Imidazopyridine amides and related compounds for use in the treatment of bacterial infections - Patents.com

Abstract

The present invention relates to the following compound (I): wherein the variables are as defined herein, which may be useful as a pharmaceutical for use (e.g., in combination) in the treatment of tuberculosis. [Formula 1] JPEG2024540052000510.jpg71128

Description

[Technical Field]

[0001] The present invention relates to novel compounds. The present invention also relates to such compounds for use as pharmaceuticals, and for use in treating bacterial diseases, including diseases caused by pathogenic mycobacteria such as Mycobacterium tuberculosis. Such compounds may act by interfering with ATP synthase in M. tuberculosis, with inhibition of cytochrome bc1 activity as their primary mode of action. Thus, primarily, such compounds are antitubercular agents. [Background technology]

[0002] Mycobacterium tuberculosis (Mycobacterium tuberculosis) is the causative agent of tuberculosis (TB), a serious and potentially fatal infectious disease distributed worldwide. Estimates from the World Health Organization indicate that over 8 million people contract TB each year, and 2 million die from it annually. Over the past decade, TB cases have increased by 20% worldwide, with the highest burden in the poorest regions. If these trends continue, TB incidence will increase by 41% over the next 20 years. Fifty years after the introduction of effective chemotherapy, TB remains the leading infectious cause of adult mortality worldwide, even in the post-AIDS era. Complicating the TB epidemic is the increasing trend toward multidrug-resistant strains and its deadly symbiosis with HIV. HIV-positive, TB-infected individuals are 30 times more likely to develop active TB than HIV-negative individuals, and TB accounts for one in three deaths worldwide with HIV / AIDS.

[0003] All existing approaches to the treatment of tuberculosis involve the combination of multiple drugs. For example, the regimen recommended by the U.S. Public Health Service is a two-month combination of isoniazid, rifampicin, and pyrazinamide, followed by an additional four months of isoniazid and rifampicin alone. These drugs are continued for an additional seven months in patients infected with HIV. For patients infected with multidrug-resistant strains of M. tuberculosis, drugs such as ethambutol, streptomycin, kanamycin, amikacin, capreomycin, ethionamide, cycloserine, ciprofloxacin, and ofloxacin are added to the combination therapy. Neither a single drug nor any combination of drugs is effective in the clinical treatment of tuberculosis, offering the possibility of a therapy lasting less than six months.

[0004] There is a high medical need for new drugs that improve current treatments by enabling a regimen that facilitates patient and provider compliance. A shorter regimen and one requiring less monitoring is the best way to achieve this. Most of the benefit from treatment is obtained during the first 2 months of the intensive phase, or during the sterilizing phase when the four drugs are given together, during which the bacterial load is significantly reduced and the patient becomes noninfectious. A 4- to 6-month continuation or sterilizing phase is necessary to eliminate any remaining bacilli and minimize the risk of relapse. A potent sterilizing agent that shortens treatment to 2 months or less would be highly beneficial. Drugs that facilitate compliance by requiring less intensive monitoring are also needed. Clearly, compounds that reduce both the total treatment duration and the frequency of drug administration would provide the greatest benefit.

[0005] Complicating the TB epidemic is the increasing incidence of multidrug-resistant strains, or MDR-TB. Up to 4% of all cases worldwide are thought to be MDR-TB (resistant to the four-drug standard's most effective drugs, isoniazid and rifampin). MDR-TB is fatal if untreated and cannot be adequately cured through standard therapy, requiring treatment with "second-line" drugs for up to two years. These drugs are often toxic, expensive, and only marginally effective. In the absence of effective therapy, infectious MDR-TB patients continue to spread the disease, resulting in new infections with MDR-TB strains. There is a high medical need for new drugs with novel mechanisms of action that are more likely to exhibit activity against drug resistance, particularly MDR strains.

[0006] The term "drug resistant" as used above and below is a term well understood by those skilled in the art of microbiology. Drug-resistant Mycobacterium is a Mycobacterium that is no longer susceptible to at least one previously effective drug and has developed the ability to resist antibiotic attack by at least one previously effective drug. Drug-resistant strains can pass on the resistance ability to their progeny. The resistance can result from random genetic mutations in bacterial cells that alter susceptibility to a single drug or to different drugs.

[0007] MDR tuberculosis is a specific form of drug-resistant tuberculosis caused by bacteria that are resistant to at least isoniazid and rifampicin, currently the two most powerful anti-TB drugs (with or without resistance to other drugs). Thus, whenever used above or below, "drug-resistant" includes multi-drug resistance.

[0008] Another factor in controlling the TB epidemic is the problem of latent TB. Despite decades of tuberculosis (TB) control programs, approximately 2 billion people are infected with Mycobacterium tuberculosis (M. tuberculosis) but are asymptomatic. Approximately 10% of these individuals are at risk of developing active TB during their lifetime. The global TB epidemic is driven by TB infection among HIV patients and the rise of multidrug-resistant TB strains (MDR-TB). Reactivation of latent TB is a high-risk factor for disease development and accounts for 32% of deaths among HIV-infected individuals. To control the TB epidemic, new drugs capable of killing dormant or latent bacilli must be discovered. Dormant TB can be reactivated and cause disease by several factors, such as suppression of host immunity through the use of immunosuppressants such as antibodies against tumor necrosis factor α or interferon-γ. For HIV-positive patients, the only preventive treatment available for latent TB is a two- to three-month course of rifampicin and pyrazinamide. The effectiveness of this treatment regimen is unclear, and the length of treatment is a significant constraint in resource-limited settings. Therefore, there is a great need to identify novel drugs that can act as chemopreventive agents in individuals harboring latent TB bacilli.

[0009] Mycobacterium tuberculosis (M. tuberculosis) enters healthy individuals via inhalation and is phagocytosed by alveolar macrophages in the lungs. This leads to a strong immune response and the formation of granulomas, consisting of M. tuberculosis-infected macrophages surrounded by T cells. After 6–8 weeks, the host immune response causes the death of infected cells by necrosis and the accumulation of caseous material containing certain extracellular bacilli surrounded by layers of macrophages, epithelioid cells, and peripheral lymphoid tissue. In healthy individuals, the majority of mycobacteria are killed in these environments, but a small percentage of bacilli remain viable and appear to exist in a non-replicating, hypometabolic state, resistant to killing by anti-TB drugs such as isoniazid. These bacilli can persist in this altered physiological environment for the life of the individual without exhibiting any clinical symptoms of disease. However, in 10% of cases, these latent bacilli may reactivate and cause disease. One hypothesis for the development of these persistent bacteria is the pathophysiological environment of human lesions, i.e., low oxygen tension, nutrient limitation, and acidic pH, which are postulated to render these bacteria phenotypically resistant to major antimycobacterial drugs.

[0010] In addition to managing the TB epidemic, there is an emerging problem of resistance to first-line antibiotics, with some important examples being penicillin-resistant Streptococcus pneumoniae, vancomycin-resistant enterococci, methicillin-resistant Staphylococcus aureus, and multi-resistant salmonellae.

[0011] The consequences of antibiotic resistance are severe. Infections caused by resistant microorganisms fail to respond to treatment, leading to prolonged illness and a greater risk of death. Treatment failure also leads to longer duration of infection, which increases the number of infected people moving through the community, thus putting the general population at risk of contracting resistant strains of infection.

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

[0013] Self-medication with antimicrobials is another major factor contributing to resistance: self-medicated antimicrobials may be unnecessary, are often inappropriately dosed, or may not contain the appropriate amount of active drug.

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

[0015] Due to the emergence of resistance to multiple antibiotics, physicians are faced with infections for which there are no effective treatments, and the morbidity, mortality, and financial costs of these infections are increasingly burdening healthcare systems worldwide.

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

[0017] Anti-infective compounds for treating tuberculosis are disclosed, for example, in WO 2011 / 113606. Such document relates to compounds that will prevent the growth of M. tuberculosis (Mycobacterium tuberculosis) within host macrophages, e.g., compounds having a bicyclic core, an imidazopyridine, linked (e.g., via an amide moiety) to an optionally substituted benzyl group.

[0018] WO 2014 / 015167 also discloses compounds that are potentially useful in the treatment of tuberculosis. These compounds disclosed herein essentially have a bicyclic ring (5,5-fused bicyclic ring) substituted with a linker group (e.g., an amide group) that can itself be linked to another bicyclic ring or an aromatic group. These compounds in this document do not contain a series of more than three rings.

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

[0020] [ka]

[0021] This clinical candidate is also discussed in the article J. Medicinal Chemistry, 2014, 57(12), pp 5293-5305. It is active against MDR tuberculosis, with an MIC of 0.28 nM in macrophages. 50It has been described as active against the M. tuberculosis strain H37Rv. Positive control data (using the well-known anti-TB compounds bedaquiline, isoniazid, and moxifloxacin) have also been reported. This literature also suggests a mode of action based on mutant studies. It may act by interfering with ATP synthase in M. tuberculosis, hypothesizing that inhibition of cytochrome bc1 activity is the primary mode of action. Cytochrome bc1 is an essential component of the electron transport chain required for ATP synthesis. Q203 appears to be highly active against both vegetative and non-vegetative bacteria.

[0022] WO 2015 / 014993 also discloses compounds as having activity against M. tuberculosis, as do WO 2014 / 4015167, WO 2017 / 001660, WO 2017 / 001661, WO 2017 / 216281, WO 2017 / 216283, and WO 2021 / 048342. WO 2013 / 033070 and WO 2013 / 033167 disclose various compounds as kinase modulators. Summary of the Invention

[0023] It is an object of the present invention to provide compounds for use in the treatment of bacterial diseases, particularly diseases caused by pathogenic bacteria such as Mycobacterium tuberculosis, including latent disease, including drug-resistant M. tuberculosis strains. Such compounds may also be novel and may act by interfering with ATP synthase in M. tuberculosis, with inhibition of cytochrome bc1 activity believed to be the primary mode of action.

[0024] Here, the following formula (I):

[0025] [ka] [In the formula, A is a six-membered ring which may be aromatic or non-aromatic; X 1 is ═N—, -CH2—, or ═C(R 10a )-, X 2 , X 3 , X 4 , X 5 and X 6 are each independently =N- or =C(R 10b )-, R 1 or R 2 are each independently halo (e.g., Cl, F), -R 6c , -OR 6d , -C(=O)-R 6e , -C(=O)-N(R 6 )(R 7 ), -CN and -N(R 6a )R 6b represents a substituent selected from R 3 is H, halo (e.g., Cl, F), and halo (e.g., F) and -OC 1~3 -C (linear, branched, or cyclic) optionally substituted with one or more substituents selected from alkyl 1~3 represents a substituent selected from alkyl, R 4 are H, F, and -C 1~3 Alkyl and -OC 1~3 represents a substituent selected from alkyl, R 5 -H, -OH, -R 8a , -C(=O)-R 8b , -SO2-R 9 , and -N(R 11a )R 11b represents one or more substituents selected from R 6 and R 7 are independently H and -C 1~3 alkyl, R 6a and R 6b are independently H, C1~6 represents alkyl, or R 6a and R 6b are linked together to form a 3- to 6-membered ring, R 6c and R 6d are independently hydrogen or halo (e.g., F), —O—CH, phenyl, —N(R 6a )R 6b -C optionally substituted by one or more substituents selected from 1~4 represents alkyl, R 6e -C 1~3 is alkyl, R 8a -CN, -C 1~4 alkyl (linear, branched, or cyclic, where the alkyl group is optionally substituted with one or more substituents selected from halo, forming, for example, -CF3, -CHF2, -CF2CH3), or -OC (optionally substituted with one or more substituents selected from halo and -O-CH3); 1~3 represents alkyl, R 8b is hydrogen or —C (optionally substituted with one or more fluoro atoms); 1~3 is alkyl, R 9 is optionally substituted by one or more substituents selected from halo (e.g., F) and —O—CH 1~4 represents alkyl, R 10a and R 10b are independently H, halo (per se, fluoro, -CN, -R 12a , -OR 12b , -N(R 12c )R 12d and / or -C(O)N(R 12e )R 12f C optionally substituted with one or more (e.g., one) substituent(s) selected from 1~4 Alkyl or (by itself, fluoro, -R 12g , -OR 12h and / or -N(R 12i )R12j and optionally substituted by one or more (e.g., one) substituent(s) selected from: 1~4 represents alkyl, R 11a and R 11b are independently hydrogen, C (optionally substituted with one or more fluoro atoms), 1~3 Alkyl or -S(O)R 6c (where R 6c denotes (as defined above), R 12a , R 12b , R 12c , R 12d , R 12e , R 12f , R 12g , R 12h , R 12i and R 12j are independently hydrogen or C (optionally substituted with one or more fluoro atoms). 1~3 represents alkyl] or a pharmaceutically acceptable salt thereof, This compound may be referred to herein as the "compound of the invention."

[0026] In the compounds of the present invention: R 8a Also, -OC 1~3 C optionally substituted with alkyl 1~4 may represent alkyl (so for example, R 5 may represent -CH2-OCH3).

[0027] 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 form or free base form of the 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, and then removing the solvent or medium using standard techniques (for example, in vacuo, by lyophilization, or by filtration).Salts can also be prepared by exchanging the counterion of the compound of the present disclosure in the form of a salt with another counterion, for example, using a suitable ion exchange resin.

[0028] The present invention also provides a compound of formula (I)

[0029] [ka] [In the formula, A is a six-membered ring, which may be aromatic or non-aromatic; B is a five-membered aromatic ring; X a and X b One of the groups represents N and the other represents C (wherein each N and C is bonded to an appropriate number of single / double bonds). X 1 is ═N—, -CH2—, or ═C(R 10a )-, X 2 , X 3 , X 4 , X 5 and X 6 are each independently =N- or =C(R 10b )-, R 1 or R 2 are each independently halo (e.g., Cl, F), -R 6c , -OR 6d , -C(=O)-R 6e , -C(=O)-N(R 6 )(R 7 ), -CN and -N(R 6a )R 6b represents a substituent selected from R 3 is H, halo (e.g., Cl, F), and halo (e.g., F) and -OC 1~3 -C (linear, branched, or cyclic) optionally substituted with one or more substituents selected from alkyl 1~3 represents a substituent selected from alkyl, R 4 are H, F, and -C 1~3 Alkyl and -OC 1~3 represents a substituent selected from alkyl, R 5 -H, -OH, -R 8a , -C(=O)-R 8b , -SO2-R 9 , and -N(R 11a )R 11b represents one or more substituents selected from R 6 and R 7 are independently H and -C 1~3 alkyl, R 6a and R 6b are independently H, C 1~6 represents alkyl, or R 6a and R 6b are linked together to form a 3- to 6-membered ring, R 6c and R 6d are independently hydrogen or halo (e.g., F), —O—CH, phenyl, —N(R 6a )R 6b -C optionally substituted with one or more substituents selected from 1~4 represents alkyl, R 6e -C 1~3 is alkyl, R 8a -CN, -C 1~4alkyl (linear, branched, or cyclic, where the alkyl group is optionally substituted with one or more substituents selected from halo, forming, for example, -CF3, -CHF2, -CF2CH3), or -OC (optionally substituted with one or more substituents selected from halo and -O-CH3); 1~3 represents alkyl, R 8b is hydrogen or —C (optionally substituted with one or more fluoro atoms); 1~3 is alkyl, R 9 is optionally substituted by one or more substituents selected from halo (e.g., F) and —O—CH 1~4 represents alkyl, R 10a and R 10b are independently H, halo (per se, fluoro, -CN, -R 12a , -OR 12b , -N(R 12c )R 12d and / or -C(O)N(R 12e )R 12f C optionally substituted with one or more (e.g., one) substituent(s) selected from 1~4 Alkyl or (by itself, fluoro, -R 12g , -OR 12h and / or -N(R 12i )R 12j and optionally substituted by one or more (e.g., one) substituent(s) selected from: 1~4 represents alkyl, R 11a and R 11b are independently hydrogen, C (optionally substituted with one or more fluoro atoms), 1~3 Alkyl or -S(O)R 6c (where R 6c denotes (as defined above), R 12a , R 12b , R 12c , R 12d , R 12e , R 12f , R12g , R 12h , R 12i and R 12j are independently hydrogen or C (optionally substituted with one or more fluoro atoms). 1~3 represents alkyl] or a pharmaceutically acceptable salt thereof, The compounds may also be referred to herein as "compounds of the invention."

[0030] The pharmaceutically acceptable acid addition salts referred to above are intended to include the therapeutically active non-toxic acid addition salt forms that the compounds of formula I are able to form. These pharmaceutically acceptable acid addition salts can be conveniently obtained by treating the base form with such an appropriate acid.

[0031] For purposes of this invention, solvates, prodrugs, N-oxides and stereoisomers of the compounds of the invention are also included within the scope of the invention.

[0032] The term "prodrug" of related compounds of the present invention includes any compound that, following oral or parenteral administration, is metabolized in vivo to form that compound in experimentally detectable amounts and within a defined time period (e.g., within a 6-24 hour dosing interval (i.e., 1-4 times daily)). For the avoidance of doubt, the term "parenteral" administration includes all forms of administration other than oral administration.

[0033] Prodrugs of the compounds of the present invention may be prepared by modifying functional groups present on the compounds such that the modifications are cleaved in vivo when such prodrugs are administered to a mammalian subject. The modification is typically accomplished by synthesizing the parent compound with a prodrug substituent. Prodrugs include compounds of the present invention in which a hydroxyl, amino, sulfhydryl, carboxy, or carbonyl group in the compounds of the present invention is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, sulfhydryl, carboxy, or carbonyl group, respectively.

[0034] Examples of prodrugs include, but are not limited to, esters and carbamates of hydroxy 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" pl-92, Elesevier, New York-Oxford (1985).

[0035] The compounds of the present invention may contain double bonds and thus may exist as E (entgegen) and Z (zusammen) geometric isomers about each individual double bond. Positional isomers may also be encompassed by the compounds of the present invention. All such isomers (e.g., if a compound of the present invention incorporates a double bond or a fused ring, cis and trans forms are encompassed) and mixtures thereof are included within the scope of the present invention (e.g., single positional isomers and mixtures of positional isomers may be included within the scope of the present invention).

[0036] The compounds of the present invention may also exhibit tautomerism. All tautomeric forms (or tautomers) and mixtures thereof are included within the scope of the present invention. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as proton tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions via reconfiguration of some of the bonding electrons.

[0037] The compounds of the present invention may also contain one or more asymmetric carbon atoms and thus may exhibit optical isomerism and / or diastereoisomerism. Diastereoisomers may be separated using conventional techniques, such as chromatography or fractional crystallization. The various stereoisomers may be isolated by separating a racemic mixture or other mixture of compounds using conventional techniques, such as fractional crystallization or HPLC (High Performance Liquid Chromatography) techniques. Alternatively, the desired optical isomer may be prepared by reaction of appropriate optically active starting materials under conditions that do not cause racemization or epimerization (i.e., "chiral pool" methods), by reaction of appropriate starting materials with a "chiral auxiliary" that can be subsequently removed at a suitable stage, by derivatization with, for example, a homochiral acid (i.e., resolution, including dynamic resolution), followed by separation of the diastereomeric derivatives by conventional means such as chromatography, or by reaction with an appropriate chiral reagent or chiral catalyst, all under conditions well known to those skilled in the art.

[0038] All stereoisomers (including, but not limited to, diastereoisomers, enantiomers and atropisomers) and mixtures thereof (eg, racemic mixtures) are included within the scope of the present invention.

[0039] In the structures shown herein, where the stereochemistry of any particular chiral atom is not specified, all stereoisomers are contemplated and included as the compounds of the invention. Where stereochemistry is specified by a solid wedge or dashed line representing a particular configuration, that stereoisomer is so specified and defined.

[0040] The compounds of the present invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the present invention encompasses both the solvated and unsolvated forms.

[0041] The present invention also encompasses isotopically labeled compounds of the present invention that are identical to those listed herein, but due to the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature (or the most abundant atom found in nature). All isotopes of any particular atom or element 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: 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 Included are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as I. Certain isotopically labeled compounds of the invention (e.g., 3 H and 14 Tritiated (C) are useful in compound and substrate tissue distribution assays. 3 H) and carbon-l4( 14 C) isotopes are useful for their ease of preparation and detectability. Additionally, heavier isotopes, such as deuterium (i.e.,2 H), may result in greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements), which may confer certain therapeutic advantages and therefore may be preferred in some circumstances. 2 H is also used herein 2 D, and in any case, in the context of the scope of the present invention, both are encompassed by "hydrogen" or H. For example, 15 O. 13 N, 11 C, and 18 Positron-emitting isotopes such as F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of the present invention can generally be prepared following procedures similar to those disclosed in the following Description / Examples by substituting isotopically labeled reagents for non-isotopically labeled reagents.

[0042] Unless otherwise specified, C as defined herein 1~q The alkyl group (where q is the upper limit of the range) may be straight chain or, provided there is a sufficient number (i.e., a minimum of 2 or 3, as appropriate) of carbon atoms, may be branched and / or cyclic (hence, C 3~q -forming a cycloalkyl group). Such cycloalkyl groups may be monocyclic or bicyclic and may further be bridged. Furthermore, when there is a sufficient number (i.e., a minimum of four) of carbon atoms, such groups may also be part cyclic. Such alkyl groups may also be saturated, or when there is a sufficient number (i.e., a minimum of two) of carbon atoms, they may also be unsaturated (e.g., C 2~q Alkenyl or C 2~q (Forming an alkynyl group). Similarly, C 1~q Alkylene groups are divided into groups according to the number of carbon atoms, q, 1~q Represents an alkyl linker group, i.e., -CH-2- (C1 alkylene or methylene), -CH2CH2-, and the like.

[0043] Specific examples of C 3~q Cycloalkyl groups (where q is the upper limit of the range) can be monocyclic or bicyclic alkyl groups, and the cycloalkyl groups can be further bridged (thus forming fused ring systems, such as, for example, three fused cycloalkyl groups). Such cycloalkyl groups can be saturated or unsaturated and contain one or more double bonds (e.g., to form cycloalkenyl groups). Substituents can be attached at any point on the cycloalkyl group. Furthermore, when a sufficient number (i.e., a minimum of four) are present, such cycloalkyl groups can also be part cyclic.

[0044] The term "halo", as used herein, preferably includes fluoro, chloro, bromo and iodo.

[0045] Heterocyclic groups, as referred to herein, can include aromatic or non-aromatic heterocyclic groups, and thus encompass heterocycloalkyl and heteroaryl. Similarly, "aromatic or non-aromatic 5- or 6-membered rings" can refer to heterocyclic groups (as well as carbocyclic groups) having 5 or 6 members in the ring.

[0046] Heterocycloalkyl groups that may be mentioned include non-aromatic monocyclic and bicyclic heterocycloalkyl groups in which at least one (e.g., 1 to 4) of the atoms in the ring system is other than carbon (i.e., a heteroatom) and the total number of atoms in the ring system is 3 to 20 (e.g., 3 to 10, e.g., 3 to 8, e.g., 5 to 8). Such heterocycloalkyl groups may be bridged. Furthermore, such heterocycloalkyl groups may be saturated or unsaturated containing one or more double and / or triple bonds, e.g., C 2~q -heterocycloalkenyl group (q is the upper limit of the range). 2~qHeterocycloalkyl groups include 7-azabicyclo[2.2.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]octanyl, aziridinyl, azetidinyl, dihydropyranyl, dihydropyridyl, dihydropyrrolyl (including 2,5-dihydropyrrolyl), dioxolanyl (including 1,3-dioxolanyl), dioxanyl (including 1,3-dioxanyl and 1,4-dioxanyl), dithianyl (including 1,4-dithianyl), dithiolanyl (including 1,3-dithiolanyl), imidazolidinyl, imidazolinyl, mol Examples of heterocycloalkyl groups include 1,2,3,4-tetrahydropyridyl, 1,2,3,6 ... The point of attachment of the heterocycloalkyl group may be via any atom in the ring system, including (where appropriate) a heteroatom (such as a nitrogen atom), or an atom on any fused carbocyclic ring that may be present as part of the ring system. Heterocycloalkyl groups may also be in N- or S-oxide form. Heterocycloalkyls referred to herein may be specifically described as monocyclic or bicyclic.

[0047] The aromatic group 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 6 to 12 (e.g., 6 to 10) ring carbon atoms, with at least one ring being aromatic. 6~10 Aryl groups include phenyl, naphthyl, and the like, for example, 1,2,3,4-tetrahydro-naphthyl. The point of attachment of the aryl group may be through any atom of the ring system. For example, if the aryl group is polycyclic, the point of attachment may be through an atom including an atom of a non-aromatic ring. However, if the aryl group is polycyclic (e.g., bicyclic or tricyclic), they are preferably attached to the rest of the molecule through an aromatic ring. The most preferred aryl group that may be mentioned herein is "phenyl."

[0048] Unless otherwise specified, "heteroaryl," as used herein, refers to an aromatic group containing one or more heteroatoms (e.g., 1 to 4 heteroatoms) preferably selected from N, O, and S. Heteroaryl groups include those having 5- to 20-membered rings (e.g., 5- to 10-membered rings) and may be monocyclic, bicyclic, or tricyclic, provided that at least one of the rings is aromatic (thus forming, for example, a monocyclic, bicyclic, or tricyclic heteroaromatic group). When heteroaryl groups are polycyclic, the point of attachment may be through any atom, including atoms of a non-aromatic ring. However, when heteroaryl groups are polycyclic (e.g., bicyclic or tricyclic), they are preferably attached to the remainder of the molecule through 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, benzodioxepinyl, benzodioxolyl (including 1,3-benzodioxolyl), benzofuranyl, benzofurazanyl, benzothiadiazolyl (including 2,1,3-benzothiadiazolyl), benzothiazolyl, benzoxazolyl, azolyl (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]pyridyl, indazolyl, indolinyl, indolyl, isobenzofuranyl, isochromanyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isothiochromanyl, isoxazolyl, naphthyridinyl (1,6-naphthyridinyl or preferably 1,5-naphthyridinyl and 1,8-naphthyridinyl), oxadiazolyl (including 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl and 1,3,4-oxadiazolyl), oxazolyl, phenazinyl, phenothiazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinolizinyl, quinoxalinyl, tetrahydroisoquinolinyl (1,2,3,4-tetrahydroisoquinolinyl and 5,6,7 Examples of heteroaryl groups include 1,2,3-, 1,2,4-, 1,3,4-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, thiophenethyl, thienyl, triazolyl (including 1,2,3-triazolyl, 1,2,4-triazolyl and 1,3,4-triazolyl). Substituents on heteroaryl groups may, where appropriate, be located on any atom in the ring system, including a heteroatom (such as a nitrogen atom), or on any fused carbocyclic ring that may be present as part of the ring system. Heteroaryl groups may also be in N- or S-oxidized forms. The heteroaryl groups referred to herein may be specifically described as monocyclic or bicyclic. When the heteroaryl group is polycyclic, the non-aromatic ring may be substituted with one or more =O groups. The most preferred heteroaryl groups referred to herein are 5- or 6-membered aromatic groups containing 1, 2, or 3 heteroatoms (e.g., preferably selected from nitrogen, oxygen, and sulfur).

[0049] Heteroaryl groups may be specifically described as monocyclic or bicyclic. If a heteroaryl is specified as bicyclic, it may consist of a 5-, 6-, or 7-membered monocyclic ring (e.g., a monocyclic heteroaryl ring) fused to another 5-, 6-, or 7-membered ring (e.g., a monocyclic aryl or heteroaryl ring).

[0050] Heteroatoms that may be mentioned include phosphorus, silicon, boron, and preferably oxygen, nitrogen and sulfur.

[0051] When "aromatic" groups are referred to herein, they may be aryl or heteroaryl. When "aromatic linker groups" are referred to herein, they may be aryl or heteroaryl as defined herein, are preferably monocyclic (but may be polycyclic), and may be attached to the rest of the molecule via any available atom of the linker group. However, particularly when carbocyclic aromatic linker groups are referred to, such aromatic groups may not contain heteroatoms, i.e., they may be aryl (but not heteroaryl).

[0052] For the avoidance of doubt, it is understood that the group may be a group having one or more substituents (e.g., C 1~6 When a group is stated herein to be substituted by groups selected from alkyl, those substituents (e.g., alkyl groups) are independent of each other; that is, such groups may be substituted with the same substituent (e.g., the same alkyl substituent) or with different (e.g., alkyl) substituents.

[0053] Every individual feature (e.g., a preferred feature) mentioned herein may be employed alone or in combination with any other feature (including a preferred feature) mentioned herein (and thus a preferred feature may be employed in conjunction with or independently of other preferred features).

[0054] Those skilled in the art will appreciate that the compounds of the present invention that are the subject of the present invention include stable compounds, i.e., compounds of the present invention include those that are sufficiently robust to survive isolation to a useful degree of purity from, for example, a reaction mixture.

