for 32% of deaths in HIV-infected individuals. To control the spread of TB, it is necessary to discover novel drugs that can kill the bacteria in a dormant or latent state. Dormant TB can be reactivated and cause disease by several factors, such as suppression of the host's immunity through the use of immunosuppressants such as antibodies against tumor necrosis factor alpha or interferon-gamma. For HIV-positive patients, the only preventive treatment available for latent TB is a 2-3 month regimen of rifampicin, pyrazinamide. The efficacy of this treatment regimen remains unclear, and furthermore, in resource-limited settings, the duration of treatment is a significant limitation.Therefore, there is a great need to identify novel agents that can act as chemopreventive agents for individuals harboring latent TB bacteria.

[0009] M. tuberculosis enters healthy individuals by inhalation and is phagocytosed by alveolar macrophages in the lungs. This leads to a strong immune response and the formation of granulomas, which consist of M. tuberculosis-infected macrophages surrounded by T cells. After 6-8 weeks, the host immune response leads to death of the infected cells by necrosis and accumulation of caseous material by specific extracellular bacteria, surrounded by layers of macrophages, epithelioid cells, and surrounding lymphoid tissue. In healthy individuals, the majority of mycobacteria die in these environments, but a small percentage of bacilli still survive and appear to exist in a non-replicating hypometabolic state, resistant to killing by anti-TB drugs, e.g., isoniazid. These bacteria can persist even for the life of an individual in altered physiological environments without showing any clinical signs of disease. However, in 10% of cases, these latent bacteria can reactivate and cause disease. One hypothesis for the emergence of these persistent bacteria is that the pathophysiological environment of human lesions, i.e., reduced oxygen tension, limited nutrient sources, and acidic pH, renders these bacteria phenotypically resistant to major antimycobacterial drugs.

[0010] In addition to addressing the TB epidemic, there is an emerging problem of resistance to first-line antibiotics, some key examples being penicillin-resistant Streptococcus pneumoniae, vancomycin-resistant enterococci, methicillin-resistant Staphylococcus aureus, and multidrug-resistant Salmonellae.

[0011] Resistance to antibiotics has serious consequences: Infections caused by resistant bacteria do not respond to treatment, resulting in longer illness and increased risk of death. Treatment failure extends the period of infectiousness, thereby increasing the number of infected people moving through the community, thus putting the general population at risk of contracting resistant infections.

[0012] Hospitals are a significant component of the antimicrobial resistance problem worldwide: the combination of susceptible patients, intensive and prolonged antibiotic use, and cross-infection leads to infections with highly resistant pathogens.

[0013] Self-medication with antibiotics is another major factor contributing to resistance: self-medication antibiotics may be unnecessary, are often inadequately dosed, and may not contain sufficient amounts of active drug.

[0014] Patient compliance with recommended treatment is another major problem: patients may forget to take medication when they start to feel better, discontinue treatment, or fail to complete the full course, thereby creating an ideal environment for the microorganisms to adapt rather than be killed.

[0015] Due to the emergence of resistance to multiple antibiotics, physicians are faced with infections for which there are no effective treatments, and the morbidity, mortality, and financial costs of such infections place an increasing burden on healthcare systems worldwide.

[0016] Thus, there is a great need for new compounds to treat bacterial infections, particularly mycobacterial infections, including drug-resistant and latent mycobacterial infections, as well as other bacterial infections, particularly bacterial infections caused by resistant bacterial strains.

[0017] Anti-infective compounds for treating tuberculosis are disclosed, for example, in International Patent Application WO 2011 / 113606, which relates to compounds that prevent M. tuberculosis growth inside host macrophages, for example compounds having a bicyclic imidazopyridine nucleus linked (e.g., via an amide moiety) to an optionally substituted benzyl group.

[0018] International Patent Application WO 2014 / 015167 also discloses compounds that are potentially useful for the treatment of tuberculosis. Such compounds disclosed therein have a bicyclic ring (5,5-fused bicyclic ring) as an essential element that is itself substituted by a linker group (e.g., an amide group) that can be linked to another bicyclic ring or to an aromatic group. Such compounds in this document do not contain a series of four or more rings.

[0019] The journal article by Pethe et al., Nature Medicine, 19, 1157-1160 (2013), "Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis," identifies a specific compound that was tested against M. tuberculosis. This compound, Q203, is shown below. [ka]

[0020] This clinical candidate is also discussed in the journal article J. Medicinal Chemistry, 2014, 57(12), pp5293-5305. Q203 has activity against MDR tuberculosis, with an MIC of 0.28 nM against M. tuberculosis strain H37Rv inside macrophages. 50 It has been described as having activity against TB. Positive control data (using the known anti-TB compounds bedaquiline, isoniazid and moxifloxacin) are also reported. The literature also suggests a mode of action based on mutant studies. It acts by interfering with ATP synthase in M. tuberculosis and inhibits the cytochrome bc 1 It is hypothesized that inhibition of cytochrome bc activity is the primary mechanism of action. 1 is an essential component of the electron transport chain required for ATP synthesis. Q203 was found to be highly active against both replicating and non-replicating bacteria.

[0021] International Patent Application WO 2015 / 014993 also discloses compounds with activity against M. tuberculosis, as do International Patent Applications WO 2014 / 4015167, WO 2017 / 001660, WO 2017 / 001661, WO 2017 / 216281, and WO 2017 / 216283. International Patent Applications WO 2013 / 033070 and WO 2013 / 033167 disclose various compounds as kinase modulators. Summary of the Invention [Problem to be solved by the invention]

[0022] It is an object of the present invention to provide compounds for use in the treatment of bacterial disease, particularly disease caused by pathogenic bacteria such as Mycobacterium tuberculosis, including latent disease, including drug-resistant M. tuberculosis strains. Such compounds may also be novel and may act by interfering with ATP synthase in M. tuberculosis, inhibiting the cytochrome bc 1 Inhibition of activity is thought to be the primary mechanism of action. [Means for solving the problem]

[0023] Here, formula (I) [ka] [In the formula, A is a 5- or 6-membered ring which may be aromatic or non-aromatic and optionally contains 1 or 2 heteroatoms selected from nitrogen and sulfur; B is a 5-membered aromatic ring containing 1 or 2 nitrogen heteroatoms; R 1 is halo (e.g. Cl, F), -R 6a , -OR6b , -C(=O)-R 6c , -C(=O)-N(R 7 )(R 8 ), -CN, and -N(R 7a )R 7b represents one or more (e.g., one, two, or three) optional substituents independently selected from: R 2 Halo and -OC 1~3 -C optionally substituted with one or more substituents selected from alkyl 1~4 is alkyl; R 3 , R 3a , R 4 , and R 4a Any two of the groups represent H, and the other two are independently H, F, or -C. 1~3 Alkyl and -OC 1~3 represents a substituent selected from alkyl; R 5 ,H,-R 9a , -C(=O)-R 9b , -SO 2 -R 10 , or Het 1 and; Any one of X and Y is -CR 11a The others are N or -CR. 11b represents; R 6a and R 6b are independently halo (e.g., F) and -O-CH 3 -C optionally substituted with one or more substituents selected from 1~4 represents alkyl; R 6c -C 1~3 is alkyl; R 7 and R 8 H and -C 1~3 independently selected from alkyl; R 7a and R 7b are independently H, C 1~6 Represents alkyl or R 7a and R 7btogether form a 3- to 6-membered ring; R 9a Ha, Halo, -OC 1~3 Alkyl and Het 2 -C optionally substituted with one or more substituents selected from 1~4 represents alkyl; R 9b is hydrogen or -C 1~3 alkyl (optionally substituted with one or more fluoro atoms); R 10 is halo (e.g., F) and -O-CH 3 -C optionally substituted with one or more substituents selected from 1~4 is alkyl; R 11a and R 11b are independently H, C 1~4 Alkyl (itself, fluoro, -CN, -R 12a , -OR 12b , -N(R 12c )R 12d and / or -C(O)N(R 12e )R 12f or -OC 1~4 Alkyl (itself, fluoro, -R 12g , -OR 12h , and / or -N(R 12i )R 12j (optionally substituted with one or more, e.g., one, substituent selected from); R 12a , R 12b , R 12c , R 12d , R 12e , R 12f , R 12g , R 12h , R 12i , and R 12j are independently hydrogen or C 1~3 represents alkyl (optionally substituted with one or more fluoro atoms); Het 1 and Het 2contains 1 or 2 heteroatoms, independently selected from nitrogen and sulfur, halo and C 1~3 represents a 5- or 6-membered aromatic ring optionally substituted with one or more substituents selected from alkyl (which itself is optionally substituted with one or more fluoro atoms). or a pharma- ceutically acceptable salt thereof, Such compounds may be referred to herein as "compounds of the invention." DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] In one embodiment, wherein formula (Ia) [ka] [In the formula, Q 1 is =N- or =C(R 4 )-represents; A is a 5- or 6-membered ring which may be aromatic or non-aromatic and optionally contains 1 or 2 heteroatoms selected from nitrogen and sulfur; B is a 5-membered aromatic ring containing 1 or 2 nitrogen heteroatoms; R 1 is halo (e.g. Cl, F), -R 6a , -OR 6b , -C(=O)-R 6c , -C(=O)-N(R 7 )(R 8 ), -CN, and -N(R 7a )R 7b or any two R 1 The groups taken together (when attached to adjacent atoms of the A ring) optionally form a 5- or 6-membered ring containing 1 or 2 heteroatoms, and this ring is preferably connected to 1 or 2 C 1~3 Optionally substituted with alkyl substituents; R 2 Halo and -OC 1~3-C optionally substituted with one or more substituents selected from alkyl 1~4 is alkyl; R 3 , R 3a , R 4 , and R 4a Any two of the groups represent H, and the other two are independently H, F, or -C. 1~3 Alkyl and -OC 1~3 represents a substituent selected from alkyl; R 5 ,H,-R 9a , -C(=O)-R 9b , -SO 2 -R 10 , or Het 1 and; Any one of X and Y is -CR 11a The others are N or -CR. 11b represents; R 6a and R 6b are independently hydrogen or halo (e.g., F), -O-CH 3 -C optionally substituted with one or more substituents selected from 1~4 represents alkyl; R 6c -C 1~3 is alkyl; R 7 and R 8 H and -C 1~3 independently selected from alkyl; R 7a and R 7b are independently H, C 1~6 Represents alkyl or R 7a and R 7b together form a 3- to 6-membered ring; R 9a Ha, Halo, -OC 1~3 Alkyl and Het 2 -C optionally substituted with one or more substituents selected from 1~4 represents alkyl; R 9b is hydrogen or -C 1~3alkyl (optionally substituted with one or more fluoro atoms); R 10 is halo (e.g., F) and -O-CH 3 -C optionally substituted with one or more substituents selected from 1~4 is alkyl; R 11a and R 11b are independently H, C 1~4 Alkyl (itself, fluoro, -CN, -R 12a , -OR 12b , -N(R 12c )R 12d and / or -C(O)N(R 12e )R 12f or -OC 1~4 Alkyl (itself, fluoro, -R 12g , -OR 12h , and / or -N(R 12i )R 12j (optionally substituted with one or more, e.g., one, substituent selected from); R 12a , R 12b , R 12c , R 12d , R 12e , R 12f , R 12g , R 12h , R 12i , and R 12j are independently hydrogen or C 1~3 represents alkyl (optionally substituted with one or more fluoro atoms); Het 1 and Het 2 contains 1 or 2 heteroatoms, independently selected from nitrogen and sulfur, halo and C 1~3 represents a 5- or 6-membered aromatic ring optionally substituted with one or more substituents selected from alkyl (which itself is optionally substituted with one or more fluoro atoms). Also provided is a compound of the formula: The compounds may also be referred to herein as "compounds of the invention."

[0025] Pharmaceutically acceptable salts include acid addition salts and base addition salts.Such salts can be produced by conventional means, for example, by reacting the compound of formula I in free acid or free base form with one or more equivalents of a suitable acid or base, optionally in a solvent or in a medium in which the salt is not soluble, followed by removing the solvent or medium using standard techniques (for example, in vacuum, by lyophilization, or by filtration).Salts can also be prepared by exchanging the counterion of the compound of the present invention in the form of a salt with another counterion, for example, by using a suitable ion exchange resin.

[0026] The aforementioned pharma- ceutically acceptable acid addition salts are intended to include the therapeutically active non-toxic acid addition salt forms that the compounds of formula (I) can form. These pharma- ceutically acceptable acid addition salts can be easily obtained by treating the base form with such a suitable acid. Suitable acids include, for example, inorganic acids, such as hydrohalic acids, e.g., hydrochloric acid or hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or organic acids, such as acetic acid, propanoic acid, hydroxyacetic acid, lactic acid, pyruvic acid, oxalic acid (i.e., ethanedioic acid), malonic acid, succinic acid (i.e., butanedioic acid), maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclamic acid, salicylic acid, p-aminosalicylic acid, pamoic acid, and the like.

[0027] For purposes of this invention, solvates, prodrugs, N-oxides and stereoisomers of the compounds of the invention are also included within the scope of the invention.

[0028] The term "prodrug" of a related compound of the invention includes any compound that, following oral or parenteral administration, is metabolized in vivo to form that compound in experimentally detectable amounts within a given time period (e.g., within a dosing interval of 6 to 24 hours (i.e., 1 to 4 times daily)). For the avoidance of doubt, the term "parenteral" administration includes all forms of administration other than oral administration.

[0029] Prodrugs of the compounds of the invention may be prepared by modifying functional groups present on the compounds in such a way that the modifications are cleaved in vivo when such prodrugs are administered to a mammalian subject. This modification is typically accomplished by synthesizing the parent compound with a prodrug substituent. Prodrugs include compounds of the invention in which a hydroxyl, amino, sulfhydryl, carboxy or carbonyl group in the compounds of the invention is bonded to any group that can be cleaved in vivo to regenerate a free hydroxyl, amino, sulfhydryl, carboxy or carbonyl group, respectively.

[0030] Examples of prodrugs include, but are not limited to, esters and carbamates of hydroxyl functional groups, ester groups of carboxyl functional groups, N-acyl derivatives and N-Mannich bases. General information on prodrugs can be found, for example, in Bundegaard, H. "Design of Prodrugs" p.1-92, Elsevier, New York-Oxford (1985).

[0031] The compounds of the present invention may contain double bonds and therefore may exist as E (entgegen) and Z (zusammen) geometric isomers with respect to each individual double bond. Positional isomers may also be included in the compounds of the present invention. All such isomers (e.g., when the compounds of the present invention contain double bonds or fused rings, cis and trans forms are included) and mixtures thereof are included within the scope of the present invention (e.g., single positional isomers and mixtures of positional isomers may be included within the scope of the present invention).

[0032] The compounds of the present invention may also exhibit tautomerism. All tautomeric forms (or tautomers) and mixtures thereof are included within the scope of the present invention. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that 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 isomerizations. Valence tautomers include interconversions via rearrangement of some of the bond electrons.

[0033] The compounds of the present invention may also contain one or more asymmetric carbon atoms and therefore may exhibit optical isomerism and / or diastereoisomerism. Diastereoisomers may be separated using conventional techniques, for example, chromatography or fractional crystallization. The various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, for example, fractional crystallization or HPLC techniques. Alternatively, the desired optical isomer may be prepared by reaction of the appropriate optically active starting material under conditions that do not cause racemization or epimerization (i.e., the "chiral pool" method), by reaction of the appropriate starting material with a "chiral auxiliary" which may be subsequently removed at a suitable stage, by derivatization (i.e., resolution such as dynamic resolution) with, for example, a homochiral acid followed by separation of the diastereomeric derivatives by conventional means (e.g., chromatography), or by reaction with a suitable chiral reagent or chiral catalyst, all under conditions known to those skilled in the art.

[0034] All stereoisomers (including, but not limited to, diastereoisomers, enantiomers and atropisomers) and mixtures thereof (eg, racemic mixtures) are included within the scope of the present invention.

[0035] In the structures depicted herein, where the stereochemistry of any particular chiral atom is not specified, all stereoisomers are contemplated and encompassed as the compounds of the present invention. Where stereochemistry is specified with a solid wedge or dashed line indicating a particular configuration, that stereoisomer is so specified and defined.

[0036] The compounds of the present invention may exist in unsolvated as well as solvated forms with pharma- ceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the present invention encompasses both the solvated and unsolvated forms.

[0037] The present invention also encompasses isotopically labeled compounds of the present invention that are identical to the compounds described herein except that one or more atoms have been replaced by an atom having an atomic mass or mass number different from that normally found in nature (or the most abundant one found in nature). All isotopes of any particular atom or element as defined herein are considered to be within the scope of the compounds of the present invention. Examples of isotopes that can be incorporated into the compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine ( 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 O. 17 O. 18 O. 32 P, 33 P, 35 S, 18 F, 36 Cl, 123 I, and 125 Certain isotopically labeled compounds of the present invention, such as, for example, 3 H and 14 C) are useful in compound and substrate tissue distribution assays. 3 H) and carbon 14 ( 14 C) isotopes are useful for their ease of preparation and detectability. Additionally, deuterium (i.e., 2Substitution with heavier isotopes, such as H, may confer certain therapeutic advantages (e.g., increased in vivo half-life or reduced dosage requirements) resulting from greater metabolic stability and therefore may be preferred in some circumstances. For example, 15 O. 13 N, 11 C, and 18 Positron emitting isotopes such as F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of the present invention can generally be prepared following procedures similar to those disclosed in the Description / Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0038] Unless otherwise specified, C as defined herein 1~q The alkyl group (where q is the upper limit of the range) may be straight chain or, if there is a sufficient number (i.e., a minimum of 2 or 3 as appropriate), branched chain and / or cyclic (hence, C 3~q -forming a cycloalkyl group). Such cycloalkyl groups may be monocyclic or bicyclic and may further be bridged. Furthermore, 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, unsaturated (e.g., C 2~q Alkenyl group or C 2~q forming an alkynyl group).

[0039] C that may be specifically mentioned 3~qCycloalkyl groups (where q is the upper limit of the range) can be monocyclic or bicyclic alkyl groups, which can further be bridged (thus forming a fused ring system, e.g., a 3-fused cycloalkyl group). Such cycloalkyl groups can be saturated or unsaturated containing one or more double bonds (e.g., forming a cycloalkenyl group). Substituents can be attached at any position on the cycloalkyl group. Furthermore, when there is a sufficient number (i.e., a minimum of four), such cycloalkyl groups can also be part cyclic.

[0040] The term "halo", as used herein, preferably includes fluoro, chloro, bromo, and iodo.

[0041] As referred to herein, a heterocyclic group includes an aromatic or non-aromatic heterocyclic group and can thus encompass heterocycloalkyl groups and heteroaryl groups. Similarly, an "aromatic or non-aromatic 5- or 6-membered ring" can be a heterocyclic group (and carbocyclic group) having 5 or 6 members in the ring.

[0042] Heterocycloalkyl groups that may be mentioned include non-aromatic monocyclic and bicyclic heterocycloalkyl groups, in which at least one (e.g., 1 to 4) of the atoms in the ring system is other than carbon (i.e., a heteroatom) and the total number of atoms in the ring system is between 3 and 20 (e.g., between 3 and 10, e.g., between 3 and 8, e.g., 5 to 8). Such heterocycloalkyl groups may also be bridged. Furthermore, such heterocycloalkyl groups may be saturated or unsaturated and contain one or more double and / or triple bonds, e.g., C 2~q Heterocycloalkenyl (where q is the upper limit of the range) groups are formed. 2~qHeterocycloalkyl groups include 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, dihydropyranyl, dihydropyridyl, dihydropyrrolyl (including 2,5-dihydropyrrolyl), dioxolanyl (including 1,3-dioxolanyl), dioxanyl (including 1,3-dioxanyl and 1,4-dioxanyl), dithianyl (including 1,4-dithianyl), dithiolanyl (including 1,3-dithiolanyl), imidazolidinyl, imidazolinyl, morpholinyl, and the like. Heterocycloalkyl groups include aryl, 7-oxabicyclo[2.2.1]heptanyl, 6-oxabicyclo[3.2.1]octanyl, oxetanyl, oxiranyl, piperazinyl, piperidinyl, non-aromatic pyranyl, pyrazolidinyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, sulfolanyl, 3-sulfonyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydropyridyl (e.g., 1,2,3,4-tetrahydropyridyl and 1,2,3,6-tetrahydropyridyl), thietanyl, thiiranyl, thiolanyl, thiomorpholinyl, trithianyl (including 1,3,5-trithianyl), tropanyl, and the like. Where appropriate, substituents on a heterocycloalkyl group may be located on any atom (including a heteroatom) in the ring system. The attachment point of the heterocycloalkyl group may be through any atom in the ring system, including (where appropriate) a heteroatom (e.g., a nitrogen atom), or an atom on any fused carbocyclic ring that may be present as part of the ring system. Heterocycloalkyl groups may also be in N- or S-oxidized form. Heterocycloalkyls referred to herein are expressly stated to be monocyclic or bicyclic.

[0043] The aromatic group may be aryl or heteroaryl. Aryl groups which may be mentioned are, for example, C 6~12 (For example, C 6~10 ) and other C 6~20 Aryl groups are included. Such groups may be monocyclic, bicyclic or tricyclic and may have 6 to 12 (e.g., 6 to 10) ring carbon atoms in which at least one ring is aromatic.6~10 Aryl groups include phenyl, naphthyl, and the like, for example, 1,2,3,4-tetrahydronaphthyl. The attachment point of the aryl group may be through any atom of the ring system. For example, if the aryl group is polycyclic, the attachment point may be through an atom, such as an atom of a non-aromatic ring. However, if the aryl group is polycyclic (e.g., bicyclic or tricyclic), they are preferably linked to the rest of the molecule through an aromatic ring. The most preferred aryl group that may be mentioned herein is the "phenyl group".

[0044] Unless otherwise indicated, as used herein, the term "heteroaryl group" refers to an aromatic group containing one or more heteroatoms (e.g., 1-4 heteroatoms) preferably selected from N, O, and S. Heteroaryl groups include those with 5-20 members (e.g., 5-10) and can be monocyclic, bicyclic, or tricyclic (provided that at least one of the rings is aromatic (thus forming, for example, a monocyclic, bicyclic, or tricyclic heteroaromatic group)). When a heteroaryl group is polycyclic, the point of attachment can be through any atom, including an atom of a non-aromatic ring. However, when heteroaryl groups are polycyclic (e.g., bicyclic or tricyclic), they are preferably linked to the remainder of the molecule through an aromatic ring. Heteroaryl groups which may be mentioned include 3,4-dihydro-1H-isoquinolinyl, 1,3-dihydroisoindolyl, 1,3-dihydroisoindolyl (e.g. 3,4-dihydro-1H-isoquinolin-2-yl, 1,3-dihydroisoindol-2-yl, 1,3-dihydroisoindol-2-yl; i.e. heteroaryl groups linked via a non-aromatic ring), or, preferably, acridinyl, benzimidazolyl, benzodioxanyl, benzodioxepinyl, benzodioxolyl (including 1,3-benzodioxolyl), benzofuranyl, benzofurazanyl, benzothiadiazolyl (including 2,1,3-benzothiadiazolyl), benzothiazolyl, benzoxadiazolyl (including 2,1,3-benzoxadiazolyl), benzyl, benzoxadiazolyl, benzoxadiazolyl, benzyl ...

[0033] Examples of such radicals include benzoxazinyl (including 3,4-dihydro-2H-1,4-benzoxazinyl), benzoxazolyl, benzomorpholinyl, benzoselenadiazolyl (including 2,1,3-benzoselenadiazolyl), benzothienyl, carbazolyl, chromanyl, cinnolinyl, furanyl, imidazolyl, imidazo[1,2-a]pyridyl, indazolyl, indolinyl, indolyl, isobenzofuranyl, isochromanyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiaziolyl, isothiochromanyl, isoxazolyl, naphthyridinyl (including 1,6-naphthyridinyl or, preferably, 1,5-naphthyridinyl and 1,8-naphthyridinyl), oxadiazolyl (including 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl and 1,3,4-oxadiazolyl), oxazolyl, phenazinyl, phenothiazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinolizinyl, quinoxalinyl, tetrahydroisoquinolinyl (including 1,2,3,4-tetrahydroisoquinolinyl and 5,6,7,8-tetrahydroisoquinolinyl), tetrahydrox Examples of heteroaryl groups include quinolinyl (including 1,2,3,4-tetrahydroquinolinyl and 5,6,7,8-tetrahydroquinolinyl), tetrazolyl, thiadiazolyl (including 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl and 1,3,4-thiadiazolyl), thiazolyl, thiochromanyl, thiophenethyl, thienyl, triazolyl (including 1,2,3-triazolyl, 1,2,4-triazolyl and 1,3,4-triazolyl). Substituents on heteroaryl groups, where appropriate, may be located on any atom (such as a heteroatom) of the ring system. The point of attachment of a heteroaryl group may be via any atom of the ring system (such as a heteroatom (e.g., nitrogen atom) (where appropriate)) or via an atom on any fused carbocyclic ring that may be present as part of a ring system. Heteroaryl groups may also be in N- or S-oxidized form. Heteroaryl groups referred to herein are expressly stated to be monocyclic or bicyclic. When the heteroaryl group is polycyclic, the non-aromatic ring may be substituted with one or more =O groups. The most preferred heteroaryl groups that may be mentioned herein may be 5- or 6-membered aromatic groups containing 1, 2 or 3 heteroatoms, preferably selected from nitrogen, oxygen and sulfur.

[0045] It may be explicitly stated that a heteroaryl group is monocyclic or bicyclic. When a heteroaryl is specified as being bicyclic, it may consist of a 5-, 6-, or 7-membered monocyclic ring (e.g., a monocyclic heteroaryl ring) fused to another 5-, 6-, or 7-membered ring (e.g., a monocyclic aryl or heteroaryl ring).

[0046] Heteroatoms that may be mentioned include phosphorus, silicon, boron and, preferably, oxygen, nitrogen and sulfur.

[0047] When "aromatic" groups are mentioned herein, they can be aryl or heteroaryl. When "aromatic linker groups" are mentioned herein, they can be aryl or heteroaryl, preferably monocyclic (but can be polycyclic), as defined herein, and are bonded to the rest of the molecule via any possible group of the linker group. However, when specifically referring to carbocyclic aromatic linker groups, such aromatic groups cannot contain heteroatoms, i.e., they can be aryl (but not heteroaryl).

[0048] For the avoidance of doubt, a group may have one or more substituents, e.g., C 1~6 When a group is stated herein to be substituted with substituents (e.g., alkyl groups) selected from alkyl groups, such substituents (e.g., alkyl groups) are independent of each other, that is, such groups may be substituted with the same substituent (e.g., the same alkyl substituent) or with different substituents (e.g., alkyl groups).

[0049] Every individual feature (e.g., a preferred feature) mentioned in this specification may be taken alone or in combination with any other feature (including a preferred feature) mentioned in this specification (and thus a preferred feature may be taken in conjunction with or independently of other preferred features).

[0050] Those of skill in the art will appreciate that the compounds of the invention that are the subject of the present invention include those that are stable, i.e., compounds of the invention include those that are sufficiently robust to survive isolation to a useful degree of purity, for example from a reaction mixture.

[0051] The compounds of the present invention may refer to compounds of formula (I) or compounds of formula (Ia). Thus, an embodiment of the present invention may refer to either (or both) compounds of formula (I) or formula (Ia). A compound of formula (I) is an embodiment of a compound of formula (Ia). In this aspect, compounds of formula (Ia) that may be referred to include those in the formula: Q 1 =(CR 4 )-represents; Two R on the A ring 1 The substituents, taken together, are as defined above (i.e., R 1 is halo (e.g. Cl, F), -R 6a , -OR 6b , -C(=O)-R 6c , -C(=O)-N(R 7 )(R 8 ), -CN, and -N(R 7a )R 7b and / or R 6a and R 6b are independently halo (e.g., F) and -O-CH 3 -C optionally substituted with one or more substituents selected from 1~4 Examples of the alkyl group include those which represent alkyl.

[0052] In one embodiment of the present invention, preferred compounds include those having the formula: There may be no R on the A ring, or one or two R 1 Substituents may be present; R 1 (if present) are F, Cl, -R 6a , -OR 6b , -C(=O)-R 6c , -C(=O)-N(R 7 )(R 8 ), -CN, and -N(R 7a )R 7b represents one or two substituents independently selected from: R 6a -OC1~2 Alkyl (e.g., -OCH 3 Optionally substituted (e.g., with one substituent) C selected from 1~3 alkyl (e.g., methyl, ethyl, n-propyl); R 6b and R 6c is preferably unsubstituted C 1~3 represents alkyl (e.g., methyl); R 7 and R 8 are independently hydrogen or preferably unsubstituted C 1~3 represents alkyl (e.g., methyl); R 7a and R 7b are combined with each other to form a 4- to 6-membered (eg, 5-membered) ring.

[0053] Thus, in one embodiment, a particular R 1 Groups are: F, Cl, -CH 3 , -CH 2 -OCH 3 , -(CH 2 ) 3 -OH, -OCH 3 , -C(O)CH 3 , -C(O)N(CH 3 ) 2 , -C(O)N(H)CH 3 , -CN, and / or pyrrolidin-1-yl.

[0054] In one embodiment of the present invention, preferred compounds include: R 2 For example, -OC 1~2 Alkyl (e.g. -OCH 3 Optionally, a straight chain -C is substituted with one or more substituents (e.g., one substituent) selected from 1~4 is alkyl; R 3 , R 3a , R 4 , and R 4a Any two of the groups represent H, and the other two are independently H, F, or -CH 3 , and -OCH3 Examples of the substituents include those represented by the following:

[0055] In one embodiment of the present invention, preferred compounds include those having the formula: R 5 ,H,-R 9a , -C(=O)-R 9b , -SO 2 -R 10 , or Het 1 and; R 9a is unsubstituted or contains one substituent, e.g., Het 2 C is substituted with 1~3 represents alkyl (e.g. methyl); R 9b is optionally substituted with H or one or more fluoro atoms 1~3 Alkyl (e.g., methyl) (hence, -CF 3 forming a radical; R 10 -Fluoro and -OC 1~2 Alkyl (e.g. -OCH 3 C optionally substituted with one or more substituents selected from 1~4 represents alkyl, and therefore R 10 -CF 3 , -CH 3 , i-propyl, -CH 2 C(H)(CH 3 ) 2 (i-Butyl), -CH 2 CH 2 -OCH 3 may represent; Het 1 and Het 2 represents a 5- or 6-membered heteroaryl ring containing 1 or 2 heteroatoms independently selected from nitrogen and sulfur (thus forming, for example, a thiazolyl ring, e.g., a 2-thiazolyl ring), which ring is unsubstituted or 1~3 Alkyl (itself optionally substituted with one or more fluoro atoms, thus -CF 3group), and thus Het 1 and Het 2 are independently -CF 3 It may represent a thiazolyl group optionally substituted with a substituent.

[0056] In a further embodiment: Either X or Y is -CR 11a The others are N or -CR. 11b (and in one embodiment, X represents N and Y represents -CR 11a represents); R 11a or R 11b But, C 1~4 When it represents alkyl, then R 11a or R 11b is unsubstituted or is, for example, -CN, -OR 12b , and / or -N(R 12c )R 12d may be substituted (e.g., by one substituent) with; R 12b is H or C 1~2 represents alkyl (e.g. methyl); R 12c and R 12d is independently 1~2 It may represent alkyl (e.g. methyl); Therefore, R 11a or R 11b But, C 1~4 When expressing alkyl, etc., R 11a or R 11b -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 -OH, -CH 2 CH 2 -OCH 3 , -C(H)(CH 3 ) 2 , -CH 2 -N(CH 3 ) 2 , or -CH2 -CN); R 11a or R 11b But, -OC 1~4 When it represents alkyl, then R 11a or R 11b is preferably unsubstituted, -OC 1~2 Alkyl (e.g. -OCH 3 ) may also be represented.

[0057] In one embodiment of the present invention, preferred compounds include those having the formula: R 2 is linear-C 1~4 Alkyl (e.g., unsubstituted C such as methyl or ethyl) 1~2 alkyl), cyclopropyl, or -CH 2 -O-CH 3 and; R 5 -H, -C 1~4 Alkyl, -C(=O)-R 9b , or -SO 2 -R 10 For the avoidance of doubt, when "Tf" is referred to herein as a substituent, "Tf" is -S(O) 2 CF 3 Refers to; R 7 and R 8 -H and -CH 3 are independently selected from; R 9b is H, or in another embodiment, -CH 3 and / or R 10 -CF 3 , linear unsubstituted -C 1~4 Alkyl or -O-CH 3 -C is substituted with 1~4 Examples of the alkyl group include those which are alkyl.

[0058] In one embodiment, for example, in formula R 5 To prepare compounds of the invention where R 5Compounds of the invention where is H are useful intermediates.

[0059] In another embodiment of the invention, the compounds of the invention include those having the formula: R 3 is H, F, or -O-CH 3 and; R 4 is H, F, -CH 3 , or -O-CH 3 and; R 3a is H; R 4a is H or F; and / or R 3 , R 4 , R 3a , and R 4a All of represent hydrogen or R 3 , R 4 , R 3a , and R 4a any one or two of R represent a substituent other than hydrogen (and the others represent hydrogen), for example: 3 is a substituent other than H (e.g., F or -OCH 3 ), and the others, namely R 4 , R 3a , and R 4a represents hydrogen; (ii) R 4 is a substituent other than H (e.g., F, -CH 3 , or -OCH 3 ), and the others, namely R 3 , R 3a , and R 4a represents hydrogen; (iii) R 4 and R 4a represents a substituent other than H (e.g., F), and the others, i.e., R 3 and R 3a represents hydrogen.

[0060] In further or alternative embodiments: Q 1 is =N- or =C(R 4 )-(in one embodiment, Q1 is =C(R 4 )-representing); and / or R 3 , R 4 , R 3a , and R 4a All of represent hydrogen or R 4 and R 4a One of represents a substituent as defined herein (e.g., represents fluoro, methyl, or methoxy; in one embodiment it represents fluoro).

[0061] In further or alternative embodiments: X stands for N and Y stands for CR 11a and / or R 11a , H, C 1~3 Alkyl (e.g., methyl or isopropyl), or -OC 1~2 Alkyl (e.g. -OCH 3 )

[0062] In one embodiment: One or two (e.g., one) R on ring A 1 Substituents are present (in one embodiment, R 1 is a substituent as defined herein but is not hydrogen); One R on ring B 2 The base exists.

[0063] In a further embodiment of the invention, preferred compounds include those of the formula: Ring A is as follows: [ka] Examples of the above-mentioned formulas are given below.

[0064] In another embodiment of the present invention, more preferred compounds include those having the formula: Ring B is: [ka] Examples of the above-mentioned formulas are given below.

[0065] In one embodiment of the present invention, preferred compounds of the present invention include those having the formula: The composite ring system, i.e. ring A and ring B, may be: [ka] Examples of the above-mentioned formulas are given below.

[0066] In another embodiment of the invention, the composite ring system, i.e. ring A and ring B, are selected from the following subgroups: [ka] [In the formula, R 2 is as defined herein, and R 1 represents one or more (e.g. one, two or three) optional substituents as defined herein (e.g. with respect to a compound of formula (I), a compound of formula (Ia), or any further embodiment).

[0067] In further or alternative embodiments, R 1 is absent or is halo (e.g., chloro, fluoro, bromo), C 1~3 Alkyl (e.g., methyl), and -N(R 7a )R 7b (In the formula, R 7a and R 7b are independently hydrogen or methyl, 1~3 alkyl, or together with each other form a 4- to 6-membered ring, thus -NH 2 , -N(H)CH 2 , -N(CH 3 ) 2 and / or pyrrolidinyl. Optionally, two R 1 The groups may be joined together to form a 5- or 6-membered ring.

[0068] In further or alternative embodiments of the invention, two R 1 The groups, taken together, form a 5- or 6-membered ring, when: - it may contain only carbon atoms or may contain one or two heteroatoms selected from nitrogen and oxygen; - which may contain no further double bonds (which may be saturated) or may contain one or two double bonds, thus forming further aromatic rings; -It includes the following parts: [ka] and / or -This is one or two (e.g. one) C 1~3 It may be optionally substituted with an alkyl (eg, methyl) group. In one embodiment, two R 1 The groups may not be taken together to form a further 5- or 6-membered ring as defined herein.

[0069] In one embodiment of the present invention: R 1 is halo (e.g. Cl, F), -R 6a , -OR 6b , -C(=O)-R 6c , -C(=O)-N(R 7 )(R 8 ), -CN, and -N(R 7a )R 7b One or more (e.g., one, two, or three) optional groups independently selected from (hence, R 1 represents a substituent which may also represent hydrogen; R 6a , R 6b , and R 6c is independently 1~3 alkyl (e.g. methyl, cyclopropyl); R 7 and R 8 H and C 1~3independently selected from alkyl; R 7a and R 7b are independently H, C 1~3 represents alkyl, or together with each other forms a 4- to 6-membered ring (e.g. 5-membered); and / or R 2 (e.g. -OC 1~3 C optionally substituted with one substituent selected from alkyl 1~4 Represents alkyl.

[0070] In further or alternative embodiments of the invention, R 2 -O-C is halo (e.g. fluoro) and 1~3 C optionally substituted with one or more substituents selected from alkyl 1~4 may represent alkyl, for example, R 2 -CF 3 , -CHF 2 , -CH 2 CH 3 , -CH 3 , cyclopropyl, -OCH 3 may be represented as:

[0071] Further embodiments of the present invention include compounds comprising the formula: R 1 are H, Cl, F, -R 6a , -OR 6b , -C(=O)-R 6c , and -C(=O)-N(R 7 )(R 8 ) represents one or two (e.g., one) substituents selected from R 6a , R 6b , and R 6c are independently -CH 3 represents; R 7 and R 8 -H and -CH 3 and / or R 2 is a linear C 1~4Alkyl, cyclopropyl, or CH 2 -O-CH 3 Examples of such items include:

[0072] In further or alternative embodiments, R 1 is absent or is halo (e.g., chloro, fluoro, bromo), C 1~3 Alkyl (e.g., methyl), and -N(R 7a )R 7b (In the formula, R 7a and R 7b are independently hydrogen or methyl, 1~3 or together with alkyl, form a 4- to 6-membered ring, thus -NH 2 , -N(H)CH 2 , -N(CH 3 ) 2 and / or may form pyrrolidinyl).

[0073] Yet further embodiments of the present invention include compounds comprising the formula: R 5 -C 1~4 Alkyl (e.g. methyl), -C(=O)-R 9b (e.g., -C(O)H, or in another embodiment, -C(O)CH 3 ), or -SO 2 -R 10 and; In the composite ring system, i.e. ring A and ring B are rings of formula (IX) or formula (X), R 5 -SO 2 -R 10 and; R 1 are H, Cl, F, -C 1~4 Alkyl (e.g., methyl, ethyl, or -CH 2 -OCH 3 ), or -OC 1~4 Alkyl (e.g. OCH 3 In a further embodiment, R 1 more preferably represents Cl; R 2-C 1~4 Alkyl (e.g., methyl, ethyl, cyclopropyl, or -CH 2 -OCH 3 ) and / or R 10 isopropyl (-CH 2 CH(CH 2 ) 2 ), -CH 3 , -CH 2 -CH 2 -OCH 3 or in certain embodiments, -CF 3 Examples of such items include:

[0074] In an alternative embodiment: -R 5 is hydrogen, -S(O) 2 R 10 Or Het 1 (and in certain embodiments, R 5 is -S(O) 2 R 10 represents); -R 10 is optionally substituted with one or more fluoro atoms 1~3 Alkyl (e.g., methyl) (thus, in certain embodiments, CF 3 and / or -Het 1 represents a 5-membered heteroaryl group containing one or two (eg one) heteroatoms (eg selected from oxygen, nitrogen and sulfur; especially sulfur), thus forming, for example, a thienyl group.

[0075] In certain embodiments, R 5 is -S(O) 2 R 10 In a further particular embodiment, R 10 is optionally substituted with one or more fluoro atoms 1~3 Alkyl (e.g., methyl) (thus, in certain embodiments, CF 3 (which forms a

[0076] Further embodiments of the present invention include compounds comprising the formula: R 11a and R 11b are independently H, -CH 3 , -CH 2 CH 3 , or -OCH 3 represents; X stands for N and Y stands for -CR 11a (In the formula, R 11a -H, -CH 3 , -CH 2 CH 3 , or -OCH 3 (representing the same).

[0077] Any one of X and Y is -CR 11a and the others are N or -CR 11b In one embodiment, X represents N and Y represents CR 11a It is stated to represent (as defined herein).

[0078] Pharmacology The compounds of the present invention have surprisingly been shown to be suitable for the treatment of bacterial infections, including mycobacterial infections, in particular diseases caused by pathogenic mycobacteria such as Mycobacterium tuberculosis, including latent and drug-resistant forms thereof. The present invention therefore also relates to the compounds of the present invention as defined above for use as a medicament, in particular for use as a medicament for the treatment of bacterial infections, including mycobacterial infections.

[0079] Such compounds of the invention may act by disrupting ATP synthase in M. tuberculosis, inhibiting the cytochrome bc 1 The main mechanism of action is inhibition of the activity of cytochrome bc 1 is an essential component of the electron transport chain required for ATP synthesis.

[0080] Additionally, the present invention also relates to the use of the compounds of the present invention and any of their pharmaceutical compositions as described below for the manufacture of a medicament for the treatment of bacterial infections, including mycobacterial infections.

[0081] Accordingly, in another aspect, the present invention provides a method of treating a patient suffering from or at risk of a bacterial infection, including a mycobacterial infection, comprising administering to the patient a therapeutically effective amount of a compound or pharmaceutical composition of the present invention.

[0082] The compounds of the invention also exhibit activity against resistant bacterial strains.

[0083] Whenever stated herein above or below, when a compound is said to be capable of treating a bacterial infection, it is meant that the compound is capable of treating an infection by one or more strains of bacteria.

