Antibacterial compound

Abstract

The present invention relates to the following compounds, as defined in their entirety in the specification, and wherein these compounds can be used as medicaments, for example for use in the treatment of tuberculosis.

Description

[0001] The present invention relates to novel compounds. The present invention also relates to compounds which are used as medicaments and further for use in the treatment of bacterial diseases, including diseases caused by pathogenic mycobacteria such as Mycobacterium tuberculosis. Such compounds can act by interfering with ATP synthase in Mycobacterium tuberculosis, wherein inhibition of cytochrome bc 1 activity serves as the primary mode of action. Thus, such compounds are primarily anti-tuberculosis drugs. Background Art

[0002] Mycobacterium tuberculosis is the causative agent of tuberculosis (TB), a serious and potentially fatal infection that is distributed worldwide. Estimates from the World Health Organization indicate that more than 8 million people are infected with TB each year, and 2 million people die from tuberculosis each year. In the last decade, TB cases have increased by 20% worldwide, becoming the heaviest burden in most poor communities. If these trends continue, the TB incidence rate will increase by 41% in the next two decades. Since the introduction of effective chemotherapy fifty years ago, TB remains the leading infectious cause of adult death in the world after AIDS. Complicating the TB epidemic is the increasing trend of multi-drug resistant strains, as well as the lethal co-infection with HIV. People who are HIV positive and infected with TB are 30 times more likely to develop active TB than those who are HIV negative, and TB is the cause of death in one out of every three people with HIV / AIDS worldwide.

[0003] Existing methods for the treatment of tuberculosis all involve combinations of multiple agents. For example, the regimen recommended by the US Public Health Service is a combination of isoniazid, rifampin, and pyrazinamide for two months, followed by isoniazid and rifampin alone for an additional four months. In patients infected with HIV, these drugs are continued for an additional seven months. For patients infected with multi-drug resistant strains of Mycobacterium tuberculosis, agents (such as ethambutol, streptomycin, kanamycin, amikacin, capreomycin, ethionamide, cycloserine, ciprofloxacin, and ofloxacin) are added to the combination therapy. There is neither an effective single agent in the clinical treatment of tuberculosis, nor any combination of agents that offers the possibility of a therapy with a duration of less than six months.

[0004] There is a high medical need for new drugs that improve current treatments by implementing regimens that facilitate patient and provider compliance. Shorter regimens and those that require less supervision are the best ways to meet this need. When four drugs are given together, during the intensive, or bactericidal, phase, most of the benefit from treatment occurs in the first 2 months; the bacterial burden is greatly reduced and the patient becomes non-infectious. A continuation, or sterilization, phase of 4 to 6 months is needed to eliminate persistent bacilli and minimize the risk of relapse. An effective sterilizing drug that shortens treatment to 2 months or less would be extremely beneficial. Drugs that facilitate compliance by requiring less intensive supervision are also needed. Clearly, compounds that reduce both the overall length of treatment and the frequency of drug administration would provide the greatest benefit.

[0005] Complicating the TB epidemic is the increasing incidence of multi-drug resistant strains, or MDR-TB. Up to four percent of all cases worldwide are thought to be MDR-TB - those that are resistant to isoniazid and rifampin, the two most effective drugs in the four-drug standard. When untreated, MDR-TB is fatal and cannot be adequately treated by standard therapy, so treatment requires up to two years of "second-line" drugs. These drugs are generally toxic, expensive and only marginally effective. In the absence of effective therapy, infectious MDR-TB patients continue to spread the disease, creating new infections with MDR-TB strains. There is a high medical need for new drugs with novel mechanisms of action that may exhibit activity against drug-resistant, particularly MDR, strains.

[0006] As used above or below, the term "drug-resistant" is a term well understood by those skilled in microbiology. A drug-resistant mycobacterium is a mycobacterium that is no longer susceptible to at least one previously effective drug; the mycobacterium has developed the ability to resist the antibiotic attack of at least one previously effective drug. A drug-resistant strain can pass on its resistance to its progeny. The tolerance can be attributed to random genetic mutations in the bacterial cell that alter its sensitivity to a single drug or to different drugs.

[0007] MDR tuberculosis is a specific form of drug-resistant tuberculosis attributable to bacteria that are resistant to at least isoniazid and rifampin (resistant or non-resistant to other drugs), isoniazid and rifampin being the two most powerful anti-TB drugs currently available. Accordingly, whenever used above or below, "drug-resistant" includes multi-drug resistant.

[0008] Another factor in controlling the TB epidemic is the problem of latent TB. Despite decades of tuberculosis (TB) control programs, approximately two billion people are still infected asymptomatically with Mycobacterium tuberculosis. Approximately 10% of these individuals are at risk of developing active TB during their lifetime. The global TB epidemic has been exacerbated by the infection of HIV patients with TB and the emergence of multidrug-resistant TB strains (MDR-TB). Reactivation of latent TB is a high-risk factor for disease development and results in death in 32% of HIV-infected individuals. To control the TB epidemic, new drugs that can kill dormant or latent bacilli are needed. Dormant TB can be reactivated to cause disease by several factors, such as the suppression of host immunity by the use of immunosuppressive agents, such as antibodies against tumor necrosis factor α or interferon-γ. In the case of HIV-positive patients, the only prophylactic treatment available for latent TB is a two- to three-month regimen of rifampicin and pyrazinamide. The efficacy of this treatment regimen is still unclear, and furthermore, the length of treatment is an important constraint in resource-limited settings. Therefore, there is a strong need for new drugs that can act as chemoprophylactic agents for individuals with latent TB bacilli.

[0009] Mycobacterium tuberculosis enters healthy individuals by inhalation; they are phagocytosed by alveolar macrophages in the lungs. This results in an effective immune response and the formation of granulomas, which consist of macrophages infected with Mycobacterium tuberculosis surrounded by T cells. After a period of six to eight weeks, the host immune response causes the death of infected cells by necrosis and the accumulation of caseous material in some extracellular bacilli, epithelioid cells, and the surrounding layer of lymphoid tissue surrounded by macrophages. In the case of healthy individuals, most mycobacteria are killed in these settings, but a small fraction of bacilli still survive and are thought to exist in a non-replicating, low-metabolic state and are resistant to killing by anti-TB drugs (such as isoniazid). These bacilli can persist in the altered physiological environment and even throughout an individual's lifetime without showing any clinical symptoms of disease. However, in 10% of these cases, these latent bacilli can reactivate to cause disease. One of the hypotheses regarding the development of these refractory bacteria is the pathophysiological environment in human lesions, namely reduced oxygen tension, nutritional restriction, and acidic pH. It has been hypothesized that these factors render these bacteria phenotypically resistant to the major anti-mycobacterial drugs.

[0010] In addition to managing the TB epidemic, there is also the emerging problem of resistance to first-line antibiotics. Some important examples include penicillin-resistant Streptococcus pneumoniae, vancomycin-resistant Enterococcus, methicillin-resistant Staphylococcus aureus, and multidrug-resistant Salmonella.

[0011] The consequences of antibiotic tolerance are severe. Infections caused by tolerant microorganisms do not respond to treatment, resulting in prolonged illness and a greater risk of death. Treatment failure also leads to longer-term infectivity, which increases the number of infected people in the community and thus exposes the general population to the risk of contracting a tolerant strain infection.

[0012] Hospitals are a key component of the antimicrobial tolerance problem worldwide. The combination of highly susceptible patients, concentrated and prolonged use of antimicrobials, and cross-infection has resulted in infections with highly tolerant bacterial pathogens.

[0013] Self-medication with antimicrobials is another major factor contributing to tolerance. Self-medication antimicrobials can be unnecessary, often inappropriately administered, or may not contain the appropriate amount of active drug.

[0014] Patient compliance with recommended treatment is another major problem. Patients forget to take their medication, discontinue their treatment when they start to feel better, or may not be able to afford the full course, thereby creating an ideal environment for the microorganisms to adapt rather than be killed.

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

[0016] Therefore, there is a high need for new compounds for the treatment of bacterial infections, especially mycobacterial infections (including drug-resistant and latent mycobacterial infections) and also other bacterial infections, especially those caused by tolerant bacterial strains.

[0017] For example, anti-infective compounds for the treatment of tuberculosis have been disclosed in international patent application WO 2011 / 113606. Such literature focuses on compounds that prevent the proliferation of Mycobacterium tuberculosis within host macrophages and relates to compounds having a bicyclic core, such as imidazopyridine, which are linked (e.g., through an amino moiety) to, for example, an optionally substituted benzyl group.

[0018] International patent application WO 2014 / 015167 also discloses compounds that are disclosed as having potential use in the treatment of tuberculosis. Such compounds disclosed herein have as an essential element a bicyclic (5,5-fused bicyclic) ring that is substituted by a linker group (e.g., an amino group), which linker group itself may be attached to another bicyclic or aromatic group. Such compounds in this literature do not contain a series of more than three rings.

[0019] The specific compounds tested against Mycobacterium tuberculosis were identified in the journal article "Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis" by Pethe et al. in Nature Medicine, 19, 1157-1160 (2013). Compound Q203 is described below.

[0020]

[0021] This clinical candidate was also discussed in the journal article in J. Medicinal Chemistry 2014, 57(12), pages 5293 - 5305. It is alleged to have activity against MDR tuberculosis at an MIC 50 of 0.28 nM within macrophages and also has activity against the strain Mycobacterium tuberculosis H37Rv. Positive control data (using the known anti-TB compounds bedaquiline, isoniazid, and moxifloxacin) were also reported. The document also proposed a mode of action based on studies of mutants. It is hypothesized to act by interfering with ATP synthase in Mycobacterium tuberculosis, and inhibition of cytochrome bc 1 activity is the main mode of action. Cytochrome bc 1 is an essential component of the electron transport chain required for ATP synthesis. It appears that Q203 has high activity against both replicating and non-replicating bacteria.

[0022] International Patent Application WO 2015 / 014993 also discloses compounds having activity against Mycobacterium 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 different compounds as kinase regulators.

[0023] The object of the present invention is to provide compounds for use in the treatment of bacterial diseases, especially those caused by pathogenic bacteria such as Mycobacterium tuberculosis (including latent diseases and including drug-resistant Mycobacterium tuberculosis strains). Such compounds are also novel and are capable of acting by interfering with ATP synthase in Mycobacterium tuberculosis, where inhibition of cytochrome bc 1 activity is considered to be the main mode of action. Summary of the Invention

[0024] Compounds of formula (I) are now provided,

[0025]

[0026] wherein

[0027] 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;

[0028] B is a 5-membered aromatic ring containing 1 or 2 nitrogen heteroatoms;

[0029] R 1 represents one or more (e.g., one, two or three) optional substituents independently selected from halo (e.g., Cl, F), -R 6a , -O-R 6b , -C(=O)-R 6c , -C(=O)-N(R 7 )(R 8 ), -CN and -N(R 7a )R 7b ;

[0030] R 2 is -C 1-4 alkyl, which is optionally substituted with one or more substituents selected from halo and -OC 1-3 alkyl;

[0031] R 3 , R 3a , R 4 and R 4a any two of which represent H, and the other two independently represent substituents selected from H, F, -C 1-3 alkyl and -O-C 1-3 alkyl;

[0032] R 5 is H, -R 9a , -C(=O)-R 9b , -SO 2 -R 10 or Het 1 ;

[0033] Either X or Y represents -CR 11a , and the other represents N or -CR 11b ;

[0034] R 6a and R 6b independently represent -C 1-4 alkyl, which is optionally substituted with substituents selected from halo (e.g., F) and -O-CH 3substituted by one or more substituents;

[0035] R 6c is -C 1-3 alkyl;

[0036] R 7 and R 8 are independently selected from H and -C 1-3 alkyl;

[0037] R 7a and R 7b independently represent H, C 1-6 alkyl, or R 7a and R 7b are joined together to form a 3- to 6-membered ring;

[0038] R 9a represents -C 1-4 alkyl, which is optionally substituted by one or more substituents selected from halo, -OC 1-3 alkyl and Het 2 ;

[0039] R 9b is hydrogen or -C 1-3 alkyl (optionally substituted by one or more fluorine atoms);

[0040] R 10 is -C 1-4 alkyl, which is optionally substituted by one or more substituents selected from halo (e.g., F) and -O-CH 3 ;

[0041] R 11a and R 11b independently represent H, C 1-4 alkyl (which is itself optionally substituted by one or more, e.g., one, substituents selected from fluorine, -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 (which is itself optionally substituted by one or more, e.g., one, substituents selected from fluorine, -R 12g , -OR 12h and / or -N(R 12i )R 12j );

[0042] R 12a 、R 12b 、R 12c 、R 12d 、R12e , R 12f , R 12g , R 12h , R 12i and R 12j independently represent hydrogen or C 1-3 alkyl (optionally substituted by one or more fluorine atoms);

[0043] Het 1 and Het 2 independently represent a 5- or 6-membered aromatic ring containing one or two heteroatoms preferably selected from nitrogen and sulfur, optionally substituted by one or more substituents selected from halo and C 1-3 alkyl (which itself is optionally substituted by one or more fluorine atoms),

[0044] or a pharmaceutically acceptable salt thereof,

[0045] These compounds may be referred to herein as "the compounds of the invention".

[0046] In an embodiment, there is also provided a compound having the formula (Ia)

[0047]

[0048] wherein

[0049] Q 1 represents =N- or =C(R 4 );

[0050] 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;

[0051] B is a 5-membered aromatic ring containing 1 or 2 nitrogen heteroatoms;

[0052] R 1 represents one or more (e.g., one, two or three) optional substituents independently selected from halo (e.g., Cl, F), -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 groups may together (when attached to adjacent atoms of the A ring) form a 5- or 6-membered ring which optionally contains one or two heteroatoms and which is optionally substituted by one or two C 1-3 alkyl substituents;

[0053] R 2 is -C 1-4 alkyl, optionally substituted with one or more substituents selected from halo and -OC 1-3 alkyl;

[0054] R 3 , R 3a , R 4 and R 4a any two of which represent H, and the other two independently represent substituents selected from H, F, -C 1-3 alkyl and -O-C 1-3 alkyl;

[0055] R 5 is H, -R 9a , -C(=O)-R 9b , -SO 2 -R 10 or Het 1 ;

[0056] Either X or Y represents -CR 11a , and the other represents N or -CR 11b ;

[0057] R 6a and R 6b independently represent hydrogen or -C 1-4 alkyl, optionally substituted with one or more substituents selected from halo (e.g., F), -O-CH 3 and phenyl;

[0058] R 6c is -C 1-3 alkyl;

[0059] R 7 and R 8 independently selected from H and -C 1-3 alkyl;

[0060] R 7a and R 7b independently represent H, C 1-6 alkyl, or R 7a and R 7b are joined together to form a 3- to 6-membered ring;

[0061] R 9a represents -C 1-4 alkyl, optionally substituted with one or more substituents selected from halo, -OC 1-3 alkyl and Het 2 ;

[0062] R 9b is hydrogen or -C 1-3alkyl (optionally substituted with one or more fluorine atoms);

[0063] R 10 is -C 1-4 alkyl, which is optionally substituted with one or more substituents selected from halo (e.g., F) and -O-CH 3 ;

[0064] R 11a and R 11b independently represent H, C 1-4 alkyl (which is itself optionally substituted with one or more, e.g., one substituent selected from fluorine, -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 (which is itself optionally substituted with one or more, e.g., one substituent selected from fluorine, -R 12g , -OR 12h and / or -N(R 12i )R 12j );

[0065] R 12a 、R 12b 、R 12c 、R 12d 、R 12e 、R 12f 、R 12g 、R 12h 、R 12i and R 12j independently represent hydrogen or C 1-3 alkyl (optionally substituted with one or more fluorine atoms);

[0066] Het 1 and Het 2 independently represent a 5- or 6-membered aromatic ring containing one or two heteroatoms preferably selected from nitrogen and sulfur, optionally substituted with one or more substituents selected from halo and C 1-3 alkyl (which is itself optionally substituted with one or more fluorine atoms),

[0067] or a pharmaceutically acceptable salt thereof,

[0068] These compounds may also be referred to herein as "compounds of the invention".

[0069] Pharmaceutically acceptable salts include acid addition salts and base addition salts. Such salts can be formed by conventional means, for example, by reacting the free acid or free base form of a compound of Formula I with one or more equivalents of a suitable acid or base, optionally in a solvent or in a medium in which the salt is insoluble, followed by removal of the solvent or the medium using standard techniques (e.g., in vacuo, by lyophilization or by filtration). Salts can also be prepared, for example, by exchanging the counterion of a compound of the invention in salt form with another counterion using a suitable ion exchange resin.

[0070] As mentioned above, pharmaceutically acceptable acid addition salts are meant to include the therapeutically active non-toxic acid addition salt forms that can be formed by a compound of Formula (I). These pharmaceutically acceptable acid addition salts can be conveniently obtained by treating the base form with 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, propionic acid, glycolic 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, cyclohexanesulfamic acid, salicylic acid, p-aminosalicylic acid, pamoic acid, and the like.

[0071] For the purposes of the present invention, solvates, prodrugs, N-oxides, and stereoisomers of the compounds of the present invention are also included within the scope of the present invention.

[0072] The term "prodrug" of a compound of the present invention includes any compound which, upon oral or parenteral administration, is metabolized in vivo to form experimentally-detectable amounts of the compound and within a predetermined time (e.g., within a dosing interval between 6 and 24 hours (i.e., one to four times a day)). For the avoidance of doubt, the term "parenteral" administration includes all forms of administration other than oral administration.

[0073] Prodrugs of the compounds of the present invention can be prepared by modifying the functional groups present in the compound in such a way that these modifications are cleaved in vivo when the prodrug is administered to a mammalian subject. Generally, these modifications are accomplished by synthesizing the parent compound with a prodrug substituent. Prodrugs include compounds of the present invention in which a hydroxyl, amino, mercapto, carboxyl, or carbonyl group in the compound of the present invention is attached to any group that can be cleaved in vivo to regenerate the free hydroxyl, amino, mercapto, carboxyl, or carbonyl group, respectively.

[0074] 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” pages 1-92, Elsevier, New York - Oxford (1985).

[0075] The compounds of the present invention may contain double bonds and may thus exist as E (trans) and Z (cis) geometric isomers with respect to each individual double bond. Positional isomers may also be included among these compounds of the present invention. All such isomers (e.g., including cis and trans forms if the compound of the present invention contains one double bond or a fused ring) and mixtures thereof are included within the scope of the present invention (e.g., both a single positional isomer and a mixture of positional isomers may be included within the scope of the present invention).

[0076] 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 terms “tautomer” or “tautomeric form” refer to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also called prototropic tautomers) include interconversions that occur via proton transfer, such as keto - enol and imine - enamine isomerization. Valence tautomers include interconversions that result from the reorganization of some bonding electrons.

[0077] The compounds of the present invention may also contain one or more asymmetric carbon atoms and may thus exhibit optical activity and / or diastereoisomerism. Diastereoisomers can be separated using conventional techniques, such as chromatography or fractional crystallization. Racemic mixtures or other mixtures of these compounds can be separated to resolve the different stereoisomers by using conventional techniques, such as fractional crystallization or HPLC. Alternatively, the desired optically active isomers can be prepared by reaction of an appropriate optically active starting material under conditions that do not cause racemization or epimerisation (i.e., the ‘chiral pool’ method); by derivatization (i.e., resolution, including dynamic resolution) of an appropriate starting material with a ‘chiral auxiliary’ (e.g., with a pure chiral acid) that can be removed at a suitable stage, followed by separation of the diastereoisomer derivatives by conventional means (e.g., chromatography); or by reaction with an appropriate chiral reagent or chiral catalyst, all under conditions known to the person skilled in the art.

[0078] All stereoisomers (including, but not limited to, diastereoisomers, enantiomers and atropisomers) and mixtures thereof (e.g., racemic mixtures) are included within the scope of the present invention.

[0079] In those structures shown herein, where the stereochemistry at any particular chiral atom is not specified, then all stereoisomers are considered to be compounds of the present invention and are included among the compounds of the present invention. Where the stereochemistry is specified by solid wedges or dashed lines representing a particular configuration, then the stereoisomer is as specified and defined.

[0080] The compounds of the present invention can exist in unsolvated forms as well as solvated forms with pharmaceutically acceptable solvents (e.g., water, ethanol, etc.), and it is intended that the invention include both solvated and unsolvated forms.

[0081] The present invention also includes isotopically labeled compounds of the present invention which are identical to those recited herein, but in fact have one or more atoms replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature (or the most abundant one found in nature). All isotopes of any specific atom or element as specified herein are considered to be within the scope of the compounds of the present invention. Exemplary isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, e.g., 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 I. Certain isotopically labeled compounds of the present invention (e.g., those labeled with 3 H and 14 C) are useful in the compounds and for substrate tissue distribution assays. Tritiated ( 3 H) and carbon-14 ( 14 C) isotopes are useful because they are readily prepared and detected. In addition, use of heavier isotopes (e.g., deuterium) (i.e., 2H) Substitution can provide certain therapeutic advantages due to greater metabolic stability (e.g., increased in vivo half-life or reduced dose requirements) and can thus be preferred in some circumstances. Positron-emitting isotopes (e.g., 15 O, 13 N, 11 C, and 18 F) can be used in positron emission tomography (PET) studies to examine substrate receptor occupancy. The isotopically labeled compounds of the invention can generally be prepared by procedures similar to those disclosed in the specification / or in the examples below, by substituting non-isotopically labeled reagents with isotopically labeled reagents.

[0082] Unless otherwise specified, the C 1-q alkyl group (where q is the upper limit of the range) can be straight-chain, or, when there are a sufficient number (i.e., if appropriate, at least two or three) of carbon atoms, can be branched and / or cyclic (thus forming a C 3-q -cycloalkyl group). Such a cycloalkyl group can be monocyclic or bicyclic and can further be bridged. In addition, when there are a sufficient number (i.e., at least four) of carbon atoms, such a group can also be partially cyclic. Such an alkyl group can also be saturated, or when there are a sufficient number (i.e., at least two) of carbon atoms, can be unsaturated (e.g., forming a C 2-q alkenyl or a C 2-q alkynyl group).

[0083] Particularly mentionable C 3-q cycloalkyl groups (where q is the upper limit of the range) can be monocyclic or bicyclic alkyl groups, and such cycloalkyl groups can further be bridged (thus forming, for example, a fused ring system, such as three fused cycloalkyl groups). Such a cycloalkyl group can be saturated or unsaturated with one or more double bonds (e.g., forming a cycloalkenyl group). Multiple substituents can be attached at any site on the cycloalkyl group. In addition, when there are a sufficient number (i.e., at least four), such a cycloalkyl group can also be partially cyclic.

[0084] When used herein, the term "halo" preferably includes fluorine, chlorine, bromine, and iodine.

[0085] When mentioned herein, heterocyclic groups can include aromatic or non-aromatic heterocyclic groups and thus encompass heterocycloalkyl and heteroaryl. Similarly, an "aromatic or non-aromatic 5- or 6-membered ring" can be a heterocyclic group (as well as a carbocyclic group) having 5 or 6 members in the ring.

[0086] Heterocycloalkyl groups that may be mentioned include non-aromatic monocyclic and bicyclic heterocycloalkyl groups, wherein at least one (e.g., one to four) of these atoms in the ring system is not carbon (i.e., a heteroatom), and wherein the total number of atoms in the ring system is between 3 and 20 (e.g., between three and ten, e.g., between 3 and 8, e.g., 5- to 8-). Such heterocycloalkyl groups may also be bridged. In addition, such heterocycloalkyl groups may be saturated or unsaturated containing one or more double bonds and / or triple bonds, thus forming, for example, C 2-q heterocycloalkenyl (where q is the upper limit of the range) groups. C 2-q Heterocycloalkyl groups that may be mentioned include 7-azabicyclo[2.2.1]heptyl, 6-azabicyclo[3.1.1]heptyl, 6-azabicyclo[3.2.1]-octyl, 8-azabicyclo-[3.2.1]octyl, 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, 7-oxabicyclo[2.2.1]heptyl, 6-oxabicyclo-[3.2.1]octyl, oxetanyl, oxiranyl, piperazinyl, piperidinyl, non-aromatic pyranyl, pyrazolidinyl, pyrrolidinone, pyrrolidinyl, pyrrolinyl, quinuclidinyl, sulfolanyl, 3-butadienesulfonyl, tetrahydropyranyl, tetrahydrofuryl, 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, etc. Where appropriate, substituents on the heterocycloalkyl group may be located on any atom (including heteroatoms) in the ring system. The point of attachment of the heterocycloalkyl group may be via any atom (where appropriate) in the ring system, including heteroatoms (e.g., nitrogen atoms), or on an atom in any fused carbocyclic ring that may be present as part of the ring system. The heterocycloalkyl group may also be in the N- or S-oxidized form. The heterocycloalkyl groups mentioned herein may be specifically designated as monocyclic or bicyclic.

[0087] Aromatic groups may be aryl or heteroaryl. Aryl groups that may be mentioned include C 6-20 , e.g., C 6-12 (e.g., C 6-10 ) aryl groups. Such groups may be monocyclic, bicyclic or tricyclic and have between 6 and 12 (e.g., 6 and 10) ring carbon atoms, wherein at least one ring is aromatic. C6-10 Aryl groups include groups such as phenyl, naphthyl, etc., for example, 1,2,3,4-tetrahydronaphthyl. The point of attachment of the aryl group can be via any atom of the ring system. For example, when the aryl group is polycyclic, the point of attachment can be via an atom, including an atom of a non-aromatic ring. However, when the aryl group is polycyclic (e.g., bicyclic or tricyclic), they are preferably attached to the remainder of the molecule via an aromatic ring. The most preferred aryl group that can be mentioned herein is "phenyl".

[0088] Unless otherwise specified, the term "heteroaryl" as used herein refers to an aromatic group containing one or more heteroatoms (e.g., one to four heteroatoms), the one or more heteroatoms being preferably selected from N, O, and S. Heteroaryl includes those having between 5 and 20 members (e.g., between 5 and 10 members), and may be monocyclic, bicyclic, or tricyclic, provided that at least one of these rings is aromatic (thereby forming, e.g., a mono-, bi-, or tricyclic heteroaromatic group). When the heteroaryl group is polycyclic, the point of attachment may be via any atom, including an atom of a non-aromatic ring. However, when the heteroaryl group is polycyclic (e.g., bicyclic or tricyclic), they are preferably attached to the remainder of the molecule via an aromatic ring.Heteroaryl groups that 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, benzodioxepanyl, benzodioxolyl (including 1,3-benzodioxolyl), benzofuranyl, benzofurazanyl, benzothiadiazolyl (including 2,1,3-benzothiadiazolyl), benzothiazolyl, benzoxadiazolyl (including 2,1,3-benzoxadiazolyl), 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]pyridinyl, indazolyl, dihydroindolyl, indolyl, isobenzofuranyl, isochromanyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, 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, pyridinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinazolinyl, quinoxalinyl, tetrahydroisoquinolinyl (including 1,2,3,4-tetrahydroisoquinolinyl and 5,6,7,8-tetrahydroisoquinolinyl), tetrahydroquinolinyl (including 1,2,3,4-tetrahydroquinolinyl and 5,6,7,8-tetrahydroquinolinyl), tetrazolyl, thiadiazolyl (including 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl and 1,3,4-thiadiazolyl), thiazolyl, thiochromanyl, thioethoxyphenyl, thienyl, triazolyl (including 1,2,3-triazolyl, 1,2,4-triazolyl and 1,3,4-triazolyl), and the like. Where appropriate, substituents on the heteroaryl group are located on any atom (including heteroatoms) in the ring system. The point of attachment of the heteroaryl group may be via any atom (where appropriate) in the ring system, including heteroatoms (such as nitrogen atoms), or on an atom in any fused carbocyclic ring that may be present as part of the ring system. The heteroaryl group may also be in the N- or S-oxidized form. The heteroaryl groups mentioned herein may be specifically designated as monocyclic or bicyclic. When the heteroaryl group is polycyclic in which there is a non-aromatic ring, the non-aromatic ring may be substituted by one or more ═O groups.The most preferred heteroaryl groups that may be mentioned herein are 5- or 6-membered aromatic groups containing 1, 2 or 3 heteroatoms (preferably selected from nitrogen, oxygen and sulfur, for example).

[0089] It may be specifically noted that the heteroaryl group is monocyclic or bicyclic. In the case where the heteroaryl is specified as bicyclic, then it may be composed of a five-, six- or seven-membered monocyclic ring (for example, a monocyclic heteroaryl ring) fused with another five-, six- or seven-membered ring (for example, a monocyclic aryl or heteroaryl ring).

[0090] Heteroatoms that may be mentioned include phosphorus, silicon, boron, and preferably oxygen, nitrogen and sulfur.

[0091] When "aromatic" groups are mentioned herein, they may be aryl or heteroaryl. When "aromatic linker groups" are mentioned herein, they may be aryl or heteroaryl as defined herein, preferably monocyclic (but may be polycyclic) and attached to the rest of the molecule via any possible atom of the linker group. However, when specifically referring to carbocyclic aromatic linker groups, such aromatic groups may be free of heteroatoms, i.e., they may be aryl (but not heteroaryl).

[0092] To avoid doubt, it is pointed out herein that when a group may be substituted by one or more substituents (for example, selected from C 1-6 alkyl), then these substituents (such as alkyl groups) are independent of each other. That is, such a group may be substituted by the same substituents (such as the same alkyl substituents) or different (such as alkyl) substituents.

[0093] All individual features mentioned herein (for example, preferred features) may be adopted independently or in combination with any other features mentioned herein (including preferred features) (thus, preferred features may be combined with other preferred features or adopted independently of them).

[0094] Those skilled in the art will understand that the compounds of the present invention that are the subject of the present invention include those that are stable. That is, the compounds of the present invention include those that are robust enough to withstand separation from, for example, a reaction mixture to a useful purity.

[0095] The compounds of the present invention may refer to compounds having formula (I) or compounds having formula (Ia). Embodiments of the present invention may thus refer to either (or both) compounds having formula (I) or compounds having formula (Ia). Compounds having formula (I) are embodiments of compounds having formula (Ia). In this regard, compounds having formula (Ia) that may be mentioned include those in which:

[0096] Q 1 represents =(CR 4 )-;

[0097] Two Rs on Ring A 1 The substituents cannot be linked together to form a 5- or 6-membered ring as defined above (i.e., R 1 represents one or more (e.g., one, two, or three) optional substituents independently selected from halo (e.g., Cl, F), -R 6a , -O-R 6b , -C(=O)-R 6c , -C(=O)-N(R 7 )(R 8 ), -CN, and -N(R 7a )R 7b ); and / or

[0098] R 6a and R 6b independently represent -C 1-4 alkyl, which is optionally substituted with one or more substituents selected from halo (e.g., F) and -O-CH 3 .

[0099] In embodiments of the present invention, preferred compounds include those in which:

[0100] There may be no, one, or two R 1 substituents on Ring A;

[0101] R 1 (when present) represents one or two substituents independently selected from 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 ;

[0102] R 6a represents C 1-3 alkyl (e.g., methyl, ethyl, n-propyl), which is optionally substituted with (e.g., one substituent) selected from: -O-C 1-2 alkyl (e.g., -OCH 3 );

[0103] R 6b and R 6c represent C 1-3 alkyl (e.g., methyl), which is preferably unsubstituted;

[0104] R 7 and R 8 independently represent hydrogen or C1-3 An alkyl group (such as a methyl group), which is preferably unsubstituted;

[0105] R 7a and R 7b are linked together to form a 4-6 (such as 5) membered ring.

[0106] Thus, in embodiments, a particular R 1 group can be: 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.

[0107] In embodiments of the present invention, preferred compounds include those wherein:

[0108] R 2 is a straight-chain -C 1-4 alkyl group, which is optionally substituted with one or more substituents (such as one substituent) selected from, for example, -O-C 1-2 alkyl groups (such as -OCH 3 );

[0109] R 3 , R 3a , R 4 and R 4a any two of which represent H, and the other two independently represent substituents selected from H, F, -CH 3 and -OCH 3 ;

[0110] In embodiments of the present invention, preferred compounds include those wherein:

[0111] R 5 is H, -R 9a , -C(=O)-R 9b , -SO 2 -R 10 or Het 1 ;

[0112] R 9a represents an unsubstituted or C 2 alkyl group (such as a methyl group) substituted with one substituent (such as selected from Het 1-3 );

[0113] R 9b represents H or C 1-3 alkyl (such as methyl), which is optionally substituted by one or more fluorine atoms (thus forming a -CF 3 group);

[0114] R 10 represents C 1-4 alkyl, which is optionally substituted by one or more substituents selected from fluorine and -OC 1-2 alkyl (such as -OCH 3 ); and thus R 10 can represent -CF 3 , -CH 3 , isopropyl, -CH 2 C(H)(CH 3 ) 2 (isobutyl), -CH 2 CH 2 -OCH 3 ;

[0115] Het 1 and Het 2 independently represent a 5- or 6-membered heteroaryl ring containing one or two heteroatoms selected from nitrogen and sulfur (thus forming, for example, a thiazolyl ring, such as a 2-thiazolyl ring), the ring being unsubstituted or substituted by one or two (such as one) substituents selected from C 1-3 alkyl (which is itself optionally substituted by one or more fluorine atoms, thus forming a -CF 3 group), and thus, Het 1 and Het 2 can independently represent a thiazolyl group optionally substituted by a -CF 3 substituent.

[0116] In a further embodiment,

[0117] either X or Y represents -CR 11a , and the other represents N or -CR 11b (and in an embodiment, X represents N and Y represents -CR 11a );

[0118] When R 11a or R 11b represents C 1-4 alkyl, it can be unsubstituted or substituted by (such as one substituent) for example -CN, -OR 12b and / or -N(R 12c )R 12d ;

[0119] R 12bRepresents H or C 1-2 Alkyl (e.g. methyl);

[0120] R 12c and R 12d Can independently represent C 1-2 Alkyl (e.g. methyl);

[0121] Therefore, when R 11a or R 11b Represents such a C 1-4 When the alkyl group is present, it can be -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;

[0122] When R 11a or R 11b Representative - OC 1-4 When alkyl is present, it is preferably unsubstituted and may represent -OC 1-2 Alkyl (e.g. -OCH 3 ).

[0123] In embodiments of the present invention, preferred compounds include those below, wherein:

[0124] R 2 It is a straight chain-C 1-4 Alkyl (e.g. unsubstituted C 1-2 alkyl, such as methyl or ethyl), cyclopropyl or -CH 2 -O-CH 3 ;

[0125] R 5 It is H, -C 1-4 Alkyl, -C(=O)-R 9b or -SO 2 -R 10 ; For the avoidance of doubt, when referring to "Tf" as a substituent, it means -S(O) 2 CF 3 ;

[0126] R 7 and R 8 are independently selected from H and -CH3 ;

[0127] R 9b is H, or in another embodiment, -CH 3 ; and / or

[0128] R 10 is -CF 3 , straight-chain unsubstituted -C 1-4 alkyl, or -C 3 alkyl substituted with -O-CH 1-4 alkyl.

[0129] In an embodiment, the compound of the invention in which R 5 is H is a useful intermediate, for example, for preparing the compound of the invention in which R 5 is not H.

[0130] In another embodiment of the invention, the compounds of the invention include those in which:

[0131] R 3 is H, F or -O-CH 3 ;

[0132] R 4 is H, F, -CH 3 or -O-CH 3 ;

[0133] R 3a is H;

[0134] R 4a is H or F; and / or

[0135] R 3 、R 4 、R 3a and R 4a all represent hydrogen, or R 3 、R 4 、R 3a and R 4a any one or two of them represent substituents other than hydrogen (the rest represent hydrogen), for example: (i) R 3 represents a substituent other than H (such as F or -OCH 3 ), and the remaining R 4 、R 3a 、R 4a represent hydrogen; (ii) R 4 represents a substituent other than H (such as F, -CH 3 or -OCH 3 ), and the remaining R 3 、R 3a 、R 4arepresents hydrogen; (iii) R 4 and R 4a represent substituents other than H (e.g., F), and the remainder, i.e., R 3 and R 3a , represent hydrogen.

[0136] In additional or alternative embodiments,

[0137] Q 1 represents =N- or =C(R 4 )- (in an embodiment, Q 1 represents =C(R 4 )-; and / or

[0138] R 3 、R 4 、R 3a and R 4a all represent hydrogen, or one of R 4 or R 4a represents a substituent as defined herein (e.g., fluorine, methyl or methoxy; in an embodiment, it represents fluorine).

[0139] In additional or alternative embodiments,

[0140] X represents N, and Y represents CR 11a ; and / or

[0141] R 11a represents H, C 1-3 alkyl (e.g., methyl or isopropyl) or -OC 1-2 alkyl (e.g., -OCH 3 ).

[0142] In an embodiment:

[0143] There is one or two (e.g., one) R 1 substituents on ring A (wherein R 1 is not hydrogen but a substituent as defined herein in one embodiment);

[0144] There is one R 2 group on ring B.

[0145] In further embodiments of the present invention, preferred compounds include those wherein:

[0146] Ring A is represented as follows:

[0147]

[0148] In another embodiment of the present invention, preferred compounds include those wherein:

[0149] Ring B is represented as follows:

[0150]

[0151] In embodiments of the present invention, preferred compounds of the present invention include those in which:

[0152] The combined ring system, namely ring A and ring B, can be represented as follows:

[0153]

[0154] In another embodiment of the present invention, the combined ring system, namely ring A and ring B, can be represented by any one of the following subgroups:

[0155]

[0156] Wherein 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 compounds having formula (I), compounds having formula (Ia), or additional embodiments of either).