[0055] In one embodiment, ring A is aromatic; X 1 represents =N- or =CH-; R 1 and R 2 each independently represents a substituent selected from hydrogen, —CH 3 , —F, —Cl, —OCH 3 , —NH 2 , and —CH 2 NH 2 .

[0056] Preferably, ring A is aromatic, X 1 represents =N-, and / or R 1 and R 2 each independently represents a substituent selected from hydrogen, —CH 3 , —F, —Cl, —OCH 3 , —NH 2 , and —CH 2 NH 2 .

[0057] In another preferred configuration, ring A is aromatic, X 1 represents =CH-, and / or R 1 and R 2 each independently represents a substituent selected from hydrogen, —CH 3 , —F, —Cl, —OCH 3 , —NH 2 , and —CH 2 NH 2 .

[0058] Alternatively, ring A is non-aromatic; X 1 represents -CH2-, and / or R 1 and R 2 each independently represents a substituent selected from hydrogen, —CH 3 , —Cl, —OCH 3 , —NH 2 , and —CH 2 NH 2 .

[0059] The compounds of the present invention are It is preferred to include R3 which represents a substituent selected from H, -CF3, -CHF2, -CH3, -CH2CH3, and cyclopropyl.

[0060] More precisely, compounds in which ring A is non-aromatic, X 1 represents -CH2-, R 1 and R 2 each independently represent a substituent selected from hydrogen, —CH3, —Cl, —OCH3, —NH2, —CH2NH2, and / or R3 is a compound that represents a substituent selected from H, -CF3, -CHF2, -CH3, -CH2CH3, and cyclopropyl.

[0061] Alternatively, in another embodiment of the present invention, a compound: Ring A is aromatic; X 1 represents =N-, R 1 and R 2 each independently represent a substituent selected from hydrogen, —CH3, —Cl, —OCH3, —NH2, —CH2NH2, and / or Compounds are provided in which R3 represents a substituent selected from H, -CF3, -CHF2, -CH3, -CH2CH3, and cyclopropyl.

[0062] Alternatively, compounds are provided in which ring A is aromatic. X 1 represents =CH-, and / or R 1 and R 2 each independently represent a substituent selected from hydrogen, —CH, —Cl, —OCH, —NH, —CHNH. In one embodiment, —CH may also specifically represent its deuterated isotope, e.g., —CD.

[0063] In a further aspect of the invention, Ring C is

[0064] [ka] is selected from R 4 is H, F, -C as disclosed above 1~3 Alkyl and -OC 1~3 Compounds are provided that exhibit a substituent selected from alkyl.

[0065] In this aspect, R in one embodiment 4 represents a substituent selected from H, F and -CH3.

[0066] In one embodiment, ring C also contains

[0067] [ka] may be selected from among:

[0068] Within this aspect, in one embodiment, R 4 -F, -C 1~3 Alkyl and -OC 1~3 represents a substituent selected from alkyl.

[0069] Within this aspect, in another embodiment, R 4 represents a substituent selected from F and —CH 3 .

[0070] In one embodiment, the present invention provides a compound wherein ring D is

[0071] [ka] is selected from According to claim 1, R 5 -H, -OH, -R 8a , -C(=O)-R 8b , -SO2-R 9 , or -N(R 11a )R 11b and / or R 10bis H, halo, (per se, fluoro, -CN, -R 12a , -OR 12b , -N(R 12c )R 12d and / or -C(O)N(R 12e )R 12f C optionally substituted with one or more (e.g., one) substituent(s) selected from 1~4 Alkyl or (by itself, fluoro, -R 12g , -OR 12h and / or -N(R 12i )R 12j and optionally substituted by one or more (e.g., one) substituent(s) selected from: 1~4 This includes compounds that represent alkyl.

[0072] In one embodiment, R 10b represents a substituent selected from H and -CH3.

[0073] In yet another embodiment, ring D is

[0074] [ka] is selected from among:

[0075] Preferably, ring D is

[0076] [ka] is selected from among:

[0077] In another embodiment, ring D is

[0078] [ka] is selected from R 5 The carbon atom to which is attached has the R configuration.

[0079] In a second alternative embodiment, ring D is

[0080] [ka] is selected from R 5 The carbon atom to which is attached has the S configuration.

[0081] In one embodiment, R 5 represents H, -CH3, -CH2CH3, -CH2CH2CH3, cyclopropyl, -OH, -OCH3, -OCF3, -OCH2CH2OCH3, -CF3, -CHF2, -CF2CH3, -NH2, -NH(SO2)CF3, -N(CH3)(SO2)CF3, and -SO2CF3.

[0082] In another embodiment, the present invention provides a compound wherein ring D is

[0083] [ka] is selected from where R 5 represents H, -CH3, -CH2CH3, -CH2CH2CH3, cyclopropyl, -OH, -OCH3, -OCF3, -OCH2CH2OCH3, -CF3, -CHF2, -CF2CH3, -NH2, -NH(SO2)CF3, -N(CH3)(SO2)CF3, and -SO2CF3.

[0084] Preferably, the present invention provides a compound of formula (IX)

[0085] [ka] [In the formula, X 1 is =N- or =C(R 10a )-, X 2 , X 5 , and X 6 are each independently =N- or =C(R 10b )-, R1 and R 2 are each independently hydrogen, halo (e.g., Cl, F), -R 6c , -OR 6d , -C(=O)-R 6e and, -C(=O)-N(R 6 )(R 7 ), -CN, and -N(R 6a )R 6b and a substituent selected from R 3 is H, halo (e.g., Cl, F), -CF3, -CHF2, and halo (e.g., F) and -OC 1~3 -C (linear, branched, or cyclic) optionally substituted with one or more substituents selected from alkyl 1~3 represents a substituent selected from alkyl, R 4 are H, F, and -C 1~3 Alkyl and -OC 1~3 represents a substituent selected from alkyl, R 5 -H, -OH, -R 8a , -C(=O)-R 8b , -SO2-R 9 , or -N(R 11a )R 11b represents R 6 and R 7 are independently H and -C 1~3 alkyl, R 6a and R 6b are independently H, C 1~6 represents alkyl, or R 6a and R 6b are linked together to form a 3- to 6-membered ring, R 6c and R 6d are independently hydrogen or halo (e.g., F), —O—CH, phenyl, —N(R 6a )R 6b -C optionally substituted by one or more substituents selected from 1~4 represents alkyl, R6e -C 1~3 is alkyl, R 8a is —C optionally substituted by one or more substituents selected from —CN, halo 1~4 -OC optionally substituted with one or more substituents selected from alkyl (e.g., -CF3, -CHF2), halo, and -O-CH3 1~3 represents alkyl, R 8b is hydrogen or —C (optionally substituted with one or more fluoro atoms); 1~3 is alkyl, R 9 is optionally substituted by one or more substituents selected from halo (e.g., F) and —O—CH 1~4 represents alkyl, R 10a and R 10b are independently H, halo (per se, fluoro, -CN, -R 12a , -OR 12b , -N(R 12c )R 12d and / or -C(O)N(R 12e )R 12f C optionally substituted with one or more (e.g., one) substituent(s) selected from 1~4 alkyl, or (by itself, fluoro, -R 12g , -OR 12h and / or -N(R 12i )R 12j and optionally substituted by one or more (e.g., one) substituent(s) selected from: 1~4 represents alkyl, R 11a and R 11b are independently hydrogen, C (optionally substituted) by one or more fluoro atoms 1~3 Alkyl, -SO2R 6c represents R 12a , R 12b , R 12c , R 12d , R 12e , R 12f, R 12g , R 12h , R 12i and R 12j are independently hydrogen or C (optionally substituted with one or more fluoro atoms). 1~3 represents alkyl] or a pharmaceutically acceptable salt thereof.

[0086] In an even more preferred embodiment, the present invention provides a compound of formula (IX) or formula (IXA)

[0087] [ka] [In the formula, X 1 represents =N- or =CH-; X 2 , X 5 , and X 6 each independently represents =N-, =CH, or =C(CH3)-; R 1 and R 2 each independently represents a substituent selected from hydrogen, —CH, —F, —Cl, —OCH, —NH, and —CHNH; R 3 represents a substituent selected from H, —CF3, —CHF2, —CH3, —CH2CH3, and cyclopropyl; R 4 represents a substituent selected from H, F, and —CH3; R 5 is attached (in compounds of formula (IXA)) either meta or para to the N atom in the ring system, R 5 represents H, -CH3, -CH2CH3, -CH2CH2CH3, cyclopropyl, -OH, -OCH3, -OCF3, -OCH2CH2OCH3, -CF3, -CHF2, -CF2CH3, -NH2, -NH(SO2)CF3, -N(CH3)(SO2)CF3, or -SO2CF3; or a pharmaceutically acceptable salt thereof.

[0088] In one embodiment of the present invention, R 5 or (in a further embodiment) C (optionally substituted with one or more substituents selected from fluoro) 1~4 Alkyl, C 3~4 Cycloalkyl (e.g., cyclopropyl), -OH, and (where the alkyl moiety itself is fluoro and -OC 1~2 optionally substituted by one or more substituents selected from alkyl 1~4 represents a substituent selected from alkyl.

[0089] In one embodiment of the present invention (including in the context of compounds of formula (I), (IX), and (IXA)): -R 1 and R 2 independently represent H, CH3, F, Cl, or —OCH3; -X 1 represents =N- or =CH-; -R 3 is C (optionally substituted with one or more fluoro atoms) 1~3 Alkyl or C 3~4 represents cycloalkyl (e.g., cyclopropyl); -X 3 and X 4 each independently represents =CH-; -X 5 represents ═CH— or ═N— (and in one embodiment represents ═CH—), -R 4 represents hydrogen, F, or CH3, -X 5 and X 6 independently represent =N-, =CH=, or =C(CH3)- (and in further embodiments, X 5 and X 6 one of which represents =N-, and the other represents =N-, =CH-, or C(CH3)-), -R 5 represents a substituent, it may be meta or para to the required N atom in the bicyclic ring, and / or -R 5represents (in one embodiment a substituent) H, —CF, —CH, —CHF, —OCH, cyclopropyl, propyl, —OH, —O—CHCHOCH, or OCF; That is, any of the above embodiments may be employed alone or in combination with other embodiments disclosed herein.

[0090] In another embodiment, the compound of formula (IA) may be represented as a compound of formula (I) or a compound of formula (IB).

[0091] [ka] where all variables are as defined herein.

[0092] In certain embodiments, the bicycle comprising ring A and ring B may be represented by any one of the following formulas:

[0093] [ka]

[0094] In one embodiment, R 1 and R 2 each represent hydrogen (thus the 6-membered rings of the rings represented by (XX), (XXI), (XXII), (XXIII), and (XXIV) are unsubstituted). 3 is C 1~3 It represents alkyl (eg ethyl).

[0095] In one embodiment, ring C may represent unsubstituted phenyl, ie, formula (XXX).

[0096] [ka]

[0097] In one embodiment, ring D (or a bicycle containing ring D) represents, in another embodiment, formula (XXXI) or formula (XXXII).

[0098] [ka]

[0099] In another embodiment, R 5 is —C optionally substituted with one or more fluoro atoms 1~3 In a further embodiment, R 5 represents -CF3.

[0100] As mentioned herein, and for the avoidance of doubt, any of the foregoing embodiments may be combined with other embodiments, such as any of the embodiments depicting ring A and ring B, any of the embodiments depicting ring C, any of the embodiments depicting ring D, and any of the other embodiments depicted herein (e.g., R 5 Substituents, etc.) may be used in combination.

[0101] The compounds according to the invention have surprisingly been shown to be suitable for the treatment of bacterial infections, including mycobacterial infections, in particular diseases caused by pathogenic mycobacteria, such as Mycobacterium tuberculosis (including its latent and drug-resistant forms). The present invention therefore also relates to the compounds of the invention as defined herein above for use as a medicament, in particular for use as a medicament for the treatment of bacterial infections, including mycobacterial infections.

[0102] Such compounds of the invention may act by interfering with ATP synthase in M. tuberculosis, with inhibition of cytochrome bc1 activity being the primary mode of action. Cytochrome bc1 is an essential component of the electron transport chain required for ATP synthesis.

[0103] Additionally, the present invention also relates to the use of the compounds of the present invention, as well as any of the pharmaceutical compositions thereof described below, for the manufacture of a medicament for the treatment of bacterial infections, including mycobacterial infections.

[0104] Thus, in another aspect, the present invention provides a method of treating a patient suffering from or at risk of a bacterial infection, including a mycobacterial infection, comprising administering to the patient a therapeutically effective amount of a compound or pharmaceutical composition according to the present invention.

[0105] The compounds of the present invention also exhibit activity against resistant bacterial strains.

[0106] Whenever used above or below, a compound may treat a bacterial infection means that the compound may treat an infection by one or more strains of bacteria.

[0107] The present invention also relates to compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to the present invention as an active ingredient. The compound according to the present invention can be formulated into various pharmaceutical forms for administration. Suitable compositions may include any composition commonly used for systemic drug administration. To prepare the pharmaceutical compositions of the present invention, an effective amount of the compound, optionally in the form of an addition salt, as the active ingredient is mixed and thoroughly mixed with a pharmaceutically acceptable carrier, which may take various forms depending on the form of preparation desired for administration. These pharmaceutical compositions are preferably in a unit dosage form suitable for oral administration or parenteral injection. For example, when preparing compositions in oral dosage form, any of the usual pharmaceutical media may be used, such as water, glycols, oils, alcohols, etc. for oral liquid preparations such as suspensions, syrups, elixirs, emulsions, and solutions, or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, and disintegrants for powders, pills, capsules, and tablets. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, although other ingredients (e.g., to aid solubility) may be included. For example, injectable solutions may be prepared in which the carrier comprises saline, glucose solution, or a mixture of saline and glucose solution. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents, and the like may be used. Also included are solid form preparations which are intended to be converted to liquid form preparations shortly before use.

[0108] Depending on the mode of administration, the pharmaceutical composition preferably comprises 0.05 to 99% by weight, more preferably 0.1 to 70% by weight, even more preferably 0.1 to 50% by weight of the active ingredient and 1 to 99.95% by weight, more preferably 30 to 99.9% by weight, even more preferably 50 to 99.9% by weight of a pharmaceutically acceptable carrier, all percentages being based on the total weight of the composition.

[0109] The pharmaceutical compositions may further contain various other ingredients well known in the art, such as lubricants, stabilizers, buffers, emulsifiers, viscosity adjusting agents, surfactants, preservatives, flavoring agents, or coloring agents.

[0110] It is particularly advantageous to formulate the above-mentioned pharmaceutical composition into unit dosage form in order to facilitate administration and ensure uniformity of dosage.As used herein, unit dosage refers to a physically separate unit suitable for single administration, and each unit contains a predetermined amount of active ingredient calculated to produce desired therapeutic effect together with necessary pharmacological carrier.The example of such unit dosage form is tablet (including scored tablet or coated tablet), capsule, pill, powder packet, wafer, suppository, injection solution or suspension etc., and their multiple portions.

[0111] The daily dosage of the compounds according to the invention will, of course, vary depending on the compound used, the mode of administration, the treatment desired and the mycobacterial disease being treated, but in general satisfactory results are obtained when the compounds according to the invention are administered in a daily dose not exceeding 1 gram, for example in the range of 10-50 mg / kg body weight.

[0112] In view of the fact that the compounds of formula (I) are active against bacterial infections, the compounds may be combined with other antibacterial agents to effectively combat bacterial infections.

[0113] Thus, the present invention also relates to the combination of (a) a compound according to the present invention and (b) one or more other antibacterial agents.

[0114] The present invention also relates to the combination of (a) a compound according to the invention and (b) one or more other antibacterial agents for use as a medicine.

[0115] The present invention also relates to the use of a combination or a pharmaceutical composition as defined immediately above for the treatment of a bacterial infection.

[0116] Also included in the present invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingredients, a therapeutically effective amount of (a) a compound according to the present invention, and (b) one or more other antibacterial agents.

[0117] The weight ratio of (a) a compound of the present invention to (b) another antibacterial agent, when given as a combination, may be determined by one of ordinary skill in the art. Such ratios, as well as the exact dosages and frequency of administration, will depend, as will be well known to those skilled in the art, on the particular compound of the present invention and the other antibacterial agent used, the particular condition being treated, the severity of the condition being treated, the age, weight, sex, diet, time of administration and general health of the particular patient, the mode of administration, and other medications the individual may be taking. Furthermore, it will be apparent that the effective daily amount may be increased or decreased depending on the response of the treated subject and / or depending on the evaluation of the physician prescribing the compound of the present invention. Particular weight ratios of a compound of the present invention to another antibacterial agent may range from 1 / 10 to 10 / 1, more particularly from 1 / 5 to 5 / 1, and even more particularly from 1 / 3 to 3 / 1.

[0118] The compounds according to the invention and one or more other antibacterial agents may be combined in a single preparation, or they may be formulated in separate preparations so that they can be administered simultaneously, separately, or sequentially. Thus, the invention also relates to products containing (a) a compound according to the invention and (b) one or more other antibacterial agents as a combined preparation for simultaneous, separate, or sequential use in the treatment of bacterial infections.

[0119] Other antibacterial agents that can be combined with the compounds of the present invention are, for example, antibacterial agents well known in the art. For example, the compounds of the present invention may be combined with antibacterial agents known to interfere with the respiratory chain of Mycobacterium tuberculosis, including, for example, direct inhibitors of ATP synthase (e.g., bedaquiline, bedaquiline fumarate, or any other compound that may be disclosed in the prior art, such as the compounds disclosed in WO 2004 / 011436), inhibitors of ndh2 (e.g., clofazimine), and inhibitors of cytochrome bd. Additional mycobacterial agents that may be combined with the compounds of the invention are, for example, rifampicin (=rifampin), isoniazid, pyrazinamide, amikacin, ethionamide, ethambutol, streptomycin, para-aminosalicylic acid, cycloserine, capreomycin, kanamycin, thioacetazone, PA-824, delamanid, quinolones / fluoroquinolones such as moxifloxacin, gatifloxacin, ofloxacin, ciprofloxacin, sparfloxacin, macrolides such as clarithromycin, amoxicillin and clavulanic acid, rifamycin, rifabutin, rifapentine, and others currently in development (but which may not yet be commercially available, see, for example, http: / / www.newtbdrugs.org / pipeline.php).

[0120] The compounds of the present invention (including forms and compositions / combinations comprising the compounds of the present invention), whether for use in the above indications or not, may have the advantage that they may be more effective, less toxic, longer acting, more potent, have fewer side effects, be more easily absorbed, and / or have a better pharmacokinetic profile (e.g., higher oral bioavailability and / or lower clearance) than compounds known in the prior art, and / or have other useful pharmacological, physical, or chemical properties. For example, the compounds of the present invention may have advantages related to lower cardiotoxicity, no formation of reactive metabolites (e.g., those that may cause toxicity problems, e.g., genotoxicity), no formation of degradants (e.g., those that may induce undesirable or unwanted side effects), and / or faster oral absorption and improved bioavailability. Certain compounds of the present invention may also have advantages over certain other compounds of the present invention, for example, the relative potency of certain compounds (e.g., R 1 and R 2 represents hydrogen (thus the six-membered rings of the rings represented by (XX), (XXI), (XXII), (XXIII), and (XXIV) are unsubstituted)) produces no or very few undesirable metabolic products (e.g., oxidative metabolic products) (this is because R 1 and / or R 2 represents a substituent such as alkyl, e.g., methyl).

[0121] General Preparation Compounds according to the invention may generally be prepared by a series of steps, each of which is well known to those skilled in the art or may be described herein.

[0122] Experimental Department Compounds of formula I may be prepared by the techniques used in the examples below (and methods well known to those skilled in the art), for example by using the following techniques: Analogous reactions may be carried out to prepare compounds of formula (IA), for example the reaction of a compound (XL) as defined herein with a compound of formula (XI) and / or the reaction of a compound of formula (XLI) as defined herein with a compound of formula (XIII).

[0123] The compound of formula (I) (i) Formula (X)

[0124] [ka] wherein the variables are as defined above. with a compound of formula (XI)

[0125] [ka] wherein the variables are as defined above. with a compound of formula (I), wherein the reaction is carried out in the presence of a suitable coupling agent 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, using a suitable coupling reagent (e.g., 1,1'-carbonyldiimidazole, N This reaction may be carried out in the presence of N,N'-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (or its hydrochloride salt) or N,N'-disuccinimidyl carbonate), optionally in the presence of a suitable base (e.g., sodium hydride, sodium bicarbonate, potassium carbonate, pyridine, triethylamine, dimethylaminopyridine, diisopropylamine, sodium hydroxide, potassium tert-butoxide and / or lithium diisopropylamide (or variations thereof), and a suitable solvent (e.g., tetrahydrofuran, pyridine, toluene, dichloromethane, chloroform, acetonitrile, dimethylformamide, trifluoromethylbenzene, dioxane, or triethylamine). Alternatively, the carboxylic acid group of the compound of formula (X) may first be converted under standard conditions (e.g., POCl, PCl 5、 or oxalyl chloride) which is then reacted with a compound of formula (XI) under conditions similar to those described above, or (ii) a compound of formula (XII),

[0126] [ka] wherein the variables are as defined herein above and R 13 represents a suitable leaving group (e.g., the type of group that can be placed for coupling), such as a suitable group, for example, a chloro, bromo, iodo, or sulfonic acid group, with a compound of formula (XIII)

[0127] [ka] [In the formula, R 4 is as defined above, and R 14 represents a suitable group, for example a suitable leaving group] under standard conditions, for example, optionally in the presence of a suitable metal catalyst (or a salt or complex thereof) such as Pd(dba)2, Pd(OAc)2, Cu, Cu(OAc)2, CuI, NiCl2, etc., with a desired additive such as Ph3P, X-phos, in the presence of a suitable base (such as t-BuONa), in a suitable solvent (such as dioxane), under reaction conditions well known to those skilled in the art.

[0128] It will be appreciated by those skilled in the art that some compounds of formula (I) may be converted to other compounds of formula (I).

[0129] Other compounds that may be used for the preparation of compounds of formula (IA) are:

[0130] [ka] is.

[0131] It is clear that in the reactions described above and below, the reaction products may be isolated from the reaction medium and, if necessary, further purified according to methods generally known in the art, such as extraction, crystallization, and chromatography. It is further clear that reaction products present in one or more enantiomeric forms may be isolated from their mixtures by well-known techniques, in particular preparative chromatography, such as preparative HPLC, chiral chromatography, etc. Individual diastereoisomers or individual enantiomers may also be obtained by supercritical fluid chromatography (SCF).

[0132] The starting materials and intermediates are compounds that are either commercially available or can be prepared according to conventional reaction procedures generally known in the art. [Example]

[0133] 1- General Information Abbreviation ACN: acetonitrile Cs2CO3: Cesium carbonate DCM: dichloromethane DIPE: Diisopropyl ether DIPEA: N,N-diisopropylethylamine DMF: dimethylformamide DMSO: dimethyl sulfoxide Et2O: Diethyl ether EtOAc: ethyl acetate Et3N or TEA: Triethylamine h: time H2: Dihydrogen gas HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HCl: Hydrochloric acid i-PrOH: Isopropyl alcohol K2CO3: Potassium carbonate LiOH: Lithium hydroxide MeOH: Methanol MgSO4: Magnesium sulfate min:minutes N2: Nitrogen gas NaHCO3: Sodium bicarbonate NaOH: Sodium hydroxide NH4Cl: Ammonium chloride NH4HCO3: Ammonium bicarbonate NMR: nuclear magnetic resonance PdCl2(PPh3)2: Dichlorobis(triphenylphosphine)palladium(II) Pd2(OAc)2 = Palladium(II) acetate rt: room temperature THF: tetrahydrofuran TFA: Trifluoroacetic acid THF: tetrahydrofuran PdCl2(dppf)2:[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) KOtBu: potassium tert-butoxide

[0134] Melting point Melting points were recorded using a differential scanning calorimeter DSC1 Mettler Toledo. Melting points were measured from 25°C to 350°C with a temperature ramp of 10°C per minute. Values ​​are peak values. This method is used unless otherwise indicated.

[0135] Another method uses open capillary tubes on a Mettler Toledo MP50 (sometimes designated "MT"). In this method, melting points are measured at a temperature ramp rate of 10°C / min. The maximum temperature is 300°C. Melting point data are read from a digital display and checked against a video recording system.

[0136] 1 H NMR An internal deuterium lock was used, and inverse double resonance ( 1a Bruker Avance DRX400 spectrometer or a Bruker Advance III400 spectrometer equipped with a Bruker Avance DRX400 spectrometer (H, 13C, SEI) probehead operating at 400 MHz for protons and 100 MHz for carbon, and a Bruker Avance 500 MHz spectrometer equipped with a Bruker 5 mm BBFO probehead with z-gradients operating at 500 MHz for protons and 125 MHz for carbon; 1 1 H NMR spectra were recorded.

[0137] NMR spectra were recorded at ambient temperature unless otherwise stated.

[0138] Data are reported as follows: chemical shift in parts per million (ppm) relative to TMS (δ=0 ppm) on the scale, integral, multiplicity (s=singlet, d=doublet, t=triplet, q=quartet, quin=quintet, sex=sextet, m=multiplet, b=broad, or a combination thereof), coupling constant J in Hertz (Hz).

[0139] Absolute positioning The absolute configuration was determined using Virtual Circular Dichroism (VCD) and infrared spectroscopy.

[0140] experiment IR and VCD spectra were recorded on a dual PEM ChiralIR-2X spectrometer (Biotools Inc, Jupiter, FL). Measurements were performed in DMSO-d6 at concentrations of 3.8 mg / 125 μL for A / B and E / F, and 1.1 mg / 175 μL for C / D. Cells with a 100 μm path length and BaF2 windows were used. Both the sample and hypothetical racemate spectra were recorded using a 4 cm -1 Both PEMs were recorded at a resolution of 1400 cm -1A total of 60,000 scans or 20 hours of measurement time were recorded, optimized with . Baseline-corrected VCD spectra were obtained by combining the raw data for the enantiomers with the spectra of the corresponding hypothetical racemates.

[0141] calculation An exhaustive conformational search is performed at the molecular mechanics level using Macromodel (version 13.3) with mixed torsion / lower mode sampling and the OPLS4 force field. The identified minima are analyzed using B3LYP-D3 / 6-31G with a Poisson-Boltzmann continuum solvation model mimicking DMSO solvent. ** The optimization was performed using Jaguar (version 11.2) at the 4 cm level using all conformations within a 10 kJ / mol interval. -1 VCD and IR spectra were simulated from the calculated optical rotation strengths and wavenumbers (scaled by a factor of 0.975) using Lorentzian curves using half-width half-height values ​​of

[0142] The assignments were made after visual comparison of the experimental and measured IR and VCD spectra.

[0143] 2-Synthesis Synthesis of intermediate I Synthesis of intermediate I-1

[0144] [ka]

[0145] To a suspension of ethyl O-(2-mesitylenesulfonyl)acetyloxamate [38202-27-6] (13 g, 45.56 mmol) in 1,4-dioxane (45 mL) was added perchloric acid [7601-90-3] dropwise over 15 minutes at 0° C. (internal temperature maintained below 15° C.). The mixture was stirred at 0° C. for 1 hour. Ice water (45 mL) and DCM (45 mL) were then added, and the organic layer was separated to give intermediate I-1 as a 1 M solution in DCM, which was used in the next step without further treatment (Caution: Do not remove solvent, it explodes when dried).

[0146] Synthesis of intermediate I-2

[0147] [ka]

[0148] 2-Amino-4-(trifluoromethyl)pyridine [106447-97-6] (2.28 g, 32.54 mmol) was added portionwise to a 1 M DCM solution of intermediate I-1 (45.56 mL, 45.56 mmol) in a round-bottom flask at 0 °C under nitrogen. The mixture was stirred at room temperature for 16 hours. The suspension was diluted with diethyl ether (10 mL), and the solid formed was filtered off and washed with additional diethyl ether to give intermediate I-2 as a white solid (11.51 g, 86%).

[0149] Synthesis of intermediate I-3

[0150] [ka]

[0151] 4-Cyanobenzoyl chloride [6068-72-0] (8.30 g, 21.79 mmol) was added to a solution of intermediate I-2 (8.25 g, 21.79 mmol) in pyridine (88 mL) at 0° C. The mixture was stirred at 90° C. for 16 hours, and then water was added. The formed solid was filtered off and washed with water (×3) and diethyl ether to give intermediate I-3 as a beige solid (5.03 g, 79%).

[0152] Synthesis of intermediate I-4

[0153] [ka]

[0154] Sodium borohydride [16940-66-2] (1.99 g, 52.59 mmol) was added portionwise to a suspension of intermediate I-3 (5.05 g, 17.53 mmol), nickel(II) chloride hexahydrate [7791-20-0] (4.17 g, 17.53 mmol), and di-tert-butyl dicarbonate [24424-99-5] (12.08 mL, 52.59 mmol) in dry methanol (60 mL) at −5° C. under N2. The reaction mixture was stirred at room temperature for 16 h. Water and 1 mL of aqueous NH3 were added, and the mixture was extracted with DCM. The combined organic layers were washed with water, separated, dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (silica, 0 / 100 to 15 / 85 EtOAc in DCM). The desired fractions were collected and concentrated in vacuo to give intermediate I-4 (7.50 g, 97%) as a yellowish solid.