[0084] The present invention also relates to a composition comprising a pharma- ceutically acceptable carrier and a therapeutically effective amount of a compound according to the present invention as an active ingredient. The compound according to the present invention may be formulated into various pharmaceutical forms for administration purposes. Suitable compositions may include all compositions normally used for systemically administered drugs. To prepare the pharmaceutical composition of the present invention, an effective amount of a particular compound as an active ingredient, optionally in addition salt form, is combined with a pharma- ceutical acceptable carrier to form a homogeneous mixture, which may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are preferably in unit dosage form, particularly suitable for oral administration or parenteral injection administration. For example, in preparing compositions in oral dosage form, any of the usual pharmaceutical media (e.g., water, glycols, oils, alcohols, and the like) may be used for oral liquid preparations such as suspensions, syrups, elixirs, emulsions, and solutions, or solid carriers (e.g., starches, sugars, kaolin, diluents, lubricants, binders, disintegrants, and the like) may be used for powders, pills, capsules, and tablets. Tablets and capsules are the most advantageous oral dosage unit forms due to their ease of administration, in which case solid pharmaceutical carriers are naturally utilized. For parenteral compositions, the carrier will usually comprise at least in large part sterile water, although other ingredients, for example, to aid solubility, may also be included. For example, injectable solutions may be prepared in which the carrier comprises saline, glucose solution, or a mixture of saline and glucose solution. Injectable suspensions may be prepared, in which case suitable liquid carriers, suspending agents, and the like may be utilized. Solid form preparations that are intended to be converted to liquid form preparations immediately prior to use are also included.

[0085] Depending on the method of administration, the pharmaceutical composition will preferably contain 0.05-99% by weight, more preferably 0.1-70% by weight, even more preferably 0.1-50% by weight of active ingredient and 1-99.95% by weight, more preferably 30-99.9% by weight, even more preferably 50-99.9% by weight of a pharma- ceutically acceptable carrier (percentages are based on the total weight of the composition).

[0086] The pharmaceutical composition may further contain various other ingredients known in the art, such as lubricants, stabilizers, buffers, emulsifiers, viscosity modifiers, surfactants, preservatives, flavoring agents or coloring agents.

[0087] It is particularly advantageous to formulate the aforementioned pharmaceutical compositions into unit dosage forms for ease of administration and uniformity of dosage. Unit dosage form, as used herein, refers to physically discrete units suitable as unitary doses, each unit containing a predetermined amount of active ingredient calculated to produce the desired therapeutic effect in association with the necessary 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, as well as separate combinations thereof. The daily dosage of the compounds according to the invention will, of course, vary with the compound used, the method of administration, the treatment desired, and the mycobacterial disease indicated. However, in general, satisfactory results will be obtained when the compounds according to the invention are administered at a daily dosage not exceeding 1 gram, for example within the range of 10-50 mg / kg body weight.

[0088] If the compounds of formula (Ia) or formula (Ib) are active against bacterial infections, they may be combined with other antibacterial agents to effectively treat bacterial infections.

[0089] Accordingly, the present invention also relates to the combination of (a) a compound according to the invention, and (b) one or more other antibacterial agents.

[0090] The present invention also relates to a combination of (a) a compound according to the invention, and (b) one or more other antibacterial agents, for use as a medicine.

[0091] The present invention also relates to the use of a combination or a pharmaceutical composition as defined immediately above for treating a bacterial infection.

[0092] Also included in the present invention is a pharmaceutical composition comprising a pharma- ceutically acceptable carrier and, as active ingredients, a therapeutically effective amount of (a) a compound of the present invention and (b) one or more other antibacterial agents.

[0093] The weight ratio of (a) the compound according to the invention and (b) the other antibacterial agent when given as a combination can be determined by one skilled in the art. The ratio, as well as the exact dosage and frequency of administration, will depend on the particular compound according to the invention used, and the other anticancer agent, the particular condition being treated, the severity of the condition being treated, the age, weight, sex, diet, time of administration, and general health of the particular patient, the mode of administration, and other pharmaceutical agents that the individual may be taking, as is well known to those skilled in the art. Furthermore, it will be apparent that the effective daily amount can be decreased or increased depending on the response of the subject being treated and / or depending on the evaluation of the physician prescribing the compound of the invention. The specific weight ratio of the compound of the invention to the other antibacterial agent may be in the range of 1 / 10 to 10 / 1, particularly in the range of 1 / 5 to 5 / 1, and more particularly in the range of 1 / 3 to 3 / 1.

[0094] The compounds according to the invention and one or more other antibacterial agents may be combined in a single preparation, or they may be formulated as separate preparations so that they may be administered simultaneously, separately or sequentially. Thus, the 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 in the treatment of bacterial infections.

[0095] Other antibacterial agents that can be combined with the compounds of the present invention are, for example, antibacterial agents known in the art.For example, the compounds of the present invention can be combined with antibacterial agents known to interfere with the respiratory chain of Mycobacterium tuberculosis, such as direct inhibitors of ATP synthase (e.g., bedaquiline, bedaquiline fumarate, or any other compound that may be disclosed in the prior art, such as compounds disclosed in WO2004 / 011436), inhibitors of ndh2 (e.g., clofazimine), and inhibitors of cytochrome bd. Further mycobacterial agents which may be combined with the compounds of the invention include, for example, rifampicin (=rifampin); isoniazid; pyrazinamide; amikacin; ethionamide; ethambutol; streptomycin; para-aminosalicylic acid; cycloserine; capreomycin; kanamycin; thioacetazone; PA-824; delamanid; quinolones / fluoroquinolones, such as moxifloxacin, gatifloxacin, ofloxacin, ciprofloxacin, sparfloxacin, etc.; macrolides, such as clarithromycin, amoxicillin / clavulanic acid, etc.; rifamycins; rifabutin; rifapentine; and other agents currently in development (but which may not yet be marketed; see, for example, http: / / www.newtbdrugs.org / pipeline.php).

[0096] The compounds of the present invention (including forms and compositions / combinations comprising the compounds of the present invention), whether or not used for the aforementioned indications, may have the advantage that they are more effective, less toxic, have a longer duration of action, have higher potency, cause fewer side effects, are more easily absorbed, and / or have better pharmacokinetic properties (e.g., higher oral bioavailability and / or lower clearance) and / or have other useful pharmacological, physical or chemical properties compared to compounds known in the prior art. For example, the compounds of the present invention may have advantages related to: lower cardiotoxicity; no formation of reactive metabolites (e.g., which may cause toxic, e.g., genotoxicity problems); no formation of degradants (e.g., which may induce undesirable or unwanted side effects); and / or faster oral absorption and improved bioavailability.

[0097] General preparation The compounds of the invention can generally be prepared by a series of steps, each of which is known to one skilled in the art or may be described herein. EXAMPLES

[0098] Compounds of formula I may be prepared according to the techniques used in the examples below (and known to those skilled in the art), for example, by using the following techniques.

[0099] The compound of formula (I) or (Ia) (i) Formula (XIV), [ka] wherein the integers are as previously defined, and a compound of formula (XV) or (XVA), respectively [ka] wherein the integers are as defined above, and in one embodiment, R 5 is as defined above, but is preferably -C 1~4Alkyl, -C(=O)-R 9b , or -S(O) 2 -R 10

[0043] may be prepared by reaction with a compound of formula (I) represented by the formula: This reaction may be carried out in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (or its hydrochloride salt) or N,N'-disuccinimidyl carbonate), optionally in the presence of a suitable base (e.g. sodium hydride, sodium bicarbonate, potassium carbonate, pyridine, triethylamine, dimethylaminopyridine, diisopropylamine, sodium hydroxide, potassium tert-butoxide and / or lithium diisopropylamide (or a variant thereof) and a suitable solvent (e.g. tetrahydrofuran, pyridine, toluene, dichloromethane, chloroform, acetonitrile, dimethylformamide, trifluoromethylbenzene, dioxane or triethylamine). Alternatively, the carboxylic acid group of the compound of formula (XIV) may first be converted to the corresponding acyl chloride under standard conditions (e.g. POCl 3 , PCl 5 , SOCl 2 or in the presence of oxalyl chloride), followed by reacting the acyl chloride with a compound of formula (XV), e.g. under conditions similar to those described above; (ii) Formula (XVII) or (XVIIA), respectively [ka] where the integers are as previously defined and R 12 represents a suitable leaving group, for example a suitable group such as a chloro, bromo, iodo, or sulfonate group (for example a type of group that can be positioned for coupling) with a compound of formula (XVI) [ka] [In the formula, R 5 is as defined above (but preferably does not represent H)] under standard conditions, for example with a compound of the formula (I) optionally containing a suitable metal catalyst (or a salt or complex thereof), for example Pd(dba) 2 , Pd(OAc) 2 , Cu, Cu(OAc) 2 , CuI, NiCl 2 In the presence of optional additives such as Ph 3 Coupling using P, X-phos, etc. in the presence of a suitable base (e.g., t-BuONa, etc.) in a suitable solvent (e.g., dioxane, etc.) under reaction conditions known to those skilled in the art; (iii) Formula (I) or (Ia) [wherein X represents N (and R 5 preferably represents H), with respect to the compounds of formula (XVIII) or (XVIIIA), respectively: [ka] [wherein the integers are as defined above (and R 5 preferably represents H), R 11x C(OCH 3 ) 3 (XIX) [In the formula, R 11x is R 11a or R 11b (where appropriate) under reaction conditions as described herein, e.g., in the Examples; (iv) Formula (I) or (Ia) [wherein X represents N (and preferably R5 represents H)], the compound of formula (XX) or (XXA), [ka] [wherein the integers are as defined above (and R 5 preferably denotes H) with a compound of formula (XIX) as defined above under reaction conditions as described herein, for example in the Examples; and / or (v) a compound represented by the formula (I) or (Ia), 5 teeth, -C(=O)-R 9b , -S(O) 2 -R 10 , or Het 1 For the preparation of a compound of formula (I) [wherein R 5 represents H], and a corresponding compound of formula (XXI), LG 1 -Z(XXI) [Wherein, Z is -C(=O)-R 9b , -S(O) 2 -R 10 , or Het 1 stands for LG 1 represents a suitable leaving group, such as a chloro, bromo, iodo, or sulfonate group, where the integers are as defined herein; Het 1 In the case of R 5 The N atom bonded to Het 1 reacts with (e.g., via a lone pair) to give LG 1 So that it can be replaced by LG 1 is attached to an appropriate C atom of the heteroaromatic ring.

[0100] It is clear that in the preceding and following reactions, the reaction products can be isolated from the reaction medium and, if necessary, further purified according to methods generally known in the art (e.g. extraction, crystallization and chromatography). It is further clear that reaction products present in two or more enantiomeric forms can be isolated from their mixtures by known techniques, in particular preparative chromatography (e.g. preparative HPLC, chiral chromatography). Individual diastereoisomers or individual enantiomers can also be obtained by supercritical fluid chromatography (SCF).

[0101] The starting materials and intermediates are compounds that are either commercially available or can be prepared according to conventional reaction procedures generally known in the art.

[0102] 1.General information Melting point Melting points were recorded using a differential scanning calorimeter DSC1 Mettler Toledo. Melting points were measured from 25 to 350 °C with a temperature gradient of 10 °C per minute. Values ​​are peak values. This method is used unless otherwise stated.

[0103] Another method uses a Mettler Toledo MP50 open capillary tube, which may be designated "MT." With this method, the melting point is measured with a temperature gradient of 10° C. / min. The maximum temperature is 300° C. The melting point data is read from a digital display and viewed with a video recording system.

[0104] 1 H NMR 1 H NMR spectra were recorded using an internal deuterium lock and inverted double resonance ( 1 H, 13C, SEI) probehead operating at 400 MHz for protons and 100 MHz for carbon, or a Bruker Avance DRX 400 spectrometer operating at 400 MHz for protons and 100 MHz for carbon, and a Bruker Avance 500 MHz spectrometer operating at 500 MHz for protons and 125 MHz for carbon, equipped with a Bruker 5 mm BBFO probehead with z-gradient. NMR spectra were recorded at ambient temperature unless otherwise stated. Data are reported as follows: chemical shifts in parts per million (ppm) relative to TMS (δ=0 ppm) used as internal standard, integrals, multiplicities (s=singlet, d=doublet, t=triplet, q=quartet, quin=quintet, sex=sexet, m=multiplet, b=broad or combinations thereof), coupling constants J in Hertz (Hz).

[0105] HPLC-LCMS Analysis method LCMS Masses of some compounds were recorded using LCMS (Liquid Chromatography Mass Spectrometry) The methods used are described below.

[0106] General procedure LCMS methods A and B High performance liquid chromatography (HPLC) measurements were performed using an LC pump, diode array (DAD) or UV detector, and column as described in each method. Additional detectors were included as required (see methods table below). The flow from the column was introduced into a mass spectrometer (MS) equipped with an atmospheric pressure ion source. It is within the knowledge of one skilled in the art to set tuning parameters (e.g., scan range, data acquisition time, etc.) to obtain ions that allow identification of the nominal monoisotopic molecular weight (MW) of the compound. Data collection was performed using appropriate software. Compounds were analyzed by their experimental retention times (R t ) and ions. Unless otherwise noted in the data tables, the reported molecular ions are [M+H] +(protonated molecule) and / or [MH] - (deprotonated molecule). If the compound cannot be directly ionized, note the type of adduct (i.e., [M+NH 4 ] + , [M+HCOO] - For molecules with multiple isotopic patterns (Br, Cl, etc.), the value reported is that obtained for the lowest isotopic mass. All results were accompanied by experimental uncertainties that are generally associated with the method used. Hereinafter, "SQD" means single quadrupole detector, "RT" means room temperature, "BEH" means crosslinked ethylsiloxane / silica hybrid, "HSS" means high strength silica, "DAD" means diode array detector, and "MSD" means mass selective detector.

[0107] [Table 1]

[0108] If the compound is a mixture of isomers giving different peaks in the LCMS method, only the retention time of the major component is shown in the LCMS table.

[0109] 2. Abbreviations (and formulas) AcOH Acetic acid AcCl Acetyl chloride BINAP 2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl BrettPhos 2-(dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl BrettPhos Pd G3 [(2-'-cyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate methanesulfonate CBr 4 Tetrabromomethane CbzCl Benzyl chloroformate CH3 CN / ACN Acetonitrile Cs 2 CO 3 Cesium Carbonate CSA Camphor-10-sulfonic acid DCE Dichloroethane DCM or CH 2 Cl 2 Dichloromethane DIPEA N,N-Diisopropylethylamine DMAP 4-(Dimethylamino)pyridine DME 1,2-dimethoxyethane DMF Dimethylformamide DMF-DMA N,N-Dimethylformamide Dimethyl Acetal DMSO Methyl sulfoxide EDCI·HCl N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride Et 2 O Diethyl ether Et 3 N or TEA Triethylamine EtOAc Ethyl acetate EtOH Ethanol h time H 2 Dihydrogen gas HATU Hexafluorophosphate azabenzotriazole tetramethyluronium HCl Hydrochloric acid HFIP Hexafluoroisopropanol HOBT·H 2 O 1-Hydroxybenzotriazole Hydrate i-PrOH Isopropyl alcohol K 2 CO 3 Potassium carbonate KHSO 4 Potassium bisulfate LiOH Lithium hydroxide LiHMDS Lithium bis(trimethylsilyl)amide MeOH Methanol MeTHF / 2-MeTHF Methyltetrahydrofuran MgSO 4 Magnesium sulfate min N 2 nitrogen NaCl Sodium chloride NaHCO 3 Sodium bicarbonate NaOH Sodium hydroxide NBS 1-Bromopyrrolidine-2,5-dione NH 3 ammonia NH 4 Cl Ammonium chloride NH 4 HCO 3 Ammonium bicarbonate NMR nuclear magnetic resonance Pd / C Palladium on carbon PdCl 2 (PPh 3 ) 2 Dichlorobis(triphenylphosphine)palladium(II) Pd(OAc) 2 Palladium(II) Acetate Pd 2 dba 3 Tris(dibenzylideneacetone)dipalladium(0) Pd(PPh 3 ) 4 Palladium-tetrakis(triphenylphosphine) PIDA (diacetoxyiodo)benzene POCl 3 Phosphorus oxychloride Ra-Ni / Ni Raney Raney (registered trademark)-Nickel rt / RT room temperature RuPhos 2-Dicyclohexylphosphino-2',6'-diisopropoxybiphenyl RuPhos Pd G3 (2-Dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) [2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate t-AmylOH tert-amyl alcohol SiOH Silica Gel TBTU O-Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate Tf 2 O Trifluoromethanesulfonic anhydride TFA Trifluoroacetic acid THF Tetrahydrofuran TMSCl Trimethylsilyl chloride TsOH or PTSA p-toluenesulfonic acid Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

[0110] 3. Procedure Synthesis of compound 1 [ka]

[0111] Preparation of intermediate A1 In a 1 L autoclave, prepare 7 M NH in MeOH. 3 A mixture of N-Boc-[2-[(4-cyanophenyl)amino]ethyl][865788-36-9] (50.0 g, 191 mmol) and Raney Nickel (2.25 g, 38.2 mmol) in 600 mL of solution was heated at room temperature under 10 bar of H 2 The mixture was hydrogenated under 50° C. for 24 hours. The reaction mixture was filtered through a pad of Celite® and washed with a mixture of DCM and MeOH (9 / 1). The filtrate was evaporated in vacuo to give 50.2 g of intermediate A1 as a greenish oil (99%).

[0112] Preparation of intermediate A2 A 2 L flask was charged with 6-chloro-2-ethylimidazo[1,2-a]pyridine-3-carboxylic acid [1216142-18-5] (15.0 g, 66.8 mmol), intermediate A1 (18.6 g, 70.1 mmol), and DIPEA (17.3 mL, 100 mmol) in DCM (600 mL) and Me-THF (100 mL). The reaction mixture was stirred at room temperature for 10 min, then HATU (27.9 g, 73.4 mmol) was added in portions over 5 min, and the reaction mixture was stirred at room temperature for 5 h. The mixture was diluted with DCM (1 L) and water (800 mL). The organic layer was separated, washed with water (400 mL), and diluted with MgSO 4 The mixture was dried over ice, filtered and evaporated in vacuo. The residue was dissolved in a minimum amount of hot EtOAc. The solution was cooled to room temperature and then to 0° C. The suspension was collected by filtration and the solid was washed with cold EtOAc and then with Et 2 O and then dried under vacuum to give 21.7 g of Intermediate A2 as an off-white solid (69%).

[0113] Preparation of intermediate A3 Intermediate A2 (5.00 g, 10.6 mmol) was dissolved in Me-THF (80 mL) and acetic acid (6.1 mL, 106 mmol) at 40° C. Isopentyl nitrite (7.12 mL, 53.0 mmol) was added dropwise and the reaction mixture was stirred at 40° C. for 3 h. The solution was diluted in EtOAc and water and treated with NaHCO 3 (sat., aq.) (twice) and brine, then washed with MgSO 4 The residue was dried over 100 ml of ethyl acetate and evaporated in vacuo. 2 Triturate in O and collect the product by filtration and wash with Et 2 O and dried under vacuum to give 4.26 g of intermediate A3 as a beige solid (80%).

[0114] Preparation of intermediate A4 A solution of intermediate A3 (5.00 g, 9.98 mmol) in THF (100 mL) and MeOH (65 mL) was treated with NaOH (1 M, aq., 100 mL). Formamidinesulfinic acid (5.40 g, 49.9 mmol) was added and the reaction mixture was stirred at 50° C. for 1.5 h. The reaction mixture was diluted in DCM and the K 2 CO 3 (10%, aq.) was added. The layers were separated. The aqueous phase was extracted with DCM and MeOH (95 / 5). The combined organic layers were washed with MgSO 4 Drying over, filtration and evaporation in vacuo gave 4.67 g of Intermediate A4 as a white solid (Quant.).

[0115] Preparation of intermediate A5 To a solution of intermediate A4 (4.67 g, 9.59 mmol) in MeOH (96 mL) was added TMSCl (9.73 mL, 76.7 mmol) dropwise. The reaction mixture was stirred at 40° C. for 1.5 h and at room temperature for an additional 17 h. The mixture was concentrated in vacuo. The residue was dissolved in Et 2 Triturate in O and collect the solid by filtration and wash with Et 2 O and dried under vacuum to give 4.76 g of Intermediate A5 as a pale yellow solid (Quant.).

[0116] Preparation of intermediate A6 A mixture of intermediate A5 (4.76 g, 10.4 mmol) and trimethyl orthoformate (3.40 mL, 31.1 mmol) in acetic acid (52 mL) was stirred at 100° C. for 1 h. The reaction mixture was concentrated in vacuo. The residue was diluted in DCM and 2 CO 3 (10%, aq.) was added. The aqueous layer was extracted twice with DCM and MeOH (95 / 5). The combined organic extracts were washed with MgSO 4 Drying over, filtration and evaporation in vacuo gave 3.44 g of intermediate A6 as a beige solid (83%).

[0117] Preparation of Compound 1 A solution of intermediate A6 (80 mg, 0.202 mmol) in DCM (6 mL) and Me-THF (3 mL) was diluted with Et 3The mixture was cooled to 0 °C and treated with Tf 2 A solution of K2O (1M in DCM, 302 μL, 0.302 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 20 min. MeOH (0.3 mL) was added, followed by K2O. 2 CO 3 (10%, aq., 5 mL) and DCM were added. The layers were separated. The organic phase was washed with MgSO 4 The mixture was dried over ice, filtered and evaporated in vacuo. The crude mixture was purified by preparative LC (amorphous SiOH, 15-40 μm, 12 g dry packing (Celite®), mobile phase: heptane / EtOAc gradient 70:30 to 0:100). The residue (62 mg) was dissolved in hot EtOAc (3 mL) and allowed to cool to room temperature. The supernatant was removed. The solid was dissolved in Et 2 Triturated in O. The product was collected by filtration and dried under vacuum to give 42 mg of compound 1 as a white solid (36%). 1 H NMR (400MHz, DMSO-d 6 )δ ppm 9.07(s,1H),8.47(br s,1H),7.67(d,J=8.1Hz,1H),7.46(br d,J=9.1Hz,1H),7.30(br d,J=8.1Hz,2H),7.20(br d,J=7.6Hz,2H),4.49(br d,J=5.1Hz,2H),4.41(s,2H),4.18(s,2H),3.39-3.31(m,1H),2.98(q,J=7.4Hz,2H),2.63-2.58(m,2H),2.34-2.29(m,2H),1.26(br t,J=7.3Hz,3H) 1 H NMR (400MHz, DMSO-d 6 )δ ppm 9.12(s,1H)8.71(m,1H)7.79(d,J=9.4Hz,1H)7.68(d,J=8.8Hz,1H)7.26-7.37(m,3H)7.19(d,J=8.7Hz,2H) 4.48(d,J=5.9Hz,2H)4.08(t,J=4.5Hz,2H)3.83(t,J=4.8Hz,2H)3.01(q,J=7.6Hz,2H)1.27(t,J=7.5Hz,3H)

[0118] Synthesis of compound 2 [ka]

[0119] Preparation of intermediate A7 A mixture of intermediate A5 (300 mg, 0.652 mmol) and trimethyl orthopropionate (0.102 mL, 0.718 mmol) in acetic acid (6 mL) was stirred at 100° C. for 1 h. An additional amount of trimethyl orthopropionate (0.102 mL, 0.718 mmol) was added and the reaction mixture was stirred at 100° C. for an additional 2 h. The reaction mixture was diluted with DCM and NaOH (3M, aq.). The layers were separated and the organic phase was separated using MgSO 4 Drying over, filtration and evaporation in vacuo gave 138 mg of intermediate A7 as a foam (50%).

[0120] Preparation of compound 2 A solution of intermediate A7 (138 mg, 0.325 mmol) in DCM (4 mL) was diluted with Et 3 The mixture was cooled to 0 °C and treated with Tf 2 A solution of 2H2O in DCM (1M in DCM, 357 μL, 0.357 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 20 min. The reaction was quenched with MeOH (0.2 mL) and pyridine (0.1 mL). Celite® was added and the mixture was evaporated in vacuo. The residue was purified by preparative LC (amorphous SiOH, 15-40 μm, 24 g dry packing (Celite®), mobile phase: heptane / EtOAc gradient 70:30 to 0:100). A second purification was performed using reversed phase (stationary phase: YMC-actus Triaroom temperature C18 10 μm 30×150 mm, mobile phase: NH 4 HCO 3 (0.2% in water / MeCN, gradient 40:60 to 10:90) to give 60 mg of compound 2 as a white solid (33%). 1 H NMR (400MHz, DMSO-d 6)δ ppm 9.07(d,J=1.6Hz,1H)8.43(t,J=5.9Hz,1H)7.66(d,J=9.5Hz,1H)7.45(dd,J=9.5,2.1Hz,1H)7.32(d,J=8.7Hz,2H)7.18(d,J=8.8Hz,2H)4.46 (d,J=5.9Hz,2H)3.91-4.02(m,2H)3.79-3.90(m,2H)2.98(q,J=7.5Hz,2H)2.61(q,J=7.3Hz,2H)1.26(t,J=7.5Hz,3H)1.18(t,J=7.3Hz,3H).

[0121] Synthesis of compound 3 [ka]

[0122] In a pressure vessel reactor, a mixture of compound 1 (250 mg, 0.473 mmol) and Pd / C (54 mg, 50.5 μmol) in EtOH (15 mL) was heated at room temperature under 5 bar of H 2 The mixture was stirred at room temperature for 20 hours. The mixture was filtered on a Celite pad. The filter cake was washed with EtOH and DCM, and the filtrate was evaporated in vacuum. The residue was combined with another batch to give 250 mg of crude mixture. The residue was purified by reverse phase (stationary phase: YMC-actus Triaroom temperature C18 10 μm 30×150 mm, mobile phase: NH 4 HCO 3 (0.2% in water / MeCN, gradient 55:45 to 30:70). The residue was purified by Et 2 Trituration in O and removal of the solvent under reduced pressure gave 165 mg of compound 3 as a white solid (58%). 1 H NMR (400MHz, DMSO-d 6)δ ppm 8.16(t,J=6.1Hz,1H)7.28(s,1H)7.26(d,J=8.6Hz,2H)7.16(d,J=8.6Hz,2H)4.35(d,J=6.1Hz,2H)4.07(t,J=4.6Hz,2H)3.97 (t,J=5.7Hz,2H)3.77-3.87(m,2H)2.68-2.75(t,J=6.4Hz,2H)2.60(q,J=7.5Hz,2H)1.73-1.90(m,4H)1.09(t,J=7.5Hz,3H).

[0123] Synthesis of compound 4 [ka]

[0124] Preparation of intermediate B1 A flask (equipped with a findenser) was charged with 4-fluorobenzonitrile [1194-02-1] (1.00 g, 8.26 mmol), DMSO (5.9 mL), and ethanolamine (0.757 g, 12.4 mmol). 3 N (1.72 mL, 12.4 mmol) was added and the reaction mixture was stirred at 120 °C for 17 h. The mixture was poured into brine. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine (3 times) and MgSO 4 It was dried over ice, filtered and evaporated in vacuo to give Intermediate B1 as a pale yellow oil (Quant.).

[0125] Preparation of intermediate B2 A solution of Intermediate B1 (2.00 g, 12.3 mmol) and triphenylphosphine (4.21 g, 16.0 mmol) in Me-THF (100 mL) was reacted with CBr 4(5.32 g, 16.0 mmol). The reaction mixture was stirred at room temperature for 17 h. The mixture was evaporated in vacuo. The residue was dissolved in EtOH (40 mL) and treated with methylhydrazine (5.19 mL, 98.6 mmol). The reaction mixture was stirred at 75° C. for 4 h and concentrated in vacuo. The residue was diluted with DCM and HCl (3 M, aq.) was added. The layers were separated and the organic phase was washed with water. The combined aqueous extracts were diluted with K 2 CO 3 The aqueous phase was extracted with DCM (x2). The combined organic layers were diluted with MgSO 4 After drying over rt, filtering and concentrating in vacuo, 2.54 g of compound B2 was obtained as an orange oil (Quant.).

[0126] Preparation of intermediate B3 A solution of Intermediate B2 (2.15 g, 11.3 mmol) and trimethyl orthoformate (3.71 mL, 33.9 mmol) in acetic acid (60 mL) was stirred at 60° C. for 17 h. The yellow solution was cooled to room temperature. Water (150 mL) and EtOAc (150 mL) were added. The aqueous layer was basified with K 2 CO 3 The organic layer was separated, washed with water and brine, and MgSO 4 Drying over, filtration and evaporation in vacuo gave 1.50 g of Intermediate B3 as an orange solid (66%).

[0127] Preparation of intermediate B4 In an autoclave, prepare 7M NH in MeOH. 3 A mixture of intermediate B3 (1.5 g, 7.49 mmol) and Raney nickel (440 mg, 7.49 mmol) in 64 mL of solution was heated at room temperature under 5 bar of H 2 The mixture was hydrogenated under reduced pressure for 17 h. The reaction mixture was filtered through a pad of Celite® and washed with a mixture of DCM and MeOH (9 / 1). The filtrate was evaporated in vacuo to give 1.53 g of intermediate B4 as a grey solid (Quant.).

[0128] Preparation of compound 4 6-Chloro-2-ethylimidazo[1,2-a]pyridine-3-carboxylic acid [1216142-18-5] (600 mg, 2.67 mmol) was dissolved in Me-THF (30 mL) and DCM (15 mL) and DIPEA (0.736 mL, 4.27 mmol) was added. After complete dissolution, intermediate B4 (627 mg, 3.07 mmol) was added followed by HATU (1.17 g, 3.07 mmol). The reaction mixture was stirred at 35° C. for 3 h. EtOAc and water were added. The organic layer was separated and washed with water and then with brine. The combined organic extracts were diluted with MgSO 4 The mixture was dried over ice, filtered and evaporated in vacuo. The residue was dissolved in a minimum amount of warm EtOAc. The solution was cooled to room temperature and the suspension was filtered. The solid was purified by distillation with EtOAc, then EtOH and Et 2 The solid was collected by filtration and dried under vacuum to give 210 mg of an off-white solid. The solid was combined with the filtrate and evaporated in vacuum. The residue was purified by preparative LC (amorphous SiOH 15-40 μm, 80 g, mobile phase: DCM / (DCM / MeOH / NH3 aq., 18 / 20 / 2), gradient 90:10-60:40). The residue was crystallized from EtOAc and purified by HPLC with Et 2 O and dried under vacuum to give 317 mg of compound 4. 1 H NMR (400MHz, DMSO-d 6 )δ ppm 9.07(d,J=1.47Hz,1H)8.45(t,J=5.81Hz,1H)7.67(d,J=9.66Hz,1H)7.46(dd,J=9.41,2.08Hz,1H)7.30-7.36(m,3H)7.11(d,J=8.56H z,2H)4.47(d,J=5.87Hz,2H)3.70(t,J=5.01Hz,2H)3.17(d,J=5.14Hz,1H)2.88-3.01(m,4H)2.54-2.65(m,4H)1.26(t,J=7.52Hz,3H).

[0129] Synthesis of compound 5 [ka]

[0130] Preparation of intermediate B5 NBS (204 mg, 1.15 mmol) was added to a solution of compound 1 (600 mg, 1.13 mmol) in MeCN (9.5 mL) and the reaction mixture was stirred at room temperature for 20 h. The mixture was diluted with EtOAc and water. The layers were separated. The organic phase was diluted with NaHCO 3 (sat., aq.), washed with MgSO 4 It was dried over, filtered and the solvent was removed under reduced pressure to give 700 mg of Intermediate B5 as a brown residue.

[0131] Preparation of compound 5 Intermediate B5 (250 mg, 0.234 mmol), trimethylboroxine (131 μL, 0.938 mmol), and Cs 2 CO 3 A mixture of (229 mg, 0.703 mmol) in DME (3.6 mL) and water (3.6 mL) was added to 10 mL of N 2 The mixture was purged with PdCl. 2 (PPh 3 ) 2 (32.9 mg, 0.0469 mmol) was added and the mixture was again purified with N 2 The reaction mixture was stirred at 100 °C for 16 h. Water and EtOAc were added. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine and MgSO 4 The mixture was dried over silica gel, filtered and evaporated to dryness in vacuo. The residue was purified by preparative LC (amorphous SiOH, 15-40 μm, 24 g dry packing (Celite®), mobile phase: DCM / MeOH gradient 99:1-95:5). A second purification was performed using reversed phase (stationary phase: YMC-actus Triaroom temperature C18 10 μm 30×150 mm, mobile phase NH 4 HCO 3 (0.2% in water / MeCN, gradient 55:45 to 35:65) to give 14 mg of a white residue which was dissolved in MeCN, made up with water and lyophilized to give 12 mg of compound 5 as a white powder (7%). 1 H NMR (400MHz, DMSO-d6 )δ ppm 9.07(d,J=1.34Hz,1H)8.48(t,J=5.99Hz,1H)7.67(d,J=9.41Hz,1H)7.46(dd,J=9.54,2.08Hz,1H )7.29(s,1H)7.22(s,1H)7.21(d,J=7.74Hz,2H)7.12-7.17(m,1H)4.49(d,J=6.11Hz,2H)4.10(br d,J=4.28Hz,2H)3.38-3.54(m,4H)3.00(q,J=7.42Hz,2H)2.67-2.69(m,1H)2.52-2.56(m,5H)2.33-2.45(m,2H)2.25(s,3H)1.19-1.33(m,3H).

[0132] Synthesis of compound 6 [ka]

[0133] Preparation of intermediate C1 In a sealed tube, a mixture of intermediate A5 (300 mg, 0.652 mmol) and molecular sieves 3 Å in MeOH (4.3 mL) was stirred at room temperature for 10 min. Tetramethyl orthocarbonate (347 μL, 2.61 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. Water and DCM were added. The layers were separated and the organic phase was washed with MgSO 4 The mixture was dried over 1000 ml, filtered and evaporated to dryness in vacuo. The residue was purified by preparative LC (amorphous SiOH, 15-40 μm, 24 g dry packing (Celite®), mobile phase: heptane / EtOAc, gradient 60:40-0:100) to give 77 mg of intermediate C1 as a white solid (24%).

[0134] Preparation of compound 6 To a solution of intermediate C1 (48 mg, 0.112 mmol) in anhydrous DCM (1.3 mL) at room temperature was added Et 3 N (23.4 μL, 0.169 mmol) was added and the mixture was stirred at room temperature for 10 min. The mixture was cooled to 0 °C and Tf 2A solution of TfO in DCM (1M in DCM, 112 μL, 0.112 mmol) was added dropwise. The mixture was stirred for 1 h while warming to room temperature. 2 A solution of O in DCM (1M in DCM, 112 μL, 0.112 mmol) was added and the mixture was stirred at room temperature for a further 1 h. 3 (sat., aq.) and DCM were added. The layers were separated and the organic phase was washed with NaHCO 3 (twice) and brine. The combined organic extracts were washed with MgSO 4 The mixture was dried over 1000 ml, filtered and concentrated in vacuo. The residue was purified by preparative LC (amorphous SiOH, 15-40 μm, 24 g dry packing (Celite®), mobile phase: heptane / EtOAc gradient 50:50 to 0:100). A second purification was performed by reverse phase (stationary phase: YMC-actus Triaroom temperature C18 10 μm 30×150 mm, mobile phase: NH 4 HCO 3 (0.2% in water / MeCN, gradient 45:55 to 25:75) to give 33 mg of compound 6 as a white solid (37%). 1 H NMR (500MHz, DMSO-d 6 )δ ppm 9.07(d,J=1.58Hz,1H)8.39(t,J=5.83Hz,1H)7.66(d,J=9.46Hz,1H)7.44(dd,J =9.46,2.21Hz,1H)7.29(d,J=8.51Hz,2H)7.15(d,J=8.83Hz,2H)4.46(d,J=5.99 Hz,2H)4.06-4.14(m,2H)3.85(s,3H)3.71-3.77(m,2H)3.32-3.46(m,2H)3.17(d ,J=5.36Hz,1H)2.97(q,J=7.36Hz,2H)2.52-2.58(m,6H)1.26(t,J=7.57Hz,3H).

[0135] Synthesis of compound 7 [ka]

[0136] Preparation of intermediate C2 To a solution of 2-amino-5-chloropyrimidine [428-89-7] (500 mg, 3.86 mmol) in Me-THF (40 mL) at 5° C. was added ethyl 3-cyclopropyl-3-oxopropanoate [24922-02-9] (0.603 g, 3.86 mmol) and (diacetoxyiodo)benzene (1.24 g, 3.86 mmol). Boron trifluoride etherate (50 μL, 0.191 mmol) was added dropwise and the reaction mixture was stirred at 5° C. for 30 min and then at room temperature for 1 h. Additional amounts of ethyl 3-cyclopropyl-3-oxopropanoate (0.301 g, 1.93 mmol), (diacetoxyiodo)benzene (0.622 g, 1.93 mmol), and boron trifluoride etherate (50 μL, 0.191 mmol) were added. The mixture was then purified by N 2 The mixture was purged with 50 mL of ethyl 3-cyclopropyl-3-oxopropanoate and stirred at room temperature for 1 h. Additional amounts of ethyl 3-cyclopropyl-3-oxopropanoate (0.301 g, 1.93 mmol), (diacetoxyiodo)benzene (0.622 g, 1.93 mmol), and boron trifluoride etherate (50 μL, 0.191 mmol) were again added. The mixture was then purified by N 2 The mixture was purged with ethyl acetate and stirred at room temperature for an additional 1 h. EtOAc and water were added. The layers were separated and the organic phase was washed with MgSO 4 The mixture was dried over hexane, filtered and concentrated in vacuo. The crude mixture was purified by preparative LC (amorphous SiOH, 15-40 μm, 80 g dry packing (Celite®), mobile phase: heptane / EtOAc, 80:20, 65:35). The residue was triturated in pentane. The solid was collected by filtration and dried under vacuum to give 598 mg of intermediate C2 as a white solid (58%).

[0137] Preparation of intermediate C3 To a solution of intermediate C2 (125 mg, 0.47 mmol) in EtOH (2.2 mL) and water (2.2 mL) was added K 2 CO 3(196 mg, 1.42 mmol) was added. The reaction mixture was stirred at 65° C. for 16 h. The mixture was cooled to room temperature and the reaction was quenched with HCl (1M in water) to pH ∼3. The mixture was evaporated in vacuo to give 294 mg of intermediate C3 as a white solid. The crude product was used directly in the next step.

[0138] Preparation of compound 7 To a solution of intermediate C3 (294 mg, 0.472 mmol) in DMF (4.5 mL) was added EDCI HCl (110 mg, 0.574 mmol), HOBt H 2 O (76 mg, 0.496 mmol), DIPEA (0.245 mL, 1.42 mmol), and intermediate E9 (185 mg, 0.516 mmol) were added. The reaction mixture was stirred at room temperature for 16 h and evaporated in vacuo. The residue was dissolved in EtOAc and NaHCO 3 The organic layer was washed with MgSO 4 The mixture was dried over hexane, filtered and evaporated in vacuum. The crude mixture was purified by preparative LC (amorphous SiOH, 15-40 μm, 24 g Buechi, dry packing (Celite®), mobile phase: heptane / (EtOAc / MeOH, 9:1), gradient 90:10-40:60) to give a pale yellow solid. The solid was crystallized from EtOAc and sonicated in pentane. The solid was collected by filtration and dried under vacuum to give 121 mg of compound 7 as a white solid (47%). 1 H NMR (400MHz, DMSO-d 6 )δ ppm 9.40(d,J=1.8Hz,1H)8.58-8.75(m,2H)7.34(d,J=8.1Hz,2H)7.29(s,1H)7.19(d,J=8.4H z,2H)4.50(d,J=5.6Hz,2H)4.08(s,2H)3.83(s,2H)2.38-2.46(m,1H)1.03-1.13(m,4H).

[0139] Synthesis of compound 8 [ka]

[0140] Preparation of intermediate C4 To a solution of 2-amino-5-chloropyridine [1072-98-6] (3.00 g, 23.3 mmol) in Me-THF (100 mL) was added iodobenzene diacetate (7.50 g, 23.3 mmol) and ethyl-4-methoxy-3-oxobutanoate [66762-68-3] (6.00 g, 34.8 mmol). Boron trifluoride etherate (0.30 mL, 1.15 mmol) was then added dropwise. The solution was stirred at 5° C. for 1 h. The mixture was allowed to warm to room temperature and stirred for an additional 1 h. EtOAc and NaHCO 3 (sat., aq.) was added. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine (2x) and MgSO 4 The crude mixture was dried over 100 ml, filtered and evaporated to give a brown liquid. The crude mixture was purified by preparative LC (amorphous SiOH, 15-40 μm, 120 g dry packing (Celite®), mobile phase: heptane / EtOAc, gradient 90:10-40:60) to give 2.44 g of intermediate C4 as a yellow solid (39%).

[0141] Preparation of intermediate C5 To a solution of intermediate C4 (1.44 g, 5.36 mmol) in EtOH (11.5 mL) and water (11.5 mL) was added NaOH (650 mg, 16.3 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with HCl (3N in water) to pH approx. 3. The mixture was filtered to give 996 mg of intermediate C5 as an off-white solid (77%).

[0142] Preparation of compound 8 To a mixture of intermediate C5 (125 mg, 0.519 mmol) and DIPEA (270 μL, 1.57 mmol) in DMF (5 mL) at room temperature was added EDCI HCl (125 mg, 0.652 mmol) and HOBt H 2 O (85 mg, 0.555 mmol) was added. Intermediate E9 (205 mg, 0.571 mmol) was added and the resulting mixture was stirred for 16 h. NaHCO 3(1%, aq.) and EtOAc were added and the layers were separated. The organic layer was washed with brine (3 times) and MgSO 4 The mixture was dried over silica gel, filtered and concentrated in vacuo to dryness to give an orange solid which was purified by preparative LC (amorphous SiOH 15-40 μm, 24 g, dry packing (Celite®), mobile phase: heptane / (EtOAc / MeOH, 9:1), gradient 75:20-30:70) to give a white solid. The residue was purified by reverse phase (spherical C18, 25 μm, 40 g YMC-ODS-25, dry packing (Celite®), mobile phase: NH 4 HCO 3 (0.2% in water / MeCN, gradient 60:40 to 0:100) to give 233 mg of compound 8 as a white solid (71%). 1 H NMR (400 MHz, CDCl 3 -d)δ ppm 9.68(dd,J=2.0,0.8Hz,1H)8.51(t,J=4.7Hz,1H)7.56(d,J=9.4Hz,1H)7.31-7.36(m,3H)7.18(d,J=7.9Hz ,2H)7.11(s,1H)4.75(s,2H)4.59(d,J=5.5Hz,2H)4.06(t,J=4.7Hz,2H)3.79(t,J=4.7Hz,2H)3.28(s,3H)

[0143] Synthesis of compound 9 [ka]

[0144] Preparation of intermediate D1 3,4-Difluorobenzonitrile [64248-62-0] (3.67 g, 26.4 mmol), N-Boc-1,2-diaminoethane (5.50 g, 34.3 mmol), and Et 3 A mixture of N (14.7 mL, 105 mmol) in DMSO (47 mL) was stirred at 120 °C for 2 h. The reaction mixture was cooled and diluted with EtOAc and water. The layers were separated and the aqueous phase was extracted with EtOAc (2x). The combined organic layers were washed with brine (3x) and diluted with MgSO 4The mixture was dried over 100 ml, filtered and evaporated in vacuo. The residue was purified by preparative LC (amorphous SiOH, 15-40 μm, 80 g, liquid injection (DCM), mobile phase: heptane / EtOAc, gradient 100:0-50:50) to give 5.02 g of intermediate D1 as a white solid (68%).