[0157] In additional or alternative embodiments, R 1 is absent or can represent a substituent selected from halo (e.g., chlorine, fluorine, bromine), C 1-3 alkyl (e.g., methyl), and -N(R 7a )R 7b (wherein R 7a and R 7b independently represent hydrogen or C 1-3 alkyl, such as methyl, or are joined together to form a 4- to 6-membered ring, and can thus form -NH 2 , -N(H)CH 2 , -N(CH 3 ) 2 and / or pyrrolidinyl). Optionally, two R 1 groups can together form a 5- or 6-membered ring.

[0158] In additional or alternative embodiments of the present invention, when two R 1 groups together form a 5- or 6-membered ring:

[0159] - It can contain only carbon atoms, or can contain one or two heteroatoms selected from nitrogen and oxygen;

[0160] - It can be free of other double bonds (it may be saturated), or it can contain one or two double bonds, and can thus form another aromatic ring;

[0161] - It can form one of the following parts:

[0162] and / or

[0163] - It can optionally be substituted by one or two (e.g., one) C 1-3 alkyl (e.g., methyl) group,

[0164] In the embodiment, two R 1 groups may not together form an additional 5- or 6-membered ring as defined herein.

[0165] In an embodiment of the present invention:

[0166] R 1 represents one or more (e.g., one, two, or three) optional (thus, R 1 can also represent hydrogen) substituents, which are independently selected from halo (e.g., Cl, F), -R 6a , -O-R 6b , -C(=O)-R 6c , -C(=O)-N(R 7 )(R 8 ), -CN, and -N(R 7a )R 7b ;

[0167] R 6a , R 6b and R 6c independently represent C 1-3 alkyl (e.g., methyl, cyclopropyl);

[0168] R 7 and R 8 are independently selected from H and C 1-3 alkyl;

[0169] R 7a and R 7b independently represent H, C 1-3 alkyl or are joined together to form a 4- to 6-membered ring (e.g., 5-membered); and / or

[0170] R 2 represents C 1-4 alkyl, which is optionally substituted by one substituent (e.g., selected from -O-C 1-3 alkyl).

[0171] In an additional or alternative embodiment of the present invention, R 2 can represent C 1-4 alkyl, which is optionally substituted by one or more substituents selected from the following: halo (e.g., fluorine) and -OC 1-3 alkyl, e.g., R 2can represent -CF 3 、-CHF 2 、-CH 2 CH 3 、-CH 3 、cyclopropyl, -OCH 3 。

[0172] Additional embodiments of the present invention include those in which:

[0173] R 1 represents one or two (e.g., one) substituents selected from: H, Cl, F, -R 6a 、-O-R 6b 、-C(=O)-R 6c and -C(=O)-N(R 7 )(R 8 );

[0174] R 6a 、R 6b and R 6c independently represent -CH 3 ;

[0175] R 7 and R 8 independently selected from H and -CH 3 ; and / or

[0176] R 2 is a straight-chain C 1-4 alkyl, cyclopropyl or CH 2 -O-CH 3 。

[0177] In additional or alternative embodiments, R 1 is absent or can represent a substituent selected from: halogenated (e.g., chlorine, fluorine, bromine), C 1-3 alkyl (e.g., methyl) and -N(R 7a )R 7b (wherein R 7a and R 7b independently represent hydrogen or C 1-3 alkyl, such as methyl, or are joined together to form a 4- to 6-membered ring and can thus form -NH 2 、-N(H)CH 2 、-N(CH 3 ) 2 and / or pyrrolidinyl).

[0178] Other embodiments of the present invention include those in which:

[0179] R 5 is -C 1-4Alkyl (such as methyl), -C(=O)-R 9b (such as -C(O)H, or in another embodiment, -C(O)CH 3 ) or -SO 2 -R 10 ;

[0180] A combined ring system, i.e., ring A and ring B are rings having formula (IX) or (X), and R 5 is -SO 2 -R 10 ;

[0181] R 1 is H, Cl, F, -C 1-4 alkyl (such as methyl, ethyl or -CH 2 -OCH 3 ) or -O-C 1-4 alkyl (such as OCH 3 ), and in a further embodiment, R 1 more preferably represents Cl;

[0182] R 2 is -C 1-4 alkyl (such as methyl, ethyl, cyclopropyl or -CH 2 -OCH 3 ); and / or

[0183] R 10 is isopropyl (-CH 2 CH(CH 2 ) 2 ), -CH 3 , -CH 2 -CH 2 -OCH 3 , or in certain embodiments is -CF 3 .

[0184] In alternative embodiments:

[0185] -R 5 represents hydrogen, -S(O) 2 R 10 or Het 1 (and in a particular embodiment, R 5 represents -S(O) 2 R 10 );

[0186] -R 10 represents C 1-3 alkyl (such as methyl), which is optionally substituted with one or more fluorine atoms (thus forming (in a particular embodiment) CF 3 ); and / or

[0187] -Het 1 represents a 5-membered heteroaryl group containing one or two (e.g., one) heteroatoms (e.g., selected from oxygen, nitrogen, and sulfur; especially sulfur), thus forming, for example, a thienyl group.

[0188] In certain embodiments, R 5 represents -S(O) 2 R 10 ; and in further certain embodiments, R 10 represents C 1-3 alkyl (e.g., methyl), which is optionally substituted by one or more fluorine atoms (thus forming (in certain embodiments) CF 3 ).

[0189] Further embodiments of the present invention include those in which:

[0190] R 11a and R 11b independently represent H, -CH 3 , -CH 2 CH 3 or -OCH 3 ;

[0191] X represents N, and Y represents -CR 11a wherein R 11a represents H, -CH 3 , -CH 2 CH 3 or -OCH 3 .

[0192] It is pointed out that either of X and Y represents -CR 11a , and the other represents N or -CR 11b , and in an embodiment, X represents N and Y represents -CR 11a (as defined herein).

[0193] Pharmacology

[0194] The compounds according to the present invention unexpectedly show suitability for the treatment of bacterial infections, including mycobacterial infections, especially those diseases caused by pathogenic mycobacteria, such as Mycobacterium tuberculosis (including its latent and drug-resistant forms). The present invention thus also relates to the compounds of the present invention as defined above, which are used as medicaments, especially as medicaments for the treatment of bacterial infections (including mycobacterial infections).

[0195] Such compounds of the present invention can act by interfering with ATP synthase in Mycobacterium tuberculosis, where the inhibition of cytochrome bc 1 activity is the main mode of action. Cytochrome bc1 It is an essential component of the electron transport chain required for ATP synthesis.

[0196] Furthermore, the present invention also relates to the use of the compounds of the present invention, together with any pharmaceutical compositions thereof (as described hereinafter), for the manufacture of a medicament for the treatment of bacterial infections (including mycobacterial infections).

[0197] Thus, in another aspect, the present invention provides a method for treating a patient suffering from or at risk of bacterial infections (including mycobacterial infections), the method comprising administering to the patient a therapeutically effective amount of a compound or pharmaceutical composition according to the present invention.

[0198] The compounds of the present invention also exhibit activity against drug-resistant bacterial strains.

[0199] Whenever used hereinabove or hereinafter, the statement that these compounds can treat bacterial infections means that these compounds can treat infections by one or more bacterial strains.

[0200] The present invention also relates to a composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to the present invention as an active ingredient. The compounds according to the present invention can be formulated into different pharmaceutical forms for the purpose of administration. All compositions commonly used for the systemic administration of drugs can be cited as suitable compositions. To prepare the pharmaceutical compositions of the present invention, an effective amount of a specific compound, optionally in the form of an addition salt, as an active ingredient is combined with a pharmaceutically acceptable carrier in a tight mixture, and the carrier can take a variety of forms, depending on the desired form of the preparation for administration. Desirably, these pharmaceutical compositions are in unit dosage forms, particularly unit dosage forms suitable for oral administration or administration by injection. For example, when preparing a composition in an oral dosage form, any common pharmaceutical medium can be used. In the case of liquid oral preparations such as suspensions, syrups, elixirs, emulsions and solutions, for example, water, glycols, oils, alcohols, etc. can be used; or in the case of powders, pills, capsules and tablets, solid carriers such as starch, sugar, kaolin, diluents, lubricants, binders, disintegrating agents, etc. can be used. Tablets and capsules represent the most advantageous oral unit dosage forms because of their ease of administration, and in this case, a solid pharmaceutical carrier is clearly used. For parenteral compositions, the carrier will generally consist at least to a large extent of sterile water, but other ingredients can also be included, for example, to assist solubility. For example, injectable solutions can be prepared, in which the carrier comprises a salt solution, a glucose solution or a mixture of saline and glucose solution. Injectable suspensions can also be prepared, in which case appropriate liquid carriers, suspending agents, etc. can be used. Also included are solid form preparations that are converted into liquid form preparations shortly before use.

[0201] Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05% to 99% by weight, more preferably from 0.1% to 70% by weight, even more preferably from 0.1% to 50% by weight of one or more active ingredients, and from 1% to 99.95% by weight, more preferably from 30% to 99.9% by weight, even more preferably from 50% to 99.9% by weight of a pharmaceutically acceptable carrier, all percentages being based on the total weight of the composition.

[0202] The pharmaceutical composition may additionally contain various other ingredients known in the art, such as, for example, lubricants, stabilizers, buffers, emulsifiers, viscosity regulators, surfactants, preservatives, flavoring agents or coloring agents.

[0203] For ease of administration and uniformity of dosage, it is particularly advantageous to formulate the above pharmaceutical composition into unit dosage forms. As used herein, a unit dosage form refers to a physically discrete unit suitable as a unit dose, each unit containing a predetermined amount of the active ingredient which is calculated to produce the desired therapeutic effect in association with the desired pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, suppositories, injectable solutions or suspensions, and the like, and their segregated multiples. Of course, the daily dosage of the compounds according to the invention will vary with the compound employed, the mode of administration, the desired treatment and the mycobacterial disease being targeted. However, in general, satisfactory results will be obtained when the compounds according to the invention are administered at a daily dosage of not more than 1 gram (e.g., in the range from 10 mg / kg to 50 mg / kg body weight).

[0204] In view of the fact that the compounds having formula (Ia) or formula (Ib) are active against bacterial infections, the compounds of the present invention can be combined with other antibacterial agents in order to effectively combat bacterial infections.

[0205] Accordingly, the present invention also relates to a combination of (a) a compound according to the invention, and (b) one or more other antibacterial agents.

[0206] The present invention also relates to a combination of (a) a compound according to the invention, and (b) one or more other antibacterial agents, which combination is used as a medicament.

[0207] The present invention also relates to the use of the combination or pharmaceutical composition as directly defined above for the treatment of bacterial infections.

[0208] The present invention may also include a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of (a) a compound according to the present invention, and (b) one or more other antibacterial agents as active ingredients.

[0209] When given as a combination, those skilled in the art can determine the weight ratio of (a) the compound according to the present invention and (b) one or more other antibacterial agents. As is well known to those skilled in the art, the ratio, as well as the precise dosage and the frequency of administration, depend on the specific compound according to the present invention and the one or more other antibacterial agents used, the specific condition being treated, the severity of the condition being treated, the age, weight, sex, diet, time of administration and general physical health of the specific patient, the mode of administration together with other drugs the individual may be taking. In addition, it is obvious that the effective daily dosage can be reduced or increased depending on the response of the subject being treated and / or depending on the assessment of the doctor prescribing the compound of the present invention. A particularly weight ratio of the compound of the present invention and another antibacterial agent may be in the range from 1 / 10 to 10 / 1, more particularly from 1 / 5 to 5 / 1, even more particularly from 1 / 3 to 3 / 1.

[0210] The compound according to the present invention and one or more other antibacterial agents may be combined in a single formulation or they may be formulated as separate formulations such that they can be administered simultaneously, separately or sequentially. Accordingly, the present invention also relates to a product containing (a) a compound according to the present invention, and (b) one or more other antibacterial agents, the product being a combined formulation for use simultaneously, separately or sequentially in the treatment of bacterial infections.

[0211] 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 known antibacterial agents to interfere with the respiratory chain of Mycobacterium tuberculosis. Known antibacterial agents include, for example, direct inhibitors of ATP synthase (such as bedaquiline, bedaquiline fumarate, or any other compound disclosed in the prior art, such as the compounds disclosed in WO 2004 / 011436), ndh2 inhibitors (such as clofazimine), and cytochrome bd inhibitors. Additional mycobacterial agents that can be combined with the compounds of the present invention are, for example, rifampicin (= rifadin); isoniazid; pyrazinamide; amikacin; ethionamide; ethambutol; streptomycin; para-aminosalicylic acid; cycloserine; capreomycin; kanamycin; thiacetazone; PA-824; delamanid; quinolones / fluoroquinolones, such as moxifloxacin, gatifloxacin, ofloxacin, ciprofloxacin, sparfloxacin; macrolides, such as clarithromycin, amoxicillin and clavulanic acid; rifamycins; rifabutin; rifapentine; and other products currently under development (but may not yet be on the market; see, for example http: / / www.newtbdrugs.org / pipeline.php ).

[0212] The compounds of the present invention (including forms and compositions / combinations comprising the compounds of the present invention), whether for the above-mentioned indications or other indications, may have the advantages of being more effective, less toxic, having a longer duration of action, being more potent, producing fewer side effects, being more easily absorbed, and / or having better pharmacokinetic properties (such as higher oral bioavailability and / or lower clearance rate) than compounds known in the prior art, and / or having other useful pharmacological, physiological, or chemical properties superior to those of compounds known in the prior art. For example, the compounds of the present invention may have advantages related to the following: lower cardiotoxicity; no formation of active metabolites (such as may cause toxicity problems, such as genotoxicity); no formation of degradation products (such as, unwanted or may cause unintended side effects); and / or faster oral absorption and improved bioavailability.

[0213] General Preparation

[0214] Compounds according to the present invention can generally be prepared by a series of steps, each of which may be known to the person skilled in the art or described herein.

[0215] Experimental Section

[0216] Compounds having the formula I can be prepared according to the techniques used in the examples below (as well as those methods known to the person skilled in the art), for example by using the following techniques.

[0217] Compounds having the formula (I) or (Ia) can be prepared by the following:

[0218] (i) React a compound having the formula (XIV),

[0219]

[0220] wherein the whole is as defined above, with a compound having the formula (XV) or (XVA) respectively,

[0221]

[0222] wherein the whole is as defined above, and in the examples, R 5 is as defined above, but preferably represents -C 1-4 alkyl, -C(=O)-R 9b or -S(O) 2 -R 10 , and the reaction can be carried out in the following cases: in the presence of a suitable coupling reagent (such as selected from diisopropylethylamine (DIPEA), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (HATU), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), 1-hydroxybenzotriazole (HOBt), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU) or a combination thereof), under suitable conditions (such as those described in the examples below); for example, in the presence of a suitable coupling reagent (such as 1,1'-carbonyldiimidazole, N,N'-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (or its hydrochloride) or N,N'-disuccinimidyl carbonate), optionally in the presence of a suitable base (such as sodium hydride, sodium bicarbonate, potassium carbonate, pyridine, triethylamine, dimethylaminopyridine, diisopropylamine, sodium hydroxide, potassium tert-butoxide and / or lithium diisopropylamide (or its variants)) and a suitable solvent (such as tetrahydrofuran, pyridine, toluene, dichloromethane, chloroform, acetonitrile, dimethylformamide, trifluoromethylbenzene, dioxane or triethylamine). Alternatively, the carboxylic acid group of the compound having the formula (XIV) can first be converted to the corresponding acyl chloride under standard conditions (such as in the presence of POCl 3 , PCl 5 , SOCl 2 or oxalyl chloride), and then, for example, under conditions similar to those mentioned above, the acyl chloride reacts with the compound having the formula (XV);

[0223] (ii) React a compound having the formula (XVII) or (XVIIA) respectively,

[0224]

[0225] wherein the whole is as defined above, and R 12 represents a suitable group, such as a suitable leaving group, such as chlorine, bromine, iodine or a sulfonate group (e.g., the types of groups that can be used for coupling), with a compound having the formula (XVI),

[0226]

[0227] wherein R 5 is as defined above (but preferably does not represent H), under standard conditions, for example, optionally in the presence of a suitable metal catalyst (or its salt or its complex) such as Pd(dba) 2 , Pd(OAc) 2 , Cu, Cu(OAc) 2 , CuI, NiCl 2 etc., using an optional additive (e.g., Ph 3 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, to carry out the coupling;

[0228] (iii) For a compound having the formula (I) or (Ia), wherein X represents N (and R 5 preferably represents H), react a compound having the formula (XVIII) or (XVIIIA) respectively,

[0229]

[0230] wherein the whole is as defined above (and R 5 preferably represents H), with a compound having the formula (XIX)

[0231] R 11x C(OCH 3 ) 3 (XIX)

[0232] and so on, wherein R 11x represents R 11a or R 11b (if appropriate), and the reaction is carried out under the reaction conditions described herein (e.g., in the examples);

[0233] (iv) For a compound having the formula (I) or (Ia), wherein X represents N (and preferably R 5 represents H), react a compound having the formula (XX) or (XXA) respectively,

[0234]

[0235] wherein the moiety is as defined above (and R 5 preferably represents H), is reacted with a compound of formula (XIX) as defined above, the reaction being carried out under reaction conditions such as described herein (e.g., in the examples); and / or

[0236] (v) for the preparation of a compound of formula (I) or (Ia) wherein R 5 represents -C(=O)-R 9b , -S(O) 2 -R 10 or Het 1 , reacting the corresponding compound of formula (I) wherein R 5 represents H, with a compound of formula (XXI)

[0237] LG 1 -Z (XXI)

[0238] wherein Z represents -C(=O)-R 9b , -S(O) 2 -R 10 or Het 1 , and LG 1 represents a suitable leaving group such as chlorine, bromine, iodine or a sulfonate group, and wherein the moiety is as defined herein, and in the case of Het 1 , the LG 1 is attached to a suitable C atom of the heteroaromatic ring such that the N atom attached to R 5 can react (e.g., via its lone pair electrons) with Het 1 and displace the LG 1 .

[0239] Obviously, in the foregoing and following reactions, the reaction product can be separated from the reaction medium and, if necessary, further purified according to methodologies commonly known in the art (e.g., extraction, crystallization, and chromatography). Even more obviously, reaction products that exist in more than one enantiomeric form can be separated from their mixtures by known techniques (particularly preparative chromatography, e.g., preparative HPLC, chiral chromatography). Separate diastereoisomers or separate enantiomers can also be obtained by supercritical fluid chromatography (SCF).

[0240] The starting materials as well as the intermediates are commercially available compounds or compounds that can be prepared according to conventional reaction procedures commonly known in the art.

[0241] Examples

[0242] 1. General Information

[0243] Melting point

[0244] The melting point was recorded using a differential scanning calorimeter DSC 1 (Mettler Toledo). The melting point was measured from 25 °C to 350 °C with a temperature gradient of 10 °C / min. The value is the peak. This method is used unless otherwise stated.

[0245] An alternative method is to use an open capillary on a Mettler Toledo MP50, which can be indicated at "MT". Using 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 the digital display and checked from the video recording system.

[0246] 1 H NMR

[0247] 1H-NMR spectra were recorded on a Bruker Avance DRX 400 spectrometer or Bruker Advance III 400 spectrometer using an internal deuterium lock and equipped with a reverse double resonance ( 1 1H, 13C, SEI) probe with a z-gradient and operating at 400 MHz for protons and 100 MHz for carbon, and on a Bruker Avance 500 MHz spectrometer equipped with a Bruker 5 mm BBFO probe with a z-gradient and operating at 500 MHz for protons and 125 MHz for carbon. 1 1H-NMR spectra.

[0248] Unless otherwise stated, NMR spectra were recorded at ambient temperature.

[0249] The data is reported as follows: in terms of scale, integration, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, quin = quintet, sex = sextet, m = multiplet, b = broad peak or combinations thereof), the chemical shift is in parts per million (ppm) relative to TMS (δ = 0 ppm), and the coupling constant J is in Hertz (Hz).

[0250] HPLC-LCMS

[0251] Analytical Methods

[0252] LCMS

[0253] The mass of some compounds was recorded using LCMS (liquid chromatography mass spectrometry). The method used is described below.

[0254] General Procedures LCMS Methods A and B

[0255] Perform high performance liquid chromatography (HPLC) measurements using an LC pump, a diode array (DAD) or UV detector, and a column as specified in the corresponding method. Include other detectors if necessary (see method table below). Bring the flow from the column to a mass spectrometer (MS) equipped with an atmospheric pressure ionization source. Set the tuning parameters (e.g., scan range, dwell time, etc.) such that ions allowing the identification of the nominal single isotope molecular weight (MW) of the compound are within the knowledge of the person skilled in the art. Perform data acquisition using appropriate software.

[0256] The compound is described by its experimental retention time (R t ) and ions. If not specified differently in the data sheet, the reported molecular ion corresponds to [M+H] + (protonated molecule) and / or [M−H] - (deprotonated molecule). In cases where the compound is not directly ionizable, specify the adduct type (i.e., [M+NH 4 + , [M+HCOO] - , etc.). For molecules with multiple isotope patterns (Br, Cl, etc.), the reported value is the value obtained for the lowest isotope mass. All results obtained have the experimental uncertainties typically associated with the methods used. Hereinafter, "SQD" means single quadrupole detector, "RT" means room temperature, "BEH" means bridged ethylsiloxane / silica hybrid, "HSS" means high strength silica, "DAD" means diode array detector, "MSD" means mass selective detector.

[0257] Table: LCMS method code (flow rate in mL / min; column temperature (T) in °C; run time in minutes).

[0258]

[0259]

[0260] When the compound is a mixture of isomers giving different peaks in the LCMS method, only the retention time of the major component is given in the LCMS table.

[0261] 2. Abbreviations (and Formulas)

[0262] AcOH Acetic acid

[0263] AcCl Acetyl chloride

[0264] BINAP 2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl

[0265] ​BrettPhos 2-(Dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl

[0266] -1,1'-Biphenyl

[0267] BrettPhos Pd G3 [(2-Di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl

[0268] -1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)] Palladium(II) mesylate CBr 4 Carbon tetrabromide

[0269] CbzCl Benzyl chloroformate

[0270] CH 3 CN / ACN Acetonitrile

[0271] Cs 2 CO 3 Cesium carbonate

[0272] CSA Camphor-10-sulfonic acid

[0273] DCE Dichloroethane

[0274] DCM or CH 2 Cl 2 Dichloromethane

[0275] DIPEA N,N-Diisopropylethylamine

[0276] DMAP 4-(Dimethylamino)pyridine

[0277] DME 1,2-Dimethoxyethane

[0278] DMF Dimethylformamide

[0279] DMF-DMA N,N-Dimethylformamide dimethyl acetal

[0280] DMSO Dimethyl sulfoxide

[0281] EDCI·HCl N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride

[0282] Et 2 O Diethyl ether

[0283] Et 3 N or TEA Triethylamine

[0284] EtOAc Ethyl acetate

[0285] EtOH Ethanol

[0286] h hour

[0287] H 2 hydrogen

[0288] HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0289] HCl hydrochloric acid

[0290] HFIP hexafluoroisopropanol

[0291] HOBT·H 2 O 1-hydroxybenzotriazole hydrate

[0292] i-PrOH isopropanol

[0293] K 2 CO 3 potassium carbonate

[0294] KHSO 4 potassium bisulfate

[0295] LiOH lithium hydroxide

[0296] LiHMDS lithium bis(trimethylsilyl)amide

[0297] MeOH methanol

[0298] MeTHF / 2-MeTHF methyltetrahydrofuran

[0299] MgSO 4 magnesium sulfate

[0300] min minute

[0301] N 2 nitrogen

[0302] NaCl sodium chloride

[0303] NaHCO 3 sodium bicarbonate

[0304] NaOH sodium hydroxide

[0305] NBS N-bromosuccinimide

[0306] NH 3 ammonia

[0307] NH 4 Cl ammonium chloride

[0308] NH 4 HCO 3 ammonium bicarbonate

[0309] NMR Nuclear Magnetic Resonance

[0310] Pd / C Palladium on Carbon

[0311] PdCl Palladium Chloride 2 (PPh 3 ) 2 Dichlorobis(triphenylphosphine)palladium(II)

[0312] Pd(OAc) Palladium(II) Acetate 2 Palladium(II) Acetate

[0313] Pd Palladium 2 dba 3 Tris(dibenzylideneacetone)dipalladium(0)

[0314] Pd(PPh 3 ) 4 Palladium - Tetrakis(triphenylphosphine)

[0315] PIDA (Diacetoxyiodo)benzene

[0316] POCl Phosphorus Oxychloride 3 Phosphorus Oxychloride

[0317] Ra-Ni / Raney Nickel -Nickel

[0318] rt / RT Room Temperature

[0319] RuPhos 2 - Dicyclohexylphosphino - 2',6'-diisopropoxybiphenyl

[0320] RuPhos Pd G3 (2 - Dicyclohexylphosphino - 2',6'-diisopropoxy - 1,1'-biphenyl)[2-(2'-amino - 1,1'-biphenyl)]palladium(II) methanesulfonate

[0321] t-AmylOH tert-Amyl Alcohol

[0322] SiOH Silica Gel

[0323] TBTU O-(Benzotriazol - 1 - yl)-N,N,N’,N’-tetramethyluronium tetrafluoroborate

[0324] Tf 2 O Trifluoromethanesulfonic Anhydride

[0325] TFA Trifluoroacetic Acid

[0326] THF Tetrahydrofuran

[0327] TMSCl Trimethylsilyl Chloride

[0328] TsOH or PTSA p-Toluenesulfonic Acid

[0329] XantPhos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

[0330] 3. Procedures

[0331] Synthesis of Compound 1

[0332]

[0333] Preparation of Intermediate A1

[0334] In a 1 L autoclave, N-Boc-[2-[(4-cyanophenyl)amino]ethyl] [865788-36-9] (50.0 g, 191 mmol) and Raney nickel (2.25 g, 38.2 mmol) were mixed in a 7 M solution of NH 3 in MeOH (600 mL). The mixture was hydrogenated at room temperature and 10 bar H 2 for 24 h. The reaction mixture was filtered through a pad 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 (99%) as a pale green oil.

[0335] Preparation of Intermediate A2

[0336] 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), dried over MgSO 4 4, filtered, and evaporated in vacuo. The residue was dissolved in the minimum amount of warm 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 2O and then dried in vacuo to give 21.7 g of intermediate A2 (69%) as an off-white solid.

[0337] Preparation of Intermediate A3

[0338] At 40 °C, intermediate A2 (5.00 g, 10.6 mmol) was dissolved in Me-THF (80 mL) and acetic acid (6.1 mL, 106 mmol). Isoamyl 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 with EtOAc and water, and washed with NaHCO 3 (saturated, aq.) (twice) and brine, dried over MgSO 4 and evaporated in vacuo. The residue was triturated in Et 2 O. The product was collected by filtration, washed with Et 2 O and dried in vacuo to give 4.26 g of intermediate A3 (80%) as a beige solid.

[0339] Preparation of Intermediate A4

[0340] 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 with DCM, and 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 extracts were dried over MgSO 4 filtered and evaporated in vacuo to give 4.67 g of intermediate A4 (quantitative) as a white solid.

[0341] Preparation of Intermediate A5

[0342] TMSCl (9.73 mL, 76.7 mmol) was added dropwise to a solution of intermediate A4 (4.67 g, 9.59 mmol) in MeOH (96 mL). The reaction mixture was stirred at 40 °C for 1.5 h and then at room temperature for an additional 17 h. The mixture was concentrated in vacuo. The residue was triturated in Et 2 O. The solid was collected by filtration, washed with Et 2 O and dried in vacuo to afford 4.76 g of intermediate A5 (quantitative) as a pale yellow solid.

[0343] Preparation of Intermediate A6

[0344] 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 K 2 CO 3 (10%, aq.) was added. The aqueous layer was extracted twice with DCM and MeOH (95 / 5). The combined organic extracts were dried over MgSO 4 , filtered and evaporated in vacuo to give 3.44 g of intermediate A6 (83%) as a beige solid.

[0345] Preparation of Compound 1

[0346] A solution of intermediate A6 (80 mg, 0.202 mmol) in DCM (6 mL) and Me-THF (3 mL) was treated with Et 3 N (70 μL, 0.50 mmol). The mixture was cooled to 0 °C and a solution of Tf 2 O (1 M 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 K 2 CO 3 (10%, aq., 5 mL) and DCM. The layers were separated. The organic phase was dried over MgSO 4 , filtered and evaporated in vacuo. The crude mixture was purified by preparative LC (irregular SiOH 15 - 40 μm, 12 g, dry load mobile phase: heptane / EtOAc, gradient from 70:30 to 0:100). The residue (62 mg) was dissolved in warm EtOAc (3 mL) and cooled to room temperature. The supernatant was removed. The solid was triturated in Et 2 O. The product was collected by filtration and dried in vacuo to afford 42 mg of compound 1 (36%) as a white solid.

[0347] 1 H NMR (400 MHz, DMSO-d 6) δ ppm 9.07 (s, 1H), 8.47 (br s, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.46 (br d, J = 9.1 Hz, 1H), 7.30 (br d, J = 8.1 Hz, 2H), 7.20 (br d, J = 7.6 Hz, 2H), 4.49 (br d, J = 5.1 Hz, 2H), 4.41 (s, 2H), 4.18 (s, 2H), 3.39 - 3.31 (m, 1H), 2.98 (q, J = 7.4 Hz, 2H), 2.63 - 2.58 (m, 2H), 2.34 - 2.29 (m, 2H), 1.26 (br t, J = 7.3 Hz, 3H)

[0348] 1 H NMR (400 MHz, DMSO - d 6 ) δ ppm 9.12 (s, 1H) 8.71 (m, 1H) 7.79 (d, J = 9.4 Hz, 1H) 7.68 (d, J = 8.8 Hz, 1H) 7.26 - 7.37 (m, 3H) 7.19 (d, J = 8.7 Hz, 2H) 4.48 (d, J = 5.9 Hz, 2H) 4.08 (t, J = 4.5 Hz, 2H) 3.83 (t, J = 4.8 Hz, 2H) 3.01 (q, J = 7.6 Hz, 2H) 1.27 (t, J = 7.5 Hz, 3H)

[0349] Synthesis of Compound 2

[0350]

[0351] Preparation of Intermediate A7

[0352] A mixture of intermediate A5 (300 mg, 0.652 mmol) and trimethyl orthoformate (0.102 mL, 0.718 mmol) in acetic acid (6 mL) was stirred at 100 °C for 1 h. An additional amount of trimethyl orthoformate (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 in DCM and NaOH (3 M, aq.). The layers were separated and the organic phase was dried over MgSO 4 dried, filtered and evaporated in vacuo to give 138 mg of intermediate A7 (50%) as a foam.

[0353] Preparation of Compound 2

[0354] A solution of intermediate A7 (138 mg, 0.325 mmol) in DCM (4 mL) was treated with Et 3Treated with N (113 μL, 0.812 mmol). The mixture was cooled to 0 °C and Tf 2 O in DCM (1 M 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). Added and the mixture was evaporated in vacuo. The residue was purified by preparative LC (irregular SiOH 15 - 40 μm, 24 g, dry load Mobile phase: heptane / EtOAc, gradient from 70:30 to 0:100). The second purification was carried out by reverse phase (stationary phase: YMC-actus Tria room temperature C18 10 μm 30*150 mm, mobile phase: NH 4 HCO 3 (0.2% in water) / MeCN, gradient from 40:60 to 10:90) to give 60 mg of compound 2 as a white solid (33%).

[0355] 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 9.07 (d, J = 1.6 Hz, 1H) 8.43 (t, J = 5.9 Hz, 1H) 7.66 (d, J = 9.5 Hz, 1H) 7.45 (dd, J = 9.5, 2.1 Hz, 1H) 7.32 (d, J = 8.7 Hz, 2H) 7.18 (d, J = 8.8 Hz, 2H) 4.46 (d, J = 5.9 Hz, 2H) 3.91 - 4.02 (m, 2H) 3.79 - 3.90 (m, 2H) 2.98 (q, J = 7.5 Hz, 2H) 2.61 (q, J = 7.3 Hz, 2H) 1.26 (t, J = 7.5 Hz, 3H) 1.18 (t, J = 7.3 Hz, 3H).

[0356] Synthesis of Compound 3

[0357]

[0358] 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 stirred at room temperature under 5 bar H 2 for 20 h. The mixture was filtered through Pad filtration. The filter cake was washed with EtOH and DCM, and the filtrate was evaporated in vacuo. The residue was combined with another batch to give 250 mg of the crude mixture. The residue was purified by reverse phase (stationary phase: YMC-actus Tria room temperature C18 10 μm 30*150 mm, mobile phase: NH 4 HCO 3 (0.2% in water) / MeCN, gradient from 55:45 to 30:70). The residue was triturated in Et 2 O and the solvent was removed under reduced pressure to give 165 mg of compound 3 as a white solid (58%).

[0359] 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.16 (t, J = 6.1 Hz, 1H) 7.28 (s, 1H) 7.26 (d, J = 8.6 Hz, 2H) 7.16 (d, J = 8.6 Hz, 2H) 4.35 (d, J = 6.1 Hz, 2H) 4.07 (t, J = 4.6 Hz, 2H) 3.97 (t, J = 5.7 Hz, 2H) 3.77 - 3.87 (m, 2H) 2.68 - 2.75 (t, J = 6.4 Hz, 2H) 2.60 (q, J = 7.5 Hz, 2H) 1.73 - 1.90 (m, 4H) 1.09 (t, J = 7.5 Hz, 3H).

[0360] Synthesis of Compound 4

[0361]

[0362] Preparation of Intermediate B1

[0363] 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). Et 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), dried over MgSO 4 and filtered and evaporated in vacuo to give intermediate B1 as a pale yellow oil (quantitative).

[0364] Preparation of Intermediate B2

[0365] 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 treated 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 basified by adding K 2 CO 3 . The aqueous phase was extracted with DCM (twice). The combined organic layers were dried over MgSO 4 , filtered and evaporated in vacuo to give 2.54 g of compound B2 as an orange oil (quantitative).

[0366] Preparation of Intermediate B3

[0367] 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. K 2 CO 3 was added portionwise until the aqueous layer was basic. The organic layer was separated, washed with water and brine, dried over MgSO 4 , filtered and evaporated in vacuo to give 1.50 g of intermediate B3 as an orange solid (66%).

[0368] Preparation of Intermediate B4

[0369] In an autoclave, a mixture of intermediate B3 (1.5 g, 7.49 mmol) and Raney nickel (440 mg, 7.49 mmol) in a 7 M solution of NH 3 in MeOH (64 mL) was hydrogenated at room temperature under 5 bar of H 2 for 17 h. The reaction mixture was filtered through a pad 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 (quantitative).

[0370] Preparation of Compound 4

[0371] Dissolve 6-chloro-2-ethylimidazo[1,2-a]pyridine-3-carboxylic acid [1216142-18-5] (600 mg, 2.67 mmol) in Me-THF (30 mL), and add DCM (15 mL) and DIPEA (0.736 mL, 4.27 mmol). After complete dissolution, add intermediate B4 (627 mg, 3.07 mmol), and then add HATU (1.17 g, 3.07 mmol). Stir the reaction mixture at 35 °C for 3 h. Add EtOAc and water. Separate the organic layer, wash with water, and then wash with brine. Combine the organic extracts, dry over MgSO 4 dry, filter, and evaporate in vacuo. Dissolve the residue in the minimum amount of warm EtOAc. Cool the solution to room temperature and filter the suspension. Wash the solid with EtOAc, and then wash with EtOH and Et 2 O. Collect the solid by filtration and dry under vacuum to obtain 210 mg of an off-white solid. Combine the solid with the filtrate and evaporate in vacuo. Purify the residue by preparative LC (irregular SiOH 15 - 40 μm, 80 g, mobile phase: DCM / (DCM / MeOH / NH 3 aq., 18 / 20 / 2), gradient from 90:10 to 60:40). Crystallize the residue from EtOAc, wash with Et 2 O and dry under vacuum to obtain 317 mg of compound 4.

[0372] 1 1H NMR (400 MHz, DMSO-d 6 ) δ ppm 9.07 (d, J = 1.47 Hz, 1H) 8.45 (t, J = 5.81 Hz, 1H) 7.67 (d, J = 9.66 Hz, 1H) 7.46 (dd, J = 9.41, 2.08 Hz, 1H) 7.30 - 7.36 (m, 3H) 7.11 (d, J = 8.56 Hz, 2H) 4.47 (d, J = 5.87 Hz, 2H) 3.70 (t, J = 5.01 Hz, 2H) 3.17 (d, J = 5.14 Hz, 1H) 2.88 - 3.01 (m, 4H) 2.54 - 2.65 (m, 4H) 1.26 (t, J = 7.52 Hz, 3H).

[0373] Synthesis of Compound 5

[0374]

[0375] Preparation of Intermediate B5

[0376] 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 washed with NaHCO 3 (saturated, aq.), dried over MgSO 4 , filtered, and the solvent was removed under reduced pressure to give 700 mg of intermediate B5 as a brown residue.

[0377] Preparation of Compound 5

[0378] Intermediate B5 (250 mg, 0.234 mmol), trimethylboroxine (131 μL, 0.938 mmol), and Cs 2 CO 3 (229 mg, 0.703 mmol) in a mixture of DME (3.6 mL) and water (3.6 mL) was purged with N 2 . PdCl 2 (PPh 3 ) 2 (32.9 mg, 0.0469 mmol) was added, and the mixture was purged with N 2 again. 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, dried over MgSO 4 , filtered and evaporated to dryness in vacuo. The residue was purified by preparative LC (irregular SiOH 15 - 40 μm, 24 g, dry load Mobile phase: DCM / MeOH, gradient from 99:1 to 95:5). The second purification was carried out by reverse phase (stationary phase: YMC-actus Tria room temperature C18 10 μm 30*150 mm, mobile phase: NH 4 HCO 3 (0.2% in water / MeCN, gradient from 55:45 to 35:65) to give 14 mg of a white residue, which was dissolved in MeCN, diluted with water and lyophilized to give 12 mg of compound 5 as a white powder (7%).