[0155] Synthesis of intermediate I-5

[0156] [ka]

[0157] To a solution of intermediate I-4 (7.50 g, 17.01 mmol) in a mixture of methanol (120 mL) and EtOAc (20 mL), palladium(II) hydroxide on carbon [12135-22-7] (2.17 g, 18.71 mmol) was added portionwise at 0 °C under N 2 . H 2 was then added, and the mixture was stirred at room temperature for 18 h. Additional palladium(II) hydroxide [12135-22-7] (0.95 g, 6.81 mmol) was then added at 0 °C under N 2 . H 2 was added, and the mixture was stirred at room temperature for an additional 4 h. The mixture was filtered through a pad of Celite®, and the solvent was concentrated in vacuo. The crude product was purified by flash column chromatography (silica, 0 / 100 to 40 / 60 EtOAc in heptane). The desired fractions were collected and concentrated in vacuo to give intermediate I-5 (1.78 g, 40%) as a white solid.

[0158] Synthesis of intermediate I-6

[0159] [ka]

[0160] A 4 M solution of HCl in dioxane [7647-01-0] (10.52 mL, 42.08 mmol) was added to a stirred solution of intermediate I-5 (2.78 g, 7.01 mmol) in DCM (35 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated in vacuo to give intermediate I-6 as a white solid, which was used in the next step without further purification (2.73 g, quantitative).

[0161] Synthesis of intermediate I-7

[0162] [ka]

[0163] NaHCO (0.57 g, 6.79 mmol) was added to a stirred solution of 2-amino-4-(trifluoromethyl)pyridine [106447-97-6] (1.0 g, 6.17 mmol) and 4-(bromoacetyl)benzonitrile [20099-89-2] (1.80 g, 8.02 mmol) in ethanol (12 mL) at room temperature. The mixture was stirred at reflux for 18 hours, and then water was added. The formed solid was filtered off and washed with water and diethyl ether to give intermediate I-7 as a beige solid (1.48 g, 82%).

[0164] Synthesis of intermediate I-8

[0165] [ka]

[0166] Sodium borohydride [16940-66-2] (0.58 g, 15.41 mmol) was added portionwise to a suspension of intermediate I-7 (1.48 g, 5.14 mmol), nickel(II) chloride hexahydrate [7791-20-0] (1.22 g, 15.41 mmol), and di-tert-butyl dicarbonate [24424-99-5] (3.54 mL, 15.41 mmol) in dry methanol (15.4 mL) at −5° C. under N. The reaction mixture was stirred at room temperature for 16 h. Water and 1 mL of aqueous NH were added, and the mixture was extracted with DCM. The combined organic layers were washed with water, separated, dried (MgSO), filtered, and concentrated in vacuo to give intermediate I-8 as a brown, viscous oil (2.05 g, quantitative).

[0167] Synthesis of intermediate I-9

[0168] [ka]

[0169] Platinum(IV) oxide [1314-15-4] (1.22 g, 5.37 mmol) was added to a solution of intermediate I-8 (2.1 g, 5.37 mmol) in a mixture of ethanol (70 mL) and dry THF (70 mL) at 0 °C under N. Then, H was added, and the mixture was stirred at room temperature for 16 h. The mixture was filtered through a pad of Celite®, and the solvent was concentrated in vacuo. The crude product was purified by flash column chromatography (silica, 0 / 100 to 20 / 80 EtOAc in DCM). The desired fractions were collected and concentrated in vacuo to give intermediate I-9 (0.45 g, 19%) as a white solid.

[0170] Synthesis of intermediate I-10

[0171] [ka]

[0172] A 4 M solution of HCl in dioxane [7647-01-0] (1.33 mL, 5.31 mmol) was added to a stirred solution of intermediate I-9 (175 mg, 0.44 mmol) in DCM (2 mL) at room temperature. The reaction mixture was stirred at room temperature for 18 hours. The solvent was evaporated in vacuo to give intermediate I-10 as a yellowish solid, which was used in the next step without further purification (146 mg, quantitative).

[0173] Synthesis of intermediate I-11

[0174] [ka]

[0175] 2-Amino-4-bromopyridine [84249-14-9] (5 g, 28.90 mmol) was added portionwise to a 1 M solution of intermediate I-1 in DCM (57.80 mL, 57.80 mmol) in a round-bottom flask at 0 °C under nitrogen. The mixture was stirred at room temperature for 16 hours. The suspension was diluted with diethyl ether (30 ml), and the solid formed was filtered off and washed with additional diethyl ether to give intermediate I-11 as a white solid (6.28 g, 87%).

[0176] Synthesis of intermediate I-12

[0177] [ka]

[0178] 4-Cyanobenzoyl chloride [6068-72-0] (6.62 g, 40 mmol) was added to a solution of intermediate I-11 (7.77 g, 20 mmol) in pyridine (24 mL) at 0° C. The mixture was stirred at 90° C. for 8 hours, and then water was added. The formed solid was filtered off and washed with water (×3) and diethyl ether to give intermediate I-12 as a white solid (3.02 g, 46%).

[0179] Synthesis of intermediate I-13

[0180] [ka]

[0181] Pd(dppf)Cl [65464-05-4] (136 mg, 0.17 mmol) was added to intermediate I-12 (0.5 g, 1.67 mmol) in a mixture of dry 1,4-dioxane (4 mL) and heptane (4 mL) in a sealed tube under N. Next, a 2 M solution of dimethylzinc in toluene [544-97-8] (2.51 mL, 5.01 mmol) was added at room temperature under N, and the mixture was stirred at 55 °C for 16 h. The solvent was evaporated in vacuo, and the crude product was purified by flash column chromatography (silica, 0 / 100 to 100 / 0 EtOAc in heptane). The desired fractions were collected and concentrated in vacuo to give intermediate I-13 (391 mg, 99%) as an orange-yellow solid.

[0182] Synthesis of intermediate I-14

[0183] [ka]

[0184] Sodium borohydride [16940-66-2] (189 mg, 5 mmol) was added portionwise to a suspension of intermediate I-13 (391 mg, 1.67 mmol), nickel(II) chloride hexahydrate [7791-20-0] (198 mg, 0.83 mmol), and di-tert-butyl dicarbonate [24424-99-5] (0.77 mL, 3.34 mmol) in a mixture of dry methanol (22 mL) and 1,4-dioxane (10 mL) at 0 °C under N. The reaction mixture was stirred at room temperature for 16 h. Saturated aqueous NH.sub.4Cl and 1 mL of aqueous NH.sub.3 were added, and the mixture was extracted with DCM. The combined organic layers were washed with water, separated, dried (MgSO.sub.4), filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (silica, 0 / 100 to 30 / 70 EtOAc in heptane). The desired fractions were collected and concentrated in vacuo to give intermediate I-14 (380 mg, 67%) as a white solid.

[0185] Synthesis of intermediate I-15

[0186] [ka]

[0187] Palladium(II) hydroxide [12135-22-7] (77 mg, 0.55 mmol) was added to a solution of intermediate I-14 (370 mg, 1.1 mmol) in a mixture of methanol (5 mL) and EtOAc (1 mL) at 0 °C under N. H was then added, and the mixture was stirred at room temperature for 16 h. The mixture was filtered through a pad of Celite®, and the solvent was concentrated in vacuo to give intermediate I-15 as a yellow solid, which was used in the next step without further purification (350 mg, 84%).

[0188] Synthesis of intermediate I-16

[0189] [ka]

[0190] A 4 M solution of HCl in dioxane [7647-01-0] (1.55 mL, 6.2 mmol) was added to a stirred solution of intermediate I-15 (350 mg, 1.02 mmol) in DCM (15 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated in vacuo to give intermediate I-16 as a white solid, which was used in the next step without further purification (340 mg, 99%).

[0191] Synthesis of intermediate I-17a

[0192] [ka]

[0193] Intermediate I-6 (113 mg, 0.34 mmol) was added to a stirred mixture of intermediate II-15 (160 mg, 0.34 mmol), HATU [148893-10-1] (130 mg, 0.34 mmol), and DIPEA [7087-68-5] (0.24 mL, 1.36 mmol) in DMF (1.7 mL) at room temperature. The mixture was stirred at room temperature for 19 hours. Saturated aqueous NaHCO3 was then added, and the mixture was extracted with DCM. The combined organic layers were dried (MgSO4), filtered, and the solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica, 80 / 20 EtOAc in heptane). The desired fractions were collected and concentrated in vacuo to give intermediate I-17a (179 mg, 67%) as a white solid.

[0194] Synthesis of intermediate I-17b

[0195] [ka]

[0196] HATU [148893-10-1] (222 mg, 0.58 mmol) and DIPEA [7087-68-5] (0.54 mL, 3.08 mmol) were added to a solution of intermediate II-17d (187 mg, 0.494 mmol) in DMF (5 mL) at room temperature. The mixture was stirred at room temperature for 10 min, and then I-6 (187 mg, 0.49 mmol) was added, and the reaction mixture was stirred at room temperature for 16 h. Saturated aqueous NaHCO was added, and the mixture was extracted with EtOAc (×3). The combined organic layers were dried (MgSO), filtered, and concentrated in vacuo, and excess DMF was distilled off with toluene (10 mL ×3). The crude product was purified by flash column chromatography (silica, DCM / MeOH (9:1), 0 / 100 to 30 / 70) in DCM. The desired fractions were collected and concentrated in vacuo to give Intermediate 17b (165 mg, 61%, 45% purity) as a beige solid.

[0197] Synthesis of intermediate I-18

[0198] [ka]

[0199] To a solution of intermediate I-7a (300 mg, 1.04 mmol) and DCM (5.3 mL) was added N-bromosuccinimide [128-08-5] (205 mg, 1.15 mmol) portionwise at 0 °C under N. The mixture was stirred at room temperature for 1 h. Water was then added and the mixture was extracted with EtOAc. The organic layer was separated, dried (MgSO), filtered, and the solvent was evaporated in vacuo to give intermediate I-18 as a beige solid (386 mg, quantitative).

[0200] Synthesis of intermediate I-19

[0201] [ka]

[0202] Methylboronic acid [13061-96-6] (192 mg, 2.36 mmol) and E were added to a solution of intermediate I-18 (288 mg, 0.79 mmol) in a mixture of water (0.7 mL) and 1,4-dioxane (2.6 mL) at room temperature. N was bubbled through for 10 min, then tetrakis(triphenylphosphine)palladium(0) [14221-01-3] (228 mg, 0.20 mmol) and NaCO (167 mg, 1.58 mmol) were added, and the mixture was stirred at 120 °C for 17 h. Additional methylboronic acid [13061-96-6] (47 mg, 0.39 mmol) and tetrakis(triphenylphosphine)palladium(0) [14221-01-3] (46 mg, 0.04 mmol) were then added and the mixture was stirred for 16 hours at 120° C. Additional methylboronic acid [13061-96-6] (47 mg, 0.39 mmol) and tetrakis(triphenylphosphine)palladium(0) [14221-01-3] (46 mg, 0.04 mmol) were then added and the mixture was stirred for 16 hours at 120° C. Methylboronic acid [13061-96-6] (47 mg, 0.39 mmol) and tetrakis(triphenylphosphine)palladium(0) [14221-01-3] (46 mg, 0.04 mmol) were then added, and the mixture was stirred at 120 °C for another 16 h. Water was added, and the mixture was extracted with EtOAc. The combined organic layers were dried (MgSO), filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (silica, 0 / 100 to 10 / 90 EtOAc in heptane). The desired fractions were collected, and the solvent was evaporated in vacuo to give intermediate I19 (340 mg, 82%) as a yellow solid.

[0203] Synthesis of intermediate I-20

[0204] [ka]

[0205] Sodium borohydride [16940-66-2] (129 mg, 3.41 mmol) was added portionwise to a suspension of intermediate I-19 (340 mg, 1.13 mmol), nickel(II) chloride hexahydrate [7791-20-0] (147 g, 1.13 mmol), and di-tert-butyl dicarbonate [24424-99-5] (0.78 mL, 3.87 mmol) in dry methanol (11 mL) at 0 °C under N. The reaction mixture was stirred at room temperature for 16 h. Water was added, and the mixture was extracted with EtOAc (3 times). The combined organic layers were dried (MgSO), filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (silica, 60 / 40 EtOAc in heptane). The desired fractions were collected and concentrated in vacuo to afford intermediate I-20 (207 mg, 24%) as a yellow solid.

[0206] Synthesis of intermediate I-21

[0207] [ka]

[0208] To a solution of intermediate I-20 (505 mg, 1.25 mmol) in methanol (8.6 mL) was added palladium(II) hydroxide on carbon [12135-22-7] (262 mg, 0.37 mmol) at 0 °C under N. H was then added and the mixture was stirred at room temperature for 5 h. Additional palladium(II) hydroxide on carbon [12135-22-7] (262 mg, 0.37 mmol) was then added at 0 °C under N. H was then added and the mixture was stirred at room temperature for 16 h. Additional palladium(II) hydroxide on carbon [12135-22-7] (262 mg, 0.37 mmol) was then added at 0 °C under N. H was then added and the mixture was stirred at room temperature for an additional 6 h. The mixture was filtered through a pad of Celite® and the solvent was concentrated in vacuo. The crude product was purified by flash column chromatography (silica, 0 / 100 to 55 / 45 EtOAc in heptane). The desired fractions were collected and concentrated in vacuo to give intermediate I-21 (428 mg, 83%) as a white solid.

[0209] Synthesis of intermediate I-22

[0210] [ka]

[0211] A 4 M solution of HCl in dioxane [7647-01-0] (2.7 mL, 10.8 mmol) was added to a stirred solution of intermediate I-21 (428 mg, 1.04 mmol) in DCM (3 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated in vacuo to give intermediate I-22 as a white solid, which was used in the next step without further purification (412 mg, 97%).

[0212] Synthesis of intermediate I-23

[0213] [ka]

[0214] A 2.5 M solution of n-butyllithium in hexane [109-72-8] (3 mL, 7.5 mmol) was added dropwise to a solution of 2-methyl-4-(trifluoromethyl)pyridine [106877-17-2] (800 mg, 4.9 mmol) in THF (25 mL) at −78°C under N2. The mixture was stirred at −78°C for 30 min. Next, ethyl 4-cyanobenzoate [7153-22-2] (0.96 g, 1.37 mmol) in THF (2 mL) was added dropwise. The mixture was stirred at −78°C for 2 h. Water was added, and the mixture was extracted with EtOAc. The crude crystals were purified by flash column chromatography (silica, 0 / 100 to 10 / 90 EtOAc in DCM). The desired fractions were collected, and the solvent was evaporated in vacuo to give intermediate I-23 as a yellow solid.

[0215] Synthesis of intermediate I-24

[0216] [ka]

[0217] A 1 M solution of intermediate I-1 in DCM (5.6 mL, 5.6 mmol) was added to a solution of intermediate I-23 (810 mg, 2.8 mmol) in DCM (30 mL) at room temperature under N2, and the mixture was stirred at room temperature for 48 h. The reaction mixture was washed with saturated aqueous NaHCO3. The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. The crude material was purified by flash column chromatography (silica, 100 / 0 to 0 / 100 EtOAc in DCM). The desired fractions were combined and the solvent removed in vacuo to give intermediate I-24 as a yellow solid.

[0218] Synthesis of intermediate I-25

[0219] [ka]

[0220] Sodium borohydride [16940-66-2] (137 mg, 0.66 mmol) was added portionwise to a suspension of intermediate I-24 (349 mg, 1.22 mmol), nickel(II) chloride hexahydrate [7791-20-0] (145 mg, 0.61 mmol) and di-tert-butyl dicarbonate [24424-99-5] (0.56 mL, 2.43 mmol) in a mixture of dry methanol (30 mL) and 1,4-dioxane (15 mL) at 0 °C under N. The reaction mixture was stirred at room temperature for 10 minutes, and then additional nickel(II) chloride hexahydrate [7791-20-0] (145 g, 0.61 mmol), di-tert-butyl dicarbonate [24424-99-5] (0.56 mL, 2.43 mmol), and sodium borohydride [16940-66-2] (137 mg, 0.66 mmol) were added. The mixture was stirred at room temperature for 16 hours, and then saturated aqueous NH4Cl and NH3 (1 mL) were added, and the mixture was extracted with DCM. The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (silica, 30 / 70 EtOAc in heptane). The desired fractions were collected and concentrated in vacuo to give intermediate I-25 (492 mg, 98%) as a white solid.

[0221] Synthesis of intermediate I-26

[0222] [ka]

[0223] Palladium on carbon (10% w / w) 50% HO [7440-05-3] (1 g, 0.94 mmol) was added to a solution of intermediate I-25 (492 mg, 1.26 mmol) in a mixture of ethanol (23 mL) and THF (23 mL) at 0 °C under N 2 . H 2 was added, and the mixture was stirred at room temperature for 16 h. Next, additional palladium on carbon (10% w / w) 50% HO [7440-05-3] (1 g, 0.94 mmol) was added at 0 °C under N 2 . H 2 was added, and the mixture was stirred at room temperature for another 16 h. The mixture was filtered through a pad of Celite®, and the solvent was concentrated in vacuo. The crude product was purified by flash column chromatography (silica, 0 / 100 to 40 / 60 EtOAc in heptane). The desired fractions were collected and concentrated in vacuo to afford intermediate I-26 (277 mg, 55%) as a white solid.

[0224] Synthesis of intermediate I-27

[0225] [ka]

[0226] A 4 M solution of HCl in dioxane [7647-01-0] (1 mL, 4 mmol) was added to a stirred solution of intermediate I-26 (135 mg, 1.04 mmol) in DCM (5 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated in vacuo to give intermediate I-27 as a white solid, which was used in the next step without further purification (126 mg, quantitative).

[0227] Synthesis of intermediate I-28

[0228] [ka]

[0229] To a solution of intermediate I-24 (200 mg, 0.7 mmol) and DCM (7 mL) was added N-bromosuccinimide [128-08-5] (136 mg, 0.77 mmol) portionwise at room temperature. The mixture was stirred at room temperature for 2 hours. Water was then added, and the mixture was extracted with DCM. The organic layer was separated, dried (MgSO), filtered, the solvent evaporated in vacuo, and the crude product was purified by flash column chromatography (silica, 0 / 100 to 15 / 85 EtOAc in heptane). The desired fractions were collected, and the solvent evaporated in vacuo to give intermediate I-28 (191 mg, 71%) as a yellow solid.

[0230] Synthesis of intermediate I-29

[0231] [ka]

[0232] A 2 M solution of dimethylzinc [544-97-8] in toluene (0.35 mL, 0.7 mmol) was added to a stirred solution of intermediate I-28 (170 mg, 0.46 mmol) in 1,4-dioxane (5 mL) at room temperature under N. Tetrakis(triphenylphosphine)palladium(0) [14221-01-3] (53 mg, 0.09 mmol) was then added, and the mixture was stirred at 55° C. for 16 h. Additional 2 M solution of dimethylzinc [544-97-8] in toluene (0.35 mL, 0.7 mmol) and tetrakis(triphenylphosphine)palladium(0) [14221-01-3] (53 mg, 0.09 mmol) were then added, and the mixture was stirred at 55° C. for an additional 16 h. Water was added, and the mixture was extracted with EtOAc (3×). The combined organic layers were dried (MgSO), filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (silica, 0 / 100 to 20 / 80 EtOAc in heptane). The desired fractions were collected and the solvent was evaporated in vacuo to give intermediate I-29 (113 mg, 80%) as a yellow solid.

[0233] Synthesis of intermediate I-30

[0234] [ka]

[0235] Sodium borohydride [16940-66-2] (43 mg, 1.12 mmol) was added portionwise to a suspension of intermediate I-29 (113 mg, 0.38 mmol), nickel(II) chloride hexahydrate [7791-20-0] (89 mg, 0.38 mmol), and di-tert-butyl dicarbonate [24424-99-5] (0.26 mL, 1.13 mmol) in a mixture of dry methanol (6 mL) and dry 1,4-dioxane (3 mL) at 0 °C under N 2 . The reaction mixture was stirred at room temperature for 16 h, then saturated aqueous NH 4 Cl and NH 3 (1 mL) were added, and the mixture was extracted with DCM. The combined organic layers were dried (MgSO 4 ), filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (silica, 30 / 70 EtOAc in heptane). The desired fractions were collected and concentrated in vacuo to afford intermediate I-30 (106 mg, 66%) as a white solid.

[0236] Synthesis of intermediate I-31

[0237] [ka]

[0238] Intermediate I-31 was prepared (63 mg, 66%) following a procedure similar to that used for the synthesis of intermediate I-26 using intermediate I-30 (90 mg, 0.22 mmol) as the starting material.

[0239] Synthesis of intermediate I-32

[0240] [ka]

[0241] Intermediate I-32 was prepared (59 mg, 99%) following a procedure similar to that used for the synthesis of intermediate I-27 using intermediate I-31 (63 mg, 0.15 mmol) as the starting material.

[0242] Synthesis of intermediate I-33

[0243] [ka]

[0244] 4-Cyano-2-fluorobenzoic acid [164149-28-4] (1 g, 6.06 mmol) was dissolved in dry DCM (12 mL) and cooled to 0 °C under N. Oxalyl chloride [79-37-8] (0.77 mL, 9.08 mmol) was then added, followed by dry DMF (0.1 mL), and the mixture was stirred at room temperature for 1 h. The solvent was removed in vacuo to give intermediate I-33 as a yellowish solid, which was used in the next reaction step without further purification (1.11 g, quantitative).

[0245] Synthesis of intermediate I-34

[0246] [ka]

[0247] Intermediate I-34 was prepared (0.66 g, 67%) following a procedure similar to that used for the synthesis of intermediate I-3 using intermediate I-33 (1.11 g, 6.06 mmol) as the starting material.

[0248] Synthesis of intermediate I-35

[0249] [ka]

[0250] Intermediate I-35 was prepared (0.97 g, 99%) following a procedure similar to that used for the synthesis of intermediate I-4 using intermediate I-34 (0.66 g, 2.16 mmol) as the starting material.

[0251] Synthesis of intermediate I-36

[0252] [ka]

[0253] To a solution of intermediate I-35 (0.97 g, 3.36 mmol) in methanol (20 mL) was added palladium(II) hydroxide on carbon [12135-22-7] (0.33 g, 3.36 mmol) portionwise at 0 °C under N. Then, H was added, and the mixture was stirred at room temperature for 18 h. The mixture was filtered through a pad of Celite®, and the solvent was concentrated in vacuo. The crude product was purified by flash column chromatography (silica, 0 / 100 to 40 / 60 EtOAc in heptane). The desired fractions were collected and concentrated in vacuo to give intermediate I-36 (0.57 g, 79%) as a white solid.

[0254] Synthesis of intermediate I-37

[0255] [ka]

[0256] Intermediate I-37 was prepared (0.47 g, quantitative) following a procedure similar to that used for the synthesis of intermediate I-6 using intermediate I-36 (0.56 g, 1.35 mmol) as the starting material.

[0257] Synthesis of intermediate I-38

[0258] [ka]

[0259] Intermediate I-38 was prepared (2.79 g, quantitative) following a procedure similar to that used to synthesize intermediate I-33, using intermediate 4-cyano-2-methylbenzoic acid (2.5 g, 15.51 mmol) as the starting material.

[0260] Synthesis of intermediate I-39

[0261] [ka]

[0262] Intermediate I-39 was prepared (1.35 g, 55%) following a procedure similar to that used for the synthesis of intermediate I-3 using intermediate I-38 (2.93 g, 7.76 mmol) as the starting material.

[0263] Synthesis of intermediate I-40

[0264] [ka]

[0265] Intermediate I-40 was prepared (0.82 g, 44%) following a procedure similar to that used for the synthesis of intermediate I-14 using intermediate I-39 (1.35 g, 4.46 mmol) as the starting material.

[0266] Synthesis of intermediate I-41

[0267] [ka]

[0268] To a solution of intermediate I-40 (0.40 g, 0.98 mmol) in a mixture of methanol (5 mL) and EtOAc (1 mL) was added palladium(II) hydroxide on carbon [12135-22-7] (70 mg, 0.5 mmol) in portions at 0 °C under N. H was then added, and the mixture was stirred at room temperature for 18 h. The mixture was filtered through a pad of Celite®, and the solvent was concentrated in vacuo to give intermediate I-41 (0.40 g, 89%) as a yellow solid.

[0269] Synthesis of intermediate I-42

[0270] [ka]

[0271] Intermediate I-42 was prepared (0.34 g, quantitative) following a procedure similar to that used for the synthesis of intermediate I-6 using intermediate I-41 (0.4 g, 0.97 mmol) as the starting material.

[0272] Synthesis of intermediate I-43

[0273] [ka]

[0274] Intermediate I-42 was prepared (3.95 g, 79%) following a procedure similar to that used to synthesize intermediate I-2, using 2-amino-4-(trifluoromethyl)pyridine [74784-70-6] (2 g, 13.34 mmol) as the starting material.

[0275] Synthesis of intermediate I-44

[0276] [ka]

[0277] Intermediate I-44 was prepared (2.2 g, 73%) following a procedure similar to that used for the synthesis of intermediate I-3 using intermediate I-43 (3.95 g, 10.23 mmol) as the starting material.

[0278] Synthesis of intermediate I-45

[0279] [ka]

[0280] Intermediate I-45 was prepared (1.1 g, 35%) following a procedure similar to that used for the synthesis of intermediate I-4 using intermediate I-44 (2.2 g, 7.63 mmol) as the starting material.

[0281] Synthesis of intermediate I-46

[0282] [ka]

[0283] Intermediate I-46 was prepared (196 mg, 64%) following a procedure similar to that used for the synthesis of intermediate I-26 using intermediate I-45 (0.3 g, 0.76 mmol) as the starting material.

[0284] Synthesis of intermediate I-47

[0285] [ka]

[0286] Intermediate I-47 was prepared (173 mg, quantitative) following a procedure similar to that used for the synthesis of intermediate I-6 using intermediate I-46 (196 mg, 0.49 mmol) as the starting material.

[0287] Synthesis of intermediate I-47

[0288] [ka]

[0289] Intermediate I-47 was prepared following a procedure similar to that used to synthesize intermediate I-2 using 4-(difluoromethyl)pyridin-2-amine [1346536-47-7] (0.5 g, 3.47 mmol) as the starting material (1.27 g, 91%).

[0290] Synthesis of intermediate I-48

[0291] [ka]

[0292] Intermediate I-48 was prepared (0.61 g, 67%) following a procedure similar to that used for the synthesis of intermediate I-3 using intermediate I-47 (1.27 g, 3.16 mmol) as the starting material.

[0293] Synthesis of intermediate I-49

[0294] [ka]

[0295] Sodium borohydride [16940-66-2] (255 mg, 6.74 mmol) was added portionwise to a suspension of intermediate I-48 (0.61 g, 2.25 mmol), nickel(II) chloride hexahydrate [7791-20-0] (0.53 mg, 2.25 mmol), and di-tert-butyl dicarbonate [24424-99-5] (1.55 mL, 6.75 mmol) in a mixture of dry methanol (12 mL) and dry 1,4-dioxane (6 mL) at 0 °C under N 2 . The reaction mixture was stirred at room temperature for 16 h, then water and aqueous NH 3 (3 mL) were added, and the mixture was extracted with DCM. The combined organic layers were dried (MgSO 4 ), filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (silica, 20 / 80 EtOAc in heptane). The desired fractions were collected and concentrated in vacuo to afford intermediate I-49 (849 mg, 45%) as a white solid.

[0296] Synthesis of intermediate I-50

[0297] [ka]

[0298] Palladium(II) hydroxide (20% w / w) 50% HO [7440-05-3] (0.42 g, 0.60 mmol) was added to a solution of intermediate I-49 (0.97 g, 3.36 mmol) in a mixture of ethanol (13.5 mL) and THF (13.5 mL) at 0 °C under N. Then, H was added, and the mixture was stirred at room temperature for 2 h. The mixture was filtered through a pad of Celite®, and the solvent was concentrated in vacuo. The crude product was purified by flash column chromatography (silica, 0 / 100 to 75 / 25 EtOAc in heptane). The desired fractions were collected and concentrated in vacuo to give intermediate I-50 (223 mg, 73%) as a white solid.

[0299] Synthesis of intermediate I-51

[0300] [ka]

[0301] Intermediate I-51 was prepared (209 mg, quantitative) following a procedure similar to that used for the synthesis of intermediate I-6 using intermediate I-50 (223 mg, 0.59 mmol) as the starting material.