[0145] Preparation of intermediate D2 In an autoclave, prepare 7M NH in MeOH. 3 A solution of intermediate D1 (2.00 g, 7.16 mmol) in water (70 mL) was purged with nitrogen and Raney Nickel (3.39 g, 57.7 mmol) was added. The reaction mixture was hydrogenated at room temperature under 7 bar for 2 hours. The mixture was filtered through a Celite® pad and rinsed with MeOH. The filtrate was concentrated in vacuo to give 2.11 g of intermediate D2 as a white solid (Quant.).

[0146] Preparation of intermediate D3 HATU (2.57 g, 6.77 mmol) was added to a mixture of 6-chloro-2-ethylimidazo[1,2-a]pyridine-3-carboxylic acid [1216142-18-5] (1.52 g, 6.77 mmol) and DIPEA (4.7 mL, 27.1 mmol) in DCM (126 mL). The reaction mixture was stirred at room temperature for 10 min, then intermediate D2 (2.11 g, 7.45 mmol) was added and the reaction mixture was stirred at room temperature for 20 h. The reaction mixture was diluted with DCM and water. The aqueous layer was extracted with DCM (2x). The combined organic layers were washed with brine (2x) and concentrated with MgSO 4 The mixture was dried over 100 ml, filtered and concentrated in vacuo. The residue was purified by preparative LC (amorphous SiOH, 15-40 μm, 120 g, liquid injection (DCM), mobile phase: heptane / EtOAc, gradient 50:50-0:100) to give 2.76 g of intermediate D3 as a light brown solid (83%).

[0147] Preparation of intermediate D4 Intermediate D3 (1.5 g, 3.06 mmol) was dissolved in Me-THF (23.2 mL) and AcOH (1.75 mL) at 40° C. Isopentyl nitrite (2.06 mL, 15.3 mmol) was added dropwise over 10 min and the reaction mixture was stirred at 40° C. for 1 h. The solution was diluted with EtOAc and NaHCO 3 (sat., qa.). The layers were separated and the organic layer was diluted with NaHCO 3 (sat., qa.) (twice), and washed with brine, MgSO 4 Drying on and evaporation in vacuo gave 1.74 g of intermediate D4 as a pale yellow oil.

[0148] Preparation of intermediate D5 A solution of intermediate D4 (1.59 g, 3.06 mmol) in THF (47 mL) and MeOH (32 mL) was treated with NaOH (1 M, aq., 37 mL). Thiourea dioxide (formamidinesulfonic acid) (1.66 g, 15.3 mmol) was added and the reaction mixture was stirred at 50° C. for 1 h (using a finders setup). The reaction mixture was diluted with DCM and diluted with K 2 CO 3 (10%, aq.) was added. The layers were separated and the organic layer was diluted with MgSO 4 It was dried over, filtered and the solvent was removed under reduced pressure to give 1.44 g of intermediate D5 as a yellow oil.

[0149] Preparation of intermediate D6 A solution of intermediate A5 (1.55 g, 3.06 mmol) in MeOH (34 mL) was treated with TMSCl (3.88 mL, 30.6 mmol) and the reaction mixture was stirred at room temperature for 20 h. The solvent was removed under reduced pressure and the resulting solid was extracted with Et 2 Triturated in O. The solvent was evaporated to give 1.51 g of intermediate D6 as a pale yellow solid (Quant.).

[0150] Preparation of intermediate D7 Trimethyl orthoformate (0.618 mL, 5.65 mmol) was added to a suspension of intermediate D6 (900 mg, 1.88 mmol) in HFIP (18 mL) and the reaction mixture was stirred at 60° C. for 1 h. The reaction mixture was cooled to room temperature, diluted with EtOAc and then with NaHCO 3 (sat., aq.). The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with MgSO 4 It was dried at 40° C., filtered and the solvent was removed under reduced pressure. The residue was purified by preparative LC (amorphous SiOH, 15-40 μm, 24 g, liquid injection (DCM), mobile phase: DCM / MeOH, gradient 100:0 to 90:10) to give 202 mg of intermediate D7 as an off-white solid (33%).

[0151] Preparation of compound 9 Et 3 N (0.169 mL, 1.22 mmol) was added to a solution of intermediate D7 (202 mg, 0.487 mmol) in DCM (9 mL) and 1,4-dioxane (6 mL). The solution was cooled to 5° C. and Tf 2 A solution of O in DCM (1M in DCM, 0.487 mL, 0.487 mmol) was added dropwise over 5 min. The reaction mixture was diluted with DCM and NaHCO 3 (sat., aq.). The layers were separated. The organic layer was washed with brine and MgSO 4 The mixture was dried over ice, filtered and the solvent was removed under reduced pressure. The residue was purified by preparative LC (amorphous SiOH, 15-40 μm, 12 g, liquid injection (DCM), mobile phase: heptane / EtOAc, gradient 70:30 to 0:100) to give 183 mg of a yellow solid. The solid was triturated in EtOAc and sonicated. The suspension was filtered off. The solid and filtrate were combined. The residue was diluted with Et 2 Triturate in O, sonicate, filter, and add Et 2 Washing with O and collection gave 125 mg of compound 9 as a white solid (47%). 1 H NMR (400MHz, DMSO-d 6)δ ppm 9.09(d,J=1.5Hz,1H)8.48(t,J=5.9Hz,1H)7.67(d,J=9.5Hz,1H)7.47(dd,J=9. 5,2.0Hz,1H)7.30-7.41(m,2H)7.16-7.30(m,2H)4.50(d,J=5.9Hz,2H)4.10(br t,J=4.2Hz,2H)3.65(t,J=4.6Hz,2H)3.00(q,J=7.5Hz,2H)1.27(t,J=7.5Hz,3H).

[0152] Synthesis of compound 10 [ka]

[0153] A solution of 2-ethyl-6-fluoroimidazo[1,2-a]pyridine-3-carboxylic acid [1368682-64-7] (82 mg, 0.393 mmol) in DMF (4.5 mL) was added with EDCI HCl (91 mg, 0.474 mmol), HOBt H 2 0 (63 mg, 0.415 mmol), and DIPEA (203 μL, 1.18 mmol) were added. The mixture was stirred at room temperature for 15 min. Intermediate B9 (155 mg, 0.432 mmol) was added and the reaction mixture was stirred at room temperature for 20 h. The solvent was removed under reduced pressure and the residue was diluted with EtOAc and water. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine (2x) and MgSO 4 The mixture was dried over ice, filtered, and the solvent was removed under reduced pressure. The residue was purified by preparative LC (amorphous SiOH, 15-40 μm, 12 g, liquid injection (DCM), mobile phase: DCM / MeOH gradient 100:0-90:10). A second purification was performed using reversed phase (stationary phase: YMC-actus Triart C18 10 μm 30*150 mm, mobile phase: NH 4 HCO 3 (0.2% in water / MeCN, gradient 50:50 to 25:75). The residue was dissolved in MeCN and MeOH (50:50), extracted with water and lyophilized to give 44 mg of compound 10 as a white solid (22%). 1H NMR (400MHz, DMSO-d 6 )δ ppm 9.40(dd,J=4.8,2.9Hz,1H)8.82(d,J=3.1Hz,1H)8.51(t,J=5.7Hz,1H)7.26-7.35(m,3H)7.18(d,J=8.7Hz,2H )4.48(d,J=5.7Hz,2H)4.08(t,J=4.6Hz,2H)3.82(t,J=4.8Hz,2H)3.02(q,J=7.5Hz,2H)1.27(t,J=7.5Hz,3H).

[0154] Synthesis of compound 11 [ka]

[0155] To a mixture of 2-ethyl-imidazo[1,2-a]pyrimidine-3-carboxylic acid [1403942-20-0] (125 mg, 0.654 mmol) and DIPEA (228 μL, 1.32 mmol) in DMF (6.5 mL) at room temperature was added EDCI HCl (150 mg, 0.782 mmol) and HOBt H 2 O (105 mg, 0.686 mmol) was added. Intermediate E9 (230 mg, 0.714 mmol) was added and the resulting mixture was stirred for 16 h. NaHCO 3 (1%, aq.) and EtOAc were added. The layers were separated and the organic layer was washed with brine (2x) and MgSO 4 The mixture was dried over hexane, filtered and concentrated in vacuo to dryness. The residue was purified by preparative LC (amorphous SiOH, 15-40 μm, 24 g dry packing (Celite®), mobile phase: heptane / (EtOAc / MeOH, 9 / 1), gradient 60:40-10:90). The residue was crystallized from EtOAc and collected by filtration to give 170 mg of compound 11 as a white solid (52%). 1 H NMR (400MHz, DMSO-d 6)δ ppm 9.30(dd,J=7.0,2.0Hz,1H)8.61(dd,J=4.2,2.0Hz,1H)8.48(t,J=5.9Hz,1H)7.27-7.35(m,3H)7.13-7.21(m, 3H)4.47(d,J=6.0Hz,2H)4.05-4.11(m,2H)3.83(t,J=4.8Hz,2H)3.01(q,J=7.5Hz,2H)1.27(t,J=7.5Hz,3H).

[0156] Synthesis of compound 12 [ka]

[0157] A mixture of 6-ethyl-2-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid [1131613-58-5] (150 mg, 0.608 mmol) and DIPEA (345 μL, 2.00 mmol) in DMF (6.5 mL) was treated with EDCI HCl (140 mg, 0.730 mmol) and HOBt H 2 O (100 mg, 0.653 mmol) was added. The mixture was stirred at room temperature for 15 min. Intermediate E9 (240 mg, 0.669 mmol) was then added and the resulting mixture was stirred for 16 h. The mixture was evaporated in vacuo. NaHCO 3 (1%, aq.) and EtOAc were added and the layers were separated. The organic layer was washed with brine and MgSO 4 The mixture was dried over ice and concentrated to dryness. The residue was purified by preparative LC (amorphous SiOH, 15-40 μm, 24 g dry packing (Celite®), mobile phase: heptane / (EtOAc / MeOH, 9 / 1), gradient 95:5-50:50). A second purification was performed by reversed phase (spherical C18, 25 μm, 40 g YMC-ODS-25, dry packing (Celite®), mobile phase: NH 4 HCO 3 (0.2% in water / MeCN, gradient 60:40 to 5:95) to give 206 mg of compound 12 as a white solid (66%). 1 H NMR (500MHz, DMSO-d 6)δ ppm 8.05(t,J=6.0Hz,1H)7.87(s,1H)7.24-7.30(m,3H)7.17(d,J=8.5Hz,2H)4.41(d,J=6.0Hz,2H)4.04-4.10(m,2H)3.81(br t,J=4.7Hz,2H)2.86(q,J=7.6Hz,2H)2.41(s,3H)1.20(t,J=7.6Hz,3H).

[0158] Synthesis of Compound 13 and Compound 14 [ka]

[0159] Preparation of intermediate E1 The reaction was carried out in two batches. The procedure for one batch is reported herein. When "Tf" is used herein, for the avoidance of doubt, it is understood to mean -S(O) 2 CH 3 Additionally, intermediate E9 may be prepared and / or used as the HCl salt. A 1 L flask equipped with a findenser was charged with 4-fluorobenzonitrile [1194-02-1] (20 g, 165 mmol), DMSO (320 mL), and N-boc-1,2-diaminoethane (39.7 g, 248 mmol). Et 3 N (92 mL, 661 mmol) was added and the reaction mixture was stirred at 120 °C for 20 h. The two batches were combined and poured into a mixture of crushed ice and water (1 L). Brine (1 kg) was added and the mixture was stirred at room temperature for 30 min. EtOAc (1 L) was added. The layers were separated and the aqueous layer was extracted with EtOAc (2 x 500 mL). The combined organic layers were washed with brine (2 x 1 L) and MgSO 4 The mixture was dried over ice, filtered and evaporated in vacuo. The residue was triturated in pentane (500 mL). The solid was collected by filtration and diluted with cold Et 2 O and dried under vacuum to give 48.28 g of intermediate E1 as a white solid (46%, 92% purity).

[0160] Preparation of intermediate E2 In a 1 L autoclave, prepare 7 M NH in MeOH. 3 A mixture of intermediate E1 (41.5 g, 159 mmol) and Raney nickel (4.66 g, 79.4 mmol) in 500 mL of solution was heated at room temperature under 6 bar of H 2 The reaction mixture was filtered through a pad of Celite®, washed with a mixture of DCM and MeOH (9 / 1), and the filtrate was evaporated in vacuo to give 41.8 g of intermediate E2 as a green oil (99%).

[0161] Preparation of intermediate E3 0°C N 2 Under reduced pressure, benzyl chloroformate (0.592 mL, 4.15 mmol) was added dropwise to a mixture of intermediate E2 (1 g, 3.8 mmol) and DIPEA (0.78 mL, 4.52 mmol) in DCM (38 mL). The reaction mixture was stirred at room temperature for 16 h and diluted with DCM. The mixture was diluted with NaHCO 3 (sat., aq.), washed with MgSO 4 After drying over rt, filtration and removal of the solvent under reduced pressure, 1.11 g of intermediate E3 was obtained as a white solid (74%).

[0162] Preparation of intermediate E4 Intermediate E3 (1.11 g, 2.78 mmol) was dissolved in Me-THF (21 mL) and AcOH (1.6 mL) at 40° C. Isopentyl nitrite (1.87 mL, 13.9 mmol) was added dropwise over 15 min and the reaction mixture was stirred at 40° C. for 1.5 h. The solution was diluted with EtOAc and NaHCO 3 (sat., aq.). The layers were separated and the organic phase was diluted with NaHCO 3 (sat., aq., twice), washed with brine, MgSO 4 Drying on and evaporation in vacuo gave 1.23 g of intermediate E4 as a pale yellow solid (Quant.).

[0163] Preparation of intermediate E5 A solution of intermediate E4 (1.24 g, 2.89 mmol) in THF (29 mL) and MeOH (19 mL) was treated with NaOH (1 M, aq., 29 mL). Thiourea dioxide (formamidinesulfonic acid) (1.56 g, 14.5 mmol) was then added and the reaction mixture was stirred at 50° C. for 1.5 h. The reaction mixture was diluted with DCM and diluted with K 2 CO 3 (10%, aq.) was added. The layers were separated. The aqueous layer was extracted with DCM and MeOH (95 / 5). The combined organic layers were washed with MgSO 4 It was dried over, filtered and concentrated in vacuo to give 970 mg of intermediate E5 as a pale yellow oil (81%).

[0164] Preparation of intermediate E6 To a solution of intermediate E5 (970 mg, 2.34 mmol) in MeOH (23 mL) was added TMSCl (2.4 mL, 18.7 mmol) dropwise. The reaction mixture was stirred at room temperature for 20 h and concentrated in vacuo to give 710 mg of intermediate E6 as a brown solid (78%).

[0165] Preparation of intermediate E7 A mixture of intermediate E6 (0.71 g, 1.83 mmol) and trimethyl orthoformate (0.602 mL, 5.50 mmol) in AcOH (9.2 mL) was stirred at 100° C. for 50 min. The reaction mixture was concentrated in vacuo. The residue was dissolved in DCM and K 2 CO 3 (10%, aq.). The layers were separated and the aqueous layer was extracted with DCM and MeOH (95 / 5) (2x). The combined organic layers were diluted with MgSO 4 The mixture was dried over 100 ml of hexane, filtered and evaporated in vacuo. The residue was purified by preparative LC (amorphous SiOH, 15-40 μm, 40 g, liquid injection (DCM), mobile phase: DCM / MeOH, gradient 100:0-90:10) to give 273 mg of intermediate E7 as a yellow residue (46%).

[0166] Preparation of intermediate E8 Et 3N (0.292 mL, 2.10 mmol) was added to a solution of intermediate E7 (273 mg, 0.842 mmol) in DCM (12 mL). The solution was then cooled to 5° C. and Tf 2 A solution of DCM (1M in DCM, 1.0 mL, 1.0 mmol) was added dropwise over 5 min. The reaction mixture was stirred for 1 h and diluted with DCM and NaHCO 3 (sat., aq.). The layers were separated. The aqueous layer was extracted with DCM (x2). The combined organic layers were washed with MgSO 4 It was dried over 100 ml, filtered and the solvent was removed under reduced pressure. The residue was purified by preparative LC (amorphous SiOH, 15-40 μm, 12 g dry packing (Celite®), mobile phase: heptane / EtOAc, gradient 100:0 to 0:100) to give 105 mg of intermediate E8 as a white solid (27%).

[0167] Preparation of intermediate E9 In a steal bomb, intermediate E8 (85 mg, 0.186 mmol) and Pd(OH) 2 A mixture of (21 mg, 0.075 mmol) in MeOH (8.5 mL) was heated at room temperature under 10 bar of H 2 The mixture was filtered through a pad of Celite® and the filtrate was evaporated in vacuo to give 65 mg of intermediate E9 as a white residue (Quant.).

[0168] Preparation of compound 13 A mixture of 6-chloro-2-ethyl-imidazo[1,2-a]pyrimidine-3-carboxylic acid [2059140-68-8] (46 mg, 0.202 mmol) and DIPEA (0.070 mL, 0.403 mmol) in DCM (3 mL) and Me-THF (3 mL) was treated with EDCI HCl (39 mg, 0.202 mmol), HOBt H 2 O (31 mg, 0.202 mmol), and intermediate E9 (65 mg, 0.202 mmol) were added. The reaction mixture was stirred at room temperature for 20 h. The reaction mixture was diluted with DCM and NaHCO 3 (sat., aq.) and the organic layer was washed with MgSO 4The solid (70 mg) was dissolved in Et 2 The residue (68 mg) was purified by reverse phase chromatography (stationary phase: YMC-actus Triart C18 10 μm 30 × 150 mm, mobile phase: NH 4 HCO 3 (0.2% in water / MeCN, gradient 55:45 to 35:65) to give 42 mg of compound 13 as a white solid (39%). 1 H NMR (400MHz, DMSO-d 6 )δ ppm 9.40(d,J=2.69Hz,1H)8.68(d,J=2.57Hz,1H)8.55(t,J=5.87Hz,1H)7.32(m,J=8.68Hz,2H)7.28(s,1H)7.19(m,J=8.68H z,2H)4.47(d,J=5.87Hz,2H)4.08(t,J=4.58Hz,2H)3.83(t,J=4.77Hz,2H)3.01(q,J=7.46Hz,2H)1.29(t,J=7.46Hz,3H).

[0169] Preparation of compound 14 Compound 14 was prepared starting from intermediate E9 and 5-methoxy-2-methylpyrazolo[1,5-a]pyridine-3-carboxylic acid [1352395-28-8] according to the procedure reported for the synthesis of compound 13, yielding 32 mg as a white fluffy solid (40%). 1 H NMR (400MHz, DMSO-d 6 )δ ppm 8.50(d,J=7.46Hz,1H)7.86(t,J=5.99Hz,1H)7.25-7.33(m,3H)7.24(d,J=2.69Hz,1H)7.18(d,J=8.68Hz,2H )6.63(dd,J=7.46,2.81Hz,1H)4.43(d,J=5.99Hz,2H)4.08(t,J=4.59Hz,2H)3.85(s,3H)3.79-3.83(m,2H).

[0170] Synthesis of compound 15 [ka]

[0171] Preparation of intermediate F1 4-Fluorobenzonitrile [1194-02-1] (10.0 g, 82.6 mmol), N-boc-N-methylethylenediamine (20.2 mL, 116 mmol), and K 2 CO 3 A mixture of (13.7 g, 99.1 mmol) in anhydrous DMSO (40 mL) was heated at 120 °C for 6 h. The reaction mixture was poured into brine and EtOAc was added. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and brine and diluted with MgSO 4 The crude mixture was dried over hexane, filtered and evaporated in vacuo. The crude mixture was purified by preparative LC (amorphous SiOH, 15-40 μm, 330 g, liquid injection (DCM), mobile phase: heptane / EtOAc, gradient 90:10-30:70) to give 18.04 g of intermediate F1 as a colorless oil (80%).

[0172] Preparation of intermediate F2 In a 1 L autoclave, a mixture of intermediate F1 (17.0 g, 61.7 mmol) and Raney Nickel (14.5 g, 247 mmol) in MeOH (330 mL) was heated at room temperature under 6 bar of H 2 The mixture was filtered over a pad of Celite®, washed with MeOH and the filtrate was evaporated in vacuo to give 17.25 g of intermediate F2 as a blue / green oil (Quant.).

[0173] Preparation of intermediate F3 To a mixture of 6-chloro-2-ethylimidazo[1,2-a]pyridine-3-carboxylic acid [1216142-18-5] (2.35 g, 10.0 mmol), intermediate F2 (3.07 g, 11.0 mmol), and DIPEA (3.45 mL, 20.0 mmol) in DCM (70 mL) and Me-THF (70 mL) was added EDCI HCl (2.30 g, 12.0 mmol) and HOBt H 2 0 (1.62 g, 12.0 mmol) was added. The reaction mixture was stirred at room temperature for 8 h. The mixture was evaporated and the crude mixture was purified by preparative LC (amorphous SiOH 15-40 μm, 220 g, dry packing (Celite®), mobile phase: heptane / EtOAc, gradient 70:30 to EtOAc 0:100) to give 3.703 g of intermediate F3 as a brown foam (76%).

[0174] Preparation of intermediate F4 Intermediate F3 (3.54 g, 7.28 mmol) was dissolved in Me-THF (62 mL) and AcOH (4.17 mL, 72.8 mmol). Isopentyl nitrite (4.89 mL, 36.4 mmol) was added dropwise and the reaction mixture was stirred at 40° C. for 1 h. The resulting solution was diluted in EtOAc. The organic layer was extracted with K 2 CO 3 (10%, aq.) (twice) and brine, then washed with MgSO 4 The mixture was dried over 100 ml and evaporated in vacuum. The residue was purified by preparative LC (amorphous SiOH, 15-40 μm, 80 g dry packing (Celite®), mobile phase: heptane / EtOAc, gradient 50:50-0:100) to give 3.54 g of intermediate F4 as an orange paste (94%).

[0175] Preparation of intermediate F5 A solution of intermediate F4 (1.13 g, 2.19 mmol) in THF (22 mL) and MeOH (14 mL) was treated with NaOH (1 M aq., 22 mL, 22 mmol). Formamidinesulfinic acid (1.19 g, 11.0 mmol) was added and the reaction mixture was stirred at 50° C. for 1.5 h. The reaction mixture was diluted in DCM and 2 CO 3(10% aq.) was added. The aqueous layer was extracted (2 times) with DCM and MeOH (95 / 5). The combined organic layers were washed with MgSO 4 Drying over, filtration and evaporation in vacuo gave 970 mg of intermediate F5 as a yellow foam (91% purity, 80%).

[0176] Preparation of intermediate F6 A solution of intermediate F5 (932 mg, 1.69 mmol) in MeOH (18 mL) was treated with TMSCl (2.15 mL, 16.9 mmol). The reaction mixture was stirred at room temperature for 20 h and evaporated in vacuo. The solid was extracted with Et 2 The supernatant was removed and the yellow powder was dried under vacuum to give 915 mg of intermediate F6 (Quant.).

[0177] Preparation of compound 15 To a solution of intermediate F6 (270 mg, 0.570 mmol) in HFIP (4.86 mL) was added trimethyl orthoformate (187 μL, 1.71 mmol) and the reaction mixture was stirred at 60° C. for 16 h. The reaction mixture was diluted with EtOAc and 2 CO 3 (10%, aq.). The organic layer was separated using H 2 2H2O (1x) and brine (1x), and then washed with MgSO 4 The mixture was dried over hexane, filtered and evaporated in vacuum. The crude mixture was purified by preparative LC (amorphous SiOH, 15-40 μm, 12 g dry packing (Celite®), mobile phase: DCM / (DCM / MeOH, 80:20), gradient 95:5-75:25). The residue was heated under reflux in EtOH for 20 min. The solution was cooled to room temperature and chilled at 0° C. The mixture was filtered. The solid was rinsed with cold EtOH and dried under vacuum at 60° C. for 7 h to give 51 mg of compound 15 as a beige fluffy solid (22%). 1 H NMR (400MHz, DMSO-d 6)δ ppm 9.03(s,1H)8.40(t,J=5.8Hz,1H)7.66(d,J=9.4Hz,1H)7.45(dd,J=9.5,2.08Hz,1H)7.18(d,J=8.7Hz,2H)7.10(d,J=8.7Hz,2H)6. 70(s,1H)4.42(d,J=5.8Hz,2H)3.51(t,J=5.2Hz,2H)3.34(t,J=5.2Hz,2H)2.96(q,J=7.6Hz,2H)2.83(s,3H)1.25(t,J=7.5Hz,3H).

[0178] Synthesis of compound 16 [ka]

[0179] Preparation of intermediate G1 A flask was charged with 6-chloro-2-ethylimidazo[1,2-a]pyridine-3-carboxylic acid [1216142-18-5] (1.00 g, 4.45 mmol), 4-bromo-2-fluorobenzylamine [112734-22-2] (0.954 g, 4.67 mmol), Me-THF (15 mL), DCM (15 mL), and DIPEA (1.23 mL, 7.12 mmol). HATU (1.86 g, 4.90 mmol) was added in small portions and the reaction mixture was stirred at room temperature for 17 h. The mixture was diluted with EtOAc and water. The layers were separated and the organic layer was washed with brine (2 times) and MgSO 4 The mixture was dried over hexane, filtered and evaporated in vacuum. The residue was dissolved in hot EtOAc. The solution was cooled to room temperature and then to 0° C. The suspension was filtered off and the solid was washed with cold EtOAc and then with Et 2 The solid was dried in vacuo to give 773 mg of intermediate G1 as an off-white solid (42%).

[0180] Preparation of intermediate G2 Intermediate G1 (740 mg, 1.80 mmol), N-boc-ethylenediamine (375 mg, 2.34 mmol), and Cs 2 CO 3A mixture of (1.06 g, 3.24 mmol) of tert-amyl alcohol (24 mL) and Me-THF (16 mL) was added to N 2 The reaction mixture was purged with N. Brettphos Pd G3 (82 mg, 0.090 mmol) and Brettphos (97 mg, 0.18 mmol) were added. 2 The mixture was purged with 0.5% water and stirred at 80° C. for 17 h. The reaction mixture was cooled to room temperature. Celite® was added and the mixture was evaporated in vacuo. The residue was purified by preparative LC (amorphous SiOH 15-40 μm, 40 g, mobile phase: heptane / EtOAc, gradient 50:50 0:100) to give 444 mg of intermediate G2 as a pale yellow foam (50%).

[0181] Preparation of intermediate G3 Intermediate G3 was prepared starting from intermediate G2 following the synthesis reported for the synthesis of intermediate F4, yielding 408 mg as a yellow solid (87%).

[0182] Preparation of intermediate G4 Intermediate G4 was prepared starting from intermediate G3 following the procedure reported for the synthesis of intermediate F5, yielding 362 mg as a beige solid (94%).

[0183] Preparation of intermediate G5 Intermediate G5 was prepared starting from intermediate G4 following the procedure reported for the synthesis of intermediate F6 to give 343 mg as a yellow powder (Quant.).

[0184] Preparation of intermediate G6 A mixture of intermediate G5 (283 mg, 0.592 mmol) and trimethyl orthoformate (194 μL, 1.78 mmol) in anhydrous DMF (3.7 mL) was stirred at 60° C. for 23 h. Further amounts of anhydrous DMF (3.7 mL) and trimethyl orthoformate (194 μL, 1.78 mmol) were added at room temperature and the reaction mixture was stirred at 60° C. for another 1.5 h. The reaction mixture was diluted with DCM and diluted with K 2 CO 3(10%, aq.). The layers were separated and the aqueous layer was extracted with DCM and MeOH (95 / 5) (2x). The combined organic layers were washed with water and brine and concentrated with MgSO 4 The crude mixture was dried over hexane, filtered and evaporated in vacuo. The crude mixture was purified by preparative LC (amorphous SiOH, 15-40 μm, 12 g dry packing (Celite®), mobile phase: DCM / (DCM / MeOH, 80 / 20), gradient 95:5-70:30) to give 156 mg of intermediate G6 as a white solid (63%).

[0185] Preparation of compound 16 N 2 Intermediate G6 (143 mg, 0.345 mmol) and Et 3 A mixture of N (240 μL, 1.72 mmol) in anhydrous DCM (5 mL), anhydrous Me-THF (5 mL), and anhydrous 1,4-dioxane (5 mL) was heated at 40° C. The reaction mixture was cooled to 0° C. and trifluoromethanesulfonic anhydride (0.517 mL, 0.517 mmol) was added dropwise. The mixture was stirred at 0° C. for 20 min and diluted with DCM. A small amount of MeOH was added and K 2 CO 3 (10%, aq.) was added. The layers were separated and the aqueous layer was extracted with DCM (x2). The combined organic layers were washed with water and brine and diluted with MgSO 4 The mixture was dried over silica gel, filtered and evaporated in vacuo. The crude mixture was purified by preparative LC (amorphous SiOH, 15-40 μm, 12 g dry packing (Celite®), mobile phase: DCM / (DCM / MeOH, 80:20), gradient 100:0 to 80:20). The residue was purified by reverse phase (stationary phase: YMC-actus Triart C18 10 μm 30×150 mm, mobile phase: NH 4 HCO 3 (0.2% in water / MeCN, gradient 55:45 to 25:75) to give 84 mg of compound 16 as a white solid (45%). 1 H NMR (500MHz, DMSO-d 6)δ ppm 9.05(s,1H)8.40(t,J=5.8Hz,1H)7.66(d,J=9.5Hz,1H)7.45(dd,J=9.5,2.1Hz,1H)7.36(t,J=8.5Hz,1H)7.02(m,2H)7. 32(s,1H)4.50(d,J=5.8Hz,2H)4.07(t,J=4.7Hz,2H)3.86(t,J=4.7Hz,2H)2.96(q,J=7.5Hz,2H)1.25(t,J=7.5Hz,3H).

[0186] Synthesis of compound 17 [ka]

[0187] Preparation of compound 17 N 2 Intermediate A6 (180 mg, 0.454 mmol) and Et 3 A mixture of N (315 μL, 2.27 mmol) in anhydrous Me-THF (7 mL), anhydrous 1,4-dioxane (7 mL), and anhydrous DCM (7 mL) was cooled to 0° C. Isobutanesulfonyl chloride (88.8 μL, 0.680 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 1 h, diluted with DCM, and diluted with K 2 CO 3 (10%, aq.). The layers were separated and the aqueous layer was extracted with DCM and MeOH (95 / 5) (2x). The combined organic layers were washed with MgSO 4 The solid was dried over hexane, filtered and evaporated in vacuum. The solid was purified by preparative LC (amorphous SiOH, 15-40 μm, 12 g dry packing (Celite®), mobile phase: DCM / (DCM:MeOH, 80:20), gradient 100:0-95:5) to give 124 mg of compound 17 as a slightly yellow solid (53%). 1 H NMR (500 MHz, CDCl 3)δ ppm 9.51-9.54(m,1H)7.51-7.55(m,1H)7.32(d,J=8.7Hz,2H)7.29(dd,J=9.5,2.0Hz,1H)7.23(s,1H)7.18(d,J=8.7Hz,2H)6.03(br t,1H)3.71(t,J=4.6Hz,2H)3.00(d,J=6.6Hz,2H)2.95(q,J=7.6,2H)2.32(m,1H)1.39(t,J=7.6Hz,3H)1.15(s,3H)1.14(s,3H).

[0188] Synthesis of compound 18 [ka]

[0189] N 2 Intermediate A6 (300 mg, 0.756 mmol) and Et 3 A mixture of N (0.525 mL, 3.78 mmol) in anhydrous DCM (11.5 mL), anhydrous Me-THF (11.5 mL), and anhydrous 1,4-dioxane (11.5 mL) was stirred at 70° C. for 2.5 h. The mixture was cooled to room temperature and then to 0° C. Acetyl chloride (53.9 μL, 0.756 mmol) was added dropwise and the reaction mixture was stirred at 0° C. for 30 min. The reaction mixture was diluted with DCM and diluted with MeOH and K. 2 CO 3 (10%, aq.). The layers were separated and the aqueous layer was extracted with DCM and MeOH (95 / 5) (2x). The combined organic layers were washed with brine and MgSO 4 The mixture was dried over 1000 ml, filtered and evaporated in vacuum. The residue was purified by preparative LC (amorphous SiOH, 15-40 μm, 12 g dry packing (Celite®), mobile phase: DCM / (DCM / MeOH, 80 / 20), gradient 95:5-85:15) to give 180 mg of compound 18 as a white solid (54%). 1 H NMR (500MHz, DMSO-d 6)δ ppm Rotamer:9.08(d,J=1.3Hz,1H)8.17(br t,J=5.4Hz,1H)7.62(d,J=9.8Hz,1H)7.58(br s,1H)7.41(dd,J=9.5,2.2Hz,1H)7.30(d,J=8.8Hz,2H)7.20(d,J=8.5Hz,2H)4.49(d,J=6.0Hz,2H)3.86(br s,2H)3.66(t,J=5.0Hz,2H)2.99(q,J=7.6Hz,2H)2.25(s,3H)1.28(t,J=7.6Hz,3H).

[0190] Synthesis of compound 19 [ka]

[0191] Intermediate A6 (100 mg, 0.252 mmol) and Et 3 To a mixture of N (0.175 mL, 1.26 mmol) in anhydrous DCM (2.7 mL) and anhydrous Me-THF (2.7 mL) was added 2-methoxy-1-ethanesulfonyl chloride (88.3 μL, 0.756 mmol) at 0° C. and the reaction mixture was stirred at 0° C. for 15 min. The reaction was quenched with a small amount of MeOH and K 2 CO 3 (10%, aq.) was added. The layers were separated and the aqueous layer was extracted with DCM (x2). The combined organic layers were washed with water (x2) and brine and diluted with MgSO 4 The mixture was dried over hexane, filtered and evaporated in vacuum. The residue was purified by preparative LC (amorphous SiOH, 15-40 μm, 12 g dry packing (Celite®), mobile phase: heptane / EtAOc, gradient 55:45-0:100, then EtOAc / MeOH 99:1). The solid was triturated in MeCN, the supernatant was removed and the solid was dried under vacuum to give 53 mg of compound 19 as a white solid (41%). 1 H NMR (400MHz, DMSO-d 6)δ ppm 9.06(d,J=1.5Hz,1H)8.43(t,J=5.9Hz,1H)7.66(d,J=9.5Hz,1H)7.45(dd,J=9.5,2.1Hz,1H)7.28(d,J=8.7Hz,2H)7.17(d,J=8.7Hz,2H)7.14(s ,1H)4.45(d,J=5.9Hz,2H)3.84(t,J=4.3Hz,2H)3.63-3.75(m,6H)3.24(s,3H)2.97(q,J=7.5Hz,2H)1.25(t,J=7.5Hz,3H)1.09(t,J=7.0Hz,1H).

[0192] Synthesis of compound 20 [ka]

[0193] Intermediate A6 (120 mg, 0.302 mmol) and Et 3 A mixture of N (210 μL, 1.51 mmol) in anhydrous THF (6 mL) was cooled to 0° C. Methanesulfonyl chloride (46.8 μL, 0.605 mmol) was added dropwise and the reaction mixture was stirred at 0° C. for 15 min. An additional amount of methanesulfonyl chloride (23.4 μL, 0.302 mmol) was added dropwise at 0° C. and the reaction mixture was stirred at 0° C. for an additional 30 min. The reaction mixture was diluted with DCM and quenched with a small amount of MeOH. 2 CO 3 (10%, aq.) was added. The layers were separated and the aqueous layer was extracted with DCM (x2). The combined organic layers were washed with water and brine and diluted with MgSO 4 The mixture was dried over hexane, filtered and evaporated in vacuum. The residue was purified by preparative LC (amorphous SiOH, 15-40 μm, 12 g dry packing (Celite®), mobile phase: heptane / EtOAc, gradient 30:70-0:100, then EtOAc / MeOH 99:1). The solid was triturated in EtOAc and the supernatant was removed to give 68 mg of compound 20 as a white solid (47%). 1 H NMR (400MHz, DMSO-d 6)δ ppm 9.06(d,J=1.6Hz,1H)8.43(t,J=5.8Hz,1H)7.66(d,J=9.5Hz,1H)7.45(dd,J=9.4,2.08Hz,1H)7.28(d,J=8.6Hz,2H)7.19(s,1H)7.17(d,J=8. 8Hz,2H)4.46(d,J=5.9Hz,2H)3.86(t,J=5.1Hz,2H)3.70(t,J=5.1Hz,2H)3.27(s,3H)2.97(d,J=7.5Hz,2H)1.99(s,1H)1.25(t,J=7.5Hz,3H).

[0194] Synthesis of compound 21 [ka]

[0195] Preparation of intermediate H6 A mixture of intermediate A5 (200 mg, 0.435 mmol) and trimethyl orthoacetate (166 μL, 1.31 mmol) in acetic acid (3.6 mL) was stirred at 100° C. for 3 h. The reaction mixture was evaporated in vacuo. The residue was diluted with DCM and diluted with K 2 CO 3 (10%, aq.) was added. The layers were separated and the aqueous layer was extracted with DCM and MeOH (95 / 5) (2x). The combined organic layers were washed with MgSO 4 The mixture was dried over 100 ml of hexane, filtered and evaporated in vacuo. The residue was purified by preparative LC (amorphous SiOH, 15-40 μm, 12 g dry packing, mobile phase: DCM / MeOH, gradient 100:0-95:5) to give 132 mg of intermediate H6 as a yellow foam (77% purity, 57%).

[0196] Preparation of compound 21 To a mixture of intermediate H6 (133 mg, 0.249 mmol) in anhydrous DCM (2.7 mL) and anhydrous Me-THF (2.5 mL) was added Et 3 N (0.17 mL, 1.3 mmol) was added. The mixture was cooled to 0° C. and trifluoromethanesulfonic anhydride (0.75 mL, 0.75 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 15 min and diluted with a small amount of MeOH and K 2 CO3 (10%, aq.). The layers were separated and the aqueous phase was extracted with DCM (x2). The combined organic extracts were washed with brine and MgSO 4 The mixture was dried over silica gel, filtered and evaporated in vacuo. The residue was purified by preparative LC (amorphous SiOH, 15-40 μm, 12 g dry packing (Celite®), mobile phase: heptane / EtAOc, gradient 80:20 to 0:100). A second purification was performed using reversed phase (stationary phase: YMC-actus Triart C18 10 μm 30×150 mm, mobile phase: NH 4 HCO 3 (0.2% in water / MeCN, gradient 40:60 to 10:90) to give 52 mg of compound 21 as an off-white solid (38%). 1 H NMR (500MHz, DMSO-d 6 )δ ppm 9.06(d,J=1.6Hz,1H)8.44(s,1H)7.66(d,J=9.5Hz,1H)7.45(dd,J=9.6,2.1Hz,1H)7.30(d,J=8.8Hz,2H)7.16(d,J=8.8Hz,2 H)4.46(d,J=6.0Hz,2H)4.00(t,J=5.4Hz,2H)3.82(t,J=5.4Hz,2H)2.97(q,J=5.6Hz,2H)2.26(s,3H)1.25(t,J=7.6Hz,3H).

[0197] Synthesis of compound 22 [ka]

[0198] Preparation of intermediate I1 4-Bromo-2-methoxybenzonitrile [330793-38-9] (1.55 g, 7.31 mmol), N-boc-ethylenediamine (1.76 g, 11.0 mmol), and Cs 2 CO 3 A mixture of (4.76 g, 14.6 mmol) in anhydrous tert-amyl alcohol (46 mL) was 2The mixture was purged with 500 mL of 1000 mL of 10000 sulphate. Brettphos Pd G3 (331 mg, 0.365 mmol) and Brettphos (392 mg, 0.731 mmol) were added and the reaction mixture was heated at 120° C. for 1 h and then for another 45 min using a single mode microwave (Biotage Initiator 60). The two batches were filtered over a Celite® pad and the filtrate was evaporated in vacuo. The residue was purified by preparative LC (amorphous SiOH, 15-40 μm, 120 g dry packing (Celite®), mobile phase: heptane / EtAOc, gradient 90:10 to 0:100) to give 1.64 g of intermediate I1 (74%).

[0199] Preparation of intermediate I2 Intermediate I2 was prepared starting from intermediate I1 following the procedure reported for the synthesis of intermediate F2 to yield 1.55 g of a grey oil (94%).

[0200] Preparation of intermediate I3 Intermediate I3 was prepared starting from intermediate I2 following the procedure reported for the synthesis of intermediate F3 to yield 765 mg of a beige solid (62%).

[0201] Preparation of intermediate I4 Intermediate I4 was prepared starting from intermediate I3 following the procedure reported for the synthesis of intermediate F4 to give 724 mg of a yellow solid (90%).

[0202] Preparation of intermediate I5 Intermediate I5 was prepared starting from intermediate I4 following the procedure reported for the synthesis of intermediate F5 to yield 692 mg of a beige foam (99%).

[0203] Preparation of intermediate I6 Intermediate E6 was prepared starting from intermediate I5 following the procedure reported for the synthesis of intermediate F6 to give 710 mg of a beige solid (Quant.).

[0204] Preparation of intermediate I7 A solution of intermediate I6 (270 mg, 0.551 mmol) and N,N-dimethylformamide dimethyl acetal (73.8 μL, 0.551 mmol) in anhydrous DMF (3.4 mL) was stirred at room temperature for 4.5 h. The reaction mixture was diluted with DCM and 2 CO 3 (10%, aq.). The layers were separated and the aqueous phase was extracted with DCM and MeOH (95 / 5) (2x). The combined organic layers were washed with MgSO 4 The mixture was dried over 100 ml of 1000 ml of 110 ml of 1000 ml of 1100 ml of 12 ...20 ml of 120 ml of 120 ml of 120 ml of 120 ml of 120 ml of 120 ml

[0205] Preparation of compound 22 N 2 Intermediate I7 ​​(92.0 mg, 0.216 mmol) and Et 3 To a mixture of N (150 μL, 1.08 mmol) in anhydrous DCM (3.1 mL), anhydrous Me-THF (3.1 mL), and anhydrous 1,4-dioxane (3.1 mL) was added trifluoromethanesulfonic anhydride (0.323 mL, 0.323 mmol) dropwise. The reaction mixture was stirred at 0° C. for 10 min and the DCM and K 2 CO 3 (10%, aq.). The layers were separated and the aqueous phase was extracted with DCM and MeOH (95 / 5) (2x). The combined organic extracts were washed with MgSO 4 The mixture was dried over hexane, filtered and evaporated in vacuum. The residue was purified by preparative LC (amorphous SiOH, 15-40 μm, 12 g dry packing (Celite®), mobile phase: DCM / (DCM / MeOH, 95 / 5), gradient 100:0-80 / 20). The solid was triturated in EtOAc. The supernatant was removed and the white solid was dried under vacuum at 60° C. for 1 h to give 28 mg of compound 22 (23%). 1 H NMR (400MHz, DMSO-d 6)δ ppm 9.04(d,J=1.5Hz,1H)8.23(t,J=5.7Hz,1H)7.66(d,J=9.7Hz,1H)7.45(dd,J=9.5,2.1Hz,1H)7.31(s,1 H)7.19(d,J=8.3Hz,1H)6.93(d,J=2.0Hz,1H)6.70(dd,J=8.3,2.0Hz,1H)4.43(d,J=5.7Hz,2H)4.07(br d,J=4.6Hz,2H)3.86(br d,J=5.3Hz,2H)3.84(s,3H)2.96(d,J=7.5Hz,2H)1.25(t,J=7.5Hz,3H).