[0379] 1 1H NMR (400 MHz, DMSO-d 6)δ ppm 9.07 (d, J = 1.34 Hz, 1H) 8.48 (t, J = 5.99 Hz, 1H) 7.67 (d, J = 9.41 Hz, 1H) 7.46 (dd, J = 9.54, 2.08 Hz, 1H) 7.29 (s, 1H) 7.22 (s, 1H) 7.21 (d, J = 7.74 Hz, 2H) 7.12 - 7.17 (m, 1H) 4.49 (d, J = 6.11 Hz, 2H) 4.10 (br d, J = 4.28 Hz, 2H) 3.38 - 3.54 (m, 4H) 3.00 (q, J = 7.42 Hz, 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).

[0380] Synthesis of Compound 6

[0381]

[0382] Preparation of Intermediate C1

[0383] In a sealed tube, a mixture of intermediate A5 (300 mg, 0.652 mmol) and molecular sieve 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 dried over MgSO 4 4, filtered and evaporated to dryness in vacuo. The residue was purified by preparative LC (irregular SiOH 15 - 40 μm, 24 g, dry load mobile phase: heptane / EtOAc, gradient from 60:40 to 0:100) to give 77 mg of intermediate C1 (24%) as a white solid.

[0384] Preparation of Compound 6

[0385] At room temperature, Et 3 3N (23.4 μL, 0.169 mmol) was added to a solution of intermediate C1 (48 mg, 0.112 mmol) in anhydrous DCM (1.3 mL), and the mixture was stirred at room temperature for 10 min. The mixture was cooled to 0 °C, and a solution of Tf 2 2O in DCM (1 M in DCM, 112 μL, 0.112 mmol) was added dropwise. The mixture was stirred while warming to room temperature for 1 h. Tf 2A solution of O in DCM (1 M in DCM, 112 μL, 0.112 mmol) was added, and the mixture was stirred for an additional 1 h at room temperature. NaHCO 3 (saturated, 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 dried over MgSO 4 , filtered, and concentrated in vacuo. The residue was purified by preparative LC (irregular SiOH 15 - 40 μm, 24 g, dry load Mobile phase: heptane / EtOAc, gradient from 50:50 to 0:100). The second purification was carried out by reverse phase (stationary phase: YMC-actus Tria room temperature C18 10 μm 30*150 mm, mobile phase: NH 4 HCO 3 (0.2% in water) / MeCN, gradient from 45:55 to 25:75), to give 33 mg of compound 6 (37%) as a white solid.

[0386] 1 1H NMR (500 MHz, DMSO-d 6 ) δ ppm 9.07 (d, J = 1.58 Hz, 1H) 8.39 (t, J = 5.83 Hz, 1H) 7.66 (d, J = 9.46 Hz, 1H) 7.44 (dd, J = 9.46, 2.21 Hz, 1H) 7.29 (d, J = 8.51 Hz, 2H) 7.15 (d, J = 8.83 Hz, 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 = 5.36 Hz, 1H) 2.97 (q, J = 7.36 Hz, 2H) 2.52 - 2.58 (m, 6H) 1.26 (t, J = 7.57 Hz, 3H).

[0387] Synthesis of Compound 7

[0388]

[0389] Preparation of Intermediate C2

[0390] At 5 °C, ethyl 3-cyclopropyl-3-oxopropionate [24922-02-9] (0.603 g, 3.86 mmol) and (diacetoxyiodo)benzene (1.24 g, 3.86 mmol) were added to a solution of 2-amino-5-chloropyrimidine [428-89-7] (500 mg, 3.86 mmol) in Me-THF (40 mL). 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. An additional amount of ethyl 3-cyclopropyl-3-oxopropionate (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 purged with N 2 and stirred at room temperature for 1 h. An additional amount of ethyl 3-cyclopropyl-3-oxopropionate (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 again. The mixture was purged with N 2 and stirred at room temperature for an additional 1 h. EtOAc and water were added. The layers were separated, and the organic phase was dried over MgSO 4 , filtered, and concentrated in vacuo. The crude mixture was purified by preparative LC (irregular SiOH 15-40 μm, 80 g, dry load mobile phase: heptane / EtOAc, 80:20, 65:35). The residue was triturated in pentane. The solid was collected by filtration and dried in vacuo to give 598 mg of Intermediate C2 as a white solid (58%).

[0391] Preparation of Intermediate C3

[0392] 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). 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 (1 M in water) until the pH was approximately 3. The mixture was evaporated in vacuo to give 294 mg of Intermediate C3 as a white solid. The crude product was used as such in the next step.

[0393] Preparation of Compound 7

[0394] 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). The reaction mixture was stirred at room temperature for 16 h and evaporated in vacuo. The residue was taken up in EtOAc and washed with NaHCO 3 (saturated, aq.) and brine. The organic layer was dried over MgSO 4 , filtered, and evaporated in vacuo. The crude mixture was purified by preparative LC (irregular SiOH 15 - 40 μm, 24 g Büchi, dry load mobile phase: heptane / (EtOAc / MeOH, 9:1), gradient from 90:10 to 40:60) to afford 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 (47%) as a white solid.

[0395] 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 9.40 (d, J = 1.8 Hz, 1H) 8.58 - 8.75 (m, 2H) 7.34 (d, J = 8.1 Hz, 2H) 7.29 (s, 1H) 7.19 (d, J = 8.4 Hz, 2H) 4.50 (d, J = 5.6 Hz, 2H) 4.08 (s, 2H) 3.83 (s, 2H) 2.38 - 2.46 (m, 1H) 1.03 - 1.13 (m, 4H).

[0396] Synthesis of Compound 8

[0397]

[0398] Preparation of Intermediate C4

[0399] 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-oxobutyrate [66762-68-3] (6.00 g, 34.8 mmol). Then boron trifluoride etherate (0.30 mL, 1.15 mmol) was added dropwise. The solution was stirred at 5 °C for 1 h. The mixture was warmed to room temperature and stirred for an additional 1 h. EtOAc and NaHCO 3(Saturated, aq.). The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine (twice), dried over MgSO 4 and filtered and evaporated to give a brown liquid. The crude mixture was purified by preparative LC (irregular SiOH 15 - 40 μm, 120 g, dry load Mobile phase: heptane / EtOAc, gradient from 90:10 to 40:60) to afford 2.44 g of Intermediate C4 as a yellow solid (39%).

[0400] Preparation of Intermediate C5

[0401] 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 overnight at room temperature. The reaction was quenched with HCl (3 N in water) until pH ~ 3. The mixture was filtered to afford 996 mg of Intermediate C5 as an off - white solid (77%).

[0402] Preparation of Compound 8

[0403] At room temperature, to a mixture of Intermediate C5 (125 mg, 0.519 mmol) and DIPEA (270 μL, 1.57 mmol) in DMF (5 mL) was added EDCI·HCl (125 mg, 0.652 mmol) and HOBt·H 2 O (85 mg, 0.555 mmol). 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), dried over MgSO 4 and filtered and concentrated in vacuo until dry to give an orange solid which was purified by preparative LC (irregular SiOH 15 - 40 μm, 24 g, dry load Mobile phase: heptane / (EtOAc / MeOH, 9:1), gradient from 75:20 to 30:70) to obtain a white solid. The residue was purified by reverse phase (spherical C18, 25 μm, 40 g YMC - ODS - 25, dry load Mobile phase: NH 4 HCO 3 (0.2% in water) / MeCN, gradient from 60:40 to 0:100) to afford 233 mg of Compound 8 as a white solid (71%).

[0404] 1 H NMR (400 MHz, CDCl 3 -d) δ ppm 9.68 (dd, J=2.0, 0.8 Hz, 1H) 8.51 (t, J=4.7 Hz, 1H) 7.56 (d, J=9.4 Hz, 1H) 7.31 - 7.36 (m, 3H) 7.18 (d, J=7.9 Hz, 2H) 7.11 (s, 1H) 4.75 (s, 2H) 4.59 (d, J=5.5 Hz, 2H) 4.06 (t, J=4.7 Hz, 2H) 3.79 (t, J=4.7 Hz, 2H) 3.28 (s, 3H)

[0405] Synthesis of Compound 9

[0406]

[0407] Preparation of Intermediate D1

[0408] At 120 °C, a mixture of 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 N (14.7 mL, 105 mmol) in DMSO (47 mL) was stirred 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 (twice). The combined organic layers were washed with brine (3 times), dried over MgSO 4 and filtered and evaporated in vacuo. The residue was purified by preparative LC (irregular SiOH 15 - 40 μm, 80 g, liquid injection (DCM), mobile phase: heptane / EtOAc, gradient from 100:0 to 50:50) to give 5.02 g of intermediate D1 as a white solid (68%).

[0409] Preparation of Intermediate D2

[0410] In an autoclave, Raney nickel (3.39 g, 57.7 mmol) was added to a solution of intermediate D1 (2.00 g, 7.16 mmol) in a 7 M solution of NH 3 in MeOH (70 mL) (purged with nitrogen). The reaction mixture was hydrogenated at 7 bar at room temperature for 2 h. The mixture was filtered through a pad and rinsed with MeOH. The filtrate was concentrated in vacuo to give 2.11 g of intermediate D2 as a white solid (quantitative).

[0411] Preparation of Intermediate D3

[0412] 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 and 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 (twice). The combined organic layers were washed with brine (twice), dried over MgSO 4 and filtered and evaporated in vacuo. The residue was purified by preparative LC (irregular SiOH 15 - 40 μm, 120 g, liquid injection (DCM), mobile phase: heptane / EtOAc, gradient from 50:50 to 0:100) to give 2.76 g of intermediate D3 as a light brown solid (83%).

[0413] Preparation of Intermediate D4

[0414] At 40 °C, intermediate D3 (1.5 g, 3.06 mmol) was dissolved in Me-THF (23.2 mL) and AcOH (1.75 mL). Isoamyl 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 in EtOAc and NaHCO 3 (saturated, aq.). The layers were separated, and the organic layer was washed with NaHCO 3 (saturated, aq.) (twice) and brine, dried over MgSO 4 and evaporated in vacuo to give 1.74 g of intermediate D4 as a pale yellow oil.

[0415] Preparation of Intermediate D5

[0416] 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 (formamidine sulfinic acid) (1.66 g, 15.3 mmol) was added, and the reaction mixture was stirred at 50 °C for 1 h (using a finderer device). The reaction mixture was diluted with DCM and K 2 CO 3 (10%, aq.) was added. The layers were separated, and the organic layer was dried over MgSO 4 and filtered and the solvent was removed under reduced pressure to give 1.44 g of intermediate D5 as a yellow oil.

[0417] Preparation of Intermediate D6

[0418] 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 triturated in Et 2 O. The solvent was evaporated to give 1.51 g of intermediate D6 as a pale yellow solid (quantitative).

[0419] Preparation of Intermediate D7

[0420] 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 basified with NaHCO 3 (saturated, aq.). The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO 4 4, filtered, and the solvent was removed under reduced pressure. The residue was purified by preparative LC (irregular SiOH 15 - 40 μm, 24 g, liquid injection (DCM), mobile phase: DCM / MeOH, gradient from 100:0 to 90:10) to give 202 mg of intermediate D7 as an off-white solid (33%).

[0421] Preparation of Compound 9

[0422] 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 a solution of Tf 2 O in DCM (1 M in DCM, 0.487 mL, 0.487 mmol) was added dropwise over 5 min. The reaction mixture was diluted with DCM and NaHCO 3 (saturated, aq.). The layers were separated. The organic layer was washed with brine, dried over MgSO 4 4, filtered, and the solvent was removed under reduced pressure. The residue was purified by preparative LC (irregular SiOH 15 - 40 μm, 12 g, liquid injection (DCM), mobile phase: heptane / EtOAc, gradient from 70:30 to 0:100) to give 183 mg of a yellow solid. The solid was triturated and sonicated in EtOAc. The suspension was filtered. The solid and filtrate were combined. The residue was in Et 2Ground in O and sonicated, filtered out, washed with Et 2 O and collected to give 125 mg of compound 9 (47%) as a white solid.

[0423] 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 9.09 (d, J = 1.5 Hz, 1H) 8.48 (t, J = 5.9 Hz, 1H) 7.67 (d, J = 9.5 Hz, 1H) 7.47 (dd, J = 9.5, 2.0 Hz, 1H) 7.30 - 7.41 (m, 2H) 7.16 - 7.30 (m, 2H) 4.50 (d, J = 5.9 Hz , 2H) 4.10 (br t, J = 4.2 Hz, 2H) 3.65 (t, J = 4.6 Hz, 2H) 3.00 (q, J = 7.5 Hz, 2H) 1.27 (t, J = 7.5 Hz, 3H).

[0424] Synthesis of Compound 10

[0425]

[0426] To 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 EDCI·HCl (91 mg, 0.474 mmol), HOBt·H 2 O (63 mg, 0.415 mmol) and DIPEA (203 μL, 1.18 mmol). 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 (twice), dried over MgSO 4 and filtered, and the solvent was removed under reduced pressure. The residue was purified by preparative LC (irregular SiOH 15 - 40 μm, 12 g, liquid injection (DCM), mobile phase: DCM / MeOH, gradient from 100:0 to 90:10). The second purification was carried out 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 from 50:50 to 25:75). The residue was dissolved in MeCN and MeOH (50:50), diluted with water and lyophilized to give 44 mg of compound 10 (22%) as a white solid.

[0427] 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 9.40 (dd, J = 4.8, 2.9 Hz, 1H) 8.82 (d, J = 3.1 Hz, 1H) 8.51 (t, J = 5.7 Hz, 1H) 7.26 - 7.35 (m, 3H) 7.18 (d, J = 8.7 Hz, 2H) 4.48 (d, J = 5.7 Hz, 2H) 4.08 (t, J = 4.6 Hz, 2H) 3.82 (t, J = 4.8 Hz, 2H) 3.02 (q, J = 7.5 Hz, 2H) 1.27 (t, J = 7.5 Hz, 3H).

[0428] Synthesis of Compound 11

[0429]

[0430] At room temperature, 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) was added EDCI·HCl (150 mg, 0.782 mmol) and HOBt·H 2 O (105 mg, 0.686 mmol). 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 (twice), dried over MgSO 4 4, filtered and concentrated in vacuo until dry. The residue was purified by preparative LC (irregular SiOH 15 - 40 μm, 24 g, dry load mobile phase: heptane / (EtOAc / MeOH, 9 / 1), gradient from 60:40 to 10:90). The residue was crystallized from EtOAc and collected by filtration to give 170 mg of compound 11 (52%) as a white solid.

[0431] 1 H NMR (400 MHz, DMSO-d 6)δ ppm 9.30 (dd, J = 7.0, 2.0 Hz, 1H) 8.61 (dd, J = 4.2, 2.0 Hz, 1H) 8.48 (t, J = 5.9 Hz, 1H) 7.27 - 7.35 (m, 3H) 7.13 - 7.21 (m, 3H) 4.47 (d, J = 6.0 Hz, 2H) 4.05 - 4.11 (m, 2H) 3.83 (t, J = 4.8 Hz, 2H) 3.01 (q, J = 7.5 Hz, 2H) 1.27 (t, J = 7.5 Hz, 3H).

[0432] Synthesis of Compound 12

[0433]

[0434] To 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 added EDCI·HCl (140 mg, 0.730 mmol) and HOBt·H 2 O (100 mg, 0.653 mmol). The mixture was stirred at room temperature for 15 min. Then intermediate E9 (240 mg, 0.669 mmol) was 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, dried over MgSO 4 and concentrated to dryness. The residue was purified by preparative LC (irregular SiOH 15 - 40 μm, 24 g, dry load mobile phase: heptane / (EtOAc / MeOH, 9 / 1), gradient from 95:5 to 50:50). The second purification was carried out by reverse phase (spherical C18, 25 μm, 40 g YMC-ODS-25, dry load mobile phase: NH 4 HCO 3 (0.2% in water) / MeCN, gradient from 60:40 to 5:95) to give 206 mg of compound 12 (66%) as a white solid.

[0435] 1 1H NMR (500 MHz, DMSO-d 6)δ ppm 8.05 (t, J = 6.0 Hz, 1H) 7.87 (s, 1H) 7.24 - 7.30 (m, 3H) 7.17 (d, J = 8.5 Hz, 2H) 4.41 (d, J = 6.0 Hz, 2H) 4.04 - 4.10 (m, 2H) 3.81 (brt, J = 4.7 Hz, 2H) 2.86 (q, J = 7.6 Hz, 2H) 2.41 (s, 3H) 1.20 (t, J = 7.6 Hz, 3H).

[0436] Synthesis of Compounds 13 and 14

[0437]

[0438] Preparation of Intermediate E1

[0439] The reaction was carried out in 2 batches. The procedure for one batch is reported herein. When “Tf” is used herein, to avoid ambiguity, it represents -S(O) 2 CH 3 . Additionally, intermediate E9 can be prepared and / or used as the HCl salt. Charge a 1 L flask equipped with a findenser with 4-fluorobenzonitrile [1194 - 02 - 1] (20 g, 165 mmol), DMSO (320 mL), and N-boc-1,2-diaminoethane (39.7 g, 248 mmol). Add Et 3 N (92 mL, 661 mmol), and stir the reaction mixture at 120 °C for 20 h. Combine the two batches and pour into a mixture of crushed ice and water (1 L). Add brine (1 kg), and stir the mixture at room temperature for 30 min. Add EtOAc (1 L). Separate the layers, and extract the aqueous layer with EtOAc (2 x 500 mL). Wash the combined organic layers with brine (2 x 1 L), dry over MgSO 4 , filter, and evaporate in vacuo. Grind the residue in pentane (500 mL). Collect the solid by filtration, wash with cold Et 2 O, and dry in vacuo to give 48.28 g of intermediate E1 as a white solid (46%, 92% purity).

[0440] Preparation of Intermediate E2

[0441] In a 1 L autoclave, a mixture of intermediate E1 (41.5 g, 159 mmol) and Raney nickel (4.66 g, 79.4 mmol) in a 7 M solution of NH 3 (in MeOH) (500 mL) was hydrogenated at room temperature under 6 bar of H 2 for 12 h. Pass the reaction mixture through Pad filter, wash with a mixture of DCM and MeOH (9 / 1), and evaporate the filtrate in vacuo to give 41.8 g of Intermediate E2 (99%) as a green oil.

[0442] Preparation of Intermediate E3

[0443] Under N 2 At 0 °C, 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 washed with NaHCO 3 (saturated, aq.), dried over MgSO 4 and filtered, and the solvent was removed under reduced pressure to give 1.11 g of Intermediate E3 (74%) as a white solid.

[0444] Preparation of Intermediate E4

[0445] At 40 °C, Intermediate E3 (1.11 g, 2.78 mmol) was dissolved in Me-THF (21 mL) and AcOH (1.6 mL). Isoamyl 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 (saturated, aq.). The layers were separated, and the organic phase was washed with NaHCO 3 (saturated, aq., twice), brine, dried over MgSO 4 and evaporated in vacuo to give 1.23 g of Intermediate E4 (quantitative) as a pale yellow solid.

[0446] Preparation of Intermediate E5

[0447] 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). Then thiourea dioxide (formamidinesulfinic acid) (1.56 g, 14.5 mmol) was added, and the reaction mixture was stirred at 50 °C for 1.5 h. The reaction mixture was diluted with DCM, and 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 dried over MgSO 4 filtered and evaporated in vacuo to give 970 mg of Intermediate E5 (81%) as a pale yellow oil.

[0448] Preparation of Intermediate E6

[0449] To a solution of intermediate E5 (970 mg, 2.34 mmol) in MeOH (23 mL) was added dropwise TMSCl (2.4 mL, 18.7 mmol). The reaction mixture was stirred at room temperature for 20 h and concentrated in vacuo to give 710 mg of intermediate E6 (78%) as a brown solid.

[0450] Preparation of Intermediate E7

[0451] At 100 °C, 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 for 50 min. The reaction mixture was concentrated in vacuo. The residue was diluted in a solution of DCM and K 2 CO 3 (10%, aq.). The layers were separated and the aqueous layer was extracted with DCM and MeOH (95 / 5) (twice). The combined organic layers were dried over MgSO 4 4, filtered and evaporated in vacuo. The residue was purified by preparative LC (irregular SiOH 15 - 40 μm, 40 g, liquid injection (DCM), mobile phase: DCM / MeOH, gradient from 100:0 to 90:10) to give 273 mg of intermediate E7 (46%) as a yellow residue.

[0452] Preparation of Intermediate E8

[0453] Et 3 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 a solution of Tf 2 2O (1 M 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 (saturated, aq.). The layers were separated. The aqueous layer was extracted with DCM (twice). The combined organic layers were dried over MgSO 4 4, filtered, and the solvent was removed under reduced pressure. The residue was purified by preparative LC (irregular SiOH 15 - 40 μm, 12 g, dry load mobile phase: heptane / EtOAc, gradient from 100:0 to 0:100) to give 105 mg of intermediate E8 (27%) as a white solid.

[0454] Preparation of Intermediate E9

[0455] In a steel bomb, a mixture of intermediate E8 (85 mg, 0.186 mmol) and Pd(OH) 2 (21 mg, 0.075 mmol) in MeOH (8.5 mL) was hydrogenated at room temperature under 10 bar H 2 for 6 h. The mixture was filtered through a pad and the filtrate was evaporated in vacuo to give 65 mg of intermediate E9 as a white residue (quantitative).

[0456] Preparation of Compound 13

[0457] To 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 added EDCI·HCl (39 mg, 0.202 mmol), HOBt·H 2 O (31 mg, 0.202 mmol) and intermediate E9 (65 mg, 0.202 mmol). The reaction mixture was stirred at room temperature for 20 h. The reaction mixture was diluted with DCM and washed with NaHCO 3 (saturated, aq.). The organic layer was dried over MgSO 4 and filtered, and the solvent was removed under reduced pressure. The residue was purified by preparative LC (irregular SiOH 15 - 40 μm, 12 g, liquid injection (DCM), mobile phase: DCM / MeOH, gradient from 100:0 to 90:10). The solid (70 mg) was triturated and sonicated in Et 2 O and the solvent was removed under reduced pressure. The residue (68 mg) 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 from 55:45 to 35:65) to give 42 mg of compound 13 as a white solid (39%).

[0458] 1 H NMR (400 MHz, DMSO-d 6) δ ppm 9.40 (d, J = 2.69 Hz, 1H) 8.68 (d, J = 2.57 Hz, 1H) 8.55 (t, J = 5.87 Hz, 1H) 7.32 (m, J = 8.68 Hz, 2H) 7.28 (s, 1H) 7.19 (m, J = 8.68 Hz, 2H) 4.47 (d, J = 5.87 Hz, 2H) 4.08 (t, J = 4.58 Hz, 2H) 3.83 (t, J = 4.77 Hz, 2H) 3.01 (q, J = 7.46 Hz, 2H) 1.29 (t, J = 7.46 Hz, 3H).

[0459] Preparation of Compound 14

[0460] Compound 14 was prepared as follows: Following the procedure reported for the synthesis of compound 13, starting from intermediate E9 and 5-methoxy-2-methylpyrazolo[1,5-a]pyridine-3-carboxylic acid [1352395-28-8], 32 mg of a white fluffy solid (40%) was obtained.

[0461] 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.50 (d, J = 7.46 Hz, 1H) 7.86 (t, J = 5.99 Hz, 1H) 7.25 - 7.33 (m, 3H) 7.24 (d, J = 2.69 Hz, 1H) 7.18 (d, J = 8.68 Hz, 2H) 6.63 (dd, J = 7.46, 2.81 Hz, 1H) 4.43 (d, J = 5.99 Hz, 2H) 4.08 (t, J = 4.59 Hz, 2H) 3.85 (s, 3H) 3.79 - 3.83 (m, 2H).

[0462] Synthesis of Compound 15

[0463]

[0464] Preparation of Intermediate F1

[0465] At 120 °C, a mixture of 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 (13.7 g, 99.1 mmol) in anhydrous DMSO (40 mL) was heated 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 dried over MgSO 4Dry, filter and evaporate in vacuo. Purify the crude mixture by preparative LC (irregular SiOH 15 - 40 μm, 330 g, liquid injection (DCM), mobile phase: heptane / EtOAc, gradient from 90:10 to 30:70) to give 18.04 g of intermediate F1 (80%) as a colorless oil.

[0466] Preparation of Intermediate F2

[0467] 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 stirred at room temperature under 6 bar H 2 for 2 h. Filter the mixture over a pad, wash with MeOH, and evaporate the filtrate in vacuo to give 17.25 g of intermediate F2 (quantitative) as a blue / green oil.

[0468] Preparation of Intermediate F3

[0469] 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 O (1.62 g, 12.0 mmol). Stir the reaction mixture at room temperature for 8 h. Evaporate the mixture and purify the crude mixture by preparative LC (irregular SiOH 15 - 40 μm, 220 g, dry load mobile phase: heptane / EtOAc, gradient from 70:30 to EtOAc 0:100) to give 3.703 g of intermediate F3 (76%) as a brown foam.

[0470] Preparation of Intermediate F4

[0471] Dissolve intermediate F3 (3.54 g, 7.28 mmol) in Me-THF (62 mL) and AcOH (4.17 mL, 72.8 mmol). Add dropwise isoamyl nitrite (4.89 mL, 36.4 mmol) and stir the reaction mixture at 40 °C for 1 h. Dilute the resulting solution in EtOAc. Wash the organic layer with K 2 CO 3 (10%, aq.) (twice) and brine, and dry over MgSO 4Dry and evaporate in vacuo. Purify the residue by preparative LC (irregular SiOH 15 - 40 μm, 80 g, dry load Mobile phase: heptane / EtOAc, gradient from 50:50 to 0:100) to give 3.54 g of intermediate F4 as an orange paste (94%).

[0472] Preparation of Intermediate F5

[0473] 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). Add formamidine sulfonic acid (1.19 g, 11.0 mmol), and stir the reaction mixture at 50 °C for 1.5 h. Dilute the reaction mixture in DCM and add K 2 CO 3 (10% aq.). Extract the aqueous layer with DCM and MeOH (95 / 5) (twice). Dry the combined organic layers over MgSO 4 dry, filter and evaporate in vacuo to give 970 mg of intermediate F5 as a yellow foam (91% purity, 80%).

[0474] Preparation of Intermediate F6

[0475] A solution of intermediate F5 (932 mg, 1.69 mmol) in MeOH (18 mL) was treated with TMSCl (2.15 mL, 16.9 mmol). Stir the reaction mixture at room temperature for 20 h and evaporate in vacuo. Grind the solid in Et 2 O. Decant the supernatant, and dry the yellow powder under vacuum to give 915 mg of intermediate F6 (quantitative).

[0476] Preparation of Compound 15

[0477] To a solution of intermediate F6 (270 mg, 0.570 mmol) in HFIP (4.86 mL) add trimethyl orthoformate (187 μL, 1.71 mmol), and stir the reaction mixture at 60 °C for 16 h. Dilute the reaction mixture with EtOAc and quench with K 2 CO 3 (10%, aq.). Wash the organic layer with H 2 O (once) and brine (once), dry over MgSO 4 dry, filter and evaporate in vacuo. Purify the crude mixture by preparative LC (irregular SiOH 15 - 40 μm, 12 g, dry load Mobile phase: DCM / (DCM / MeOH, 80:20), gradient from 95:5 to 75:25). The residue was heated in EtOH under reflux for 20 min. The solution was cooled to room temperature and 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 (22%) as a beige soft solid.

[0478] 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 9.03 (s, 1H) 8.40 (t, J = 5.8 Hz, 1H) 7.66 (d, J = 9.4 Hz, 1H) 7.45 (dd, J = 9.5, 2.08 Hz, 1H) 7.18 (d, J = 8.7 Hz, 2H) 7.10 (d, J = 8.7 Hz, 2H) 6.70 (s, 1H) 4.42 (d, J = 5.8 Hz, 2H) 3.51 (t, J = 5.2 Hz, 2H) 3.34 (t, J = 5.2 Hz, 2H) 2.96 (q, J = 7.6 Hz, 2H) 2.83 (s, 3H) 1.25 (t, J = 7.5 Hz, 3H).

[0479] Synthesis of Compound 16

[0480]

[0481] Preparation of Intermediate G1

[0482] Charge the flask 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). Add HATU (1.86 g, 4.90 mmol) in portions and stir the reaction mixture at room temperature for 17 h. Dilute the mixture with EtOAc and water. Separate the layers and wash the organic layer with brine (twice), dry over MgSO 4 dry, filter and evaporate in vacuo. Dissolve the residue in warm EtOAc. Cool the solution to room temperature and 0 °C. Filter off the suspension and wash the solid with cold EtOAc and then with Et 2 O wash. Dry the solid in vacuo to afford 773 mg of intermediate G1 (42%) as an off-white solid.

[0483] Preparation of Intermediate G2

[0484] Intermediate G1 (740 mg, 1.80 mmol), N-boc-ethylenediamine (375 mg, 2.34 mmol) and Cs 2 CO 3 (1.06 g, 3.24 mmol) in a mixture of tert-amyl alcohol (24 mL) and Me-THF (16 mL) was purged with N 2 . BrettphosPd G3 (82 mg, 0.090 mmol) and Brettphos (97 mg, 0.18 mmol) were added. The reaction mixture was purged with N 2 again and stirred at 80 °C for 17 h. The reaction mixture was cooled to room temperature. was added and the mixture was evaporated in vacuo. The residue was purified by preparative LC (irregular SiOH 15 - 40 μm, 40 g, mobile phase: heptane / EtOAc, gradient from 50:50 to 0:100) to give 444 mg of Intermediate G2 (50%) as a pale yellow foam.

[0485] Preparation of Intermediate G3

[0486] Intermediate G3 was prepared as follows: Following the synthesis reported for the synthesis of Intermediate F4, starting from Intermediate G2, and 408 mg of yellow solid (87%) was obtained.

[0487] Preparation of Intermediate G4

[0488] Intermediate G4 was prepared as follows: Following the procedure reported for the synthesis of Intermediate F5, starting from Intermediate G3, and 362 mg of off-white solid (94%) was obtained.

[0489] Preparation of Intermediate G5

[0490] Intermediate G5 was prepared as follows: Following the procedure reported for the synthesis of Intermediate F6, starting from Intermediate G4, and 343 mg of yellow powder (quantitative) was obtained.

[0491] Preparation of Intermediate G6

[0492] 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. At room temperature, an additional amount of anhydrous DMF (3.7 mL) and trimethyl orthoformate (194 μL, 1.78 mmol) were added and the reaction mixture was stirred at 60 °C for an additional 1.5 h. The reaction mixture was diluted with DCM and washed with K 2 CO 3Quenched with (10%, aq.). The layers were separated and the aqueous layer was extracted with DCM and MeOH (95 / 5) (twice). The combined organic layers were washed with water and brine, dried over MgSO 4 and filtered and evaporated in vacuo. The crude mixture was purified by preparative LC (irregular SiOH 15 - 40 μm, 12 g, dry load Mobile phase: DCM / (DCM / MeOH, 80 / 20), gradient from 95:5 to 70:30) to give 156 mg of Intermediate G6 as a white solid (63%).

[0493] Preparation of Compound 16

[0494] Under a N 2 atmosphere, a mixture of Intermediate G6 (143 mg, 0.345 mmol) and Et 3 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 (twice). The combined organic layers were washed with water and brine, dried over MgSO 4 and filtered and evaporated in vacuo. The crude mixture was purified by preparative LC (irregular SiOH 15 - 40 μm, 12 g, dry load Mobile phase: DCM / (DCM / MeOH, 80:20), gradient from 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 from 55:45 to 25:75) to give 84 mg of Compound 16 as a white solid (45%).

[0495] 1 H NMR (500 MHz, DMSO - d 6)δ ppm 9.05 (s, 1H) 8.40 (t, J = 5.8 Hz, 1H) 7.66 (d, J = 9.5 Hz, 1H) 7.45 (dd, J = 9.5, 2.1 Hz, 1H) 7.36 (t, J = 8.5 Hz, 1H) 7.02 (m, 2H) 7.32 (s, 1H) 4.50 (d, J = 5.8 Hz, 2H) 4.07 (t, J = 4.7 Hz, 2H) 3.86 (t, J = 4.7 Hz, 2H) 2.96 (q, J = 7.5 Hz, 2H) 1.25 (t, J = 7.5 Hz, 3H).

[0496] Synthesis of Compound 17

[0497]

[0498] Preparation of Compound 17

[0499] In N 2 atmosphere, intermediate A6 (180 mg, 0.454 mmol) and Et 3 N (315 μL, 2.27 mmol) in a mixture of anhydrous Me-THF (7 mL), anhydrous 1,4-dioxane (7 mL) and anhydrous DCM (7 mL) were 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 and diluted with DCM, and quenched with K 2 CO 3 (10%, aq.). The layers were separated, and the aqueous layer was extracted with DCM and MeOH (95 / 5) (twice). The combined organic layers were dried over MgSO 4 and filtered and evaporated in vacuo. The solid was purified by preparative LC (irregular SiOH 15 - 40 μm, 12 g, dry load mobile phase: DCM / (DCM:MeOH, 80:20), gradient from 100:0 to 95:5) to give 124 mg of compound 17 (53%) as a pale yellow solid.

[0500] 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 = 8.7 Hz, 2H) 7.29 (dd, J = 9.5, 2.0 Hz, 1H) 7.23 (s, 1H) 7.18 (d, J = 8.7 Hz, 2H) 6.03 (br t, 1H) 3.71 (t, J = 4.6 Hz, 2H) 3.00 (d, J = 6.6 Hz, 2H) 2.95 (q, J = 7.6, 2H) 2.32 (m, 1H) 1.39 (t, J = 7.6 Hz, 3H) 1.15 (s, 3H) 1.14 (s, 3H).

[0501] Synthesis of Compound 18

[0502]

[0503] In N 2 atmosphere, intermediate A6 (300 mg, 0.756 mmol) and Et 3 N (0.525 mL, 3.78 mmol) in a mixture of anhydrous DCM (11.5 mL), anhydrous Me-THF (11.5 mL) and anhydrous 1,4-dioxane (11.5 mL) were stirred at 70 °C for 2.5 h. The mixture was cooled to room temperature and then cooled 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 quenched 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) (twice). The combined organic layers were washed with brine, dried over MgSO 4 and filtered and evaporated in vacuo. The residue was purified by preparative LC (irregular SiOH 15 - 40 μm, 12 g, dry load mobile phase: DCM / (DCM / MeOH, 80 / 20), gradient from 95:5 to 85:15) to give 180 mg of compound 18 as a white solid (54%).

[0504] 1 H NMR (500 MHz, DMSO-d 6)δ ppm rotamers: 9.08 (d, J = 1.3 Hz, 1H) 8.17 (br t, J = 5.4 Hz, 1H) 7.62 (d, J = 9.8 Hz, 1H) 7.58 (br s, 1H) 7.41 (dd, J = 9.5, 2.2 Hz, 1H) 7.30 (d, J = 8.8 Hz, 2H) 7.20 (d, J = 8.5 Hz, 2H) 4.49 (d, J = 6.0 Hz, 2H) 3.86 (br s, 2H) 3.66 (t, J = 5.0 Hz, 2H) 2.99 (q, J = 7.6 Hz, 2H) 2.25 (s, 3H) 1.28 (t, J = 7.6 Hz, 3H).

[0505] Synthesis of Compound 19

[0506]

[0507] At 0 °C, 2-Methoxy-1-ethanesulfonyl chloride (88.3 μL, 0.756 mmol) was added to a mixture of Intermediate A6 (100 mg, 0.252 mmol) and Et 3 N (0.175 mL, 1.26 mmol) in anhydrous DCM (2.7 mL) and anhydrous Me-THF (2.7 mL), 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 (twice). The combined organic layers were washed with water (twice) and brine, dried over MgSO 4 , filtered and evaporated in vacuo. The residue was purified by preparative LC (irregular SiOH 15 - 40 μm, 12 g, dry load Mobile phase: heptane / EtAOc, gradient from 55:45 to 0:100, then EtOAc / MeOH 99:1). The solid was triturated in MeCN, the supernatant was removed, and the solid was dried in vacuo to give 53 mg of Compound 19 (41%) as a white solid.

[0508] 1 1H NMR (400 MHz, DMSO-d 6)δ ppm 9.06 (d, J = 1.5 Hz, 1H) 8.43 (t, J = 5.9 Hz, 1H) 7.66 (d, J = 9.5 Hz, 1H) 7.45 (dd, J = 9.5, 2.1 Hz, 1H) 7.28 (d, J = 8.7 Hz, 2H) 7.17 (d, J = 8.7 Hz, 2H) 7.14 (s, 1H) 4.45 (d, J = 5.9 Hz, 2H) 3.84 (t, J = 4.3 Hz, 2H) 3.63 - 3.75 (m, 6H) 3.24 (s, 3H) 2.97 (q, J = 7.5 Hz, 2H) 1.25 (t, J = 7.5 Hz, 3H) 1.09 (t, J = 7.0 Hz, 1H).

[0509] Synthesis of Compound 20

[0510]

[0511] A mixture of intermediate A6 (120 mg, 0.302 mmol) and Et 3 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, 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 (twice). The combined organic layers were washed with water and brine, dried over MgSO 4 4, filtered, and evaporated in vacuo. The residue was purified by preparative LC (irregular SiOH 15 - 40 μm, 12 g, dry load Mobile phase: heptane / EtOAc, gradient from 30:70 to 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 (47%) as a white solid.