[0302] Synthesis of intermediate I-52

[0303] [ka]

[0304] Intermediate I-52 was prepared following a procedure similar to that used to synthesize intermediate I-2 using 2-amino-4-methoxypyridine [10201-73-7] (0.5 g, 4.03 mmol) as the starting material (0.81 g, 51%, 87% purity).

[0305] Synthesis of intermediate I-53

[0306] [ka]

[0307] Intermediate I-53 was prepared (0.33 g, 56%) following a procedure similar to that used for the synthesis of intermediate I-3 using intermediate I-52 (0.8 g, 2.35 mmol) as the starting material.

[0308] Synthesis of intermediate I-54

[0309] [ka]

[0310] Intermediate I-54 was prepared (0.33 g, 67%) following a procedure similar to that used for the synthesis of intermediate I-4 using intermediate I-53 (0.33 g, 1.32 mmol) as the starting material.

[0311] Synthesis of intermediate I-55

[0312] [ka]

[0313] Intermediate I-55 was prepared (0.25 g, 63%) following a procedure similar to that used for the synthesis of intermediate I-36 using intermediate I-54 (0.40 g, 1.09 mmol) as the starting material.

[0314] Synthesis of intermediate I-56

[0315] [ka]

[0316] Intermediate I-56 was prepared (201 mg, 99%) following a procedure similar to that used for the synthesis of intermediate I-6 using intermediate I-55 (0.25 g, 0.68 mmol) as the starting material.

[0317] Synthesis of intermediate I-57

[0318] [ka]

[0319] Pd(OAc)2[3375-31-3] (19 mg, 0.08 mmol) and SPhos[657408-07-6] (34 mg, 0.08 mmol) were added to a stirred solution of intermediate I-12 (0.5 g, 1.67 mmol), cyclopropylboronic acid [411235-57-9] (144 mg, 1.77 mmol), and K3PO4 (1.77 g, 8.36 mmol) in dry 1,4-dioxane (4 mL) in a sealed tube under N2. The mixture was stirred at 95 °C for 16 h. Water was added, and the mixture was extracted with EtOAc (x3). The combined organic layers were separated, dried (MgSO4), filtered, and concentrated in vacuo to give intermediate I-13 (317 mg, 70%) as a white solid.

[0320] Synthesis of intermediate I-58

[0321] [ka]

[0322] Intermediate I-58 was prepared (318 mg, 78%) following a procedure similar to that used for the synthesis of intermediate I-14 using intermediate I-57 (287 mg, 1.1 mmol) as the starting material.

[0323] Synthesis of intermediate I-59

[0324] [ka]

[0325] To a solution of intermediate I-58 (167 mg, 0.45 mmol) in a mixture of ethanol (2 mL), THF (2 mL), and acetic acid (0.2 mL) was added palladium(II) hydroxide on carbon [12135-22-7] (31 mg, 0.11 mmol) at 0 °C under N. H was then added, and the mixture was stirred at room temperature for 16 h. The mixture was filtered through a pad of Celite®, and the solvent was concentrated in vacuo to give intermediate I-15 as a yellow solid, which was used in the next step without further purification (166 mg, 51%, 50% purity).

[0326] Synthesis of intermediate I-60

[0327] [ka]

[0328] Intermediate I-60 was prepared following a procedure similar to that used to synthesize intermediate I-16 using intermediate I-59 (166 mg, 0.45 mmol) as the starting material (154 mg, 32%, 32% purity).

[0329] Synthesis of intermediate I-61

[0330] [ka]

[0331] Pd(OAc)2[3375-31-3] (170 mg, 0.76 mmol) and BredttPhos[1070663-78-3] (410 mg, 0.76 mmol) were added to a stirred solution of intermediate I-12 (3.8 g, 19.03 mmol), benzyl alcohol [100-51-6] (2 mL, 1.77 mmol), and Cs2CO3 (6.2 g, 8.36 mmol) in toluene (22 mL) in a sealed tube under N2. The mixture was stirred at 75 °C for 16 h. Water was added, and the mixture was extracted with DCM (x3). The combined organic layers were separated, dried (MgSO4), filtered, and concentrated in vacuo to give intermediate I-61 (8 g, 47%, 55% purity) as a yellow solid.

[0332] Synthesis of intermediate I-62

[0333] [ka]

[0334] Intermediate I-62 was prepared (0.87 g, 27%) following a procedure similar to that used for the synthesis of intermediate I-4 using intermediate I-61 (3.5 g, 7.29 mmol) as the starting material.

[0335] Synthesis of intermediate I-63

[0336] [ka]

[0337] Intermediate I-63 was prepared (488 mg, 70%) following a procedure similar to that used for the synthesis of intermediate I-9 using intermediate I-62 (0.87 g, 2.01 mmol) as the starting material.

[0338] Synthesis of intermediate I-64

[0339] [ka]

[0340] Intermediate I-64 was prepared (93 mg, quantitative) following a procedure similar to that used for the synthesis of intermediate I-5 using intermediate I-63 (100 mg, 0.29 mmol) as the starting material.

[0341] Synthesis of intermediate I-65

[0342] [ka]

[0343] Intermediate I-65 was prepared following a procedure similar to that used to synthesize intermediate I-61 using 2-methoxyethanol [109-86-4] (0.40 mL, 5.01 mmol) as the starting material (0.97 g, 85%, 86% purity).

[0344] Synthesis of intermediate I-66

[0345] [ka]

[0346] Intermediate I-66 was prepared (0.6 g, 52%) following a procedure similar to that used for the synthesis of intermediate I-4 using intermediate I-65 (0.97 g, 2.83 mmol) as the starting material.

[0347] Synthesis of intermediate I-67

[0348] [ka]

[0349] Palladium on carbon (10% w / w) 50% HO [7440-05-3] (0.4 g, 0.38 mmol) was added to a solution of intermediate I-66 (200 mg, 0.50 mmol) in a mixture of methanol (15 mL) and EtOAc (2 mL) at 0 °C under N. H was added, and the mixture was stirred at 50 °C for 16 h. Next, additional palladium on carbon (10% w / w) 50% HO [7440-05-3] (0.4 g, 0.38 mmol) was added at 0 °C under N. H was added, and the mixture was stirred at room temperature for another 16 h. The mixture was filtered through a pad of Celite®, and the solvent was concentrated in vacuo. The crude product was purified by flash column chromatography (silica, 0 / 100 to 100 / 0 EtOAc in DCM). The desired fractions were collected and concentrated in vacuo to afford intermediate I-67 (77 mg, 36%) as a white solid.

[0350] Synthesis of intermediate I-68

[0351] [ka]

[0352] Intermediate I-68 was prepared (199 mg, quantitative) following a procedure similar to that used for the synthesis of intermediate I-6 using intermediate I-67 (213 mg, 0.53 mmol) as the starting material.

[0353] Synthesis of intermediate I-69

[0354] [ka]

[0355] Intermediate I-69 was prepared (5.17 g, 89%) following a procedure similar to that used to synthesize intermediate I-2 using 2-aminopyridine [504-29-0] (1.75 g, 18.57 mmol) as the starting material.

[0356] Synthesis of intermediate I-70a

[0357] [ka]

[0358] Intermediate I-70a was prepared (1.09 g, 76%) following a procedure similar to that used for the synthesis of intermediate I-3 using intermediate I-69 (2 g, 6.44 mmol) as the starting material.

[0359] Synthesis of intermediate I-70b

[0360] [ka]

[0361] Intermediate I-70b was prepared (1.6 g, 65%) following a procedure similar to that used for the synthesis of intermediate I-3 using intermediate I-33 (3.75 g, 20.43 mmol) as the starting material.

[0362] Synthesis of intermediate I-71a

[0363] [ka]

[0364] Intermediate I-71a was prepared following a procedure similar to that used to synthesize intermediate I-4 using intermediate I-70a (1.08 g, 4.90 mmol) as the starting material (1.37 g, 73%, 85% purity).

[0365] Synthesis of intermediate I-71b

[0366] [ka]

[0367] Intermediate I-71b was prepared (1.95 g, 79%) following a procedure similar to that used for the synthesis of intermediate I-4 using intermediate I-70b (1.59 g, 6.67 mmol) as the starting material.

[0368] Synthesis of intermediate I-72a

[0369] [ka]

[0370] Intermediate I-72a was prepared (1 g, 84%) following a procedure similar to that used for the synthesis of intermediate I-5 using intermediate I-71a (1.34 g, 3.51 mmol) as the starting material.

[0371] Synthesis of intermediate I-72b

[0372] [ka]

[0373] Intermediate I-72b was prepared (1.25 g, 68%) following a procedure similar to that used for the synthesis of intermediate I-5 using intermediate I-71b (1.93 g, 5.19 mmol) as the starting material.

[0374] Synthesis of intermediate I-73a

[0375] [ka]

[0376] Intermediate I-73a was prepared (0.93 g, quantitative) following a procedure similar to that used for the synthesis of intermediate I-6 using intermediate I-72a (1 g, 2.95 mmol) as the starting material.

[0377] Synthesis of intermediate I-73b

[0378] [ka]

[0379] Intermediate 73b was prepared (1.13 g, quantitative) following a procedure similar to that used for the synthesis of intermediate I-6 using intermediate 72b (1.25 g, 3.5 mmol) as the starting material.

[0380] Synthesis of intermediate I-74

[0381] [ka]

[0382] To a mixture of intermediate I-63 (150 mg, 0.4 mmol), N-fluoro-N'-(chloromethyl)triethylenediaminebis(tetrafluoroborate) [140681-55-6] (500 mg, 1.4 mmol), silver trifluoromethanesulfonate [2923-28-6] (700 mg, 2.7 mmol), 2-fluoropyridine (250 μL, 2.9 mmol), and potassium fluoride (230 mg, 4 mmol) in EOAc (15 mL) was added trimethyl(trifluoromethyl)silane [81290-20-2] (0.42 μL, 2.6 mmol). The reaction mixture was stirred at room temperature for 4 days in the dark. The reaction mixture was filtered through a Celite® pad and washed with EtOAc. The solvent was evaporated in vacuo and the crude product was purified by flash column chromatography (silica, DCM / MeOH (9:1), 100 / 0 to 0 / 100 in DCM). The desired fractions were collected and concentrated in vacuo to give intermediate I-74 (105 mg, 47%, 80% purity) as a yellow solid.

[0383] Synthesis of intermediate I-75

[0384] [ka]

[0385] Intermediate I-75 was prepared (136 mg, quantitative) following a procedure similar to that used for the synthesis of intermediate I-6 using intermediate I-74 (100 mg, 0.24 mmol) as the starting material.

[0386] Synthesis of intermediate I-76

[0387] [ka]

[0388] Tributyl(1-ethoxyvinyl)tin [97674-02-7] (5.9 mL, 14.46 mmol) was added to a stirred solution of 6-chloro-3-pyridinecarbonitrile [623-00-7] (2 g, 14.43 mmol) and bis(triphenylphosphine)palladium(II) chloride [13965-03-2] in dry toluene (20 mL) at room temperature under N2. The mixture was stirred at 130 °C for 2 hours. The mixture was then cooled to 0 °C in an ice bath, and 6 M aqueous HCl (5.3 mL) was added. The mixture was stirred at room temperature for 1 hour. The reaction was cooled to 0 °C in an ice bath, and the pH was adjusted to 8 by the addition of 4 M aqueous NaOH and saturated aqueous NaHCO3. The resulting suspension was filtered through a Celite® pad. The filtrate was extracted with EtOAc, dried (MgSO), filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (silica, 0 / 100 to 40 / 60 EtOAc in heptane). The desired fractions were collected and concentrated in vacuo to give intermediate I-76 (1.78 g, 83%) as a yellow solid.

[0389] Synthesis of intermediate I-77

[0390] [ka]

[0391] Pyridinium tribromide [39416-48-3] (3.54 g, 11.06 mmol) was added to a solution of intermediate I-76 (1.62 g, 11.05 mmol) in THF (50 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 h and then diluted with EtOAc and saturated aqueous NaSO. The aqueous layer was extracted with EtOAc (x3), and the combined organic extracts were dried (MgSO), filtered, and the solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica, 0 / 100 to 30 / 70 EtOAc in heptane). The desired fractions were collected and concentrated in vacuo to give intermediate I-77 (0.68 g, 25%) as a yellow solid.

[0392] Synthesis of intermediate I-78

[0393] [ka]

[0394] NaHCO (218 mg, 2.60 mmol) was added to a solution of 2-amino-4-(trifluoromethyl)pyridine [106447-97-6] (375 mg, 2.31 mmol) and intermediate I-77 (680 mg, 3.02 mmol) in ethanol (16 mL) at room temperature. The mixture was stirred at reflux for 16 h. HO was added, and the formed precipitate was filtered off and washed with water and diethyl ether. The solid was dried in vacuo to give intermediate I-78 (380 mg, 57%) as a brown solid. The filtrate was extracted with DCM, and the organic layer was dried (MgSO), filtered, and the solvent was concentrated in vacuo. The residue was purified by flash column chromatography (silica, 0 / 100 to 30 / 70 EtOAc in heptane). The desired fractions were collected and concentrated in vacuo to give additional intermediate I-78 (96 mg, 14%) as a yellow solid.

[0395] Synthesis of intermediate I-79

[0396] [ka]

[0397] Sodium borohydride [16940-66-2] (187 mg, 4.94 mmol) was added portionwise to a suspension of intermediate I-78 (476 mg, 1.65 mmol), nickel(II) chloride hexahydrate [7791-20-0] (393 g, 1.65 mmol), and di-tert-butyl dicarbonate [24424-99-5] (1.14 mL, 4.96 mmol) in a mixture of dry methanol (8 mL) and 1,4-dioxane (4 mL) at 0 °C under N. The reaction mixture was stirred at room temperature for 16 h. Water and 3 mL of aqueous NH were added, and the mixture was extracted with DCM (3 times). The combined organic layers were washed with water, separated, dried (MgSO), filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (silica, 0 / 100 to 40 / 60 EtOAc in heptane). The desired fractions were collected and concentrated in vacuo to give intermediate I-79 (349 mg, 53%) as a brown solid.

[0398] Synthesis of intermediate I-80

[0399] [ka]

[0400] Intermediate I-80 was prepared (175 mg, 56%) following a procedure similar to that used for the synthesis of intermediate I-9 using intermediate I-79 (306 mg, 0.78 mmol) as the starting material.

[0401] Synthesis of intermediate I-81

[0402] [ka]

[0403] Intermediate I-81 was prepared (171 mg, quantitative) following a procedure similar to that used for the synthesis of intermediate I-10 using intermediate I-80 (175 mg, 0.44 mmol) as the starting material.

[0404] Synthesis of Intermediate II Synthesis of intermediate II-1a

[0405] [ka]

[0406] Boron trifluoride diethyl etherate [109-63-7] (0.35 mL, 2.87 mmol) was added dropwise to a solution of 2-amino-5-bromopyrimidine [7752-82-1] (5 g, 28.74 mmol), ethyl propionylacetate [4949-44-4] (6.33 mL, 43.10 mmol), and (diacetoxyiodo)benzene [3240-34-4] (13.88 g, 43.09 mmol) in dry 2-methyltetrahydrofuran (125 mL) in a two-necked round-bottom flask equipped with a condenser at room temperature under N2. The mixture was stirred at 60 °C for 16 h. Saturated aqueous NaHCO3 was added, and the mixture was extracted with EtOAc. The organic phase was separated, dried (MgSO4), filtered, and the solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica, 0 / 100 to 40 / 60 EtOAc in heptane). The desired fractions were collected and concentrated in vacuo to give intermediate II-1a (3.75 g, 43%) as a yellow solid.

[0407] Synthesis of intermediate II-1b

[0408] [ka]

[0409] Intermediate II-1b was prepared (2.68 mg, 47%) following a procedure similar to that used to synthesize intermediate II-1a, using ethyl 3-cyclopropyl-3-oxopropionate [24922-02-9] (3.82 mL, 25.86 mmol) as the starting material.

[0410] Synthesis of intermediate II-1c

[0411] [ka]

[0412] Boron trifluoride diethyl etherate [109-63-7] (0.2 mL, 1.62 mmol) was added dropwise to a solution of 2-amino-5-chloropyrimidine [5428-89-7] (2.0 g, 15.438 mmol), ethyl propionylacetate [4949-44-4] (3.14 mL, 21.38 mmol), and (diacetoxyiodo)benzene [3240-34-4] (7.5 g, 23.29 mmol) in dry 2-methyltetrahydrofuran (75 mL) at 0 °C under N2. The mixture was stirred at room temperature for 16 h, then poured into 10% aqueous NaHCO3 and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated in vacuo. The crude crystals were purified by flash column chromatography (silica, 0 / 100 to 20 / 80 EtOAc in heptane). The desired fractions were collected and concentrated in vacuo to give intermediate II-1c as a yellow solid.

[0413] Synthesis of intermediate II-1d

[0414] [ka]

[0415] Boron trifluoride diethyl etherate [109-63-7] (66 μL, 0.53 mmol) was added dropwise to a solution of 2-aminopyridine [4949-44-4] (1 g, 10.62 mmol), ethyl propionylacetate [4949-44-4] (2.34 mL, 15.94 mmol), and (diacetoxyiodo)benzene [3240-34-4] (1.71 g, 5.31 mmol) in dry 2-methyltetrahydrofuran (25 mL) at 5 °C under N2. The mixture was stirred at 5 °C for 15 min, then slowly warmed to room temperature and stirred for an additional 5 h. Saturated aqueous NaHCO3 was added. The organic phase was separated, dried (MgSO4), filtered, and the solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica, 0 / 100 to 50 / 50 EtOAc in heptane). The desired fractions were collected and concentrated in vacuo to give intermediate II-1d (0.78 g, 32%) as a white solid.

[0416] Synthesis of intermediate II-2a

[0417] [ka]

[0418] A 2 M solution of trimethylaluminum in hexane [75-24-1] (22.05 mL, 44.11 mmol) was added dropwise to a solution of intermediate II-1a (3.78 g, 12.60 mmol) and tetrakis(triphenylphosphine)-palladium(0)

[14221] -01-3] in dry THF (90 mL) at room temperature under N2, and the mixture was stirred at 65 °C for 2 h. The mixture was cooled to 0 °C and diluted with DCM. Next, 10 mL of water was added dropwise. The resulting mixture was filtered through a pad of Celite®, and the pad was washed with EtOAc. Anhydrous MgSO4 was then added to the filtrate. The filtrate was filtered, and the solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica, 0 / 100 to 40 / 60 EtOAc in heptane). The desired fractions were collected and concentrated in vacuo to give intermediate II-2a (2.45 g, 75%) as a yellow solid.

[0419] Synthesis of intermediate II-2b

[0420] [ka]

[0421] Intermediate II-2b was prepared (1.46 mg, 72%) following a procedure similar to that used for the synthesis of intermediate II-1a using intermediate II-1b (2.57 mL, 8.10 mmol) as the starting material.

[0422] Synthesis of intermediate II-3a

[0423] [ka]

[0424] Sodium hydroxide [1310-73-2] (1.13 g, 28.29 mmol) was added to a solution of intermediate II-2a in a mixture of ethanol (74 mL) and water (19 mL) at room temperature. The mixture was stirred at 50° C. for 2 hours. The reaction mixture was adjusted to pH 7 by adding 1 M aqueous HCl and concentrated in vacuo to give intermediate II-3a as a pale orange-yellow solid, which was used in the next step without further purification (2.76 g, quantitative, 90% purity).

[0425] Synthesis of intermediate II-4a

[0426] [ka]

[0427] N-Bromosuccinimide [128-08-5] (14.69 g, 82.56 mmol) was added to a stirred solution of ethyl 4,4,4-trifluoroacetoacetate [372-31-6] (14.48 g, 78.63 mmol) in DMSO (72 mL). The reaction mixture was stirred at room temperature for 1 h. Saturated aqueous NH4Cl was added, and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure to give intermediate II-4a as a colorless oil, which was used in the next step without further purification (14.1 g, 55%, 80% purity).

[0428] Synthesis of intermediate II-4b

[0429] [ka]

[0430] Bromine [7726-95-6] (0.70 mL, 13.75 mmol) was added dropwise to a mixture of ethyl 4,4-difluoroacetoacetate [7726-95-6] (1.8 mL, 13.75 mmol) and CaCO3 (1.6 g, 15.95 mmol) in dry methanol (20 mL) at 0 °C. The mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure. The crude product was triturated with diethyl ether, the formed solid was filtered off, and the filtrate was concentrated in vacuo to give II-4b (3.37, quantitative) as a yellow oil.

[0431] Synthesis of intermediate II-5a

[0432] [ka]

[0433] 2-Aminopyridine [504-29-0] (3.2 g, 34 mmol) was added to a stirred solution of intermediate II-4a (18 g, 68.43 mmol) in ethanol (100 mL) in a sealed tube at room temperature. The reaction mixture was stirred at 80 °C for 48 h, and the solvent was evaporated under reduced pressure. Saturated aqueous NaHCO3 was added, and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (silica, 100 / 0 to 80 / 20 EtOAc in heptane). The desired fractions were collected and concentrated in vacuo to give intermediate II-5a (2.0 g, 22%) as a pale yellow solid.

[0434] Synthesis of intermediate II-5b

[0435] [ka]

[0436] 2-Aminopyridine [504-29-0] (0.51 g, 5.44 mmol) was added to a stirred solution of intermediate II-4b (2 g, 8.16 mmol) in ethanol (30 mL) at room temperature. The reaction mixture was stirred at 65 °C for 16 h. Saturated aqueous NaHCO3 was added, and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (silica, 100 / 0 to 40 / 26 EtOAc in heptane). The desired fractions were collected and concentrated in vacuo to give intermediate II-5a (0.81 g, 59%) as a colorless solid.

[0437] Synthesis of intermediate II-6a

[0438] [ka]

[0439] A 1 M solution of aqueous sodium hydroxide [1310-73-2] (1.32 mL, 1.32 mmol) was added to a solution of intermediate II-5a (113 mg, 0.44 mmol) in a mixture of ethanol (3 mL) and water (1 mL) at room temperature. The mixture was stirred at room temperature for 16 hours. The reaction mixture was adjusted to pH 5 by the addition of 1 M aqueous HCl and concentrated in vacuo to give intermediate II-6a as a white solid, which was used in the next step without further purification (101 mg, quantitative).

[0440] Synthesis of intermediate II-6b

[0441] [ka]

[0442] Intermediate II-6b was prepared (106 mg, quantitative) following a procedure similar to that used for the synthesis of intermediate II-6a using intermediate II-2b (120 mg, 0.49 mmol) as the starting material.

[0443] Synthesis of intermediate II-7a

[0444] [ka]

[0445] KHCO3 (688 mg, 6.87 mmol) and ethyl propionylacetate [4949-44-4] (0.98 mL, 6.87 mmol) were added to a stirred solution of 2-amino-4-methylpyrimidine [108-52-1] (500 mg, 4.58 mmol) in dry ACN (9.18 mL) at room temperature in a sealed tube. The reaction mixture was stirred at 80 °C for 16 h, after which saturated aqueous NaHCO3 was added and the mixture was extracted with EtOAc (3 times). The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (silica, DCM / MeOH (9:1), 0 / 100 to 20 / 80) in DCM. The desired fractions were collected and concentrated in vacuo to give intermediate II-7a (206 mg, 19%) as a brown solid.

[0446] Synthesis of intermediate II-7b

[0447] [ka]

[0448] Intermediate II-7b was prepared (407 mg, 40%) following a procedure similar to that used to synthesize intermediate II-7a, using 2-amino-4-methylpyrimidine [13418-77-4] (500 mg, 4 mmol) as the starting material.

[0449] Synthesis of intermediate II-7c

[0450] [ka]

[0451] Ethyl propionylacetate [4949-44-4] (1.87 mL, 12.71 mmol) and tetrabromoethane [558-13-4] (11.24 g, 33.90 mmol) were added to a stirred solution of 4-fluoro-2-aminopyridine [944401-77-8] (1 g, 8.47 mmol) in dry ACN (15.25 mL) in a sealed tube at room temperature. The reaction mixture was stirred at 80 °C for 20 hours, and then additional ethyl propionylacetate [4949-44-4] (1.24 mL, 8.47 mmol) and tetrabromoethane [558-13-4] (2.81 g, 8.48 mmol) were added. The reaction mixture was stirred at 80 °C for 5 h, and then additional ethyl propionylacetate [4949-44-4] (0.62 mL, 4.24 mmol) and tetrabromoethane [558-13-4] (1.41 g, 4.24 mmol) were added. The reaction mixture was stirred at 80 °C for an additional 16 h, then poured into 10% aqueous NaHCO and extracted with EtOAc (3 times). The combined organic layers were dried (MgSO), filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (silica, DCM / MeOH (9:1), 0 / 100 to 20 / 80) in DCM. The desired fractions were collected and concentrated in vacuo to give intermediate II-7c (529 mg, 25%) as a pale yellow solid.

[0452] Synthesis of intermediate II-7d

[0453] [ka]

[0454] KHCO (610 mg, 69 mmol) and ethyl propionylacetate [4949-44-4] (0.87 mL, 6.09 mmol) were added to a stirred solution of 4,5-dimethyl-2-pyrimidinamine [1193-74-4] (500 mg, 4.06 mmol) in dry ACN (8.14 mL). Bromotrichloromethane [75-62-7] (1.2 mL, 12.18 mmol) was then added, and the reaction mixture was stirred at 80 °C for 16 h. Additional ethyl propionylacetate [4949-44-4] (0.43 mL, 3.04 mmol) and bromotrichloromethane [75-62-7] (0.6 mL, 6.09 mmol) were then added. The reaction mixture was stirred at 80° C. for an additional 16 hours, then saturated aqueous NaHCO3 was added, and the mixture was extracted with EtOAc (3 times). The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (silica, MeOH in DCM from 0 / 100 to 2 / 98). The desired fractions were collected and concentrated in vacuo to give intermediate II-7d (219 mg, 20%) as a brown solid.

[0455] Synthesis of intermediate II-7f

[0456] [ka]

[0457] Intermediate II-7f was prepared (0.23 g, 24%) following a procedure similar to that used to synthesize intermediate II-7d, using 5-methoxy-4-methylpyrimidin-2-amine [1749-71-9] (0.5 g, 3.59 mmol) as the starting material.

[0458] Synthesis of Intermediate II-7g

[0459] [ka]

[0460] Intermediate II-7g was prepared (8.85 g, 82%) following a procedure similar to that used to synthesize intermediate II-7d, using 5-methyl-pyridin-2-ylamine [1603-41-4] (5 g, 46.24 mmol) as the starting material.

[0461] Synthesis of intermediate II-8a

[0462] [ka]

[0463] Sodium hydroxide [1310-73-2] (72 mg, 1.8 mmol) was added to a solution of intermediate II-7a (140 mg, 0.6 mmol) in a mixture of ethanol (4.7 mL) and water (1.2 mL) at room temperature. The mixture was stirred at 50° C. for 2 hours. The reaction mixture was adjusted to pH 7 by the addition of 1 M aqueous HCl and concentrated in vacuo to give intermediate II-8a as a pale orange-yellow solid, which was used in the next step without further purification (2.76 g, quantitative, 90% purity).

[0464] Synthesis of intermediate II-8b

[0465] [ka]

[0466] Intermediate II-8b was prepared (135 mg, quantitative) following a procedure similar to that used for the synthesis of intermediate II-8a using intermediate II-7b (150 mg, 0.6 mmol) as the starting material.

[0467] Synthesis of intermediate II-8c

[0468] [ka]

[0469] Intermediate II-8c was prepared (219 mg, quantitative) following a procedure similar to that used for the synthesis of intermediate II-8a using intermediate II-7c (248 mg, 1.04 mmol) as the starting material.

[0470] Synthesis of intermediate II-8d

[0471] [ka]

[0472] Intermediate II-8d was prepared (115 mg, 99%) following a procedure similar to that used for the synthesis of intermediate II-8a using intermediate II-7d (110 mg, 0.44 mmol) as the starting material.

[0473] Synthesis of intermediate II-8e

[0474] [ka]

[0475] A 15% aqueous solution of KCO (1.2 mL, 1.30 mmol) was added to a solution of intermediate II-1d (143 mg, 0.56 mmol) in EtOH (1.5 mL) in a screw-cap vial at room temperature. The mixture was stirred at 90 °C for 16 h and then brought to pH 3-4 by the addition of 2 M aqueous HCl. The solvent was evaporated in vacuo to give intermediate II-8e (108 mg, 85%) as a brownish solid.

[0476] Synthesis of intermediate II-8f

[0477] [ka]

[0478] Intermediate II-8f was prepared (112 mg, quantitative) following a procedure similar to that used for the synthesis of intermediate II-8a using intermediate II-7f (95 mg, 0.36 mmol) as the starting material.