[0206] Synthesis of compound 23 [ka]

[0207] Preparation of intermediate J1 Intermediate E7 (400 mg, 1.23 mmol) and Et 3 To a mixture of N (0.857 mL, 6.17 mmol) in anhydrous DCM (18 mL) was added isobutanesulfonyl chloride (0.161 mL, 1.23 mmol) dropwise at 0° C. The reaction mixture was stirred at room temperature for 1 h. The reaction was cooled to 30° C. with NaHCO 3 (sat., aq.). The layers were separated and the aqueous phase was extracted with DCM and MeOH (95 / 5) (2x). The combined organic extracts were washed with MgSO 4 The residue was dried over hexane, filtered and evaporated in vacuo. The residue was purified by preparative LC (amorphous SiOH, 15-40 μm, 24 g dry packing (Celite®), mobile phase: heptane / EtOAc, gradient 100:0 to 0:100, then mobile phase EtOAc / MeOH, gradient 100:0 to 95:5) to give 406 mg of intermediate J1 as a green solid (74%).

[0208] Preparation of intermediate J2 Intermediate J1 (406 mg, 0.913 mmol) and Pd(OH) 2A mixture of (264 mg, 0.941 mmol) in MeOH (20 mL), EtOAc (20 mL), and THF (5 mL) was heated at room temperature under 15 bar of H 2 The mixture was stirred at RT for 18 h. The reaction mixture was filtered and rinsed with MeOH, EtOAc, and THF. The filtrate was evaporated in vacuo to give 180 mg of intermediate J2 as a yellow solid (60%).

[0209] Preparation of compound 23 6-Chloro-2-ethyl-imidazo[1,2-a]pyrimidine-3-carboxylic acid [2059140-68-8] (113 mg, 0.501 mmol), intermediate J2 (180 mg, 0.551 mmol), EDCI·HCl (96.0 mg, 0.501 mmol), HOBt·H 2 A mixture of O (76.7 mg, 0.501 mmol) and DIPEA (431 μL, 2.50 mmol) in DCM (10 mL) and Me-THF (6 mL) was stirred at room temperature for 18 h. The reaction mixture was diluted with DCM and washed with water (2 times) and brine. The organic phase was diluted with MgSO 4 The residue was dried over 100 ml, filtered and evaporated in vacuum. The residue was purified by preparative LC (amorphous SiOH, 15-40 μm, 12 g dry packing (Celite®), mobile phase: heptane / EtAOc, gradient 90:10-0:100, then mobile phase: EtOAc / MeOH, gradient 100:0-95:5) to give 101 mg of compound 23 as a slightly yellow solid (39%). 1 H NMR (500MHz, DMSO-d 6 )δ ppm 9.39(d,J=2.8Hz,1H)8.67(d,J=2.6Hz,1H)8.51(t,J=6.0Hz,1H)7.28(d,J=8.7Hz,2H)7.19(s,1H),7.17(d,J=8.8Hz,3H)4.46(d,J=6.0Hz,2H)3 .86(t,J=4.8Hz,2H)3.69(t,J=4.9Hz,2H)3.32(d,J=6.6Hz,3H)3.01(q,J=7.5Hz,2H)2.13(m,1H)1.27(t,J=7.6Hz,3H)1.06(s,3H)1.04(s,3H).

[0210] Synthesis of compound 24 [ka]

[0211] Preparation of intermediate K1 Intermediate E7 (550 mg, 1.70 mmol) at 0° C. and Et 3 To a mixture of N (1.18 mL, 8.48 mmol) in anhydrous DCM (24 mL) was added acetyl chloride (0.145 mL, 2.04 mmol) dropwise. The reaction mixture was stirred at room temperature for 15 min and the reaction was cooled to 0° C. with NaHCO 3 (sat., aq.). The layers were separated and the aqueous phase was extracted with DCM and MeOH (95 / 5) (2x). The combined organic extracts were washed with MgSO 4 The mixture was dried over hexane, filtered and evaporated in vacuo. The residue was triturated in EtOAc and the solid was collected by filtration to give 320 mg of intermediate K1 as a slightly yellow solid (52%).

[0212] Preparation of intermediate K2 Intermediate K1 (256mg, 0.698mmol), Pd(OH) 2 (157 mg, 0.558 mmol), and HCl (H 2 A mixture of 1M in 20O, 0.698 mL, 0.698 mmol) in MeOH (6.4 mL) and EtOAc (6.4 mL) was heated at rt under 5 bar H 2 The mixture was stirred under reduced pressure for 1 h. The reaction mixture was filtered and rinsed with EtOAc and MeOH. The yellow solid was purified by preparative LC (amorphous SiOH 15-40 μm, 12 g, dry packing (Celite®), mobile phase DCM / (DCM / MeOH / NH 3 aq., 80 / 20 / 0.5), gradient 100:0 to 70:30) to give 130 mg of intermediate K2 (75%).

[0213] Preparation of compound 24 To a mixture of 6-chloro-2-ethyl-imidazo[1,2-a]pyrimidine-3-carboxylic acid [2059140-68-8] (98.5 mg, 0.436 mmol), intermediate K2 (129 mg, 0.480 mmol), and DIPEA (752 μL, 4.36 mmol) in DCM (8.8 mL) and Me-THF (5.2 mL) was added EDCI·HCl (83.7 mg, 0.436 mmol) and HOBt·H 2 O (66.8 mg, 0.436 mmol) was added. The reaction mixture was stirred at room temperature for 16 h, filtered, and the solid was washed with DCM to give 114 mg of compound 24 as a slightly yellow fluffy solid (59%). 1 H NMR (500MHz, DMSO-d 6 )δ ppm 9.38(d,J=2.2Hz,1H)8.61(d,J=2.5Hz,1H)8.26(br t,J=6.0Hz,1H)7.56(br s,1H)7.28(br d,J=8.5Hz,2H)7.18(d,J=8.5Hz,2H)4.47(d,J=5.7Hz,2H)3.84(br s,2H)3.64(t,J=5.0Hz,2H)3.01(q,J=7.6Hz,3H)2.23(br s,3H)1.28(t,J=7.4Hz,3H).

[0214] Synthesis of compound 25 [ka]

[0215] Preparation of intermediate L1 To a mixture of 4-fluoro-3-methoxy-benzonitrile [243128-37-2] (4.88 g, 32.3 mmol) and N-boc-ethylenediamine (18.0 mL, 0.129 mol) in DMSO (58 mL) was added Et 3 N (6.65 mL, 42.0 mmol) was added. The reaction mixture was stirred at 120 °C for 16 h. The reaction mixture was cooled and poured into brine. EtOAc was added. The layers were separated and the aqueous phase was extracted with EtOAc (2x). The combined organic extracts were washed with a mixture of water and brine (1 / 1) (3x) and washed with MgSO4 The mixture was dried over 100 ml of hexane, filtered and evaporated in vacuo. The residue was purified by preparative LC (amorphous SiOH, 15-40 μm, 330 g dry packing (Celite®), mobile phase: heptane / EtOAc, gradient 100:0-30:70) to give 5.23 g of intermediate L1 as a white solid (56%).

[0216] Preparation of intermediate L2 Intermediate L2 was synthesized starting from intermediate L1 following the procedure reported for the synthesis of intermediate F2 to give 1.09 g of a green oil (Quant.).

[0217] Preparation of intermediate L3 To a mixture of 6-chloro-2-ethylimidazo[1,2-a]pyridine-3-carvone [1216142-18-5] (701 mg, 3.12 mmol), intermediate L2 (1.01 g, 3.43 mmol), and DIPEA (2.69 mL, 15.6 mmol) in DCM (60 mL) and Me-THF (40 mL) was added EDCI HCl (598 mg, 3.12 mmol) and HOBt H 2 O (478 mg, 3.12 mmol) was added. The reaction mixture was stirred at room temperature for 16 h and diluted with DCM and water. The layers were separated and the aqueous phase was extracted with DCM (x2). The combined organic extracts were washed with brine (x2) and MgSO 4 The mixture was dried over 1000 ml, filtered and evaporated in vacuum. The residue was purified by preparative LC (amorphous SiOH, 15-40 μm, 80 g dry packing (Celite®), mobile phase: heptane / EtOAc, gradient 60:40-0:100) to give 1.078 g of intermediate L3 as a yellow solid (69%).

[0218] Preparation of intermediate L4 Intermediate L3 (1.08 g, 2.15 mmol) was dissolved in Me-THF (21 mL) and acetic acid (1.23 mL, 21.5 mmol). Isopentyl nitrite (1.44 mL, 10.7 mmol) was added dropwise and the reaction mixture was stirred at 40° C. for 1.5 h. The reaction mixture was diluted with EtOAc and NaHCO 3(sat., aq.). The layers were separated. The organic phase was diluted with NaHCO 3 (sat., aq.) (twice) and brine, then washed with MgSO 4 The mixture was dried over hexane, filtered and evaporated in vacuo. The residue was triturated in pentane and the supernatant was removed to give a yellow solid which was dried under vacuum to give 1.127 g of intermediate L4 (99%).

[0219] Preparation of intermediate L5 Intermediate L5 was prepared starting from intermediate L4 following the procedure reported for the synthesis of intermediate F5 to yield 1.07 g of an orange foam (97%).

[0220] Preparation of intermediate L6 Intermediate L6 was prepared starting from intermediate L5 following the procedure reported for the synthesis of intermediate F6 to yield 1.10 g of a yellow powder (Quant.).

[0221] Preparation of intermediate L7 A mixture of intermediate L6 (600 mg, 1.14 mmol) and trimethyl orthoformate (374 μL, 3.42 mmol) in HFIP (10.8 mL) was stirred at 60° C. for 1 h. The reaction mixture was diluted with EtOAc and diluted with K 2 CO 3 (10%, aq.). The layers were separated and the organic phase was washed with H 2 Wash with MgSO and brine. 4 The mixture was dried over 100 ml, filtered and evaporated in vacuum. The residue was purified by preparative LC (amorphous SiOH, 15-40 μm, 25 g dry packing (Celite®), mobile phase: DCM / (DCM / MeOH, 80 / 20), gradient 100:0-50:50) to give 290 mg of intermediate L7 as a slightly orange solid (60%).

[0222] Preparation of compound 25 Intermediate L7 (290 mg, 0.679 mmol) and Et 3To a mixture of N (0.472 mL, 3.40 mmol) in anhydrous DCM (10 mL) and anhydrous Me-THF (10 mL) was added trifluoromethanesulfonic anhydride (0.815 mL, 0.815 mmol) dropwise at 0° C. The reaction mixture was stirred at 0° C. for 15 min and diluted with DCM. Then, small amounts of MeOH and K were added. 2 CO 3 (10%, aq.) was added. The layers were separated and the aqueous phase was extracted with DCM and MeOH (95 / 5) (2x). The combined organic extracts were washed with water and brine and diluted with MgSO 4 The mixture was dried over 1000 ml, filtered and evaporated. The residue was purified by preparative LC (amorphous SiOH, 15-40 μm, 25 g dry packing (Celite®), mobile phase: heptane / EtOAc gradient 70:30 to 0:100). The yellow solid was dissolved in Et 2 Trituration in O, sonication, and collection by filtration gave 135 mg of compound 25 as a beige solid (36%). 1 H NMR (500MHz, DMSO-d 6 )δ ppm 9.06(d,J=1.6Hz,1H)8.47(br t,J=6.0Hz,1H)7.66(d,J=9.5Hz,1H)7.46(dd,J=9.5,2.2Hz,1H)7.29(s,1H)7.2 1(d,J=7.9Hz,1H)7.08(s,1H)6.96(d,J=7.9Hz,1H)4.52(d,J=6.0Hz,2H)4.06(br t,J=4.4Hz,2H)3.82(s,3H)3.55(br t,J=4.7Hz,2H)3.01(d,J=7.6Hz,2H)1.27(t,J=7.6Hz,3H).

[0223] Synthesis of compound 26 [ka]

[0224] Preparation of intermediate M1 To a mixture of 2-amino-5-methoxypyrimidine [13418-77-4] (4.75 g, 38.0 mmol), ethyl 3-oxovalerate [4949-44-4] (9.48 mL, 66.4 mmol), and (diacetoxyiodo)benzene (iodobenzene diacetate) (12.2 g, 38.0 mmol) in anhydrous Me-THF (150 mL) was added dropwise boron trifluoride etherate (0.993 mL, 3.80 mmol). The reaction mixture was stirred at room temperature for 3 h. The two batches were combined and the mixture was diluted with EtOAc. NaHCO 3 (sat., aq.) was added. The layers were separated and the organic phase was washed with brine and MgSO 4 The mixture was dried over 100 ml, filtered and concentrated in vacuo. The residue was purified by preparative LC (amorphous SiOH, 15-40 μm, 330 g, liquid injection (DCM), mobile phase: heptane / EtOAc, gradient 85:15-50:50) to give 4.94 g of intermediate M1 as a yellow solid (26%).

[0225] Preparation of intermediate M2 To a solution of intermediate M1 (500 mg, 2.01 mmol) in THF (10 mL), LiOH H 2 A solution of 253 mg of 2H2O (6.02 mmol) in water (5 mL) was added. The reaction mixture was stirred at 45 °C for 2 h, cooled to room temperature and HCl (1 M, aq., 6 mL) was added followed by EtOAc. The layers were separated and the aqueous phase was extracted with DCM and then with a mixture of DCM and MeOH (95 / 5). The combined organic extracts were washed with MgSO 4 It was dried over, filtered and evaporated in vacuo to give 80 mg of intermediate M2 (18%).

[0226] Preparation of compound 26 To a mixture of intermediate M2 (80 mg, 0.362 mmol) and intermediate E9 (117 mg, 0.362 mmol) in DMF (2.44 mL) were successively added DIPEA (0.156 mL, 0.904 mmol) and TBTU (128 mg, 0.398 mmol). The reaction mixture was stirred at room temperature for 17 h. The reaction mixture was poured into EtOAc. The organic phase was washed with brine (2 times) and diluted with MgSO 4The mixture was dried over 100 ml of hexane, filtered and evaporated in vacuo. The residue was purified by preparative LC (amorphous SiOH, 15-40 μm, 24 g, liquid injection (DCM), mobile phase: heptane / EtOAc, gradient 50:50 to 0:100) to give 78 mg of compound 26 as a white solid (41%). 1 H NMR (400MHz, DMSO-d 6 )δ ppm 9.40(d,J=2.57Hz,1H)8.68(d,J=2.69Hz,1H)8.53(t,J=5.87Hz,1H)7.30(d,J=8.68Hz,2H)7.15(d,J=8.68Hz,2H)4 .46(d,J=5.87Hz,2H)4.06-4.18(m,2H)3.85(s,3H)3.69-3.78(m,2H)3.01(q,J=7.54Hz,2H)1.27(t,J=7.52Hz,3H).

[0227] Synthesis of compound 27 [ka]

[0228] Preparation of intermediate N1 A solution of intermediate E6 (3.00 g, 7.75 mmol) in acetic acid (30 mL) was treated with tetramethoxymethane (2.58 mL, 19.4 mmol) and stirred at room temperature for 2 h. The reaction mixture was poured into DCM and 2 CO 3 (10%, aq.). The layers were separated and the aqueous phase was extracted with DCM and MeOH (98 / 2). The combined organic extracts were washed with MgSO 4 The crude mixture was dried over 100 ml, filtered and evaporated in vacuo. The crude mixture was purified by preparative LC (amorphous SiOH, 15-40 μm, 80 g, liquid injection (DCM), mobile phase: heptane / EtOAc, gradient 70:30-0:100) to give 1.09 g of intermediate N1 as an oil (40%).

[0229] Preparation of intermediate N2 To a mixture of intermediate N1 (1.00 g, 2.82 mmol) and DIPEA (0.972 mL, 5.64 mmol) in DCM (15 mL) was added Tf2 A solution of O in DCM (1M in DCM, 2.96 mL, 2.96 mmol) was added dropwise over 10 min. The reaction mixture was stirred at room temperature for 30 min and diluted with DCM. The mixture was diluted with NaHCO 3 (sat., aq.), washed with MgSO 4 The mixture was dried over 100 ml, filtered and evaporated in vacuo. The residue was purified by preparative LC (amorphous SiOH, 15-40 μm, 40 g, liquid injection (DCM), mobile phase: heptane / EtOAc, gradient 80:20-40:60) to give 680 mg of intermediate N2 as a white solid (50%).

[0230] Preparation of intermediate N3 In a steal bomb, intermediate N2 (630 mg, 1.30 mmol), Pd(OH) 2 (132 mg, 0.470 mmol), and HCl (H 2 A mixture of 1,2-dichlorophenyl ether (3M in 2H2O, 0.432 mL, 1.30 mmol) in MeOH (5 mL) and EtOAc (5 mL) was heated at room temperature under 5 bar of H2O. 2 The mixture was filtered over a Celite® pad to give 503 mg of intermediate N3 as a white solid (Quant.).

[0231] Preparation of compound 27 A mixture of intermediate N3 (150 mg, 0.665 mmol), 6-chloro-2-ethyl-imidazo[1,2-a]pyrimidine-3-carboxylic acid [2059140-68-8] (284 mg, 0.731 mmol), and DIPEA (0.344 mL, 1.99 mmol) in DMF (4.5 mL) was treated with TBTU (235 mg, 0.731 mmol) and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with EtOAc, washed with water and brine, and diluted with MgSO 4 The mixture was dried over ice, filtered and concentrated in vacuo. The residue was purified by preparative LC (amorphous SiOH 40 μm, 24 g, liquid injection (DCM), mobile phase: heptane / EtOAc gradient 80:20 to 20:80). The white solid was dissolved in hot EtOAc and the solution was cooled to room temperature and then to 0° C. The suspension was filtered off and ethyl acetate was added. 2The mixture was washed with 50 ml of 1000 ml of ethyl acetate and dried in vacuum to give a solid (71 mg). The filtrate was evaporated in vacuum and combined with the solid. The residue was dissolved in hot i-PrOH and cooled to room temperature. The suspension was slowly concentrated under vacuum (120 mbar) to give a thick solution. After filtration, the solid was extracted with Et 2 O and dried under vacuum to give 135 mg of compound 27 as a white solid (36%). 1 H NMR (400MHz, DMSO-d 6 )δ ppm 8.94(d,J=3.06Hz,1H)8.51(d,J=3.06Hz,1H)8.40(t,J=5.87Hz,1H)7.32(d,J=8.68Hz,2H)7.28(s,1H)7.19(d,J=8.68Hz,2 H)4.48(d,J=5.87Hz,2H)4.08(t,J=4.65Hz,2H)3.86(s,3H)3.79-3.84(m,2H)2.99(q,J=7.50Hz,2H)1.25(t,J=7.52Hz,3H).

[0232] Synthesis of compound 28 [ka] PTSA (108 mg, 567 μmol) was added to a suspension of compound 1 (300 mg, 567 mmol) in MeOH (7.8 mL). After sonication, the solution was stirred at room temperature for 1 h and the solvent was removed under reduced pressure. The residue was dissolved in Et 2 Trituration in O and removal of the solvent under reduced pressure (repeated twice) gave 406 mg of compound 28 as an off-white solid (Quant.). 1 H NMR (400MHz, DMSO-d 6)δ ppm 9.14(s,1H)8.80(t,J=5.7Hz,1H)7.74-7.89(m,2H)7.47(d,J=8.1Hz,2H)7.27-7.37(m,3H)7.19(d,J=8.7Hz,2H)7.11(d,J=7.8 Hz,2H)4.49(d,J=5.9Hz,3H)4.08(t,J=4.4Hz,2H)3.83(t,J=4.8Hz,2H)3.02(q,J=7.5Hz,2H)2.29(s,3H)1.27(t,J=7.5Hz,3H).

[0233] Synthesis of compound 29 [ka] MeSO 3 A solution of H in MeOH (9.1% v / v, 368 μL, 516 μmol) was added to a mixture of compound 1 (300 mg, 567 μmol) in MeOH (15 mL). The reaction mixture was stirred at room temperature for 45 min and evaporated to dryness. The residue was extracted with Et 2 It was triturated in O and the solvent was removed under reduced pressure. The solid was dried under vacuum to give 355 mg of compound 29 as an off-white solid (Quant.). 1 H NMR (400MHz, DMSO-d 6 )δ ppm 9.13(s,1H)8.74(t,J=5.3Hz,1H)7.82(d,J=9.4Hz,1H)7.73(d,J=9.4Hz,1H)7.33(m,J=8.7Hz,2H)7.29(s,1H)7.19(m,J=8.7H z,2H)4.49(d,J=5.9Hz,2H)4.08(t,J=4.6Hz,2H)3.83(t,J=4.8Hz,2H)3.02(q,J=7.5Hz,2H)2.32(s,3H)1.27(t,J=7.5Hz,3H).

[0234] Synthesis of compound 30 [ka] (1R)-(-)-Camphor-10-sulfonic acid (110 mg, 473 μmol) was added to a solution of compound 1 (250 mg, 473 μmol) in anhydrous MeOH (5 mL). The reaction mixture was stirred at room temperature for 30 min and the solvent was removed under reduced pressure. The residue was dissolved in Et 2 Trituration in O and removal of the solvent under reduced pressure gave 359 mg of compound 30 as a white solid (Quant.). 1 H NMR (400MHz, DMSO-d 6 )δ ppm 9.12(d,J=1.3Hz,1H)8.69(t,J=5.3Hz,1H)7.80(m,1H)7.69(m,1H)7.33(d,J=8.6Hz,2H)7.28(s,1H)7 .19(d,J=8.7Hz,2H)4.48(d,J=5.7Hz,3H)4.08(t,J=4.6Hz,2H)3.83(t,J=4.8Hz,2H)3.01(q,J=7.6Hz ,2H)2.86(d,J=14.7Hz,1H)2.65-2.75(m,1H)2.37(d,J=14.7Hz,1H)2.23(dt,J=18.1,3.9Hz,1H)1.93 (t,J=4.5Hz,1H)1.83-1.91(m,1H)1.82(s,1H)1.77(s,1H)1.21-1.32(m,5H)1.05(s,3H)0.74(s,3H).

[0235] Synthesis of compound 31 [ka] A solution of HCl in EtOH (2.5 M, 89 μL, 473 μmol) was added to a mixture of compound 1 (250 mg, 473 μmol) in MeOH (2.7 mL). The reaction mixture was stirred at room temperature for 30 min and then evaporated to dryness in vacuo. The residue was extracted with Et 2 Trituration in O and removal of the solvent under reduced pressure gave 269 mg of compound 31 as a white solid (Quant.). 1 H NMR (400MHz, DMSO-d 6)δ ppm 9.12(s,1H)8.71(m,1H)7.79(d,J=9.4Hz,1H)7.68(d,J=8.8Hz,1H)7.26-7.37(m,3H)7.19(d,J=8.7Hz,2H)4 .48(d,J=5.9Hz,2H)4.08(t,J=4.5Hz,2H)3.83(t,J=4.8Hz,2H)3.01(q,J=7.6Hz,2H)1.27(t,J=7.5Hz,3H).

[0236] Synthesis of compound 32 [ka] H 2 SO 4 (13 μL, 238 μmol) was added to a solution of compound 1 (252 mg, 476 μmol) in MeOH (4.2 mL). The reaction mixture was stirred at room temperature for 30 min and then evaporated to dryness. The residue was dissolved in Et 2 The white solid was dried under vacuum at 60° C. for 6 h to give 271 mg of compound 32 as a white solid (98%). 1 H NMR (400MHz, DMSO-d 6 )δ ppm 9.11(s,1H)8.63(t,J=5.5Hz,1H)7.76(d,J=9.5Hz,1H)7.62(d,J=9.8Hz,1H)7.26-7.36(m,3H)7.19(d,J=8.7Hz, 2H)4.48(d,J=5.9Hz,2H)4.07(t,J=4.7Hz,2H)3.83(t,J=4.7Hz,2H)3.00(q,J=7.5Hz,2H)1.26(t,J=7.5Hz,3H).

[0237] Synthesis of compound 33 [ka]

[0238] Preparation of intermediate O1 A 2 L round bottom flask equipped with an addition funnel was charged with a solution of 2-amino-5-chloropyrimidine [5428-89-7] (10 g, 77 mmol) in Me-THF (350 L) at 5° C. Ethyl 3-oxovalerate [4949-44-4] (20 mL, 140 mmol) and (diacetoxyiodo)benzene (iodobenzene diacetate) (25 g, 78 mmol) were added. Boron trifluoride diethyl etherate (1 mL, 3.8 mmol) was added dropwise over 30 min and the solution was stirred at 5° C. for 2 h. The mixture was allowed to warm to room temperature and stirred for 1 h. The mixture was filtered. EtOAc and NaHCO 3 (sat., aq.) was added to the filtrate. The organic layer was washed with MgSO 4 The crude mixture was dried over hexane, filtered and concentrated in vacuo. The crude mixture was purified by preparative LC (amorphous SiOH, 15-40 μm, 330 g, liquid injection (DCM), mobile phase: heptane / EtOAc, gradient 85:15-50:50) to give intermediate O1 (2.98 g, 15%).

[0239] Preparation of intermediate O2 Intermediate O1 (1.00 g; 3.94 mmol), potassium (methoxymethyl) trifluoroborate [910251-11-5] (1.80 g, 11.8 mmol), and Cs 2 CO 3 A solution of (3.85 g, 11.8 mmol) in 1,4-dioxane (10 mL) and water (1.4 mL) was purged with nitrogen. RuPhos (184 mg, 0.394 mmol) and RuPhos Pd G3 (330 mg, 0.394 mmol) were added. The reaction mixture was purged again with nitrogen and stirred at 100 °C for 17 h. The reaction mixture was concentrated in vacuo and purified by preparative LC (amorphous SiOH 15-40 μm, 40 g, liquid injection (DCM), mobile phase: heptane / EtOAc gradient 75:25-0:100). The residue was purified by reverse phase (stationary phase: YMC-actus Triart C18 10 μm 30 × 150 mm, mobile phase: (aq.NH 4 HCO 3 0.2%) / MeCN, gradient 70:30 to 30:70) to give intermediate O2 (212 mg, 20%) as a white solid.

[0240] Preparation of intermediate O3 A mixture of intermediate O2 (130 mg, 0.494 mmol) and LiOH (14 mg, 0.585 mmol) in THF (2.3 mL) and water (2.3 mL) was stirred at room temperature for 36 h. The reaction mixture was evaporated in vacuo to give 168 mg of intermediate O3 as a light yellow gum. The crude product was used as such in the next step.

[0241] Preparation of compound 33 To a mixture of intermediate O3 (168 mg, 0.529 mmol) and DIPEA (0.275 mL, 1.59 mmol) in DMF (5 mL) was added HOBt H 2 2H2O (83.0 mg, 0.542 mmol), EDCI●HCl (102 mg, 0.533 mmol), and intermediate E9 (223 mg, 0.536 mmol) were added successively. The reaction mixture was stirred at room temperature for 20 h. DCM and water were added. The layers were separated and the organic layer was washed with NaHCO 3 (sat., aq.) and brine (3 times), then washed with MgSO 4 The mixture was dried over silica gel, filtered and evaporated. The crude mixture was purified by preparative LC (amorphous SiOH, 15-40 μm, 24 g dry packing (Celite®), mobile phase: heptane / (EtOAc / MeOH, 9 / 1), gradient 90:10 to 0:100). The residue (175 mg) was purified by reverse phase (stationary phase: YMC-actus Triart C18 10 μm 30×150 mm, 40 g, dry packing (Celite®), mobile phase: (aq.NH 4 HCO 3 0.2%) / MeCN, gradient 90:10 to 30:70). MeCN was evaporated and the product was extracted with DCM (2x). The organic layer was washed with MgSO 4 The mixture was dried over ice, filtered and evaporated in vacuo to give 154 mg of a white solid. The product was purified by reverse phase (stationary phase: YMC-actus Triart C18 10 μm 30×150 mm, 40 g, dry packing (Celite®), mobile phase: (aq.NH 4 HCO 30.2%) / MeCN, gradient 60:40 to 45:55). MeCN was evaporated and the product was extracted with DCM (2x). The organic layer was washed with MgSO 4 The mixture was dried over ice, filtered and evaporated in vacuo. The product was triturated in MeCN and EtOAc, filtered and dried under high vacuum at 50° C. for 16 hours to give compound 33 (119 mg, 42%) as a white solid. 1 H NMR (400MHz, DMSO-d 6 )δ ppm 9.27(d,J=2.3Hz,1H)8.60(d,J=2.4Hz,1H)8.50(t,J=6.0Hz,1H)7.27-7.34(m,3H)7.19(d,J=8.7Hz,2H)4.53(s,2H) )4.47(d,J=5.9Hz,2H)4.03-4.12(m,2H)3.79-3.86(m,2H)3.34(s,3H)3.00(q,J=7.5Hz,2H)1.27(t,J=7.5Hz,3H).

[0242] Synthesis of compound 34 [ka] To a mixture of 5-methoxy-2-methylpyrazolo[1,5-a]pyridine-3-carboxylic acid [1352395-28-8] (80 mg, 0.39 mmol), intermediate N3 (151 mg, 0.39 mmol), and DIPEA (201 μL, 1.17 mmol) in DMF (5 mL) was added EDCI HCl (74 mg, 0.39 mmol) and HOBt H 2 O (59 mg, 0.39 mmol) was added. The reaction mixture was stirred at room temperature for 18 h and concentrated in vacuo. The residue was diluted in EtOAc and water. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic layers were washed with MgSO 4 The residue (229 mg) was purified by reverse phase chromatography (stationary phase: YMC-actus Triart C18 (30 × 150 mm), mobile phase: (aq.NH 4 HCO 3 0.2%) / MeCN, gradient 50:50 to 25:75) to give 118 mg of compound 34. 1 H NMR (400MHz, DMSO-d 6 )δ ppm 8.49(d,J=7.5Hz,1H)7.85(t,J=5.9Hz,1H)7.22-7.29(m,3H)7.14(d,J=8.7Hz,2H)6.62(dd,J=7.5,2 .8Hz,1H)4.41(d,J=6.0Hz,2H)4.07-4.12(m,2H)3.84(d,J=2.3Hz,6H)3.69-3.75(m,2H)2.52(s,3H).

[0243] Synthesis of compound 35 [ka]

[0244] Preparation of intermediate P1 In a round-bottom flask, 3,4,5-trifluorobenzonitrile [134227-45-5] (5 g, 31.8 mmol), N-boc-1,2-diaminoethane [57260-73-8] (5.2 mL, 32.8 mmol), and Et 3 A solution of N (17.7 mL, 127 mmol) in anhydrous DMSO (57 mL) was stirred at 120 °C for 16 h. The reaction mixture was cooled to room temperature and DMSO was evaporated in a Genevac. EtOAc, water, and NaCl were added. The layers were separated and the organic layer was washed with brine (3 times) and MgSO 4 The mixture was dried over hexane, filtered and evaporated in vacuum. The crude mixture was dissolved in EtOAc and SiOH was added. The dry packing was evaporated and washed with heptane (100 mL). The product was eluted with heptane / EtOAc (1:1, 3×100 mL). The filtrate was evaporated to give 9.30 g of intermediate P1 as a colorless oil that crystallized on standing (98%).

[0245] Preparation of intermediate P2 Intermediate P2 was prepared starting from intermediate P1 (31.3 mmol) following the synthesis reported for intermediate E2 to yield 9.3 g as a light blue gum (99%) that crystallized on standing.

[0246] Preparation of intermediate P3 Intermediate P3 was prepared starting from intermediate P2 (6.64 mmol) following the synthesis reported for intermediate E3 to give 1.63 g as a colorless oil (56%) that crystallized on standing.

[0247] Preparation of intermediate P4 Intermediate P4 was prepared starting from intermediate P3 (3.74 mmol) following the synthesis reported for intermediate E4 to give 1.91 g as a yellow oil (91%).

[0248] Preparation of intermediate P5 Intermediate P5 was prepared starting from intermediate P4 (3.74 mmol) following the synthesis reported for intermediate E5 to give 1.69 g as a yellow oil (100%) that crystallized on standing.

[0249] Preparation of intermediate P6 A solution of intermediate P5 (1.69 g, 3.75 mmol) in anhydrous DCM (35 mL) was treated with TFA (3.5 mL, 45.7 mmol) and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was evaporated in vacuo to give 3.42 g of intermediate P6 as an orange gum.

[0250] Preparation of intermediate P7 Trimethyl orthoformate (1.24 mL, 11.3 mmol) was added to a solution of intermediate P6 (3.42 g, 3.78 mmol) in HFIP (35 mL) and the mixture was stirred at 60° C. for 2 h. The reaction mixture was cooled to room temperature, diluted with EtOAc and added with NaHCO 3 (sat., aq.). The layers were separated and the aqueous layer was extracted with EtOAc (x1). The combined organic layers were washed with MgSO 4 It was dried over, filtered and the solvent was removed under reduced pressure to give 2.0 g of intermediate P7 as a yellow gum.

[0251] Preparation of intermediate P8 Triethylamine (1 mL, 7.19 mmol) was added to a solution of intermediate P7 (1.5 g, 2.83 mmol) in DCM (28 mL). The solution was then cooled to 0° C. (ice / water bath) and Tf2 O (1M in DCM, 3.4 mL, 3.4 mmol) was added dropwise over 5 min. The reaction mixture was stirred at 0° C. for 30 min. The mixture was allowed to warm slowly to room temperature and stirred for 2 h. DCM, water, and NaHCO 3 (10%, aq.) was added. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were dried over MgSO4, filtered and evaporated. The residue (1.61 g) was purified by preparative LC (amorphous SiOH, 30 μm, 80 g, liquid injection (DCM), mobile phase: heptane / EtOAc, gradient 95:5 to 50:550) to give 317 mg of intermediate P8 as an orange gum (23% total 3 steps).

[0252] Preparation of intermediate P9 In a steal bomb, a mixture of intermediate P8 (317 mg, 0.644 mmol), palladium hydroxide on carbon, Pd 20%, nominally 50% water (120 mg, 0.171 mmol), and HCl (1 M, aq., 0.64 mL, 0.64 mmol) in EtOAc (3.2 mL) and MeOH (3.2 mL) was heated to 5 bar H 2 The mixture was hydrogenated at room temperature for 4 hours under 5 bar H. The mixture was filtered. An additional amount of palladium hydroxide on carbon, Pd 20%, nominal 50% water (60 mg, 0.085 mmol) and HCl (1 M, aq., 0.64 mL, 0.64 mmol) were added. The mixture was hydrogenated at 5 bar H. 2 The mixture was hydrogenated at room temperature under reduced pressure for 1.5 hours. The reaction mixture was filtered and the filtrate was evaporated in vacuo to give 269 mg of intermediate P9 as an orange gum. The crude product was used directly in the next step.

[0253] Preparation of compound 35 A mixture of 6-chloro-2-ethylimidazo[1,2-a]pyridine-3-carboxylic acid [1216142-18-5] (80 mg, 0.356 mmol) and DIPEA (0.245 mL, 1.42 mmol) in DMF (3.5 mL) was treated with EDCI HCl (72 mg, 0.376 mmol), HOBt HCl (1.2 mg, 0.376 mmol), and 1,2-dichloro-2,4-diphenyl-3-pyridine-2-carboxylic acid (1216142-18-5) (80 mg, 0.356 mmol). 2O (60 mg, 0.392 mmol) and intermediate P9 (270 mg, 0.356 mmol) were added successively. The reaction mixture was stirred at room temperature for 20 h. The crude product was dissolved in DCM and NaHCO 3 (sat., aq.) was added. The layers were separated and the organic layer was washed with brine (2x) and MgSO 4 The mixture was dried over silica gel, filtered and evaporated in vacuo. The residue (409 mg) was purified by preparative LC (SiOH amorphous 30 μm, 24 g, mobile phase: heptane / (EtOAc / MeOH, 9 / 1), gradient 80:20 to 20:80). A second purification was performed using reversed phase (stationary phase: YMC-actus Triart C18 25 μm 30×150 mm, 40 g, dry packing (Celite®), mobile phase: (aq.NH 4 HCO 3 0.2%) / MeCN, gradient 65:35 to 25:75). The desired fractions were combined and MeCN was evaporated. The product was extracted with DCM (3 times) and the organic layer was washed with MgSO 4 The product was extracted with pentane and Et 2 Trituration in O (1 / 1), evaporation and drying under high vacuum at 50° C. for 5 h gave 66 mg of compound 35 as a light yellow solid (24%). 1 H NMR (400MHz, DMSO-d 6 )δ ppm 9.11(m,1H)8.45-8.53(m,1H)7.69(d,J=9.4Hz,1H)7.48(dd,J=9.7,1.8Hz,1H)7.29(s,1H)7.18(d,J=9.5Hz,2 H)4.54(d,J=5.6Hz,2H)4.05-4.13(m,2H)3.61-3.70(m,2H)3.03(q,J=7.4Hz,2H)1.23-1.35(t,J=7.4Hz,3H).

[0254] Synthesis of compound 36 [ka]

[0255] Preparation of intermediate Q1 Carbon tetrabromide (16 g; 43.4 mmol) was added to a mixture of 2-amino-5-methoxypyridine [10167-97-2] (3 g, 24.2 mmol) and ethyl 3-oxovalerate [4949-44-4] (5.2 mL, 36.6 mmol) in MeCN (50 mL). The reaction mixture was heated at 80° C. for 2 h. The reaction mixture was cooled to room temperature and concentrated to dryness. The residue (20 g) was purified by preparative LC (SiOH 30 μm amorphous, 330 g, dry packing (SiOH), mobile phase: heptane / EtOAc, gradient 80:20 to 0:100) to give 1.89 g of intermediate Q1 as a greenish solid (32%).

[0256] Preparation of intermediate Q2 To a solution of intermediate Q1 (1.89 g, 7.61 mmol) in water (20 mL) and EtOH (25 mL) was added NaOH (913 mg, 22.8 mmol). The reaction mixture was stirred at room temperature for 16 h. An additional amount of NaOH (304 mg, 7.61 mmol) was added and the reaction mixture was stirred for 3 h. EtOH was concentrated. The mixture was acidified to pH 2-3 with HCl (1N). The white precipitate was filtered, washed with water and dried under high vacuum to give 750 mg of intermediate Q2 as a white solid (45%).

[0257] Preparation of compound 36 To a mixture of intermediate Q2 (150 mg, 0.681 mmol) and DIPEA (0.48 mL, 2.79 mmol) in DMF (7 mL) was added EDCI HCl (174 mg, 0.908 mmol), HOBt H 2 O (144 mg, 0.94 mmol) and intermediate N3 (265 mg, 0.681 mmol) were added successively. The reaction mixture was stirred at room temperature for 16 h and evaporated. The residue was dissolved in DCM and NaHCO 3 (sat., aq.) was added. The layers were separated and the organic layer was washed with water and brine (twice) and MgSO 4The crude mixture was purified by preparative LC (SiOH 30 μm amorphous, 24 g, liquid injection (DCM), mobile phase: heptane / (EtOAc / MeOH, 9 / 1), gradient 80:20 to 20:80). The product-containing fractions were combined and evaporated to give a white solid (304 mg). The product was recrystallized from MeCN, filtered and dried under high vacuum at 50° C. for 3 h to give 200 mg of compound 36 as a white solid (53%). 1 H NMR (400MHz, DMSO-d 6 )δ ppm 8.65(d,J=2.2Hz,1H)8.23-8.32(m ,1H)7.53(d,J=9.5Hz,1H)7.29(d,J=8.7Hz,2H)7.13-7.21(m,3H)4.46(d,J=5.9Hz,2H)4. 06-4.17(m,2H)3.85(s,3H)3.72-3.82(m,5H)2.95(q,J=7.5Hz,2H)1.24(t,J=7.5Hz,3H).

[0258] Synthesis of compound 37 [ka]

[0259] Preparation of intermediate R1 Intermediate R1 was prepared starting from intermediate D2 (7.06 mmol) following the synthesis reported for intermediate E3 to give 2.53 g as an off-white solid (86%).

[0260] Preparation of intermediate R2 Intermediate R2 was prepared starting from intermediate R1 (6.06 mmol) following the synthesis reported for intermediate E4 to give 3.2 g of a yellow oil that was used as is in the next step without purification.

[0261] Preparation of intermediate R3 Intermediate R3 was prepared starting from intermediate R2 (6.06 mmol theoretical) following the synthesis reported for intermediate E5 to give 2.22 g as a yellow oil (87% overall two steps).

[0262] Preparation of intermediate R4 To a solution of intermediate R3 (2.22 g, 5.13 mmol) in MeOH (52 mL) was added TMSCl (5.2 mL, 41 mmol) dropwise. The reaction mixture was stirred at room temperature for 20 h and concentrated in vacuo. Et 2 O was added to the residue and the gum was triturated. The solvent was removed under reduced pressure to give 2.06 g of intermediate R4 as a pale green solid (99%).

[0263] Preparation of intermediate R5 A solution of intermediate R4 (1.00 g, 2.47 mmol) in acetic acid (25 mL) was treated with tetramethoxymethane (0.82 mL, 6.17 mmol) and stirred at room temperature for 1 h. An additional amount of tetramethoxymethane (0.82 mL, 6.17 mmol) was added and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into DCM and water. The mixture was diluted with K 2 CO 3 The layers were separated. The aqueous layer was extracted with DCM (x1) and the combined organic layers were washed with MgSO 4 The residue (685 mg) was purified by preparative LC (amorphous SiOH 40 μm, 24 g, liquid injection (DCM), mobile phase: DCM / MeOH, gradient 100:0 to 85:15) to give 445 mg of intermediate R5 as a colorless oil (48%).