[0512] 1 1H NMR (400 MHz, DMSO - d 6) δ ppm 9.06 (d, J = 1.6 Hz, 1H) 8.43 (t, J = 5.8 Hz, 1H) 7.66 (d, J = 9.5 Hz, 1H) 7.45 (dd, J = 9.4, 2.08 Hz, 1H) 7.28 (d, J = 8.6 Hz, 2H) 7.19 (s, 1H) 7.17 (d, J = 8.8 Hz, 2H) 4.46 (d, J = 5.9 Hz, 2H) 3.86 (t, J = 5.1 Hz, 2H) 3.70 (t, J = 5.1 Hz, 2H) 3.27 (s, 3H) 2.97 (d, J = 7.5 Hz, 2H) 1.99 (s, 1H) 1.25 (t, J = 7.5 Hz, 3H).

[0513] Synthesis of Compound 21

[0514]

[0515] Preparation of Intermediate H6

[0516] 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 K 2 CO 3 (10%, aq.) was added. The layers were separated and the aqueous layer was extracted with DCM and MeOH (95 / 5) (twice). The combined organic layers were dried over MgSO 4 , filtered and evaporated in vacuo. The residue was purified by preparative LC (irregular SiOH 15 - 40 μm, 12 g, dry load, mobile phase: DCM / MeOH, gradient from 100:0 to 95:5) to give 132 mg of intermediate H6 as a yellow foam (77% purity, 57%).

[0517] Preparation of Compound 21

[0518] 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). 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 quenched with a small amount of MeOH and K 2 CO 3 (10%, aq.). The layers were separated and the aqueous phase was extracted with DCM (twice). The combined organic extracts were washed with brine, dried over MgSO4 Dry, filter and evaporate in vacuo. Purify the residue by preparative LC (irregular SiOH 15 - 40 μm, 12 g, dry load Mobile phase: heptane / EtAOc, gradient from 80:20 to 0:100). The second purification is carried out via 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 from 40:60 to 10:90), to give 52 mg of compound 21 (38%) as an off-white solid.

[0519] 1 1H NMR (500 MHz, DMSO-d 6 ) δ ppm 9.06 (d, J = 1.6 Hz, 1H) 8.44 (s, 1H) 7.66 (d, J = 9.5 Hz, 1H) 7.45 (dd, J = 9.6, 2.1 Hz, 1H) 7.30 (d, J = 8.8 Hz, 2H) 7.16 (d, J = 8.8 Hz, 2H) 4.46 (d, J = 6.0 Hz, 2H) 4.00 (t, J = 5.4 Hz, 2H) 3.82 (t, J = 5.4 Hz, 2H) 2.97 (q, J = 5.6 Hz, 2H) 2.26 (s, 3H) 1.25 (t, J = 7.6 Hz, 3H).

[0520] Synthesis of Compound 22

[0521]

[0522] Preparation of Intermediate I1

[0523] A mixture of 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 (4.76 g, 14.6 mmol) in anhydrous tert-amyl alcohol (46 mL) was purged with N 2 2. Add Brettphos Pd G3 (331 mg, 0.365 mmol) and Brettphos (392 mg, 0.731 mmol), and heat the reaction mixture at 120 °C for 1 h using a single-mode microwave (Biotage Initiator60), and then heat for an additional 45 min. Combine the two batches at Filter on a pad and evaporate the filtrate in vacuo. Purify the residue by preparative LC (irregular SiOH 15 - 40 μm, 120 g, dry load Mobile phase: heptane / EtAOc, gradient from 90:10 to 0:100), to give 1.64 g of intermediate I1 (74%).

[0524] Preparation of Intermediate I2

[0525] Intermediate I2 was prepared as follows: Follow the procedure reported for the synthesis of intermediate F2, starting from intermediate I1, and obtain 1.55 g of a grey oil (94%).

[0526] Preparation of Intermediate I3

[0527] Intermediate I3 was prepared as follows: Follow the procedure reported for the synthesis of intermediate F3, starting from intermediate I2, and obtain 765 mg of a beige solid (62%).

[0528] Preparation of Intermediate I4

[0529] Intermediate I4 was prepared as follows: Follow the procedure reported for the synthesis of intermediate F4, starting from intermediate I3, and obtain 724 mg of a yellow solid (90%).

[0530] Preparation of Intermediate I5

[0531] Intermediate I5 was prepared as follows: Follow the procedure reported for the synthesis of intermediate F5, starting from intermediate I4, and obtain 692 mg of a beige foam (99%).

[0532] Preparation of Intermediate I6

[0533] Intermediate E6 was prepared as follows: Follow the procedure reported for the synthesis of intermediate F6, starting from intermediate I5, and obtain 710 mg of a beige solid (quantitative).

[0534] Preparation of Intermediate I7

[0535] 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. Dilute the reaction mixture with DCM and quench with K 2 CO 3 (10%, aq.). Separate the layers and extract the aqueous phase with DCM and MeOH (95 / 5) (twice). Combine the organic layers over MgSO 4Dry, filter and evaporate in vacuo. Purify the residue by preparative LC (irregular SiOH 15 - 40 μm, 12 g, dry load Mobile phase: DCM / (DCM:MeOH, 80 / 20), gradient from 95:5 to 85:15), to give 100 mg of intermediate I7 (42%) as a white solid.

[0536] Preparation of Compound 22

[0537] Under N 2 atmosphere, and at 0 °C, trifluoromethanesulfonic anhydride (0.323 mL, 0.323 mmol) was added dropwise to a mixture of intermediate I7 (92.0 mg, 0.216 mmol) and Et 3 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). The reaction mixture was stirred at 0 °C for 10 min and diluted with DCM and K 2 CO 3 (10%, aq.). The layers were separated and the aqueous phase was extracted with DCM and MeOH (95 / 5) (twice). The combined organic extracts were dried over MgSO 4 dry, filtered and evaporated in vacuo. Purify the residue by preparative LC (irregular SiOH 15 - 40 μm, 12 g, dry load Mobile phase: DCM / (DCM / MeOH, 95 / 5), gradient from 100:0 to 80 / 20). Grind the solid in EtOAc. Decant the supernatant and dry the white solid under vacuum at 60 °C for 1 h to give 28 mg of compound 22 (23%).

[0538] 1 H NMR (400 MHz, DMSO - d 6 ) δ ppm 9.04 (d, J = 1.5 Hz, 1H) 8.23 (t, J = 5.7 Hz, 1H) 7.66 (d, J = 9.7 Hz, 1H) 7.45 (dd, J = 9.5, 2.1 Hz, 1H) 7.31 (s, 1H) 7.19 (d, J = 8.3 Hz, 1H) 6.93 (d, J = 2.0 Hz, 1H) 6.70 (dd, J = 8.3, 2.0 Hz, 1H) 4.43 (d, J = 5.7 Hz, 2H) 4.07 (br d, J = 4.6 Hz, 2H) 3.86 (br d, J = 5.3 Hz, 2H) 3.84 (s, 3H) 2.96 (d, J = 7.5 Hz, 2H) 1.25 (t, J = 7.5 Hz, 3H).

[0539] Synthesis of Compound 23

[0540]

[0541] Preparation of Intermediate J1

[0542] At 0 °C, isobutanesulfonyl chloride (0.161 mL, 1.23 mmol) was added dropwise to a mixture of intermediate E7 (400 mg, 1.23 mmol) and Et 3 N (0.857 mL, 6.17 mmol) in anhydrous DCM (18 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction was quenched with NaHCO 3 (saturated, aq.). The layers were separated and the aqueous phase was extracted with DCM and MeOH (95 / 5) (twice). The combined organic extracts were dried over MgSO 4 and filtered and evaporated in vacuo. The residue was purified by preparative LC (irregular SiOH 15 - 40 μm, 24 g, dry load mobile phase: heptane / EtOAc, gradient from 100:0 to 0:100, then mobile phase EtOAc / MeOH, gradient from 100:0 to 95:5) to give 406 mg of intermediate J1 as a green solid (74%).

[0543] Preparation of Intermediate J2

[0544] Intermediate J1 (406 mg, 0.913 mmol) and Pd(OH) 2 (264 mg, 0.941 mmol) in a mixture of MeOH (20 mL), EtOAc (20 mL) and THF (5 mL) was stirred at room temperature under 15 bar H 2 for 18 h. The reaction mixture was filtered off and washed with MeOH, EtOAc and THF. The filtrate was evaporated in vacuo to give 180 mg of intermediate J2 as a yellow solid (60%).

[0545] Preparation of Compound 23

[0546] 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 2A 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 (twice) and brine. The organic phase was dried over MgSO 4 and filtered and evaporated in vacuo. The residue was purified by preparative LC (irregular SiOH 15 - 40 μm, 12 g, dry load Mobile phase: heptane / EtAOc, gradient from 90:10 to 0:100, then mobile phase: EtOAc / MeOH, gradient from 100:0 to 95:5), to give 101 mg of compound 23 (39%) as a pale yellow solid.

[0547] 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 9.39 (d, J = 2.8 Hz, 1H) 8.67 (d, J = 2.6 Hz, 1H) 8.51 (t, J = 6.0 Hz, 1H) 7.28 (d, J = 8.7 Hz, 2H) 7.19 (s, 1H), 7.17 (d, J = 8.8 Hz, 3H) 4.46 (d, J = 6.0 Hz, 2H) 3.86 (t, J = 4.8 Hz, 2H) 3.69 (t, J = 4.9 Hz, 2H) 3.32 (d, J = 6.6 Hz, 3H) 3.01 (q, J = 7.5 Hz, 2H) 2.13 (m, 1H) 1.27 (t, J = 7.6 Hz, 3H) 1.06 (s, 3H) 1.04 (s, 3H).

[0548] Synthesis of Compound 24

[0549]

[0550] Preparation of Intermediate K1

[0551] At 0 °C, acetyl chloride (0.145 mL, 2.04 mmol) was added dropwise to a mixture of intermediate E7 (550 mg, 1.70 mmol) and Et 3 N (1.18 mL, 8.48 mmol) in anhydrous DCM (24 mL). The reaction mixture was stirred at room temperature for 15 min and the reaction was quenched with NaHCO 3 (saturated, aq.). The layers were separated and the aqueous phase was extracted with DCM and MeOH (95 / 5) (twice). The combined organic extracts were dried over MgSO 4Dry, filter, and evaporate in vacuo. The residue was triturated in EtOAc and the solid was collected by filtration to afford 320 mg of Intermediate K1 (52%) as a pale yellow solid.

[0552] Preparation of Intermediate K2

[0553] Intermediate K1 (256 mg, 0.698 mmol), Pd(OH) 2 (157 mg, 0.558 mmol), and HCl (1 M in H 2 O, 0.698 mL, 0.698 mmol) in a mixture of MeOH (6.4 mL) and EtOAc (6.4 mL) were stirred at room temperature under 5 bar H 2 for 1 h. The reaction mixture was filtered and washed with EtOAc and MeOH. The yellow solid was purified by preparative LC (irregular SiOH 15 - 40 μm, 12 g, dry load mobile phase DCM / (DCM / MeOH / NH 3 aq., 80 / 20 / 0.5), gradient from 100:0 to 70:30) to give 130 mg of Intermediate K2 (75%).

[0554] Preparation of Compound 24

[0555] 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). The reaction mixture was stirred at room temperature for 16 h, filtered, and the solid was washed with DCM to afford 114 mg of Compound 24 (59%) as a pale yellow soft solid.

[0556] 1 1H NMR (500 MHz, DMSO-d 6)δ ppm 9.38 (d, J = 2.2 Hz, 1H) 8.61 (d, J = 2.5 Hz, 1H) 8.26 (br t, J = 6.0 Hz, 1H) 7.56 (br s, 1H) 7.28 (br d, J = 8.5 Hz, 2H) 7.18 (d, J = 8.5 Hz, 2H) 4.47 (d, J = 5.7 Hz, 2H) 3.84 (br s, 2H) 3.64 (t, J = 5.0 Hz, 2H) 3.01 (q, J = 7.6 Hz, 3H) 2.23 (br s, 3H) 1.28 (t, J = 7.4 Hz, 3H).

[0557] Synthesis of Compound 25

[0558]

[0559] Preparation of Intermediate L1

[0560] 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). 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 (twice). The combined organic extracts were washed with a mixture of water and brine (1 / 1) (3 times), dried over MgSO 4 and filtered and evaporated in vacuo. The residue was purified by preparative LC (irregular SiOH 15 - 40 μm, 330 g, dry load mobile phase: heptane / EtOAc, gradient from 100:0 to 30:70) to give 5.23 g of intermediate L1 as a white solid (56%).

[0561] Preparation of Intermediate L2

[0562] Intermediate L2 was synthesized as follows: Starting from intermediate L1 according to the procedure reported for the synthesis of intermediate F2, 1.09 g of a green oil was obtained (quantitative).

[0563] Preparation of Intermediate L3

[0564] To a mixture of 6-chloro-2-ethylimidazo[1,2-a]pyridine-3-carboxylic acid [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). 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 (twice). The combined organic extracts were washed with brine (twice), dried over MgSO 4 , filtered and evaporated in vacuo. The residue was purified by preparative LC (irregular SiOH 15 - 40 μm, 80 g, dry load mobile phase: heptane / EtOAc, gradient from 60:40 to 0:100) to give 1.078 g of Intermediate L3 as a yellow solid (69%).

[0565] Preparation of Intermediate L4

[0566] Intermediate L3 (1.08 g, 2.15 mmol) was dissolved in Me-THF (21 mL) and acetic acid (1.23 mL, 21.5 mmol). Isoamyl 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 (saturated, aq.). The layers were separated. The organic phase was washed with NaHCO 3 (saturated, aq.) (twice) and brine, dried over MgSO 4 , filtered and evaporated in vacuo. The residue was triturated in pentane and the supernatant was decanted to give a yellow solid which was dried in vacuo to afford 1.127 g of Intermediate L4 (99%).

[0567] Preparation of Intermediate L5

[0568] Intermediate L5 was prepared as follows: Following the procedure reported for the synthesis of Intermediate F5, starting from Intermediate L4, and 1.07 g of an orange foam was obtained (97%).

[0569] Preparation of Intermediate L6

[0570] Intermediate L6 was prepared as follows: Following the procedure reported for the synthesis of Intermediate F6, starting from Intermediate L5, and 1.10 g of a yellow powder was obtained (quantitative).

[0571] Preparation of Intermediate L7

[0572] 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 quenched with K 2 CO 3 (10%, aq.). The layers were separated, and the organic phase was washed with H 2 O and brine, dried over MgSO 4 , filtered and evaporated in vacuo. The residue was purified by preparative LC (irregular SiOH 15 - 40 μm, 25 g, dry load Mobile phase: DCM / (DCM / MeOH, 80 / 20), gradient from 100:0 to 50:50) to give 290 mg of intermediate L7 (60%) as a pale orange solid.

[0573] Preparation of Compound 25

[0574] At 0 °C, trifluoromethanesulfonic anhydride (0.815 mL, 0.815 mmol) was added dropwise to a mixture of intermediate L7 (290 mg, 0.679 mmol) and Et 3 N (0.472 mL, 3.40 mmol) in anhydrous DCM (10 mL) and anhydrous Me-THF (10 mL). The reaction mixture was stirred at 0 °C for 15 min and diluted with DCM. Small amounts of MeOH and K 2 CO 3 (10%, aq.) were added successively. The layers were separated, and the aqueous phase was extracted with DCM and MeOH (95 / 5) (twice). The combined organic extracts were washed with water and brine, dried over MgSO 4 , filtered and evaporated. The residue was purified by preparative LC (irregular SiOH 15 - 40 μm, 25 g, dry load Mobile phase: heptane / EtOAc, gradient from 70:30 to 0:100). The yellow solid was triturated in Et 2 O, sonicated and collected by filtration to give 135 mg of compound 25 (36%) as a beige solid.

[0575] 1 1H NMR (500 MHz, DMSO-d 6)δ ppm 9.06 (d, J = 1.6 Hz, 1H) 8.47 (br t, J = 6.0 Hz, 1H) 7.66 (d, J = 9.5 Hz, 1H) 7.46 (dd, J = 9.5, 2.2 Hz, 1H) 7.29 (s, 1H) 7.21 (d, J = 7.9 Hz, 1H) 7.08 (s, 1H) 6.96 (d, J = 7.9 Hz, 1H) 4.52 (d, J = 6.0 Hz, 2H) 4.06 (br t, J = 4.4 Hz, 2H) 3.82 (s, 3H) 3.55 (br t, J = 4.7 Hz, 2H) 3.01 (d, J = 7.6 Hz, 2H) 1.27 (t, J = 7.6 Hz, 3H).

[0576] Synthesis of Compound 26

[0577]

[0578] Preparation of Intermediate M1

[0579] To a mixture of 2-amino-5-methoxypyrimidine [13418-77-4] (4.75 g, 38.0 mmol), ethyl 3-oxopentanoate [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 (saturated, aq.) was added. The layers were separated and the organic phase was washed with brine, dried over MgSO 4 4, filtered and concentrated in vacuo. The residue was purified by preparative LC (irregular SiOH 15 - 40 μm, 330 g, liquid injection (DCM), mobile phase: heptane / EtOAc, gradient from 85:15 to 50:50) to give 4.94 g of intermediate M1 as a yellow solid (26%).

[0580] Preparation of Intermediate M2

[0581] To a solution of intermediate M1 (500 mg, 2.01 mmol) in THF (10 mL) was added LiOH·H 2A solution of O (253 mg, 6.02 mmol) in water (5 mL). 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 dried over MgSO 4 and filtered and evaporated in vacuo to give 80 mg of Intermediate M2 (18%).

[0582] Preparation of Compound 26

[0583] To a mixture of Intermediate M2 (80 mg, 0.362 mmol) and Intermediate E9 (117 mg, 0.362 mmol) in DMF (2.44 mL) was 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 (twice), dried over MgSO 4 and filtered and evaporated in vacuo. The residue was purified by preparative LC (irregular SiOH 15 - 40 μm, 24 g, liquid injection (DCM), mobile phase: heptane / EtOAc, gradient from 50:50 to 0:100) to give 78 mg of Compound 26 as a white solid (41%).

[0584] 1 H NMR (400 MHz, DMSO - d 6 ) δ ppm 9.40 (d, J = 2.57 Hz, 1H) 8.68 (d, J = 2.69 Hz, 1H) 8.53 (t, J = 5.87 Hz, 1H) 7.30 (d, J = 8.68 Hz, 2H) 7.15 (d, J = 8.68 Hz, 2H) 4.46 (d, J = 5.87 Hz, 2H) 4.06 - 4.18 (m, 2H) 3.85 (s, 3H) 3.69 - 3.78 (m, 2H) 3.01 (q, J = 7.54 Hz, 2H) 1.27 (t, J = 7.52 Hz, 3H).

[0585] Synthesis of Compound 27

[0586]

[0587] Preparation of Intermediate N1

[0588] 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 quenched with K 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 dried over MgSO 4 , filtered and evaporated in vacuo. The crude mixture was purified by preparative LC (irregular SiOH 15 - 40 μm, 80 g, liquid injection (DCM), mobile phase: heptane / EtOAc, gradient from 70:30 to 0:100) to give 1.09 g of intermediate N1 (40%) as an oil.

[0589] Preparation of Intermediate N2

[0590] After 10 min, a solution of Tf 2 O in DCM (1 M in DCM, 2.96 mL, 2.96 mmol) was added dropwise to a mixture of intermediate N1 (1.00 g, 2.82 mmol) and DIPEA (0.972 mL, 5.64 mmol) in DCM (15 mL). The reaction mixture was stirred at room temperature for 30 min and diluted with DCM. The mixture was washed with NaHCO 3 (saturated, aq.), dried over MgSO 4 , filtered and evaporated in vacuo. The residue was purified by preparative LC (irregular SiOH 15 - 40 μm, 40 g, liquid injection (DCM), mobile phase: heptane / EtOAc, gradient from 80:20 to 40:60) to give 680 mg of intermediate N2 (50%) as a white solid.

[0591] Preparation of Intermediate N3

[0592] In a steel bomb, a mixture of intermediate N2 (630 mg, 1.30 mmol), Pd(OH) 2 (132 mg, 0.470 mmol) and HCl (3 M in H 2 O, 0.432 mL, 1.30 mmol) in MeOH (5 mL) and EtOAc (5 mL) was hydrogenated at 5 bar H 2 at room temperature for 2 h. The mixture was filtered through a pad to give 503 mg of intermediate N3 (quantitative) as a white solid.

[0593] Preparation of Compound 27

[0594] 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, dried over MgSO 4 4, filtered and concentrated in vacuo. The residue was purified by preparative LC (irregular SiOH 40 μm, 24 g, liquid injection (DCM), mobile phase: heptane / EtOAc, gradient from 80:20 to 20:80). The white solid was dissolved in warm EtOAc, and the solution was cooled to room temperature and then to 0 °C. The suspension was filtered off, washed with Et 2 2O and dried in vacuo to give a solid (71 mg). The filtrate was evaporated in vacuo and combined with the solid. The residue was dissolved in warm i-PrOH and cooled to room temperature. The suspension was slowly concentrated under vacuum (120 mbar) to obtain a thick solution. After filtration, the solid was washed with Et 2 2O and dried in vacuo to give 135 mg of compound 27 (36%) as a white solid.

[0595] 1 1H NMR (400 MHz, DMSO-d 6 6) δ ppm 8.94 (d, J = 3.06 Hz, 1H) 8.51 (d, J = 3.06 Hz, 1H) 8.40 (t, J = 5.87 Hz, 1H) 7.32 (d, J = 8.68 Hz, 2H) 7.28 (s, 1H) 7.19 (d, J = 8.68 Hz, 2H) 4.48 (d, J = 5.87 Hz, 2H) 4.08 (t, J = 4.65 Hz, 2H) 3.86 (s, 3H) 3.79 - 3.84 (m, 2H) 2.99 (q, J = 7.50 Hz, 2H) 1.25 (t, J = 7.52 Hz, 3H).

[0596] Synthesis of Compound 28

[0597]

[0598] p-Toluenesulfonic acid (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 taken up in Et2 It was ground in EtOAc and the solvent was removed under reduced pressure (the operation was repeated twice) to give 406 mg of Compound 28 as an off-white solid (quantitative).

[0599] 1 1H NMR (400 MHz, DMSO-d 6 ) δ ppm 9.14 (s, 1H) 8.80 (t, J = 5.7 Hz, 1H) 7.74 - 7.89 (m, 2H) 7.47 (d, J = 8.1 Hz, 2H) 7.27 - 7.37 (m, 3H) 7.19 (d, J = 8.7 Hz, 2H) 7.11 (d, J = 7.8 Hz, 2H) 4.49 (d, J = 5.9 Hz, 3H) 4.08 (t, J = 4.4 Hz, 2H) 3.83 (t, J = 4.8 Hz, 2H) 3.02 (q, J = 7.5 Hz, 2H) 2.29 (s, 3H) 1.27 (t, J = 7.5 Hz, 3H).

[0600] Synthesis of Compound 29

[0601]

[0602] A solution of MeSO2H 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 ground in Et 3 OAc and the solvent was removed under reduced pressure. The solid was dried under reduced pressure to give 355 mg of Compound 29 as an off-white solid (quantitative). 2 OAc and the solvent was removed under reduced pressure. The solid was dried under reduced pressure to give 355 mg of Compound 29 as an off-white solid (quantitative).

[0603] 1 1H NMR (400 MHz, DMSO-d 6 ) δ ppm 9.13 (s, 1H) 8.74 (t, J = 5.3 Hz, 1H) 7.82 (d, J = 9.4 Hz, 1H) 7.73 (d, J = 9.4 Hz, 1H) 7.33 (m, J = 8.7 Hz, 2H) 7.29 (s, 1H) 7.19 (m, J = 8.7 Hz, 2H) 4.49 (d, J = 5.9 Hz, 2H) 4.08 (t, J = 4.6 Hz, 2H) 3.83 (t, J = 4.8 Hz, 2H) 3.02 (q, J = 7.5 Hz, 2H) 2.32 (s, 3H) 1.27 (t, J = 7.5 Hz, 3H).

[0604] Synthesis of Compound 30

[0605]

[0606] (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 triturated in Et 2 O and the solvent was removed under reduced pressure to afford 359 mg of compound 30 as a white solid (quantitative).

[0607] 1 1H NMR (400 MHz, DMSO-d 6 ) δ ppm 9.12 (d, J = 1.3 Hz, 1H) 8.69 (t, J = 5.3 Hz, 1H) 7.80 (m, 1H) 7.69 (m, 1H) 7.33 (d, J = 8.6 Hz, 2H) 7.28 (s, 1H) 7.19 (d, J = 8.7 Hz, 2H) 4.48 (d, J = 5.7 Hz, 3H) 4.08 (t, J = 4.6 Hz, 2H) 3.83 (t, J = 4.8 Hz, 2H) 3.01 (q, J = 7.6 Hz, 2H) 2.86 (d, J = 14.7 Hz, 1H) 2.65 - 2.75 (m, 1H) 2.37 (d, J = 14.7 Hz, 1H) 2.23 (dt, J = 18.1, 3.9 Hz, 1H) 1.93 (t, J = 4.5 Hz, 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).

[0608] Synthesis of Compound 31

[0609]

[0610] 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 triturated in Et 2 O and the solvent was removed under reduced pressure to afford 269 mg of compound 31 as a white solid (quantitative).

[0611] 1 1H NMR (400 MHz, DMSO-d 6) δ ppm 9.12 (s, 1H) 8.71 (m, 1H) 7.79 (d, J = 9.4 Hz, 1H) 7.68 (d, J = 8.8 Hz, 1H) 7.26 - 7.37 (m, 3H) 7.19 (d, J = 8.7 Hz, 2H) 4.48 (d, J = 5.9 Hz, 2H) 4.08 (t, J = 4.5 Hz, 2H) 3.83 (t, J = 4.8 Hz, 2H) 3.01 (q, J = 7.6 Hz, 2H) 1.27 (t, J = 7.5 Hz, 3H).

[0612] Synthesis of Compound 32

[0613]

[0614] Add H 2 SO 4 (13 μL, 238 μmol) to a solution of compound 1 (252 mg, 476 μmol) in MeOH (4.2 mL). Stir the reaction mixture at room temperature for 30 min and then evaporate to dryness. Grind the residue in Et 2 O and remove the solvent under reduced pressure. Dry the white solid under vacuum at 60 °C for 6 h to give 271 mg of compound 32 as a white solid (98%).

[0615] 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 9.11 (s, 1H) 8.63 (t, J = 5.5 Hz, 1H) 7.76 (d, J = 9.5 Hz, 1H) 7.62 (d, J = 9.8 Hz, 1H) 7.26 - 7.36 (m, 3H) 7.19 (d, J = 8.7 Hz, 2H) 4.48 (d, J = 5.9 Hz, 2H) 4.07 (t, J = 4.7 Hz, 2H) 3.83 (t, J = 4.7 Hz, 2H) 3.00 (q, J = 7.5 Hz, 2H) 1.26 (t, J = 7.5 Hz, 3H).

[0616] Synthesis of Compound 33

[0617]

[0618] Preparation of Intermediate O1

[0619] At 5 °C, a 2 L round-bottom flask equipped with a dropping funnel was charged with a solution of 2-amino-5-chloropyrimidine [5428-89-7] (10 g, 77 mmol) in Me-THF (350 L). Ethyl 3-oxopentanoate [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 warmed to room temperature and stirred for 1 h. The mixture was filtered. EtOAc and NaHCO 3 (saturated, aq.) were added to the filtrate. The organic layer was dried over MgSO 4 , filtered, and concentrated in vacuo. The crude mixture was purified by preparative LC (irregular SiOH, 15 - 40 μm, 330 g, liquid injection (DCM), mobile phase: heptane / EtOAc, gradient from 85:15 to 50:50) to give intermediate O1 (2.98 g, 15%).

[0620] Preparation of Intermediate O2

[0621] A solution of 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 (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 with nitrogen again and stirred at 100 °C for 17 h. The reaction mixture was concentrated in vacuo and purified by preparative LC (irregular SiOH 15 - 40 μm, 40 g, liquid injection (DCM), mobile phase: heptane / EtOAc, gradient from 75:25 to 0:100). The residue was purified by reverse phase (stationary phase: YMC-actus Triart C18 10 μm 30*150 mm, mobile phase: (aqueous NH 4 HCO 3 0.2%) / MeCN, gradient from 70:30 to 30:70) to give intermediate O2 (212 mg, 20%) as a white solid.

[0622] Preparation of Intermediate O3

[0623] 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 pale yellow gum. The crude product was used as such in the next step.

[0624] Preparation of Compound 33

[0625] HOBt·H 2 O (83.0 mg, 0.542 mmol), EDCI·HCl (102 mg, 0.533 mmol) and intermediate E9 (223 mg, 0.536 mmol) were successively added to a mixture of intermediate O3 (168 mg, 0.529 mmol) and DIPEA (0.275 mL, 1.59 mmol) in DMF (5 mL). 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 (saturated, aq.) and brine (3 times), dried over MgSO 4 , filtered and evaporated. The crude mixture was purified by preparative LC (irregular SiOH 15 - 40 μm, 24 g, dry load mobile phase: heptane / (EtOAc / MeOH, 9 / 1), gradient from 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 load mobile phase: (aqueous NH 4 HCO 3 0.2%) / MeCN, gradient from 90:10 to 30:70). The MeCN was evaporated and the product was extracted with DCM (twice). The organic layer was dried over MgSO 4 , 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 load mobile phase: (aqueous NH 4 HCO 3 0.2%) / MeCN, gradient from 60:40 to 45:55). The MeCN was evaporated and the product was extracted with DCM (twice). The organic layer was dried over MgSO 4 , filtered and evaporated in vacuo. The product was triturated in MeCN and EtOAc, filtered and dried at 50 °C under high vacuum for 16 h to give compound 33 (119 mg, 42%) as a white solid.

[0626] 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 9.27 (d, J = 2.3 Hz, 1H) 8.60 (d, J = 2.4 Hz, 1H) 8.50 (t, J = 6.0 Hz, 1H) 7.27 - 7.34 (m, 3H) 7.19 (d, J = 8.7 Hz, 2H) 4.53 (s, 2H) 4.47 (d, J = 5.9 Hz, 2H) 4.03 - 4.12 (m, 2H) 3.79 - 3.86 (m, 2H) 3.34 (s, 3H) 3.00 (q, J = 7.5 Hz, 2H) 1.27 (t, J = 7.5 Hz, 3H).

[0627] Synthesis of Compound 34

[0628]

[0629] 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). The reaction mixture was stirred at room temperature for 18 h and concentrated in vacuo. The residue was diluted with EtOAc and water. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic layers were dried over MgSO 4 and filtered and concentrated. The residue (229 mg) was purified by reverse phase (stationary phase: YMC-actus Triart C18 10 μm (30 * 150 mm), mobile phase: (aqueous NH 4 HCO 3 0.2%) / MeCN, gradient from 50:50 to 25:75) to give 118 mg of compound 34.

[0630] 1 H NMR (400 MHz, DMSO-d 6)δ ppm 8.49 (d, J = 7.5 Hz, 1H) 7.85 (t, J = 5.9 Hz, 1H) 7.22 - 7.29 (m, 3H) 7.14 (d, J = 8.7 Hz, 2H) 6.62 (dd, J = 7.5, 2.8 Hz, 1H) 4.41 (d, J = 6.0 Hz, 2H) 4.07 - 4.12 (m, 2H) 3.84 (d, J = 2.3 Hz, 6H) 3.69 - 3.75 (m, 2H) 2.52 (s, 3H).

[0631] Synthesis of Compound 35

[0632]

[0633] Preparation of Intermediate P1

[0634] In a round-bottom flask, a solution of 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 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 using a Genevac. EtOAc, water, and NaCl were added. The layers were separated, and the organic layer was washed with brine (3 times), dried over MgSO 4 4, filtered, and evaporated in vacuo. The crude mixture was dissolved in EtOAc, and SiOH was added. The dry load was evaporated, and the residue was washed with heptane (100 mL). The product was eluted with heptane / EtOAc (1:1, 3 x 100 mL). The filtrate was evaporated to give 9.30 g of intermediate P1 as a colorless oil, which was allowed to stand for crystallization (98%).

[0635] Preparation of Intermediate P2

[0636] Intermediate P2 was prepared as follows: Following the synthesis reported for intermediate E2, starting from intermediate P1 (31.3 mmol), 9.3 g of a pale blue gum (99%) was obtained, which was allowed to stand for crystallization.

[0637] Preparation of Intermediate P3

[0638] Intermediate P3 was prepared as follows: Following the synthesis reported for intermediate E3, starting from intermediate P2 (6.64 mmol), 1.63 g of a colorless oil (56%) was obtained, which was allowed to stand for crystallization.

[0639] Preparation of Intermediate P4

[0640] Intermediate P4 was prepared as follows: Following the synthesis reported for intermediate E4, starting from intermediate P3 (3.74 mmol), and 1.91 g of a yellow oil (91%) was obtained.

[0641] Preparation of Intermediate P5

[0642] Intermediate P5 was prepared as follows: Following the synthesis reported for intermediate E5, starting from intermediate P4 (3.74 mmol), and 1.69 g of a yellow oil (100%) was obtained, which was allowed to stand for crystallization.

[0643] Preparation of Intermediate P6

[0644] 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.

[0645] Preparation of Intermediate P7

[0646] 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 basified with NaHCO 3 (saturated, aq.). The layers were separated, and the aqueous layer was extracted with EtOAc (once). The combined organic layers were dried over MgSO 4 and filtered, and the solvent was removed under reduced pressure to give 2.0 g of intermediate P7 as a yellow gum.

[0647] Preparation of Intermediate P8

[0648] 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 Tf 2 O (1 M 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 slowly warmed to room temperature and stirred for 2 h. DCM, water and NaHCO 3(10%, aq.). 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 (irregular SiOH, 30 μm, 80 g, liquid injection (DCM), mobile phase: heptane / EtOAc, gradient from 95:5 to 50:550) to afford 317 mg of intermediate P8 as an orange gum (23%, over 3 steps).

[0649] Preparation of Intermediate P9

[0650] In a steel bomb, a mixture of intermediate P8 (317 mg, 0.644 mmol), palladium hydroxide, Pd (20% on carbon), nominal 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 hydrogenated at 5 bar H 2 2 at room temperature for 4 h. The mixture was filtered. An additional amount of palladium hydroxide, Pd (20% on carbon), nominal 50% water (60 mg, 0.085 mmol) and HCl (1 M, aq., 0.64 mL, 0.64 mmol) was added. The mixture was hydrogenated at 5 bar H 2 2 at room temperature for 1.5 h. The reaction mixture was filtered and the filtrate was evaporated in vacuo to afford 269 mg of intermediate P9 as an orange gum. The crude product was used as such in the next step.

[0651] Preparation of Compound 35

[0652] To 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 successively added EDCI·HCl (72 mg, 0.376 mmol), HOBt·H 2 2O (60 mg, 0.392 mmol) and intermediate P9 (270 mg, 0.356 mmol). The reaction mixture was stirred at room temperature for 20 h. The crude mixture was taken up in DCM and NaHCO 3 (saturated, aq.) was added. The layers were separated and the organic layer was washed with brine (twice), dried over MgSO 4Dry, filter and evaporate in vacuo. The residue (409 mg) was purified by preparative LC (regular SiOH 30 μm, 24 g, mobile phase: heptane / (EtOAc / MeOH, 9 / 1), gradient from 80:20 to 20:80). The second purification was carried out by reverse phase (stationary phase: YMC-actus Triart C18 25 μm 30*150 mm, 40 g, dry load Mobile phase: (aqueous NH 4 HCO 3 0.2%) / MeCN, gradient from 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 dried over MgSO 4 dried, filtered and evaporated to give a colorless gum (81 mg). The product was triturated in pentane and Et 2 O (1 / 1), evaporated and dried under high vacuum at 50 °C for 5 h to give 66 mg of compound 35 as a pale yellow solid (24%).

[0653] 1 1H NMR (400 MHz, DMSO-d 6 ) δ ppm 9.11 (m, 1H) 8.45 - 8.53 (m, 1H) 7.69 (d, J = 9.4 Hz, 1H) 7.48 (dd, J = 9.7, 1.8 Hz, 1H) 7.29 (s, 1H) 7.18 (d, J = 9.5 Hz, 2H) 4.54 (d, J = 5.6 Hz, 2H) 4.05 - 4.13 (m, 2H) 3.61 - 3.70 (m, 2H) 3.03 (q, J = 7.4 Hz, 2H) 1.23 - 1.35 (t, J = 7.4 Hz, 3H).

[0654] Synthesis of Compound 36

[0655]

[0656] Preparation of Intermediate Q1

[0657] 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-oxopentanoate [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 (regular SiOH 30 μm, 330 g, dry load (SiOH), mobile phase: heptane / EtOAc, gradient from 80:20 to 0:100) to give 1.89 g of intermediate Q1 (32%) as a pale green solid.

[0658] Preparation of Intermediate Q2

[0659] NaOH (913 mg, 22.8 mmol) was added to a solution of intermediate Q1 (1.89 g, 7.61 mmol) in water (20 mL) and EtOH (25 mL). 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. The EtOH was concentrated. The mixture was acidified to pH 2 - 3 with HCl (1 N). The white precipitate was filtered, washed with water and dried under high vacuum to give 750 mg of intermediate Q2 (45%) as a white solid.