[0479] Synthesis of Intermediate II-9

[0480] [ka]

[0481] Trichloroisocyanuric acid [87-90-1] (1.54 g, 7.72 mmol) was added to a solution of 2-amino-4-chloropyrimidine [3993-78-0] (2 g, 15.44 mmol) and acetic acid (2 mL, 34.94 mmol) in water (18 mL) at room temperature. The mixture was then stirred at 50° C. for 15 hours, then cooled to room temperature and poured into a flask containing ice. The mixture was basified by the addition of 10 M aqueous NaOH solution and stirred for 4 hours. The formed solid was collected by filtration and washed with water (14 mL). The solid was suspended in 24 mL of 0.5 M aqueous NaOH solution and stirred for 1 hour. The solid was collected by filtration and washed with 24 mL of water. The solid was dissolved in EtOAc and concentrated in vacuo. Diethyl ether was then added and the mixture was again concentrated in vacuo to give intermediate II-9 (1.7 g, 60%) as a beige solid.

[0482] Synthesis of Intermediate II-10

[0483] [ka]

[0484] Ethyl propionyl acetate [4949-44-4] (2.43 mL, 16.59 mmol) and (diacetoxyiodo)benzene [3240-34-4] (5.01 g, 15.54 mmol) were added to a solution of intermediate II-9 (1.7 g, 10.37 mmol) in dry 2-methyltetrahydrofuran (49.4 mL) at 0 °C under N2. Then, boron trifluoride diethyl etherate [109-63-7] (0.13 mL, 1.03 mmol) was added dropwise. The mixture was stirred at 5 °C for 5 minutes and then at room temperature for 2 hours. Additional ethyl propionylacetate [4949-44-4] (1.21 mL, 8.29 mmol), (diacetoxyiodo)benzene [3240-34-4] (2.50 g, 7.78 mmol), and boron trifluoride diethyl etherate [109-63-7] (0.06 mL, 0.48 mmol) were added at 0 °C, and the mixture was stirred at 5 °C for 5 min and then at room temperature for 2 h. The mixture was poured into 10% NaHCO3 solution and extracted with EtOAc. The organic phase was dried (MgSO4), filtered, and the solvent was evaporated in vacuo. The crude crystals were purified by flash column chromatography (silica, 0 / 100 to 15 / 85 EtOAc in heptane). The desired fractions were collected and concentrated in vacuo. The residue was repurified by reverse-phase HPLC (Phenomenex Gemini, C18 100 × 30 mm 5 μm column, 59% (25 mM NH4HCO3) / 41% (ACN:MeOH 1:1) to 17% (25 mM NH4HCO3) / 83% (ACN:MeOH 1:1)). The desired fractions were collected and concentrated in vacuo to remove the organic solvent, and the resulting aqueous layer was extracted with DCM. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated in vacuo to give intermediate II-10 (510 mg, 16%) as a white solid.

[0485] Synthesis of Intermediate II-11

[0486] [ka]

[0487] 2,4-Dimethoxybenzylamine [20781-20-8] (0.36 mL, 2.4 mmol) was added to a solution of intermediate II-10 (485 mg, 1.6 mmol) in dry 1,4-dioxane at room temperature. The suspension was stirred at room temperature for 2 hours. Next, additional 2,4-dimethoxybenzylamine [20781-20-8] (0.18 mL, 1.2 mmol) was added, and the mixture was stirred at 50 °C for 16 hours. The solvent was removed in vacuo, then water was added, and the mixture was extracted with DCM. The organic phase was separated, dried (MgSO4), filtered, and the solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica, 0 / 100 to 25 / 75 EtOAc in heptane). The desired fractions were collected and concentrated in vacuo to give intermediate II-11 (544 mg, 80%) as a white solid.

[0488] Synthesis of intermediate II-12a

[0489] [ka]

[0490] Methylboronic acid [13061-96-6] (37 mg, 0.62 mmol) and KPO (176 mg, 0.83 mmol) were added to a solution of intermediate II-11 in a mixture of water (0.33 mL) and toluene (1.66 mL). The mixture was purged with N for 10 min, and then palladium(II) acetate [3375-31-3] (9 mg, 0.042 mmol) and SPhos [657408-07-6] (26 mg, 0.062 mmol) were added at room temperature. The reaction mixture was stirred at 110 °C for 2 h. The solvent was removed in vacuo, and the crude product was purified by flash column chromatography (silica, 0 / 100 to 50 / 50 EtOAc in heptane). The desired fractions were collected and concentrated in vacuo to give intermediate II-12a as a colorless oil.

[0491] Synthesis of intermediate II-12b

[0492] [ka]

[0493] The experiment was set up with 6 batches of 50 mg each of intermediate II-1a.

[0494] A mixture of intermediate II-1a (250 mg, 0.85 mmol), potassium (((tert-butoxycarbonyl)amino)methyl)trifluoroborate [1314538-55-0] (240 mg, 1 mmol), [4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine]nickel(II) dichloride [1034901-50-2] (35 mg, 0.085 mmol), Ir[dF(CF)ppy](dtbbpy)PF [870987-63-6] (25 mg, 0.02 mmol), and CsO (430 mg, 1.3 mmol) in dioxane (4 mL) was degassed in a screw-cap vial by bubbling N for 5 min. The vial was then sealed, and the reaction mixture was irradiated with blue LED light at room temperature for 48 hours. The reaction mixture was diluted with EtOAc and washed with water. The organic layer was separated, dried (MgSO), filtered, and the solvent was evaporated in vacuo. The crude crystals were purified by flash column chromatography (silica, 00 / 100 to 100 / 0 EtOAc in heptane). The desired fractions were collected, and the solvent was removed in vacuo to give intermediate II-12b (160 mg, 23%, 50% purity) as a yellow solid.

[0495] Synthesis of Intermediate II-13

[0496] [ka]

[0497] Di-tert-butyl dicarbonate [24424-99-5] (0.12 mL, 0.51 mmol) was added to a stirred solution of intermediate II-12a (136 mg, 0.34 mmol), triethylamine [121-44-8] (0.14 mL, 102 mmol), and 4-(dimethylamino)pyridine [1122-58-3] (2 mg, 0.017 mmol) in 1,4-dioxane (1.16 mL) at room temperature. The mixture was stirred at room temperature for 16 hours, and then additional triethylamine [121-44-8] (47 μL, 0.34 mmol) and di-tert-butyl dicarbonate [24424-99-5] (78 μL, 0.34 mmol) were added, and the mixture was stirred at 50° C. for 20 hours. Additional triethylamine [121-44-8] (71 μL, 0.51 mmol) and di-tert-butyl dicarbonate [24424-99-5] (117 μL, 0.51 mmol) were added, and the mixture was stirred at 80° C. for 2 h. Next, additional triethylamine [121-44-8] (94 μL, 0.68 mmol), 4-(dimethylamino)pyridine [1122-58-3] (2 mg, 0.017 mmol), and di-tert-butyl dicarbonate [24424-99-5] (117 μL, 0.51 mmol) were added, and the reaction mixture was stirred at 100° C. for an additional 16 h. The reaction mixture was diluted with water and brine and extracted with DCM (3×). The combined organic layers were dried (MgSO), filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (silica, 0 / 100 to 30 / 70 EtOAc in heptane). The desired fractions were collected and concentrated in vacuo to give intermediate I-14 (170 mg, 86%, 86% purity) as a beige solid.

[0498] Synthesis of Intermediate II-15

[0499] [ka]

[0500] Lithium hydroxide monohydrate [1310-66-3] (43 mg, 1.02 mmol) was added to a solution of intermediate II-14 (170 mg, 0.34 mmol) in a mixture of ethanol (5.12 mL) and water (1.71 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The mixture was then brought to pH 7 by the addition of 1 M aqueous HCl. The solvent was evaporated in vacuo to give intermediate II-15 as an orange-yellow solid, which was used in the next step without further purification (198 mg, quantitative).

[0501] Synthesis of Intermediate II-16

[0502] [ka]

[0503] Platinum(IV) oxide [1314-15-4] (73 mg, 0.32 mmol) was added to a stirred solution of intermediate II-1d (0.78 g, 3.56 mmol) in methanol (8 mL) under N. Concentrated aqueous HCl (2 μL) was then added, and the resulting suspension was stirred at room temperature under an H atmosphere for 16 h. The reaction was filtered through a pad of Celite®, and the filtrate was evaporated in vacuo to give intermediate II-16 (785 mg, 94%) as a colorless oil.

[0504] Synthesis of intermediate II-17a

[0505] [ka]

[0506] Lithium hydroxide monohydrate [1310-66-3] (85 mg, 2.02 mmol) was added to a stirred solution of intermediate II-16 (300 mg, 1.35 mmol) in a mixture of ethanol (5 mL) and water (2 mL) at room temperature. The mixture was stirred at 50° C. for 16 hours, and then the solvent was evaporated in vacuo to give intermediate II-17a (262 mg, quantitative) as a brown solid.

[0507] Synthesis of intermediate II-17b

[0508] [ka]

[0509] Lithium hydroxide monohydrate [1310-66-3] (29 mg, 0.69 mmol) was added to a stirred solution of intermediate II-5b (111 mg, 0.46 mmol) in a mixture of THF (4 mL) and water (1.5 mL) at room temperature. The mixture was stirred at room temperature for 16 hours and then neutralized by the addition of 1 M aqueous HCl. The solvent was evaporated in vacuo to give intermediate II-17b (120 mg, quantitative) as a white solid.

[0510] Synthesis of intermediate II-17c

[0511] [ka]

[0512] Lithium hydroxide monohydrate [1310-66-3] (135 mg, 3.23 mmol) was added to a stirred solution of intermediate II-Id (250 mg, 1.08 mmol) in a mixture of ethanol (4.4 mL) and water (2.2 mL) at room temperature. The mixture was stirred at 50 °C for 16 hours and then neutralized by the addition of 1 M aqueous HCl. The solvent was evaporated in vacuo to give intermediate II-17c (448 mg, quantitative) as an orange-yellow solid.

[0513] Synthesis of intermediate II-17d

[0514] [ka]

[0515] Sodium hydroxide (61 mg, 0.3 mmol) was added to a solution of intermediate II-12b (172 mg, 0.49 mmol) at room temperature. The mixture was stirred at room temperature for 16 hours. The reaction mixture was adjusted to pH 7 by the addition of 1 M aqueous HCl, and the solvent was evaporated in vacuo to give intermediate II-17d as a yellow solid, which was used in the next step without further purification (187 mg, 80%, 80% purity).

[0516] Synthesis of intermediate I Synthesis of intermediate I-82

[0517] [ka]

[0518] Intermediate I-82 was prepared following a procedure similar to that used to synthesize intermediate I-23 using 2-methylpyridine [109-06-8] (2.1 mL, 2.13 mmol) and ethyl 4-cyanobenzoate [7153-22-2] (4.1 g, 23.4 mmol) as starting materials. (1.8 g, 36%) was obtained as a light yellow solid.

[0519] Synthesis of intermediate I-83

[0520] [ka]

[0521] Intermediate I-83 was prepared following a procedure similar to that used for the synthesis of intermediate I-24, using intermediate I-23 (1.8 g, 8.1 mmol) and intermediate I-1 (5.8 g, 20.2 mmol) as starting materials. (179 mg, 9.6%) was obtained as a yellow solid.

[0522] Synthesis of intermediate I-84

[0523] [ka]

[0524] Intermediate I-84 was prepared following a procedure similar to that used for the synthesis of intermediate I-25 using intermediate I-83 (176 mg, 0.8 mmol) as the starting material. (219 mg, 83.5%) was obtained as a white solid.

[0525] Synthesis of intermediate I-85

[0526] [ka]

[0527] Intermediate I-85 was prepared following a procedure similar to that used for the synthesis of intermediate I-26 using intermediate I-84 (206 mg, 0.6 mmol) as the starting material. (100 mg, 47.5%) was obtained as a pale yellow solid.

[0528] Synthesis of intermediate I-86

[0529] [ka]

[0530] Intermediate I-86 was prepared following a procedure similar to that used for the synthesis of intermediate I-27 using intermediate I-85 (97 mg, 0.3 mmol) as the starting material. (89 mg, 99.1%) was obtained as a white solid.

[0531] Synthesis of intermediates I-87(S) and I-88(R)

[0532] [ka]

[0533] Intermediate I-6 (3 g, 8.125 mmol) was purified by chiral SFC on a Jasco SFC prep system using Phenomenex Lux Cellulose-1 250 mm long x 30 mm ID. The system was in isocratic mode with a 5 μm particle size, 100 ml / min of CO (65%)-methanol (40%) + 0.1% DEA, 30°C, and 150 bar BPR. The DAD detector capture frequency was set to 220 nm. The desired fractions were collected, evaporated, and dried under vacuum to give intermediate I-87(S) (1.3 g, 42.7%) and intermediate I-88(R) (1.1 g, 34.7%) as white solids.

[0534] Synthesis of intermediate I-89

[0535] [ka]

[0536] (Diethylamino)sulfur trifluoride [38078-09-0] (58 uL, 0.439 mmol) was added dropwise to a solution of I-63 (72 mg, 0.210 mmol) in anhydrous DCM (3 mL) at −78° C. The reaction mixture was allowed to warm slowly to room temperature for 2 h. A solution of saturated aqueous NaHCO was added, and the mixture was extracted with DCM (3×). The combined organic layers were dried over MgSO, filtered, and concentrated in vacuo to afford intermediate I-89 (72 mg, 95%) as a yellow solid.

[0537] Synthesis of intermediate I-90

[0538] [ka]

[0539] 4 M HCl in dioxane (369 μL, 1.476 mmol) was added to a stirred solution of I-89 (85 mg, 0.245 mmol) in DCM (3 mL) in a round-bottom flask at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The reaction was concentrated in vacuo to give intermediate I-90 (78 mg, 99%) as a white solid.

[0540] Synthesis of intermediate I-91

[0541] [ka]

[0542] To a solution of 2-methoxyacetyl chloride [38870-89-2] (2.1 mL, 22.969 mmol) in DCM (25 mL) cooled to 0 °C, N,O-dimethylhydroxylamine hydrochloride [6638-79-5] (1.5 g, 24.557 mmol) and triethylamine [121-44-8] (9.6 mL, 68.876 mmol) were added, and the reaction mixture was warmed to room temperature and stirred for 16 hours. The reaction mixture was poured into saturated aqueous NaHCO3. The reaction mixture was cooled to room temperature and extracted with DCM. The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated in vacuo to give intermediate I-91 (1.6 g, 52%) as a yellow oil.

[0543] Synthesis of intermediate I-92

[0544] [ka]

[0545] A 2 M solution of isopropylmagnesium chloride [1068-55-9] (4.9 mL, 9.8 mmol) in THF was added to an ice-cold solution of 4-iodobenzonitrile [3058-39-7] (1.9 g, 8.296 mmol) in anhydrous THF (17 mL). The solution was stirred at this temperature for 10 minutes and then cooled to −78° C. An ice-cold solution of intermediate I-91 (1.6 g, 12.017 mmol) in anhydrous THF (8 mL) was added dropwise, and the reaction was stirred at −78° C. for 1 hour. It was then stirred at room temperature for 1 hour. The reaction mixture was treated with ammonium chloride solution and extracted with DCM. The organic phase was dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica, 25 g, 100 / 0 to 60 / 40 EtOAc in heptane / EtOAc). The desired fractions were collected to give intermediate I-92 (920 mg, 63%) as a white solid.

[0546] Synthesis of intermediate I-93

[0547] [ka]

[0548] A sealed tube was charged with intermediate I-92 (965 mg, 5.509 mmol), 2-amino-4-(trifluoromethyl)pyridine [106447-97-6] (2.7 g, 16.655 mmol), iodine [7553-56-2] (2.8 g, 11.032 mmol), and 1,2-dichloroethane (110 mL). The reaction mixture was stirred at 100 °C for 30 min. The mixture was diluted with saturated aqueous sodium bisulfite solution and then extracted with DCM. The combined organic layers were dried over anhydrous MgSO4. This was purified by flash chromatography (silica, 80 g, ethyl acetate in heptane, 0 / 100 to 50 / 50). The desired fractions were collected, and the solvent was evaporated in vacuo to give intermediate I-93 (1.4 g, 61%) as an orange-yellow solid.

[0549] Synthesis of intermediate I-94

[0550] [ka]

[0551] NaBH4 [16940-66-2] (358 mg, 9.463 mmol) was added portionwise to a suspension of intermediate I-93 (1.3 g, 3.155 mmol), nickel(II) chloride hexahydrate [7791-20-0] (750 mg, 3.155 mmol), and di-tert-butyl dicarbonate [24424-99-5] (2.2 mL, 9.463 mmol) in MeOH (13 mL) and 1,4-dioxane (6 mL) in a round-bottom flask at 0 °C under nitrogen. The reaction mixture was stirred at room temperature for 1 h. HO and 25% aqueous ammonia were added, and the mixture was extracted with DCM. The combined organic layers were separated and dried over MgSO4. This was purified by flash chromatography (silica 80 g, ethyl acetate in DCM from 0 / 100 to 10 / 90). The desired fractions were collected to give intermediate I-94 as a pale yellow solid (834 mg, 61%).

[0552] Synthesis of intermediate I-95

[0553] [ka]

[0554] In a round-bottom flask under a nitrogen atmosphere, Pd / C[7440-05-3] (300 mg, 0.282 mmol) was added to a solution of intermediate I-94 (340 mg, 0.807 mmol) in methanol (12 mL) and ethyl acetate (3.2 mL) at 0 °C. The mixture was stirred under H2[1333-74-0] at 50 °C for 16 h. The mixture was filtered through a pad of Celite®, and the solvent was concentrated in vacuo. The crude product was purified by flash column chromatography (silica, 25 g, 0 / 100 to 50 / 50 EtOAc in heptane) and the desired fractions were collected to give intermediate I-95 (53 mg, 15%) as a white solid.

[0555] Synthesis of intermediate I-96

[0556] [ka]

[0557] 4 M HCl [7647-01-0] in 1,4-dioxane (330 μL, 1.312 mmol) was added to a solution of intermediate I-95 (53 mg, 0.125 mmol) and VILL_scobos_124_1 (40 mg, 0.094 mmol) in dichloromethane (2 mL) in a round-bottom flask at room temperature. The mixture was stirred at room temperature for 18 hours. The mixture was removed in vacuo to give intermediate I-96 (88 mg, 99%) as a yellow solid.

[0558] Synthesis of intermediate I-97

[0559] [ka]

[0560] In a screw-cap vial, Pd(dppf)Cl·CHCl [95464-05-4] (600 mg, 0.7355 mmol) was added to a solution of intermediate I-12 (2 g, 6.68 mmol), bis(pinacolato)diboron [73183-34-3] (3.3 g, 13.13 mmol), and potassium acetate [127-08-2] (2.67 g, 27.2 mmol) in dry 1,4-dioxane (20 mL) while bubbling with nitrogen gas for 10 minutes. The mixture was then stirred at 80 °C for 16 hours. The mixture was filtered through a pad of Celite® and rinsed with EtOAc. The solvent was concentrated in vacuo to give intermediate I-97 (2.43 g, 79%) as a brown solid.

[0561] Synthesis of intermediate I-98

[0562] [ka]

[0563] A solution of intermediate I-97 (2.43 g, 1.44 mmol) and 1-iodo-222-trifluoroethane [353-83-3] (1.38 mL, 14 mmol) in 1,4-dioxane (52 mL) was added to a suspension of Pd2(dba)3 [51364-51-3] (64 mg, 0.07 mmol), Xantphos [161265-03-8] (162 mg, 0.28 mmol), and cesium carbonate [534-17-8] (4.5 g, 14.0 mmol) at room temperature under nitrogen. The mixture was stirred at room temperature for 1 minute, and then water (2.5 mL) was added. The mixture was stirred at 80 °C for 12 hours. The mixture was cooled to room temperature. The mixture was diluted with water and extracted with AcOEt. The organic layer was separated, washed with brine, dried (MgSO), filtered, and evaporated in vacuo. The crude product was purified by flash column chromatography (silica, 0 / 100 to 30 / 70 AcOEt in heptane). The desired fractions were collected and concentrated in vacuo to give intermediate I-98 (700 mg, 23%) as a brown solid.

[0564] Synthesis of intermediate I-99

[0565] [ka]

[0566] Sodium borohydride [16940-66-2] (264 mg, 6.9 mmol) was added portionwise to a suspension of intermediate I-98 (700 mg, 2.3 mmol), nickel(II) chloride hexahydrate [7791-20-0] (552 mg, 2.3 mmol), and di-tert-butyl dicarbonate [24424-99-5] (1.6 mL, 6.9 mmol) in methanol (33 mL) and 1,4-dioxane (15 mL) in a round-bottom flask at 0 °C. The reaction mixture was stirred at room temperature for 16 h. Water and aqueous NH3 were added, and the mixture was extracted with DCM (3 times). The crude product was purified by flash column chromatography (dry-loaded on 80 g silica, 0 / 100 to 30 / 60 EtOAc in heptane). The desired fractions were collected and concentrated in vacuo to afford intermediate I-99 as a brown solid (404 mg, 37%).

[0567] Synthesis of intermediate I-100a

[0568] [ka]

[0569] Pd(OH)2 [12135-22-7] (41 mg, 0.058 mmol) was added to a solution of the resulting intermediate I-99 (25 mg, 0.058 mmol) in MeOH (3 mL) and EtOAc (1 mL) in a round-bottom flask at 0 °C under a nitrogen atmosphere. The mixture was stirred at room temperature under H2 [1333-74-0] for 16 h. The mixture was filtered through a pad of Celite®, and the solvent was concentrated in vacuo. The crude product was purified by flash column chromatography (silica 25 g, 0 / 100 to 80 / 20 EtOAc in heptane). The desired fractions were collected and concentrated in vacuo to give intermediate I-100a (155 mg, 43%) as a white solid.

[0570] Synthesis of intermediate I-100b

[0571] [ka]

[0572] 4M HCl in 1,4-dioxane [7647-01-0] (0.56 mL, 2.26 mmol, 4M) was added to a solution of intermediate I-100a (155 mg, 0.38 mmol) in DCM (3 mL) in a round-bottom flask at room temperature. The mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo to give intermediate 100b (152 mg, 95%) as a white solid.

[0573] Synthesis of intermediate I-101

[0574] [ka]

[0575] In a round-bottom flask, 9.300 mL (78.851 mmol) of ethoxycarbonyl isothiocyanate was added to a solution of methyl 2-aminopyridine-4-carboxylate (10 g, 65.724 mmol) in 1,4-dioxane (70 mL) at room temperature. The mixture was stirred at room temperature for 16 hours. The solvent was removed in vacuo, and the crude crystals were triturated with diethyl ether. The solid was filtered and dried in vacuo to give intermediate I-101 (19.356 g, 99%) as a yellow solid.

[0576] Synthesis of intermediate I-102

[0577] [ka]

[0578] In a round-bottom flask, a mixture of intermediate I-101 (19.356 g, 68.322 mmol), hydroxylamine hydrochloride (27.461 g, 395.176 mmol), DIPEA (42.1 mL, 241.707 mmol), and methanol (180 mL) was stirred at 66 °C for 16 hours. The solvent was removed in vacuo, and the residue was washed with water. The solid was collected by filtration and washed with diethyl ether. The product was then dried under vacuum to give intermediate I-102 (7.857 g, 57%) as a gray solid.

[0579] Synthesis of intermediate I-103

[0580] [ka]

[0581] In a round-bottom flask, di-tert-butyl dicarbonate [24424-99-5] (23.5 mL, 102.292 mmol) was added to a solution of intermediate I-102 (7.857 g, 40.885 mmol), 4-(dimethylamino)pyridine (504 mg, 4.125 mmol), and triethylamine (11.4 mL, 81.791 mmol) in acetonitrile (100 mL) at room temperature. The mixture was stirred at 70 °C for 8 h. The reaction mixture was diluted with HO and brine and extracted with DCM (3 times). The combined organic layers were dried over anhydrous MgSO, filtered, and concentrated in vacuo to give a dark oil. The crude product was purified by flash column chromatography (silica, 80 g, AcOEt in heptane from 0 / 100 to 35 / 65). The desired fractions were collected and concentrated in vacuo to afford intermediate I-103 as a brown solid (11.520 g, 71%).

[0582] Synthesis of intermediate I-104

[0583] [ka]

[0584] Pd / C [7440-05-3] (6.5 g, 6.1 mmol) was added to a solution of intermediate I-103 (4 g, 10.1 mmol) in methanol (60 mL) and ethyl acetate (20 mL) in a round-bottom flask at 0 °C under a nitrogen atmosphere. The mixture was stirred at 50 °C under an H atmosphere [1333-74-0] for 16 hours. Pd / C [7440-05-3] (3.2 g, 3.0 mmol) was added to the reaction at 0 °C under a nitrogen atmosphere. The mixture was stirred at 50 °C under an H atmosphere [1333-74-0] for 16 hours. The reaction was filtered through a pad of Celite®. The solvent was concentrated in vacuo to give a colorless oil. The crude product was purified by flash column chromatography (silica 120 g, 0 / 100 to 60 / 40 EtOAc in heptane). The desired fractions were collected and concentrated in vacuo to give intermediate I-104 (2.6 g, 61%) as a white solid.

[0585] Synthesis of intermediate I-105

[0586] [ka]

[0587] HBr[10035-10-6] (4.3 mL, 38 mmol) was added to a solution of the obtained intermediate I-104 (5.0 g, 12.6 mmol) in dichloromethane (38 mL) in a round-bottom flask at room temperature. The mixture was stirred at room temperature for 16 hours. HBr[10035-10-6] (4.3 mL, 38 mmol) was added to the reaction, and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo to give intermediate I-105 (3.642 g, 99%) as a white solid.

[0588] Synthesis of intermediate I-106

[0589] [ka]

[0590] In a round-bottom flask, hydrobromic acid [10035-10-6] (9.100 mL, 50.1 mmol) was added to a stirred suspension of intermediate I-105 (3.6 g, 12.3 mmol) and acetic acid [64-19-7] (11 mL, 192.1 mmol) at 0 °C. Next, sodium nitrite [7632-00-0] (1.0 g, 14.5 mmol) was dissolved in water (19 mL) and added dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. Next, copper(I) bromide [7787-70-4] (448 mg, 3.1 mmol) was added at 0 °C, and the mixture was heated at 90 °C for 16 h. The reaction was cooled, and methanol (50 mL) was added at room temperature. The mixture was stirred at 65 °C for 16 h. The reaction mixture was cooled, quenched with a solution of saturated aqueous NaHCO3, and extracted with DCM (3 times). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give intermediate I-106 (2.33 g, 69%) as a yellowish oil.

[0591] Synthesis of intermediate I-107

[0592] [ka]

[0593] In a round-bottom flask, LiHDMS [4039-32-1] (7.7 mL, 7.7 mmol) was added to a solution of intermediate I-106 (1 g, 3.845 mmol) in anhydrous THF (50 mL) at −78 °C under a N atmosphere. The mixture was stirred at −78 °C for 15 min, then at 0 °C for 15 min. After that, iodomethane (0.6 mL, 9.638 mmol) was added at −78 °C, and the mixture was stirred at room temperature. The mixture was diluted with DCM, and the excess reactant was consumed by the addition of a saturated aqueous solution of NH Cl. The organic layer was washed with brine and concentrated in vacuo to give intermediate I-107 (1.16 mg, 99.1%) as a yellow solid.

[0594] Synthesis of intermediate I-108

[0595] [ka]

[0596] LiBH4[16949-15-8] (131 mg, 5.713 mmol) was added to a solution of intermediate I-107 (1.16 g, 3.809 mmol) in dry THF (60 mL) under a nitrogen atmosphere, and the reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with DCM, and the excess reactant was consumed by the addition of a saturated aqueous solution of NH4Cl. The crude product was purified by flash column chromatography (silica 20 g, 0 / 100 to 100 / 0 EtOAc in DCM). The desired fractions were collected and concentrated in vacuo to give intermediate I-108 (345 mg, 36.4% yield) as a white solid.

[0597] Synthesis of intermediate I-109

[0598] [ka]

[0599] Sodium hydride [7646-69-7] (59 mg, 1.475 mmol) was added to a solution of intermediate I-108 (200 mg, 0.813 mmol) in DMF (10 mL) at 0 °C under a nitrogen atmosphere. The mixture was stirred at the same temperature for 30 minutes, followed by the addition of iodomethane [74-88-4] (76 uL, 1.221 mmol). The reaction mixture was stirred at room temperature for 16 hours. Sodium hydride [7646-69-7] (33 mg, 0.825 mmol) and iodomethane [74-88-4] (25 uL, 0.402 mmol) were added to the mixture at 0 °C. The mixture was stirred at room temperature for 16 hours. The mixture was diluted with DCM, and the excess reactant was consumed by the addition of a saturated aqueous solution of NH4Cl. The organic layer was washed with brine and concentrated in vacuo to give intermediate I-109 (212 mg, yield: 99.3%) as a yellow solid.