[0264] Preparation of intermediate R6 Intermediate R6 was prepared starting from intermediate R5 (1.19 mmol) following the synthesis reported for intermediate P8 to give 0.45 g as a colorless oil (72%).

[0265] Preparation of intermediate R7 Intermediate R7 was prepared starting from intermediate R6 (0.61 mmol) following the synthesis reported for intermediate P9 to give 0.24 g as a colorless oil (96%).

[0266] Preparation of compound 37 To a mixture of 6-chloro-2-ethylimidazo[1,2-a]pyridine-3-carboxylic acid [1216142-18-5] (87.3 mg, 0.388 mmol), intermediate R7 (158 mg, 0.388 mmol), and DIPEA (0.335 mL, 1.94 mmol) in DMF (5.3 mL) was added EDCI HCl (74.5 mg, 0.388 mmol) and HOBt H 2 2H2O (59.5 mg, 0.388 mmol) was added successively. The reaction mixture was stirred at room temperature for 16 h and evaporated in vacuum. The crude mixture was purified by preparative LC (amorphous SiOH, 15-40 μm, 12 g dry packing (Celite®), mobile phase: heptane / EtOAc gradient 80:20-30:70). The desired fractions were combined and evaporated under vacuum. The product (163 mg) was purified by hexane / EtOAc gradient 80:20-30:70. 2 Sonication in O and filtration gave 118 mg of compound 37 as a white solid (53%). 1 H NMR (400MHz, DMSO-d 6 )δ ppm 9.09(d,J=1.6Hz,1H)8.47(t,J=5.9Hz,1H)7.68(d,J=9.5Hz,1H)7.42-7.50(m,2H)7.16-7.25(m,2H)4.49( d,J=5.9Hz,2H)4.07-4.15(m,2H)3.83(s,3H)3.53-3.61(m,2H)3.00(q,J=7.5Hz,2H)1.27(t,J=7.5Hz,3H).

[0267] Synthesis of compound 38 [ka]

[0268] Preparation of intermediate S1 To a solution of DMF (103 μL, 1.33 mmol) in DCE (6.5 mL) at room temperature, POCl 3(123 μL, 1.33 mmol) was added and the mixture was stirred at room temperature for 30 min. The mixture was then cooled to 0° C. and intermediate E7 (430 mg, 1.33 mmol) in DCE (6.5 mL) was added dropwise and the mixture was stirred at 0° C. for 2 h. Water and DCM were added. The aqueous layer was washed with NaHCO 3 Slowly basify with (S) to pH 8. The layers are separated and the aqueous layer is extracted with DCM. The combined organic layers are washed with brine and MgSO 4 It was dried over, filtered off and evaporated to give 421 mg of intermediate S1 as a yellow solid, which was used crude as is in the next step.

[0269] Preparation of intermediate S2 In a steel vessel, intermediate S1 (421 mg, 1.20 mmol), palladium hydroxide (100 mg, 0.14 mmol), and H 2 A mixture of 1M HCl in O (1.2 mL, 1.2 mmol) in MeOH (10.5 mL) and EtOAc (10.5 mL) was heated at room temperature under 5 bar of H 2 The mixture was hydrogenated under 50° C. for 3 hours. The mixture was filtered on a Celite® pad to give 413 mg of intermediate S2 as a yellow solid. The crude was used as is in the next step.

[0270] Preparation of compound 38 A solution of 6-chloro-2-ethylimidazo[1,2-a]pyridine-3-carboxylic acid (CAS[1216142-18-5], 240 mg, 1.07 mmol) and diisopropylethylamine (0.75 mL, 4.35 mmol) in DCM (11 mL) was treated with EDCI HCl (210 mg, 1.10 mmol) and HOBt HCl. 2 O (170 mg, 1.11 mmol) was added, followed by Intermediate S2 (410 mg, 1.13 mmol) and the mixture was stirred at room temperature for 16 h. DCM and water were added. The layers were separated and the organic layer was diluted with NaHCO 3The crude was washed with a saturated aqueous solution of 1,2-dichloromethane and brine. The organic layer was dried over MgSO4, filtered and evaporated. The crude was purified by reverse phase (stationary phase: YMC-actus Triart C18 10 μm 30×150 mm, 40 g, dry packing (on Celite®), mobile phase: gradient 80% (aq. NH 4 HCO 3 0.2%), 20% MeCN~40% (aq.NH 4 HCO 3 The mixture was purified by evaporation of MeCN and extraction of the product with DCM / MeOH (9:1) (3 times). The organic layer was washed with MgSO 4 The mixture was dried over ice, filtered and evaporated to give 176 mg of a light yellow solid, which was purified by reverse phase (stationary phase: YMC-actus Triart C18 10 μm 30×150 mm, 40 g, dry packing (on Celite®), mobile phase: gradient 60% (aq. NH 4 HCO 3 0.2%), 40% MeCN~45% (aq.NH 4 HCO 3 0.2%, 55% MeCN (total 16 CV). All fractions were combined to give 139 mg as a yellow solid. This was purified by reverse phase (stationary phase: YMC-actus Triart C18 10 μm 30×150 mm, liquid packing (DMSO), mobile phase: gradient 70% (aq.NH 4 HCO 3 0.2%), 30% ACN~50% (aq. NH 4 HCO 3 0.2%, 50% ACN) to give 39 mg as a white solid. This was dissolved in DCM / MeOH then combined with the previous fraction, evaporated and dried under high vacuum (50° C., 2 h) to give 68 mg of an off-white solid. This was co-evaporated with MeOH (5 times) then dried under high vacuum (50° C., 6 h) to give 65 mg of compound 38 as an off-white solid (12%). Many rotamers (84%) 1H NMR(500MHz,DMSO-d6,350K)δ ppm 9.07(s,1H),8.57(s,1H),8.15(br t,J=5.2Hz,1H),7.61(d,J=9.5Hz,1H),7.53(s,1H),7.39(dd,J=9.6,2.0Hz,1H ),7.28(d,J=8.5Hz,2H),7.19(d,J=8.5Hz,2H),4.47(d,J=6.0Hz,2H),3.78(br t,J=4.7Hz,2H)3.64(br t,J=4.8Hz,2H),2.97(q,J=7.6Hz,2H),1.26(t,J=7.6Hz,3H). A small number of reversed isomers (16%) 1 H NMR(500MHz,DMSO-d6,350K)δ ppm 9.07(s,1H),8.57(s,1H),8.15(br t,J=5.2Hz,1H),7.61(d,J=9.5Hz,1H),7.53(s,1H),7.39(dd,J=9.6,2.0Hz,1H),7.28(d,J=8.5Hz,2H),7.19( d,J=8.5Hz,2H),4.47(d,J=6.0Hz,2H),3.90(m,2H)3.73(m,2H),2.97(q,J=7.6Hz,2H),1.26(t,J=7.6Hz,3H).

[0271] Synthesis of compound 39

change

[0272] Modulation of intermediate T1 5℃にてN 2To a solution of 3-chloro-4-methoxypyridin-2-amine (CAS[1232431-05-8], 0.2 g, 1.26 mmol) below in 2-MeTHF (6 mL) was added ethyl 3-oxovalerate (CAS[4949-44-4], 0.18 mL, 1.26 mmol) and iodobenzene diacetate ((diacetoxyiodo)benzene) (0.406 g, 1.26 mmol.), followed by dropwise addition of boron trifluoride etherate (16.5 μL, 0.063 mmol). The solution was stirred at 5° C. for 30 min, then allowed to warm to room temperature and stirred for 2 h. Additional amounts of ethyl 3-oxovalerate (0.09 mL, 0.63 mmol), iodobenzene diacetate (0.203 g, 0.63 mmol), and boron trifluoride etherate (16.5 μL, 0.063 mmol) were added and the mixture was purified by N 2 The mixture was purged with 500 mL of ethyl acetate and stirred at rt for 1 h. EtOAc and water were added. The layers were separated and the organic layer was washed with MgSO 4 The crude was dried over, filtered off and concentrated. The crude was purified by preparative LC (SiOH amorphous, 30 μm, 24 g liquid packing (DCM), mobile phase: heptane 95%, EtOAc 5% isocratic over 3 CV, then gradient to heptane 60%, EtOAc 40% over 12 CV) to give 295 mg of intermediate T1 as a white solid (83%).

[0273] Preparation of intermediate T2 To a solution of intermediate T1 (270 mg, 0.96 mmol) in water (4.8 mL) and EtOH (4.8 mL) was added NaOH (115 mg, 2.88 mmol) and the mixture was stirred at room temperature for 4 days. The mixture was evaporated to give 371 mg of intermediate T2 as a light yellow solid (71% purity). The crude was used as is in the next step.

[0274] Preparation of compound 39 To a solution of intermediate T2 (371 mg, 0.952 mmol) and diisopropylethylamine (0.50 mL, 2.90 mmol) in DMF (9.5 mL) was added HOBtH 22H2O (160 mg, 1.05 mmol) and EDCI●HCl (195 mg, 1.02 mmol) were added, followed by intermediate E9 (400 mg, 0.959 mmol). The mixture was stirred at rt for 20 h. The mixture was evaporated and then dissolved in DCM and NaHCO 3 A saturated aqueous solution of was added. The organic layer was separated, washed with brine and MgSO 4 The crude was purified by preparative LC (amorphous SiOH, 15-40 μm, 50 g, liquid packing in DCM, mobile phase gradient: heptane 75%, EtOAc / MeOH (9:1) 25% to heptane 25%, EtOAc / MeOH (9:1) 75% total 12 CV). The clean fractions were combined and evaporated to give 312 mg as a light yellow solid. This was purified by reverse phase (stationary phase: YMC-actus Triart C18 10 μm 30×150 mm, 40 g, dry packing on Celite®, mobile phase: gradient 55% (aq. NH 4 HCO 3 0.2%), 45% MeCN~5% (aq.NH 4 HCO 3 0.2%), 95% MeCN total 12 CV) to give 286 mg as an off-white solid, which was sonicated in MeCN (suspension) and then filtered off. The solid was dried under high vacuum (50° C., 6 h) to give 230 mg of compound 39 as a white solid (43%). 1 H NMR(400MHz,DMSO-d6)δ ppm 8.94(d,J=7.7Hz,1H),8.35(t,J=5.9Hz,1H),7.26-7.35(m,3H),7.12-7.23(m,3H),4.45(br d,J=5.9Hz,2H),4.07(br d,J=4.4Hz,2H),3.99(s,3H),3.82(t,J=4.6Hz,2H),2.95(q,J=7.6Hz,2H),1.24(t,J=7.5Hz,3H).

[0275] Synthesis of Compound 40 and Compound 41 [ka]

[0276] Preparation of intermediate U1 A mixture of intermediate E6 (1.00 g, 2.58 mmol), ethyl-3-ethoxy-3-iminopropanoate hydrochloride (CAS [2318-25-4], 2.17 g, 7.75 mmol), and triethylamine (1.08 mL, 7.75 mmol) in NMP (14 mL) was stirred at 150 °C for 18 h in a sealed tube. The reaction mixture was diluted with EtOAc and water. The aqueous phase was extracted with EtOAc (x3). The combined organic phase was washed with NaCl sat. and MgSO 4 After drying over 50° C. and concentration, 1.85 g was obtained as a brown oil, which was diluted in EtOAc and washed with a dilute solution of NaCl. The organic layer was washed with MgSO. 4 After drying and concentration, 1.03 g of intermediate U1 was obtained. The crude product was used directly in the next step based on theoretical amount.

[0277] Preparation of intermediate U2 To a solution of intermediate U1 (900 mg, 2.19 mmol) and triethylamine (914 μL, 6.58 mmol) in dry DCM (45 mL) at −78° C., 1 M Tf 2 O (3.1 mL, 3.1 mmol) was added dropwise and the reaction mixture was stirred for 15 min. The reaction mixture was diluted with DCM and water. The organic phase was washed with MgSO 4 The residue was dried over ice, filtered off and evaporated to give 1.0 g. The residue was purified by preparative LC (amorphous SiOH 15-40 μm, 40 g, liquid packing (DCM), mobile phase gradient: (EtOAc / MeOH (90:10)) in heptane 0-50% total 5 CV then isocratic with 5 CV) to give 456 mg of intermediate U2 as an orange-brown oil (38%).

[0278] Preparation of intermediate U3 Lithium borohydride (276 μL; 0.553 mmol) was added to a solution of intermediate U2 (150 mg; 0.276 mmol) in THF (5 mL), and the solution was stirred at room temperature for 15 h. Further, lithium borohydride (276 μL, 0.553 mmol) was added, and the reaction mixture was stirred for 6 h. The reaction mixture was diluted with EtOAc and water. The aqueous layer was extracted once more with EtOAc, and the combined organic layers were washed with brine (3 times), dried over MgSO 4 and filtered, evaporated to dryness, and 132 mg of intermediate U3 (95%) was obtained as a yellow residue.

[0279] Preparation of Intermediate U4 Accordingly, intermediate U4 was prepared starting from intermediate U3 (0.132 g, 0.26 mmol) in the same manner as intermediate S2, and 0.11 g (quantitative) was obtained.

[0280] Preparation of Compound 40 To a solution of 6-chloro-2-ethylimidazo[1,2-a]pyridine-3-carboxylic acid (CAS [1216142-18-5], 67 mg, 0.300 mmol), intermediate U4 (110 mg, 0.300 mmol), and diisopropylethylamine (155 μL, 0.901 mmol) in DMF (4 mL) were added EDCI●HCl (58 mg, 0.30 mmol) and HOBt●H 2 O (46 mg, 0.30 mmol), and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated. The residue was dissolved in EtOAc and water. The organic layer was washed with NaCl sat, dried over MgSO 4 filtered, concentrated, and 143 mg was obtained. The crude product was purified by preparative LC (amorphous SiOH 15 - 40 μm, 80 g, liquid packing material (DCM), mobile phase gradient: 0 - 50% in heptane (EtOAc / MeOH (90:10)) for a total of 5 CV and then 5 CV at a uniform concentration), and 100 mg was obtained as a white solid. This was purified by reverse phase (spherical C18, 25 μm, 40 g YMC-ODS-25, dry packing material (Celite (registered trademark))), mobile phase gradient: 55% (aq. NH 4 HCO 3 0.2%), 45% MeCN - 75% (aq. NH 4HCO 3 0.2%) MeCN) to give 19 mg and 59 mg of residues, which were co-evaporated with EtOH and MeCN to give 80 mg of compound 40 as a yellowish solid (combined yield: 57%). 1 H NMR(500MHz,DMSO-d6)δ ppm 9.03-9.13(m,1H)8.41(br t,J=6.0Hz,1H)7.66(d,J=9.5Hz,1H)7.45(dd,J=9.5,1.9Hz,1H)7.32(d,J=8.5 Hz,2H)7.16(d,J=8.5Hz,2H)4.66(t,J=5.7Hz,1H)4.47(d,J=6.0Hz,2H)3.96(br t,J=5.0Hz,2H)3.84(t,J=4.9Hz,2H)3.73(q,J=6.6Hz,2H)2.98(q,J=7.6Hz,2H)2.74(t,J=6.9Hz,2H)1.26(t,J=7.6Hz,3H)

[0281] Preparation of compound 41 Thus, compound 41 was prepared in the same manner as compound 40 starting from 6-chloro-2-ethyl-imidazo[1,2-a]-pyrimidine-3-carboxylic acid (CAS[2059140-68-8], 0.32 mmol) and intermediate U4 (0.32 mmol) to give 0.067 g (37%) as a light green solid. 1 H NMR(500MHz,DMSO-d6)δ ppm 9.39(d,J=2.5Hz,1H)8.68(d,J=2.5Hz,1H)8.55(t,J=5.8Hz,1H)7.31(m,J=8.5 Hz,2H)7.15(m,J=8.5Hz,2H)4.70(t,J=5.7Hz,1H)4.47(d,J=6.0Hz,2H)3.95(br t,J=4.9Hz,2H)3.79-3.88(m,2H)3.72(q,J=6.6Hz,2H)3.01(q,J=7.4Hz,2H)2.73(t,J=6.8Hz,2H)1.27(t,J=7.6Hz,3H)

[0282] Synthesis of compound 42 [ka] A solution of intermediate Q2 (125 mg, 0.568 mmol) in diisopropylethylamine (0.4 mL, 2.32 mmol) and DMF (6 mL) was added with EDCI HCl (145 mg, 0.756 mmol), HOBt H 2 O (120 mg, 0.784 mmol) was added, followed by intermediate E9 (205 mg, 0.571 mmol). The mixture was stirred at room temperature for 16 h. The reaction mixture was evaporated and diluted with DCM and NaHCO 3 The layers were separated and the organic layer was washed with water, brine (twice) and MgSO 4 The crude was purified by preparative LC (SiOH amorphous, 30 μm, 24 g, liquid packing (DCM), mobile phase gradient: heptane 80%, EtOAc / MeOH (9:1) 20% to heptane 20%, EtOAc / MeOH (9:1) 80% total 12 CV) to give 166 mg of a white solid, which was recrystallized from MeCN, then filtered off and dried under high vacuum to give 107 mg of compound 42 as a white solid (36%). 1 H NMR(400MHz,DMSO-d6)δ ppm 8.64(d,J=2.2Hz,1H),8.30(t,J=5.8Hz,1H),7.53(d,J=9.5Hz,1H),7.27-7.36(m,3H),7.14-7.22(m,3H),4.47(d,J=5.9Hz,2H),4.08(br t,J=4.5Hz,2H),3.83(br t,J=4.5Hz,2H)3.76(s,3H),2.95(q,J=7.5Hz,2H),1.24(t,J=7.5Hz,3H).

[0283] Synthesis of compound 43 [ka]

[0284] Preparation of intermediate V1 In a sealed tube, a suspension of imidazo[1,2-a]-pyridine-3-carboxylic acid, 6-bromo-2-ethyl-ether ester (CAS[1908481-13-9], 400 mg, 1.35 mmol), potassium (methoxymethyl) trifluoroborate (614 mg, 4.04 mmol), and cesium carbonate (1.32 g, 4.04 mmol) in 1,4-dioxane (3.44 mL) and water (0.49 mL) was added under N 2 RuPhos (62.8 mg, 0.135 mmol) and RuPhos Pd G3 (113 mg, 0.135 mmol) were added and the mixture was again purged with N 2 The mixture was purged with 500 ml of ethyl acetate and then stirred at 100° C. overnight. The mixture was filtered off and the filtrate was then evaporated. The crude was purified by preparative LC (SiOH amorphous, 30 μm, 50 g, dry packing (on Celite®), mobile phase gradient: heptane 90%, EtOAc / MeOH (9:1) 10% to heptane 50%, EtOAc / MeOH (9:1) 50% total 12 CV) to give 317 mg of intermediate V1 as a colorless gum that crystallized on standing (66%).

[0285] Preparation of intermediate V2 To a solution of intermediate V1 (317 mg, 0.894 mmol) in water (4 mL) and EtOH (4 mL) was added NaOH (107 mg, 2.68 mmol) and the mixture was stirred at room temperature for 24 h. The mixture was evaporated to give 518 mg of intermediate V2 as a yellow gum. The crude was used as such in the next step.

[0286] Preparation of compound 43 Thus, compound 43 was prepared in the same manner as compound 42 starting from intermediate V2 (0.9 mmol) and intermediate E9 (0.84 mmol) to give 0.113 g (22%) as a white solid. 1H NMR(500MHz,DMSO-d6)δ ppm 8.93(s,1H),8.38(t,J=6.0Hz,1H),7.58(d,J=9.1Hz,1H),7.26-7.36(m,4H),7.19(d,J=8.5Hz,2H),4.43-4.51(m,4H),4.08(br t,J=4.6Hz,2H),3.83(t,J=4.7Hz,2H),3.30(s,3H),2.96(q,J=7.4Hz,2H),1.25(t,J=7.6Hz,3H).

[0287] Synthesis of compound 44 [ka] Thus, compound 44 was prepared in the same manner as compound 42 starting from 5-methoxy-2-methylpyrazolo[1,5-a]-pyridine-3-carboxylic acid (CAS[1352395-28-8], 0.37 mmol) and intermediate N3 (0.37 mmol) to give 0.19 g (42%) as a white solid. 1 H NMR (500MHz, DMSO-d 6 )δ ppm 8.51(d,J=7.6Hz,1H)7.91(t,J=6.0Hz,1H)7.43(t,J=8.7Hz,1H)7.26(d,J=2.8Hz,1H)7.12-7.23(m,2H)6.64(dd ,J=7.6,2.8Hz,1H)4.44(d,J=5.7Hz,2H)4.07-4.15(m,2H)3.86(s,3H)3.82(s,3H)3.53-3.60(m,2H)2.53(s,3H)

[0288] Synthesis of compound 45 [ka]

[0289] Preparation of intermediate W1 To a solution of 4-chloro-5-methoxypyridin-2-amine (CAS[867131-26-8], 500 mg, 3.15 mmol) in dry acetonitrile (7.5 mL) was added ethyl 3-oxovalerate (0.90 mL, 6.3 mmol), bromotrichloromethane (1.1 mL, 11 mmol), and potassium bicarbonate (947 mg, 9.46 mmol). The mixture was stirred at 80 °C for 16 h. The reaction mixture was diluted in EtOAc and water. The organic layer was then washed with brine and MgSO 4 The residue was dried over 100 ml, filtered off and evaporated. The residue was purified by preparative LC (amorphous SiOH, 15-40 μm, 40 g dry packing (Celite®) with a mobile phase gradient: heptane / EtOAc 95 / 5 to heptane / EtOAc 40 / 60 15 CV) to give 458 mg of intermediate W1 as a yellow solid (51% yield).

[0290] Preparation of intermediate W2 A mixture of intermediate W1 (456 mg, 1.61 mmol) and NaOH (194 mg, 4.86 mmol) in water (8.1 mL), EtOH (8.1 mL), and MeOH (9.8 mL) was stirred at room temperature for 16 h. The reaction mixture was evaporated. The residue was dissolved with MeOH and acidified with a 3N aqueous solution of HCl. The solution was evaporated to give 726 mg of a yellow solid. DCM and MeOH were added to the yellow solid. The mixture was then filtered off and the filtrate was evaporated to give 443 mg of intermediate W2 as a beige solid (93% purity, quantitative).

[0291] Preparation of compound 45 Thus, compound 45 was prepared in the same manner as compound 42 starting from intermediate W2 (0.46 mmol) and intermediate N3 (0.46 mmol) to yield 0.19 g (69%) as a beige solid. 1 H NMR (400MHz, DMSO-d 6)δ ppm 8.77(s,1H)8.32(t,J=5.8Hz,1H)7.86(s,1H)7.29(d,J=8.6Hz,2H)7.15(d,J=8.7Hz,2H)4.46(br d,J=5.7Hz,2H)4.10(br t,J=4.8Hz,2H)3.87(s,3H)3.85(s,3H)3.74(br t,J=4.8Hz,2H)2.95(q,J=7.5Hz,2H)1.24(t,J=7.5Hz,3H)

[0292] Synthesis of compound 46 [ka]

[0293] Preparation of intermediate X1 Thus, intermediate X1 was prepared in the same manner as intermediate T1 starting from 5-chloro-4-methoxypyridin-2-amine CAS[662117-63-7] (6.31 mmol) to yield 1.23 g (69%) as a light yellow solid.

[0294] Preparation of intermediate X2 Thus, intermediate X2 was prepared in the same manner as intermediate V2 starting from intermediate X1 (4.35 mmol) to give 0.83 g (75%) as a light yellow solid.

[0295] Preparation of compound 46 Thus, compound 46 was prepared in the same manner as compound compound 42 starting from intermediate X2 (0.45 mmol) and intermediate R7 (0.43 mmol) to yield 0.14 g (48%) as a white solid. 1 H NMR(500MHz,DMSO-d6)δ ppm 9.11(s,1H),8.27(br t,J=5.8Hz,1H),7.44(t,J=8.5Hz,1H),7.16-7.25(m,3H),4.47(br d,J=5.7Hz,2H),4.08-4.13(m,2H),3.95(s,3H),3.83(s,3H),3.54-3.59(m,2H),2.96(q,J=7.5Hz,2H),1.27(t,J=7.5Hz,3H)

[0296] Synthesis of compound 47 [ka] Thus, compound 47 was prepared in the same manner as compound 42 starting from intermediate 6-chloro-2-ethyl-imidazo[1,2-a]-pyrimidine-3-carboxylic acid CAS [2059140-68-8] (0.38 mmol) and intermediate P9 (0.31 mmol) to yield 0.027 g (15%) as a fluffy white solid. 1 H NMR (400MHz, DMSO-d 6 )δ ppm 9.35(d,J=2.7Hz,1H),8.63(d,J=2.7Hz,1H),8.52(t,J=5.9Hz,1H),7.21(s,1H),7.12(d,J=9.4Hz,2H),4.46(br d,J=5.7Hz,2H),4.01(br s,2H),3.57(br t,J=4.3Hz,2H),2.98(q,J=7.5Hz,2H),1.23(t,J=7.5Hz,3H)

[0297] Synthesis of compound 48 [ka] Thus, compound 48 was prepared in the same manner as compound 42 starting from intermediate Q2 (0.52 mmol) and intermediate R7 (0.51 mmol) to give 0.15 g (52%) as a white solid. 1 H NMR(500MHz,DMSO-d6)δ ppm 8.67(d,J=2.2Hz,1H),8.31(t,J=5.8Hz,1H),7.54(d,J=9.8Hz,1H),7.45(t,J=8.7Hz,1H),7.15-7.25(m,3H),4.49(d,J= 5.7Hz,2H),4.07-4.14(m,2H),3.83(s,3H),3.78(s,3H),3.54-3.60(m,2H),2.98(q,J=7.6Hz,2H),1.26(t,J=7.6Hz,3H)

[0298] Synthesis of compound 49 [ka] Thus, compound 49 was prepared in the same manner as compound 42 starting from intermediate W2 (0.44 mmol) and intermediate R7 (0.44 mmol) to give 0.164 g (62%) as a white solid. 1 H NMR (500MHz, DMSO-d 6 )δ ppm 8.80(s,1H)8.36(br t,J=5.8Hz,1H)7.87(s,1H)7.45(t,J=8.5Hz,1H)7.15-7.26(m,2H)4.50(br d,J=5.7Hz,2H)4.10(br t,J=5.0Hz,2H)3.87(s,3H)3.82(s,3H)3.56(br t,J=5.0Hz,2H)2.98(q,J=7.6Hz,2H)1.26(t,J=7.6Hz,3H)

[0299] Synthesis of compound 50 [ka]

[0300] Preparation of intermediate Y1 Thus, intermediate Y1 was prepared in the same manner as intermediate X1 starting from 2-amino-5-methoxypyrimidine CAS[13418-77-4] (75.92 mmol) to give 4.94 g (26%) as a yellow solid.

[0301] Preparation of intermediate Y2 To a solution of intermediate Y1 (150 mg, 0.602 mmol) in THF (3 mL) was added a solution of LiOH (75.8 mg, 1.81 mmol) in water (1.5 mL). The reaction mixture was stirred at 45° C. for 2 h. The mixture was evaporated to give 218 mg of intermediate Y2 as a yellow solid. The crude was used as such in the next step.

[0302] Preparation of compound 50 Thus, compound 50 was prepared in the same manner as compound 42 starting from intermediate Y2 (0.6 mmol) and intermediate R7 (0.55 mmol) to give 0.098 g (31%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 8.96(d,J=2.9Hz,1H),8.52(d,J=2.9Hz,1H),8.41(t,J=5.9Hz,1H),7.45(t,J=8.6Hz,1H),7.15-7.26(m,2H),4.50(d,J= 5.7Hz,2H),4.08-4.14(m,2H),3.86(s,3H),3.83(s,3H),3.53-3.59(m,2H),3.02(q,J=7.5Hz,2H),1.28(t,J=7.5Hz,3H)

[0303] Synthesis of Compound 51 and Compound 52 [ka]

[0304] Preparation of compound 51 Thus, compound 51 was prepared in the same manner as compound 42 starting from 2-ethyl-7-methoxyimidazo[1,2-a]-pyridine-3-carboxylic acid (CAS[1536994-62-3], 0.46 mmol) and intermediate E9 (0.46 mmol) to give 0.195 g (72%) as a white solid. 1 H NMR (400MHz, DMSO-d 6 )δ ppm 8.83(d,J=7.6Hz,1H)8.19(t,J=5.9Hz,1H)7.25-7.34(m,3H)7.18(d,J=8.7Hz,2 H)7.00(d,J=2.4Hz,1H)6.70(dd,J=7.6,2.6Hz,1H)4.44(d,J=5.9Hz,2H)4.07(br t,J=4.4Hz,2H)3.78-3.88(m,5H)2.92(q,J=7.5Hz,2H)1.24(t,J=7.5Hz,3H)

[0305] Preparation of compound 52 Thus, compound 52 was prepared in the same manner as compound 42 starting from 2-ethyl-7-methoxyimidazo[1,2-a]-pyridine-3-carboxylic acid (CAS[1536994-62-3], 0.46 mmol) and intermediate N3 (0.46 mmol) to give 0.178 g (69%) as a white solid. 1 H NMR (500MHz, DMSO-d 6 )δ ppm 8.84(d,J=7.6Hz,1H)8.16(t,J=6.0Hz,1H)7.28(d,J=8.7Hz,2H)7.14(d,J=8.7Hz, 2H)6.99(d,J=2.5Hz,1H)6.70(dd,J=7.7,2.7Hz,1H)4.43(d,J=5.7Hz,2H)4.10(br t,J=5.0Hz,2H)3.84(m,6H)3.73(br t,J=5.0Hz,2H)2.91(q,J=7.6Hz,2H)1.25(t,J=7.6Hz,3H)

[0306] Synthesis of compound 53 [ka]

[0307] Preparation of intermediate Z1 Thus, intermediate Z1 was prepared in the same manner as intermediate X1 starting from 4,5-dimethoxy-pyridin-2-ylamine CAS [1000843-61-7] (1.3 mmol) to yield 0.135 g (37%) as a light yellow solid.

[0308] Preparation of intermediate Z2 Thus, intermediate Z2 was prepared in the same manner as intermediate X2 starting from intermediate Z1 (0.49 mmol) to give 0.209 g (63%) as a light yellow solid.

[0309] Preparation of compound 53 Thus, compound 53 was prepared in the same manner as compound 42 starting from intermediate Z2 (0.48 mmol) and intermediate R7 (0.4 mmol) to give 0.149 g (39% for the last two steps) as a white solid. 1H NMR(400MHz,DMSO-d6)δ ppm 8.67(s,1H),8.11(t,J=5.8Hz,1H),7.44(t,J=8.6Hz,1H),7.15-7.23(m,2H),7.05(s,1H),4.47(d,J=5.7Hz,2H),4.0 7-4.14(m,2H),3.87(s,3H),3.83(s,3H),3.76(s,3H),3.53-3.59(m,2H),2.95(q,J=7.5Hz,2H),1.25(t,J=7.5Hz,3H)

[0310] Synthesis of compound 54 [ka] A mixture of intermediate C1 (190 mg, 0.445 mmol), 2-bromothiazole (48.1 μL, 0.534 mmol), and sodium tert-butoxide (214 mg, 2.23 mmol) in dry 1,4-dioxane (5 mL) was diluted with N 2 The mixture was purged with xantphos (51.5 mg, 89.0 μmol) and Pd(OAc). 2 (9.99 mg, 44.5 μmol) was added and the mixture was treated with N 2 The reaction mixture was stirred at 100° C. for 2 h. The reaction mixture was diluted with EtOAc / MeOH (95 / 5) and water. The aqueous layer was extracted with EtOAc (2 times). The combined organic layers were washed with brine and diluted with MgSO 4 The solid was dried over ice, filtered off and evaporated to give a yellow solid. The solid was purified by preparative LC (SiOH 30 μm, 25 g, dry packing (Celite®), mobile phase gradient: DCM 100% to DCM / (DCM:MeOH 80:20) 90 / 10 with 15 CV). The fractions containing the product were combined and evaporated under vacuum to give a pale yellow solid. The solid was purified by distillation with Et 2 Triturate in O, filter, and add Et 2 O and then dried under vacuum to give 153 mg of compound 54 as a white solid (67% yield). 1 H NMR (500MHz, DMSO-d 6)δ ppm 9.08(d,J=1.5Hz,1H)8.42(t,J=5.9Hz,1H)7.66(d,J=9.6Hz,1H)7.45(dd, J=9.5,2.1Hz,1H)7.40(d,J=3.7Hz,1H)7.27(d,J=8.7Hz,2H)7.22(d,J=8. 7Hz,2H)7.17(d,J=3.7Hz,1H)4.46(d,J=5.8Hz,2H)4.20(t,J=5.1Hz,2H)3 .92(s,3H)3.67(t,J=5.1Hz,2H)2.98(q,J=7.6Hz,2H)1.26(t,J=7.6Hz,3H)

[0311] Synthesis of compound 55 [ka]

[0312] Preparation of intermediate AA1 In a sealed tube, a mixture of intermediate A5 (300 mg, 0.652 mmol), 3-methoxypropionimidic acid ether ester hydrochloride (328 mg, 1.96 mmol) and triethanolamine (272 μL, 1.96 mmol) in 2-propanol (6 mL) was stirred at 90° C. for 1.5 h. After cooling to room temperature, the reaction mixture was concentrated. The residue was dissolved in EtOAc and NaHCO 3 Aqueous solution (1%) was added. After separation, the aqueous phase was extracted with EtOAc (2x). The combined organic layers were washed with MgSO 4 Drying over, filtration and concentration afforded 280 mg of intermediate AA1 as a light yellow oil that crystallized on standing (94%).

[0313] Preparation of compound 55 Triethylamine (0.281 mL, 2.02 mmol) was added to a solution of intermediate AA1 (230 mg, 0.506 mmol) in dry DCM (4.6 mL). The solution was then cooled at 0° C. (ice / water bath). 2 A 1M solution of O (1.01 mL, 1.01 mmol) was added dropwise and the reaction mixture was stirred at 0° C. for 30 min. DCM and NaHCO 3An aqueous solution of (10%) was added. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were washed with MgSO 4 The residue was dried over ice, filtered off and evaporated to give a brown gum which was purified by preparative LC (SiOH amorphous, 30 μm, 24 g, liquid packing (DCM), mobile phase gradient: heptane 90%, EtOAc / MeOH (9:1) 10% to heptane 25%, EtOAc / MeOH (9:1) 75% total 12 CV). Fractions containing the product were combined and evaporated to give 208 mg as a yellow solid. This was purified by reverse phase (stationary phase: YMC-actus Triart C18 25 μm 30×150 mm, 40 g, dry packing (Celite®), mobile phase: gradient 60% (aq. NH 4 HCO 3 0.2%, 40% MeCN to 100% MeCN total 12 CV). Fractions containing the product were combined and evaporated to give 175 mg as a yellow solid. This was purified by preparative LC (SiOH amorphous, 30 μm, 24 g, liquid packing (DCM), mobile phase gradient: heptane 90%, EtOAc / MeOH (9:1) 10% to heptane 25%, EtOAc / MeOH (9:1) 75% total 12 CV). Fractions containing the product were combined and evaporated to give 146 mg as a white solid. This was purified by reverse phase (stationary phase: YMC-actus Triart C18 25 μm 30×150 mm, 40 g, dry packing (Celite®), mobile phase: gradient 60% (aq.NH 4 HCO 3 0.2%), 40%MeCN / MeOH(1:1)~15%(aq.NH 4 HCO 3 0.2%), 85% MeCN / MeOH (1:1) total 14 CV). Fractions containing the product were combined and evaporated to give 129 mg as a white solid, which was purified by achiral SFC (stationary phase: diethylaminopropyl 5 μm 150×21.2 mm, mobile phase: 90% CO 2, 10% MeOH). The product-containing fractions were combined and evaporated to give 94 mg as a white solid. This was sonicated in MeCN (10 mL), evaporated (3 times), then MeCN (5 mL) was added, the product was filtered and dried under high vacuum (50° C., 2 h) to give 84 mg of compound 55 as a white solid (28%). 1 H NMR(400MHz,DMSO-d6)δ ppm 9.07(d,J=1.5Hz,1H),8.44(br t,J=5.7Hz,1H),7.67(d,J=9.4Hz,1H),7.45(dd,J=9.4,2.1Hz,1H),7.32(m,J=8.7Hz,2H),7.16(m,J=8.7Hz,2H),4.47(br d,J=5.9Hz,2H),3.90-4.00(m,2H),3.81-3.89(m,2H),3.66(t,J=6.7Hz,2H),3.2 6-3.29(m,3H),2.98(q,J=7.5Hz,2H),2.82(t,J=6.7Hz,2H),1.26(t,J=7.5Hz,3H)

[0314] The following compounds were prepared according to the procedures described herein: [ka] [ka] [ka] [ka] [ka] [ka]

[0315] Synthesis of compound 73 [ka]

[0316] Preparation of intermediate AB1 To a solution of 2-amino-5-cyanopyridine (CAS [4214-73-7]; 5 g, 42.0 mmol) in Me-THF (200 mL) at 5° C., iodobenzene diacetate (13.5 g, 41.9 mmol) and ethyl 3-oxovalerate (10 mL, 70.1 mmol) were added. Boron trifluoride etherate (550 μL, 2.10 mmol) was then added dropwise. The solution was stirred at 5° C. for 1 h. The mixture was allowed to warm to room temperature and stirred for 2 h. EtOAc and NaHCO 3 A saturated aqueous solution was added. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine (2x) and MgSO 4 After drying over 100° C., filtration and evaporation gave 26 g of a brown liquid that crystallized on standing. The crude product was purified by preparative LC (amorphous SiOH, 15-40 μm, 330 g, Grace, dry packing (Celite®), mobile phase gradient: heptane 85%, EtOAc 15% to heptane 30%, EtOAc 70%) to give 3.14 g of intermediate AB1 as a yellow solid (30%).

[0317] Preparation of intermediate AB2 Under nitrogen, NaH 60% (0.677 g; 16.9 mmol) was added to a solution of 2-(trimethylsilyl)ethanol (2.43 mL; 16.9 mmol) in dry toluene (50 mL) at 0° C. The reaction mixture was stirred at 0° C. for 15 min, then intermediate AB1 (0.823 g; 3.38 mmol) was added and the reaction mixture was stirred for 16 h while warming to room temperature. The reaction mixture was hydrolyzed with a saturated aqueous solution of NH4Cl and extracted with EtOAc. The aqueous layer was extracted with EtOAc (2 times). The combined organic layers were washed with MgSO 4The mixture was dried over silica gel, filtered, evaporated to dryness and purified by preparative LC (SiOH amorphous, 30-40 μm, 40 g, packing material (DCM), mobile phase gradient: heptane / EtOAc 100:0 to 50:50). The fractions containing the product were evaporated to give 559 mg of intermediate AB2 as a white solid (52%).

[0318] Preparation of compound 73 Cesium fluoride (289 mg, 1.90 mmol) was added to a solution of intermediate AB2 (200 mg, 0.634 mmol) in F (8.4 mL) and the reaction mixture was stirred at 60° C. for 2 h. Then diisopropylethylamine (139 μL, 0.817 mmol) and HATU (267 mg, 0.701 mmol) were added and the reaction mixture was stirred at room temperature for 15 min (the reaction mixture turned brown). Intermediate R7 (266 mg, 0.634 mmol) was added and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was extracted with EtOAc and the organic layer was washed with 1% aqueous NaHCO3, then with water and brine, and diluted with MgSO 4 The mixture was dried over ice, filtered off and concentrated. DCM and MeOH were added to the residue. The mixture was filtered. The precipitate was dried under vacuum at 50° C. to give 160 mg of crude product as a white solid. The crude product was heated to reflux in EtOAc (15 mL) for 20 min and then cooled slowly to room temperature with slow stirring for 18 h. The solid was filtered, rinsed with cold EtOAc and dried under vacuum at 60° C. to give 128 mg of compound 73 as a white solid (36%). 1H NMR(400MHz,DMSO-d6)δ ppm 9.50(s,1H)8.63(t,J=5.9Hz,1H)7.78(d,J=9.3Hz,1H)7.66(dd,J=9.3,1.7Hz,1H)7.45(t,J=8.6Hz,1H)7.13-7.3 1(m,2H)4.51(d,J=5.87Hz,2H)4.06-4.19(m,2H)3.53-3.62(m,2H)3.02(q,J=7.50Hz,2H)1.28(t,J=7.46Hz,3H).

[0319] Synthesis of compound 74 [ka]

[0320] Preparation of intermediate AC1 A mixture of intermediate A5 (500 mg, 1.09 mmol), methyl-2,2-diethoxyacetimidate (526 mg, 3.26 mmol), and triethylamine (453 μL, 3.26 mmol) in iPrOH (9.4 mL) was stirred at 90° C. for 2 h. After cooling to room temperature, the reaction mixture was concentrated. The residue was dissolved in EtOAc and water. After separation, the aqueous phase was extracted with EtOAc (×1). The combined organic layers were washed with brine and concentrated with MgSO 4 The mixture was dried over 100 ml of ethyl acetate, filtered off and concentrated. The residue was purified by preparative LC (amorphous SiOH 15-40 μm, 80 g, liquid packing (DCM), mobile phase gradient: 20-80% EtOAc in heptane then isocratic). The product-containing fractions were combined and evaporated to give 343 mg of intermediate AC1 as a white solid (63%).

[0321] Preparation of intermediate AC2 Diisopropylethylamine (0.311 mL, 1.80 mmol) was added to a solution of intermediate AC1 (300 mg, 0.601 mmol) in DCM (5.5 mL). The solution was then cooled at 0° C. (ice / water bath). 2 A 1M solution of O (0.721 mL, 1.2 eq., 0.721 mmol) was added dropwise and the reaction mixture was stirred at 0° C. for 1 h. An additional amount of Tf in DCM was added 2 A 1M solution of O (0.721 mL, 1.2 eq., 0.721 mmol) was added and the mixture was stirred at 0 °C for 1 h. 3 A saturated aqueous solution of and DCM were added. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were washed with MgSO 4 The crude product was dried over hexane, filtered off and evaporated to give a brown gum. The crude product was purified by preparative LC (SiOH amorphous, 30 μm, 24 g, liquid packing (DCM), mobile phase gradient: DCM 100% to DCM 85%, MeOH / AcOH (9:1) 15%) to give 94 mg of intermediate AC2 as an orange gum.