[0660] Preparation of Compound 36

[0661] 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 successively added to a mixture of intermediate Q2 (150 mg, 0.681 mmol) and DIPEA (0.48 mL, 2.79 mmol) in DMF (7 mL). The reaction mixture was stirred at room temperature for 16 h and evaporated. The residue was taken up in DCM, and NaHCO 3 (saturated, aq.) was added. The layers were separated, and the organic layer was washed with water and brine (twice), dried over MgSO 4Dry, filter and evaporate. Purify the crude mixture by preparative LC (regular SiOH 30 μm, 24 g, liquid injection (DCM), mobile phase: heptane / (EtOAc / MeOH, 9 / 1), gradient from 80:20 to 20:80). Combine the fractions containing the product and evaporate to give a white solid (304 mg). Recrystallize the product from MeCN, filter and dry at 50 °C under high vacuum for 3 h to give 200 mg of compound 36 as a white solid (53%).

[0662] 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.65 (d, J = 2.2 Hz, 1H) 8.23 - 8.32 (m, 1H) 7.53 (d, J = 9.5 Hz, 1H) 7.29 (d, J = 8.7 Hz, 2H) 7.13 - 7.21 (m, 3H) 4.46 (d, J = 5.9 Hz, 2H) 4.06 - 4.17 (m, 2H) 3.85 (s, 3H) 3.72 - 3.82 (m, 5H) 2.95 (q, J = 7.5 Hz, 2H) 1.24 (t, J = 7.5 Hz, 3H).

[0663] Synthesis of Compound 37

[0664]

[0665] Preparation of Intermediate R1

[0666] Intermediate R1 was prepared as follows: Follow the synthesis reported for intermediate E3, starting from intermediate D2 (7.06 mmol), and obtain 2.53 g of an off-white solid (86%).

[0667] Preparation of Intermediate R2

[0668] Intermediate R2 was prepared as follows: Follow the synthesis reported for intermediate E4, starting from intermediate R1 (6.06 mmol), and obtain 3.2 g of a yellow oil, which was used as such without purification in the next step.

[0669] Preparation of Intermediate R3

[0670] Intermediate R3 was prepared as follows: Follow the synthesis reported for intermediate E5, starting from intermediate R2 (6.06 mmol theoretical), and obtain 2.22 g of a yellow oil (87%, over 2 steps).

[0671] Preparation of Intermediate R4

[0672] To a solution of intermediate R3 (2.22 g, 5.13 mmol) in MeOH (52 mL) was added dropwise TMSCl (5.2 mL, 41 mmol). 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 (99%) as a pale green solid.

[0673] Preparation of Intermediate R5

[0674] 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 basified with K 2 CO 3 powder and the layers were separated. The aqueous layer was extracted with DCM (once) and the combined organic layers were dried over MgSO 4 filtered and evaporated in vacuo. The residue (685 mg) was purified by preparative LC (irregular SiOH 40 μm, 24 g, liquid injection (DCM), mobile phase: DCM / MeOH, gradient from 100:0 to 85:15) to give 445 mg of intermediate R5 (48%) as a colorless oil.

[0675] Preparation of Intermediate R6

[0676] Intermediate R6 was prepared as follows: Following the synthesis reported for intermediate P8, starting from intermediate R5 (1.19 mmol), and 0.45 g of colorless oil (72%) was obtained.

[0677] Preparation of Intermediate R7

[0678] Intermediate R7 was prepared as follows: Following the synthesis reported for intermediate P9, starting from intermediate R6 (0.61 mmol), and 0.24 g of colorless oil (96%) was obtained.

[0679] Preparation of Compound 37

[0680] 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 successively EDCI·HCl (74.5 mg, 0.388 mmol) and HOBt·H 2 O (59.5 mg, 0.388 mmol). The reaction mixture was stirred at room temperature for 16 h and evaporated in vacuo. The crude mixture was purified by preparative LC (irregular SiOH 15 - 40 μm, 12 g, dry load Mobile phase: heptane / EtOAc, gradient from 80:20 to 30:70). The desired fractions were combined and evaporated in vacuo. The product (163 mg) was sonicated in Et 2 O and filtered to give 118 mg of compound 37 (53%) as a white solid.

[0681] 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 9.09 (d, J = 1.6 Hz, 1H) 8.47 (t, J = 5.9 Hz, 1H) 7.68 (d, J = 9.5 Hz, 1H) 7.42 - 7.50 (m, 2H) 7.16 - 7.25 (m, 2H) 4.49 (d, J = 5.9 Hz, 2H) 4.07 - 4.15 (m, 2H) 3.83 (s, 3H) 3.53 - 3.61 (m, 2H) 3.00 (q, J = 7.5 Hz, 2H) 1.27 (t, J = 7.5 Hz, 3H).

[0682] Synthesis of Compound 38

[0683]

[0684] Preparation of Intermediate S1

[0685] At room temperature, POCl was added to a solution of DMF (103 μL, 1.33 mmol) in DCE (6.5 mL), and the mixture was stirred at room temperature for 30 min. Then the mixture was 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 (123 μL, 1.33 mmol), and the mixture was stirred at room temperature for 30 min. Then the mixture was 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 3Alkalize slowly to pH 8. Separate the layers and extract the aqueous layer with DCM. Wash the combined organic layers with brine and dry over MgSO 4 421 mg of intermediate S1 as a yellow solid was obtained by filtering and evaporating. Use the crude product as it is in the next step.

[0686] Preparation of Intermediate S2

[0687] In a steel vessel, a mixture of intermediate S1 (421 mg, 1.20 mmol), palladium hydroxide (100 mg, 0.14 mmol) and HCl (1 M in H 2 O) (1.2 mL, 1.2 mmol) in MeOH (10.5 mL) and EtOAc (10.5 mL) was hydrogenated at 5 bar H 2 at room temperature for 3 hours. Filter the mixture over to give 413 mg of intermediate S2 as a yellow solid. Use the crude product as it is in the next step.

[0688] Preparation of Compound 38

[0689] To 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 added EDCI·HCl (210 mg, 1.10 mmol) and HOBt·H 2 O (170 mg, 1.11 mmol), then intermediate S2 (410 mg, 1.13 mmol) was added and the mixture was stirred at room temperature for 16 hours. Add DCM and water. Separate the layers and wash the organic layer with saturated NaHCO 3 aqueous solution and brine. Dry the organic layer over MgSO4, filter and evaporate. Purify the crude product by reverse phase (stationary phase: YMC-actus Triart C18 10μm 30*150mm, 40 g, dry load (on ), mobile phase: gradient from 80% (aqueous NH 4 HCO 3 0.2%), 20% MeCN to 40% (aqueous NH 4 HCO 3 0.2%), 60% MeCN). Evaporate the MeCN and extract the product with DCM / MeOH (9:1) (3 times). Dry the organic layer over MgSO 4Dry, filter, and evaporate to obtain 176 mg of a pale yellow solid. Purify it by reverse phase (stationary phase: YMC-actus Triart C18 10 μm 30*150 mm, 40 g, dry load (on ), mobile phase: gradient from 60% (aqueous NH 4 HCO 3 0.2%), 40% MeCN to 45% (aqueous NH 4 HCO 3 0.2%), 55% MeCN, over 16 CV). Combine all fractions to obtain 139 mg of a yellow solid. Purify it by reverse phase (stationary phase: YMC-actus Triart C18 10 μm 30*150 mm, liquid load (DMSO), mobile phase: gradient from 70% (aqueous NH 4 HCO 3 0.2%), 30% ACN to 50% (aqueous NH 4 HCO 3 0.2%), 50% ACN) to obtain 39 mg of a white solid. Dissolve it in DCM / MeOH, then combine with the previous fraction, evaporate, and dry under high vacuum (50 °C, 2 h) to obtain 68 mg of an off-white solid. Co-evaporate it in MeOH (5 times), then dry under high vacuum (50 °C, 6 h) to give 65 mg of compound 38 as an off-white solid (12%)

[0690] Major rotamer (84%) 1 1H NMR (500 MHz, DMSO-d6, 350 K) δ ppm 9.07 (s, 1H), 8.57 (s, 1H), 8.15 (br t, J = 5.2 Hz, 1H), 7.61 (d, J = 9.5 Hz, 1H), 7.53 (s, 1H), 7.39 (dd, J = 9.6, 2.0 Hz, 1H), 7.28 (d, J = 8.5 Hz, 2H), 7.19 (d, J = 8.5 Hz, 2H), 4.47 (d, J = 6.0 Hz, 2H), 3.78 (br t, J = 4.7 Hz, 2H) 3.64 (br t, J = 4.8 Hz, 2H), 2.97 (q, J = 7.6 Hz, 2H), 1.26 (t, J = 7.6 Hz, 3H). Minor rotamer (16%) 11H NMR (500 MHz, DMSO-d6, 350 K) δ ppm 9.07 (s, 1H), 8.57 (s, 1H), 8.15 (br t, J = 5.2 Hz, 1H), 7.61 (d, J = 9.5 Hz, 1H), 7.53 (s, 1H), 7.39 (dd, J = 9.6, 2.0 Hz, 1H), 7.28 (d, J = 8.5 Hz, 2H), 7.19 (d, J = 8.5 Hz, 2H), 4.47 (d, J = 6.0 Hz, 2H), 3.90 (m, 2H) 3.73 (m, 2H), 2.97 (q, J = 7.6 Hz, 2H), 1.26 (t, J = 7.6 Hz, 3H).

[0691] Synthesis of Compound 39

[0692]

[0693] Preparation of Intermediate T1

[0694] At 5 °C, under N 2 To a solution of 3-chloro-4-methoxypyridin-2-amine (CAS [1232431-05-8], 0.2 g, 1.26 mmol) in 2-MeTHF (6 mL) was added ethyl 3-oxopentanoate (CAS [4949-44-4], 0.18 mL, 1.26 mmol) and iodobenzene diacetate ((diacetoxyiodo)benzene) (0.406 g, 1.26 mmol), and then boron trifluoride etherate (16.5 μL, 0.063 mmol) was added dropwise. The solution was stirred at 5 °C for 30 min, then warmed to room temperature and stirred for 2 h. An additional amount of ethyl 3-oxopentanoate (0.09 mL, 0.63 mmol), iodobenzene diacetate (0.203 g, 0.63 mmol) and boron trifluoride etherate (16.5 μL, 0.063 mmol) was added, and the mixture was purged with N 2 and stirred at rt for 1 h. EtOAc and water were added. The layers were separated, and the organic layer was dried over MgSO 4 and filtered and concentrated. The crude product was purified by preparative LC (regular SiOH, 30 μm, 24 g liquid load (DCM), mobile phase: 95% heptane, 5% EtOAc, isocratic 3 CV; then gradient to 60% heptane, 40% EtOAc, over 12 CV) to give 295 mg of intermediate T1 as a white solid (83%).

[0695] Preparation of Intermediate T2

[0696] 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 (purity 71%) as a pale yellow solid. The crude product was used as such in the next step.

[0697] Preparation of Compound 39

[0698] 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 HOBt·H 2 O (160 mg, 1.05 mmol) and EDCI·HCl (195 mg, 1.02 mmol), and then intermediate E9 (400 mg, 0.959 mmol) was added. The mixture was stirred at rt for 20 h. The mixture was evaporated, then taken up in DCM, and saturated NaHCO 3 aqueous solution was added. The organic layer was separated, washed with brine, dried over MgSO 4 , filtered and evaporated to give an orange gum. The crude product was purified by preparative LC (irregular SiOH, 15 - 40 μm, 50 g, liquid load (in DCM), mobile phase gradient: from heptane 75%, EtOAc / MeOH (9:1) 25% to heptane 25%, EtOAc / MeOH (9:1) 75%, over 12 CV). The clean fractions were combined and evaporated to give 312 mg of a pale yellow solid. It was purified by reverse phase (stationary phase: YMC-actus Triart C18 10 μm 30*150 mm, 40 g, dry load (on ), mobile phase: gradient from 55% (aqueous NH 4 HCO 3 0.2%), 45% MeCN to 5% (aqueous NH 4 HCO 3 0.2%), 95% MeCN (over 12 CV)) to give 286 mg of an off-white solid. It was sonicated in MeCN (suspension) and then filtered out. The solid was dried under high vacuum (50 °C, 6 h) to give 230 mg of compound 39 (43%) as a white solid.

[0699] 11H NMR (400 MHz, DMSO-d6) δ ppm 8.94 (d, J = 7.7 Hz, 1H), 8.35 (t, J = 5.9 Hz, 1H), 7.26 - 7.35 (m, 3H), 7.12 - 7.23 (m, 3H), 4.45 (br d, J = 5.9 Hz, 2H), 4.07 (br d, J = 4.4 Hz, 2H), 3.99 (s, 3H), 3.82 (t, J = 4.6 Hz, 2H), 2.95 (q, J = 7.6 Hz, 2H), 1.24 (t, J = 7.5 Hz, 3H).

[0700] Synthesis of Compound 40 and Compound 41

[0701]

[0702] Preparation of Intermediate U1

[0703] In a sealed tube, a mixture of intermediate E6 (1.00 g, 2.58 mmol), ethyl 3-ethoxy-3-iminopropionate 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. The reaction mixture was diluted with EtOAc and water. The aqueous phase was extracted with EtOAc (x3). The combined organic phases were washed with saturated NaCl, dried over MgSO 4 and concentrated to give 1.85 g of a brown oil. It was diluted in EtOAc and washed with a dilute solution of NaCl. The organic layer was dried over MgSO 4 and concentrated to give 1.03 g of intermediate U1. The crude product was used as such in the next step based on the theoretical amount.

[0704] Preparation of Intermediate U2

[0705] At -78 °C, a solution of Tf 2 O 1 M (3.1 mL, 3.1 mmol) in DCM was added dropwise to a solution of intermediate U1 (900 mg, 2.19 mmol) and triethylamine (914 μL, 6.58 mmol) in dry DCM (45 mL), and the reaction mixture was stirred for 15 min. The reaction mixture was diluted with DCM and water. The organic phase was dried over MgSO 4Dry, filter and evaporate to give 1.0 g. Purify the residue by preparative LC (irregular SiOH 15 - 40 μm, 40 g, liquid load (DCM), mobile phase gradient: (EtOAc / MeOH (90:10)) in heptane, from 0 to 50% over 5 CV, then isocratic 5 CV) to give 456 mg of intermediate U2 as an orange - brown oil (38%).

[0706] Preparation of Intermediate U3

[0707] Add lithium borohydride (276 μL; 0.553 mmol) to a solution of intermediate U2 (150 mg; 0.276 mmol) in THF (5 mL) and stir the solution at room temperature for 15 h. Add an additional lithium borohydride (276 μL, 0.553 mmol) and stir the reaction mixture for 6 h. Dilute the reaction mixture with EtOAc and water. Extract the aqueous layer with EtOAc again and wash the combined organic layers with brine (3 times), over MgSO 4 Dry, filter and evaporate to dryness to give 132 mg of intermediate U3 as a yellow residue (95%).

[0708] Preparation of Intermediate U4

[0709] Thus, the preparation of intermediate U4 is the same as that of intermediate S2, starting from intermediate U3 (0.132 g, 0.26 mmol), to give 0.11 g (quantitative).

[0710] Preparation of Compound 40

[0711] Add EDCI·HCl (58 mg, 0.30 mmol) and HOBt·H 2 O (46 mg, 0.30 mmol) 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) and stir the reaction mixture at room temperature for 18 h. Concentrate the reaction mixture. Absorb the residue into EtOAc and water. Wash the organic layer with saturated NaCl, over MgSO 4Dry, filter and concentrate to give 143 mg. Purify the crude by preparative LC (irregular SiOH 15 - 40 μm, 80 g, liquid load (DCM), mobile phase gradient: (EtOAc / MeOH (90:10)) in heptane, from 0 to 50% over 5 CV, then isocratic 5 CV) to give 100 mg of a white solid. Purify this by reverse phase (spherical C18, 25 μm, 40 g YMC - ODS - 25, dry load Mobile phase gradient: from 55% (aqueous NH 4 HCO 3 0.2%), 45% MeCN to 75% (aqueous NH 4 HCO3 0.2%) MeCN), to give 19 mg and 59 mg of residue, which are co - evaporated with EtOH and MeCN to give 80 mg of compound 40 as a pale yellow solid (combined yield: 57%).

[0712] 1 1H NMR (500 MHz, DMSO - d6) δ ppm 9.03 - 9.13 (m, 1H) 8.41 (br t, J = 6.0 Hz, 1H) 7.66 (d, J = 9.5 Hz, 1H) 7.45 (dd, J = 9.5, 1.9 Hz, 1H) 7.32 (d, J = 8.5 Hz, 2H) 7.16 (d, J = 8.5 Hz, 2H) 4.66 (t, J = 5.7 Hz, 1H) 4.47 (d, J = 6.0 Hz, 2H) 3.96 (br t, J = 5.0 Hz, 2H) 3.84 (t, J = 4.9 Hz, 2H) 3.73 (q, J = 6.6 Hz, 2H) 2.98 (q, J = 7.6 Hz, 2H) 2.74 (t, J = 6.9 Hz, 2H) 1.26 (t, J = 7.6 Hz, 3H)

[0713] Preparation of Compound 41

[0714] Thus, the preparation of compound 41 is the same as that of 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%) of a pale green solid.

[0715] 11H NMR (500 MHz, DMSO-d6) δ ppm 9.39 (d, J = 2.5 Hz, 1H) 8.68 (d, J = 2.5 Hz, 1H) 8.55 (t, J = 5.8 Hz, 1H) 7.31 (m, J = 8.5 Hz, 2H) 7.15 (m, J = 8.5 Hz, 2H) 4.70 (t, J = 5.7 Hz, 1H) 4.47 (d, J = 6.0 Hz, 2H) 3.95 (br t, J = 4.9 Hz, 2H) 3.79 - 3.88 (m, 2H) 3.72 (q, J = 6.6 Hz, 2H) 3.01 (q, J = 7.4 Hz, 2H) 2.73 (t, J = 6.8 Hz, 2H) 1.27 (t, J = 7.6 Hz, 3H)

[0716] Synthesis of Compound 42

[0717]

[0718] To a solution of intermediate Q2 (125 mg, 0.568 mmol) in diisopropylethylamine (0.4 mL, 2.32 mmol) and DMF (6 mL) was added EDCI·HCl (145 mg, 0.756 mmol), HOBt·H 2 O (120 mg, 0.784 mmol), and then intermediate E9 (205 mg, 0.571 mmol) was added. The mixture was stirred at room temperature for 16 h. The reaction mixture was evaporated and taken up in DCM and saturated NaHCO 3 aqueous solution. The layers were separated and the organic layer was washed with water, brine (twice), dried over MgSO 4 4, filtered and evaporated. The crude product was purified by preparative LC (regular SiOH, 30 μm, 24 g, liquid load (DCM), mobile phase gradient: from heptane 80%, EtOAc / MeOH (9:1) 20% to heptane 20%, EtOAc / MeOH (9:1) 80%, over 12 CV) to give 166 mg of a white solid. It was recrystallized from MeCN, then filtered off and dried under high vacuum to give 107 mg of compound 42 (36%) as a white solid.

[0719] 11H NMR (400 MHz, DMSO-d6) δ ppm 8.64 (d, J = 2.2 Hz, 1H), 8.30 (t, J = 5.8 Hz, 1H), 7.53 (d, J = 9.5 Hz, 1H), 7.27 - 7.36 (m, 3H), 7.14 - 7.22 (m, 3H), 4.47 (d, J = 5.9 Hz, 2H), 4.08 (br t, J = 4.5 Hz, 2H), 3.83 (br t, J = 4.5 Hz, 2H) 3.76 (s, 3H), 2.95 (q, J = 7.5 Hz, 2H), 1.24 (t, J = 7.5 Hz, 3H).

[0720] Synthesis of Compound 43

[0721]

[0722] Preparation of Intermediate V1

[0723] In a sealed tube, a suspension of imidazo[1,2-a]pyridine-3-carboxylic acid, 6-bromo-2-ethyl-ethyl 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 purged with N 2 purged. RuPhos (62.8 mg, 0.135 mmol) and RuPhos Pd G3 (113 mg, 0.135 mmol) were added, and the mixture was purged with N 2 again, then stirred at 100 °C overnight. The mixture was filtered and the filtrate evaporated. The crude product was purified by preparative LC (regular SiOH, 30 μm, 50 g, dry load (on ), mobile phase gradient: from 90% heptane, 10% EtOAc / MeOH (9:1) to 50% heptane, 50% EtOAc / MeOH (9:1), over 12 CV) to afford 317 mg of intermediate V1 as a colorless gum, which was allowed to stand to crystallize (66%).

[0724] Preparation of Intermediate V2

[0725] 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 product was used as such in the next step.

[0726] Preparation of Compound 43

[0727] Therefore, the preparation of compound 43 was the same as that of compound 42, starting from intermediate V2 (0.9 mmol) and intermediate E9 (0.84 mmol), to give 0.113 g (22%) of a white solid.

[0728] 1 H NMR (500 MHz, DMSO-d6) δ ppm 8.93 (s, 1H), 8.38 (t, J = 6.0 Hz, 1H), 7.58 (d, J = 9.1 Hz, 1H), 7.26 - 7.36 (m, 4H), 7.19 (d, J = 8.5 Hz, 2H), 4.43 - 4.51 (m, 4H), 4.08 (br t, J = 4.6 Hz, 2H), 3.83 (t, J = 4.7 Hz, 2H), 3.30 (s, 3H), 2.96 (q, J = 7.4 Hz, 2H), 1.25 (t, J = 7.6 Hz, 3H).

[0729] Synthesis of Compound 44

[0730]

[0731] Therefore, the preparation of compound 44 was the same as that of 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%) of a white solid.

[0732] 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 8.51 (d, J = 7.6 Hz, 1H) 7.91 (t, J = 6.0 Hz, 1H) 7.43 (t, J = 8.7 Hz, 1H) 7.26 (d, J = 2.8 Hz, 1H) 7.12 - 7.23 (m, 2H) 6.64 (dd, J = 7.6, 2.8 Hz, 1H) 4.44 (d, J = 5.7 Hz, 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)

[0733] Synthesis of Compound 45

[0734]

[0735] Preparation of Intermediate W1

[0736] 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-oxopentanoate (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 with EtOAc and water. Then the organic layer was washed with brine, dried over MgSO 4 and filtered and evaporated. The residue was purified by preparative LC (irregular SiOH 15 - 40 μm, 40 g, dry loaded onto and eluted with a gradient of heptane / EtOAc 95 / 5 to heptane / EtOAc 40 / 60 over 15 CV) to give 458 mg of intermediate W1 as a yellow solid (51% yield).

[0737] Preparation of Intermediate W2

[0738] Intermediate W1 (456 mg, 1.61 mmol) and NaOH (194 mg, 4.86 mmol) in a mixture of water (8.1 mL), EtOH (8.1 mL) and MeOH (9.8 mL) were stirred at room temperature for 16 h. The reaction mixture was evaporated. The residue was dissolved in MeOH and acidified with 3 N aqueous HCl. The solution was evaporated to give 726 mg of a yellow solid. DCM and MeOH were added to the yellow solid. Then the mixture was filtered and the filtrate was evaporated to give 443 mg of intermediate W2 as a beige solid (93% purity, quantitative).

[0739] Preparation of Compound 45

[0740] Thus, the preparation of compound 45 was the same as that of compound 42, starting from intermediate W2 (0.46 mmol) and intermediate N3 (0.46 mmol), to give 0.19 g (69%) of a beige solid.

[0741] 1 H NMR (400 MHz, DMSO-d 6)δ ppm 8.77 (singlet, 1H), 8.32 (triplet, J = 5.8 Hz, 1H), 7.86 (singlet, 1H), 7.29 (doublet, J = 8.6 Hz, 2H), 7.15 (doublet, J = 8.7 Hz, 2H), 4.46 (broad doublet, J = 5.7 Hz, 2H), 4.10 (broad triplet, J = 4.8 Hz, 2H), 3.87 (singlet, 3H), 3.85 (singlet, 3H), 3.74 (broad triplet, J = 4.8 Hz, 2H), 2.95 (quartet, J = 7.5 Hz, 2H), 1.24 (triplet, J = 7.5 Hz, 3H)

[0742] Synthesis of Compound 46

[0743]

[0744] Preparation of Intermediate X1

[0745] Therefore, the preparation of intermediate X1 was the same as that of intermediate T1, starting from 5-chloro-4-methoxypyridin-2-amine CAS [662117-63-7] (6.31 mmol), to give 1.23 g (69%) of a pale yellow solid.

[0746] Preparation of Intermediate X2

[0747] Therefore, the preparation of intermediate X2 was the same as that of intermediate V2, starting from intermediate X1 (4.35 mmol), to give 0.83 g (75%) of a pale yellow solid.

[0748] Preparation of Compound 46

[0749] Therefore, the preparation of compound 46 was the same as that of compound 42, starting from intermediate X2 (0.45 mmol) and intermediate R7 (0.43 mmol), to give 0.14 g (48%) of a white solid.

[0750] 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.11 (singlet, 1H), 8.27 (broad triplet, J = 5.8 Hz, 1H), 7.44 (triplet, J = 8.5 Hz, 1H), 7.16 - 7.25 (multiplet, 3H), 4.47 (broad doublet, J = 5.7 Hz, 2H), 4.08 - 4.13 (multiplet, 2H), 3.95 (singlet, 3H), 3.83 (singlet, 3H), 3.54 - 3.59 (multiplet, 2H), 2.96 (quartet, J = 7.5 Hz, 2H), 1.27 (triplet, J = 7.5 Hz, 3H)

[0751] Synthesis of Compound 47

[0752]

[0753] Therefore, 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 give 0.027 g (15%) of a white fluffy solid.

[0754] 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 9.35 (d, J = 2.7 Hz, 1H), 8.63 (d, J = 2.7 Hz, 1H), 8.52 (t, J = 5.9 Hz, 1H), 7.21 (s, 1H), 7.12 (d, J = 9.4 Hz, 2H), 4.46 (br d, J = 5.7 Hz, 2H), 4.01 (br s, 2H), 3.57 (br t, J = 4.3 Hz, 2H), 2.98 (q, J = 7.5 Hz, 2H), 1.23 (t, J = 7.5 Hz, 3H)

[0755] Synthesis of Compound 48

[0756]

[0757] Therefore, 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%) of a white solid.

[0758] 1 H NMR (500 MHz, DMSO-d6) δ ppm 8.67 (d, J = 2.2 Hz, 1H), 8.31 (t, J = 5.8 Hz, 1H), 7.54 (d, J = 9.8 Hz, 1H), 7.45 (t, J = 8.7 Hz, 1H), 7.15 - 7.25 (m, 3H), 4.49 (d, J = 5.7 Hz, 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 = 7.6 Hz, 2H), 1.26 (t, J = 7.6 Hz, 3H)

[0759] Synthesis of Compound 49

[0760]

[0761] Therefore, 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%) of a white solid.

[0762] 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 8.80 (s, 1H) 8.36 (br t, J = 5.8 Hz, 1H) 7.87 (s, 1H) 7.45 (t, J = 8.5 Hz, 1H) 7.15 - 7.26 (m, 2H) 4.50 (br d, J = 5.7 Hz, 2H) 4.10 (br t, J = 5.0 Hz, 2H) 3.87 (s, 3H) 3.82 (s, 3H) 3.56 (br t, J = 5.0 Hz, 2H) 2.98 (q, J = 7.6 Hz, 2H) 1.26 (t, J = 7.6 Hz, 3H)

[0763] Synthesis of Compound 50

[0764]

[0765] Preparation of Intermediate Y1

[0766] Therefore, 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%) of a yellow solid.

[0767] Preparation of Intermediate Y2

[0768] 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 product was used as such in the next step.

[0769] Preparation of Compound 50

[0770] Therefore, 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%) of a white solid.

[0771] 11H NMR (400 MHz, DMSO-d6) δ ppm 8.96 (d, J = 2.9 Hz, 1H), 8.52 (d, J = 2.9 Hz, 1H), 8.41 (t, J = 5.9 Hz, 1H), 7.45 (t, J = 8.6 Hz, 1H), 7.15 - 7.26 (m, 2H), 4.50 (d, J = 5.7 Hz, 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 = 7.5 Hz, 2H), 1.28 (t, J = 7.5 Hz, 3H)

[0772] Synthesis of Compound 51 and Compound 52

[0773]

[0774] Preparation of Compound 51

[0775] Therefore, the preparation of compound 51 was the same as that of 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%) of a white solid.

[0776] 1 1H NMR(400MHz,DMSO-d 6 ) δ ppm 8.83 (d, J = 7.6 Hz, 1H) 8.19 (t, J = 5.9 Hz, 1H) 7.25 - 7.34 (m, 3H) 7.18 (d, J = 8.7 Hz, 2H) 7.00 (d, J = 2.4 Hz, 1H) 6.70 (dd, J = 7.6, 2.6 Hz, 1H) 4.44 (d, J = 5.9 Hz, 2H) 4.07 (br t, J = 4.4 Hz, 2H) 3.78 - 3.88 (m, 5H) 2.92 (q, J = 7.5 Hz, 2H) 1.24 (t, J = 7.5 Hz, 3H)

[0777] Preparation of Compound 52

[0778] Therefore, the preparation of compound 52 was the same as that of 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%) of a white solid.

[0779] 1 1H NMR(500MHz,DMSO-d6 ) δ ppm 8.84 (d, J = 7.6 Hz, 1H) 8.16 (t, J = 6.0 Hz, 1H) 7.28 (d, J = 8.7 Hz, 2H) 7.14 (d, J = 8.7 Hz, 2H) 6.99 (d, J = 2.5 Hz, 1H) 6.70 (dd, J = 7.7, 2.7 Hz, 1H) 4.43 (d, J = 5.7 Hz, 2H) 4.10 (br t, J = 5.0 Hz, 2H) 3.84 (m, 6H) 3.73 (br t, J = 5.0 Hz, 2H) 2.91 (q, J = 7.6 Hz, 2H) 1.25 (t, J = 7.6 Hz, 3H)

[0780] Synthesis of Compound 53

[0781]

[0782] Preparation of Intermediate Z1

[0783] Therefore, the preparation of intermediate Z1 is the same as that of intermediate X1, starting from 4,5-dimethoxypyridin-2-ylamine CAS [1000843-61-7] (1.3 mmol), to give 0.135 g (37%) of a pale yellow solid

[0784] Preparation of Intermediate Z2

[0785] Therefore, the preparation of intermediate Z2 is the same as that of intermediate X2, starting from intermediate Z1 (0.49 mmol), to give 0.209 g (63%) of a pale yellow solid.

[0786] Preparation of Compound 53

[0787] Therefore, the preparation of compound 53 is the same as that of compound 42, starting from intermediate Z2 (0.48 mmol) and intermediate R7 (0.4 mmol), to give 0.149 g (39%, over the last 2 steps) of a white solid.

[0788] 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.67 (s, 1H), 8.11 (t, J = 5.8 Hz, 1H), 7.44 (t, J = 8.6 Hz, 1H), 7.15 - 7.23 (m, 2H), 7.05 (s, 1H), 4.47 (d, J = 5.7 Hz, 2H), 4.07 - 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 = 7.5 Hz, 2H), 1.25 (t, J = 7.5 Hz, 3H)

[0789] Synthesis of Compound 54

[0790]

[0791] 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 purged with N 2 2 (3 times). XantPhos (51.5 mg, 89.0 μmol) and Pd(OAc) 2 2 (9.99 mg, 44.5 μmol) were added, and the mixture was purged with N 2 2 (3 times). 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 (twice). The combined organic layers were washed with brine, dried over MgSO 4 4, filtered and evaporated to give a yellow solid. The solid was purified by preparative LC (regular SiOH 30 μm, 25 g, dry load mobile phase gradient: 100% DCM to DCM / (DCM:MeOH 80:20) 90 / 10, over 15 CV). The fractions containing the product were combined and evaporated in vacuo to give a pale yellow solid. The solid was triturated in Et 2 2O, filtered, washed with Et 2 2O and then dried in vacuo to give 153 mg of compound 54 as a white solid (67% yield).

[0792] 1 1H NMR (500 MHz, DMSO-d 6 6) δ ppm 9.08 (d, J = 1.5 Hz, 1H) 8.42 (t, J = 5.9 Hz, 1H) 7.66 (d, J = 9.6 Hz, 1H) 7.45 (dd, J = 9.5, 2.1 Hz, 1H) 7.40 (d, J = 3.7 Hz, 1H) 7.27 (d, J = 8.7 Hz, 2H) 7.22 (d, J = 8.7 Hz, 2H) 7.17 (d, J = 3.7 Hz, 1H) 4.46 (d, J = 5.8 Hz, 2H) 4.20 (t, J = 5.1 Hz, 2H) 3.92 (s, 3H) 3.67 (t, J = 5.1 Hz, 2H) 2.98 (q, J = 7.6 Hz, 2H) 1.26 (t, J = 7.6 Hz, 3H)

[0793] Synthesis of Compound 55

[0794]

[0795] Preparation of Intermediate AA1

[0796] In a sealed tube, a mixture of intermediate A5 (300 mg, 0.652 mmol), ethyl 3-methoxypropionimidate hydrochloride (328 mg, 1.96 mmol) and triethylamine (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 taken up in EtOAc and aqueous NaHCO 3 solution (1%) was added. After separation, the aqueous phase was extracted with EtOAc (twice). The combined organic layers were dried over MgSO 4 4, filtered and concentrated to give 280 mg of intermediate AA1 as a pale yellow oil, which was allowed to crystallize upon standing (94%).

[0797] Preparation of Compound 55

[0798] 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 to 0 °C (ice / water bath). A 1 M solution of Tf 2 O (1.01 mL, 1.01 mmol) was added dropwise and the reaction mixture was stirred at 0 °C for 30 min. DCM and aqueous NaHCO 3 solution (10%) were added. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were dried over MgSO 4 4, filtered and evaporated to obtain a brown gum, which was purified by preparative LC (regular SiOH, 30 μm, 24 g, liquid load (DCM), mobile phase gradient: from 90% heptane, 10% EtOAc / MeOH (9:1) to 25% heptane, 75% EtOAc / MeOH (9:1), over 12 CV). The fractions containing the product were combined and evaporated to give 208 mg of a yellow solid. It was purified by reverse phase (stationary phase: YMC-actus Triart C18 25 μm 30*150 mm, 40 g, dry load mobile phase: gradient from 60% (aqueous NH 4 HCO 30.2%), 40% MeCN to 100% MeCN, over 12 CV). The fractions containing the product were combined and evaporated to give 175 mg of a yellow solid. It was purified by preparative LC (regular SiOH, 30 μm, 24 g, liquid load (DCM), mobile phase gradient: from 90% heptane, 10% EtOAc / MeOH (9:1) to 25% heptane, 75% EtOAc / MeOH (9:1), over 12 CV). The fractions containing the product were combined and evaporated to give 146 mg of a white solid. It was purified by reverse phase (stationary phase: YMC-actus Triart C18 25 μm 30*150 mm, 40 g, dry load Mobile phase: gradient from 60% (aqueous NH 4 HCO 3 0.2%), 40% MeCN / MeOH (1:1) to 15% (aqueous NH 4 HCO 3 0.2%), 85% MeCN / MeOH (1:1), over 14 CV). The fractions containing the product were combined and evaporated to give 129 mg of a white solid. It was purified by chiral SFC (stationary phase: diethylaminopropyl 5 μm 150x21.2 mm, mobile phase: 90% CO 2 , 10% MeOH). The fractions containing the product were combined and evaporated to give 94 mg of a white solid. It was sonicated in MeCN (10 mL) and 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%)

[0799] 1 1H NMR (400 MHz, DMSO-d6) δ ppm 9.07 (d, J = 1.5 Hz, 1H), 8.44 (br t, J = 5.7 Hz, 1H), 7.67 (d, J = 9.4 Hz, 1H), 7.45 (dd, J = 9.4, 2.1 Hz, 1H), 7.32 (m, J = 8.7 Hz, 2H), 7.16 (m, J = 8.7 Hz, 2H), 4.47 (br d, J = 5.9 Hz, 2H), 3.90 - 4.00 (m, 2H), 3.81 - 3.89 (m, 2H), 3.66 (t, J = 6.7 Hz, 2H), 3.26 - 3.29 (m, 3H), 2.98 (q, J = 7.5 Hz, 2H), 2.82 (t, J = 6.7 Hz, 2H), 1.26 (t, J = 7.5 Hz, 3H)

[0800] The following compounds were prepared according to the procedures described herein:

[0801] Compound 56

[0802]

[0803] Compound 57

[0804]

[0805] Compound 58

[0806]

[0807] Compound 59

[0808]

[0809] Compound 60

[0810]

[0811] Compound 61

[0812]

[0813] Compound 62

[0814]

[0815] Compound 63

[0816]

[0817] Compound 64

[0818]

[0819] Compound 65

[0820]

[0821] Compound 66

[0822]

[0823] Compound 67

[0824]

[0825] Compound 68

[0826]

[0827] Compound 69

[0828]

[0829] Compound 70

[0830]

[0831] Compound 71

[0832]

[0833] Compound 72

[0834]

[0835] Synthesis of Compound 73

[0836]

[0837] Preparation of Intermediate AB1

[0838] At 5 °C, to a solution of 2-amino-5-cyanopyridine (CAS [4214-73-7]; 5 g, 42.0 mmol) in Me-THF (200 mL) was added iodobenzene diacetate (13.5 g, 41.9 mmol) and ethyl 3-oxopentanoate (10 mL, 70.1 mmol). Then boron trifluoride etherate (550 μL, 2.10 mmol) was added dropwise. The solution was stirred at 5 °C for 1 h. The mixture was warmed to room temperature and stirred for 2 h. EtOAc and saturated NaHCO 3 solution were added. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine (twice), dried over MgSO 4 and filtered and then evaporated to give 26 g of a brown liquid (which was allowed to stand and crystallize). The crude product was purified by preparative LC (irregular SiOH, 15 - 40 μm, 330 g, Grace, dry load mobile phase gradient: from 85% heptane, 15% EtOAc to 30% heptane, 70% EtOAc) to give 3.14 g of intermediate AB1 as a yellow solid (30%).