[0600] Synthesis of intermediate I-110

[0601] [ka]

[0602] In a glass pressure tube, tert-butyl N-{[4-(tetramethyl-132-dioxaborolan-2-yl)phenyl]methyl}carbamate [330794-35-9] (301 mg, 0.903 mmol), CsCO [534-17-8] (584 mg, 1.792 mmol), and Pd(dppf)Cl [95464-05-4] (100 mg, 0.122 mmol) were added to a solution of intermediate I-109 (212 mg, 0.815 mmol) in dioxane (6.4 mL) and water (2.6 mL) while bubbling with N. The reaction mixture was stirred at 90 °C for 16 h. Water was added, and then the mixture was extracted with EtOAc (3 times). The combined organic layers were washed with brine, dried over anhydrous MgSO, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (25 g silica in DCM, DCM:MeOH (9:1), 0 / 100 to 50 / 50). The desired fractions were collected and concentrated in vacuo to give intermediate I-110 (277 mg, 87.1% yield) as a brown wax.

[0603] Synthesis of intermediate I-111

[0604] [ka]

[0605] A 4 M solution of HCl in 1,4-dioxane [7647-01-0] (1.1 mL, 4.4 mmol) was added to a stirred solution of intermediate I-110 (277 mg, 0.710 mmol) in DCM (5 mL) in a round-bottom flask at room temperature. The reaction mixture was stirred at room temperature for 5 minutes. A 4 M solution of HCl in 1,4-dioxane [7647-01-0] (1.1 mL, 4.4 mmol) was added to the reaction. The mixture was stirred at room temperature for 6 hours. The crude product was concentrated in vacuo to give intermediate I-111 (255 mg, yield: 99.0%) as a brown solid.

[0606] Synthesis of intermediate I-112

[0607] [ka]

[0608] In a glass pressure tube, 4-cyanophenylboronic acid [126747-14-6] (525 mg, 3.57 mmol), CsCO [534-17-8] (2.30 g, 7.06 mmol), and Pd(dppf)Cl [95464-05-4] (395 mg, 0.48 mmol) were added to a solution of intermediate I-108 (790 mg, 3.42 mmol) in 1,4-dioxane (20 mL) and water (8 mL) while bubbling with N. The reaction mixture was stirred at 90 °C for 16 h. Water was added, and then the mixture was extracted with EtOAc (3 times). The combined organic layers were washed with brine, dried over anhydrous MgSO, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (25 g silica, 0 / 100 to 80 / 20 EtOAc in DCM). The desired fractions were collected and concentrated in vacuo to give intermediate I-112 (490 mg, 55%) as a pale brown solid.

[0609] Synthesis of intermediate I-113

[0610] [ka]

[0611] Methanesulfonyl chloride [124-63-0] (0.18 mL, 2.33 mmol) was added dropwise to a stirred solution of intermediate I-112 (485 mg, 1.81 mmol), triethylamine [121-44-8] (0.37 mL, 0.280 mmol), and DMAP [1122-58-3] (12 mg, 0.10 mmol) in DCM (25 mL). The mixture was stirred at room temperature for 16 hours. The mixture was diluted with water and extracted with DCM (3 times). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to give intermediate I-113 (562 mg, 89%) as a pale brown solid.

[0612] Synthesis of intermediate I-114

[0613] [ka]

[0614] Zinc powder [7440-66-6] (526 mg, 8.04 mmol) and sodium iodide [7681-82-5] (483 mg, 3.22 mmol) were added to a solution of intermediate I-113 (560 mg, 1.62 mmol) in DMF (15 mL). The reaction mixture was stirred at 110° C. for 18 hours. Zinc powder [7440-66-6] (5 equivalents, 526 mg, 8.04 mmol) and sodium iodide [7681-82-5] (2 equivalents, 483 mg, 3.22 mmol) were added to the reaction mixture and stirred at 110° C. for 6 hours. Zinc powder [7440-66-6] (5 equivalents, 526 mg, 8.04 mmol) and sodium iodide [7681-82-5] (2 equivalents, 483 mg, 3.22 mmol) were added to the reaction mixture and stirred at 110 °C for 21 hours. The reaction mixture was filtered, and the filtrate was diluted with water and extracted with EtOAc (3 times). The combined organic layers were concentrated in vacuo to give intermediate I-114 (375 mg, 83%) as a yellow solid.

[0615] Synthesis of intermediate I-115

[0616] [ka]

[0617] In a round-bottom flask, sodium borohydride [16940-66-2] (167 mg, 4.41 mmol) was added portionwise to a suspension of intermediate I-114 (375 mg, 1.49 mmol), nickel(II) chloride hexahydrate [7791-20-0] (267 mg, 1.12 mmol), and di-tert-butyl dicarbonate [24424-99-5] (0.51 mL, 2.22 mmol) in dry methanol (20 mL) and dioxane (10 mL) at 0 °C. The reaction mixture was stirred at room temperature for 18 h. Water and aqueous NH were added, and the mixture was stirred for 10 min. The mixture was filtered through a pad of Celite, washed with MeOH, and concentrated under reduced pressure with MeOH. The mixture was extracted with DCM (3 times). The combined organic layers were dried over anhydrous MgSO, and the solvent was concentrated in vacuo. The crude product was purified by flash column chromatography (silica, 25 g, 0 / 100 to 50 / 50 EtOAc in DCM). The desired fractions were collected and the solvent was evaporated in vacuo to give intermediate I-115 (291 mg, 53%) as a white solid.

[0618] Synthesis of intermediate I-116

[0619] [ka]

[0620] To a stirred solution of intermediate I-115 (194 mg, 0.54 mmol) in DCM (2 mL) was added 1.1 mL (4.4 mmol) of a 4 M solution of 1,4-dioxane [7647-01-0] at room temperature, and the resulting mixture was stirred at room temperature for 16 hours. The solvent was removed under high vacuum to give intermediate I-116 (179 mg, 99%) as a white solid.

[0621] Synthesis of intermediate I-117

[0622] [ka]

[0623] In a screw-cap vial, CsCO[534-17-8] (3.8 mg, 11.66 mmol) was added to a solution of intermediate I-12 (876 mg, 2.92 mmol) and potassium methoxymethyltrifluoroborate [910251-11-5] (946 mg, 5.9 mmol) in 1,4-dioxane (7.5 mL) and water (1 mL) at room temperature while bubbling with N. The mixture was then sparged with N for 10 min. RuPhos Pd G[1445085-77-7] (245 mg, 0.29 mmol) and RuPhos[787618-22-8] (140 mg, 0.3 mmol) were added at room temperature, and the mixture was sparged with N for 10 min. The mixture was then stirred at 100 °C for 16 h. The reaction was filtered through a pad of Celite® and the solvent was evaporated in vacuo. The crude crystals were purified by flash column chromatography (80 g silica, 0 / 100 to 50 / 50 AcOEt in heptane). The desired fractions were collected and concentrated in vacuo. The product was repurified by flash column chromatography (2 x 25 g silica, 0 / 100 to 10 / 90 AcOEt in DCM). The desired fractions were collected and concentrated in vacuo to give intermediate I-117 (324 mg, 41%) as a white solid.

[0624] Synthesis of intermediate I-118

[0625] [ka]

[0626] Sodium borohydride [16940-66-2] (140 mg, 3.7 mmol) was added portionwise to a suspension of intermediate I-117 (324 g, 1.22 mmol), nickel(II) chloride hexahydrate [7791-20-0] (350 mg, 1.47 mmol), and di-tert-butyl dicarbonate [24424-99-5] (0.85 mL, 2.87 mmol) in methanol (20 mL) and dioxane (10 mL) in a round-bottom flask at 0 °C. The reaction mixture was stirred at room temperature for 16 h. Water and 3 mL of aqueous NH3 were added, and the mixture was extracted with DCM (3 times). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (silica 25 g, AcOEt in heptane from 0 / 100 to 70 / 30). The desired fractions were collected and concentrated in vacuo to give intermediate I-118 (336 mg, yield: 73.6%) as a brown solid.

[0627] Synthesis of intermediate I-119

[0628] [ka]

[0629] To a solution of intermediate I-118 (311 mg, 0.844 mmol) in methanol (11.8 mL) and ethyl acetate (6.2 mL) in a round-bottom flask was added Pd(OH)2[12135-22-7] (1.0 equiv., 119 mg, 0.847 mmol) at 0 °C under a nitrogen atmosphere. The mixture was stirred at room temperature under a H2 atmosphere for 18 h. The mixture was filtered through a pad of Celite, and the solvent was concentrated in vacuo. The crude product was purified by flash column chromatography (silica 25 g, 0 / 100 to 50 / 50 EtOAc in DCM). The desired fractions were collected and concentrated in vacuo to give intermediate I-119 (289 mg, 91%) as a white solid.

[0630] Synthesis of intermediate I-120

[0631] [ka]

[0632] HCl [7647-01-0] (1.16 mL, 4.639 mmol) in dioxane was added to a solution of intermediate I-119 (288 mg, 0.773 mmol) in dichloromethane (6 mL) in a round-bottom flask at room temperature. The mixture was stirred at room temperature for 4 hours. The mixture was concentrated in vacuo to give intermediate I-120 (251 mg, yield: 93%) as a white solid.

[0633] The intermediates contained in the following table were synthesized following methods similar to those described above.

[0634] [Table 1-1]

[0635] [Table 1-2]

[0636] [Table 1-3]

[0637] [Table 1-4]

[0638] Synthesis of intermediates I-151a and I-151b

[0639] [ka]

[0640] Intermediates I-151a and I-151b were prepared using intermediate I-10 (2.2 g, 7.4 mmol) as the starting material following a procedure similar to that used to synthesize intermediates I-6a and I-6b. Intermediate I-151a (508 mg, 998% purity, 22.9%) and intermediate I-151b (415 mg, 92% purity, 17.4%) were obtained as white solids.

[0641] Synthesis of intermediates I-152a and I-152b

[0642] [ka]

[0643] Intermediate I-14 (394 g, 1150.55 mmol) was purified by chiral SFC using Phenomenex Lux Cellulose-SZ 50 mm long x 30 mm ID. 3 μm particle size, CO₂ / methanol 10 / 90 to 50 / 50 + 20 mM NH₃, gradient mode 100 mL / min, 35 °C, BPR 2200 psi. The DAD detector capture frequency was set to 220 nm. This afforded intermediate I-152a (144 g, 36.55%, separated twice by SFC) as a white solid and intermediate I-152b (161 g, 40.86%) as a white solid.

[0644] Synthesis of intermediate I-153

[0645] [ka]

[0646] To a 5 L four-neck round-bottom flask, intermediate I-152a (144 g) and DCM (3.2 L) were added at room temperature. To the above mixture, HCl (gas) in 1,4-dioxane (705 mL, 4.0 M) was added dropwise at room temperature. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The precipitated solid was collected by filtration and washed with DCM (2 x 1 L). This afforded I-153 (142.4 g, 96.08%) as a pale yellow solid.

[0647] Synthesis of intermediate I-154

[0648] [ka]

[0649] Intermediate I-154 was prepared following a procedure similar to that used for the synthesis of intermediate I-153 using intermediate 152b (161 g, 470.151 mmol) as the starting material. (142.4 g, 96.08%) was obtained as a light yellow solid.

[0650] Synthesis of intermediate I-155

[0651] [ka]

[0652] Intermediate I-155 was prepared following a procedure similar to that used for the synthesis of intermediate I-76 using intermediate I-12 (4.5 g, 15 mmol) as the starting material. (4.2 g, 95%) was obtained as a light brown solid.

[0653] Synthesis of intermediate I-156

[0654] [ka]

[0655] 6M aqueous HCl (82 mL, 492 mmol) was added to a solution of I-155 (4.193 g, 14.443 mmol) in dioxane (15 mL) in a round-bottom flask at room temperature. The mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water, basified to pH 11 with a 6N aqueous NaOH solution, and extracted with DCM (3 times). The combined organic layers were separated, dried (MgSO), filtered, and the solvent was evaporated in vacuo to give intermediate I-156 (3.665 g, 92%) as a brown solid.

[0656] Synthesis of intermediate I-157

[0657] [ka]

[0658] In a round-bottom flask, DAST [38078-09-0] (1.755 mL, 13.280 mmol) was added dropwise to a solution of intermediate I-156 (1.161 g, 4.427 mmol) in dry dichloroethane (33 mL) at 0 °C under a nitrogen atmosphere. The reaction mixture was stirred at 45 °C for 120 h. The mixture was diluted with saturated aqueous NaHCO3 at 0 °C and extracted with DCM. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The crude product was purified by flash column chromatography (80 g silica, dry loaded, 0 / 100 to 0 / 100 EtOAc in heptane). The desired fractions were collected and concentrated to give intermediate I-157 (337 mg, 26%) as a brown solid.

[0659] Synthesis of intermediate I-158

[0660] [ka]

[0661] Intermediate I-158 was prepared following a procedure similar to that used for the synthesis of intermediate I-4 using intermediate I-157 (922 mg, 3.2 mmol) as the starting material. (870 mg, 67.7%) was obtained as a white solid.

[0662] Synthesis of intermediate I-159

[0663] [ka]

[0664] Intermediate I-159 was prepared following a procedure similar to that used for the synthesis of intermediate I-5 using intermediate I-158 (805 mg, 2 mmol) as the starting material. (651 mg, 83.4%) was obtained as a white solid.

[0665] Synthesis of intermediate I-160

[0666] [ka]

[0667] Intermediate I-160 was prepared following a procedure similar to that used for the synthesis of intermediate I-6 using intermediate I-159 (651 mg, 1.7 mmol) as the starting material. (614 mg, quantitative) was obtained as a white solid.

[0668] Synthesis of Intermediate II Intermediate II-18

[0669] [ka]

[0670] Intermediate II-18 was prepared following a procedure similar to that used to synthesize Intermediate II-1a, starting from 2-amino-5-(trifluoromethyl)pyridine [74784-70-6] (3 g, 18.5 mmol). II-18 was obtained as an orange-yellow solid (1.7 g, 28%, 88% purity).

[0671] Intermediate II-19-LiCl salt

[0672] [ka]

[0673] Lithium hydroxide monohydrate [1310-66-3] (77 mg, 1.8 mmol) was added to a stirred solution of intermediate II-18 (190 mg, 0.6 mmol) in 10 mL of a mixture of ethanol and water (1:1) at room temperature. The reaction mixture was stirred at room temperature or 50 °C for 16 h and then neutralized with a solution of HCl (1 M, aq.). The solvent was evaporated in vacuo to give intermediate II-19 (189 mg, quantitative).

[0674] Intermediate II-20

[0675] [ka]

[0676] Intermediate II-20 was prepared following a procedure similar to that used to synthesize Intermediate II-1a, using 2-amino-4-chloropyrimidine [3993-78-0] (2 g, 15.4 mmol) as the starting material. Intermediate II-20 was obtained as a yellow solid (1.8 g, 44.7%).

[0677] Intermediate II-21

[0678] [ka]

[0679] Intermediate II-21 was prepared using Intermediate II-20 (300 mg, 1.2 mmol) as the starting material following a procedure similar to that used for the synthesis of Intermediate 12b. Intermediate I-21 was obtained as a yellow solid (90 mg, 85% purity, 18.6%).

[0680] Intermediate II-22-NaCl salt

[0681] [ka]

[0682] Intermediate II-22 was prepared using II-21 (120 mg, 0.3 mmol) as the starting material following a procedure similar to that used for the synthesis of intermediate II-8a. Intermediate I-22 was obtained as a yellow solid (120 mg, 90% purity, 97.4%).

[0683] Intermediate II-23

[0684] [ka]

[0685] Intermediate II-23 was prepared following a procedure similar to that used to synthesize Intermediate II-1a, using 2-aminopyrimidine [109-12-6] (5 g, 52.6 mmol) as the starting material. Intermediate II-23 was obtained as an orange-yellow solid (8.7 g, 74.5%).

[0686] Intermediate II-24

[0687] [ka]

[0688] Intermediate II-24 was prepared following a procedure similar to that used to synthesize Intermediate II-1a, using 5-(trifluoromethyl)pyrimidin-2-amine [69034-08-8] (1.2 g, 7.4 mmol) as the starting material. Intermediate II-24 was obtained as a yellow solid (825 mg, 90% purity, 35.1%).

[0689] Intermediate II-25

[0690] [ka]

[0691] In a round-bottom flask, concentrated hydrochloric acid [7647-01-0] (5 mL) was added to intermediate II-24 (250 mg, 0.870 mmol), and the reaction mixture was stirred at 85° C. for 30 hours. Additional concentrated hydrochloric acid [7647-01-0] (2 mL) was added to the reaction mixture, which was stirred at 90° C. for 46 hours. The solvent was concentrated in vacuo to give intermediate II-25 (226 mg, yield: 70%) as a brown solid.

[0692] Synthesis of Intermediate II-26

[0693] [ka]

[0694] Intermediate II-26 was prepared following a procedure similar to that used to synthesize intermediate II-7d, starting from 2-amino-4-picoline [695-34-1] (3 g, 27.7 mmol). II-26 was obtained as an orange-yellow solid (4.7 g, 71.9%).

[0695] Synthesis of Intermediate II-27

[0696] [ka]

[0697] Intermediate II-27 was prepared following a procedure similar to that used to synthesize Intermediate II-7d, starting from 5-(benzyloxy)pyridin-2-amine [96166-00-6] (1 g, 5 mmol). Intermediate II-27 was obtained as an orange-yellow solid (1.1 g, 62.1%).

[0698] Synthesis of Intermediate II-28

[0699] [ka]

[0700] Intermediate II-28 was prepared following a procedure similar to that used to synthesize Intermediate II-7d, starting from 4-(benzyloxy)pyridin-2-amine [85333-26-2] (0.8 g, 4.2 mmol). Intermediate II-28 was obtained as a yellow solid (1.1 g, 84.3%).

[0701] Synthesis of Intermediate II-29

[0702] [ka]

[0703] Intermediate II-29 was prepared (6.7 g, 67%) following a procedure similar to that used to synthesize intermediate II-7d using 2-amino-4-methoxypyridine [10201-73-7] (5 g, 40.3 mmol) as the starting material.

[0704] Synthesis of Intermediate II-30

[0705] [ka]

[0706] Intermediate II-30 was prepared following a procedure similar to that used to synthesize Intermediate II-7d, starting from 4-(trifluoromethyl)-2-pyridinylamine [106447-97-6] (5 g, 30.8 mmol). II-30 was obtained as a yellow solid (3.61 g, 56.8%).

[0707] Synthesis of Intermediate II-31

[0708] [ka]

[0709] Intermediate II-31 was prepared following a procedure similar to that used to synthesize intermediate II-7d1, starting from 2-amino-5-methoxypyridine [10167-97-2] (2 g, 16.1 mmol). II-31 was obtained as an orange-yellow solid (2.3 g, 56.4%).

[0710] Synthesis of Intermediate II-32

[0711] [ka]

[0712] Intermediate II-32 was synthesized to intermediate II-40 (R * ) (142 mg, 0.6 mmol) as starting material to afford intermediate II-32 (126 mg, quantitative) as a white oil.

[0713] Synthesis of Intermediate II-33

[0714] [ka]

[0715] Intermediate II-33 was synthesized into intermediate II-39 (S *) (142 mg, 0.6 mmol) as starting material to give intermediate II-33 (126 mg, quantitative) as a white oil.

[0716] Synthesis of intermediate II-34-LiCl salt.

[0717] [ka]

[0718] Intermediate II-34 was synthesized to intermediate II-44 (R * ) (124 mg, 0.5 mmol) as starting material to give intermediate II-34 (131 mg, 98.8%) as a pale yellow solid.

[0719] Synthesis of intermediate II-35-LiCl salt.

[0720] [ka]

[0721] Intermediate II-35 was converted to intermediate II-45 (S * ) (121 mg, 0.5 mmol) as starting material to give intermediate II-35 (127 mg, 99%) as a pale yellow solid.

[0722] Synthesis of intermediate II-36-LiCl salt.

[0723] [ka]

[0724] Intermediate II-36 was prepared following a procedure similar to that used for the synthesis of intermediate II-17a, starting from intermediate II-48 (160 mg, 0.6 mmol). II-36 was obtained as a white solid (215 mg, 96.5%).

[0725] Synthesis of intermediate II-37-LiCl salt.

[0726] [ka]

[0727] Intermediate II-37 was prepared following a procedure similar to that used for the synthesis of intermediate II-17a, starting from intermediate II-98 (130 mg, 0.5 mmol), to give I-37 (144 mg, 99.4%) as a white solid.

[0728] Synthesis of Intermediate II-38

[0729] [ka]

[0730] Intermediate II-38 (939 mg, 91%, pale yellow solid) was prepared starting from intermediate II-7g (1 g, 4.3 mmol) following a procedure similar to that used for the synthesis of intermediate II-16.

[0731] Intermediate II-39(S * ) and II-40(R * ) synthesis

[0732] [ka]

[0733] A batch of intermediate II-38 (939 mg, 4 mmol) was purified by chiral SFC on a Jasco SFC prep system using Phenomenex Lux Cellulose-1 250 mm long x 30 mm ID. The system was in isocratic mode at 100 ml / min CO2 (65%)-isopropanol (35%) + 0.1% DEA, 30 °C, and 150 bar BPR. The DAD detector capture frequency was set to 252 nm. The desired fractions were collected, evaporated, and dried under vacuum to give intermediate II-39 (S * ) (243 mg, 25.6%) and Intermediate II-40 (R * ) (270 mg, 28.5%) was obtained as a pale yellow oil.

[0734] Intermediate II-41(R * ) and II-42(S * ) synthesis

[0735] [ka]

[0736] Intermediate II-41(R * ) and II-42(S * ) to intermediate II-39 (S * ) and II-40(R * ) using intermediate II-50 (512 mg, 2 mmol) as the starting material. * ) (164 mg, 31.7%) and intermediate II-42 (S * ) (164 mg, 31.7%) was obtained as a white solid.

[0737] Intermediate II-43, II-44(R * ), and II-45(S * ) synthesis

[0738] [ka]

[0739] Platinum(IV) oxide [1314-15-4] (177 mg, 0.8 mmol) was added to a stirred solution of intermediate II-7e (1 g, 4.3 mmol) in methanol (9.5 mL) under N. Concentrated aqueous HCl (2.5 μL) was then added, and the resulting suspension was stirred at 50° C. under an H atmosphere for 16 h. The reaction was filtered through a pad of Celite®, and the filtrate was evaporated in vacuo to give intermediate II-43 (1 g, 96%) as a light beige solid.

[0740] Intermediate II-43 was purified by chiral SFC on a Jasco SFC prep system using Phenomenex Lux Cellulose-1 250 mm long x 30 mm ID. 5 μm particle size, 100 ml / min CO (65%)-isopropanol (10%) + 0.1% DEA, isocratic mode at 30° C., BPR 150 bar. The capture frequency of the DAD detector was set to 220 nm. The desired fractions were collected, evaporated, and dried under vacuum to give intermediate II-44 (R * ) (372 mg, 35.8%) and Intermediate II-45 (S * ) (364 mg, 35.1%) as a pale yellow solid.

[0741] Intermediate II-46(R * ) and II-47(S * ) synthesis

[0742] [ka]

[0743] Intermediate II-46(R * ) (161 mg, 31.4%) and II-47 (S * ) (103 mg, 20.1%) was prepared following a procedure similar to that used for the synthesis of intermediate II-16 using intermediate II-31 (500 mg, 2 mmol) as the starting material.

[0744] Synthesis of Intermediate II-48

[0745] [ka]

[0746] Intermediate II-48 (845 mg, 63.3%, colorless oil) was prepared using intermediate II-5a (1.3 g, 5.4 mmol) as the starting material following a procedure similar to that used for the synthesis of intermediate II-16.

[0747] Synthesis of Intermediate II-49

[0748] [ka]

[0749] Intermediate II-49 (670 mg, 43.5%, colorless oil) was prepared following a procedure similar to that used for the synthesis of intermediate II-16 using intermediate II-5b (1.5 g, 5.8 mmol) as the starting material.

[0750] Synthesis of Intermediate II-50

[0751] [ka]

[0752] Intermediate II-50 (512 mg, 75%, colorless oil) was prepared following a procedure similar to that used for the synthesis of intermediate II-16 using intermediate II-29 (665 mg, 2.7 mmol) as the starting material.

[0753] Synthesis of Intermediate II-51

[0754] [ka]

[0755] Intermediate II-51 (698 mg, 73.4%, white solid) was prepared following a procedure similar to that used for the synthesis of intermediate II-16 using intermediate II-30 (938 mg, 3.3 mmol) as the starting material.

[0756] Synthesis of Intermediate II-52

[0757] [ka]

[0758] In a round-bottom flask, thionyl chloride (120 mL, 1.645 mol) was added dropwise to intermediate II-17a (8 g, 41.188 mmol) at room temperature. The reaction mixture was stirred at 60° C. for 2 hours. Toluene was added, and the mixture was concentrated in vacuo to give intermediate II-52 (8.8 g, 99.5%) as a yellow solid.

[0759] Synthesis of Intermediate II-53

[0760] [ka]

[0761] Intermediate II-53 was prepared using Intermediate II-37 (144 mg, 0.5 mmol) as the starting material following a procedure similar to that used to synthesize Intermediate II-52. Intermediate II-53 was obtained as a pale orange-yellow solid (154 mg, 99.8%).

[0762] Synthesis of Intermediate II-54

[0763] [ka]

[0764] Intermediate II-54 (242 mg, 70% purity, 100%, dark brown solid) was prepared using intermediate II-25 (226 mg, 0.6 mmol) as the starting material following a procedure similar to that used for the synthesis of intermediate II-52. Intermediate II-54 was obtained as a dark brown solid (242 mg, 70% purity, 100%).

[0765] Synthesis of Intermediate II-55

[0766] [ka]

[0767] Intermediate II-55 was prepared using Intermediate II-83 (10 g, 0.6 mmol) as the starting material following a procedure similar to that used to synthesize Intermediate II-52. Intermediate II-55 was obtained as a dark brown solid (115 g, 95% purity, 100%).

[0768] Synthesis of Intermediate II-56

[0769] [ka]

[0770] Intermediate II-56 (470 mg, 89.5%, pale orange solid) was prepared using intermediate II-3a (472 mg, 2.3 mmol) as the starting material following a procedure similar to that used to synthesize intermediate II-52. Intermediate II-56 was obtained as a pale orange solid (470 mg, 89.5%).

[0771] Synthesis of Intermediate II-57

[0772] [ka]

[0773] In a vial, a dry EtOH / THF (1:1) mixture (30 mL) was added to intermediate II-7h (1.068 g, 3.292 mmol) and Pd / C 10% (700.8 mg, 0.7 mmol). The vial was placed in a steel vessel, purged with hydrogen gas three times, and pressurized with 10 bar of hydrogen. The mixture was stirred at 30 °C for 19 h and then stirred under 20 bar of hydrogen at 30 °C for 4 h. The reaction mixture was filtered, and the solvent was evaporated. The crude material was purified by flash chromatography (silica, MeOH in DCM 0 / 100 to 10 / 90). The desired fractions were collected, and the solvent was removed in vacuo to give intermediate II-57 (340 mg, 41.2%) as an off-white solid.

[0774] Synthesis of Intermediate II-58

[0775] [ka]

[0776] Intermediate II-58 was prepared using Intermediate II-28 (1 g, 3.2 mmol) as the starting material following a procedure similar to that used to synthesize Intermediate II-57. Intermediate II-58 was obtained as a pale yellow solid (540 mg, 69.4%).

[0777] Intermediate II-59(R * ) and II-60(S * ) synthesis

[0778] [ka]

[0779] Intermediate II-57 (200 mg, 0.8 mmol) was purified by SFC (Jasco SFC prep system, amylose-1 column, 250 *The fractions were separated by a 30 mm, 5 μm, 100 ml / min CO (20%) / MeOH (80%) / DEA (0.1%) in isocratic mode at 30 °C and 150 bar. The capture frequency of the DAD detector was set at 220 nm. Each fraction was diluted with a solution of saturated aqueous NaHCO and then extracted with DCM (twice). The combined organic layer was dried over anhydrous MgSO, filtered, and concentrated in vacuo to give intermediate II-59 (R * ) (72 mg, 35.6%) and Intermediate II-60 (S * ) (73 mg, 36.1%) was obtained.

[0780] Intermediate II-61(R * ) and II-62(S * )(VILL_mcalles_1382_1 and 2)

[0781] [ka]

[0782] Intermediate II-59(R * ) and II-60(S * ) using intermediate II-58 (200 mg, 0.8 mmol) as the starting material to obtain intermediate II-61 (R * ) (72 mg, 36.3%) and Intermediate II-62 (S * ) (59 mg, 29.8%) was prepared.