[0322] Preparation of compound 74 To a solution of intermediate AC2 (94 mg, 0.17 mmol) in AcOH (29 μL, 0.51 mmol) and DCM (1.5 mL), a 2 M solution of dimethylamine in THF (0.25 mL, 0.51 mmol) was added and the mixture was stirred at room temperature for 6 h. Sodium triacetoxyborohydride (71.5 mg, 0.34 mmol) was then added and the mixture was stirred at room temperature for 16 h. NaHCO 3 A saturated aqueous solution of was carefully added and then the layers were separated. The aqueous layer was extracted with DCM (2x) and the combined organic layers were washed with MgSO 4 The crude product was purified by preparative LC (SiOOH amorphous, 30 μm, 12 g, liquid packing (DCM), mobile phase gradient: heptane 80%, EtOAc / MeOH (9:1) 20% to heptane 15%, EtOAc / MeOH (9:1) 85%). The product-containing fractions were combined and evaporated to give 68 mg as a light yellow oil, which was purified by reverse phase (stationary phase: YMC-actus Triart C18 25 μm 30×150 mm, 12 g, dry packing (Celite®), mobile phase: gradient 55% (aq. NH 4 HCO 3 0.2%), 45% MeCN to 100% MeCN). The product-containing fractions were combined and evaporated to give a colorless oil which was dissolved in Et 2 Trituration in O and drying under high vacuum (50 °C, 1 h) gave 40 mg of compound 74 as a white solid (40%). 1 H NMR (400MHz, DMSO-d 6 )δ ppm 9.06(d,J=1.0Hz,1H)8.44(br t,J=5.8Hz,1H)7.67(d,J=9.7Hz,1H)7.45(dd,J=9.4,1.8Hz,1H)7.33(br d,J=8.6Hz,2H)7.19(br d,J=8.6Hz,2H)4.47(br d,J=5.5Hz,2H)3.90(br dd,J=16.6,4.2Hz,4H)2.97(q,J=7.5Hz,2H)2.19(s,7H)1.26(t,J=7.5Hz,4H).

[0323] Synthesis of compound 75 [ka]

[0324] Preparation of intermediate AD1 Carbon tetrabromide (26.9 g, 81.0 mmol) was added to a solution of 2-amino-4-methoxypyridine [CAS: 10201-73-7] (5.02 g, 40.4 mmol) and ethyl 3-oxovalerate (8.69 mL, 60.8 mmol) in MeCN (85 mL) and the reaction mixture was stirred for 4 h at 80° C. The reaction mixture was evaporated to dryness and then purified by preparative LC (SiOH amorphous, 30 μm, 330 g, dry packing (Celite®), mobile phase gradient: heptane / EtOAc 95 / 5 to EtOAc) to give 669 mg of intermediate AD1 (16%).

[0325] Preparation of intermediate AD2 To a mixture of intermediate AD1 (1.55 g, 6.24 mmol) in water (20 mL) and EtOH (20 mL) was added NaOH (752 mg, 18.8 mmol) and the mixture was stirred at room temperature for 2 days. The reaction mixture was evaporated to give 2.16 g of intermediate AD2 (Quant.).

[0326] Preparation of compound 75 A mixture of intermediate AD2 (138 mg, 0.397 mmol), intermediate R7 (160 mg, 397 μmol), EDCI●HCl (99.1 mg, 0.517 mmol), HOBt (79.1 mg, 0.517 mmol), and diisopropylethylamine (205 μL, 1.19 mmol) in DMF (6 mL) was stirred at room temperature for 20 h. The residue was dissolved in EtOAc and water. The aqueous layer was extracted with EtOAc (2 times). The combined organic layers were washed with MgSO 4The mixture was dried over ice, filtered off and evaporated to give an orange oil which was purified by preparative LC (SiOH 30 μm amorphous, 12 g, dry packing (Celite®), mobile phase gradient: heptane / EtOAc 70 / 30 to EtOAc 100%). The product-containing fractions were combined and evaporated under vacuum to give a yellow solid which was then dissolved in Et 2 The supernatant was removed by pipette and the solid was dried under vacuum to give 124 mg of a white solid, which was triturated in Et 2 Co-evaporation with O (3 times) gave 120 mg of compound 75 as a white solid (46% yield). 1 H NMR (400MHz, DMSO-d 6 )δ ppm 8.86(d,J=7.7Hz,1H)8.21(br t,J=5.8Hz,1H)7.44(t,J=8.5Hz,1H)7.12-7.26(m,2H)7.01(d,J=2.3Hz,1H)6.71(dd,J=7.6,2.5Hz,1H)4.47(br d,J=5.9Hz,2H)4.07-4.15(m,2H)3.84(d,J=8.2Hz,6H)3.52-3.61(m,2H)2.94(q,J=7.5Hz,2H)1.26(t,J=7.5Hz,3H).

[0327] Synthesis of compound 76 [ka] A mixture of intermediate A6 (30.0 mg, 75.6 μmol), 2-bromothiazole (8.18 μL, 90.7 μmol), and NaOtBu (36.3 mg, 0.378 mmol) in dry 1,4-dioxane (1.3 mL) was diluted with N 2 Xantphos (8.7 mg, 15 μmol) and palladium(II) acetate (1.7 mg, 7.6 μmol) were then added and the mixture was purged with N 2 The reaction mixture was stirred at 80° C. for 22 h. The reaction mixture was diluted with EtOAc / MeOH and water. The aqueous layer was extracted with EtOAc (2 times). The combined organic layers were washed with brine and washed with MgSO 4The mixture was dried over 100° C., filtered off and evaporated to give a brown solid. The solid was purified by preparative LC (SiOH 30 μm, 12 g, dry packing (Celite®), mobile phase gradient: DCM 100% to DCM / (DCM:MeOH 80:20) 30 / 70). The product-containing fractions were combined and evaporated under vacuum to give 17 mg of compound 76 as a yellow solid (47% yield). 1 H NMR (500MHz, DMSO-d 6 )δ ppm 9.07(d,J=1.4Hz,1H)8.45(t,J=5.9Hz,1H)7.63-7.69(m,2H)7.45(dd,J=9.5,2.0Hz,1H)7.39(d,J=3.5Hz,1H)7.26(dd,J=36.7,8.7Hz ,2H)7.16(d,J=3.5Hz,1H)4.46(d,J=5.6Hz,2H)4.00(t,J=5.0Hz,2H)3.78(t,J=5.0Hz,2H)2.98(q,J=7.5Hz,2H)1.26(t,J=7.5Hz,4H).

[0328] The following compounds were also prepared according to the procedures described herein: compound 77 [ka]

[0329] B. Further Procedures Synthesis of compound 127 [ka] HATU (0.099 g, 0.26 mmol) was dissolved in N 2To a solution of 2-(trifluoromethyl)-imidazo[1,2-A]pyridine-3-carboxylic acid (CAS[73221-19-9], 0.052 g, 0.23 mmol) and DIPEA (0.097 mL, 0.56 mmol) in dry Me-THF (1.52 mL) and DCM (0.51 mL) was added under reduced pressure. The solution was stirred at room temperature for 15 min, then intermediate E9 (0.08 g, 0.25 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. The solvent was then evaporated and the residue was diluted in ethyl acetate and treated with NaHCO 3 The organic layer was washed with a saturated aqueous solution of MgSO 4 The residue was dried over ice, filtered and evaporated in vacuo to give 0.167 g of a yellow oil. Purification was carried out by flash chromatography on silica gel (12 g, amorphous SiOH 25-40 μM, DCM / MeOH 100 / 0-97 / 3). Pure fractions were collected and evaporated to give 0.102 g of a colourless oil which crystallised on standing. Reverse phase (stationary phase: YMC-actus Triart C18 10 μm 30 × 150 mm, mobile phase: gradient 40% NH 4 HCO 3 0.2%, 60%ACN~10%NH 4 HCO 3 Purification was carried out by elution with 0.037 g (0.2%, 90% ACN). The pure fractions were collected and evaporated to give 0.037 g as a white foam, which was triturated with DIPE and a little heptane, the precipitate was filtered off and dried under vacuum at 60° C. to give compound 127 as a white powder 0.032 g (26%). 1 H NMR (500MHz, DMSO-d 6 )δ ppm 9.23(br s,1H),8.53(br d,J=6.4Hz,1H),7.79(br d,J=8.9Hz,1H),7.55(br t,J=7.5Hz,1H),7.25-7.37(m,3H),7.20(br d,J=8.1Hz,3H),4.42-4.56(m,2H),4.08(br s,2H),3.84(br s,2H)

[0330] Synthesis of compound 128 [ka] Thus, compound 128 was prepared in the same manner as compound 127 starting from 2-(difluoromethyl)-imidazo[1,2-A]pyridine-3-carboxylic acid (CAS[2059954-47-9], 0.23 mmol) and intermediate E9 to yield 0.045 g (39%) of a white powder. 1 H NMR (500MHz, DMSO-d 6 )δ ppm 8.96(br t,J=5.6Hz,1H),8.79(d,J=7.0Hz,1H),7.76(d,J=9.0Hz,1H),7.52(t,J=7.8Hz,1H),7.25-7. 45(m,4H),7.20(d,J=8.7Hz,2H),7.16(td,J=6.9,1.1Hz,1H),4.48(d,J=5.6Hz,2H),4.08(br t,J=4.5Hz,2H),3.84(t,J=4.8Hz,2H)

[0331] Synthesis of compound 137 [ka] HATU (0.093 g, 0.24 mmol) was dissolved in N 2 To a solution of 2-(difluoromethyl)-5H,6H,7H,8H-imidazo[1,2-A]pyridine-3-carboxylic acid (0.046 g, 0.21 mmol) and DIPEA (0.091 mL, 0.53 mmol) in dry Me-THF (1.43 mL) and DCM (0.48 mL) was added under reduced pressure. The solution was stirred at room temperature for 15 min. Intermediate R7 (0.095 g, 0.23 mmol) was then added and the reaction mixture was stirred at room temperature for 16 h. The solvent was then evaporated and the residue was diluted in ethyl acetate and treated with NaHCO 3 The organic layer was washed with a saturated aqueous solution of MgSO 4The residue was dried over hexane, filtered and evaporated in vacuum to give 0.271 g of a yellow oil. Purification was carried out by flash chromatography on silica gel (12 g, amorphous SiOH 25-40 μM, DCM / MeOH 100 / 0-97 / 3). The pure fractions were collected and evaporated to give 0.112 g of a colorless oil that crystallized on standing. This was triturated with DIPE and a little heptane, the precipitate was filtered off and dried under vacuum at 60° C. to give compound 137 as a white powder 0.096 g (79%). 1 H NMR (500MHz, DMSO-d 6 )δ ppm 8.77(br t,J=5.6Hz,1H),7.44(t,J=8.6Hz,1H),7.10-7.19(m,2H),6.95(t,J=54.3Hz,1H),4.40(br d,J=5.8Hz,2H),4.06-4.15(m,2H),4.02(br t,J=5.5Hz,2H),3.83(s,3H),3.54-3.60(m,2H),2.78(br t,J=6.3Hz,2H),1.89(br d,J=4.6Hz,2H),1.83(br d,J=5.5Hz,2H)

[0332] Synthesis of compound 79 [ka] Thus, compound 79 was prepared in the same manner as compound 137 starting from 2-(trifluoromethyl)-imidazo[1,2-A]pyridine-3-carboxylic acid (CAS[73221-19-9], 0.21 mmol) and intermediate R-7 (0.23 mmol) to yield 0.09 g (70%) of a white powder. 1 H NMR(500MHz,DMSO-d6)δ ppm 9.27(t,J=5.8Hz,1H),8.57(d,J=6.9Hz,1H),7.80(d,J=9.2Hz,1H),7.40-7.62(m,2H), 7.14-7.27(m,3H),4.47-4.56(m,2H),4.08-4.14(m,2H),3.84(s,3H),3.52-3.63(m,2H)

[0333] Synthesis of compound 132 [ka]

[0334] Preparation of intermediate AB-1 In a sealed tube, to a solution of 2-amino-5-chloropicoline (CAS[36936-27-3], 1.00 g, 7.01 mmol) in ACN (12 mL) was added ethyl-ethyl 3-oxovalerate (CAS[4949-44-4], 2.00 mL, 14.0 mmol), bromotrichloromethane (2.40 mL, 24.4 mmol), and potassium bicarbonate (2.12 g, 21.2 mmol). The mixture was stirred at 80 °C for 16 h. EtOAc and water were added. The organic layer was washed with brine and dried (MgSO 4 ), evaporated and purified by preparative LC (amorphous SiOH 15-40 μm, 80 g, mobile phase gradient: heptane / EtOAc 90:10-10:90). The product-containing fractions were combined and evaporated to give 0.95 g of intermediate AB-1 as an orange solid (51%).

[0335] Preparation of intermediate AB-2 To a mixture of intermediate AB-1 (180 mg, 0.675 mmol) in water (2.2 mL) and EtOH (2.2 mL) was added NaOH (81 mg, 2.03 mmol) and the mixture was stirred for 18 h at 40° C. The reaction mixture was evaporated to give 270 mg g of intermediate AB-2 (Quant. purity 65%).

[0336] Preparation of compound 132 A mixture of intermediate AB-2 (150 mg, 0.374 mmol, 65% purity), intermediate R7 (151 mg, 0.374 mmol), HATU (157 mg, 0.414 mmol), DIPEA (82 μL, 0.48 mmol), and DMF (2.3 mL) was stirred at room temperature for 2 h. The reaction mixture was diluted with EtOAc and the organic layer was washed with 1% NaHCO 3 aqueous solution, then washed with water and brine, and MgSO 4It was dried over ice, filtered off, concentrated and purified by preparative LC (amorphous SiOH, 15-40 μm, 40 g Grace, packing (DCM), mobile phase gradient: heptane / EtOAc: 50 / 50-0 / 100 in 7 CV, then 100% EtOAc in 7 CV). Fractions containing the product were combined and evaporated to give 116 mg as a white solid. This was purified by preparative LC (spherical C18, 25 μm, 40 g YMC-ODS-25, (MeOH / MeCN), mobile phase gradient 0.2% aq.NH 4 + HCO 3 - / MeCN 70:30 to 0:100) The product-containing fractions were combined and evaporated to give 86 mg of compound 132 as a white solid (39%). 1H NMR(400MHz,DMSO-d6)δ ppm 9.12(s,1H),8.35(t,J=5.9Hz,1H),7.64(s,1H),7.45(t,J=8.6Hz,1H),7.11-7.27(m,2H),4.48(d,J=5.9Hz,2H),4.11(br t,J=5.2Hz,2H),3.83(s,3H),3.57(br t,J=4.9Hz,2H),2.99(q,J=7.5Hz,2H),2.40(s,3H),1.26(t,J=7.5Hz,3H)

[0337] Synthesis of compound 141 [ka]

[0338] Preparation of intermediate AC-1 To a solution of 5-chloro-4-fluoro-2-pyridinamine (CAS [1393574-54-3], 250 mg, 1.71 mmol) in Me-THF (8 mL) at 5° C., iodobenzene diacetate (550 mg, 1.71 mmol) and ethyl-ethyl 3-oxovalerate (0.4 mL, 2.80 mmol) were added. Boron trifluoride etherate (25 μL, 95.5 μmol) was then added dropwise. The solution was stirred at 5° C. for 1 h. The mixture was allowed to warm to room temperature and stirred for 18 h. EtOAc and water were added. The organic layer was washed with brine, dried (MgSO4), evaporated and purified by preparative LC (amorphous SiOH 15-40 μm, 40 g, grace, packing material (DCM) mobile phase gradient: heptane / EtOAc 90:10-10:90 total 10 CV) to give 119 mg of intermediate AC-1 as a light brown solid (P1; 26%).

[0339] Preparation of intermediate AC-2 A mixture of intermediate AC-1 (200 mg, 0.739 mmol), lithium hydroxide (177 mg, 7.39 mmol), water (3.2 mL), and THF (4.4 mL) was stirred at 50 °C for 18 h. EtOAc and aq. KHSO 4 10% was added. The organic layer was dried (MgSO 4 ), and evaporated to give 179 mg of intermediate AC-2 as a yellow solid (Quant.).

[0340] Preparation of Compound 141 Thus, compound 141 was prepared in the same manner as compound 132 starting from intermediate AC-2 (0.78 mmol) and intermediate R7 to give 0.127 g (27%) as a white powder. 1H NMR(400MHz,DMSO-d6)δ ppm 9.24(d,J=7.3Hz,1H),8.45(br t,J=5.8Hz,1H),7.79(d,t,J=9.9Hz,1H),7.45(t,t,J=8.7Hz,1H),7.12-7.27(m,2H),4.49(d,t,J=5.9Hz,2H) ,4.11(t,t,J=4.9Hz,2H),3.83(s,3H),3.57(t,t,J=4.9Hz,2H),2.99(q,t,J=7.5Hz,2H),1.27(t,J=7.5Hz,3H)

[0341] Synthesis of compound 158 [ka]

[0342] Preparation of intermediate AD-1 Thus, compound AD-1 was prepared in the same manner as compound AC-1 starting from 6,7-dihydro-5h-cyclopenta[d]pyrimidin-2-amine (CAS[108990-72-3], 7.4 mmol) to give 0.726 g (38%).

[0343] Preparation of intermediate AD-2 Thus, compound AD-2 was prepared starting from AD-1 (0.77 mmol) in the same manner as compound AB-2 to give 0.446 g (44%).

[0344] Preparation of compound 158 Thus, compound 158 was prepared in the same manner as compound 132 starting from intermediate AD-2 (0.77 mmol) and intermediate R7 to give 0.145 g (32%) as a white powder. 1H NMR(500MHz,DMSO-d6)δ ppm 9.10(s,1H),8.39(t,J=6.0Hz,1H),7.44(t,J=8.5Hz,1H),7.12-7.26(m,2H),4.47(d,J=5.9Hz,2H),4.10(t, J=4.8Hz,2H),3.83(s,3H),3.56(t,J=4.8Hz,2H),2.89-3.03(m,6H),2.05-2.16(m,2H),1.26(t,J=7.6Hz,3H)

[0345] Preparation of compound 193 [ka] Thus, compound 193 was prepared in the same manner as compound 158 starting from intermediate AI-3 (0.44 mmol) and intermediate R-7 (0.37 mmol) to give 0.108 g (52%) of a white solid. 1 H NMR(400MHz,DMSO)d 9.19-9.10(m,1H),8.51(d,J=2.4Hz,1H),8.44(t,J=5.9Hz,1H),7.44(t,J=8.6Hz,1H),7.26-7.14(m,2H),4.49(d,J=5.9Hz, 2H),4.14-4.03(m,2H),3.83(s,3H),3.59-3.53(m,2H),3.01(q,J=7.5Hz,2H),2.34(d,J=0.6Hz,3H),1.28(t,J=7.5Hz,3H).

[0346] Preparation of compound 194 [ka] Thus, compound 194 was prepared in the same manner as compound 158 starting from 6-chloro-2-(trifluoromethyl)imidazo[1,2-a]pyridine-3-carboxylic acid (CAS[874830-60-1] (0.7 mmol) and intermediate R-7 (0.47 mmol) to give 0.110 g (39%) of a white solid. 1H NMR(400MHz,DMSO)d 9.23(t,J=5.8Hz,1H),8.35(s,1H),7.70(d,J=9.3Hz,1H),7.52-7.37(m,2H),7.19(m,2H) ),4.51(d,J=5.8Hz,2H),4.17-4.07(m,2H),3.84(s,3H),3.63-3.55(m,2H),2.34(s,3H).

[0347] Preparation of compound 204 [ka] Thus, compound 204 was prepared in the same manner as compound 158 starting from 2-ethyl-6-fluoroimidazo[1,2-a]pyridine-3-carboxylic acid (CAS[1368682-64-7], 0.84 mmol) and intermediate R-7 (0.7 mmol) to give 0.132 g (34%) of a white solid. 1 H NMR(400MHz,DMSO)d 9.09-9.01(m,1H),8.40(t,J=5.9Hz,1H),7.73-7.64(m,1H),7.53-7.41(m,2H),7.25-7.14(m,2H),4.49(d,J =5.9Hz,2H),4.15-4.05(m,2H),3.83(s,3H),3.61-3.51(m,2H),3.00(q,J=7.5Hz,2H),1.27(t,J=7.5Hz,3H).

[0348] Preparation of Compound 206 [ka] Thus, compound 206 was prepared in the same manner as compound 158 starting from intermediate AM-2 (0.61 mmol) and intermediate R-7 (0.47 mmol) to yield 0.07 g (24%) of a beige powder. 1H NMR(400MHz,DMSO)d 9.02(t,J=5.7Hz,1H),8.92(d,J=1.7Hz,1H),7.83(d,J=9.6Hz,1H),7.61(dd,J=9.6,2.0Hz,1H ),7.52-7.16(m,4H),4.51(d,J=5.7Hz,2H),4.13-4.07(m,2H),3.83(s,3H),3.60-3.55(m,2H).

[0349] Preparation of compound 209 [ka] Thus, compound 209 was prepared in the same manner as compound 158 starting from intermediate AQ-2 (0.56 mmol) and intermediate R-7 (0.4 mmol) to yield 0.142 g (59%) as a white powder. 1 H NMR(400MHz,DMSO)d 8.95(s,1H),8.41(t,J=5.9Hz,1H),7.80(s,1H),7.44(t,J=8.6Hz,1H),7.26-7.14(m,2H),4.48(d,J=5.9Hz,2H) ),4.15-4.06(m,2H),3.83(s,3H),3.60-3.52(m,2H),2.97(q,J=7.5Hz,2H),2.32(s,3H),1.26(t,J=7.5Hz,3H).

[0350] Preparation of Compound 210 [ka] Thus, compound 210 was prepared in the same manner as compound 158 starting from intermediate AL-2 (0.55 mmol) and intermediate R-7 (0.4 mmol) to yield 0.161 g (68%) of a white solid. 1H NMR(400MHz,DMSO)d 8.92(d,J=1.4Hz,1H),8.60(t,J=5.9Hz,1H),7.62(dd,J=10.6,1.6Hz,1H),7.45(t,J=8.6Hz,1H),7.26-7.15(m,2H),4 .50(d,J=5.8Hz,2H),4.15-4.06(m,2H),3.83(s,3H),3.61-3.52(m,2H),3.01(q,J=7.5Hz,2H),1.27(t,J=7.5Hz,3H).

[0351] Preparation of intermediate AA-3 [ka]

[0352] Preparation of intermediate AA-1 A solution of intermediate R4 (19.6 g, 48.4 mmol) and trimethyl orthoformate (15.9 mL, 145 mmol) in HFIP (490 mL) was stirred at 60° C. for 45 min. The reaction mixture was evaporated. The residue was diluted in DCM and 2 CO 3 A 10% aqueous solution of was added. The aqueous layer was extracted twice with DCM / MeOH (95 / 5). The combined organic layers were washed with MgSO 4 The crude (m=25.6 g) was purified by preparative LC (SiOH 30 μm regular, 330 g, dry packing (Celite®), mobile phase gradient: heptane 75%, EtOAc / MeOH (9:1) 25% to heptane 25%, EtOAc / MeOH (9:1)). The product-containing fractions were combined and evaporated to give 14.61 g of intermediate AA-1 as a colorless oil that crystallized on standing (85%).

[0353] Preparation of intermediate AA-2 To a solution of intermediate AA-1 (14.6 g, 42.7 mmol) and DIPE (22.1 mL, 128 mmol) in dry DCM (340 mL) at −5° C. (ice / NaCl solid) was added 1 M of Tf 2O (47 mL, 47 mmol) was added dropwise over 15 min and stirring was continued for 5 min. The reaction mixture was diluted with NaHCO 3 The mixture was quenched with a saturated aqueous solution of MgSO. The layers were separated and the aqueous layer was extracted with DCM (2x). The combined organic layers were washed with MgSO. 4 The crude (m=36.4 g) was purified by preparative LC (SiOH amorphous, 30 μm, 120 g, dry packing (Celite®), mobile phase gradient: heptane / EtOAc 90 / 10 to 70 / 30). The product-containing fractions were combined and evaporated under vacuum to give 10.18 g of intermediate AA-2 as a white solid (50%).

[0354] Preparation of intermediate AA-3 In a steal bomb, a mixture of intermediate AA-2 (10.2 g, 21.5 mmol), 20% palladium hydroxide on carbon, nominally 50% water (3.01 g, 2.15 mmol), and 3 M aqueous HCl (7.15 mL, 7.15 mmol) in MeOH (150 mL) and EtOAc (150 mL) was heated at room temperature under 5 bar H 2 The mixture was hydrogenated under 50° C. for 1 h. The mixture was filtered over a pad of Celite® and washed with MeOH. The filtrate was then co-evaporated with MeOH (2×) to give 7.86 g of intermediate AA-3.

[0355] Synthesis of compound 163 [ka] HATU (0.083 g, 0.22 mmol) was dissolved in N 2 To a solution of 6-ethyl-2-methylimidazo[2,1-b][1,3]thiazole-5-carboxylic acid (CAS[1131613-58-5], 0.04 g, 0.19 mmol) and DIPEA (0.082 mL, 0.48 mmol) in dry Me-THF (1.28 mL) and DCM (0.43 mL) was added under reduced pressure. The solution was stirred at room temperature for 15 min. Intermediate AA-3 (0.083 g, 0.22 mmol) was then added and the reaction mixture was stirred at room temperature for 16 h. The solvent was then evaporated and the residue was diluted in ethyl acetate and treated with NaHCO3 The organic layer was washed with a saturated aqueous solution of MgSO 4 The residue was dried over hexane, filtered and evaporated in vacuum to give a colourless oil. Purification was carried out by flash chromatography on silica gel (12 g, amorphous SiOH 25-40 μM, DCM / MeOH 100 / 0-97 / 3). The pure fractions were collected and evaporated to give 0.096 g of a white foam. This was triturated with DIPE and a little heptane, the precipitate was filtered off and dried under vacuum at 60° C. to give compound 163 as a white powder 0.088 g, 86%. 1 H NMR (500MHz, DMSO-d 6 )δ ppm 8.14(br t,J=5.8Hz,1H),7.90(s,1H),7.38(s,1H),7.32(t,J=8.5Hz,1H),7.20(br d,J=13.1Hz,1H),7.16(br d,J=8.2Hz,1H),4.44(br d,J=6.0Hz,2H),4.10(br s,2H),3.59-3.68(m,2H),2.88(q,J=7.5Hz,2H),2.42(s,3H),1.22(t,J=7.5Hz,3H)

[0356] Synthesis of compound 147 [ka] Thus, compound 147 was prepared in the same manner as compound 163 starting from 2-(difluoromethyl)-5H,6H,7H,8H-imidazo[1,2-A]pyridine-3-carboxylic acid (CAS[2060043-79-8], 0.19 mmol) and intermediate AA-3 to give 0.08 g (77%) of a white powder. 1 H NMR (400MHz, DMSO-d 6)δ ppm 8.79(br t,J=5.6Hz,1H),7.38(s,1H),7.33(t,J=8.6Hz,1H),7.07-7.23(m,2H),6.95(t,J=54.2Hz,1H),4.41(br d,J=5.9Hz,2H),4.10(br s,2H),4.02(br t,J=5.5Hz,2H),3.65(br t,J=4.6Hz,2H),2.68-2.91(m,2H),1.89(br d,J=4.3Hz,2H),1.83(br d,J=5.3Hz,2H)

[0357] Synthesis of compound 159 [ka] Thus, compound 159 was prepared in the same manner as compound 163 starting from 2-(difluoromethyl)-imidazo[1,2-A]pyridine-3-carboxylic acid (CAS[2059954-47-9], 0.19 mmol) and intermediate AA-3 to yield 0.084 g (82%) of a white powder. 1 H NMR (400MHz, DMSO-d 6 )δ ppm 9.00(br s,1H),8.81(br d,J=7.0Hz,1H),7.77(d,J=9.0Hz,1H),7.08-7.59(m,7H),4.52(br s,2H),4.10(br s,2H),3.66(br t,J=4.5Hz,2H)

[0358] Synthesis of compound 135 [ka] Thus, compound 135 was prepared in the same manner as compound 163 starting from 2-chloro-6-ethyl-2-methylimidazo[2,1-b][1,3]thiazole-5-carboxylic acid (CAS[2089471-58-7], 0.21 mmol) and intermediate AA-3 to yield 0.056 g (49%) as a white powder. 1 H NMR (500MHz, DMSO-d 6)δ ppm 8.31(m,1H),8.28(br t,J=5.8Hz,1H),7.38(m,1H),7.33(br t,J=8.5Hz,1H),7.21(br d,J=13.4Hz,1H),7.16(br d,J=8.2Hz,1H),4.45(br d,J=5.8Hz,2H),4.10(br s,2H),3.64(br t,J=4.4Hz,2H),2.89(q,J=7.4Hz,2H),1.22(br t,J=7.5Hz,3H)

[0359] Synthesis of compound 152 [ka] Thus, compound 152 was prepared in the same manner as compound 163 starting from 2-(trifluoromethyl)-imidazo[1,2-A]pyridine-3-carboxylic acid (CAS[73221-19-9], 0.92 mmol) and intermediate AA-3 to yield 0.418 g (82%) of a white powder. 1 H NMR (500MHz, DMSO-d 6 )δ ppm 9.29(t,J=5.8Hz,1H),8.57(d,J=6.9Hz,1H),7.80(d,J=9.2Hz,1H),7.56(ddd,J=9.1,6.9,1.1Hz,1H),7 .39(s,1H),7.36(t,J=8.5Hz,1H),7.22-7.26(m,1H),7.18-7.22(m,2H),4.53(d,J=5.8Hz,2H),4.11(br t,J=4.3Hz,2H),3.67(t,J=4.7Hz,2H)

[0360] Synthesis of compound 124 [ka] To a solution of 6-chloro-2-(trifluoromethyl)imidazo[1,2-a]pyridine-3-carboxylic acid (CAS[874830-60-1], 100 mg, 0.378 mmol) and DIPEA (0.306 mL, 1.80 mmol) in DMF (1.7 mL) was added HATU (164 mg, 0.432 mmol). After 10 min of stirring, intermediate AA-3 (137 mg, 0.360 mmol) was added and the reaction mixture was stirred at room temperature for 18 h. The brown paste was purified by preparative LC (SiOH 30 μm amorphous, 25 g, dry packing (celite®), mobile phase gradient: heptane / EtOAc 90 / 10 to 30 / 70). The fractions containing the product were combined and evaporated to give 216 mg as a yellow solid. This was purified by HPLC using Et 2 The mixture was filtered off and the solid was triturated in Et 2 Rinsing with O, collecting and drying under vacuum gave 172 mg as a white solid, which was dissolved in EtOAc and evaporated (3 times) to give 158 mg as a white solid, which was co-evaporated with MeCN (3 times) and dried under vacuum to give 143 mg of compound 124 as a white solid (50%). 1H NMR(400MHz,DMSO-d6)δ ppm 9.28(br s,1H),8.75(m,1H),7.87(d,J=9.4Hz,1H),7.65(dd,J=9.4,1.8Hz,1H),7.31-7.41(m,2H),7.15-7.30(m,2H),4.54(br d,J=4.1Hz,2H),4.10(br t,J=4.0Hz,2H),3.67(br t,J=4.6Hz,2H)

[0361] Synthesis of compound 129 [ka] Thus, compound 129 was prepared in the same manner as compound 124 starting from 8-chloro-2-ethylimidazo[1,2-a]pyridine-3-carboxylic acid (CAS[1517795-25-3], 0.6 mmol) and intermediate AA-3 to give 0.136 g (41%) as a white solid. 1H NMR(400MHz,DMSO-d6)δ ppm 8.90(br d,J=6.9Hz,1H),8.59(br t,J=5.6Hz,1H),7.59(br d,J=7.5Hz,1H),7.30-7.46(m,2H),7.15-7.29(m,2H),7.01(br t,J=7.1Hz,1H),4.50(d,J=5.9Hz,2H),4.10(br t,J=4.4Hz,2H),3.65(br t,J=4.9Hz,2H),3.01(q,J=7.5Hz,2H),1.27(br t,J=7.6Hz,3H)

[0362] Synthesis of compound 133 [ka] Thus, compound 133 was prepared in the same manner as compound 124 starting from 2-chloro-6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid (CAS[2089471-57-6], 0.52 mmol) and intermediate AA-3 to give 0.142 g (51%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 8.31(s,1H),8.25(br t,J=5.9Hz,1H),7.38(br s,1H),7.33(t,J=8.5Hz,1H),7.14-7.25(m,2H),4.45(br d,J=5.9Hz,2H),4.10(br t,J=4.5Hz,2H),3.64(br t,J=4.8Hz,2H),2.52(s,1H)

[0363] Synthesis of compound 136 [ka] Thus, compound 136 was prepared in the same manner as compound 124 starting from 2-methyl-6-(trifluoromethyl)imidazo[2,1-b]thiazole-5-carboxylic acid (CAS[1369332-25-1], 0.58 mmol) and intermediate AA-3 to yield 0.173 g (56%) as a white powder. 1 H NMR(500MHz,DMSO-d6)δ ppm 8.99(br t,J=4.3Hz,1H),7.86(br s,1H),7.39,(m,1H),7.35(br t,J=8.5Hz,1H),7.14-7.24(m,2H),4.47(br d,J=5.5Hz,2H),4.11(m,2H),3.67(br t,J=4.3Hz,2H),2.48(br s,3H)

[0364] Synthesis of compound 164 [ka] Thus, compound 164 was prepared in the same manner as compound 124 starting from 2-ethyl-6-methylimidazo[1,2-a]pyridine-3-carboxylic acid (CAS[1216036-36-0], 0.64 mmol) and intermediate AA-3 to give 0.11 g (33%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 8.75-8.84(br s,1H),8.37(t,J=6.0Hz,1H),7.52(d,J=8.9Hz,1H),7.32-7.41(m,2H),7.17-7.28(m,3H),4.50(br d,J=5.9Hz,2H),4.11(br t,J=4.2Hz,2H),3.66(t,J=4.7Hz,2H),2.98(q,J=7.5Hz,2H),2.31(s,3H),1.37(t,J=7.5Hz,3H)

[0365] Synthesis of compound 157 [ka] Thus, compound 157 was prepared in the same manner as compound 124 starting from intermediate AC-2 (0.78 mmol) and intermediate AA-3 to give 0.106 g (24%) as a white powder. 1H NMR(400MHz,DMSO-d6)δ ppm 9.23(d,J=7.3Hz,1H),8.42-8.53(m,1H),7.80(d,J=9.7Hz,1H),7.29-7.40( m,2H),7.17-7.28(m,2H),4.50(d,J=5.9Hz,2H),4.07-4.13(m,2H),3.65(br t,J=4.6Hz,2H),2.99(q,J=7.5Hz,2H),1.27(t,J=7.5Hz,3H)

[0366] Synthesis of compound 154 [ka] Thus, compound 154 was prepared in the same manner as compound 124 starting from intermediate AD-2 (0.78 mmol) and intermediate AA-3 to give 0.092 g (21%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 9.23(d,J=7.3Hz,1H),8.42-8.54(br t,J=5.9Hz,1H),7.80(d,J=9.8Hz,1H),7.30-7.41(m,2H),7.16-7.28(m,2H),4.50(br d,J=5.9Hz,2H),4.10(br t,J=4.9Hz,2H),3.65(br t,J=4.7Hz,2H),2.99(br q,J=7.4Hz,2H),1.27(br t,J=7.5Hz,3H)

[0367] Synthesis of compound 156 [ka] Thus, compound 156 was prepared in the same manner as compound 124 starting from 2-ethyl-6-fluoroimidazo[1,2-a]pyridine-3-carboxylic acid (CAS[1368682-64-7], 0.27 mmol) and intermediate AA-3 to give 0.096 g (68%) of a white solid. 1H NMR(400MHz,DMSO-d6)δ ppm 8.99-9.12(m,1H),8.41(br t,J=7.5Hz,1H),7.65-7.77(m,1H),7.44-7.57(m,1H),7.32-7.40(m,2H),7.18-7.28(m,2H),4.51(br t,J=5.9Hz,2H),4.11(br t,J=4.5Hz,2H),3.66(t,J=4.6Hz,2H),3.01(q,J=7.5Hz,2H),1.28(br t,J=7.5Hz,3H)

[0368] Synthesis of compound 153 [ka] Thus, compound 153 was prepared in the same manner as compound 124 starting from 2,6-dimethylimidazo[2,1-b][1,3]thiazole-5-carboxylic acid (CAS[1007875-19-5], 0.67 mmol) and intermediate AA-3 to give 0.138 g (42%) of a white solid. 1 H NMR(500MHz,DMSO-d6)δ ppm 8.11(t,J=6.0Hz,1H),7.84-7.95(m,1H),7.38(br s,1H),7.32(br t,J=8.7Hz,1H),7.14-7.23(m,2H),4.45(d,J=6.0Hz,2H),4.10(br t,J=4.4Hz,2H),3.64(br t,J=4.9Hz,2H),2.51(s,3H),2.41(d,J=1.2Hz,3H)

[0369] Synthesis of compound 146 [ka] Thus, compound 146 was prepared in the same manner as compound 124 starting from 6-chloro-2-ethyl-imidazo[1,2-a]pyrimidine-3-carboxylic acid (CAS[2059140-68-8], 0.26 mmol) and intermediate AA-3 to give 0.154 g (74%) of a white solid. 1H NMR(400MHz,DMSO-d6)δ ppm 9.41(d,J=2.7Hz,1H),8.69(d,J=2.7Hz,1H),8.58(m,1H),7.31-7.40(m,2H),7.18-7.28(m,2H),4.51(m,2H),4.10(br t,J=4.5Hz,2H),3.65(br t,J=4.8Hz,2H),3.04(br q,J=7.5Hz,2H),1.29(br t,J=7.5Hz,3H)

[0370] Synthesis of compound 175 [ka] Thus, compound 175 was prepared in the same manner as compound 124 starting from 6-methyl-2-(trifluoromethyl)imidazo[1,2-a]pyridine-3-carboxylic acid (CAS[874830-67-8], 0.53 mmol) and intermediate AA-3 to give 0.117 g (53%) as a white powder. 1 H NMR(400MHz,DMSO-d6)δ ppm 9.08(s,1H),7.66(d,J=9.2Hz,1H),7.44(t,J=8.4Hz,1H),7.32(dd,J=9.2,1.6Hz,1H),7.19(s,1H),7.17-7.08(m,2H),6.63(br s,1H),4.64(d,J=5.7Hz,2H),4.13-4.04(m,2H),3.74-3.65(m,2H),2.41(s,3H).

[0371] Synthesis of compound 125 [ka]

[0372] Preparation of intermediate AE-1 Thus, intermediate AE-1 was prepared in the same manner as intermediate AC-1 starting from 2-amino-4-chloropyrimidine (CAS [3993-78-0], 15.4 mmol) to give 0.94 g (26%).

[0373] Preparation of intermediate AE-2 Thus, intermediate AE-2 was prepared starting from intermediate AE-1 (1.25 mmol) in the same manner as intermediate AC-2, yielding 0.26 g (92%).

[0374] Preparation of intermediate AE-3 A mixture of intermediate AE-2 (175 mg, 0.776 mmol) in thionyl chloride (4.4 mL) was stirred at 60° C. for 20 h. The reaction mixture was evaporated to give 0.288 g as a brown paste (purity was calculated to give a quantitative yield).

[0375] Preparation of Compound 125 A mixture of intermediate AE-3 (288 mg, 0.779 mmol) and intermediate AA-3 (295 mg, 0.779 mmol) and DIPEA (0.331 mL, 1.95 mmol) in dry DCM (4.8 mL) was stirred at room temperature for 10 min. Water was added. The aqueous layer was extracted with DCM (1x). The combined organic layers were washed with brine and diluted with MgSO 4 The mixture was dried over ice, filtered off and evaporated to give 0.4 g of a brown foam, which was purified by preparative LC (SiOH 30 μm, 25 g, dry packing (Celite®), mobile phase gradient: heptane / EtOAc 90 / 10 to 50 / 50). The fractions containing the product were combined and evaporated to give 0.229 g of a yellow foam. The yellow foam was purified by distillation with Et 2 Sonicated in O. The precipitate was filtered off to give 146 mg of compound 125 as a white solid (33%). 1 H NMR(500MHz,DMSO-d6)δ ppm 9.29(d,J=7.2Hz,1H),8.53-8.61(m,1H),7.38(br s,1H),7.34(br t,J=8.7Hz,1H),7.17-7.28(m,3H),4.49(br d,J=5.9Hz,2H),4.08-4.12(m,2H),3.65(br t,J=4.9Hz,2H),3.01(br q,J=7.4Hz,2H),1.27(br t,J=7.4Hz,3H)

[0376] Synthesis of compound 130 [ka]

[0377] Preparation of intermediate AF-1 Thus, intermediate AF-1 was prepared in the same manner as intermediate AC-1 starting from 2-amino-5-fluoropyrimidine (CAS [1683-85-8], 17.68 mmol) to give 1.18 g (27%).

[0378] Preparation of intermediate AF-2 To a solution of intermediate AF-1 (1.1 g, 4.64 mmol) in EtOH (24 mL) and water (24 mL) was added potassium carbonate (3.2 g, 23.2 mmol) and the mixture was heated at 65° C. and stirred for 3 h. (Alternative conditions are shown in the scheme above.) The mixture was acidified with 3 M HCl to pH=1 (no precipitate occurred) and then evaporated in vacuo. The residue was dissolved in EtOH / water (1:1), sonicated, and then filtered off (the precipitate contained K 2 CO 3 The filtrate was concentrated and then evaporated twice with DCM to give 0.92 g of intermediate AF-2 as a brown solid (95%). The crude was used as is.

[0379] Preparation of Compound 130 Thus, compound 130 was prepared in the same manner as compound 124 starting from intermediate AF-2 (0.96 mmol) and intermediate AA-3 to give 0.194 g (39%) of a white solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 9.39-9.48(m,1H),8.77-8.89(m,1H),8.50-8.59(m,1H),7.17-7.42(m,4H),4.52(br d,J=4.4Hz,2H),4.07-4.13(m,2H),3.62-3.68(m,2H),3.05(br q,J=7.2Hz,2H),1.29(br t,J=7.5Hz,3H)

[0380] Synthesis of compound 131 [ka]

[0381] Preparation of intermediate AG-1 To a solution of 2H,3H-furo[2,3-c]pyridin-5-amine (CAS[1785357-12-1], 500 mg, 3.67 mmol) in ACN (8.4 mL) was added ethyl oxovalerate (1.05 mL, 7.35 mmol) and boron tetrabromide (2.44 g, 7.35 mmol) and the reaction mixture was stirred at 80 °C for 18 h. The reaction mixture was diluted with EtOAc and the organic layer was washed with water and brine and diluted with MgSO 4 It was dried over hexane, filtered off, concentrated and purified by preparative LC (amorphous SiOH, 15-40 μm, 40 g, liquid packing (DCM), mobile phase gradient: heptane / EtOAc: 100 / 0-0 / 100 over 10 CV, then 100% EtOAc over 5 CV). The product-containing fractions were combined and evaporated to give 0.21 g of intermediate AG-1 (22%).