[0839] Preparation of Intermediate AB2

[0840] Under nitrogen, at 0 °C, 60% NaH (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). 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 and warmed to room temperature. The reaction mixture was hydrolyzed with saturated aqueous NH4Cl and extracted with EtOAc. The aqueous layer was extracted with EtOAc (twice). The combined organic layers were dried over MgSO 4Dry, filter, evaporate to dryness and purify by preparative LC (regular SiOH, 30 - 40 μm, 40 g, loading (DCM), mobile phase gradient: heptane / EtOAc, from 100:0 to 50:50). Evaporate the fractions containing the product to give 559 mg of intermediate AB2 as a white solid (52%).

[0841] Preparation of Compound 73

[0842] Add cesium fluoride (289 mg, 1.90 mmol) to a solution of intermediate AB2 (200 mg, 0.634 mmol) in F (8.4 mL), and stir the reaction mixture at 60 °C for 2 h. Then add diisopropylethylamine (139 μL, 0.817 mmol) and HATU (267 mg, 0.701 mmol), and stir the reaction mixture at room temperature for 15 min (the reaction mixture turns brown). Add intermediate R7 (266 mg, 0.634 mmol), and stir the reaction mixture at room temperature for 2 h.

[0843] Dilute the reaction mixture with EtOAc, and wash the organic layer with 1% aqueous NaHCO3, then with water and brine, dry over MgSO 4 Dry, filter off and concentrate. Add DCM and MeOH to the residue. Filter the mixture. Dry the precipitate under vacuum at 50 °C to give 160 mg of the crude product as a white solid.

[0844] Heat the crude product with EtOAc (15 mL) to reflux for 20 min, then slowly cool to room temperature over 18 h (with slow stirring).

[0845] Filter the solid, wash with cooled EtOAc and dry under vacuum at 60 °C to give 128 mg of compound 73 as a white solid (36%).

[0846] 1H NMR (400 MHz, DMSO-d6) δ ppm 9.50 (s, 1H) 8.63 (t, J = 5.9 Hz, 1H) 7.78 (d, J = 9.3 Hz, 1H) 7.66 (dd, J = 9.3, 1.7 Hz, 1H) 7.45 (t, J = 8.6 Hz, 1H) 7.13 - 7.31 (m, 2H) 4.51 (d, J = 5.87 Hz, 2H) 4.06 - 4.19 (m, 2H) 3.53 - 3.62 (m, 2H) 3.02 (q, J = 7.50 Hz, 2H) 1.28 (t, J = 7.46 Hz, 3H).

[0847] Synthesis of Compound 74

[0848]

[0849] Preparation of Intermediate AC1

[0850] A mixture of intermediate A5 (500 mg, 1.09 mmol), methyl-2,2-diethoxyiminoacetoacetate (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 taken up in EtOAc and water. After separation, the aqueous phase was extracted with EtOAc (once). The combined organic layers were washed with brine, dried over MgSO 4 4, filtered and concentrated. The residue was purified by preparative LC (irregular SiOH 15 - 40 μm, 80 g, liquid load (DCM), mobile phase gradient: EtOAc in heptane, from 20 to 80%, then isocratic). The fractions containing the product were combined and evaporated to give 343 mg of intermediate AC1 (63%) as a white solid.

[0851] Preparation of Intermediate AC2

[0852] 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 to 0 °C (ice / water bath). A 1 M solution of Tf 2 2O in DCM (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 a 1 M solution of Tf 2 2O in DCM (0.721 mL, 1.2 eq., 0.721 mmol) was added and the mixture was stirred at 0 °C for 1 h. Saturated aqueous NaHCO 3 3 and DCM were added. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were dried over MgSO 4 4, filtered and evaporated to give a brown gum. The crude product was purified by preparative LC (regular SiOH, 30 μm, 24 g, liquid load (DCM), mobile phase gradient: from 100% DCM to 85% DCM, 15% MeOH / AcOH (9:1)) to give 94 mg of intermediate AC2 as an orange gum.

[0853] Preparation of Compound 74

[0854] To a solution of intermediate AC2 (94 mg, 0.17 mmol) in AcOH (29 μL, 0.51 mmol) and DCM (1.5 mL) was added a 2 M solution of dimethylamine in THF (0.25 mL, 0.51 mmol), and the mixture was stirred at room temperature for 6 h. Then, sodium triacetoxyborohydride (71.5 mg, 0.34 mmol) was added, and the mixture was stirred at room temperature for 16 h. Saturated NaHCO 3 aqueous solution was added carefully, and then the layers were separated. The aqueous layer was extracted with DCM (twice), and then the combined organic layers were dried over MgSO 4 , filtered, and evaporated. The crude product was purified by preparative LC (regular SiOH, 30 μm, 12 g, liquid load (DCM), mobile phase gradient: from 80% heptane, 20% EtOAc / MeOH (9:1) to 15% heptane, 85% EtOAc / MeOH (9:1)). The fractions containing the product were combined and evaporated to give 68 mg of a pale yellow oil, which was purified by reverse phase (stationary phase: YMC-actus Triart C18 25 μm 30*150 mm, 12 g, dry load mobile phase: gradient from 55% (aqueous NH 4 HCO 3 0.2%), 45% MeCN to 100% MeCN). The fractions containing the product were combined and evaporated to give a colorless oil, which was triturated in Et 2 O, dried under high vacuum (50 °C, 1 h) to give 40 mg of compound 74 as a white solid (40%).

[0855] 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 9.06 (d, J = 1.0 Hz, 1H) 8.44 (br t, J = 5.8 Hz, 1H) 7.67 (d, J = 9.7 Hz, 1H) 7.45 (dd, J = 9.4, 1.8 Hz, 1H) 7.33 (br d, J = 8.6 Hz, 2H) 7.19 (br d, J = 8.6 Hz, 2H) 4.47 (br d, J = 5.5 Hz, 2H) 3.90 (br dd, J = 16.6, 4.2 Hz, 4H) 2.97 (q, J = 7.5 Hz, 2H) 2.19 (s, 7H) 1.26 (t, J = 7.5 Hz, 4H).

[0856] Synthesis of Compound 75

[0857]

[0858] Preparation of Intermediate AD1

[0859] 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-oxopentanoate (8.69 mL, 60.8 mmol) in MeCN (85 mL), and the reaction mixture was stirred at 80 °C for 4 h. The reaction mixture was evaporated to dryness and then purified by preparative LC (regular SiOH, 30 μm, 330 g, dry load Mobile phase gradient: from heptane / EtOAc 95 / 5 to EtOAc), to give 669 mg of intermediate AD1 (16%).

[0860] Preparation of Intermediate AD2

[0861] NaOH (752 mg, 18.8 mmol) was added to a mixture of intermediate AD1 (1.55 g, 6.24 mmol) in water (20 mL) and EtOH (20 mL), and the mixture was stirred at room temperature for 2 days. The reaction mixture was evaporated to give 2.16 g of intermediate AD2 (quantitative)

[0862] Preparation of Compound 75

[0863] 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.

[0864] The residue was dissolved in EtOAc and water. The aqueous layer was extracted with EtOAc (twice). The combined organic layers were dried over MgSO 4 dried, filtered and evaporated to give an orange oil. The oil was purified by preparative LC (regular SiOH 30 μm, 12 g, dry load Mobile phase gradient: heptane / EtOAc 70 / 30 to 100% EtOAc). The fractions containing the product were combined and evaporated in vacuo to give a yellow solid, which was triturated in Et 2 O. The supernatant was removed by pipette and the solid was dried in vacuo to give 124 mg of a white solid, which was co-evaporated with Et 2 O (3 times) to give 120 mg of compound 75 as a white solid (46% yield).

[0865] 11H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.86 (d, J = 7.7 Hz, 1H) 8.21 (br t, J = 5.8 Hz, 1H) 7.44 (t, J = 8.5 Hz, 1H) 7.12 - 7.26 (m, 2H) 7.01 (d, J = 2.3 Hz, 1H) 6.71 (dd, J = 7.6, 2.5 Hz, 1H) 4.47 (br d, J = 5.9 Hz, 2H) 4.07 - 4.15 (m, 2H) 3.84 (d, J = 8.2 Hz, 6H) 3.52 - 3.61 (m, 2H) 2.94 (q, J = 7.5 Hz, 2H) 1.26 (t, J = 7.5 Hz, 3H).

[0866] Synthesis of Compound 76

[0867]

[0868] 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 purged with N 2 2 (3 times). Then XanthPhos (8.7 mg, 15 μmol) and palladium(II) acetate (1.7 mg, 7.6 μmol) were added and the mixture was purged with N 2 2 (3 times). 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 (twice). The combined organic layers were washed with brine, dried over MgSO 4 , filtered off and evaporated to give a brown solid. The solid was purified by preparative LC (regular SiOH 30 μm, 12 g, dry load mobile phase gradient: DCM 100% to DCM / (DCM:MeOH 80:20) 30 / 70). The fractions containing the product were combined and evaporated in vacuo to give 17 mg of compound 76 as a yellow solid (47% yield).

[0869] 1 1H NMR (500 MHz, DMSO-d 6)δ ppm 9.07 (d, J = 1.4 Hz, 1H) 8.45 (t, J = 5.9 Hz, 1H) 7.63 - 7.69 (m, 2H) 7.45 (dd, J = 9.5, 2.0 Hz, 1H) 7.39 (d, J = 3.5 Hz, 1H) 7.26 (dd, J = 36.7, 8.7 Hz, 2H) 7.16 (d, J = 3.5 Hz, 1H) 4.46 (d, J = 5.6 Hz, 2H) 4.00 (t, J = 5.0 Hz, 2H) 3.78 (t, J = 5.0 Hz, 2H) 2.98 (q, J = 7.5 Hz, 2H) 1.26 (t, J = 7.5 Hz, 4H).

[0870] The following compounds were also prepared according to the procedures described herein:

[0871] Compound 77

[0872]

[0873] B. Additional Procedures

[0874] Synthesis of Compound 127

[0875]

[0876] Under N 2 HATU (0.099 g, 0.26 mmol) was added to 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). 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 evaporated and the residue was diluted in ethyl acetate and washed with saturated NaHCO 3 aqueous solution, water, and then brine. The organic layer was dried over MgSO 4 filtered and evaporated in vacuo to give a yellow oil, 0.167 g. Purification was carried out by flash chromatography on silica gel (12 g, irregular SiOH 25 - 40 μM, DCM / MeOH, from 100 / 0 to 97 / 3). The pure fractions were collected and evaporated to give a colorless oil which was allowed to crystallize, 0.102 g. Purification was carried out via reverse phase (stationary phase: YMC-actus Triart C18 10 μm 30*150 mm, mobile phase: gradient from 40% NH 4 HCO 30.2%, 60% ACN to 10% NH 4 HCO 3 0.2%, 90% ACN). The pure fractions were collected and evaporated to give 0.037 g as a white foam. It was triturated with DIPE and a little heptane, the precipitate was filtered off and dried in vacuo at 60 °C to give 0.032 g (26%) of compound 127 as a white powder.

[0877] 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 9.23 (br s, 1H), 8.53 (br d, J = 6.4 Hz, 1H), 7.79 (br d, J = 8.9 Hz, 1H), 7.55 (br t, J = 7.5 Hz, 1H), 7.25 - 7.37 (m, 3H), 7.20 (br d, J = 8.1 Hz, 3H), 4.42 - 4.56 (m, 2H), 4.08 (br s, 2H), 3.84 (br s, 2H)

[0878] Synthesis of Compound 128

[0879]

[0880] Thus, the preparation of compound 128 was the same as that of 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 give 0.045 g (39%) of a white powder.

[0881] 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 8.96 (br t, J = 5.6 Hz, 1H), 8.79 (d, J = 7.0 Hz, 1H), 7.76 (d, J = 9.0 Hz, 1H), 7.52 (t, J = 7.8 Hz, 1H), 7.25 - 7.45 (m, 4H), 7.20 (d, J = 8.7 Hz, 2H), 7.16 (td, J = 6.9, 1.1 Hz, 1H), 4.48 (d, J = 5.6 Hz, 2H), 4.08 (br t, J = 4.5 Hz, 2H), 3.84 (t, J = 4.8 Hz, 2H)

[0882] Synthesis of Compound 137

[0883]

[0884] In N 2Under this condition, HATU (0.093 g, 0.24 mmol) was added 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). The solution was stirred at room temperature for 15 min. Then intermediate R7 (0.095 g, 0.23 mmol) was added, and the reaction mixture was stirred at room temperature for 16 h. The solvent was evaporated, and the residue was diluted with ethyl acetate and washed with saturated NaHCO 3 aqueous solution, water, and then brine. The organic layer was dried over MgSO 4 , filtered and evaporated in vacuo to give a yellow oil, 0.271 g. Purification was carried out by flash chromatography on silica gel (12 g, irregular SiOH 25 - 40 μM, DCM / MeOH, from 100 / 0 to 97 / 3). The pure fractions were collected and evaporated to give 0.112 g (as a colorless oil), which was allowed to crystallize. It was triturated with DIPE and a small amount of heptane, the precipitate was filtered off and dried in vacuo at 60 °C to give compound 137 as a white powder, 0.096 g (79%).

[0885] 1 1H NMR (500 MHz, DMSO-d 6 ) δ ppm 8.77 (br t, J = 5.6 Hz, 1H), 7.44 (t, J = 8.6 Hz, 1H), 7.10 - 7.19 (m, 2H), 6.95 (t, J = 54.3 Hz, 1H), 4.40 (br d, J = 5.8 Hz, 2H), 4.06 - 4.15 (m, 2H), 4.02 (br t, J = 5.5 Hz, 2H), 3.83 (s, 3H), 3.54 - 3.60 (m, 2H), 2.78 (br t, J = 6.3 Hz, 2H), 1.89 (br d, J = 4.6 Hz, 2H), 1.83 (br d, J = 5.5 Hz, 2H)

[0886] Synthesis of Compound 79

[0887]

[0888] Thus, the preparation of compound 79 was the same as that of 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 give a white powder, 0.09 g (70%).

[0889] 1 1H NMR (500 MHz, DMSO-d6) δ ppm 9.27 (t, J = 5.8 Hz, 1H), 8.57 (d, J = 6.9 Hz, 1H), 7.80 (d, J = 9.2 Hz, 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)

[0890] Synthesis of Compound 132

[0891]

[0892] Preparation of Intermediate AB-1

[0893] In a sealed tube, ethyl ethyl 3-oxopentanoate (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) were added to a solution of 2-amino-5-chloromethylpyridine (CAS [36936-27-3], 1.00 g, 7.01 mmol) in ACN (12 mL). The mixture was stirred at 80 °C for 16 h. EtOAc and water were added. The organic layer was washed with brine, dried (MgSO 4 4) and evaporated and purified by preparative LC (irregular SiOH, 15 - 40 μm, 80 g, mobile phase gradient: from heptane / EtOAc 90:10 to 10:90). The fractions containing the product were combined and evaporated to give 0.95 g of intermediate AB-1 (51%) as an orange solid.

[0894] Preparation of Intermediate AB-2

[0895] 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 at 40 °C for 18 h.

[0896] The reaction mixture was evaporated to give 270 mg of intermediate AB-2 (quantitative, purity 65%).

[0897] Preparation of Compound 132

[0898] A mixture of intermediate AB-2 (150 mg, 0.374 mmol, purity 65%), 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 a 1% aqueous solution of NaHCO 3 1, and then washed with water and brine, dried over MgSO4, filtered, concentrated and purified by preparative LC (irregular SiOH, 15 - 40 μm, 40 g Grace, loading (DCM), mobile phase gradient: from heptane / EtOAc: 50 / 50 to 0 / 100 over 7 CV, then 100% EtOAc over 7 CV). The fractions containing the product were combined and evaporated to give 116 mg of a white solid. It was purified by preparative LC (spherical C18 25 μm, 40 g YMC-ODS-25, (MeOH / MeCN), mobile phase gradient 0.2% aqueous NH 4 + HCO 3 - / MeCN, from 70:30 to 0:100). The fractions containing the product were combined and evaporated to give 86 mg of compound 132 (39%) as a white solid.

[0899] 1H NMR (400 MHz, DMSO-d6) δ ppm 9.12 (s, 1H), 8.35 (t, J = 5.9 Hz, 1H), 7.64 (s, 1H), 7.45 (t, J = 8.6 Hz, 1H), 7.11 - 7.27 (m, 2H), 4.48 (d, J = 5.9 Hz, 2H), 4.11 (br t, J = 5.2 Hz, 2H), 3.83 (s, 3H), 3.57 (br t, J = 4.9 Hz, 2H), 2.99 (q, J = 7.5 Hz, 2H), 2.40 (s, 3H), 1.26 (t, J = 7.5 Hz, 3H)

[0900] Synthesis of Compound 141

[0901]

[0902] Preparation of Intermediate AC-1

[0903] At 5 °C, to a solution of 5-chloro-4-fluoro-2-pyridinamine (CAS [1393574-54-3], 250 mg, 1.71 mmol) in Me-THF (8 mL) was added iodobenzene diacetate (550 mg, 1.71 mmol) and ethyl-ethyl 3-oxopentanoate (0.4 mL, 2.80 mmol). Then boron trifluoride etherate (25 μL, 95.5 μmol) was added dropwise. The solution was stirred at 5 °C for 1 h. The mixture was warmed 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 (irregular SiOH, 15 - 40 μm, 40 g, grace, loading (DCM) mobile phase gradient: from heptane / EtOAc 90:10 to 10:90, over 10 CV) to give 119 mg of intermediate AC-1 (P1; 26%) as a light brown solid.

[0904] Preparation of Intermediate AC-2

[0905] 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 aqueous KHSO 4 10% were added. The organic layer was dried (MgSO 4 ) and evaporated to give 179 mg of intermediate AC-2 (quantitative) as a yellow solid.

[0906] Preparation of Compound 141

[0907] Thus, the preparation of compound 141 was the same as that of compound 132, starting from intermediate AC-2 (0.78 mmol) and intermediate R7, to give 0.127 g (27%) of a white powder.

[0908] 1H NMR (400 MHz, DMSO-d6) δ ppm 9.24 (d, J = 7.3 Hz, 1H), 8.45 (br t, J = 5.8 Hz, 1H), 7.79 (d, t, J = 9.9 Hz, 1H), 7.45 (t, t, J = 8.7 Hz, 1H), 7.12 - 7.27 (m, 2H), 4.49 (d, t, J = 5.9 Hz, 2H), 4.11 (t, t, J = 4.9 Hz, 2H), 3.83 (s, 3H), 3.57 (t, t, J = 4.9 Hz, 2H), 2.99 (q, t, J = 7.5 Hz, 2H), 1.27 (t, J = 7.5 Hz, 3H)

[0909] Synthesis of Compound 158

[0910]

[0911] Preparation of Intermediate AD-1

[0912] Therefore, the preparation of compound AD-1 was the same as that of compound AC-1, starting from 6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine (CAS [108990-72-3], 7.4 mmol), and 0.726 g (38%) was obtained.

[0913] Preparation of Intermediate AD-2

[0914] Therefore, the preparation of compound AD-2 was the same as that of compound AB-2, starting from AD-1 (0.77 mmol), and 0.446 g (44%) was obtained.

[0915] Preparation of Compound 158

[0916] Therefore, the preparation of compound 158 was the same as that of compound 132, starting from intermediate AD-2 (0.77 mmol) and intermediate R7, and 0.145 g (32%) of white powder was obtained.

[0917] 1H NMR (500 MHz, DMSO-d6) δ ppm 9.10 (s, 1H), 8.39 (t, J = 6.0 Hz, 1H), 7.44 (t, J = 8.5 Hz, 1H), 7.12 - 7.26 (m, 2H), 4.47 (d, J = 5.9 Hz, 2H), 4.10 (t, J = 4.8 Hz, 2H), 3.83 (s, 3H), 3.56 (t, J = 4.8 Hz, 2H), 2.89 - 3.03 (m, 6H), 2.05 - 2.16 (m, 2H), 1.26 (t, J = 7.6 Hz, 3H)

[0918] Preparation of Compound 193

[0919]

[0920] Therefore, the preparation of compound 193 was the same as that of compound 158, starting from intermediate AI-3 (0.44 mmol) and intermediate R-7 (0.37 mmol), and 0.108 g (52%) of white solid was obtained.

[0921] 11H NMR (400 MHz, DMSO) δ 9.19 - 9.10 (m, 1H), 8.51 (d, J = 2.4 Hz, 1H), 8.44 (t, J = 5.9 Hz, 1H), 7.44 (t, J = 8.6 Hz, 1H), 7.26 - 7.14 (m, 2H), 4.49 (d, J = 5.9 Hz, 2H), 4.14 - 4.03 (m, 2H), 3.83 (s, 3H), 3.59 - 3.53 (m, 2H), 3.01 (q, J = 7.5 Hz, 2H), 2.34 (d, J = 0.6 Hz, 3H), 1.28 (t, J = 7.5 Hz, 3H).

[0922] Preparation of Compound 194

[0923]

[0924] Therefore, 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 a white solid, 0.110 g (39%).

[0925] 1 1H NMR (400 MHz, DMSO) δ 9.23 (t, J = 5.8 Hz, 1H), 8.35 (s, 1H), 7.70 (d, J = 9.3 Hz, 1H), 7.52 - 7.37 (m, 2H), 7.19 (m, 2H), 4.51 (d, J = 5.8 Hz, 2H), 4.17 - 4.07 (m, 2H), 3.84 (s, 3H), 3.63 - 3.55 (m, 2H), 2.34 (s, 3H).

[0926] Preparation of Compound 204

[0927]

[0928] Therefore, 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 a white solid, 0.132 g (34%).

[0929] 11H NMR (400 MHz, DMSO) δ 9.09 - 9.01 (m, 1H), 8.40 (t, J = 5.9 Hz, 1H), 7.73 - 7.64 (m, 1H), 7.53 - 7.41 (m, 2H), 7.25 - 7.14 (m, 2H), 4.49 (d, J = 5.9 Hz, 2H), 4.15 - 4.05 (m, 2H), 3.83 (s, 3H), 3.61 - 3.51 (m, 2H), 3.00 (q, J = 7.5 Hz, 2H), 1.27 (t, J = 7.5 Hz, 3H).

[0930] Preparation of Compound 206

[0931]

[0932] Therefore, the preparation of compound 206 was the same as that of compound 158, starting from intermediate AM - 2 (0.61 mmol) and intermediate R - 7 (0.47 mmol), to give a beige powder, 0.07 g (24%).

[0933] 1 1H NMR (400 MHz, DMSO) δ 9.02 (t, J = 5.7 Hz, 1H), 8.92 (d, J = 1.7 Hz, 1H), 7.83 (d, J = 9.6 Hz, 1H), 7.61 (dd, J = 9.6, 2.0 Hz, 1H), 7.52 - 7.16 (m, 4H), 4.51 (d, J = 5.7 Hz, 2H), 4.13 - 4.07 (m, 2H), 3.83 (s, 3H), 3.60 - 3.55 (m, 2H).

[0934] Preparation of Compound 209

[0935]

[0936] Therefore, the preparation of compound 209 was the same as that of compound 158, starting from intermediate AQ - 2 (0.56 mmol) and intermediate R - 7 (0.4 mmol), to give a white powder, 0.142 g (59%).

[0937] 11H NMR (400 MHz, DMSO) δ 8.95 (s, 1H), 8.41 (t, J = 5.9 Hz, 1H), 7.80 (s, 1H), 7.44 (t, J = 8.6 Hz, 1H), 7.26 - 7.14 (m, 2H), 4.48 (d, J = 5.9 Hz, 2H), 4.15 - 4.06 (m, 2H), 3.83 (s, 3H), 3.60 - 3.52 (m, 2H), 2.97 (q, J = 7.5 Hz, 2H), 2.32 (s, 3H), 1.26 (t, J = 7.5 Hz, 3H).

[0938] Preparation of Compound 210

[0939]

[0940] Therefore, the preparation of compound 210 was the same as that of compound 158, starting from intermediate AL-2 (0.55 mmol) and intermediate R-7 (0.4 mmol), to give a white solid, 0.161 g (68%).

[0941] 1 1H NMR (400 MHz, DMSO) δ 8.92 (d, J = 1.4 Hz, 1H), 8.60 (t, J = 5.9 Hz, 1H), 7.62 (dd, J = 10.6, 1.6 Hz, 1H), 7.45 (t, J = 8.6 Hz, 1H), 7.26 - 7.15 (m, 2H), 4.50 (d, J = 5.8 Hz, 2H), 4.15 - 4.06 (m, 2H), 3.83 (s, 3H), 3.61 - 3.52 (m, 2H), 3.01 (q, J = 7.5 Hz, 2H), 1.27 (t, J = 7.5 Hz, 3H).

[0942] Preparation of Intermediate AA-3

[0943]

[0944] Preparation of Intermediate AA-1

[0945] 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 10% aqueous solution of K 2 CO 3 was added. The aqueous layer was extracted twice with DCM / MeOH (95 / 5). The combined organic layers were dried over MgSO 4Dry on top, filter off and evaporate. Purify the crude product (m = 25.6 g) by preparative LC (regular SiOH 30 μm, 330 g, dry load Mobile phase gradient: from 75% heptane, 25% EtOAc / MeOH (9:1) to 25% heptane, 75% EtOAc / MeOH (9:1). Combine the fractions containing the product and evaporate to give 14.61 g of intermediate AA-1 as a colorless oil, which is allowed to stand and crystallize (85%).

[0946] Preparation of Intermediate AA-2

[0947] At -5 °C, over 15 min, using a dropping funnel, add dropwise Tf in DCM 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) (ice / NaCl solid) 2 O 1 M (47 mL, 47 mmol), and continue stirring for 5 min. Quench the reaction mixture with saturated NaHCO 3 aqueous solution. Separate the layers, and extract the aqueous layer with DCM (twice). Dry the combined organic layers over MgSO 4 dry, filter off and concentrate. Purify the crude product (m = 36.4 g) by preparative LC (regular SiOH, 30 μm, 120 g, dry load Mobile phase gradient: heptane / EtOAc 90 / 10 to 70 / 30). Combine the fractions containing the product and evaporate in vacuo to give 10.18 g of intermediate AA-2 as a white solid (50%).

[0948] Preparation of Intermediate AA-3

[0949] In a steel bomb, hydrogenate a mixture of intermediate AA-2 (10.2 g, 21.5 mmol), palladium hydroxide (20% on carbon), nominal 50% water (3.01 g, 2.15 mmol) and aqueous HCl 3 M (7.15 mL, 7.15 mmol) in MeOH (150 mL) and EtOAc (150 mL) at 5 bar H 2 at room temperature for 1 h. Filter the mixture over a pad and wash with MeOH. Evaporate the filtrate and then co-evaporate with MeOH (twice) to give 7.86 g of intermediate AA-3.

[0950] Synthesis of Compound 163

[0951]

[0952] In N2 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 HATU (0.083 g, 0.22 mmol). The solution was stirred at room temperature for 15 min. Then intermediate AA-3 (0.083 g, 0.22 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. The solvent was evaporated and the residue was diluted in ethyl acetate and washed with saturated NaHCO 3 aqueous solution, water, and then brine. The organic layer was dried over MgSO 4 , filtered and evaporated in vacuo to give a colorless oil. Purification was carried out by flash chromatography on silica gel (12 g, irregular SiOH 25-40 μM, DCM / MeOH, from 100 / 0 to 97 / 3). The pure fractions were collected and evaporated to give a white foam, 0.096 g, which was triturated with DIPE and a small amount of heptane. The precipitate was filtered off and dried at 60 °C in vacuo to give compound 163 as a white powder, 0.088 g, 86%.

[0953] 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 8.14 (br t, J = 5.8 Hz, 1H), 7.90 (s, 1H), 7.38 (s, 1H), 7.32 (t, J = 8.5 Hz, 1H), 7.20 (br d, J = 13.1 Hz, 1H), 7.16 (br d, J = 8.2 Hz, 1H), 4.44 (br d, J = 6.0 Hz, 2H), 4.10 (br s, 2H), 3.59 - 3.68 (m, 2H), 2.88 (q, J = 7.5 Hz, 2H), 2.42 (s, 3H), 1.22 (t, J = 7.5 Hz, 3H)

[0954] Synthesis of Compound 147

[0955]

[0956] Thus, the preparation of compound 147 was the same as that of 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 a white powder, 0.08 g (77%).

[0957] 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.79 (br t, J = 5.6 Hz, 1H), 7.38 (s, 1H), 7.33 (t, J = 8.6 Hz, 1H), 7.07 - 7.23 (m, 2H), 6.95 (t, J = 54.2 Hz, 1H), 4.41 (br d, J = 5.9 Hz, 2H), 4.10 (br s, 2H), 4.02 (br t, J = 5.5 Hz, 2H), 3.65 (br t, J = 4.6 Hz, 2H), 2.68 - 2.91 (m, 2H), 1.89 (br d, J = 4.3 Hz, 2H), 1.83 (br d, J = 5.3 Hz, 2H)

[0958] Synthesis of Compound 159

[0959]

[0960] Therefore, the preparation of compound 159 was the same as that of 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 give a white powder, 0.084 g (82%).

[0961] 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 9.00 (br s, 1H), 8.81 (br d, J = 7.0 Hz, 1H), 7.77 (d, J = 9.0 Hz, 1H), 7.08 - 7.59 (m, 7H), 4.52 (br s, 2H), 4.10 (br s, 2H), 3.66 (br t, J = 4.5 Hz, 2H)

[0962] Synthesis of Compound 135

[0963]

[0964] Therefore, the preparation of compound 135 was the same as that of 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 give a white powder, 0.056 g (49%).

[0965] 1 H NMR (500 MHz, DMSO-d 6)δ ppm 8.31 (m, 1H), 8.28 (br t, J = 5.8 Hz, 1H), 7.38 (m, 1H), 7.33 (br t, J = 8.5 Hz, 1H), 7.21 (br d, J = 13.4 Hz, 1H), 7.16 (br d, J = 8.2 Hz, 1H), 4.45 (br d, J = 5.8 Hz, 2H), 4.10 (br s, 2H), 3.64 (br t, J = 4.4 Hz, 2H), 2.89 (q, J = 7.4 Hz, 2H), 1.22 (br t, J = 7.5 Hz, 3H)

[0966] Synthesis of Compound 152

[0967]

[0968] Therefore, the preparation of compound 152 was the same as that of 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 give a white powder, 0.418 g (82%).

[0969] 1 H NMR (500 MHz, DMSO-d 6 )δ ppm 9.29 (t, J = 5.8 Hz, 1H), 8.57 (d, J = 6.9 Hz, 1H), 7.80 (d, J = 9.2 Hz, 1H), 7.56 (ddd, J = 9.1, 6.9, 1.1 Hz, 1H), 7.39 (s, 1H), 7.36 (t, J = 8.5 Hz, 1H), 7.22 - 7.26 (m, 1H), 7.18 - 7.22 (m, 2H), 4.53 (d, J = 5.8 Hz, 2H), 4.11 (br t, J = 4.3 Hz, 2H), 3.67 (t, J = 4.7 Hz, 2H)

[0970] Synthesis of Compound 124

[0971]

[0972] 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 stirring for 10 min, 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 (regular SiOH 30 μm, 25 g, dry load Mobile phase gradient: heptane / EtOAc 90 / 10 to 30 / 70). The fractions containing the product were combined and evaporated to give 216 mg of a yellow solid. It was triturated in Et 2 O. The mixture was filtered. The solid was rinsed with Et 2 O, collected and dried under vacuum to give 172 mg of a white solid. It was dissolved in EtOAc and evaporated (3 times) to give 158 mg of a white solid. It was co-evaporated with MeCN (3 times) and dried under vacuum to give 143 mg of compound 124 (50%) as a white solid.

[0973] 1H NMR (400 MHz, DMSO-d6) δ ppm 9.28 (br s, 1H), 8.75 (m, 1H), 7.87 (d, J = 9.4 Hz, 1H), 7.65 (dd, J = 9.4, 1.8 Hz, 1H), 7.31 - 7.41 (m, 2H), 7.15 - 7.30 (m, 2H), 4.54 (br d, J = 4.1 Hz, 2H), 4.10 (br t, J = 4.0 Hz, 2H), 3.67 (br t, J = 4.6 Hz, 2H)

[0974] Synthesis of Compound 129

[0975]

[0976] Thus, the preparation of compound 129 was the same as that of 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%) of a white powder.

[0977] 11H NMR (400 MHz, DMSO-d6) δ ppm 8.90 (br d, J = 6.9 Hz, 1H), 8.59 (br t, J = 5.6 Hz, 1H), 7.59 (br d, J = 7.5 Hz, 1H), 7.30 - 7.46 (m, 2H), 7.15 - 7.29 (m, 2H), 7.01 (br t, J = 7.1 Hz, 1H), 4.50 (d, J = 5.9 Hz, 2H), 4.10 (br t, J = 4.4 Hz, 2H), 3.65 (br t, J = 4.9 Hz, 2H), 3.01 (q, J = 7.5 Hz, 2H), 1.27 (br t, J = 7.6 Hz, 3H)

[0978] Synthesis of Compound 133

[0979]

[0980] Therefore, the preparation of compound 133 was the same as that of 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%) of a white solid.

[0981] 1 1H NMR (400 MHz, DMSO-d6) δ ppm 8.31 (s, 1H), 8.25 (br t, J = 5.9 Hz, 1H), 7.38 (brs, 1H), 7.33 (t, J = 8.5 Hz, 1H), 7.14 - 7.25 (m, 2H), 4.45 (br d, J = 5.9 Hz, 2H), 4.10 (br t, J = 4.5 Hz, 2H), 3.64 (br t, J = 4.8 Hz, 2H), 2.52 (s, 1H)

[0982] Synthesis of Compound 136

[0983]

[0984] Therefore, the preparation of compound 136 was the same as that of 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 give 0.173 g (56%) of a white powder.

[0985] 11H NMR (500 MHz, DMSO-d6) δ ppm 8.99 (br t, J = 4.3 Hz, 1H), 7.86 (br s, 1H), 7.39, (m, 1H), 7.35 (br t, J = 8.5 Hz, 1H), 7.14 - 7.24 (m, 2H), 4.47 (br d, J = 5.5 Hz, 2H), 4.11 (m, 2H), 3.67 (br t, J = 4.3 Hz, 2H), 2.48 (br s, 3H)

[0986] Synthesis of Compound 164

[0987]

[0988] Therefore, the preparation of compound 164 was the same as that of 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%) of a white solid.

[0989] 1 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 - 8.84 (br s, 1H), 8.37 (t, J = 6.0 Hz, 1H), 7.52 (d, J = 8.9 Hz, 1H), 7.32 - 7.41 (m, 2H), 7.17 - 7.28 (m, 3H), 4.50 (br d, J = 5.9 Hz, 2H), 4.11 (br t, J = 4.2 Hz, 2H), 3.66 (t, J = 4.7 Hz, 2H), 2.98 (q, J = 7.5 Hz, 2H), 2.31 (s, 3H), 1.37 (t, J = 7.5 Hz, 3H)

[0990] Synthesis of Compound 157

[0991]

[0992] Therefore, the preparation of compound 157 was the same as that of compound 124, starting from intermediate AC-2 (0.78 mmol) and intermediate AA-3, to give 0.106 g (24%) of a white powder.

[0993] 11H NMR (400 MHz, DMSO-d6) δ ppm 9.23 (d, J = 7.3 Hz, 1H), 8.42 - 8.53 (m, 1H), 7.80 (d, J = 9.7 Hz, 1H), 7.29 - 7.40 (m, 2H), 7.17 - 7.28 (m, 2H), 4.50 (d, J = 5.9 Hz, 2H), 4.07 - 4.13 (m, 2H), 3.65 (br t, J = 4.6 Hz, 2H), 2.99 (q, J = 7.5 Hz, 2H), 1.27 (t, J = 7.5 Hz, 3H)

[0994] Synthesis of Compound 154

[0995]

[0996] Therefore, the preparation of compound 154 was the same as that of compound 124, starting from intermediate AD-2 (0.78 mmol) and intermediate AA-3, to give 0.092 g (21%) of a white solid.

[0997] 1 1H NMR (400 MHz, DMSO-d6) δ ppm 9.23 (d, J = 7.3 Hz, 1H), 8.42 - 8.54 (br t, J = 5.9 Hz, 1H), 7.80 (d, J = 9.8 Hz, 1H), 7.30 - 7.41 (m, 2H), 7.16 - 7.28 (m, 2H), 4.50 (br d, J = 5.9 Hz, 2H), 4.10 (br t, J = 4.9 Hz, 2H), 3.65 (br t, J = 4.7 Hz, 2H), 2.99 (br q, J = 7.4 Hz, 2H), 1.27 (br t, J = 7.5 Hz, 3H)

[0998] Synthesis of Compound 156

[0999]

[1000] Therefore, the preparation of compound 156 was the same as that of 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 a white solid, 0.096 g (68%).

[1001] 11H NMR (400 MHz, DMSO-d6) δ ppm 8.99 - 9.12 (m, 1H), 8.41 (br t, J = 7.5 Hz, 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 = 5.9 Hz, 2H), 4.11 (br t, J = 4.5 Hz, 2H), 3.66 (t, J = 4.6 Hz, 2H), 3.01 (q, J = 7.5 Hz, 2H), 1.28 (br t, J = 7.5 Hz, 3H)

[1002] Synthesis of Compound 153

[1003]

[1004] Therefore, the preparation of compound 153 was the same as that of 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 a white solid, 0.138 g (42%).