[0783] Intermediate II-63(R * ) and II-64(S * ) synthesis

[0784] [ka]

[0785] Intermediate II-63(R * ) (235 mg, 32.9%, white solid) and II-64 (S * ) (232 mg, 32.8%, white solid) was treated with Intermediate II-59 (R* ) and II-60(S * Prepared following a procedure similar to that used for the synthesis of ) using intermediate II-51 (700 mg, 2.4 mmol) as the starting material.

[0786] Intermediate II-65--Synthesis of NaCl Salt

[0787] [ka]

[0788] Intermediate II-65 (81.2 mg, quantitative, pale orange-yellow solid) was synthesized into intermediate II-59 (R * ) (72 mg, 0.3 mmol) as starting material.

[0789] Synthesis of Intermediate II-66-NaCl Salt

[0790] [ka]

[0791] Intermediate II-66 (82 mg, quantitative, pale yellow solid) was synthesized into intermediate II-60 (S * ) (73 mg, 0.3 mmol) as starting material.

[0792] Synthesis of Intermediate II-67-NaCl Salt

[0793] [ka]

[0794] Intermediate II-67 (78.9 mg, 99%, white solid) was prepared as intermediate II-61 (R *) (70 mg, 0.3 mmol) as starting material.

[0795] Synthesis of Intermediate II-68-NaCl Salt

[0796] [ka]

[0797] Intermediate II-68 (70 mg, quantitative, white solid) was synthesized into intermediate II-62 (S * ) (59 mg, 0.2 mmol) as starting material.

[0798] Synthesis of Intermediate II-69-NaCl Salt

[0799] [ka]

[0800] Intermediate II-69 (70 mg, 98.9%, yellow solid) was synthesized into intermediate II-41 (R * ) (60 mg, 0.2 mmol) as starting material.

[0801] Synthesis of Intermediate II-70-NaCl Salt

[0802] [ka]

[0803] Intermediate II-70 (89.6 mg, 99%, yellow solid) was synthesized into intermediate II-42 (R * ) (80 mg, 0.3 mmol) as starting material.

[0804] Synthesis of Intermediate II-71-NaCl Salt

[0805] [ka]

[0806] Intermediate II-71 (92 mg, 98.9%, white solid) was prepared as intermediate II-63 (R * ) (80 mg, 0.3 mmol) as starting material.

[0807] Synthesis of Intermediate II-72-NaCl Salt

[0808] [ka]

[0809] Intermediate II-72 (88.4 mg, 99%, white solid) was prepared as intermediate II-64 (R * ) (80 mg, 0.3 mmol) as starting material.

[0810] Synthesis of Intermediate II-73-NaCl Salt

[0811] [ka]

[0812] Intermediate II-73 (113 mg, 98.8%, beige solid) was synthesized into intermediate II-46 (R * ) (100 mg, 0.4 mmol) as starting material.

[0813] Synthesis of Intermediate II-74-NaCl Salt

[0814] [ka]

[0815] Intermediate II-74 (112 mg, 95%, yellow solid) was synthesized into intermediate II-47 (R * ) (100 mg, 0.4 mmol) as starting material.

[0816] Synthesis of Intermediate II-75

[0817] [ka]

[0818] 4-Methylpyridine [108-89-4] (0.50 mL, 5 mmol) was added to a solution of o-(2,4-dinitrophenyl)hydroxylamine [17508-17-7] (1.00 g, 5.02 mmol) in ACN (25 mL). The reaction mixture was stirred at 40 °C for 24 hours. The solvent was removed in vacuo, and the reaction mixture was dissolved in DMF (25 mL). Ethyl 2-pentynoate [55314-57-3] (1.00 mL, 7.36 mmol) and K2CO3 (2.09 g, 15.12 mmol) were added, and the reaction mixture was stirred at room temperature for 24 hours. The mixture was diluted with EtOAc (75 mL), washed with water and brine, dried (anhydrous MgSO4), filtered, and concentrated in vacuo. The crude material was purified by flash column chromatography (silica, 0 / 100 to 50 / 50 EtOAc in heptane). The desired fractions were collected and the solvent was removed in vacuo to give intermediate II-75 (655 mg, 55%) as a yellow solid.

[0819] Synthesis of Intermediate II-76

[0820] [ka]

[0821] Intermediate II-76 (652 mg, 46.9%, yellowish solid) was prepared following a procedure similar to that used for the synthesis of intermediate II-75, using 1-aminopyridin-1-ium iodide [6295-87-0] (1.4 g, 6.3 mmol) as the starting material.

[0822] Synthesis of Intermediate II-77

[0823] [ka]

[0824] Platinum(IV) oxide [1314-15-4] (66 mg, 0.29 mmol) was added to a stirred solution of intermediate II-75 (655 mg, 2.82 mmol) in EtOH (6 mL) under a nitrogen atmosphere. HCl (concentrated, aqueous) (5 μL) was then added, and the resulting suspension was stirred at 60° C. for 16 h under a nitrogen atmosphere. Platinum(IV) oxide (66 mg, 0.29 mmol) was added, and the reaction mixture was stirred at 60° C. for an additional 18 h under a nitrogen atmosphere. Since the reaction was not complete, platinum(IV) oxide (66 mg, 0.29 mmol) was added four times over 30 h, and the reaction mixture was stirred at 60° C. The reaction mixture was filtered through a pad of Celite®, and the solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica, 0 / 100 to 50 / 50 EtOAc in heptane) to afford intermediate II-77 as a pale yellow solid (432 mg, 64%).

[0825] Synthesis of Intermediate II-78

[0826] [ka]

[0827] Intermediate II-78 (653 mg, 97.7%, white solid) was prepared following a procedure similar to that used for the synthesis of intermediate II-77 using intermediate II-76 (650 mg, 3 mmol) as the starting material.

[0828] Intermediate II-79(R * ) and II-80(S * ) synthesis

[0829] [ka]

[0830] Intermediate II-59(R * ) and II-60(S * ) using intermediate II-77 (432 mg, 0.8 mmol) as the starting material to obtain intermediate II-79 (R * ) (161 mg, 36.9%) and II-80 (S * ) (165 mg, 37.8%) was prepared.

[0831] Synthesis of Intermediate II-81-NaCl Salt

[0832] [ka]

[0833] Intermediate II-81 (122 mg, 92%, pale yellow solid) was synthesized into intermediate II-79 (R * ) (140 mg, 0.6 mmol) as starting material.

[0834] Synthesis of Intermediate II-82-NaCl Salt

[0835] [ka]

[0836] Intermediate II-82 (197 mg, 99.4%, white solid) was synthesized into intermediate II-80 (R * ) (158 mg, 0.7 mmol) as starting material.

[0837] Synthesis of Intermediate II-83

[0838] [ka]

[0839] Intermediate II-83 (22 g, 99.9%, pale yellow solid) was prepared following a procedure similar to that used for the synthesis of intermediate II-8a using intermediate II-23 (25 g, 112.9 mmol) as the starting material.

[0840] Synthesis of Intermediate II-84-NaCl Salt

[0841] [ka]

[0842] Intermediate II-84 (133 mg, 99%, pale yellow solid) was prepared following a procedure similar to that used for the synthesis of intermediate II-8a using intermediate II-78 (80 mg, 112.9 mmol) as the starting material.

[0843] Synthesis of Intermediate II-85

[0844] [ka]

[0845] Intermediate II-85 (26.9 g, quantitative, yellow solid) was prepared following a procedure similar to that used for the synthesis of intermediate II-52 using intermediate II-83 (24 g, 125.5 mmol) as the starting material.

[0846] Intermediate II-86

[0847] [ka]

[0848] In a sealed tube, a mixture of 2-chloro-5-(trifluoromethoxy)pyrimidine [1261812-52-5] (300 mg, 1.436 mmol) and ammonium hydroxide [1336-21-6] (13 mL, 83.926 mmol) was stirred at 85° C. for 16 hours. The mixture was evaporated in vacuo to give intermediate II-86 (295 mg, 94%) as a brown solid.

[0849] Intermediate II-87

[0850] [ka]

[0851] Intermediate II-87 (69 mg, 72% purity, 12.1%) was prepared following a procedure similar to that used for the synthesis of intermediate II-1a using intermediate II-86 (295 mg, 1.4 mmol) as the starting material.

[0852] Intermediate II-88-NaCl salt

[0853] [ka]

[0854] Intermediate II-88 (53 mg, 97.8%) was prepared following a procedure similar to that used for the synthesis of intermediate II-8a using intermediate II-87 (53 mg, 0.2 mmol) as the starting material.

[0855] Intermediate II-89

[0856] [ka]

[0857] Pd / C [7440-05-3] (0.2 g, 0.188 mmol) was added to a solution of 2-amino-5-nitropyrimidine [3073-77-6] (1 g, 7.138 mmol) in methanol (16 mL) in a round-bottom flask at 0 °C under a nitrogen atmosphere. The mixture was stirred at room temperature for 16 h under a H atmosphere [1333-74-0]. Next, di-tert-butyl dicarbonate [24424-99-5] (2.04 mL, 6.786 mmol) was added at 0 °C, and the mixture was stirred at 0 °C for 6 h. The reaction was filtered through a pad of Celite. The solvent was concentrated in vacuo to give a colorless oil. The crude product was purified by flash column chromatography (silica 80 g, AcOEt in heptane from 0 / 100 to 60 / 40). The desired fractions were collected and concentrated in vacuo to afford intermediate II-89 (1.052 g, 69%) as a yellow solid.

[0858] Synthesis of Intermediate II-90

[0859] [ka]

[0860] Intermediate II-90 (127 mg, 20%) was prepared following a procedure similar to that used for the synthesis of intermediate II-89 (400 mg, 1.9 mmol) as starting material.

[0861] Synthesis of Intermediate II-91-NaCl Salt

[0862] [ka]

[0863] Intermediate II-91 (183 mg, 99.6%, yellow solid) was prepared following a procedure similar to that used for the synthesis of intermediate II-8a using intermediate II-90 (160 mg, 0.5 mmol) as the starting material.

[0864] Synthesis of Intermediate II-92

[0865] [ka]

[0866] Intermediate II-92 (464 mg, 25%, yellow solid) was prepared following a procedure similar to that used for the synthesis of Intermediate II-1a using 2-amino-5-bromopyrimidine [7152-82-1] (1 g, 5.7 mmol) and ethyl isobutyrylacetate [7752-15-0] (1.5 mL, 8.6 mmol) as starting materials.

[0867] Synthesis of Intermediate II-93

[0868] [ka]

[0869] Intermediate II-93 (331 mg, 95.9%, yellow solid) was prepared following a procedure similar to that used for the synthesis of intermediate II-1a using intermediate II-92 (454 mg, 1.4 mmol) as the starting material.

[0870] Synthesis of Intermediate II-94-KCl Salt

[0871] [ka]

[0872] Aqueous potassium carbonate solution (1.1 mL, 1.20 mmol) was added to a solution of intermediate II-93 (130 mg, 0.50 mmol) in ethanol (3.0 mL) at room temperature. The mixture was stirred at 90° C. for 16 hours. Aqueous potassium carbonate solution (1.4 mL, 1.52 mmol) was added to the mixture, which was stirred at 90° C. for 1 hour. The solution was acidified with 1 M HCl until pH=7, and the solvent was concentrated in vacuo to give intermediate II-94 (147 mg, 82%) as a yellowish solid.

[0873] Synthesis of Intermediate II-95

[0874] [ka]

[0875] Intermediate II-95 (1.8 g, 95%) was prepared following a procedure similar to that used to synthesize intermediate II-1a using 2-aminopyrimidine [109-12-6] (2.5 g, 25.5 mmol) and ethyl 4,4,4-trifluoroacetoacetate [372-31-6] (4.6 mL, 25.5 mmol) as starting materials.

[0876] Intermediate II - Synthesis of 96-Li Salt

[0877] [ka]

[0878] Intermediate II-96 (174 mg, 80% purity, 83.4%) was prepared following a procedure similar to that used for the synthesis of intermediate II-17a using intermediate II-95 (158 mg, 0.6 mmol) as the starting material.

[0879] Synthesis of Intermediate II-97

[0880] [ka]

[0881] In a round-bottom flask, Zn(Cd) in solution in EtO 23(850 mg, 8.37 mmol) was added to a mixture of Pd(dppf)Cl (560 mg, 0.69 mmol) and intermediate II-92 (2.0 g, 6.7 mmol) in anhydrous dioxane (50 ml) under a nitrogen atmosphere. The reaction mixture was stirred at 55 °C for 16 h. A solution of NaHCO (saturated aqueous solution) was added dropwise at 0 °C. The solid was filtered off and washed with a solution of DCM and MeOH (9:1). The organic layer was dried (anhydrous MgSO), filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (silica, 80 g, gradient: 0 / 100 to 50 / 50 EtOAc in heptane). The desired fractions were collected and concentrated in vacuo to give intermediate II-97 (1.2 g, 72%) as a brown solid.

[0882] Synthesis of Intermediate II - 98-NaCl Salt

[0883] [ka]

[0884] Intermediate II-98 (223 mg, 99.8%) was prepared following a procedure similar to that used for the synthesis of intermediate II-8a using intermediate II-97 (200 mg, 0.8 mmol) as the starting material.

[0885] Synthesis of Intermediate II-98

[0886] [ka]

[0887] Intermediate II-98 was prepared using intermediate II-99 (1.3 g, 5.41 mmol) as the starting material following a procedure similar to that used for the synthesis of intermediate II-16. I-98 was obtained as a colorless oil (845 mg, 63%).

[0888] Synthesis of Intermediate II-99

[0889] [ka]

[0890] Intermediate II-99 (0.23 g, 24%) was prepared following a procedure similar to that used for the synthesis of intermediate II-7d using 2-aminopyridine [504-29-0] (1.32 g, 14.02 mmol) as the starting material.

[0891] Synthesis of Intermediate II-100

[0892] [ka]

[0893] Intermediate II-100 was prepared following a procedure similar to that used to synthesize intermediate II-1a, using ethyl propionylacetate [4949-44-4] (500 mg, 4.5 mmol) and 2-amino-5-fluoropyridine [21717-96-4] (983 μL, 6.7 mmol) as starting materials. (573 mg, 53.8%) was obtained as a yellowish solid.

[0894] Synthesis of Intermediate II-101-KCl Salt

[0895] [ka]

[0896] Intermediate II-101 was prepared following a procedure similar to that used for the synthesis of intermediate II-3a using intermediate II-100 (180 mg, 0.8 mmol) as the starting material. (215 mg, 98.8%) was obtained as a yellow solid.

[0897] Synthesis of intermediate II-102-LiCl salt.

[0898] [ka]

[0899] Intermediate II-102 (149 mg, 99.9%, white solid) was prepared following a procedure similar to that used for the synthesis of intermediate II-8e using intermediate II-1d (133 mg, 0.6 mmol) as the starting material.

[0900] Synthesis of Intermediate II-103

[0901] [ka]

[0902] Intermediate II-103 was prepared using Intermediate II-1a (500 mg, 1.6 mmol) as the starting material following a procedure similar to that used to synthesize Intermediate II-2a. Intermediate II-103 was obtained as a yellow solid (135 mg, 34.3%).

[0903] Synthesis of Intermediate II-104-NaCl Salt

[0904] [ka]

[0905] Intermediate II-104 was prepared using Intermediate II-103 (110 mg, 0.4 mmol) as the starting material following a procedure similar to that used for the synthesis of Intermediate II-8a. Intermediate II-104 was obtained as a yellow solid (116 mg, 99%).

[0906] Intermediate II - Synthesis of 105-KCl salt

[0907] [ka]

[0908] Intermediate II-105 was prepared using intermediate II-1c (485 mg, 1.9 mmol) as the starting material following a procedure similar to that used to synthesize intermediate II-94. Intermediate II-105 was obtained as a yellow solid (1.2 g, 95.4%).

[0909] Intermediate II - Synthesis of 106-KCl salt

[0910] [ka]

[0911] Intermediate II-106 was prepared using Intermediate II-105 (1.2 g, 1.8 mmol) as the starting material following a procedure similar to that used to synthesize Intermediate II-25. Intermediate II-106 was obtained as a brown solid (1.3 g, 99.9%).

[0912] Intermediate II - Synthesis of 107-LiCl salt

[0913] [ka]

[0914] Intermediate II-107 was prepared using Intermediate II-37 (144 mg, 0.5 mmol) as the starting material following a procedure similar to that used to synthesize Intermediate II-25. Intermediate II-107 was obtained as a pale orange-yellow solid (154 mg, 99.8%).

[0915] Intermediate II - Synthesis of 108-KCl salt

[0916] [ka]

[0917] Intermediate II-108 was prepared using Intermediate II-96 (207 mg, 0.7 mmol) as the starting material following a procedure similar to that used to synthesize Intermediate II-25. Intermediate II-108 was obtained as a pale orange-yellow solid (230 mg, 99.5%).

[0918] Synthesis of Intermediate II-109

[0919] [ka]

[0920] In a round-bottom flask, iron(III) acetylacetonate [14024-18-1] (237 mg, 0.65 mmol) was added to a solution of intermediate II-10 (1.88 g, 6.52 mmol) in anhydrous THF (27 mL) and NMP (2.2 mL) at 0 °C under a nitrogen atmosphere. Methylmagnesium bromide (3 M solution in EtO, 4.35 mL, 13.05 mmol) was added. The reaction mixture was stirred at 0 °C for 3 h. A solution of NH Cl (saturated aqueous solution) was added, and the mixture was extracted with EtOAc. The organic layer was dried (anhydrous MgSO), filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (silica, 80 g, gradient: 0 / 100 to 65 / 35 EtOAc in heptane). The desired fractions were collected and concentrated in vacuo to afford intermediate II-109 (215 mg, 12%) as an orange-yellow sticky oil.

[0921] Intermediate II - Synthesis of 110-KCl salt

[0922] [ka]

[0923] Intermediate II-110 was prepared using Intermediate II-109 (290 mg, 1 mmol) as the starting material following a procedure similar to that used for the synthesis of Intermediate II-94. Intermediate II-110 (337 mg, 100%) was obtained as a yellowish solid.

[0924] Synthesis of the final compound Synthesis of compound 1ab

[0925] [ka]

[0926] HATU [148893-10-1] (3.84 g, 10.1 mmol) and DIPEA [7087-68-5] (8.21 mL, 41.13 mmol) were added to a solution of intermediate II-3a (2.76 g, 9.43 mmol) in DMF (160 mL) at room temperature, and the mixture was stirred for 10 minutes. Intermediate I-6 (2.49 g, 6.73 mmol) was then added, and the reaction mixture was stirred at room temperature for an additional hour. Saturated aqueous NaHCO3 was then added, and the mixture was extracted with DCM (3 times). The combined organic extracts were dried (MgSO4), filtered, and the solvent was evaporated in vacuo. The crude product was triturated with saturated aqueous NaHCO3 and filtered. The solid was washed with water (3 times), DCM (3 times), and finally diethyl ether to give the final compound 1ab (1.59 g, 48%) as a white solid. The mother liquor was concentrated in vacuo and purified by flash column chromatography (silica, DCM / MeOH (9:1), 0 / 100 to 30 / 70 in DCM). The desired fractions were collected and concentrated in vacuo to give two additional fractions of compound 1ab as a light brown solid (0.27 g, 8%) and a white solid (0.44 g, 13%).

[0927] 1H NMR(400MHz,DMSO)δ9.16(d,J=1.0Hz,1H),8.55-8.47(m,2H),7.95(d,J=8.2Hz,2H), 7.45(d,J=8.2Hz,2H),4.57(d,J=5.9Hz,2H),4.33(dd,J=12.8,3.7Hz,1H),4.17(td, J=12.1,4.8Hz,1H),3.27-3.12(m,2H),3.02(q,J=7.5Hz,2H),2.92(dd,J=17.4,11.9 Hz,1H),2.34(s,3H),2.30(d,J=2.3Hz,1H),2.20-2.02(m,1H),1.28(t,J=7.5Hz,3H).

[0928] Synthesis of Compounds 1a and 1b

[0929] [ka]

[0930] A batch of compound 1ab (0.32 mg, 0.66 mmol), prepared following a procedure similar to that outlined above, was purified by chiral SFC on a Jasco SFC prep system using Phenomenex Lux Cellulose-1 250 mm long x 30 mm ID. The elution was in isocratic mode at 30 ml / min CO2 (55%)-methanol (45%) + 0.1% diethylamine, 30 °C, and 150 bar BPR. The DAD detector acquisition frequency was set to 220 nm. The desired fractions were collected and evaporated to dryness under vacuum. The residue was triturated with diethyl ether to give compound 1a (90 mg) and 1b (68 mg) as white solids.

[0931] Compound 1a 1H NMR (400MHz, DMSO) δ9.16 (s, 1H), 8.51 (d, J = 2.4 Hz, 1H), 8.50 (d, J = 8.0 Hz, 1H), 7.95 (d, J = 8.2 Hz, 2H), 7.45 (d, J = 8.2 Hz, 2H), 4.57 (d, J = 5.8 Hz, 2H), 4.33 (dd, J = 12.6, 3.7 Hz, 1 H),4.17(td,J=12.1,4.8Hz,1H),3.23-3.15(m,2H),3.02(q,J=7.5Hz,2H),2.94-2.85 (m,1H),2.34(s,3H),2.31(s,1H),2.11(qd,J=11.4,5.7Hz,1H),1.28(t,J=7.5Hz,3H).

[0932] Compound 1b 1H NMR (400MHz, DMSO) δ9.16 (d, J = 1.1Hz, 1H), 8.52 (d, J = 2.4Hz, 1H), 8.50 (d, J = 6.1Hz, 1H), 7.95 (d, J = 8.2Hz, 2H), 7.45 (d, J = 8.2Hz, 2H), 4.57 (d, J = 5.9Hz, 2H), 4.33 (dd, J = 12.9, 3.8 Hz,1H),4.17(td,J=12.0,4.6Hz,1H),3.24-3.14(m,2H),3.02(q,J=7.5Hz,2H),2.93(dd, J=17.5,12.1Hz,1H),2.34(s,3H),2.31(s,1H),2.18-2.06(m,1H),1.28(t,J=7.5Hz,3H).

[0933] Synthesis of compound 2ab

[0934]

change

[0935] HATU [148893-10-1] (275 mg, 0.72 mmol) was added to a mixture of intermediate I-6 (120 mg, 0.36 mmol), intermediate II-6a (100 mg, 0.43 mmol), and DIPEA [7087-68-5] (0.37 mL, 2.17 mmol) in DMF (5 mL) at room temperature. The mixture was stirred at room temperature for 16 h. Then, 1 M aqueous Na2CO3 solution was added, and the mixture was extracted with EtOAc. The organic layer was dried (MgSO4), filtered, and the solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica, 0 / 100 to 100 / 0 EtOAc in heptane). The desired fractions were collected and concentrated in vacuo, and the residue was repurified by reverse-phase HPLC (Phenomenex Gemini C18 100 × 30 mm 5 μm column, 72% [0.1% HCOOH]-28% [ACN:MeOH (1:1)] to 36% [0.1% HCOOH]-64% [ACN:MeOH (1:1)]). The desired fractions were collected and concentrated in vacuo to give compound 2ab (122 mg, 65%) as a brown solid.

[0936] 1H NMR(400MHz,DMSO)δ9.33(t,J=5.8Hz,1H),8.57(d,J=7.0Hz,1H),7.97(d,J=8.2Hz,2H ),7.79(d,J=9.1Hz,1H),7.59-7.50(m,1H),7.45(d,J=8.2Hz,2H),7.20(t,J=6.5Hz,1H ),4.59(d,J=5.8Hz,2H),4.33(dd,J=12.9,3.5Hz,1H),4.18(td,J=11.9,4.7Hz,1H),3 .25-3.14(m,2H),2.93(dd,J=17.7,12.2Hz,1H),2.37-2.27(m,1H),2.18-2.09(m,1H).

[0937] Synthesis of Compounds 2a and 2b

[0938] [ka]

[0939] A batch of compound 2ab (350 mg, 0.69 mmol), prepared following a procedure similar to that outlined above, was purified by chiral SFC on a Jasco SFC prep system using Phenomenex Lux Amylose-1 250 mm long x 30 mm ID. The mixture was eluted in isocratic mode with a 5 μm particle size, 30 ml / min CO₂ (60%)-ethanol (40%) + 0.1% diethylamine, at 30 °C and 120 bar BPR. The DAD detector acquisition frequency was set to 220 nm. The desired fractions were collected and evaporated to dryness under high vacuum. The residue was triturated with diethyl ether to give compounds 2a (87 mg) and 2b (89 mg) as off-white solids.

[0940] Compound 2a 1H NMR(400MHz,DMSO)δ9.33(t,J=5.8Hz,1H),8.57(d,J=7.0Hz,1H),7.97(d,J=8.2Hz,2H),7.8 0(d,J=9.1Hz,1H),7.61-7.50(m,1H),7.45(d,J=8.2Hz,2H),7.20(dd,J=9.9,3.9Hz,1H),4. 59(d,J=5.4Hz,2H),4.33(dd,J=12.5,3.6Hz,1H),4.18(td,J=12.2,4.9Hz,1H),3.20(d,J=1 3.5Hz, 2H), 2.93 (dd, J=17.6, 12.1Hz, 1H), 2.37-2.27 (m, 1H), 2.12 (qd, J=11.6, 6.0Hz, 1H).

[0941] Compound 2b 1H NMR(400MHz,DMSO)δ9.34(d,J=5.4Hz,1H),8.57(d,J=7.0Hz,1H),7.97(d,J=8.2Hz,2H),7.7 9(d,J=9.2Hz,1H),7.55(dd,J=12.0,3.9Hz,1H),7.45(d,J=8.2Hz,2H),7.20(t,J=6.9Hz,1H) ,4.59(d,J=5.2Hz,2H),4.33(dd,J=12.7,3.4Hz,1H),4.24-4.10(m,1H),3.20(d,J=13.5Hz,2 H),2.93(dd,J=17.6,12.3Hz,1H),2.33(dd,J=6.4,4.4Hz,1H),2.12(qd,J=11.5,5.8Hz,1H).

[0942] Synthesis of compound 3ab

[0943] [ka]

[0944] HATU [148893-10-1] (286 mg, 0.52 mmol) was added to a mixture of intermediate I-10 (125 mg, 0.86 mmol), intermediate II-3a (93 mg, 0.45 mmol), and DIPEA [7087-68-5] (0.38 mL, 2.26 mmol) in DMF (5 mL) at room temperature. The mixture was stirred at room temperature for 16 h. Then, 1 M aqueous Na2CO3 solution was added, and the mixture was extracted with EtOAc. The organic layer was dried (MgSO4), filtered, and the solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica, 0 / 100 to 100 / 0 EtOAc in heptane). The desired fractions were collected and concentrated in vacuo, and the residue was repurified by reverse-phase HPLC (Phenomenex Gemini C18 100 × 30 mm 5 μm column, 70% [25 mM NH4HCO3]-30% [ACN:MeOH (1:1)] to 27% [25 mM NH4HCO3]-73% [ACN:MeOH (1:1)]). The desired fractions were collected and concentrated in vacuo to give compound 3ab as a white solid (12 mg, 7%).

[0945] 1H NMR (400MHz, DMSO) δ9.15(dd,J=2.3,1.1Hz,1H),8.51(d,J=2.4Hz,1H),8.47(t,J=5.9Hz,1H),7.69( d,J=8.2Hz,2H),7.53(s,1H),7.34(d,J=8.2Hz,2H),4.52(d,J=5.9Hz,2H),4.16(dd,J=12.5,3.6Hz,1 H),3.98(td,J=12.2,4.6Hz,1H),3.12-3.05(m,2H),3.01(q,J=7.5Hz,2H),2.78(dd,J=17.3,12.8Hz, 1H),2.34(s,3H),2.23(d,J=11.3Hz,1H),1.95(ddd,J=24.8,11.9,5.6Hz,1H),1.27(t,J=7.5Hz,3H).

[0946] Synthesis of compounds 3a and 3b

[0947]

change

[0948] A batch of compound 3ab (350 mg, 0.69 mmol), prepared following a procedure similar to that outlined above, was purified by chiral SFC on a Jasco SFC prep system using Phenomenex Lux Amylose-1 250 mm long x 30 mm ID. The elution was in isocratic mode at 30 ml / min CO2 (50%) - 2-propanol (50%) + 0.1% diethylamine, 30 °C, and 120 bar BPR. The DAD detector acquisition frequency was set to 220 nm. The desired fractions were collected and evaporated to dryness under high vacuum. Both SFC elution products were repurified by flash column chromatography (silica, 0 / 100 to 100 / 0 EtOAc in heptane). The desired fractions were collected and concentrated in vacuo. The first SFC elution peak product was triturated with a 1:1 mixture of DIPE / DCM and dried under high vacuum at 60°C, then triturated with DIPE and dried under high vacuum to give compound 3a as an off-white solid (40 mg). The second SFC elution peak product was triturated with a 1:1 mixture of DIPE / DCM and dried under high vacuum at 60°C to give compound 3b as an off-white solid (71 mg).