[0382] Preparation of intermediate AG-2 A mixture of intermediate AG-1 (186 mg, 0.715 mmol), aqueous 3 M NaOH (1.19 mL, 3.57 mmol), and MeOH (2 mL) was stirred for 2 days at 60° C. The mixture was evaporated to give 0.33 g of intermediate AG-2 (quantitative yield based on purity).

[0383] Preparation of Compound 131 Thus, compound 131 was prepared in the same manner as compound 124 starting from intermediate AG-2 (0.71 mmol) and intermediate AA-3 to give 0.09 g (23%) of a white solid. 1H NMR(400MHz,DMSO-d6)δ ppm 8.50(s,1H),8.19-8.32(m,1H),7.47(s,1H),7.38(br s,1H),7.29-7.36(m,1H),7.14-7.25(m,2H),4.61(t,J=8.2Hz,2H),4.47(br d,J=5.7Hz,2H),4.09(br t,J=4.3Hz,2H),3.65(t,J=4.7Hz,2H),3.25-3.32(m,2H),2.94(q,J=7.5Hz,2H),1.24(t,J=7.5Hz,3H)

[0384] Synthesis of compound 134 [ka]

[0385] Preparation of intermediate AH-1 A solution of 6-bromo-1,3-dioxolo[4,5-c]-pyridine (CAS [2230730-23-9], 3.87 g, 19.2 mmol) in dry toluene (100 mL) was diluted with N 2 (3 times). Pd 2 (dba) 3 (1.75 g, 1.92 mmol) and CyJohnPhos (2.80 g, 7.66 mmol) were added and the reaction mixture was flushed with N 2 The mixture was degassed with 500 mL of 10 ... 4 It was dried over, filtered off and evaporated to give 1.84 g of intermediate AH-1 as a brown solid (70%).

[0386] Preparation of intermediate AH-2 Thus, intermediate AH-2 was prepared starting from intermediate AH-1 (3.62 mmol) in the same manner as intermediate AB-1, yielding 0.165 g (17%).

[0387] Preparation of intermediate AH-3 Thus, intermediate AH-3 was prepared starting from intermediate AH-2 (0.95 mmol) in the same manner as intermediate AB-2 to give 0.421 g (quantitative yield based on purity).

[0388] Preparation of compound 134 Thus, compound 134 was prepared in the same manner as compound 124 starting from intermediate AH-3 (0.45 mmol) and intermediate AA-3 to give 0.194 g (84%) of a white solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 8.62(br s,1H),8.24(t,J=6.0Hz,1H),7.38(s,1H),7.34(t,J=8.6Hz,1H),7.14-7.24(m,2H),7.08(s,1H),6.16(br s,2H),4.47(br d,J=5.8Hz,2H),4.07-4.12(m,2H),3.65(br t,J=4.6Hz,2H),2.91(q,J=7.5Hz,2H),1.23(t,J=7.5Hz,3H)

[0389] Synthesis of compound 161 [ka]

[0390] Preparation of intermediate AI-1 2-Amino-5-bromopyrimidine (10.0 g; 57.5 mmol) was suspended in dry 2-MeTHF (250 mL). Ethyl 3-oxovalerate (8.2 mL, 57.5 mmol, 1 eq.) and iodobenzene diacetate (18.5 g, 57.5 mmol, 1 eq.) were added. Boron trifluoride etherate (0.75 mL, 2.87 mmol, 0.05 eq.) was then added dropwise and the reaction mixture was stirred at 60° C. for 1.5 h. Additional amounts of ethyl-ethyl 3-oxovalerate (4.10 mL, 28.7 mmol, 0.5 eq.), iodobenzene diacetate (9.25 g, 28.7 mmol, 0.5 eq.), and boron trifluoride etherate (0.75 mL, 2.87 mmol, 0.05 eq.) were added at room temperature and the mixture was stirred at 60° C. for 1 h. The mixture was cooled to room temperature, and then EtOAc and water were added. The organic layer was separated and diluted with NaHCO 3 The organic layer was washed with saturated aqueous solution (2 times) and then with brine (2 times). 4 The mixture was dried over ice, filtered off and evaporated to give 19.7 g as a brown oil. The crude was purified by preparative LC (amorphous SiOH, 15-40 μm, 330 g, dry packing (SiOH), mobile phase gradient: DCM 100% to DCM 85%, EtOAc 15%) to give intermediate AI-1, 9.03 g as yellow crystals (53%).

[0391] Preparation of intermediate AI-2 N 2 In a sealed tube below, intermediate AI-1 (500 mg, 1.68 mmol) and Pd(PPh 3 ) 4 To a solution of (96.9 mg, 0.084 mmol) in THF (12 mL) was added 2 m triethylaluminum in hexanes (2 eq., 1.68 mL, 3.35 mmol). The mixture was purged again with N2 and heated at 65 °C for 1 h. An additional amount of 2 m triethylaluminum in hexanes (1 eq., 0.839 mL, 1.68 mmol) was added and the mixture was stirred at 65 °C for 1 h. The mixture was diluted with DCM, cooled to 0 °C and 1 mL of water was carefully added. The mixture was stirred at room temperature overnight and then diluted with MgSO 4was added. After 30 min with stirring, the mixture was filtered through a plug of Celite® and evaporated to give 412 mg of an orange gum. The crude was purified by preparative LC (SiOH amorphous, 30 μm, 40 g, dry packing (Celite®), mobile phase eluent: heptane 95%, EtOAc 5% to heptane 50%, EtOAc 50%). The product-containing fractions were combined and concentrated to give 354 mg of a yellow gum (90%), intermediate AI-2.

[0392] Preparation of intermediate AI-3 To a solution of intermediate AI-2 (120 mg, 0.514 mmol) in water (1 mL) and EtOH (4 mL) was added NaOH (62 mg, 1.55 mmol) and the mixture was stirred at room temperature overnight. The mixture was evaporated and then co-evaporated with EtOH to give intermediate AI-3, 190 mg, as a yellow solid. The crude was used as such in the next step.

[0393] Preparation of Compound 161 A mixture of intermediate AI-3 (190 mg, 0.518 mmol), HATU (280 mg, 0.736 mmol), DIPEA (0.163 mL, 0.958 mmol), and DMF (2.5 mL) was stirred at room temperature for 15 min, then intermediate AA-3 (180 mg, 0.473 mmol) was added and stirring was continued for 3 days. DMF was evaporated. The residue was dissolved in DCM and water, then NaHCO 3 (twice), brine (twice), and MgSO 4 The crude (m=378 mg) was purified by preparative LC (SiOH amorphous, 30 μm, 24 g, mobile phase gradient: heptane 85%, EtOAc / MeOH (9:1) 15% to heptane 25%, EtOAc / MeOH (9:1) 75%). The product-containing fractions were combined and concentrated to give 277 mg as a white solid. The solid was recrystallized from EtOAc, filtered off and dried under high vacuum to give 162 mg of compound 161 as a white solid (54%). 1H NMR(400MHz,DMSO-d6)δ ppm 9.15(d,J=1.2Hz,1H),8.52(br d,J=2.3Hz,1H),8.44-8.49(m,1H),7.38(br s,1H),7.34(m,J=8.6Hz ,1H),7.17-7.27(m,2H),4.50(br d,J=5.9Hz,2H),4.07-4.13(m,2H),3.65(br t,J=4.6Hz,2H),3.01(q,J=7.5Hz,2H),2.34(br s,3H),1.28(t,J=7.5Hz,3H)

[0394] Synthesis of Compounds 162, 148, and 151 [ka]

[0395] Preparation of intermediate AJ-1 The reaction was carried out under anhydrous conditions under a nitrogen atmosphere. 2 To a solution of 3-fluoro-5-methylpyridin-2-amine (2.00 g, 15.9 mmol) in 2-MeTHF (60 mL) at 5° C. was added ethyl propionylacetate (3.60 mL, 24.8 mmol), iodobenzene diacetate (7.80 g, 24.2 mmol), and boron trifluoride etherate (200 μL, 1.62 mmol). The reaction was stirred at 5° C. for 1 h and then at room temperature for 48 h. EtOAc (200 mL) and water (200 mL) were added. The layers were separated and the organic layer was washed with NaHCO 3 Wash with saturated aqueous solution (200 mL), brine (2×100 mL), and Na 2 SO 4 The crude was purified by preparative LC (SiOH, 120 g, 50 μm, eluent: cyclohexane / EtOAc, 95:05 to 50:5) and the fractions containing the product were collected, evaporated and triturated with pentane (2×20 mL) to give 1.68 g of intermediate AJ-1 as a white solid (42%).

[0396] Preparation of intermediate AJ-2 To a solution of intermediate AJ-1 (500 mg, 2.00 mmol) in water (12.5 mL) and EtOH (12.5 mL) was added NaOH (275 mg, 6.880 mmol). The reaction mixture was stirred at 40° C. for 16 h. The crude was washed with DCM (30 mL) and EtOAc (30 mL) and the aqueous phase was acidified with aqueous HCl (3N) until pH=2. The formed precipitate was recovered using a sintered glass under vacuum, washed with water (2×2 mL) and dried overnight in a vacuum chamber at 50° C. to give 415 mg of intermediate AJ-2 as an off-white solid (93%).

[0397] Preparation of compound 162 Thus, compound 162 was prepared in the same manner as compound 161 starting from intermediate AJ-2 (0.36 mmol) and intermediate AA-3 to give 0.113 g (48%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 8.61(br s,1H),8.53(br t,J=5.9Hz,1H),7.31-7.40(m,2H),7.17-7.27(m,3H),4.50(d,J=5.9Hz,2H),4.10(br t,J=4.5Hz,2H),3.65(br t,J=4.5Hz,2H),2.98(q,J=7.5Hz,2H),2.31(s,3H),1.26(t,J=7.5Hz,3H)

[0398] Preparation of intermediate AK-1 Thus, intermediate AK-1 was prepared in the same manner as intermediate AJ-1 starting from 2-amino-3,5-difluoropyridine (CAS [732306-31-9], 15.37 mmol) to give 0.89 g (23%) as a white solid.

[0399] Preparation of intermediate AK-2 Thus, intermediate AK-2 was prepared starting from intermediate AK-1 (1.97 mmol) in the same manner as intermediate AJ-2, yielding 0.345 g (78%).

[0400] Preparation of compound 148 Thus, compound 148 was prepared in the same manner as compound 161 starting from intermediate AK-2 (0.35 mmol) and intermediate AA-3 to give 0.189 g (82%) as a white solid. 1 H NMR(500MHz,DMSO-d6)δ ppm 8.92(dd,J=4.7,1.8Hz,1H),8.58(t,J=5.9Hz,1H),7.64-7.74(m,1H),7.38(br s,1H),7.35(t,J=8.5Hz,1H),7.18-7.27(m,2H),4.50(d,J=5.9Hz,2H),4.10(br t,J=4.7Hz,2H),3.65(t,J=4.9Hz,2H),3.01(q,J=7.5Hz,2H),1.27(t,J=7.6Hz,3H)

[0401] Preparation of intermediate AL-1 Thus, intermediate AL-1 was prepared in the same manner as intermediate AJ-1 starting from 2-amino-5-chloro-3-fluoropyridine (CAS [20712-16-7], 17.06 mmol) to give 0.52 g (11%) as a white solid.

[0402] Preparation of intermediate AL-2 Thus, intermediate AL-2 was prepared starting from intermediate AL-1 (1.77 mmol) in the same manner as intermediate AJ-2, yielding 0.26 g (60%).

[0403] Preparation of Compound 151 Thus, compound 151 was prepared in the same manner as compound 161 starting from intermediate AL-2 (0.43 mmol) and intermediate AA-3 to give 0.104 g (38%) as a white solid. 1H NMR(400MHz,DMSO-d6)δ ppm 8.92(d,J=1.0Hz,1H),8.58-8.67(m,1H),7.63(dd,J=10.6,1.4Hz,1H),7.31-7.40(m,2H),7.17-7.28(m,2H),4.51(br d,J=5.6Hz,2H),4.07-4.13(m,2H),3.65(t,J=4.6Hz,2H),3.01(q,J=7.4Hz,2H),1.27(t,J=7.4Hz,3H)

[0404] Synthesis of compounds 145 and 144 [ka]

[0405] Preparation of intermediate AM-1 Thus, intermediate AM-1 was prepared in the same manner as AJ-1 starting from 2-amino-5-chloropyridine (CAS[1072-98-6], 3.89 mmol) and ethyl 4,4-difluoro-3-oxobutyrate (CAS[352-24-9]) to give 0.248 g (23%) as a white solid.

[0406] Preparation of intermediate AM-2 Thus, intermediate AM-2 was prepared starting from intermediate AM-1 (0.73 mmol) in the same manner as intermediate AJ-2, yielding 0.175 g (96%).

[0407] Preparation of compound 145 Thus, compound 145 was prepared in the same manner as compound 161 starting from intermediate AM-2 (0.39 mmol) and intermediate AA-3 to give 0.164 g (64%) as a white solid. 1H NMR(500MHz,DMSO-d6)δ ppm 9.04(s,1H),8.88-8.96(m,1H),7.83(dd,J=9.6,1Hz,1H),7.61(dd,J=9.6,2.1Hz,1H),7.46-7. 47(m,1H),7.33-7.40(m,2H),7.19-7.30(m,2H),4.51-4.54(m,2H),4.08-4.12(m,2H),3.66(br t,J=4.9Hz,2H)

[0408] Preparation of intermediate AN-1 Thus, intermediate AN-1 was prepared in the same manner as AJ-1 starting from 5-chloro-4-fluoropyridin-2-amine (CAS[1393574-54-3], 6.82 mmol) and ethyl 4,4-difluoro-3-oxobutyrate (CAS[352-24-9]) to give 0.57 g (28%) as a white solid.

[0409] Preparation of intermediate AN-2 Thus, intermediate AN-2 was prepared starting from intermediate AN-1 (0.85 mmol) in the same manner as intermediate AJ-2, yielding 0.145 g (64%).

[0410] Preparation of compound 144 Thus, compound 144 was prepared in the same manner as compound 161 starting from intermediate AM-2 (0.41 mmol) and intermediate AA-3 to give 0.204 g (72%) as a white solid. 1 H NMR(500MHz,DMSO-d6)δ ppm 9.09(d,J=7.2Hz,1H),9.03-9.07(m,1H),7.98(d,J=9.6Hz 1H),7.20-7.40(m,4H),4.52(br d,J=4.6Hz,2H),4.09-4.13(m,2H),3.65-3.68(m,2H),2.53(br s,1H)

[0411] Synthesis of Compounds 138, 139, and 140, and Compound 143 [ka]

[0412] Preparation of intermediate AO-1 Thus, intermediate AO-1 was prepared in the same manner as AJ-1 starting from 4-bromo-5-methylpyridin-2-amine (CAS[1033203-32-5], 5.35 mmol) and ethyl 3-oxovalerate (CAS[4949-44-4]) to give 0.88 g (50%) as a white solid.

[0413] Preparation of intermediate AO-2 Thus, intermediate AO-2 was prepared starting from intermediate AO-1 (0.48 mmol) in the same manner as intermediate AJ-2, yielding 0.205 g (78%).

[0414] Preparation of intermediate AO-3 Thus, intermediate AO-3 was prepared in the same manner as compound 161 starting from intermediate AO-2 (0.49 mmol) and intermediate AA-3 to give 0.27 g (71%) as a white solid.

[0415] Preparation of compound 138 A mixture of intermediate AO-3 (210 mg, 0.347 mmol), benzophenone imine (116 μL, 0.694 mmol), cesium carbonate (226 mg, 0.694 mmol), and 1,4-dioxane (1.75 mL) was dissolved in 100 mL of N 2 Purge with Pd(OAc) 2 (3.9 mg, 0.017 mmol), and BINAP (21.6 mg, 0.0347 mmol) were added. The mixture was then subjected to N 2 The mixture was purged with ethyl acetate and stirred at 100° C. for 18 h. The mixture was filtered through a pad of Celite® and the cake was washed with EtOAc. The organic layer was then concentrated and the residue was stirred in 1,4-dioxane (2.5 mL) and 1 M aqueous HCl (2.5 mL) at room temperature for 16 h. The mixture was diluted with EtOAc and added NaHCO 3 It was slowly quenched with saturated aqueous solution. The layers were separated and the aqueous layer was extracted with EtOAc (2x). The organic layers were combined and washed with MgSO 4The residue was purified by preparative LC (SiOOH 30 μm amorphous, 24 g, mobile phase eluent: heptane 90%, EtOAc / MeOH / aq.NH 3 (90:9.5:0.5) 10% to Heptane 20%, EtOAc / MeOH / aq.NH 3 (90:9.5:0.5) 80%). The product-containing fractions were combined and concentrated to give 0.125 g as a white solid. This solid was recrystallized from EtOAc, filtered off, and dried under high vacuum to give 97 mg of compound 138 as a white solid (52%). 1 H NMR(400MHz,DMSO-d6)δ ppm 8.61-8.70(m,1H),7.89(t,J=6.0Hz,1H),7.38(s,1H),7.32(t,J=8.5Hz,1H),7.14-7.22(m,2H),6.46-6.47(m,1H),5.69-5.72(m,2H),4.44(br d,J=5.8Hz,2H),4.10(br t,J=4.3Hz,2H),3.64(t,J=4.6Hz,2H),2.87(q,J=7.5Hz,2H),2.08(s,3H),1.21(t,J=7.5Hz,3H)

[0416] Preparation of intermediate AP-1 Thus, intermediate AP-1 was prepared in the same manner as AJ-1 starting from 4,5-dimethylpyridin-2-amine (CAS[57963-11-8], 4.09 mmol) and ethyl 3-oxovalerate (CAS[4949-44-4]) to give 0.73 g (72%) as a white solid.

[0417] Preparation of intermediate AP-2 Thus, intermediate AP-2 was prepared starting from intermediate AP-1 (0.81 mmol) in the same manner as intermediate AJ-2, yielding 0.3 g (quantitative).

[0418] Preparation of Compound 139 Thus, compound 139 was prepared in the same manner as compound 161 starting from intermediate AP-2 (0.49 mmol) and intermediate AA-3 to give 0.142 g (58%) as a white solid. 1 H NMR(500MHz,DMSO-d6)δ ppm 8.78(br s,1H),8.24(t,J=5.9Hz,1H),7.38(s,2H),7.34(t,J=8.5Hz,1H),7.16-7.25(m,2H),4.48(d,J=5.9Hz,2H),4.10(br t,J=4.7Hz,2H),3.65(t,J=4.5Hz,2H),2.95(q,J=7.5Hz,2H),2.30(s,3H),2.22(s,3H),1.25(t,J=7.5Hz,3H)

[0419] Preparation of intermediate AQ-1 Thus, intermediate AQ-1 was prepared in the same manner as AJ-1 starting from 4-chloro-5-methylpyridin-2-amine (CAS[1033203-31-4], 7.01 mmol) and ethyl 3-oxovalerate (CAS[4949-44-4]) to give 0.39 g (20%) as a white solid.

[0420] Preparation of intermediate AQ-2 Thus, intermediate AQ-2 was prepared starting from intermediate AQ-1 (0.45 mmol) in the same manner as intermediate AJ-2 to give 0.15 g (quantitative).

[0421] Preparation of Compound 140 Thus, compound 140 was prepared in the same manner as compound 161 starting from intermediate AQ-2 (0.45 mmol) and intermediate AA-3 to give 0.23 g (68%) as a white powder. 1 H NMR(500MHz,DMSO-d6)δ ppm 8.95(s,1H),8.45(br t,J=5.9Hz,1H),7.81(br s,1H),7.38(br s,1H),7.34(t,J=8.5Hz,1H),7.17-7.26(m,2H),4.50(d,J=5.9Hz,2H),4.10(br t,J=4.4Hz,2H),3.65(t,J=4.7Hz,2H),2.97(q,J=7.3Hz,2H),2.32(s,3H),1.26(t,J=7.4Hz,3H)

[0422] Preparation of intermediate AR-1 Thus, intermediate AR-1 was prepared in the same manner as AJ-1 starting from 4-bromo-5-chloropyridin-2-amine (CAS[1187449-01-9], 9.64 mmol) and ethyl 3-oxovalerate (CAS[4949-44-4]) to yield 0.655 g (21%).

[0423] Preparation of intermediate AR-2 Thus, intermediate AR-2 was prepared starting from intermediate AR-1 (2.05 mmol) in the same manner as intermediate AJ-2 to give 0.94 g (quantitative).

[0424] Preparation of intermediate AR-3 Thus, intermediate AR-3 was prepared in the same manner as compound 161 starting from intermediate AR-2 (2.06 mmol) and intermediate AA-3 to give 0.42 g (33%) as an off-white solid.

[0425] Preparation of compound 143 Thus, compound 143 was prepared in the same manner as compound 138 starting from intermediate AR-3 (0.4 mmol) to give 0.08 g (33%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 9.03(s,1H),8.01(t,J=5.7Hz,1H),7.38(s,1H),7.33(t,J=8.6Hz,1H),7.15-7.24(m,2H),6.63(br s,1H),6.12(br s,2H),4.45(d,J=5.9Hz,2H),4.07-4.12(m,2H),3.64(t,J=4.5Hz,2H),2.90(q,J=7.5Hz,2H),1.22(t,J=7.5Hz,3H)

[0426] Synthesis of compound 126 [ka]

[0427] Preparation of intermediate AS-1 To a solution of 4,5-dichloropyrimidin-2-amine (CAS [403854-21-7], 12.5 g, 76.2 mmol) in Me-THF (315 mL) at 0° C. was added iodobenzene diacetate (73.7 g, 229 mmol) and ethyl 3-oxovalerate (16.5 mL, 116 mmol). Boron trifluoride etherate (1.92 mL, 15.2 mmol) was then added dropwise. The mixture was stirred at 5° C. for 1 h and then at room temperature for 16 h. Additional boron trifluoride etherate (1.92 mL, 15.2 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 28 h. EtOAc and water were added. The organic layer was washed with brine and diluted with MgSO 4 The mixture was dried on a kettle and evaporated to give a brown oil. The oil was purified by preparative LC (amorphous SiOH, 15-40 μm, 330 g, gradient: heptane 100% to heptane / EtOAc 75 / 25). The fractions containing the product were combined and evaporated to give a yellow mixture which was triturated in pentane. The supernatant was removed by pipette and the residue was dried under vacuum to give 1.16 g of intermediate AS-1 as a white solid (5%). The supernatant was evaporated to give a yellow mixture. The supernatant was removed by pipette to give 5.02 g of intermediate AS-1 as a yellow paste (32%).

[0428] Preparation of intermediate AS-2 A mixture of intermediate AS-1 (5.02 g, 5.58 mmol, 32% purity), 4-methoxybenzylamine (CAS [2393-23-9], 2.19 mL, 16.7 mmol), and 1,4-dioxane (16 mL) was stirred at 100° C. for 1 h. The mixture was evaporated and purified by preparative LC (amorphous SiOH, 15-40 μm, 120 g, dry packing (celite®), mobile phase gradient: heptane / EtOAc: 70 / 30-30 / 70). The product-containing fractions were combined and evaporated to give 1.6 g of intermediate AS-2 (74%).

[0429] Preparation of intermediate AS-3 A mixture of intermediate AS-2 (0.900 g, 2.31 mmol), NaOH (278 mg, 6.94 mmol), and MeOH (9.2 mL) was stirred for 40 h at 60° C. The mixture was evaporated to give 1.05 g of intermediate AS-3 (quantitative).

[0430] Preparation of intermediate AS-4 Intermediate AS-3 (1.05g, 2.30mmol, purity 84%), EDCI.HCl (0.8783g, 4.61mmol), HOBT.H 2 A mixture of 0 (0.706 mg, 4.61 mmol), DIPEA (1.19 mL, 6.91 mmol), and DMF (35 mL) was stirred at 50 °C for 30 min. Intermediate AA-3 (865 mg, 2.42 mmol) was added and the mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with EtOAc and the organic layer was washed with water and brine and diluted with MgSO 4 It was dried over, filtered off, concentrated and purified by preparative LC (amorphous SiOH, 15-40 μm, 120 g, mobile phase gradient: heptane / EtOAc 50 / 50-0 / 100). The product-containing fractions were combined and evaporated to give 560 mg of intermediate AS-4 (36%).

[0431] Preparation of Compound 126 A mixture of intermediate AS-4 (560 mg, 0.820 mmol), TFA (4.5 mL), and DCE (4.5 mL) was stirred at 80° C. for 20 h. The mixture was evaporated and purified by preparative LC (spherical C18 25 μm, 120 g YMC-ODS-25, liquid packing (DMSO), mobile phase gradient 0.2% aq. NH 4 + HCO 3 - / MeCN 75:25 to 20:80). The product-containing fractions were combined and evaporated to give 204 mg as a white solid, and 350 mg of impure desired product. This second fraction was purified by preparative LC (spherical C18 25 μm, 120 g YMC-ODS-25, liquid packing (DMSO), mobile phase gradient 0.2% aq.NH 4 + HCO 3 - / MeCN 75:25 to 20:80). The fractions containing the product were evaporated to give 65 mg as a white solid. The pure compound fractions were dissolved with EtOAc at reflux. The mixture was slowly cooled to room temperature with gentle stirring. The precipitate was filtered to give 0.355 g of compound 126 as a white solid (93%). 1 H NMR(500MHz,DMSO-d6)δ ppm 9.06(s,1H),8.12(t,J=6.0Hz,1H),6.99-7.64(m,6H),4.45(d,J=6.0Hz,2H),4.09(br d,J=5.2Hz,2H),3.64(t,J=4.7Hz,2H),2.87(q,J=7.4Hz,2H),1.21(t,J=7.5Hz,3H)

[0432] Synthesis of compound 155 [ka]

[0433] Preparation of intermediate AT-1 Thus, intermediate AT-1 was prepared in the same manner as AJ-1 starting from 5-chloro-4-methylpyrimidin-2-amine (CAS[40439-76-7], 6.96 mmol) and ethyl 3-oxovalerate (CAS[4949-44-4]) to give 0.37 g (20%) as a white solid.

[0434] Preparation of intermediate AT-2 Thus, intermediate AT-2 was prepared starting from intermediate AT-1 (0.37 mmol) in the same manner as intermediate AJ-2 to give 0.165 g (quantitative).

[0435] Preparation of compound 155 Thus, compound 155 was prepared in the same manner as compound 161 starting from intermediate AT-2 (0.38 mmol) and intermediate AA-3 to give 0.055 g (26%) as a white powder. 1 H NMR (500MHz, DMSO-d 6)δ ppm 9.35(br s,1H),8.48(t,J=6.1Hz,1H),7.30-7.40(m,2H),7.16-7.28(m,2H),4.50(br d,J=5.6Hz,2H),4.06-4.13(m,2H),3.65(br t,J=4.5Hz,2H),3.01(q,J=7.5Hz,2H),2.62(s,3H),1.27(t,J=7.5Hz,3H)

[0436] Synthesis of compound 150 [ka] HATU (0.097 g, 0.26 mmol) was dissolved in N 2 To a solution of 2-(trifluoromethyl)-imidazo[1,2-A]pyridine-3-carboxylic acid (CAS[73221-19-9], 0.051 g, 0.22 mmol) and DIPEA (0.096 mL, 0.56 mmol) in dry Me-THF (1.5 mL) and DCM (0.5 mL) was added. The solution was stirred at room temperature for 15 min. Intermediate N3 (0.095 g, 0.24 mmol) was then added and the reaction mixture was stirred at room temperature for 16 h. The solvent was then evaporated and the residue was diluted in ethyl acetate and treated with NaHCO 3 The residue was washed with a saturated aqueous solution of 150H 2 O, water, and then brine. The organic layer was dried over MgSO4, filtered, and evaporated in vacuo to give 0.314 g of a yellow oil. Purification was carried out by flash chromatography on silica gel (12 g, amorphous SiOH 25-40 μM, DCM / MeOH 100 / 0-97 / 3). The pure fractions were collected and evaporated to give 0.119 g as a white foam. This was triturated with DIPE and a little heptane, the precipitate was filtered off, and dried under vacuum at 60° C. to give compound 150 as a white powder 0.103 g (82%). 1 H NMR (500MHz, DMSO-d 6)δ ppm 9.21(br t,J=5.3Hz,1H),8.53(br d,J=6.7Hz,1H),7.79(br d,J=9.0Hz,1H),7.55(br t,J=7.8Hz,1H),7.29(br d,J=8.4Hz,2H),7.13-7.22(m,3H),4.47(br d,J=5.5Hz,2H),4.07-4.15(m,2H),3.86(s,3H),3.76(br t,J=4.6Hz,2H)

[0437] Synthesis of compound 88 [ka] Thus, compound 88 was prepared in the same manner as compound 150 starting from 2-(difluoromethyl)-imidazo[1,2-A]pyridine-3-carboxylic acid (CAS[2059954-47-9], 0.23 mmol) and intermediate N3 to yield 0.104 g (86%) of a white powder. 1 H NMR (500MHz, DMSO-d 6 )δ ppm 8.94(br t,J=5.1Hz,1H),8.79(d,J=7.0Hz,1H),7.76(d,J=9.0Hz,1H),7.52(t,J=7.9Hz,1H),7.19-7.43(m,3H),7.14-7.19(m,3H),4.47(br d,J=5.2Hz,2H),4.07-4.14(m,2H),3.85(s,3H),3.71-3.79(m,2H)

[0438] Preparation of Compound 200 [ka] Thus, compound 200 was prepared in the same manner as compound 150 starting from intermediate AI-3 (0.64 mmol) and intermediate N3 (0.51 mmol) to yield 0.085 g (31%) of a white powder. 1H NMR(400MHz,DMSO)d 9.15-9.11(m,1H),8.51(d,J=2.3Hz,1H),8.41(t,J=5.9Hz,1H),7.29(d,J=8.7Hz,2H),7.15(d,J=8.7Hz,2H),4.45(d,J= 5.8Hz,2H),4.15-4.06(m,2H),3.85(s,3H),3.76-3.70(m,2H),2.98(q,J=7.5Hz,2H),2.34(s,3H),1.26(t,J=7.5Hz,3H).

[0439] Synthesis of Compound 169 and Compound 180 [ka]

[0440] Preparation of intermediate AU-1 In a screw-top vial, a mixture of ethyl propionylacetate (0.105 g, 0.73 mmol), 5H,6H,8H-pyrano[3,4-d]pyrimidin-2-amine (CAS[1781072-41-0], 0.11 g, 0.73 mmol), potassium bicarbonate (0.08 g, 0.8 mmol), and bromotrichloromethane (0.143 mL, 1.45 mmol) in acetonitrile (12 mL) at room temperature was stirred at 80° C. for 16 hours. Additional ethyl propionylacetate (0.105 g, 0.73 mmol), potassium bicarbonate (0.08 g, 0.8 mmol), and bromotrichloromethane (0.143 mL, 1.45 mmol) was added to the mixture, which was stirred at 80° C. for 24 hours. The mixture was then diluted with EtOAc and added sat.NaHCO 3 The organic layer was washed with MgSO 4 The mixture was dried over hexane, filtered and concentrated in vacuo. The crude was purified by flash column chromatography on silica gel (12 g, EtOAc / heptane 0 / 100 to 100 / 0). The desired fractions were collected and the solvent was evaporated in vacuo to give intermediate AU-1 as a yellow sticky solid (0.084 g, 42%).

[0441] Preparation of intermediate AU-2 In a screw-top vial, 15% aqueous potassium carbonate (0.8 mmol, 0.87 mmol) was added onto a solution of intermediate AU-1 in EtOH (4 mL) at room temperature. The reaction mixture was heated at 75° C. and stirred for 36 h. 2 M aqueous HCl was then added until pH 3 and the solvent was evaporated in vacuo to give intermediate AU-2 as an orange solid, which was used in the next step without further purification (0.18 g, quantitative) /

[0442] Preparation of compound 169 Thus, compound 169 was prepared in the same manner as compound 161 starting from intermediate AU-2 (0.41 mmol) and intermediate AA-3 to give 0.051 g (28%) as a white powder. 1H NMR(400MHz,CDCl3)δ ppm 9.54(s,1H),7.44(t,J=8.5Hz,1H),7.19(s,1H),7.16-7.05(m,2H),6.18(br t,J=5.6Hz,1H),4.84(s,2H),4.64(d,J=5.8Hz,2H),4.13-4.05(m,2H),4.02( t,J=5.7Hz,2H),3.71-3.63(m,2H),3.05-2.89(m,4H),1.45(t,J=7.5Hz,3H).

[0443] Preparation of Compound 180 Thus, compound 180 was prepared in the same manner as compound 161 starting from intermediate AU-2 (0.081 mmol) and intermediate R-7 to yield 0.012 g (30%) as a white powder. 1 H NMR(400MHz,CDCl3)δ ppm 9.54(s,1H),7.46(t,J=8.6Hz,1H),7.10(m,2H),6.17(br t,J=5.5Hz,1H),4.84(s,2H),4.63(d,J=5.8Hz,2H),4.15-4.05(m,2H),4.02(t,J=5 .7Hz,2H),3.89(s,3H),3.65-3.55(m,2H),3.07-2.92(m,4H),1.45(t,J=7.5Hz,3H).

[0444] Synthesis of compound 177 [ka]

[0445] Preparation of intermediate AV-1 The reaction was split into two batches of 1.5 g each. 2,4-Dimethoxybenzylamine (CAS[20781-20-8], 2.97 mL, 19.76 mmol) was added dropwise to a solution of 2,4-dichloro-5-fluoropyrimidine (CAS[2927-71-1], 3 g, 17.97 mmol) and triethylamine (3 mL, 21.5 mmol) in dry THF in a round-bottom flask under nitrogen at 0° C. The reaction mixture was allowed to warm to room temperature for 16 h, and the mixture was diluted with NaHCO 3 Dilute with saturated aqueous solution and extract with EtOAc. Separate the organic layer and add MgSO 4 It was dried at 40° C., filtered and the solvent was evaporated in vacuum. The crude product was purified by flash column chromatography on silica gel (80 g, ethyl acetate in heptane 100 / 0 to 20 / 80). The desired fractions were collected and concentrated in vacuum to give intermediate AV-1 as a beige solid 4.8 g (85%).

[0446] Preparation of intermediate AV-2 The reaction was split into two batches of 2.4 g each. Tris(dibenzylideneacetone)dipalladium(0) (0.7 g, 0.77 mmol) and XPhos (0.73 g, 1.53 mmol) were added to a solution of AV-1 (4.32 g, 15.32 mmol) in dry dioxane (31 mL) while bubbling nitrogen in a glass pressure bottle. A 1 M solution of lithium bis(trimethylsilyl)amide in THF (33.7 mL, 33.7 mmol) was then added dropwise and the resulting solution was heated at 80° C. for 3 h. Tris(dibenzylideneacetone)dipalladium(0) (0.7 g, 0.77 mmol), XPhos (0.73 g, 1.53 mmol), and a 1 M solution of lithium bis(trimethylsilyl)amide in THF (33.7 mL, 33.7 mmol) were added with bubbling nitrogen and the reaction mixture was heated at 80 °C for 16 h. The reaction was acidified with 1 N HCl solution and stirred for 30 min. The resultant was then extracted with EtOAc. The aqueous layer was neutralized with 1 N NaOH solution and extracted with DCM. The organic layer was separated and dried (MgSO 4 ), filtered and the solvent was evaporated in vacuo to give intermediate AV-2 as a brown solid, 3.4 g (76%).

[0447] Preparation of intermediate AV-3 The reaction was set up in two batches with the same amount of reactive AV-2. Potassium bicarbonate (0.6 g, 6.04 mmol) and ethyl propionylacetate (0.89 mL, 6.04 mmol) were added to a solution of AV-2 (1.12 g, 4.02 mmol) in ACN (8.1 mL) in a screw-top vial at rt. Bromotrichloromethane (1.19 mL, 12.07 mmol) was then added at room temperature and the mixture was stirred at 80 °C for 16 h. The batches were mixed and worked up together. The mixture was diluted with water and extracted with EtOAc. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The crude was purified by flash chromatography column on silica gel (25 g; EtOAc in heptane 0 / 100 to 35 / 65). The desired fractions were collected and concentrated in vacuo to give intermediate AV-3 as a yellow foam solid 0.42 g (22%).

[0448] Preparation of intermediate AV-4 TFA (9.64 mL, 128.43 mmol) was added to AV-3 (1.06 g, 2.37 mmol) in a round-bottom flask at 0 °C. The mixture was stirred at room temperature for 16 h. The mixture was diluted with NaHCO 3 Neutralized with saturated aqueous solution and extracted with DCM. The organic layer was washed with water and concentrated in vacuo. The resulting material was triturated with DIPE and the solid was filtered to give intermediate AV-4 as a beige solid, 0.6 g (95%).

[0449] Preparation of intermediate AV-5 Isoamylnitrile (CAS[110-46-3], 0.46 mL, 3.38 mmol) and copper(II) chloride (0.318 g, 2.36 mmol) were added to a suspension of AV-4 (0.6 g, 2.25 mmol) in dry ACN (36 mL) in a round-bottom flask at room temperature. The mixture was stirred at reflux for 3 h. Water was added and the mixture was extracted with EtOAc. The organic layer was separated and dried (MgSO 4 ), filtered and the solvent was evaporated in vacuum. The crude was purified by flash chromatography column on silica gel (12 g; 0 / 100 to 10 / 90 EtOAc in heptane). The desired fractions were collected and concentrated in vacuum to give intermediate AV-5 as a white solid 0.315 g (51%).

[0450] Preparation of intermediate AV-6 Iron(III) acetylacetonate (0.051 g, 0.14 mmol) was added to a solution of AV-5 (0.39 g, 1.41 mmol) in dry THF (8 mL) and NMP (0.7 mL) in a round-bottom flask under nitrogen at 0° C. Then, a 3.0 M solution of methylmagnesium bromide in diethyl ether (0.71 mL, 2.12 mmol) was added dropwise and the reaction mixture was stirred at 0° C. for 30 min. TLC showed complete conversion. The reaction was purified by HCl distillation with NH 4 The mixture was quenched with saturated aqueous Cl. The mixture was extracted with ethyl acetate. The organic layer was separated and washed with MgSO. 4It was dried over 100 ml, filtered and the solvent was evaporated in vacuum. The crude product was purified by flash column chromatography on silica gel (12 g; 0 / 100 to 15 / 75 EtOAc in heptane). The desired fractions were collected and concentrated in vacuum to give 0.325 g (91%) of intermediate AV-6 as a white solid.

[0451] Preparation of intermediate AV-7 15% aqueous potassium carbonate (0.88 mL, 0.96 mmol) was added to a solution of AV-6 (0.152 g, 0.6 mmol) in EtOH (2 mL) in a screw-top vial at room temperature. The mixture was stirred at 90° C. for 18 h, and 15% aqueous potassium carbonate (0.88 mL, 0.96 mmol) was added to the reaction mixture. The mixture was stirred at 90° C. for 2 h. Then, 1 M aqueous HCl was added until pH 7. The mixture was concentrated in vacuo to give intermediate AV-7 as a white solid (0.188 g, quantitative).

[0452] Preparation of compound 177 Intermediate AA-3 (0.158 g, 0.4 mmol) was added to a solution of AV-7 (0.187 g, 0.6 mmol), HATU (0.198 g, 0.52 mmol), and DIPEA (0.42 mL, 2.4 mmol) in dry DMF (5 mL) in a round-bottom flask at room temperature. The mixture was stirred at room temperature for 1 h. NaHCO 3 Saturated aqueous solution of sodium hydroxide was added and the mixture was extracted with EtOAc (×3). The combined organic layers were washed with MgSO 4 The mixture was dried over hexane, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (12 g; DCM / MeOH 9:1 0 / 100 to 10 / 90 in DCM). The desired fractions were collected and concentrated in vacuo. The resulting material was triturated with DIPE and the solid was filtered to give compound 177 as a beige solid 0.092 g (41%). 1H NMR(400MHz,DMSO-d6)δ ppm 9.32(d,J=5.5Hz,1H),8.44(br t,J=5.9Hz,1H),7.38(s,1H),7.34(t,J=8.6Hz,1H),7.25(br d,J=13.2Hz,1H),7.20(br d,J=8.3Hz,1H),4.50(d,J=5.8Hz,2H),4.17-4.02(m,2H),3.72-3.58(m,2H),3.02(q,J=7.5Hz,2H),2.56(d,J=2.7Hz,3H),1.28(t,J=7.5Hz,3H).

[0453] Synthesis of Compound 142 and Compound 181 [ka]

[0454] Preparation of intermediate AW-1 6-Chloro-5-fluoronicotinonitrile (CAS[1020253-14-8], 13.57 g, 86.68 mmol), n-boc-1,2-diaminoethane (CAS[57260-73-8], 17.8 mL, 113 mmol), and Et 3 A solution of N (48.2 mL, 347 mmol) in dry DMSO (155 mL) was stirred at 120° C. for 16 h. EtOAc and water were added to the reaction mixture. The layers were separated and the organic layer was washed with brine (5 times), dried over MgSO4, filtered off and evaporated to give an orange solid. The solid was purified by preparative LC (SiOH 30 μm amorphous, 330 g, liquid packing (DCM), mobile phase gradient: heptane / EtOAc 95 / 5 to heptane / EtOAc 40 / 60). The fractions containing the product were combined and evaporated to give 22.55 g of intermediate AW-1 as a yellow solid (93% yield).

[0455] Preparation of intermediate AW-2 NH of AW-1 (3.2 g, 11.42 mmol) purged with nitrogen 3To a solution in (7M in MeOH) (179 mL) was added Raney Nickel (5.3 g, 91.3 mmol), then the reaction mixture was hydrogenated at room temperature under atmospheric pressure for 16 h. The mixture was filtered through a Celite® pad, the Celite® was rinsed with MeOH, and the filtrate was concentrated in vacuo. The residue was diluted in DCM and diluted with MgSO 4 The mixture was filtered through a pad of Celite®, the Celite® was washed with DCM and the filtrate was evaporated in vacuo to give mmotte_8598_1, 3.18 g as a colorless oil (96%).