[1005] 1 1H NMR (500 MHz, DMSO-d6) δ ppm 8.11 (t, J = 6.0 Hz, 1H), 7.84 - 7.95 (m, 1H), 7.38 (br s, 1H), 7.32 (br t, J = 8.7 Hz, 1H), 7.14 - 7.23 (m, 2H), 4.45 (d, J = 6.0 Hz, 2H), 4.10 (brt, J = 4.4 Hz, 2H), 3.64 (br t, J = 4.9 Hz, 2H), 2.51 (s, 3H), 2.41 (d, J = 1.2 Hz, 3H)

[1006] Synthesis of Compound 146

[1007]

[1008] Therefore, the preparation of compound 146 was the same as that of 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 a white solid, 0.154 g (74%).

[1009] 11H NMR (400 MHz, DMSO-d6) δ ppm 9.41 (d, J = 2.7 Hz, 1H), 8.69 (d, J = 2.7 Hz, 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 = 4.5 Hz, 2H), 3.65 (br t, J = 4.8 Hz, 2H), 3.04 (br q, J = 7.5 Hz, 2H), 1.29 (br t, J = 7.5 Hz, 3H)

[1010] Synthesis of Compound 175

[1011]

[1012] Therefore, 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%) of a white powder.

[1013] 1 1H NMR (400 MHz, DMSO-d6) δ ppm 9.08 (s, 1H), 7.66 (d, J = 9.2 Hz, 1H), 7.44 (t, J = 8.4 Hz, 1H), 7.32 (dd, J = 9.2, 1.6 Hz, 1H), 7.19 (s, 1H), 7.17 - 7.08 (m, 2H), 6.63 (br s, 1H), 4.64 (d, J = 5.7 Hz, 2H), 4.13 - 4.04 (m, 2H), 3.74 - 3.65 (m, 2H), 2.41 (s, 3H).

[1014] Synthesis of Compound 125

[1015]

[1016] Preparation of Intermediate AE-1

[1017] Therefore, 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%).

[1018] Preparation of Intermediate AE-2

[1019] Therefore, intermediate AE-2 was prepared in the same manner as intermediate AC-2, starting from intermediate AE-1 (1.25 mmol), to give 0.26 g (92%).

[1020] Preparation of Intermediate AE-3

[1021] 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 of a brown paste. (Calculated purity to give quantitative yield).

[1022] Preparation of Compound 125

[1023] A mixture of intermediate AE-3 (288 mg, 0.779 mmol), 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 (once). The combined organic layers were washed with brine, dried over MgSO 4 filtered and evaporated to give 0.4 g of a brown foam. It was purified by preparative LC (regular SiOH 30 μm, 25 g, dry load 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 sonicated in Et 2 O. The precipitate was filtered off to give 146 mg of compound 125 (33%) as a white solid.

[1024] 1 1H NMR (500 MHz, DMSO-d6) δ ppm 9.29 (d, J = 7.2 Hz, 1H), 8.53 - 8.61 (m, 1H), 7.38 (br s, 1H), 7.34 (br t, J = 8.7 Hz, 1H), 7.17 - 7.28 (m, 3H), 4.49 (br d, J = 5.9 Hz, 2H), 4.08 - 4.12 (m, 2H), 3.65 (br t, J = 4.9 Hz, 2H), 3.01 (br q, J = 7.4 Hz, 2H), 1.27 (br t, J = 7.4 Hz, 3H)

[1025] Synthesis of Compound 130

[1026]

[1027] Preparation of Intermediate AF-1

[1028] Therefore, the preparation of intermediate AF-1 was the same as that of intermediate AC-1, starting from 2-amino-5-fluoropyrimidine (CAS [1683-85-8], 17.68 mmol), to give 1.18 g (27%).

[1029] Preparation of Intermediate AF-2

[1030] Potassium carbonate (3.2 g, 23.2 mmol) was added to a solution of intermediate AF-1 (1.1 g, 4.64 mmol) in EtOH (24 mL) and water (24 mL), and the mixture was heated at 65 °C and stirred for 3 h. (Alternative conditions are described in the above protocol) The mixture was acidified to pH = 1 with 3 M HCl (no precipitate formed), and then evaporated in vacuo. The residue was taken up in EtOH / water (1:1), sonicated, and then filtered off (the precipitate contained only K 2 CO 3 ), and the filtrate was concentrated and then co-evaporated twice with DCM to give 0.92 g of intermediate AF-2 (95%) as a brown solid. The crude product was used as such.

[1031] Preparation of Compound 130

[1032] Therefore, the preparation of compound 130 was the same as that of compound 124, starting from intermediate AF-2 (0.96 mmol) and intermediate AA-3, to give a white solid, 0.194 g (39%).

[1033] 1 H NMR (400 MHz, 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 = 4.4 Hz, 2H), 4.07 - 4.13 (m, 2H), 3.62 - 3.68 (m, 2H), 3.05 (br q, J = 7.2 Hz, 2H), 1.29 (br t, J = 7.5 Hz, 3H)

[1034] Synthesis of Compound 131

[1035]

[1036] Preparation of Intermediate AG-1

[1037] 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 oxopentanoate (1.05 mL, 7.35 mmol) and boron tribromide (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, dried over MgSO 4 and filtered, concentrated and purified by preparative LC (irregular SiOH, 15 - 40 μm, 40 g, liquid load (DCM), mobile phase gradient: from heptane / EtOAc: 100 / 0 to 0 / 100, over 10 CV; then 100% EtOAc, 5 CV). The fractions containing the product were combined and evaporated to give 0.21 g of intermediate AG-1 (22%).

[1038] Preparation of Intermediate AG-2

[1039] A mixture of intermediate AG-1 (186 mg, 0.715 mmol), aqueous NaOH 3 M (1.19 mL, 3.57 mmol) and MeOH (2 mL) was stirred at 60 °C for 2 days. The mixture was evaporated to give 0.33 g of intermediate AG-2 (estimated purity to give quantitative yield).

[1040] Preparation of Compound 131

[1041] Thus, the preparation of compound 131 was the same as that of compound 124, starting from intermediate AG-2 (0.71 mmol) and intermediate AA-3, to give a white solid, 0.09 g (23%).

[1042] 1 H NMR (400 MHz, 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 = 8.2 Hz, 2H), 4.47 (br d, J = 5.7 Hz, 2H), 4.09 (br t, J = 4.3 Hz, 2H), 3.65 (t, J = 4.7 Hz, 2H), 3.25 - 3.32 (m, 2H), 2.94 (q, J = 7.5 Hz, 2H), 1.24 (t, J = 7.5 Hz, 3H)

[1043] Synthesis of Compound 134

[1044]

[1045] Preparation of Intermediate AH-1

[1046] 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 treated 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 degassed with N 2 (3 times). Then LiHMDS (1.0 M in THF) (23 mL, 23 mmol) was added dropwise at room temperature, and the reaction mixture was stirred at 60 °C for 18 h. The reaction mixture was diluted with EtOAc and water, acidified with aqueous HCl (1 N). The aqueous layer was extracted with EtOAc (twice). Then the aqueous layer was basified with NaOH solution (3 M) and extracted with EtOAc (3 times). The combined organic layers were dried over MgSO 4 and filtered and evaporated to give 1.84 g of intermediate AH-1 as a brown solid (70%).

[1047] Preparation of Intermediate AH-2

[1048] Thus, the preparation of intermediate AH-2 was the same as that of intermediate AB-1, starting from intermediate AH-1 (3.62 mmol), to give 0.165 g (17%).

[1049] Preparation of Intermediate AH-3

[1050] Thus, the preparation of intermediate AH-3 was the same as that of intermediate AB-2, starting from intermediate AH-2 (0.95 mmol), to give 0.421 g (estimated purity to give quantitative yield).

[1051] Preparation of Compound 134

[1052] Thus, the preparation of compound 134 was the same as that of compound 124, starting from intermediate AH-3 (0.45 mmol) and intermediate AA-3, to give a white solid, 0.194 g (84%).

[1053] 11H NMR (400 MHz, DMSO-d6) δ ppm 8.62 (br s, 1H), 8.24 (t, J = 6.0 Hz, 1H), 7.38 (s, 1H), 7.34 (t, J = 8.6 Hz, 1H), 7.14 - 7.24 (m, 2H), 7.08 (s, 1H), 6.16 (br s, 2H), 4.47 (br d, J = 5.8 Hz, 2H), 4.07 - 4.12 (m, 2H), 3.65 (br t, J = 4.6 Hz, 2H), 2.91 (q, J = 7.5 Hz, 2H), 1.23 (t, J = 7.5 Hz, 3H)

[1054] Synthesis of Compound 161

[1055]

[1056] Preparation of Intermediate AI-1

[1057] 2-Amino-5-bromopyrimidine (10.0 g; 57.5 mmol) was suspended in dry 2-MeTHF (250 mL). Ethyl 3-oxopentanoate (8.2 mL, 57.5 mmol, 1 eq.) and iodobenzene diacetate (18.5 g, 57.5 mmol, 1 eq.) were added. Then boron trifluoride etherate (0.75 mL, 2.87 mmol, 0.05 eq.) was added dropwise, and the reaction mixture was stirred at 60 °C for 1.5 h. An additional amount of ethyl 3-oxopentanoate (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.) was added at room temperature, and the mixture was stirred at 60 °C for 1 h. The mixture was cooled to room temperature, then EtOAc and water were added. The organic layer was separated and washed with saturated NaHCO 3 solution (twice), then with brine (twice). The organic layer was dried over MgSO 4 4, filtered and concentrated to give 19.7 g of a brown oil. The crude product was purified by preparative LC (irregular SiOH, 15 - 40 μm, 330 g, dry load (SiOH), mobile phase gradient: from 100% DCM to 85% DCM, 15% EtOAc) to give the intermediate AI-1 as yellow crystals, 9.03 g (53%).

[1058] Preparation of Intermediate AI-2

[1059] In a sealed tube, under N 2 2, to the intermediate AI-1 (500 mg, 1.68 mmol) and Pd(PPh3 ) 4 (96.9 mg, 0.084 mmol) in a solution of trimethylaluminum 2m (2 eq., 1.68 mL, 3.35 mmol) in hexane was added to a solution of (96.9 mg, 0.084 mmol) in THF (12 mL) (degassed under N₂). The mixture was purged with N₂ again and heated at 65 °C for 1 h. An additional amount of trimethylaluminum 2m (1 eq., 0.839 mL, 1.68 mmol) in hexane 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 MgSO 4 . After stirring for 30 min, the mixture was filtered through a plug and evaporated to give 412 mg of an orange gum. The crude product was purified by preparative LC (regular SiOH, 30 μm, 40 g, dry load Mobile phase eluent: 95% heptane, 5% EtOAc to 50% heptane, 50% EtOAc). The fractions containing the product were combined and concentrated to obtain intermediate AI-2, 354 mg of a yellow gum (90%).

[1060] Preparation of Intermediate AI-3

[1061] 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 of a yellow solid. The crude product was used as such in the next step.

[1062] Preparation of Compound 161

[1063] 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. The DMF was evaporated. The residue was taken up in DCM and water, and then washed with saturated NaHCO 3 aqueous solution (twice), brine (twice), dried over MgSO 4Dry, filter and concentrate. Purify the crude product (m = 378 mg) by preparative LC (regular SiOH, 30 μm, 24 g, mobile phase gradient: from 85% heptane, 15% EtOAc / MeOH (9:1) to 25% heptane, 75% EtOAc / MeOH (9:1)). Combine and concentrate the fractions containing the product to give 277 mg of a white solid. Recrystallize the solid from EtOAc, filter and dry under high vacuum to give 162 mg of compound 161 (54%) as a white solid.

[1064] 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.15 (d, J = 1.2 Hz, 1H), 8.52 (br d, J = 2.3 Hz, 1H), 8.44 - 8.49 (m, 1H), 7.38 (br s, 1H), 7.34 (m, J = 8.6 Hz, 1H), 7.17 - 7.27 (m, 2H), 4.50 (brd, J = 5.9 Hz, 2H), 4.07 - 4.13 (m, 2H), 3.65 (br t, J = 4.6 Hz, 2H), 3.01 (q, J = 7.5 Hz, 2H), 2.34 (br s, 3H), 1.28 (t, J = 7.5 Hz, 3H)

[1065] Synthesis of Compounds 162, 148 and 151

[1066]

[1067] Preparation of Intermediate AJ-1

[1068] Carry out the reaction under anhydrous conditions and under a nitrogen atmosphere.

[1069] At 5 °C, under N 2 2, add ethyl propionylacetate (3.60 mL, 24.8 mmol), iodobenzene diacetate (7.80 g, 24.2 mmol) and boron trifluoride diethyl etherate (200 μL, 1.62 mmol) to a solution of 3-fluoro-5-methylpyridin-2-amine (2.00 g, 15.9 mmol) in 2-MeTHF (60 mL). Stir the reaction at 5 °C for 1 h and then at room temperature for 48 h. Add EtOAc (200 mL) and water (200 mL). Separate the layers and wash the organic layer with saturated NaHCO 3 aqueous solution (200 mL), brine (2 x 100 mL), and dry over Na 2 SO 4Dry, filter and evaporate to afford 4.92 g of a brown paste. The crude product was purified via preparative LC (SiOH, 120 g, 50 μm, eluent: cyclohexane / EtOAc, from 95:05 to 50:5), fractions containing the product were collected, evaporated and triturated with pentane (2 x 20 mL) to afford 1.68 g of intermediate AJ-1 as a white solid (42%).

[1070] Preparation of Intermediate AJ-2

[1071] 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 product was washed with DCM (30 mL) and EtOAc (30 mL), and the aqueous phase was acidified with aqueous HCl (3 N) until pH = 2. The precipitate formed was recovered under vacuum using a sintered glass, washed with water (2 x 2 mL) and dried overnight at 50 °C in a vacuum chamber to afford 415 mg of intermediate AJ-2 as an off-white solid (93%).

[1072] Preparation of Compound 162

[1073] Thus, the preparation of compound 162 was the same as that of compound 161, starting from intermediate AJ-2 (0.36 mmol) and intermediate AA-3, to afford 0.113 g (48%) of a white solid.

[1074] 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.61 (br s, 1H), 8.53 (br t, J = 5.9 Hz, 1H), 7.31 - 7.40 (m, 2H), 7.17 - 7.27 (m, 3H), 4.50 (d, J = 5.9 Hz, 2H), 4.10 (br t, J = 4.5 Hz, 2H), 3.65 (br t, J = 4.5 Hz, 2H), 2.98 (q, J = 7.5 Hz, 2H), 2.31 (s, 3H), 1.26 (t, J = 7.5 Hz, 3H)

[1075] Preparation of Intermediate AK-1

[1076] Thus, the preparation of intermediate AK-1 was the same as that of intermediate AJ-1, starting from 2-amino-3,5-difluoropyridine (CAS [732306-31-9], 15.37 mmol), to afford 0.89 g (23%) of a white solid.

[1077] Preparation of Intermediate AK-2

[1078] Therefore, the preparation of intermediate AK-2 was the same as that of intermediate AJ-2, starting from intermediate AK-1 (1.97 mmol), and 0.345 g (78%) was obtained.

[1079] Preparation of Compound 148

[1080] Therefore, the preparation of compound 148 was the same as that of compound 161, starting from intermediate AK-2 (0.35 mmol) and intermediate AA-3, and 0.189 g (82%) of a white solid was obtained.

[1081] 1 H NMR (500 MHz, DMSO-d6) δ ppm 8.92 (dd, J = 4.7, 1.8 Hz, 1H), 8.58 (t, J = 5.9 Hz, 1H), 7.64 - 7.74 (m, 1H), 7.38 (br s, 1H), 7.35 (t, J = 8.5 Hz, 1H), 7.18 - 7.27 (m, 2H), 4.50 (d, J = 5.9 Hz, 2H), 4.10 (br t, J = 4.7 Hz, 2H), 3.65 (t, J = 4.9 Hz, 2H), 3.01 (q, J = 7.5 Hz, 2H), 1.27 (t, J = 7.6 Hz, 3H)

[1082] Preparation of Intermediate AL-1

[1083] Therefore, the preparation of intermediate AL-1 was the same as that of intermediate AJ-1, starting from 2-amino-5-chloro-3-fluoropyridine (CAS [20712-16-7], 17.06 mmol), and 0.52 g (11%) of a white solid was obtained.

[1084] Preparation of Intermediate AL-2

[1085] Therefore, the preparation of intermediate AL-2 was the same as that of intermediate AJ-2, starting from intermediate AL-1 (1.77 mmol), and 0.26 g (60%) was obtained.

[1086] Preparation of Compound 151

[1087] Therefore, the preparation of compound 151 was the same as that of compound 161, starting from intermediate AL-2 (0.43 mmol) and intermediate AA-3, and 0.104 g (38%) of a white solid was obtained.

[1088] 11H NMR (400 MHz, DMSO-d6) δ ppm 8.92 (d, J = 1.0 Hz, 1H), 8.58 - 8.67 (m, 1H), 7.63 (dd, J = 10.6, 1.4 Hz, 1H), 7.31 - 7.40 (m, 2H), 7.17 - 7.28 (m, 2H), 4.51 (br d, J = 5.6 Hz, 2H), 4.07 - 4.13 (m, 2H), 3.65 (t, J = 4.6 Hz, 2H), 3.01 (q, J = 7.4 Hz, 2H), 1.27 (t, J = 7.4 Hz, 3H)

[1089] Synthesis of Compounds 145 and 144

[1090]

[1091] Preparation of Intermediate AM-1

[1092] Therefore, the preparation of intermediate AM-1 was the same as that of 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%) of a white solid.

[1093] Preparation of Intermediate AM-2

[1094] Therefore, the preparation of intermediate AM-2 was the same as that of intermediate AJ-2, starting from intermediate AM-1 (0.73 mmol), to give 0.175 g (96%).

[1095] Preparation of Compound 145

[1096] Therefore, the preparation of compound 145 was the same as that of compound 161, starting from intermediate AM-2 (0.39 mmol) and intermediate AA-3, to give 0.164 g (64%) of a white solid.

[1097] 1 1H NMR (500 MHz, DMSO-d6) δ ppm 9.04 (s, 1H), 8.88 - 8.96 (m, 1H), 7.83 (dd, J = 9.6, 1 Hz, 1H), 7.61 (dd, J = 9.6, 2.1 Hz, 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 = 4.9 Hz, 2H)

[1098] Preparation of Intermediate AN-1

[1099] Therefore, the preparation of intermediate AN-1 was the same as that of AJ-1, starting from 5-chloro-4-fluoropyridin-2-amine (CAS [1393574-54-3], 6.82 mmol) and ethyl 4,4-difluoro-3-oxobutanoate (CAS [352-24-9]), to give 0.57 g (28%) of a white solid.

[1100] Preparation of Intermediate AN-2

[1101] Therefore, the preparation of intermediate AN-2 was the same as that of intermediate AJ-2, starting from intermediate AN-1 (0.85 mmol), to give 0.145 g (64%).

[1102] Preparation of Compound 144

[1103] Therefore, the preparation of compound 144 was the same as that of compound 161, starting from intermediate AM-2 (0.41 mmol) and intermediate AA-3, to give 0.204 g (72%) of a white solid.

[1104] 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.09 (d, J = 7.2 Hz, 1H), 9.03 - 9.07 (m, 1H), 7.98 (d, J = 9.6 Hz 1H), 7.20 - 7.40 (m, 4H), 4.52 (br d, J = 4.6 Hz, 2H), 4.09 - 4.13 (m, 2H), 3.65 - 3.68 (m, 2H), 2.53 (br s, 1H)

[1105] Synthesis of Compounds 138, 139 and 140 and Compound 143

[1106]

[1107] Preparation of Intermediate AO-1

[1108] Therefore, the preparation of intermediate AO-1 was the same as that of AJ-1, starting from 4-bromo-5-methylpyridin-2-amine (CAS [1033203-32-5], 5.35 mmol) and ethyl 3-oxopentanoate (CAS [4949-44-4]), to give 0.88 g (50%) of a white solid.

[1109] Preparation of Intermediate AO-2

[1110] Therefore, the preparation of intermediate AO-2 was the same as that of intermediate AJ-2, starting from intermediate AO-1 (0.48 mmol), to give 0.205 g (78%).

[1111] Preparation of Intermediate AO-3

[1112] Therefore, the preparation of intermediate AO-3 was the same as that of compound 161, starting from intermediate AO-2 (0.49 mmol) and intermediate AA-3, to give 0.27 g (71%) of a white solid.

[1113] Preparation of Compound 138

[1114] A mixture of intermediate AO-3 (210 mg, 0.347 mmol), diphenylmethanimine (116 μL, 0.694 mmol), cesium carbonate (226 mg, 0.694 mmol) and 1,4-dioxane (1.75 mL) was purged with N 2 and Pd(OAc) 2 (3.9 mg, 0.017 mmol) and BINAP (21.6 mg, 0.0347 mmol) were added. The mixture was purged with N 2 and stirred at 100 °C for 18 h. The mixture was filtered through a pad and the cake was washed with EtOAc. The organic layer was concentrated, and the residue was then stirred in 1,4-dioxane (2.5 ml) and aqueous HCl 1 M (2.5 mL) at room temperature for 16 h. The mixture was diluted with EtOAc and quenched slowly with saturated NaHCO 3 aqueous solution. The layers were separated and the aqueous layer was extracted with EtOAc (twice). The organic layers were combined, dried over MgSO 4 and filtered and evaporated. The residue was purified by preparative LC (regular SiOH, 30 μm, 24 g, mobile phase eluent: from 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 fractions containing the product were combined and concentrated to give 0.125 g of a white solid. The solid was recrystallized from EtOAc, filtered and dried under high vacuum to give 97 mg of compound 138 (52%) as a white solid.

[1115] 11H NMR (400 MHz, DMSO-d6) δ ppm 8.61 - 8.70 (m, 1H), 7.89 (t, J = 6.0 Hz, 1H), 7.38 (s, 1H), 7.32 (t, J = 8.5 Hz, 1H), 7.14 - 7.22 (m, 2H), 6.46 - 6.47 (m, 1H), 5.69 - 5.72 (m, 2H), 4.44 (br d, J = 5.8 Hz, 2H), 4.10 (br t, J = 4.3 Hz, 2H), 3.64 (t, J = 4.6 Hz, 2H), 2.87 (q, J = 7.5 Hz, 2H), 2.08 (s, 3H), 1.21 (t, J = 7.5 Hz, 3H)

[1116] Preparation of Intermediate AP-1

[1117] Therefore, the preparation of intermediate AP-1 was the same as that of AJ-1, starting from 4,5-dimethylpyridin-2-amine (CAS [57963-11-8], 4.09 mmol) and ethyl 3-oxopentanoate (CAS [4949-44-4]), to give 0.73 g (72%) of a white solid.

[1118] Preparation of Intermediate AP-2

[1119] Therefore, the preparation of intermediate AP-2 was the same as that of intermediate AJ-2, starting from intermediate AP-1 (0.81 mmol), to give 0.3 g (quantitative).

[1120] Preparation of Compound 139

[1121] Therefore, the preparation of compound 139 was the same as that of compound 161, starting from intermediate AP-2 (0.49 mmol) and intermediate AA-3, to give 0.142 g (58%) of a white solid.

[1122] 1 1H NMR (500 MHz, DMSO-d6) δ ppm 8.78 (br s, 1H), 8.24 (t, J = 5.9 Hz, 1H), 7.38 (s, 2H), 7.34 (t, J = 8.5 Hz, 1H), 7.16 - 7.25 (m, 2H), 4.48 (d, J = 5.9 Hz, 2H), 4.10 (br t, J = 4.7 Hz, 2H), 3.65 (t, J = 4.5 Hz, 2H), 2.95 (q, J = 7.5 Hz, 2H), 2.30 (s, 3H), 2.22 (s, 3H), 1.25 (t, J = 7.5 Hz, 3H)

[1123] Preparation of Intermediate AQ-1

[1124] Therefore, the preparation of intermediate AQ-1 was the same as that of AJ-1, starting from 4-chloro-5-methylpyridin-2-amine (CAS [1033203-31-4], 7.01 mmol) and ethyl 3-oxopentanoate (CAS [4949-44-4]), to give 0.39 g (20%) of a white solid.

[1125] Preparation of Intermediate AQ-2

[1126] Therefore, the preparation of intermediate AQ-2 was the same as that of intermediate AJ-2, starting from intermediate AQ-1 (0.45 mmol), to give 0.15 g (quantitative).

[1127] Preparation of Compound 140

[1128] Therefore, the preparation of compound 140 was the same as that of compound 161, starting from intermediate AQ-2 (0.45 mmol) and intermediate AA-3, to give 0.23 g (68%) of a white powder.

[1129] 1 H NMR (500 MHz, DMSO-d6) δ ppm 8.95 (s, 1H), 8.45 (br t, J = 5.9 Hz, 1H), 7.81 (brs, 1H), 7.38 (br s, 1H), 7.34 (t, J = 8.5 Hz, 1H), 7.17 - 7.26 (m, 2H), 4.50 (d, J = 5.9 Hz, 2H), 4.10 (br t, J = 4.4 Hz, 2H), 3.65 (t, J = 4.7 Hz, 2H), 2.97 (q, J = 7.3 Hz, 2H), 2.32 (s, 3H), 1.26 (t, J = 7.4 Hz, 3H)

[1130] Preparation of Intermediate AR-1

[1131] Therefore, the preparation of intermediate AR-1 was the same as that of AJ-1, starting from 4-bromo-5-chloropyridin-2-amine (CAS [1187449-01-9], 9.64 mmol) and ethyl 3-oxopentanoate (CAS [4949-44-4]), to give 0.655 g (21%).

[1132] Preparation of Intermediate AR-2

[1133] Therefore, the preparation of intermediate AR-2 was the same as that of intermediate AJ-2, starting from intermediate AR-1 (2.05 mmol), to give 0.94 g (quantitative).

[1134] Preparation of Intermediate AR-3

[1135] Therefore, the preparation of intermediate AR-3 was the same as that of compound 161, starting from intermediate AR-2 (2.06 mmol) and intermediate AA-3, to give 0.42 g (33%) of an off-white solid.

[1136] Preparation of Compound 143

[1137] Therefore, the preparation of compound 143 was the same as that of compound 138, starting from intermediate AR-3 (0.4 mmol), to give 0.08 g (33%) of a white solid.

[1138] 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.03 (s, 1H), 8.01 (t, J = 5.7 Hz, 1H), 7.38 (s, 1H), 7.33 (t, J = 8.6 Hz, 1H), 7.15 - 7.24 (m, 2H), 6.63 (br s, 1H), 6.12 (br s, 2H), 4.45 (d, J = 5.9 Hz, 2H), 4.07 - 4.12 (m, 2H), 3.64 (t, J = 4.5 Hz, 2H), 2.90 (q, J = 7.5 Hz, 2H), 1.22 (t, J = 7.5 Hz, 3H)

[1139] Synthesis of Compound 126

[1140]

[1141] Preparation of Intermediate AS-1

[1142] At 0 °C, to a solution of 4,5-dichloropyrimidin-2-amine (CAS [403854-21-7], 12.5 g, 76.2 mmol) in Me-THF (315 mL) was added iodobenzene diacetate (73.7 g, 229 mmol) and ethyl 3-oxopentanoate (16.5 mL, 116 mmol). Then boron trifluoride etherate (1.92 mL, 15.2 mmol) was 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, over MgSO 4Dry and evaporate to give a brown oil. Purify the oil by preparative LC (irregular SiOH, 15 - 40 μm, 330 g, gradient: 100% heptane to heptane / EtOAc 75 / 25). Combine the fractions containing the product and evaporate to give a yellow mixture, which is triturated in pentane. Remove the supernatant by pipette and dry the residue under vacuum to give 1.16 g of intermediate AS-1 (5%) as a white solid. Evaporate the supernatant to give a yellow mixture. Remove the supernatant by pipette to give 5.02 g of intermediate AS-1 (32%) as a yellow paste.

[1143] Preparation of Intermediate AS-2

[1144] 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 (irregular SiOH, 15 - 40 μm, 120 g, dry load Mobile phase gradient: from heptane / EtOAc: 70 / 30 to 30 / 70). Combine the fractions containing the product and evaporate to give 1.6 g of intermediate AS-2 (74%).

[1145] Preparation of Intermediate AS-3

[1146] 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 at 60 °C for 40 h. The mixture was evaporated to give 1.05 g of intermediate AS-3 (quantitative).

[1147] Preparation of Intermediate AS-4

[1148] A mixture of intermediate AS-3 (1.05 g, 2.30 mmol, 84% purity), EDCI.HCl (0.8783 g, 4.61 mmol), HOBT.H 2 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, over MgSO 4Dry, filter, concentrate and purify by preparative LC (irregular SiOH, 15 - 40 μm, 120 g, mobile phase gradient: from heptane / EtOAc 50 / 50 to 0 / 100). Combine the fractions containing the product and evaporate to give 560 mg of intermediate AS - 4 (36%).

[1149] Preparation of Compound 126

[1150] 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 load (DMSO), mobile phase gradient 0.2% aqueous NH 4 + HCO 3 - / MeCN, from 75:25 to 20:80). The fractions containing the product were evaporated to give 204 mg of white solid and 350 mg of impure desired product. The second fraction was purified by preparative LC (spherical C18 25 μm, 120 g YMC - ODS - 25, liquid load (DMSO), mobile phase gradient 0.2% aqueous NH 4 + HCO 3 - / MeCN, from 75:25 to 20:80). The fractions containing the product were evaporated to give 65 mg of white solid. The pure compound fraction was dissolved in EtOAc under reflux. The mixture was slowly cooled to room temperature with slow stirring. The precipitate was filtered to give 0.355 g of compound 126 as a white solid (93%).

[1151] 1 1H NMR (500 MHz, DMSO - d6) δ ppm 9.06 (s, 1H), 8.12 (t, J = 6.0 Hz, 1H), 6.99 - 7.64 (m, 6H), 4.45 (d, J = 6.0 Hz, 2H), 4.09 (br d, J = 5.2 Hz, 2H), 3.64 (t, J = 4.7 Hz, 2H), 2.87 (q, J = 7.4 Hz, 2H), 1.21 (t, J = 7.5 Hz, 3H) Synthesis of Compound 155

[1152]

[1153] Preparation of Intermediate AT-1

[1154] Therefore, the preparation of intermediate AT-1 was the same as that of AJ-1, starting from 5-chloro-4-methylpyrimidin-2-amine (CAS [40439-76-7], 6.96 mmol) and ethyl 3-oxopentanoate (CAS [4949-44-4]), to give 0.37 g (20%) of a white solid.

[1155] Preparation of Intermediate AT-2

[1156] Therefore, the preparation of intermediate AT-2 was the same as that of intermediate AJ-2, starting from intermediate AT-1 (0.37 mmol), to give 0.165 g (quantitative).

[1157] Preparation of Compound 155

[1158] Therefore, the preparation of compound 155 was the same as that of compound 161, starting from intermediate AT-2 (0.38 mmol) and intermediate AA-3, to give 0.055 g (26%) of a white powder.

[1159] 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 9.35 (br s, 1H), 8.48 (t, J = 6.1 Hz, 1H), 7.30 - 7.40 (m, 2H), 7.16 - 7.28 (m, 2H), 4.50 (br d, J = 5.6 Hz, 2H), 4.06 - 4.13 (m, 2H), 3.65 (br t, J = 4.5 Hz, 2H), 3.01 (q, J = 7.5 Hz, 2H), 2.62 (s, 3H), 1.27 (t, J = 7.5 Hz, 3H)

[1160] Synthesis of Compound 150

[1161]

[1162] Under N 2 atmosphere, HATU (0.097 g, 0.26 mmol) was added 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). The solution was stirred at room temperature for 15 min. Then intermediate N3 (0.095 g, 0.24 mmol) was added, and the reaction mixture was stirred at room temperature for 16 h. The solvent was evaporated, and the residue was diluted in ethyl acetate and washed with saturated NaHCO 3Wash with aqueous solution, water, and then brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give a yellow oil, 0.314 g. Purify by flash chromatography on silica gel (12 g, irregular SiOH 25 - 40 μM, DCM / MeOH, from 100 / 0 to 97 / 3). Collect the pure fractions and evaporate to give 0.119 g of a white foam. Triturate it with DIPE and a small amount of heptane, filter off the precipitate, and dry in vacuo at 60 °C to give 0.103 g (82%) of Compound 150 as a white powder.

[1163] 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 9.21 (br t, J = 5.3 Hz, 1H), 8.53 (br d, J = 6.7 Hz, 1H), 7.79 (br d, J = 9.0 Hz, 1H), 7.55 (br t, J = 7.8 Hz, 1H), 7.29 (br d, J = 8.4 Hz, 2H), 7.13 - 7.22 (m, 3H), 4.47 (br d, J = 5.5 Hz, 2H), 4.07 - 4.15 (m, 2H), 3.86 (s, 3H), 3.76 (br t, J = 4.6 Hz, 2H)

[1164] Synthesis of Compound 88

[1165]

[1166] Thus, the preparation of Compound 88 is the same as that of 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 give 0.104 g (86%) of a white powder.

[1167] 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 8.94 (br t, J = 5.1 Hz, 1H), 8.79 (d, J = 7.0 Hz, 1H), 7.76 (d, J = 9.0 Hz, 1H), 7.52 (t, J = 7.9 Hz, 1H), 7.19 - 7.43 (m, 3H), 7.14 - 7.19 (m, 3H), 4.47 (br d, J = 5.2 Hz, 2H), 4.07 - 4.14 (m, 2H), 3.85 (s, 3H), 3.71 - 3.79 (m, 2H)

[1168] Preparation of Compound 200

[1169]

[1170] Therefore, the preparation of compound 200 was the same as that of compound 150, starting from intermediate AI-3 (0.64 mmol) and intermediate N3 (0.51 mmol), to give a white powder, 0.085 g (31%).

[1171] 1 H NMR (400 MHz, DMSO) δ 9.15 - 9.11 (m, 1H), 8.51 (d, J = 2.3 Hz, 1H), 8.41 (t, J = 5.9 Hz, 1H), 7.29 (d, J = 8.7 Hz, 2H), 7.15 (d, J = 8.7 Hz, 2H), 4.45 (d, J = 5.8 Hz, 2H), 4.15 - 4.06 (m, 2H), 3.85 (s, 3H), 3.76 - 3.70 (m, 2H), 2.98 (q, J = 7.5 Hz, 2H), 2.34 (s, 3H), 1.26 (t, J = 7.5 Hz, 3H).

[1172] Synthesis of Compounds 169 and 180

[1173]

[1174] Preparation of Intermediate AU-1

[1175] In a screw-cap 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 h. 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) were added to the mixture, and it was stirred at 80 °C for 24 h. Then, the mixture was diluted with EtOAc and washed with saturated NaHCO 3 aqueous solution (3x). The organic layer was dried over MgSO 4 4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (12 g, EtOAc / heptane, from 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 viscous solid (0.084 g, 42%).

[1176] Preparation of Intermediate AU-2

[1177] In a screw-cap vial, at room temperature, a solution of intermediate AU-1 in EtOH (4 mL) was added to an aqueous solution of potassium carbonate 15% (0.8 mmol, 0.87 mmol). The reaction mixture was heated at 75 °C and stirred for 36 h. Then, 2 M aqueous HCl was 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).

[1178] Preparation of Compound 169

[1179] Thus, the preparation of compound 169 was the same as that of compound 161, starting from intermediate AU-2 (0.41 mmol) and intermediate AA-3, to give 0.051 g (28%) of a white powder.

[1180] 1H NMR (400 MHz, CDCl3) δ ppm 9.54 (s, 1H), 7.44 (t, J = 8.5 Hz, 1H), 7.19 (s, 1H), 7.16 - 7.05 (m, 2H), 6.18 (br t, J = 5.6 Hz, 1H), 4.84 (s, 2H), 4.64 (d, J = 5.8 Hz, 2H), 4.13 - 4.05 (m, 2H), 4.02 (t, J = 5.7 Hz, 2H), 3.71 - 3.63 (m, 2H), 3.05 - 2.89 (m, 4H), 1.45 (t, J = 7.5 Hz, 3H).

[1181] Preparation of Compound 180

[1182] Thus, the preparation of compound 180 was the same as that of compound 161, starting from intermediate AU-2 (0.081 mmol) and intermediate R-7, to give 0.012 g (30%) of a white powder.

[1183] 1 1H NMR (400 MHz, CDCl3) δ ppm 9.54 (s, 1H), 7.46 (t, J = 8.6 Hz, 1H), 7.10 (m, 2H), 6.17 (br t, J = 5.5 Hz, 1H), 4.84 (s, 2H), 4.63 (d, J = 5.8 Hz, 2H), 4.15 - 4.05 (m, 2H), 4.02 (t, J = 5.7 Hz, 2H), 3.89 (s, 3H), 3.65 - 3.55 (m, 2H), 3.07 - 2.92 (m, 4H), 1.45 (t, J = 7.5 Hz, 3H).

[1184] Synthesis of Compound 177

[1185]

[1186] Preparation of Intermediate AV-1

[1187] The reaction was divided into two batches, 1.5 g per batch.

[1188] Under nitrogen, at 0 °C, 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. The reaction mixture was warmed to room temperature for 16 h. The mixture was diluted with saturated NaHCO 3 aqueous solution and extracted with EtOAc. The organic layer was separated, dried over MgSO 4 and filtered, and the solvent was evaporated in vacuo. The crude product was purified by flash column chromatography on silica gel (80 g, ethyl acetate in heptane, from 100 / 0 to 20 / 80). The desired fractions were collected and concentrated in vacuo to give the intermediate AV-1 as a beige solid, 4.8 g (85%).

[1189] Preparation of Intermediate AV-2

[1190] The reaction was divided into two batches, 2.4 g per batch.