[0456] Preparation of intermediate AW-3 A round-bottom flask was charged with a solution of AW-2 (3.18 g, 10.96 mmol), DIPEA (2.17 mL, 12.6 mmol), and DMAP (0.04 g, 0.33 mmol) in dry DCM (68.2 mL). The reaction mixture was connected to a nitrogen stream and then cooled to 0° C. Benzyl chloroformate (1.72 mL, 12.06 mmol) was added dropwise. The reaction mixture was then stirred at 0° C. for 1 h. The reaction mixture was quenched by addition of water and stirred at room temperature for 10 min. The aqueous layer was extracted with DCM (2 times). The combined organic layers were dried over MgSO4, filtered off, and evaporated to give 5.38 g crude. Purification was performed by flash chromatography on silica gel (120 g, amorphous SiOH 25-40 μM, DCM / MeOH 100 / 0-97 / 3). The pure fractions were collected and evaporated to yield intermediate AW-3 as a pale beige solid 3.54 g (77%).

[0457] Preparation of intermediate AW-4 AW-3 (3.54 g, 8.46 mmol) was dissolved in Me-THF (65 mL) and AcOH (4.84 mL, 84.59 mmol) at 40° C. Then, isoamylnitrile (5.68 mL, 42.3 mmol) was added dropwise and the mixture was stirred at 40° C. for 2 h. The solution was diluted in EtOAc (60 mL) and water (30 mL) and added with NaHCO 3 Wash with saturated solution (twice), brine, and MgSO 4Drying on HCl and evaporation gave 4.67 g as a pale yellow oil. Purification was carried out by flash chromatography on silica gel (80 g, amorphous SiOH 25-40 μM, DCM / MeOH 100 / 0-97 / 3). Pure fractions were collected and evaporated to give intermediate AW-4 as a yellow oil 3.99 g (97% at 92% purity, used as is in the next step).

[0458] Preparation of intermediate AW-5 Zinc dust (4.29 g, 65.63 mmol) was added to a solution of AW-4 (3.99 g, 8.2 mmol) and AcOH (7 mL, 123.05 mmol) in EtOH (170.9 mL) and water (42.7 mL) at room temperature. The mixture was stirred at room temperature for 1.5 h. Water was added and the aqueous layer was extracted three times with DCM and the combined organic layers were washed with MgSO 4 Drying over 500° C. and concentration under reduced pressure gave 4.12 g of a colorless oil. Purification was carried out by flash chromatography on silica gel (80 g, SiOH amorphous 25-40 μM, DCM / MeOH 100 / 0-97 / 3). Pure fractions were collected and evaporated to give intermediate AW-5, 1.88 g as a colorless oil (50%).

[0459] Preparation of intermediate AW-6 To a solution of AW-5 (1.88 g, 4.08 mmol) in MeOH (40.2 mL) was added TMSCl (4.14 mL, 32.61 mmol) dropwise. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo to give intermediate AW-6, 1.45 g (80%), which was used as such in the next step.

[0460] Preparation of intermediate AW-7 A solution of AW-6 (1.45 g, 3.21 mmol) and B (1.41 mL, 12.85 mmol) in C (32.4 mL) was stirred at 70° C. overnight. The reaction mixture was evaporated. The residue was dissolved in DCM and K 2 CO 3 The aqueous layer was extracted twice with DCM / MeOH (95 / 5). The combined organic layers were diluted with MgSO 4The residue was dried over hexane, filtered off and evaporated to give a yellow solid. Purification was carried out by flash chromatography on silica gel (12 g, amorphous SiOH 25-40 μM, DCM / MeOH 100 / 0-90 / 10). Pure fractions were collected and evaporated to give intermediate AW-7 as a colorless oil, 0.58 g, which was used directly in the next step.

[0461] Preparation of intermediate AW-8 To a solution of AW-7 (0.58 g, 1.69 mmol) and DIPEA (0.87 mL, 5.07 mmol) in dry DCM (14.6 mL) cooled to 5 °C in an ice bath was added 1 M of Tf 2 O (1.69 mL, 1.69 mmol) was added dropwise. The reaction mixture was stirred at 5° C. for 15 min. The reaction mixture was diluted with NaHCO 3 It was immediately quenched with saturated solution. The aqueous layer was extracted with DCM (x2). The combined organic layers were washed with brine (x1) and MgSO 4 The residue was dried over silica gel, filtered off and evaporated. Purification was carried out by flash chromatography on silica gel (24 g, amorphous SiOH 25-40 μM, DCM / MeOH 100 / 0-97 / 3). Pure fractions were collected and evaporated to give intermediate AW-8 as a pale yellow oil that crystallized on standing, 0.59 g (73%).

[0462] Preparation of intermediate AW-9 In a steal bomb, a mixture of AW-8 (0.59 g, 1.24 mmol), 20% palladium hydroxide on carbon, nominally 50% water (0.17 g, 0.12 mmol), and 3 M aqueous HCl (0.41 mL, 1.24 mmol) in MeOH (8.7 mL) and EtOAc (8.7 mL) was heated to 3 bar H 2 The mixture was hydrogenated at room temperature under reduced pressure for 3 hours. The mixture was filtered over a pad of Celite® and washed with MeOH. The filtrate was evaporated and then co-evaporated with MeOH (twice) to give intermediate AW-9, 0.484 g (90%), as a pale beige powder.

[0463] Preparation of compound 142 [ka] HATU (0.15 g, 0.4 mmol) was dissolved in N 2 To a solution of 6-chloro-2-ethylimidazo[1,2-a]pyridine-3-carboxylic acid (CAS[1216142-18-5], 0.078 g, 0.35 mmol) and DIPEA (0.21 mL, 1.21 mmol) in dry Me-THF (2.8 mL) and dry DCM (2 mL) was added under reflux. The solution was stirred at room temperature for 15 min. AW-9 (0.118 g, 0.35 mmol) was then added and the reaction mixture was stirred at room temperature for 16 h. The solvent was then evaporated and the residue was diluted in ethyl acetate and treated with NaHCO 3 The mixture was washed with a saturated aqueous solution of ethyl acetate, water and then with brine. The organic layer was dried over MgSO4, filtered and evaporated in vacuo to give a brown residue. Purification was carried out by flash chromatography on silica gel (40 g, amorphous SiOH 25-40 μM, solid deposit on Celite®, DCM / MeOH 100 / 0-97 / 3). Pure fractions were collected and evaporated to give 0.512 g of a pale yellow powder. Achiral SFC (stationary phase: Whelk-O1(S,S) 5 μm 250×30 mm, mobile phase: 60% CO 2 , MeOH / DCM 80 / 20v / v+0.3%iPrNH 2 Purification was carried out by elution with 142 (40% mixture of 142 and 143). The pure fractions were collected and evaporated to give 0.31 g of a white solid, which was triturated with DIPE and a little heptane, the precipitate was filtered off and dried under vacuum at 60° C. to give compound 142 as a white powder 0.29 g (47%). 1 H NMR(500MHz,DMSO-d6)δ ppm 9.09(d,J=1.4Hz,1H),8.46(t,J=5.8Hz,1H),8.13(br s,1H),7.63-7.75(m,2H),7.47(dd,J=9.4,2.1Hz,1H),7.37(s,1H),4.51(br d,J=5.8Hz 2H),4.13(br t,J=4.5Hz,2H),3.92(t,J=4.8Hz,2H),2.99(q,J=7.5Hz,2H),1.26(t,J=7.5Hz,3H)

[0464] Preparation of Compound 181 [ka] AW-9 (0.09 g, 0.24 mmol) was added to a solution of AJ-2 (0.099 g, 0.38 mmol), HATU (0.12 g, 0.31 mmol), and DIPE (0.25 mL, 1.43 mmol) in dry DMF (5 mL) in a round-bottom flask at room temperature. The mixture was stirred at room temperature for 16 h. The mixture was diluted with NaHCO 3 It was diluted with saturated aqueous solution and extracted with DCM. The organic layer was separated and dried (MgSO 4 ), filtered and the solvent concentrated in vacuo to give a brown oil. The crude product was triturated with DCM and the solid was filtered and dried in vacuo to give compound 181, 0.059 g (45%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 8.62(s,1H),8.51(br t,J=5.8Hz,1H),8.13(s,1H),7.69(dd,J=12.7,1.7Hz,1H),7.37(s,1H),7.22(dd,J=11.7,0.9Hz,1H),4.51(d, J=5.8Hz,2H),4.17-4.10(m,2H),3.96-3.89(m,2H),2.97(q,J=7.5Hz,2H),2.31(s,3H),1.26(t,J=7.5Hz,3H).

[0465] Preparation of Compound 201 [ka] Thus, compound 201 was prepared in the same manner as compound 142 starting from intermediate AI-3 (0.64 mmol) and intermediate AW-9 (0.4 mmol) to yield 0.063 g (30%) of a white solid. 1H NMR(400MHz,DMSO)d 9.19-9.12(m,1H),8.51(d,J=2.4Hz,1H),8.44(t,J=5.8Hz,1H),8.13(s,1H),7.69(dd,J=12.7,1.7Hz,1H),7.36(s,1H),4 .51(d,J=5.8Hz,2H),4.13(t,J=4.6Hz,2H),3.96-3.87(m,2H),3.00(q,J=7.5Hz,2H),2.34(s,3H),1.27(t,J=7.5Hz,3H).

[0466] Synthesis of compound 213 [ka]

[0467] Preparation of intermediate AX-1 N,N-dimethylacetamide dimethyl acetal (0.2 mL; 1.26 mmol) was added to a solution of intermediate D6 (0.3 g; 0.63 mmol) in HFIP (10.8 mL) and the mixture was stirred at room temperature for 20 h. The reaction mixture was diluted with EtOAc and added NaHCO 3 Treat with saturated aqueous solution of MgSO. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with MgSO. 4 The mixture was dried over hexane, filtered and the solvent was removed under reduced pressure to give a colorless oil. Purification was carried out by flash chromatography on silica gel (24 g, amorphous SiOH 25-40 μM, DCM / MeOH 95 / 5-90 / 10). Pure fractions were collected and evaporated to give intermediate AX-1 as a colorless oil, 0.176 g (65%).

[0468] Preparation of compound 213 To a solution of intermediate AX-1 (0.139 g, 0.32 mmol) and DIPEA (0.17 mL, 0.97 mmol) in dry DCM (2.8 mL) cooled to 5 °C in an ice bath was added 1M Tf 2 O (0.32 mL, 0.32 mmol) was added dropwise. The reaction mixture was stirred at 5° C. for 15 min. The reaction mixture was diluted with NaHCO 3It was immediately quenched with saturated solution. The aqueous layer was extracted with DCM (x2). The combined organic layers were washed with brine (x1) and MgSO 4 Dry DCM (2.8 mL) was added to the crude and the solution was cooled to 5° C., then DIPEA (0.056 mL, 0.32 mmol) was added followed by 1M Tf in DCM. 2 O (0.13 mL, 0.13 mmol) was added. The reaction mixture was stirred at 5° C. for 15 min. The reaction mixture was diluted with NaHCO 3 It was immediately quenched with saturated solution. The aqueous layer was extracted with DCM (x2). The combined organic layers were washed with brine (x1) and MgSO 4 The residue was dried over 100° C., filtered off and 0.217 g was obtained as an oil. Purification was carried out by flash chromatography on silica gel (12 g, amorphous SiOH 25-40 μM, DCM / MeOH 100 / 0-97 / 3). The pure fractions were collected and evaporated to give compound 213 as a beige powder 0.093 g (51%). Purification was carried out by flash chromatography on silica gel (12 g, amorphous SiOH 25-40 μM, DCM / MeOH 100 / 0-97 / 3). The pure fractions were collected and evaporated to give compound 213 as a beige powder 0.075 g (41%). This was crystallized from DIPE / heptane, triturated, filtered off and dried under vacuum at 60° C. to give compound 213 as a white powder 0.063 g (35%). 1 H NMR (500MHz, DMSO-d 6 )δ ppm 9.04-9.11(m,1H),8.47(t,J= 5.9Hz ,1H),7.64-7.72(m,1H),7.46(dd,J=9.5,2.1Hz,1H),7.29-7.38(m,1H),7.13-7.27(m,2H),5.12-5.18(m,1H),4.49(d ,J=6.0Hz,2H),3.95-4.06(m,2H),3.67-3.77(m,2H),3.01(q,J=7.5Hz,2H),2.25(s,3H),1.22-1.31(t,J=7.5Hz,3H).

[0469] Synthesis of intermediate AY-3 [ka]

[0470] Preparation of intermediate AY-1 N,N-dimethylacetamide dimethyl acetal (1.68 mL; 10.33 mmol) was added to a solution of intermediate E6 (2 g; 5.16 mmol) in HFIP (88 mL) and the mixture was stirred at room temperature for 20 h. The reaction mixture was diluted with EtOAc and added NaHCO 3 Treat with saturated aqueous solution of MgSO. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with MgSO. 4 It was dried over hexane, filtered and the solvent was removed under reduced pressure. The residue was purified by preparative LC (amorphous SiOH 40 μm, 40 g, DCM / MeOH 95 / 5 to 90 / 10) to give 442 mg of intermediate AY-1 as a colorless residue that crystallized on standing (25%).

[0471] Preparation of intermediate AY-2 Thus, intermediate AY-2 was prepared starting from AY-1 (1.31 mmol) in the same manner as compound 213, yielding 0.388 g (63%) of a beige powder.

[0472] Preparation of intermediate AY-3 In a steal bomb, a mixture of AY-2 (0.39 g, 0.82 mmol), palladium hydroxide on carbon, Pd 20%, nominally 50% water (0.12 g, 0.082 mmol), and 1 M aqueous HCl (0.82 mL, 0.82 mmol) in MeOH (5.8 mL) and EtOAc (5.8 mL) was heated to 5 bar H 2 The mixture was hydrogenated at room temperature under reduced pressure for 1.5 hours. The mixture was filtered over a pad of celite and washed with MeOH. The filtrate was evaporated to give intermediate AY-3, 0.32 g (96%, purity 92%), which was used directly in the next step.

[0473] Preparation of compound 214 [ka] Thus, compound 214 was prepared in the same manner as compound 181 starting from 2-(trifluoromethyl)-imidazo[1,2-A]pyridine-3-carboxylic acid (CAS[73221-19-9], 0.34 mmol) and intermediate AY-3 (0.39 mmol) to yield 0.098 g (52%) of a white powder. 1 H NMR (500MHz, DMSO-d 6 )δ ppm 9.17-9.29(m,1H),8.48-8.58(m,1H),7.73-7.83(m,1H),7.49-7.60(m,1H),7.30(br d,J=8.2Hz,2H),7.13-7.24(m,3H),4.42-4.52(m,2H),4.01(br s,2H),3.84(br d,J=4.3Hz,2H),2.27(s,3H)

[0474] Preparation of Compound 215 [ka] Thus, compound 215 was prepared in the same manner as compound 181 starting from 2-ethyl-6-methylimidazo[1,2-a]pyridine-3-carboxylic acid (CAS[1216036-36-0], 0.34 mmol) and intermediate AY-3 (0.39 mmol) to yield 0.129 g (72%) of a white powder. 1 H NMR(500MHz,DMSO-d6)δ ppm 8.77(s,1H),8.29-8.36(m,1H),7.47-7.54(m,1H),7.27-7.33(m,2H),7.21-7.25(m,1H),7.14-7.19(m,2H),4.41-4.49(m, 2H),4.06-4.09(m,1H),3.96-4.05(m,2H),3.79-3.84(m,2H),2.90-3.02(m,2H),2.31(s,3H)2.26(s,3H),1.20-1.30(m,3H)

[0475] Preparation of compound 217 [ka] Thus, compound 217 was prepared in the same manner as compound 181 starting from intermediate AU-2 (0.31 mmol) and intermediate AY-3 to yield 0.018 g (10%) of a white foam. 1 H NMR (500MHz, DMSO-d 6 )δ ppm 9.17(s,1H),8.40(t,J=6.0Hz,1H),7.27-7.35(m,2H),7.12-7.21(m,2H),4.69-4.77(m,2H),4.41-4.49(m,2H),3.98-4 .04(m,2H),3.91-3.97(m,2H),3.79-3.84(m,2H),2.95-3.01(m,2H),2.89-2.94(m,2H),2.25(s,3H),1.22-1.29(m,4H)

[0476] Preparation of compound 218 [ka] Thus, compound 218 was prepared in the same manner as compound 181 starting from 6-ethyl-2-methylimidazo[2,1-b][1,3]thiazole-5-carboxylic acid (CAS[1131613-58-5], 0.29 mmol) and intermediate AY-3 to yield 0.059 g (38%) of a white foam. 1 H NMR (500MHz, DMSO-d 6 )δ ppm 8.09(t,J=6.0Hz,1H),7.80-7.91(m,1H),7.21-7.32(m,2H),7.08-7.19(m,2H),4.40(d,J=6.0Hz,2H),4.00(t,J=4 .9Hz,2H),3.81(t,J=4.9Hz,2H),2.85(q,J=7.5Hz,2H),2.40-2.46(m,3H),2.22-2.28(m,3H),1.20(t,J=7.5Hz,3H)

[0477] Synthesis of compound 216 [ka]

[0478] Preparation of intermediate AZ-1 Trimethyl orthoisobutyrate (0.2 mL; 1.26 mmol) was added to a solution of intermediate D (0.3 g; 0.63 mmol) in HFIP (10.8 mL) and the mixture was stirred at room temperature for 20 h. The reaction mixture was diluted with EtOAc and diluted with NaHCO 3 Treat with saturated aqueous solution of MgSO. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with MgSO. 4 The mixture was dried over hexane, filtered and the solvent was removed under reduced pressure to give an oil. Purification was carried out by flash chromatography on silica gel (4 g, amorphous SiOH, DCM / MeOH 95 / 5 to 85 / 15). The pure fractions were collected and evaporated to give intermediate AZ-1 as a colorless oil, 0.105 g (37%).

[0479] Preparation of Compound 216 To a solution of AZ-1 (0.11 g, 0.23 mmol) and DIPEA (0.12 mL, 0.69 mmol) in dry DCM (2 mL) cooled to 5 °C in an ice bath was added 1 M Tf 2 O (0.23 mL, 0.23 mmol) was added dropwise. The reaction mixture was stirred at 5° C. for 15 min. The reaction mixture was diluted with NaHCO 3 It was immediately quenched with saturated solution. The aqueous layer was extracted with DCM (x2). The combined organic layers were washed with brine (x1) and MgSO 4 The mixture was dried over ice, filtered off and evaporated. DCM (2 mL) was added to the residue and the solution was cooled to 5° C., then DIPEA (0.04 mL, 0.23 mmol) was added, followed by 1M Tf in DCM. 2 O (0.092 mL, 0.092 mmol) was added. The reaction mixture was stirred at 5° C. for 15 min. The reaction mixture was diluted with NaHCO 3It was immediately quenched with saturated solution. The aqueous layer was extracted with DCM (2x). The combined organic layers were washed with brine (1x), dried over MgSO4 and filtered off to give 0.725g. Purification was carried out by flash chromatography on silica gel (4g, amorphous SiOH 25-40μM, heptane / EtOAc 90 / 10 to 70 / 30). The pure fractions were collected and evaporated to give 0.06g of a beige powder. This was triturated with DIPE and a little heptane, the precipitate was filtered off and dried under vacuum at 60°C to give compound 216 as a white powder 0.040g. 1 H NMR (500MHz, DMSO-d 6 )δ ppm 9.03-9.18(m,1H),8.47(br t,J=5.5Hz,1H),7.63-7.73(m,1H),7.43-7.50(m,1H),7.30-7.38(m,1H),7.16-7.27(m,2H),4.50(br d,J=5.6Hz,2H),3.87-3.94(m,2H),3.80(br s,2H),2.93-3.05(m,3H),1.24-1.32(m,3H),1.14-1.21(m,6H)

[0480] Synthesis of intermediate BA-3 [ka]

[0481] Preparation of intermediate BA-1 Thus, intermediate BA-1 was prepared in the same manner as AZ-1 starting from intermediate E6 (6.45 mol) to give 1.82 g (77%) of a colorless oil.

[0482] Preparation of intermediate BA-2 Thus, intermediate BA-2 was prepared in the same manner as compound 216 starting from BA-1 (4.97 mmol) to yield 1.58 g (58%) of a beige powder.

[0483] Preparation of intermediate BA-3 Thus, intermediate BA-3 was prepared starting from intermediate BA-2 (3.17 mol) in the same manner as AY-3 to give 1.39 g of a beige solid (91%, approximately 90% pure, used as is in the next step).

[0484] The following compounds have also been prepared / prepared according to the methods described herein: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

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[0485]

Table 2

[0486]

Table 3

[0487]

Table 4

[0488] [Table 5]

[0489] [Table 6]

[0490] [Table 7]

[0491] [Table 8]

[0492] [Table 9]

[0493] 5. Biological Assays / Pharmacological Examples Determination of MIC of test compounds against M. tuberculosis. Test 1 Test and reference compounds were dissolved in DMSO and 1 μL of solution was spotted per well of a 96-well plate at 200x the final concentration. Columns 1 and 12 were left without compound, while columns 2-11 were diluted 3x the compound concentration. Frozen stocks of Mycobacterium tuberculosis EH4.0 strain expressing green fluorescent protein (GFP) were prepared and titrated in advance. To prepare the inoculum, one vial of frozen bacterial stock was thawed to room temperature and titrated at 5 × 10 per mL in 7H9 broth. 5 The cells were diluted to 1 × 10 colony forming units. 5200 μL of inoculum, equivalent to 1 colony forming unit per well, was transferred to the entire plate except column 12. 200 μL of 7H9 broth was transferred to the wells in column 12. Plates were incubated at 37 °C in plastic bags to prevent evaporation. After 7 days, fluorescence was measured on a Gemini EM microplate reader at an excitation wavelength of 485 and an emission wavelength of 538 nm, and IC 50 and / or pIC 50 Value (e.g. IC 50 ,I C 90 , pIC 90 , etc.) have been calculated (or can be calculated).

[0494] Test 2 Appropriate solutions of experimental / test compounds and reference compounds were made in 96-well plates with 7H9 medium. Samples of Mycobacterium tuberculosis strain H37Rv were taken from exponentially growing cultures. These were first diluted to obtain an optical density of 0.3 at a wavelength of 600 nm and then diluted 1 / 100 to obtain approximately 5×10 per mL. 5 An inoculum of 5 × 10 colony-forming units was obtained. 4 100 μL of inoculum, equivalent to 1 colony forming unit per well, was transferred to the entire plate except column 12. Plates were incubated at 37°C in plastic bags to prevent evaporation. After 7 days, resazurin was added to all wells. After 2 days, fluorescence was measured on a Gemini EM microplate reader at an excitation wavelength of 543 and an emission wavelength of 590 nm to determine the MIC. 50 Value and / or pIC 50 Value (e.g., IC 50 ,I C 90 , pIC 90 , etc.) have been calculated (or can be calculated).

[0495] Test 3: Time-kill assay The bactericidal or bacteriostatic activity of the compounds can be measured in a time-kill kinetic assay using the broth dilution method. In this assay, a starting inoculum of M. tuberculosis (strains H37Rv and H37Ra) was 10 mL in Middlebrook (1x) 7H9 broth. 6 CFU / mL. Test compounds are tested alone or in combination with other compounds (e.g., compounds with a different mechanism of action, such as cytochrome bd inhibitors) at concentrations ranging from 10-30 μM to 0.9-0.3 μM, respectively. Tubes containing no antibiotic serve as controls for culture growth. Tubes containing microorganisms and test compounds are incubated at 37°C. After 0, 1, 4, 7, 14, and 21 days of incubation, serial dilutions (10 0 ~10 -6 ) and remove a sample for determination of viable count by plating (100 μL) onto Middlebrook 7H11 agar. Plates are incubated at 37° C. for 21 hours and colony counts are determined. Log per mL versus time is calculated. 10 By plotting the CFU, a bactericidal curve can be constructed. The bactericidal effect of the test compounds (either alone or in combination) generally shows a 2-log increase (in CFU per mL) compared to day 0. 10 The potential for drug carryover effects is limited by the use of 0.4% charcoal on the agar plates and eliminated by serial dilutions and counting of colonies at the highest dilution available for plating.

[0496] result Compounds of the invention / examples typically exhibit pIC 50 may be 3 to 10 (for example, 4.0 to 9.0, such as 5.0 to 8.0).

[0497] 6. Biological results The compounds of the examples were tested in Test 1 above (section "Pharmacological Examples") with the following results:

[0498] [Table 10]

[0499] [Table 11]

[0500] [Table 12]

[0501] 7. Further Data for Representative Compounds of the Invention / Examples The compounds of the present invention / examples may have advantages related to in vitro potency, in vitro killing kinetics (i.e. bactericidal effect), PK properties, food effect, safety / toxicity (including hepatotoxicity, coagulation, 5-LO oxygenase), metabolic stability, AmesII negativity, MNT negativity, water-based solubility (and formulation ability), and / or cardiovascular effects, for example in animals (e.g. anesthetized guinea pigs). The following data generated / calculated may be obtained, for example, using standard methods / assays available in the literature or that may be performed by the supplier (e.g. microsomal stability assay-Cyprotex, mitochondrial toxicity (Glu / Gal) assay-Cyprotex, as well as CYP cocktail inhibition assay literature). In some cases, GSH is measured (reactive metabolite, glucuronidation) and observed by LCMS (fragmentation ions) to see if a dihydrodiol is observed, which corresponds to the dihydroxylation of the core heterocycle.

[0502] The following data was generated for compound 1: cLogP=4.3 / TPSA=107.7 CVS (Na Ch, Ca Ch, hERG dof), IC 50 =>10,>10,>10 Cocktail Cyp-450, IC 50 =>20 (excluding CYP3A4, which was inconclusive) CLint(μL / min / mg plot)=(H)29.6 / (M)21.5

[0503] The following data was produced with compound 13: cLogP=3.3 / TPSA=120.7 CVS (Na Ch, Ca Ch, hERG dof), IC 50 =>10,>10,7.4 Cocktail Cyp-450, IC 50 =>20 (excluding CYP3A4 and CY2D6, which were inconclusive) CLint(μL / min / mg plot)=(H)16.3 / (M)13.3

[0504] The following data was produced with compound 20: cLogP=3.75 / TPSA=107.7 CVS (Na Ch, Ca Ch, hERG dof), IC 50 =>10,>10,>10 Cocktail Cyp-450, IC 50 =>20 (excluding CYP3A4, IC 50 = 13.2 μM) CLint(μL / min / mg plot)=(H)56.6 / (M)15.9

[0505] The following data was produced with compound 73: This has been tested and shows no measurement of GSH. cLogP=3.2 / TPSA140.8 CVS (Ca, Na, Herg), IC 50 =>10 Cocktail Cyp-450, IC 50 =>20 (for everything) CLint(μL / min / mg plot)=(H)18 / (M)93

[0506] The following data was generated using compound 9: cLogP=4.4 / TPSA107,8 CVS (Ca, Na, Herg), IC50 =>10 Cocktail Cyp-450, IC 50 =>20 (for everything) CLint(μL / min / mg plot)=(H)19 / (M)41

[0507] The following data was generated using compound 26: cLogP=3.1 / TPSA129.9 CVS (Ca, Na, Herg), IC 50 =>10 Cocktail Cyp-450, IC 50 =>20 (for everything) CLint(μL / min / mg plot)=(H)37 / (M)35

[0508] The following data was generated using compound 16: cLogP=4.4 / TPSA107,8 CVS (Ca, Na, Herg), IC 50 =>10 Cocktail Cyp-450, IC 50 =>20 (for everything) CLint(μL / min / mg plot)=(H)24 / (M)18

[0509] The following data was generated using compound 6: This has been tested and shows no measurement of GSH. cLogP=4.3 / TPSA117 CVS (Ca, Na, Herg), IC 50 =>10 Cocktail Cyp-450, IC 50 =>20 (for everything) CLint(μL / min / mg plot)=(H)37.6 / (M)49

[0510] The following further data / results were generated: Compound 1: Mitochondrial toxicity was found to be low (Glu / Gal assay <3) – therefore, no mitochondrial toxicity alert It had good bioavailability (as shown in rodents)

[0511] Compound 6: Mitochondrial toxicity was found to be low (Glu / Gal assay <3) – therefore, no mitochondrial toxicity alert Did not produce unwanted reactive metabolites (GSH measurements not shown)

[0512] Compound 152: Mitochondrial toxicity was found to be low (Glu / Gal assay <3) – therefore, no mitochondrial toxicity alert It had good bioavailability (as shown in rodents) The formation of reactive metabolites was blocked

[0513] Compound 161: Mitochondrial toxicity was found to be low (Glu / Gal assay <3) – therefore, no mitochondrial toxicity alert It had good bioavailability (as shown in rodents) The formation of reactive metabolites was blocked

[0514] Specific data for compound 161: TPSA=120.6 HTEq Sol(μg / mL)-pH2:33,pH7:<0.02,FaSSIF:5,FeSSIF:16 Cocktail Cyp-450, IC 50 (μM)=>20 Cyp 3A4 induction (% control) - at 1 μM = 3.0 CLint Hep(mL / min / 10 6 number of cells)=(M)0.012 / (R)0.019 / (D)0.0047 / (H)0.0067 PPB(%unbound)(H)1.5 / (M)2.45 AMESII-Negative (score 1) Glu / Gal-negative (ratio <3) No GSH / CN-reactive metabolites Kinase Panel – Negative CTCM (μM) - Clean up to 5 μM CVS (Na Ch, Ca Ch, hERG dof), IC 50 =>10,>10,15.85

[0515] Oral bioavailability of compound 161 in rats Compound 161 was administered PO to rats (5 mg / kg, PEG4000 (solution), 0.5 w / v Methocel (suspension) with the following results obtained for the solution and suspension:

[0516] [Table 13]

[0517] conclusion Thus, the compounds of the invention / examples (e.g. as exemplified by compound 161) may have the following advantages: No cardiotoxicity is observed in vitro (eg, by either CVS results or Glu / Gal assay results). No formation of reactive metabolites is observed (e.g., GSH); and / or For example, there is a relatively high unbound fraction compared to other compounds, such as prior art compounds.

[0518] Certain compounds of the invention / Examples may also have the additional advantage that they do not form degradants which may, for example, induce unwanted or undesirable side effects.

[0519] Compounds of the present invention / examples (e.g., as represented by compound 161) may have the advantage of exhibiting faster oral absorption and improved bioavailability (as can be shown by oral bioavailability data in rats). The present invention includes the following embodiments. [Claim 1] Formula (Ia)

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Claims

1. Formula (Ia) 【Chemistry 1】 [In the formula, Q １ is ═N- or ═C(R ４ )-represents; A is a 5- or 6-membered ring which may be aromatic or non-aromatic and optionally contains 1 or 2 heteroatoms selected from nitrogen and sulfur; B is a 5-membered aromatic ring containing 1 or 2 nitrogen heteroatoms; R １ is halo, -R ６ａ , -O-R ６ｂ , -C(=O)-R ６ｃ , -C(=O)-N(R ７ ) (R ８ ), -CN, and -N(R ７ａ ) R ７ｂ or any two R １ The groups taken together (when attached to adjacent atoms of the A ring) optionally form a 5- or 6-membered ring containing 1 or 2 heteroatoms, and the ring is preferably １～３ Optionally substituted with alkyl substituents; R ２ is halo and -OC １～３ -C optionally substituted with one or more substituents selected from alkyl １～４ is alkyl; R ３ , R ３ａ , R ４ , and R ４ａ Any two of the groups represent H, and the other two are independently H, F, or -C. １～３ Alkyl, and —O—C １～３ represents a substituent selected from alkyl; R ５ is H, -R ９ａ , -C(=O)-R ９ｂ , -SO ２ -R １０ , or Het １ and Any one of X and Y is -CR １１ａ and the others are N or -CR １１ｂ represents; R ６ａ and R ６ｂ are independently hydrogen or halo, —O—CH ３ -C optionally substituted with one or more substituents selected from １～４ represents alkyl; R ６ｃ is -C １～３ is alkyl; R ７ and R ８ is H and -C １～３ independently selected from alkyl; R ７ａ and R ７ｂ are independently H, C １～６ represents an alkyl group, or R ７ａ and R ７ｂ taken together form a 3- to 6-membered ring; R ９ａ is halo, -OC １～３ Alkyl, and Het ２ -C optionally substituted with one or more substituents selected from １～４ represents alkyl; R ９ｂ is hydrogen or -C １～３ alkyl (optionally substituted with one or more fluoro atoms); R １０ is halo and -O-CH ３ -C optionally substituted with one or more substituents selected from １～４ is alkyl; R １１ａ and R １１ｂ are independently H, C １～４ Alkyl (which itself is fluoro, -CN, -R １２ａ , -OR １２ｂ , -N(R １２ｃ ) R １２ｄ and / or -C(O)N(R １２ｅ ) R １２ｆ or -O-C １～４ Alkyl (itself, fluoro, -R １２ｇ , -OR １２ｈ and / or -N(R １２ｉ ) R １２ｊ optionally substituted with one or more substituents selected from R １２ａ , R １２ｂ , R １２ｃ , R １２ｄ , R １２ｅ , R １２ｆ , R １２ｇ , R １２ｈ , R １２ｉ , and R １２ｊ are independently hydrogen or C １～３ represents alkyl (optionally substituted with one or more fluoro atoms); Het １ and Het ２ independently contains 1 or 2 heteroatoms, halo and C １～３ represents a 5- or 6-membered aromatic ring optionally substituted with one or more substituents selected from alkyl (which itself is optionally substituted with one or more fluoro atoms). or a pharma- ceutically acceptable salt thereof.

2. Formula (I) 【Chemistry 2】 [In the formula, A is a 5- or 6-membered ring which may be aromatic or non-aromatic and optionally contains 1 or 2 heteroatoms selected from nitrogen and sulfur; B is a 5-membered aromatic ring containing 1 or 2 nitrogen heteroatoms; R １ is halo, -R ６ａ , -O-R ６ｂ , -C(=O)-R ６ｃ , -C(=O)-N(R ７ ) (R ８ ), -CN, and -N(R ７ａ ) R ７ｂ represents one or more optional substituents independently selected from R ２ is halo and -OC １～３ -C optionally substituted with one or more substituents selected from alkyl １～４ is alkyl; R ３ , R ３ａ , R ４ , and R ４ａ Any two of the groups represent H, and the other two are independently H, F, or -C. １～３ Alkyl, and —O—C １～３ represents a substituent selected from alkyl; R ５ is H, -R ９ａ , -C(=O)-R ９ｂ , -SO ２ -R １０ , or Het １ and Any one of X and Y is -CR １１ａ and the others are N or -CR １１ｂ represents; R ６ａ and R ６ｂ are independently halo and -O-CH ３ -C optionally substituted with one or more substituents selected from １～４ represents alkyl; R ６ｃ is -C １～３ is alkyl; R ７ and R ８ is H and -C １～３ independently selected from alkyl; R ７ａ and R ７ｂ are independently H, C １～６ represents an alkyl group, or R ７ａ and R ７ｂ taken together form a 3- to 6-membered ring; R ９ａ is halo, -OC １～３ Alkyl, and Het ２ -C optionally substituted with one or more substituents selected from １～４ represents alkyl; R ９ｂ is hydrogen or -C １～３ alkyl (optionally substituted with one or more fluoro atoms); R １０ is halo and -O-CH ３ -C optionally substituted with one or more substituents selected from １～４ is alkyl; R １１ａ and R １１ｂ are independently H, C １～４ Alkyl (which itself is fluoro, -CN, -R １２ａ , -OR １２ｂ , -N(R １２ｃ ) R １２ｄ and / or -C(O)N(R １２ｅ ) R １２ｆ or -O-C １～４ Alkyl (itself, fluoro, -R １２ｇ , -OR １２ｈ and / or -N(R １２ｉ ) R １２ｊ optionally substituted with one or more substituents selected from R １２ａ , R １２ｂ , R １２ｃ , R １２ｄ , R １２ｅ , R １２ｆ , R １２ｇ , R １２ｈ , R １２ｉ , and R １２ｊ are independently hydrogen or C １～３ represents alkyl (optionally substituted with one or more fluoro atoms); Het １ and Het ２ independently contains 1 or 2 heteroatoms, halo and C １～３ represents a 5- or 6-membered aromatic ring optionally substituted with one or more substituents selected from alkyl (which itself is optionally substituted with one or more fluoro atoms). or a pharma- ceutically acceptable salt thereof.

3. There may be no substituents on the A ring, or one or two R １ Substituents may be present; R １ (if present) is F, Cl, -R ６ａ , -O-R ６ｂ , -C(=O)-R ６ｃ , -C(=O)-N(R ７ ) (R ８ ), -CN, and -N(R ７ａ ) R ７ｂ represents one or two substituents independently selected from R ６ａ is -O-C １～２ C optionally substituted with a substituent selected from alkyl １～３ represents alkyl; R ６ｂ and R ６ｃ is C １～３ represents alkyl; R ７ and R ８ are independently hydrogen or C １～３ represents alkyl; R ７ａ and R ７ｂ The compound according to claim 1 or 2, wherein:

4. Ring A is as follows: 【Chemistry 3】 The compound according to any one of claims 1 to 3, which is represented as follows:

5. Ring B is the following: 【Chemistry 4】 The compound according to any one of claims 1 to 4, which is represented as follows:

6. The composite ring system, i.e. ring A and ring B, may be: 【Chemistry 5】 The compound according to any one of claims 1 to 5, which may be represented as follows:

7. R ２ is -O-C １～２ A straight chain -C optionally substituted with one or more substituents selected from alkyl １～４ is alkyl; R ３ , R ３ａ , R ４ , and R ４ａ Any two of the groups represent H, and the other two are independently H, F, or -CH ３ , and -OCH ３ represents a substituent selected from R ５ is H, -R ９ａ , -C(=O)-R ９ｂ , -SO ２ -R １０ , or Het １ and R ９ａ is unsubstituted or He ２ C substituted with one substituent selected from １～３ represents alkyl; R ９ｂ is H or C optionally substituted with one or more fluoro atoms １～３ represents alkyl; R １０ is fluoro and -OC １～２ C optionally substituted with one or more substituents selected from alkyl １～４ represents alkyl, and therefore R １０ is -CF ３ , -CH ３ , i-propyl, -CH ２ C(H)(CH ３ ) ２ (i-butyl), -CH ２ CH ２ -OCH ３ and / or Het １ and Het ２ represents a 5- or 6-membered heteroaryl ring containing 1 or 2 heteroatoms independently selected from nitrogen and sulfur, which ring is unsubstituted or １～３ alkyl, itself optionally substituted with one or more fluoro atoms, and thus Het １ and Het ２ are independently -CF ３ A compound according to any one of claims 1 to 6, which may represent a thiazolyl group optionally substituted with a substituent.

8. Any one of X and Y is -CR １１ａ and the others are N or -CR １１ｂ represents; R １１ａ Or R １１ｂ But, C １～４ When R represents alkyl, １１ａ Or R １１ｂ is unsubstituted or is -CN, -OR １２ｂ and / or -N(R １２ｃ ) R １２ｄ may be substituted with; R １２ｂ is H or C １～２ represents alkyl; R １２ｃ and R １２ｄ is independently １～２ may represent alkyl, Therefore, R １１ａ Or R １１ｂ But, C １～４ When R represents alkyl, １１ａ Or R １１ｂ is -CH ３ , -CH ２ CH ３ , -CH ２ CH ２ -OH, -CH ２ CH ２ -OCH ３ , -C(H)(CH ３ ) ２ , -CH ２ -N(CH ３ ) ２ , or -CH ２ -CN; R １１ａ Or R １１ｂ But -O-C １～４ When R represents alkyl, １１ａ Or R １１ｂ may be unsubstituted, -OC １～２ A compound according to any one of claims 1 to 7, which may represent alkyl. 【Request 9】 【Chemical 100】 2. The compound of claim 1, wherein:

10. A compound according to any one of claims 1 to 9 for use as a medicament.

11. A pharmaceutical composition comprising a pharma- ceutically acceptable carrier and, as an active ingredient, a therapeutically effective amount of a compound according to any one of claims 1 to 9.

12. A compound according to any one of claims 1 to 9 for use in the treatment of a mycobacterial infection.

13. Use of a compound according to any one of claims 1 to 9 for the manufacture of a medicament for the treatment of a mycobacterial infection.

14. A pharmaceutical composition for the treatment of mycobacterial infections, comprising a compound according to any one of claims 1 to 9.

15. A pharmaceutical composition comprising: (a) a compound according to any one of claims 1 to 9; and (b) in combination with one or more other antimycobacterial agents.

16. A product containing (a) a compound according to any one of claims 1 to 9, and (b) one or more other antimycobacterial agents as a combined preparation for simultaneous, separate or sequential use in the treatment of bacterial infections.

17. A process for preparing a compound of formula (I) according to claim 2 or a compound of formula (Ia) according to claim 1, said process comprising: (i) Formula (XIV), 【Chemistry 6】 wherein R 1 , R 2 , A and B are as defined in claim 1 , and a compound of formula (XV) or (XVA), respectively 【Chemistry 7】 with a compound of formula (I) wherein R 3 , R 3a , R 4 , R 4a , R 5 , Q 1 , X and Y are as defined in claim 1 ; (ii) Formula (XVII) or (XVIIA), respectively 【Chemistry 8】 wherein R 1 , R 2 , R 3 , R 3a , R 4 , R 4a , A, B, and Q 1 are as defined in claim 1 , and R １２ represents a leaving group selected from chloro, bromo, iodo, and sulfonate groups, with a compound of formula (XVI) 【Chemistry 9】 [In the formula, R ５ is as defined in claim 1. coupling with a compound of formula (I); (iii) for compounds of formula (I) or (Ia) [wherein X represents N], 【Chemistry 10】 wherein R 1 , R 2 , R 3 , R 3a , R 4 , R 4a , R 5 , A, B and Q 1 are as defined in claim 1 , reacting a compound of formula (XIX) R １１ｘ C(OCH) ３ ) ３ (XIX) [In the formula, R １１ｘ is R １１ａ Or R １１ｂ and R 11a and R 11b are as defined in claim 1 ; (iv) for compounds of formula (I) or (Ia) [wherein Y represents N], a compound of formula (XX) or (XXA), respectively 【Chemistry 11】 in which R 1 , R 2 , R 3 , R 3a , R 4 , R 4a , R 5 , A, B and Q 1 are as defined in claim 1 , with a compound of formula (XIX) as defined above; and / or (v) a compound represented by the formula (I) or (Ia), ５ is -C(=O)-R ９ｂ , -S(O) ２ -R １０ , or Het １ For the preparation of a compound of formula (I) ５ represents H], and a corresponding compound of formula (XXI), LG １ -Z (XXI) [In the formula, Z is —C(═O)—R ９ｂ , -S(O) ２ -R １０ , or Het １ represents LG １ represents a leaving group selected from chloro, bromo, iodo, and sulfonate groups, where R 9b , R 10 , and Het 1 are as defined in claim 1 , and Het １ In the case of LG １ is attached to a suitable C atom of the heteroaromatic ring The method includes:

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