[1191] 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. Then a solution of lithium bis(trimethylsilyl)amide (1 M in THF) (33.7 mL, 33.7 mmol) was 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 solution of lithium bis(trimethylsilyl)amide (1 M in THF, 33.7 mL, 33.7 mmol) were added while 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. Then the resulting mixture was extracted with EtOAc. The aqueous layer was neutralized with 1 N NaOH solution and extracted with DCM. The organic layer was separated, dried (MgSO 4 ), filtered, and the solvent was evaporated in vacuo to give the intermediate AV-2 as a brown solid, 3.4 g (76%).

[1192] Preparation of Intermediate AV-3

[1193] React in 2 batches with the same amount of reactive AV-2.

[1194] In a screw-cap vial, at rt, add potassium bicarbonate (0.6 g, 6.04 mmol) and ethyl propionylacetate (0.89 mL, 6.04 mmol) to a solution of AV-2 (1.12 g, 4.02 mmol) in ACN (8.1 mL). Then, add bromotrichloromethane (1.19 mL, 12.07 mmol) at room temperature, and stir the mixture at 80 °C for 16 h. Mix the batches together for calculation. Dilute the mixture with water and extract with EtOAc. Dry the organic layer (MgSO4), filter and concentrate in vacuo. Purify the crude product by flash chromatography on silica gel (25 g; EtOAc in heptane 0 / 100 to 35 / 65). Collect the desired fractions and concentrate in vacuo to give the intermediate AV-3 as a yellow foam solid, 0.42 g (22%).

[1195] Preparation of Intermediate AV-4

[1196] In a round-bottom flask, at 0 °C, add TFA (9.64 mL, 128.43 mmol) to AV-3 (1.06 g, 2.37 mmol). Stir the mixture at room temperature for 16 h. Neutralize the mixture with saturated NaHCO 3 aqueous solution and extract with DCM. Wash the organic layer with water and concentrate in vacuo. Grind the resulting product with DIPE and filter the solid to give the intermediate AV-4 as a beige solid, 0.6 g (95%).

[1197] Preparation of Intermediate AV-5

[1198] In a round-bottom flask, at room temperature, add isoamyl nitrite (CAS [110-46-3], 0.46 mL, 3.38 mmol) and copper(II) chloride (0.318 g, 2.36 mmol) to a suspension of AV-4 (0.6 g, 2.25 mmol) in dry ACN (36 mL). Stir the mixture under reflux for 3 h. Add water and extract the mixture with EtOAc. Separate the organic layer, dry (MgSO 4 )), filter, and evaporate the solvent in vacuo. Purify the crude product by flash chromatography on silica gel (12 g; EtOAc in heptane 0 / 100 to 10 / 90). Collect the desired fractions and concentrate in vacuo to give the intermediate AV-5 as a white solid, 0.315 g (51%).

[1199] Preparation of Intermediate AV-6

[1200] In a round-bottom flask, under nitrogen, at 0 °C, 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). Then, a solution of methylmagnesium bromide (3.0 M 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 quenched with saturated NH 4 Cl aqueous solution. The mixture was extracted with ethyl acetate. The organic layer was separated, dried over MgSO 4 4, filtered, and the solvent was evaporated in vacuo. The crude product was purified by flash column chromatography on silica gel (12 g; EtOAc in heptane 0 / 100 to 15 / 75). The desired fractions were collected and concentrated in vacuo to give a white solid, intermediate AV-6, 0.325 g (91%).

[1201] Preparation of Intermediate AV-7

[1202] In a screw-cap vial, at room temperature, 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). The mixture was stirred at 90 °C for 18 h. 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 solution was added until pH 7. The mixture was concentrated in vacuo to give intermediate AV-7 as a white solid (0.188 g, quantitative).

[1203] Preparation of Compound 177

[1204] In a round-bottom flask, at room temperature, 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). The mixture was stirred at room temperature for 1 h. Saturated NaHCO 3 3 aqueous solution was added, and the mixture was extracted with EtOAc (x3). The combined organic layers were dried over MgSO 4 4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (12 g; (DCM / MeOH 9:1) in DCM, 0 / 100 to 10 / 90). The desired fractions were collected and concentrated in vacuo. The resulting solid was triturated with DIPE, and the solid was filtered to give compound 177 as a beige solid, 0.092 g (41%).

[1205] 1 1H NMR (400 MHz, DMSO-d6) δ ppm 9.32 (d, J = 5.5 Hz, 1H), 8.44 (br t, J = 5.9 Hz, 1H), 7.38 (s, 1H), 7.34 (t, J = 8.6 Hz, 1H), 7.25 (br d, J = 13.2 Hz, 1H), 7.20 (br d, J = 8.3 Hz, 1H), 4.50 (d, J = 5.8 Hz, 2H), 4.17 - 4.02 (m, 2H), 3.72 - 3.58 (m, 2H), 3.02 (q, J = 7.5 Hz, 2H), 2.56 (d, J = 2.7 Hz, 3H), 1.28 (t, J = 7.5 Hz, 3H).

[1206] Synthesis of Compounds 142 and 181

[1207]

[1208] Preparation of Intermediate AW-1

[1209] A solution of 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 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 and evaporated to give an orange solid. The solid was purified by preparative LC (regular SiOH 30 μm, 330 g, liquid load (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).

[1210] Preparation of Intermediate AW-2

[1211] To a solution of AW-1 (3.2 g, 11.42 mmol) in NH 3 (7 M in MeOH) (179 mL) (purged with nitrogen) was added Raney nickel (5.3 g, 91.3 mmol), and then the reaction mixture was hydrogenated at atmospheric pressure at room temperature for 16 h. The mixture was filtered through a pad and Wash with MeOH and concentrate the filtrate in vacuo. Dilute the residue in DCM and add MgSO 4 . Filter the mixture through a pad, wash the with DCM and evaporate the filtrate in vacuo to give mmotte_8598_1, 3.18 g, as a colorless oil (96%).

[1212] Preparation of Intermediate AW-3

[1213] Charge a round-bottom flask 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). Connect the reaction mixture to a nitrogen stream and then cool to 0 °C. Add dropwise benzyl chloroformate (1.72 mL, 12.06 mmol). Then stir the reaction mixture at 0 °C for 1 h. Quench the reaction mixture by adding water and stir at room temperature for 10 minutes. Extract the aqueous layer with DCM (twice). Dry the combined organic layers over MgSO4, filter off and evaporate to give 5.38 g of crude product. Purify by flash column chromatography on silica gel (120 g, irregular SiOH 25 - 40 μM, DCM / MeOH, from 100 / 0 to 97 / 3). Collect the pure fractions and evaporate to give the intermediate AW-3 as a light beige solid, 3.54 g (77%).

[1214] Preparation of Intermediate AW-4

[1215] At 40 °C, dissolve AW-3 (3.54 g, 8.46 mmol) in Me-THF (65 mL) and AcOH (4.84 mL, 84.59 mmol). Then add dropwise isoamyl nitrite (5.68 mL, 42.3 mmol) and stir the mixture at 40 °C for 2 h. Dilute the solution in EtOAc (60 mL) and water (30 mL), wash with saturated NaHCO 3 solution (twice), brine, dry over MgSO 4 and evaporate to give 4.67 g of a pale yellow oil. Purify by flash column chromatography on silica gel (80 g, irregular SiOH 25 - 40 μM, DCM / MeOH, from 100 / 0 to 97 / 3). Collect the pure fractions and evaporate to give the intermediate AW-4 as a yellow oil, 3.99 g (97%, 92% purity, used as such in the next step).

[1216] Preparation of Intermediate AW-5

[1217] At room temperature, zinc powder (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). The mixture was stirred at room temperature for 1.5 h. Water was added and the aqueous layer was extracted 3 times with DCM. The combined organic layers were dried over MgSO 4 and concentrated under reduced pressure to give a colorless oil, 4.12 g. Purification was carried out by flash chromatography on silica gel (80 g, irregular SiOH 25 - 40 μM, DCM / MeOH, from 100 / 0 to 97 / 3). The pure fractions were collected and evaporated to give the intermediate AW-5 as a colorless oil, 1.88 g (50%).

[1218] Preparation of Intermediate AW-6

[1219] To a solution of AW-5 (1.88 g, 4.08 mmol) in MeOH (40.2 mL) was added dropwise TMSCl (4.14 mL, 32.61 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo to give the intermediate AW-6, 1.45 g (80%), which was used as such in the next step.

[1220] Preparation of Intermediate AW-7

[1221] At 70 °C, 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 overnight. The reaction mixture was evaporated. The residue was diluted in DCM and 10% K 2 CO 3 aqueous solution. The aqueous layer was extracted twice with DCM / MeOH (95 / 5). The combined organic layers were dried over MgSO 4 and filtered and evaporated to give a yellow solid. Purification was carried out by flash chromatography on silica gel (12 g, irregular SiOH 25 - 40 μM, DCM / MeOH, from 100 / 0 to 90 / 10). The pure fractions were collected and evaporated to give the intermediate AW-7 as a colorless oil, 0.58 g, which was used as such in the next step.

[1222] Preparation of Intermediate AW-8

[1223] 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 in an ice bath at 5 °C) was added dropwise Tf in DCM 2O 1M (1.69 mL, 1.69 mmol). The reaction mixture was stirred at 5 °C for 15 min. The reaction mixture was immediately quenched with saturated NaHCO 3 solution. The aqueous layer was extracted with DCM (twice). The combined organic layers were washed with brine (once), dried over MgSO 4 4, filtered and evaporated. Purification was carried out by flash column chromatography on silica gel (24 g, irregular SiOH 25 - 40 μM, DCM / MeOH, from 100 / 0 to 97 / 3). The pure fractions were collected and evaporated to give the intermediate AW-8 as a pale yellow oil, 0.59 g (73%), which was allowed to stand to crystallize.

[1224] Preparation of Intermediate AW-9

[1225] In a steel bomb, a mixture of AW-8 (0.59 g, 1.24 mmol), palladium hydroxide (20% on carbon), nominal 50% water (0.17 g, 0.12 mmol) and aqueous HCl 3M (0.41 mL, 1.24 mmol) in MeOH (8.7 mL) and EtOAc (8.7 mL) was hydrogenated at 3 bar H 2 2 at room temperature for 3 h. The mixture was filtered through a pad and washed with MeOH. The filtrate was evaporated and then co-evaporated with MeOH (twice) to give the intermediate AW-9 as a pale beige powder, 0.484 g (90%).

[1226] Preparation of Compound 142

[1227]

[1228] Under a stream of N 2 2, HATU (0.15 g, 0.4 mmol) was added 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). The solution was stirred at room temperature for 15 min. Then AW-9 (0.118 g, 0.35 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. The solvent was evaporated and the residue was diluted in ethyl acetate and washed with saturated NaHCO 3 aqueous solution, water and then brine. The organic layer was dried over MgSO4, filtered and evaporated in vacuo to give a brown residue. Purification was carried out by flash column chromatography on silica gel (40 g, irregular SiOH 25 - 40 μM, solid deposited on Above, DCM / MeOH, from 100 / 0 to 97 / 3). The pure fractions were collected and evaporated to give a pale yellow powder, 0.512 g. Purification was carried out via chiral SFC (stationary phase: Whelk-O1 (S,S) 5 μm 250*30 mm, mobile phase: 60% CO 2 , 40% mixture of MeOH / DCM 80 / 20 v / v + 0.3% iPrNH 2 ). The pure fractions were collected and evaporated to give a white solid, 0.31 g, which was triturated with DIPE and a small amount of heptane. The precipitate was filtered off and dried in vacuo at 60 °C to give Compound 142 as a white powder, 0.29 g (47%).

[1229] 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.09 (d, J = 1.4 Hz, 1H), 8.46 (t, J = 5.8 Hz, 1H), 8.13 (br s, 1H), 7.63 - 7.75 (m, 2H), 7.47 (dd, J = 9.4, 2.1 Hz, 1H), 7.37 (s, 1H), 4.51 (br d, J = 5.8 Hz 2H), 4.13 (br t, J = 4.5 Hz, 2H), 3.92 (t, J = 4.8 Hz, 2H), 2.99 (q, J = 7.5 Hz, 2H), 1.26 (t, J = 7.5 Hz, 3H)

[1230] Preparation of Compound 181

[1231]

[1232] In a round-bottom flask, at room temperature, 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). The mixture was stirred at room temperature for 16 h. The mixture was diluted with saturated NaHCO 3 aqueous solution and extracted with DCM. The organic layer was separated, dried (MgSO 4 ), filtered, and the solvent was concentrated in vacuo to give a brown oil. The crude product was triturated with DCM, and the solid was filtered off and dried in vacuo to give a white solid, Compound 181, 0.059 g (45%).

[1233] 11H NMR (400 MHz, DMSO-d6) δ ppm 8.62 (s, 1H), 8.51 (br t, J = 5.8 Hz, 1H), 8.13 (s, 1H), 7.69 (dd, J = 12.7, 1.7 Hz, 1H), 7.37 (s, 1H), 7.22 (dd, J = 11.7, 0.9 Hz, 1H), 4.51 (d, J = 5.8 Hz, 2H), 4.17 - 4.10 (m, 2H), 3.96 - 3.89 (m, 2H), 2.97 (q, J = 7.5 Hz, 2H), 2.31 (s, 3H), 1.26 (t, J = 7.5 Hz, 3H).

[1234] Preparation of Compound 201

[1235]

[1236] Therefore, the preparation of compound 201 was the same as that of compound 142, starting from intermediate AI-3 (0.64 mmol) and intermediate AW-9 (0.4 mmol), to give a white solid, 0.063 g (30%).

[1237] 1 1H NMR (400 MHz, DMSO) d 9.19 - 9.12 (m, 1H), 8.51 (d, J = 2.4 Hz, 1H), 8.44 (t, J = 5.8 Hz, 1H), 8.13 (s, 1H), 7.69 (dd, J = 12.7, 1.7 Hz, 1H), 7.36 (s, 1H), 4.51 (d, J = 5.8 Hz, 2H), 4.13 (t, J = 4.6 Hz, 2H), 3.96 - 3.87 (m, 2H), 3.00 (q, J = 7.5 Hz, 2H), 2.34 (s, 3H), 1.27 (t, J = 7.5 Hz, 3H).

[1238] Synthesis of Compound 213

[1239]

[1240] Preparation of Intermediate AX-1

[1241] 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 treated with saturated NaHCO 3 aqueous solution. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO 4Dry, filter, and remove the solvent under reduced pressure to give a colorless oil. Purify by flash chromatography on silica gel (24 g, irregular SiOH 25 - 40 μM, DCM / MeOH, from 95 / 5 to 90 / 10). Collect the pure fractions and evaporate to give the intermediate AX-1 as a colorless oil, 0.176 g (65%).

[1242] Preparation of Compound 213

[1243] 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 in an ice bath at 5 °C) was added dropwise Tf 2 O 1 M in DCM (0.32 mL, 0.32 mmol). Stir the reaction mixture at 5 °C for 15 min. Quench the reaction mixture immediately with saturated NaHCO 3 solution. Extract the aqueous layer with DCM (twice). Wash the combined organic layers with brine (once), dry over MgSO 4 and filter to give the crude product. Add dry DCM (2.8 mL) to the crude product, cool the solution to 5 °C, then add DIPEA (0.056 mL, 0.32 mmol), followed by Tf 2 O 1 M in DCM (0.13 mL, 0.13 mmol). Stir the reaction mixture at 5 °C for 15 min. Quench the reaction mixture immediately with saturated NaHCO 3 solution. Extract the aqueous layer with DCM (twice). Wash the combined organic layers with brine (once), dry over MgSO 4 and filter to give 0.217 g of an oil. Purify by flash chromatography on silica gel (12 g, irregular SiOH 25 - 40 μM, DCM / MeOH, from 100 / 0 to 97 / 3). Collect the pure fractions and evaporate to give compound 213 as a beige powder, 0.093 g (51%). Purify by flash chromatography on silica gel (12 g, irregular SiOH 25 - 40 μM, DCM / MeOH, from 100 / 0 to 97 / 3). Collect the pure fractions and evaporate to give compound 213 as a beige powder, 0.075 g (41%). Crystallize it from DIPE / heptane, grind, filter, and dry in vacuo at 60 °C to give compound 213 as a white powder, 0.063 g (35%).

[1244] 1 H NMR (500 MHz, DMSO-d 6)δ ppm 9.04 - 9.11 (m, 1H), 8.47 (t, J = 5.9 Hz, 1H), 7.64 - 7.72 (m, 1H), 7.46 (dd, J = 9.5, 2.1 Hz, 1H), 7.29 - 7.38 (m, 1H), 7.13 - 7.27 (m, 2H), 5.12 - 5.18 (m, 1H), 4.49 (d, J = 6.0 Hz, 2H), 3.95 - 4.06 (m, 2H), 3.67 - 3.77 (m, 2H), 3.01 (q, J = 7.5 Hz, 2H), 2.25 (s, 3H), 1.22 - 1.31 (t, J = 7.5 Hz, 3H).

[1245] Synthesis of Intermediate AY-3

[1246]

[1247] Preparation of Intermediate AY-1

[1248] 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 treated with saturated NaHCO 3 aqueous solution. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO 4 4, filtered, and the solvent was removed under reduced pressure. The residue was purified by preparative LC (irregular SiOH 40 μm, 40 g, from DCM / MeOH 95 / 5 to 90 / 10) to give 442 mg of intermediate AY - 1 as a colorless residue, which was allowed to crystallize (25%).

[1249] Preparation of Intermediate AY-2

[1250] Thus, the preparation of intermediate AY - 2 was the same as that of compound 213, starting from AY - 1 (1.31 mmol), to give a beige powder, 0.388 g (63%).

[1251] Preparation of Intermediate AY-3

[1252] In a steel bomb, a mixture of AY - 2 (0.39 g, 0.82 mmol), palladium hydroxide (20% on carbon), nominal 50% water (0.12 g, 0.082 mmol), and aqueous HCl 1 M (0.82 mL, 0.82 mmol) in MeOH (5.8 mL) and EtOAc (5.8 mL) was hydrogenated at 5 bar H 2Below, hydrogenate at room temperature for 1.5 hours. Filter the mixture through a celite pad and wash with MeOH. Evaporate the filtrate to give intermediate AY-3, 0.32 g (96%, purity 92%), which is used as such in the next step.

[1253] Preparation of Compound 214

[1254]

[1255] Thus, the preparation of compound 214 was the same as that of 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 give a white powder, 0.098 g (52%).

[1256] 1 H NMR (500 MHz, 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 = 8.2 Hz, 2H), 7.13 - 7.24 (m, 3H), 4.42 - 4.52 (m, 2H), 4.01 (br s, 2H), 3.84 (br d, J = 4.3 Hz, 2H), 2.27 (s, 3H)

[1257] Preparation of Compound 215

[1258]

[1259] Thus, the preparation of compound 215 was the same as that of 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 give a white powder, 0.129 g (72%).

[1260] 11H NMR (500 MHz, 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)

[1261] Preparation of Compound 217

[1262]

[1263] Therefore, the preparation of compound 217 was the same as that of compound 181, starting from intermediate AU-2 (0.31 mmol) and intermediate AY-3, to give a white foam, 0.018 g (10%).

[1264] 1 1H NMR (500 MHz, DMSO-d 6 ) δ ppm 9.17 (s, 1H), 8.40 (t, J = 6.0 Hz, 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)

[1265] Preparation of Compound 218

[1266]

[1267] Therefore, the preparation of compound 218 was the same as that of 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 give a white foam, 0.059 g (38%).

[1268] 1 1H NMR (500 MHz, DMSO-d 6)δ ppm 8.09 (t, J = 6.0 Hz, 1H), 7.80 - 7.91 (m, 1H), 7.21 - 7.32 (m, 2H), 7.08 - 7.19 (m, 2H), 4.40 (d, J = 6.0 Hz, 2H), 4.00 (t, J = 4.9 Hz, 2H), 3.81 (t, J = 4.9 Hz, 2H), 2.85 (q, J = 7.5 Hz, 2H), 2.40 - 2.46 (m, 3H), 2.22 - 2.28 (m, 3H), 1.20 (t, J = 7.5 Hz, 3H)

[1269] Synthesis of Compound 216

[1270]

[1271] Preparation of Intermediate AZ-1

[1272] Trimethyl ortho - isobutyrate (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 treated with saturated NaHCO 3 aqueous solution. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO 4 4, filtered, and the solvent was removed under reduced pressure to give an oil. Purification was carried out by flash column chromatography on silica gel (4 g, irregular SiOH, DCM / MeOH, from 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%).

[1273] Preparation of Compound 216

[1274] 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 in an ice bath at 5 °C) was added dropwise Tf 2 O 1M in DCM (0.23 mL, 0.23 mmol). The reaction mixture was stirred at 5 °C for 15 min. The reaction mixture was immediately quenched with saturated NaHCO 3 solution. The aqueous layer was extracted with DCM (twice). The combined organic layers were washed with brine (once), dried over MgSO4, filtered, and evaporated. DCM (2 mL) was added to the residue, the solution was cooled to 5 °C, then DIPEA (0.04 mL, 0.23 mmol) was added, followed by Tf 2O1M (0.092 mL, 0.092 mmol). The reaction mixture was stirred at 5 °C for 15 min. The reaction mixture was immediately quenched with saturated NaHCO 3 solution. The aqueous layer was extracted with DCM (twice). The combined organic layers were washed with brine (once), dried over MgSO4 and filtered to give 0.725 g. Purification was carried out by flash column chromatography on silica gel (4 g, irregular SiOH 25 - 40 μM, heptane / EtOAc, from 90 / 10 to 70 / 30). The pure fractions were collected and evaporated to give a beige powder, 0.06 g, which was triturated with DIPE and a small amount of heptane. The precipitate was filtered off and dried under vacuum at 60 °C to give compound 216 as a white powder, 0.040 g.

[1275] 1 1H NMR (500 MHz, DMSO-d 6 ) δ ppm 9.03 - 9.18 (m, 1H), 8.47 (br t, J = 5.5 Hz, 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 = 5.6 Hz, 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)

[1276] Synthesis of Intermediate BA-3

[1277]

[1278] Preparation of Intermediate BA-1

[1279] Accordingly, the preparation of intermediate BA-1 was the same as that of AZ-1, starting from intermediate E6 (6.45 mmol), to give a colorless oil, 1.82 g (77%).

[1280] Preparation of Intermediate BA-2

[1281] Thus, the preparation of intermediate BA-2 was the same as that of compound 216, starting from BA-1 (4.97 mmol), to give a beige powder, 1.58 g (58%).

[1282] Preparation of Intermediate BA-3

[1283] Accordingly, the intermediate BA-3 was prepared in the same manner as AY-3, starting from intermediate BA-2 (3.17 mol), to give a beige solid, 1.39 g (91%, purity about 90%, used as such in the next step).

[1284] The following compounds were also prepared according to the methods described herein:

[1285] Compound 191

[1286]

[1287] Compound 195

[1288]

[1289] Compound 205

[1290]

[1291] Compound 208

[1292]

[1293] Compound 211

[1294]

[1295] Compound 212

[1296]

[1297] Compound 219

[1298]

[1299] Compound 107

[1300]

[1301] Compound 93

[1302]

[1303] Compound 116

[1304]

[1305] Compound 108

[1306]

[1307] Compound 120

[1308]

[1309] Compound 92

[1310]

[1311] Compound 94

[1312]

[1313] Compound 110

[1314]

[1315] Compound 96

[1316]

[1317] Compound 91

[1318]

[1319] Compound 99

[1320]

[1321] Compound 123

[1322]

[1323] Compound 122

[1324]

[1325] Compound 103

[1326]

[1327] Compound 118

[1328]

[1329] Compound 119

[1330]

[1331] Compound 86

[1332]

[1333] Compound 115

[1334]

[1335] Compound 111

[1336]

[1337] Compound 98

[1338]

[1339] Compound 109

[1340]

[1341] Compound 149

[1342]

[1343] Compound 101

[1344]

[1345] Compound 104

[1346]

[1347] Compound 87

[1348]

[1349] Compound 112

[1350]

[1351] Compound 160

[1352]

[1353] Compound 113

[1354]

[1355] Compound 85

[1356]

[1357] Compound 95

[1358]

[1359] Compound 114

[1360]

[1361] Compound 117

[1362]

[1363] Compound 102

[1364]

[1365] Compound 89

[1366]

[1367] Compound 105

[1368]

[1369] Compound 106

[1370]

[1371] Compound 100

[1372]

[1373] Compound 90

[1374]

[1375] Compound 97

[1376]

[1377] Compound 83

[1378]

[1379] Compound 121

[1380]

[1381] Compound 80

[1382]

[1383] Compound 84

[1384]

[1385] Compound 81

[1386]

[1387] Compound 82

[1388]

[1389] Compound 165

[1390]

[1391] Compound 166

[1392]

[1393] Compound 167

[1394]

[1395] Compound 168

[1396]

[1397] Compound 170

[1398]

[1399] Compound 171

[1400]

[1401] Compound 173

[1402]

[1403] Compound 174

[1404]

[1405] Compound 176

[1406]

[1407] Compound 178

[1408]

[1409] Compound 179

[1410]

[1411] Compound 182

[1412]

[1413] Compound 183

[1414]

[1415] Compound 184

[1416]

[1417] Compound 185

[1418]

[1419] Compound 186

[1420]

[1421] Compound 187

[1422]

[1423] Compound 188 (depicted as a tautomer)

[1424]

[1425] Compound 189

[1426]

[1427] Compound 190

[1428]

[1429] Compound 192

[1430]

[1431] Compound 196

[1432]

[1433] Compound 198

[1434]

[1435] Compound 199

[1436]

[1437] Compound 202

[1438]

[1439] Compound 203

[1440]

[1441] Compound 207

[1442]

[1443] Compound 220

[1444]

[1445] Compound 221

[1446]

[1447] Compound 222

[1448]

[1449] Compound 223

[1450]

[1451] Compound 224

[1452]

[1453] Compound 225

[1454]

[1455] Compound 226

[1456]

[1457] 4. Characteristic data table

[1458]

[1459]

[1460]

[1461] Additional characteristic data

[1462]

[1463]

[1464]

[1465]

[1466]

[1467]

[1468] 5. Biological Assay / Pharmacological Examples

[1469] Determination of MIC of Test Compounds against Mycobacterium tuberculosis

[1470] Test 1

[1471] The test compound and the reference compound were dissolved in DMSO and 1 μl of the solution was spotted onto a 96-well plate at a final concentration of 200x / well. Columns 1 and 12 were reserved without adding compounds, and the comp...

Claims

1. A compound of formula (Ia) wherein Q 1 represents =N- or =C(R 4 )-; 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 hydrogen or represents one or more substituents independently selected from 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 when attached to adjacent atoms of the A ring, any two R 1 groups may together form a 5- or 6-membered ring which optionally contains one or two heteroatoms and which is optionally substituted by one or two C 1-3 alkyl substituents; R 2 is -C 1-4 alkyl, which is optionally substituted by one or more substituents selected from halo and -OC 1-3 alkyl; R 3 、R 3a 、R 4 and R 4a Any two of which represent H, and the other two independently represent substituents selected from H, F, -C 1-3 alkyl and -O-C 1-3 alkyl; R 5 is H, -R 9a , -C(=O)-R 9b , -SO 2 -R 10 or Het 1 ; Either X or Y represents -CR 11a and the other represents N or -CR 11b ; R 6a and R 6b each independently represents hydrogen or -C 1-4 alkyl, optionally substituted with one or more substituents selected from halo, -O-CH 3 and phenyl; R 6c is - C 1-3 alkyl; R 7 and R 8 are independently selected from H and -C 1-3 alkyl; R 7a and R 7b each independently represents H, C 1-6 alkyl, or R 7a and R 7b are joined together to form a 3- to 6-membered ring; R 9a represents -C 1-4 alkyl, which is optionally substituted by one or more substituents selected from halo, -OC 1-3 alkyl and Het 2 ; R 9b is hydrogen or -C 1-3 alkyl, optionally substituted by one or more fluorine atoms; R 10 is -C 1-4 alkyl, which is optionally substituted by one or more substituents selected from halo and -O-CH 3 ; R 11a and R 11b independently represent H; C 1-4 alkyl, optionally substituted with one or more substituents selected from: fluorine, -CN, -R 12a , -OR 12b , -N(R 12c )R 12d and -C(O)N(R 12e )R 12f ; or -O-C 1-4 alkyl, optionally substituted with one or more substituents selected from: fluorine, -R 12g , -OR 12h and -N(R 12i )R 12j ; R 12a 、R 12b 、R 12c 、R 12d 、R 12e 、R 12f 、R 12g 、R 12h 、R 12i and R 12j each independently represents hydrogen or C 1-3 alkyl, which is optionally substituted with one or more fluorine atoms; Het 1 and Het 2 each independently represents a 5- or 6-membered aromatic ring containing one or two heteroatoms selected from nitrogen and sulfur, and optionally substituted with one or more substituents selected from halo and C 1-3 alkyl, said C 1-3 alkyl being optionally substituted with one or more fluorine atoms, or a pharmaceutically acceptable salt thereof.

2. A compound of formula (I) wherein 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 hydrogen or represents one or more substituents independently selected from halo, -R 6a , -O-R 6b , -C(=O)-R 6c , -C(=O)-N(R 7 )(R 8 ), -CN and -N(R 7a )R 7b ; R 2 is -C 1-4 alkyl, which is optionally substituted by one or more substituents selected from halo and -OC 1-3 alkyl; R 3 、R 3a 、R 4 and R 4a Any two of which represent H, and the other two independently represent substituents selected from H, F, -C 1-3 alkyl and -O-C 1-3 alkyl; R 5 is H, -R 9a , -C(=O)-R 9b , -SO 2 -R 10 or Het 1 ; Either X or Y represents -CR 11a and the other represents N or -CR 11b ; R 6a and R 6b each independently represents -C 1-4 alkyl, which is optionally substituted with one or more substituents selected from halo and -O-CH 3 ; R 6c is - C 1-3 alkyl; R 7 and R 8 are independently selected from H and -C 1-3 alkyl; R 7a and R 7b each independently represents H, C 1-6 alkyl, or R 7a and R 7b are joined together to form a 3- to 6-membered ring; R 9a represents -C 1-4 alkyl, which is optionally substituted with one or more substituents selected from halo, -OC 1-3 alkyl and Het 2 ; R 9b is hydrogen or -C 1-3 alkyl, which is optionally substituted by one or more fluorine atoms; R 10 is -C 1-4 alkyl, which is optionally substituted by one or more substituents selected from halo and -O-CH 3 ; R 11a and R 11b independently represent H; C 1-4 alkyl, optionally substituted with one or more substituents selected from: fluorine, -CN, -R 12a , -OR 12b , -N(R 12c )R 12d and -C(O)N(R 12e )R 12f ; or -O-C 1-4 alkyl, optionally substituted with one or more substituents selected from: fluorine, -R 12g , -OR 12h and -N(R 12i )R 12j ; R 12a 、R 12b 、R 12c 、R 12d 、R 12e 、R 12f 、R 12g 、R 12h 、R 12i and R 12j independently represent hydrogen or C 1-3 alkyl, which is optionally substituted by one or more fluorine atoms; Het 1 and Het 2 each independently represents a 5- or 6-membered aromatic ring containing one or two heteroatoms selected from nitrogen and sulfur, and optionally substituted with one or more substituents selected from halogen and C 1-3 alkyl, said C 1-3 alkyl being optionally substituted with one or more fluorine atoms, or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 or claim 2, wherein: There may be no, one or two R substituents on ring A; 1 substituents; R 1 When present, represents one or two substituents independently selected from 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 ; R 6a represents C 1-3 alkyl, which is optionally substituted by -O-CH 3 substituted; R 6b and R 6c represent C 1-3 alkyl; R 7 and R 8 each independently represents hydrogen or C 1-3 alkyl; R 7a and R 7b are joined together to form a 4- to 6-membered ring.

4. The compound according to claim 1 or claim 2, wherein: The combination of ring A and R 1 is represented as follows:

5. The compound according to claim 1 or claim 2, wherein: Ring B and R 2 The combination of is represented as follows:

6. The compound according to claim 1 or claim 2, wherein: Combined ring systems, namely ring A, ring B, R 1 and R 2 The combination of is represented as follows:

7. The compound according to claim 1 or claim 2, wherein: R 2 is a straight-chain -C 1-4 alkyl group, which is optionally substituted by one or more substituents selected from -O-C 1-2 alkyl groups.

8. The compound according to claim 1 or claim 2, wherein: R 3 , R 3a , R 4 and R 4a Any two of them represent H, and the other two independently represent a group consisting of H, F, -CH 3 and -OCH 3 substituent.

9. The compound according to claim 1 or claim 2, wherein: R 5 is H, -R 9a , -C(=O)-R 9b , -SO 2 -R 10 or Het 1 。 10. The compound according to claim 1 or claim 2, wherein: R 9a represents an unsubstituted or C 1-3 alkyl substituted with a substituent selected from halo, -OC 2 alkyl and Het 1-3 alkyl.

11. The compound according to claim 1 or claim 2, wherein: R 9b represents H or C 1-3 an alkyl group, which is optionally substituted by one or more fluorine atoms 12. The compound according to claim 1 or claim 2, wherein: R 10 represents -CF 3 , -CH 3 , isopropyl, -CH 2 C(H)(CH 3 ) 2 or -CH 2 CH 2 -OCH 3 .

13. The compound according to claim 1 or claim 2, wherein: Het 1 and Het 2 each independently represents a thiazolyl group optionally substituted with a -CF 3 substituent.

14. The compound according to claim 1 or claim 2, wherein: Either X or Y represents -CR 11a and the other represents N or -CR 11b ; When R 11a or R 11b represents C 1-4 alkyl, it is unsubstituted or substituted with one or more substituents selected from -CN, -OR 12b and -N(R 12c )R 12d ; R 12b represents H or C 1-2 alkyl; R 12c and R 12d each independently represents C 1-2 alkyl; When R 11a or R 11b represents -O-C 1-4 alkyl, it is unsubstituted and represents -OC 1-2 alkyl.

15. The compound according to claim 14, wherein: When R 11a or R 11b represents C 1-4 alkyl, it 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.

16. The compound according to claim 1, the compound is or a pharmaceutically acceptable salt thereof.

17. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound according to any one of claims 1 to 16 as an active ingredient.

18. Use of the compound according to any one of claims 1 to 16 for the manufacture of a medicament for the treatment of mycobacterial infections.

19. A combination of (a) the compound according to any one of claims 1 to 16 and (b) one or more other anti-mycobacterial agents or anti-tuberculosis agents.

20. Use of a product in the preparation of a medicament for use in the treatment of bacterial infections either simultaneously or separately, the product comprising (a) the compound according to any one of claims 1 to 16, and (b) one or more other anti-mycobacterial agents or anti-tuberculosis agents, the product being in the form of a combined preparation.

21. A method for preparing the compound of formula (Ia) according to claim 1, the method comprising: reacting a compound of formula (XIV), wherein the whole is as defined in claim 1, with a compound of formula (XVA), wherein the whole is as defined in claim 1.

22. A method for preparing the compound of formula (Ia) according to claim 1, the method comprising: reacting a compound of formula (XVIIA), wherein the whole is as defined in claim 1 and R 12 represents a leaving group and is reacted with a compound of formula (XVI) wherein R 5 coupled as defined in claim 1 23. A method for preparing the compound of formula (Ia) according to claim 1, the method comprising: For a compound of formula (Ia) wherein X represents N, a compound of formula (XVIIIA) is used, wherein the whole is as defined in claim 1 and reacts with a compound of formula (XIX), R 11x C(OCH 3 ) 3 (XIX) wherein R 11x represents R 11a , as defined in claim 1.

24. A process for preparing a compound of formula (Ia) as claimed in claim 1, the process comprising: For a compound of formula (Ia) wherein Y represents N, a compound of formula (XXA) is used, wherein the whole is as defined in claim 1 and reacts with a compound of formula (XIX), R 11x C(OCH 3 ) 3 (XIX) wherein R 11x represents R 11a , as defined in claim 1.

25. A process for preparing a compound of formula (I) as claimed in claim 2, the process comprising: using a compound of formula (XIV) wherein the whole is as defined in claim 2, and reacting it with a compound of formula (XV) wherein the whole is as defined in claim 2.

26. A process for preparing a compound of formula (I) as claimed in claim 2, the process comprising: using a compound of formula (XVII) wherein the whole is as defined in claim 2 and R 12 represents a leaving group and, with a compound of formula (XVI), wherein R 5 couple as defined in claim 2.

27. A process for preparing a compound of formula (I) as claimed in claim 2, the process comprising: For a compound of formula (I) wherein X represents N, a compound of formula (XVIII) is used, wherein the whole is as defined in claim 2 and reacts with a compound of formula (XIX), R 11x C(OCH 3 ) 3 (XIX) where R 11x represents R 11a , as defined in claim 2.

28. A process for preparing a compound of formula (I) as claimed in claim 2, the process comprising: For a compound of formula (I) wherein Y represents N, a compound of formula (XX) is used, wherein the whole is as defined in claim 2 and reacts with a compound of formula (XIX), R 11x C(OCH 3 ) 3 (XIX) wherein R 11x represents R 11a , as defined in claim 2.

29. A process for preparing a compound of formula (I) as claimed in claim 2, the process comprising: For the preparation of a compound of formula (I), wherein R 5 represents -C(=O)-R 9b -S(O) 2 -R 10 or Het 1 , reacting a compound of formula (I) as defined in claim 2, wherein R 5 represents H, with a compound of formula (XXI) LG 1 -Z(XXI) wherein Z represents -C(=O)-R 9b 、-S(O) 2 -R 10 or Het 1 and LG 1 represents a suitable leaving group and wherein the whole is as defined in claim 2 and in the case of Het 1 the LG 1 is attached to a suitable C atom of the heteroaromatic ring.

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