[0949] Compound 3a 1H NMR(400MHz,DMSO)δ9.15(d,J=1.1Hz,1H),8.51(d,J=2.4Hz,1H),8.47(t,J=5.9Hz,1H),7.69( d,J=8.2Hz,2H),7.54(s,1H),7.34(d,J=8.2Hz,2H),4.52(d,J=5.9Hz,2H),4.17(dd,J=12.6,3. 3Hz,1H),3.98(td,J=12.2,4.6Hz,1H),3.14-3.05(m,2H),3.01(q,J=7.5Hz,2H),2.79(dd,J=17 .3,12.6Hz,1H),2.34(s,3H),2.24(d,J=11.3Hz,1H),2.02-1.88(m,1H),1.27(t,J=7.5Hz,3H).

[0950] compound 3b 1 HNMR(400MHz,DMSO)δ9.19-9.11(m,1H),8.51(d,J=2.4Hz,1H),8.47(t,J=5.9Hz,1H),7.69(d ,J=8.2Hz,2H),7.55(s,1H),7.35(d,J=8.2Hz,2H),4.52(d,J=5.9Hz,2H),4.17(dd,J=12.6,3 .5Hz,1H),3.98(td,J=12.1,4.5Hz,1H),3.15-3.05(m,2H),3.01(q,J=7.5Hz,2H),2.79(dd,J =17.4,12.6Hz,1H),2.34(s,3H),2.28-2.19(m,1H),2.03-1.87(m,1H),1.27(t,J=7.5Hz,3H).

[0951] Synthesis of compound 4ab

[0952] [ka]

[0953] Intermediate I-16 (150 mg, 0.48 mmol) was added to a stirred mixture of intermediate II-3a (189 mg, 0.67 mmol), HATU [148893-10-1] (272 mg, 0.72 mmol), and DIPEA [7087-68-5] (0.58 mL, 3.33 mmol) in DMF (10 mL) at room temperature. The mixture was stirred at room temperature for 16 h. Saturated aqueous NaHCO3 was then added, and the mixture was extracted with DCM (3 times). The combined organic layers were dried (MgSO4), filtered, and the solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica, DCM in DCM, DCM / MeOH (9:1), 0 / 100 to 100 / 0). The desired fractions were collected and concentrated in vacuo, and the residue was triturated with DIPE to give compound 4ab (105 mg, 49%) as a white solid.

[0954] 1H NMR(400MHz,DMSO)δ9.16(dd,J=2.3,1.1Hz,1H),8.50(dd,J=7.1,4.1Hz,2H),7.94(d,J=8.3 Hz,2H),7.43(d,J=8.3Hz,2H),4.57(d,J=5.8Hz,2H),4.22(ddd,J=12.6,5.6,2.8Hz,1H),4.1 5-4.01(m,1H),3.08-2.93(m,3H),2.47-2.39(m,1H),2.37-2.31(m,3H),2.05(dt,J=18.1,13 .1Hz,2H),1.74(dtd,J=13.4,10.9,5.8Hz,1H),1.28(t,J=7.5Hz,3H),1.10(d,J=6.6Hz,3H).

[0955] Synthesis of compound 5ab

[0956] [ka]

[0957] Intermediate I-6 (130 mg, 0.33 mmol) was added to a stirred mixture of intermediate II-8a (167 mg, 0.60 mmol), HATU [148893-10-1] (191 mg, 0.50 mmol), and DIPEA [7087-68-5] (0.41 mL, 2.34 mmol) in DMF (5 mL) at room temperature. The mixture was stirred at room temperature for 16 h. Then, saturated aqueous NaHCO3 was added, and the mixture was extracted with EtOAc (twice). The combined organic layers were dried (MgSO4), filtered, and the solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica, DCM / MeOH (9:1), 0 / 100 to 30 / 70) in DCM. The desired fractions were collected and concentrated in vacuo to give compound 5ab (92 mg, 56%) as a white solid.

[0958] 1H NMR(400MHz,DMSO)δ9.20(d,J=7.0Hz,1H),8.46(t,J=5.5Hz,1H),7.95(d,J=7.9 Hz,2H),7.44(d,J=7.9Hz,2H),7.06(d,J=7.0Hz,1H),4.56(d,J=5.6Hz,2H),4.3 9-4.09(m,2H),3.19(d,J=13.1Hz,2H),3.01(q,J=7.4Hz,2H),2.97-2.88(m,1H) ,2.55(s,3H),2.32(d,J=11.3Hz,1H),2.18-2.05(m,1H),1.27(t,J=7.4Hz,3H).

[0959] Synthesis of Compounds 5a and 5b

[0960] [ka]

[0961] A batch of compound 5ab (1.34 g, 2.87 mmol), prepared following a procedure similar to that outlined above, was purified by chiral SFC on a Jasco SFC prep system using a 250 mm long x 30 mm i-cellulose-C column (Regis Technologies). The column was run in isocratic mode at 100 ml / min CO2 (65%)-methanol (45%) at 30 °C and 150 bar BPR. The DAD detector acquisition frequency was set to 220 nm. The desired fractions were collected and concentrated in vacuo to give compound 5a (430 mg, 79%) and compound 5b (420 mg, 77% yield) as white solids.

[0962] Compound 5a 1H NMR (400MHz, DMSO) δ9.20 (d, J = 7.0Hz, 1H), 8.45 (t, J = 6.0Hz, 1H), 7.95 (d, J = 8.2Hz, 2H), 7.44 (d, J = 8.3Hz, 2H), 7.05 (d, J = 7.1Hz, 1H), 4.56 (d, J = 5.9Hz, 2H), 4.33 (dd, J = 12.8, 3.8Hz, 1H),4.26-4.07(m,1H),3.24-3.13(m,2H),3.01(q,J=7.5Hz,2H),2.96-2.85(m,1H),2.55( s,3H),2.32(d,J=10.8Hz,1H),2.11(ddd,J=17.3,12.2,5.8Hz,1H),1.27(t,J=7.5Hz,3H).

[0963] Compound 5b 1H NMR (400MHz, DMSO) δ9.20 (d, J = 7.0Hz, 1H), 8.45 (t, J = 5.9Hz, 1H), 7.95 (d, J = 8.3Hz, 2H), 7.44 (d, J = 8.3Hz, 2H), 7.05 (d, J = 7.1Hz, 1H), 4.56 (d, J = 5.9Hz, 2H), 4.37-4.26 (m, 1H), 4.23-4.11(m,1H),3.19(d,J=13.3Hz,2H),3.01(q,J=7.5Hz,2H),2.92(dd,J=17.2,11. 8Hz,1H),2.55(s,3H),2.30(t,J=10.4Hz,1H),2.20-2.03(m,1H),1.27(t,J=7.5Hz,3H).

[0964] Synthesis of compound 6ab

[0965]

change

[0966] Intermediate I-6 (130 mg, 0.33 mmol) was added to a stirred mixture of intermediate II-8b (171 mg, 0.60 mmol), HATU [148893-10-1] (176 mg, 0.46 mmol), and DIPEA [7087-68-5] (0.38 mL, 2.16 mmol) in DMF (5 mL) at room temperature. The mixture was stirred at room temperature for 16 h. Then, saturated aqueous NaHCO3 was added, and the mixture was extracted with EtOAc (twice). The combined organic layers were dried (MgSO4), filtered, and the solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica, DCM / MeOH (9:1), 0 / 100 to 30 / 70) in DCM. The desired fractions were collected and concentrated in vacuo to give compound 6ab (113 mg, 67%) as a white solid.

[0967] 1H NMR(400MHz,DMSO)δ8.97(d,J=3.0Hz,1H),8.52(d,J=3.0Hz,1H),8.47(t,J=5.8Hz,1H) ,7.96(d,J=8.2Hz,2H),7.45(d,J=8.2Hz,2H),4.58(d,J=5.8Hz,2H),4.37-4.28(m,1H) ,4.23-4.11(m,1H),3.86(s,3H),3.21(s,1H),3.17(d,J=5.2Hz,1H),3.03(q,J=7.5Hz, 2H),2.98-2.87(m,1H),2.32(d,J=8.7Hz,1H),2.19-2.02(m,1H),1.28(t,J=7.5Hz,3H).

[0968] Synthesis of compound 7ab

[0969] [ka]

[0970] HATU [148893-10-1] (450 mg, 1.18 mmol) was added to a mixture of intermediate I-6 (196 mg, 0.59 mmol), intermediate II-8c (100 mg, 0.43 mmol), and DIPEA [7087-68-5] (0.6 mL, 3.53 mmol) in DMF (5 mL) at room temperature. The mixture was stirred at room temperature for 16 h. Then, 1 M aqueous NaHCO3 was added, and the mixture was extracted with DCM. The organic layer was dried (MgSO4), filtered, and the solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica, DCM / MeOH in DCM (9:1) 0 / 100 to 30 / 70). The desired fractions were collected and concentrated in vacuo to give compound 7ab (97 mg, 34%) as an off-white solid.

[0971] 1H NMR(400MHz,DMSO)δ9.03(dd,J=7.5,6.2Hz,1H),8.46(t,J=6.0Hz,1H),7.95(d,J=8.2Hz,2H),7.49 (dd,J=9.8,2.6Hz,1H),7.44(d,J=8.3Hz,2H),7.06(td,J=7.6,2.7Hz,1H),4.57(d,J=5.9Hz,2H),4 .32(dd,J=12.8,3.6Hz,1H),4.17(td,J=12.1,4.9Hz,1H),3.26-3.13(m,2H),2.99(dd,J=15.0,7.5 Hz,2H),2.95-2.87(m,1H),2.37-2.26(m,1H),2.11(qd,J=11.4,5.8Hz,1H),1.27(t,J=7.5Hz,3H).

[0972] Synthesis of compound 8ab

[0973] [ka]

[0974] HATU [148893-10-1] (306 mg, 0.81 mmol) was added to a mixture of intermediate I-6 (134 mg, 0.40 mmol), intermediate II-6b (105 mg, 0.48 mmol), and DIPEA [7087-68-5] (0.41 mL, 2.42 mmol) in DMF (5 mL) at room temperature. The mixture was stirred at room temperature for 16 h. The mixture was then washed with 1 M aqueous Na2CO3 and brine and extracted with EtOAc. The organic layer was dried (MgSO4), filtered, and the solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica, 0 / 100 to 100 / 0 EtOAc in heptane). The desired fractions were collected and concentrated in vacuo, and the residue was repurified by reverse-phase HPLC (Phenomenex Gemini C18 100 × 30 mm 5 μm column, 59% [0.1% HCOOH] to 41% [ACN:MeOH (1:1)] to 17% [0.1% HCOOH] to 83% [ACN:MeOH (1:1)]). The desired fractions were collected and concentrated in vacuo, and the residue was purified by flash column chromatography (silica, 0 / 100 to 100 / 0 EtOAc / heptane) to give compound 8ab (13 mg, 6%) as a white solid.

[0975] 1H NMR(400MHz,DMSO)δ9.18(s,1H),8.64(t,J=5.8Hz,1H),8.48(d,J=2.1Hz,1H),7.95(d,J= 8.1Hz,2H),7.46(d,J=8.1Hz,2H),4.59(d,J=5.8Hz,2H),4.32(dd,J=12.4,4.1Hz,1H),4.2 0-4.11(m,1H),3.19(d,J=13.3Hz,2H),2.92(dd,J=17.6,12.2Hz,1H),2.47-2.40(m,1H),2 .32(s,3H),2.31-2.28(m,1H),2.11(ddd,J=24.4,11.6,5.7Hz,1H),1.06(d,J=6.4Hz,4H).

[0976] Synthesis of compound 9ab

[0977] [ka]

[0978] HATU [148893-10-1] (114 mg, 0.30 mmol) was added to a mixture of intermediate I-6 (100 mg, 0.30 mmol), intermediate II-8d (114 mg, 0.52 mmol), and DIPEA [7087-68-5] (0.21 mL, 1.20 mmol) in DMF (1.5 mL) at room temperature. The mixture was stirred at room temperature for 19 h. Saturated aqueous NaHCO3 was then added, and the mixture was extracted with DCM. The organic layer was washed with brine, dried (MgSO4), filtered, and the solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica, MeOH in DCM from 0 / 100 to 2 / 98). The desired fractions were collected and concentrated in vacuo to give compound 9ab (15 mg, 6%) as a white solid.

[0979] 1H NMR(400MHz,DMSO)δ9.06(s,1H),8.42(t,J=6.0Hz,1H),7.95(d,J=8.2Hz,2H),7.4 4(d,J=8.2Hz,2H),4.56(d,J=5.9Hz,2H),4.32(dd,J=12.7,3.8Hz,1H),4.17(td,J= 12.1,4.9Hz,1H),3.23-3.15(m,2H),2.99(q,J=7.6Hz,2H),2.96-2.87(m,1H),2.5 1(s,3H),2.35-2.29(m,1H),2.27(s,3H),2.17-2.08(m,1H),1.26(t,J=7.5Hz,3H).

[0980] Synthesis of compound 10ab

[0981] [ka]

[0982] A mixture of intermediate II-8e (105 mg, 0.42 mmol), HATU [148893-10-1] (229 mg, 0.60 mmol), and DIPEA [7087-68-5] (0.31 mL, 1.80 mmol) in DMF (7.8 mL) was stirred at room temperature for 10 minutes, and then intermediate I-6 (100 mg, 0.30 mmol) was added. The mixture was stirred at room temperature for 16 hours. Then, saturated aqueous NaHCO3 was added, and the mixture was extracted with EtOAc (3 times). The combined organic layers were dried (MgSO4), filtered, and the solvent was evaporated in vacuo. The crude product was triturated with DIPE, dissolved in DCM, and extracted with saturated aqueous NaHCO3. The organic layer was dried (MgSO4), filtered, and evaporated in vacuo to give compound 10ab (15 mg, 10%) as a white solid.

[0983] 1H NMR(400MHz,DMSO)δ9.43(d,J=2.6Hz,1H),8.69(d,J=2.6Hz,1H),8.62(t,J=5.9Hz,1H),7.9 5(d,J=8.2Hz,2H),7.46(d,J=8.1Hz,2H),4.58(d,J=5.8Hz,2H),4.33(dd,J=12.6,4.2Hz,1H) ,4.17(td,J=11.9,4.8Hz,1H),3.19(d,J=13.1Hz,2H),3.05(q,J=7.5Hz,2H),2.93(dd,J=17 .8,12.3Hz,1H),2.32(d,J=10.5Hz,1H),2.11(qd,J=12.0,5.8Hz,1H),1.29(t,J=7.5Hz,3H).

[0984] Synthesis of Compounds 10a and 10b

[0985] [ka]

[0986] A batch of compound 10ab, prepared following a procedure similar to that outlined above starting from intermediate I-6 (0.74 g, 1.89 mmol), was purified by chiral SFC on a Jasco SFC prep system using Phenomenex Lux Cellulose-1 250 mm long x 30 mm ID. The mixture was purified in isocratic mode using a 5 μm particle size column, 30 ml / min of CO (50%)-methanol (40%) + 0.1% diethylamine, at 30 °C and 150 bar BPR. The DAD detector acquisition frequency was set to 220 nm. The desired fractions were collected and concentrated in vacuo to give compound 10a (107 mg, 11%) and compound 10b (118 mg, 12% yield) as beige solids.

[0987] Compound 10a 1H NMR(400MHz,DMSO)δ9.43(d,J=2.6Hz,1H),8.68(d,J=2.6Hz,1H),8.62(t,J=5.8Hz,1H),7 .95(d,J=8.2Hz,2H),7.46(d,J=8.2Hz,2H),4.58(d,J=5.8Hz,2H),4.33(dd,J=12.9,3.6Hz ,1H),4.17(td,J=12.2,4.9Hz,1H),3.23-3.14(m,2H),3.05(q,J=7.5Hz,2H),2.92(dd,J= 17.7,12.2Hz,1H),2.32(dd,J=10.8,2.1Hz,1H),2.20-2.03(m,1H),1.29(t,J=7.5Hz,3H).

[0988] Compound 10b 1H NMR(400MHz,DMSO)δ9.43(d,J=2.6Hz,1H),8.68(d,J=2.6Hz,1H),8.62(t,J=5.9Hz,1H),7 .94(t,J=8.3Hz,2H),7.46(d,J=8.3Hz,2H),4.58(d,J=5.8Hz,2H),4.33(dd,J=13.1,3.4Hz ,1H),4.17(td,J=12.0,4.8Hz,1H),3.24-3.14(m,2H),3.05(q,J=7.5Hz,2H),2.92(dd,J= 17.5,12.1Hz,1H),2.32(dd,J=10.9,2.1Hz,1H),2.19-2.04(m,1H),1.29(t,J=7.5Hz,3H).

[0989] Synthesis of compound 11ab

[0990] [ka]

[0991] Intermediate I-6 (110 mg, 0.33 mmol) was added to a solution of intermediate II-8f (106 mg, 0.36 mmol), HATU [148893-10-1] (189 mg, 0.50 mmol), and DIPEA [7087-68-5] (0.40 mL, 2.31 mmol) in DMF (4 mL) at room temperature. The mixture was stirred at room temperature for 19 h. Then, saturated aqueous NaHCO3 was added, and the mixture was extracted with EtOAc (twice). The combined organic layers were dried (MgSO4), filtered, and the solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica, DCM / MeOH in DCM (9:1) 0 / 100 to 30 / 70). The desired fractions were collected and concentrated in vacuo to give compound 11ab (27 mg, 15%) as a pale orange-yellow solid.

[0992] 1H NMR(400MHz,DMSO)δ8.88(s,1H),8.36(t,J=5.6Hz,1H),7.95(d,J=8.1Hz,2H),7 .45(d,J=8.2Hz,2H),4.57(d,J=5.6Hz,2H),4.36-4.28(m,1H),4.17(td,J=12.0 ,4.7Hz,1H),3.86(s,3H),3.23-3.14(m,2H),3.00(q,J=7.4Hz,2H),2.97-2.86( m,1H),2.46(s,3H),2.36-2.27(m,1H),2.19-2.05(m,1H),1.26(t,J=7.5Hz,3H).

[0993] Synthesis of compound 12ab

[0994] [ka]

[0995] Trifluoroacetic acid [76-05-1] (2.7 mL, 36.35 mmol) was added to intermediate I-17a (179 mg, 0.24 mmol) at 0 °C. The mixture was stirred at room temperature for 1 h. The mixture was neutralized with saturated aqueous NaHCO3 and extracted with DCM (3 times). The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by reverse-phase HPLC (Phenomenex Gemini C18 30 × 100 mm 5 μm column, 95% [0.1% HCOOH] - 5% [ACN:MeOH (1:1)] to 63% [0.1% HCOOH] - 37% [ACN:MeOH (1:1)]). The desired fractions were collected, and then saturated aqueous NaHCO3 was added, and the mixture was extracted with DCM (3 times). The combined organic layers were dried (MgSO4), filtered, concentrated to dryness in vacuo, and the solid was triturated with DIPE and n-pentane to give compound 12ab (30 mg, 24%) as a white solid.

[0996] 1H NMR(400MHz,DMSO)δ8.74(s,1H),8.06(t,J=5.9Hz,1H),7.95(d,J=8.1Hz,2H),7.42 (d,J=8.2Hz,2H),6.86(s,2H),4.52(d,J=5.8Hz,2H),4.33(dd,J=12.5,3.9Hz,1H),4 .17(td,J=12.1,4.7Hz,1H),3.23-3.15(m,2H),2.98-2.91(m,1H),2.87(q,J=7.5Hz ,2H),2.33(d,J=11.5Hz,1H),2.18-2.10(m,1H),2.06(s,3H),1.22(t,J=7.5Hz,3H).

[0997] Synthesis of compound 13ab

[0998] [ka]

[0999] HATU [148893-10-1] (570 mg, 1.5 mmol) was added to a mixture of intermediate I-6 (250 mg, 0.75 mmol), intermediate II-17a (248 mg, 1.28 mmol), and DIPEA [7087-68-5] (0.21 mL, 1.20 mmol) in DMF (10 mL) at room temperature. The mixture was stirred at room temperature for 16 h. Saturated aqueous NaHCO3 was then added, and the mixture was extracted with DCM. The organic layer was washed with brine, dried (MgSO4), filtered, and the solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica, DCM / MeOH in DCM (9:1) 0 / 100 to 40 / 60). The desired fractions were collected and concentrated in vacuo, and the residue was repurified by reverse-phase HPLC (Phenomenex Gemini C18 100 × 30 mm 5 μm column, 95% [0.1% HCOOH]-5% [ACN:MeOH (1:1)] to 63% [0.1% HCOOH]-37% [ACN:MeOH (1:1)]). The desired fractions were collected and concentrated in vacuo to give compound 13ab (79 mg, 22%) as a white solid.

[1000] 1H NMR(400MHz,DMSO)δ8.25(t,J=6.0Hz,1H),7.93(d,J=8.2Hz,2H),7.38(d,J=8.3Hz,2H),4.4 5(d,J=6.0Hz,2H),4.36-4.28(m,1H),4.17(td,J=12.0,4.9Hz,1H),3.99(t,J=5.8Hz,2H),3 .18(dd,J=9.5,8.3Hz,2H),2.92(dd,J=17.6,12.2Hz,1H),2.71(t,J=6.3Hz,2H),2.64(q,J= 7.5Hz,2H),2.36-2.27(m,1H),2.18-2.03(m,1H),1.91-1.73(m,4H),1.10(t,J=7.5Hz,3H).

[1001] Synthesis of compound 14ab

[1002]

change

[1003] Intermediate I-6 (110 mg, 0.33 mmol) was added to a solution of intermediate II-17b (120 mg, 0.46 mmol), HATU [148893-10-1] (189 mg, 0.50 mmol), and DIPEA [7087-68-5] (0.4 mL, 2.31 mmol) in DMF (4 mL) at room temperature. The mixture was stirred at room temperature for 72 h. Saturated aqueous NaHCO3 was then added, and the mixture was extracted with EtOAc (twice). The organic layer was washed with brine, separated, dried (MgSO4), filtered, and the solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica, in DCM, DCM / methanol (9:1), 0 / 100 to 30 / 70). The desired fractions were collected and concentrated in vacuo, and the residue was purified by reverse-phase HPLC (Phenomenex Gemini C18 21.2 × 100 mm 5 µm column, 72% [(65 mM NHOAc) + ACN (90:10) pH 7] - 28% (ACN / methanol 1:1) to 36% [(65 mM NHOAc) + ACN (90:10) pH 7] - 28% (ACN / methanol 1:1). The desired fractions were collected and concentrated in vacuo to give compound 14ab as a white solid (41 mg, 25%).

[1004] 1H NMR(400MHz,DMSO)δ9.04(t,J=5.7Hz,1H),8.82(d,J=7.0Hz,1H),7.96(d,J=8.2Hz,2H),7 .76(d,J=9.1Hz,1H),7.56-7.50(m,1H),7.48(s,1H),7.45(s,1H),7.35(t,J=53.8Hz,1H) ,7.17(td,J=6.9,1.1Hz,1H),4.59(d,J=5.7Hz,2H),4.37-4.29(m,1H),4.23-4.13(m,1H) ,3.24-3.16(m,2H),2.93(dd,J=17.8,12.3Hz,1H),2.36-2.28(m,1H),2.18-2.05(m,1H).

[1005] Synthesis of compound 15ab

[1006] [ka]

[1007] To a mixture of intermediate I-6 (234 mg, 0.55 mmol), intermediate II-17c (440 mg, 1.06 mmol), and DIPEA [7087-68-5] (0.6 mL, 3.31 mmol) in DMF (4 mL) was added HATU [148893-10-1] (420 mg, 1.10 mmol), and the mixture was stirred at room temperature for 24 h. The mixture was washed with saturated aqueous NaHCO3 and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated in vacuo. The crude product was washed twice with toluene and then purified by flash column chromatography on silica gel (MeOH in DCM 20, 0 / 100 to 5 / 95). The desired fractions were collected and concentrated in vacuo, and the residue was triturated sequentially with DIPE:DCM (9:1), DIPE:DCM (1:9), DIPE:DCM (1:1), and EtO. The solid was dried in vacuo and repurified by reverse-phase HPLC (Phenomenex Gemini C18 30 × 100 mm 5 μm column, 70% [25 mM NH4HCO3]-30% [ACN:MeOH (1:1)] to 27% [25 mM NH4HCO3]-73% [ACN:MeOH (1:1)]). The desired fractions were collected, concentrated, and dried under vacuum at 60 °C to give compound 15ab (69 mg, 26%) as a white solid.

[1008] 1H NMR(400MHz,DMSO)δ8.81(s,1H),8.40(t,J=6.0Hz,1H),7.96(d,J=8.3Hz,2H),7.51(d,J=9. 1Hz,1H),7.45(d,J=8.3Hz,2H),7.25(dd,J=9.1,1.7Hz,1H),4.57(d,J=5.9Hz,2H),4.37-4. 28(m,1H),4.17(td,J=12.1,4.9Hz,1H),3.24-3.11(m,2H),3.03-2.95(m,2H),2.92(dd,J=1 6.0,10.6Hz,1H),2.36-2.32(m,1H),2.31(s,3H),2.18-2.04(m,1H),1.26(t,J=7.5Hz,3H).

[1009] Synthesis of Compound 16ab and Compound 17ab

[1010] [ka]

[1011] 4 M HCl in dioxane (0.42 mL, 1.66 mmol) was added to a stirred solution of intermediate I-17b (165 mg, 0.28 mmol) in DCM (5 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 h, and then the solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica, 12, DCM / MeOH / NH3 9:1:0.1, 0 / 100 to 100 / 0 in DCM). The desired fractions were collected and concentrated in vacuo to give compound 16ab as a brown solid (33 mg, 23%) and compound 17ab as a white solid (35 mg, 27%).

[1012] Compound 16ab 1H NMR(400MHz,DMSO)δ9.24(d,J=2.4Hz,1H),8.61(d,J=2.4Hz,1H),8.52(t,J=5.8Hz,1H),7. 95(d,J=8.2Hz,2H),7.45(d,J=8.2Hz,2H),4.58(d,J=5.8Hz,2H),4.32(dd,J=11.7,4.4Hz, 1H),4.17(td,J=12.0,4.9Hz,1H),3.80(s,2H),3.24-3.13(m,2H),3.03(q,J=7.5Hz,2H),2 .92(dd,J=17.4,12.0Hz,1H),2.36-2.27(m,1H),2.19-2.02(m,1H),1.28(t,J=7.5Hz,3H).

[1013] Compound 17ab 1H NMR(400MHz,DMSO)δ9.34(dd,J=6.9,2.0Hz,1H),8.63(dd,J=4.2,2.0Hz,1H),8.56(t,J=5.9Hz,1 H),7.96(d,J=8.2Hz,2H),7.46(d,J=8.3Hz,2H),7.18(dd,J=6.9,4.2Hz,1H),4.59(d,J=5.8Hz,2H ),4.33(dd,J=12.7,3.8Hz,1H),4.17(td,J=12.1,4.9Hz,1H),3.25-3.14(m,2H),3.05(q,J=7.5Hz ,2H),2.93(dd,J=17.5,12.0Hz,1H),2.37-2.27(m,1H),2.20-2.05(m,1H),1.30(t,J=7.5Hz,3H).

[1014] Synthesis of compound 18ab

[1015] [ka]

[1016] Intermediate I-10 (122 mg, 0.33 mmol) was added to a solution of intermediate II-6a (132 mg, 0.57 mmol), HATU [148893-10-1] (126 mg, 0.33 mmol), and DIPEA [7087-68-5] (0.23 mL, 1.33 mmol) in DMF (1.7 mL) at room temperature. The mixture was stirred at room temperature for 3 h. Saturated aqueous NaHCO3 was then added, and the mixture was extracted with DCM. The organic layer was washed with brine, separated, dried (MgSO4), filtered, and the solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica, 0 / 100 to 80 / 20 EtOAc in heptane). The desired fractions were collected and concentrated in vacuo to give compound 18ab (85 mg, 48%) as a white solid.

[1017] 1H NMR(400MHz,DMSO)δ9.28(t,J=5.7Hz,1H),8.56(d,J=7.0Hz,1H),7.80(d,J=9.2Hz,1H) ,7.72(d,J=8.2Hz,2H),7.59-7.53(m,2H),7.35(d,J=8.2Hz,2H),7.21(t,J=6.9Hz,1H), 4.54(d,J=5.8Hz,2H),4.17(dd,J=12.9,3.5Hz,1H),3.99(td,J=11.9,4.4Hz,1H),3.17 -3.03(m,2H),2.79(dd,J=17.3,12.6Hz,1H),2.24(d,J=11.5Hz,1H),2.06-1.93(m,1H).

[1018] Synthesis of compound 19ab

[1019] [ka]

[1020] Intermediate I-22 (200 mg, 0.52 mmol) was added to a solution of intermediate II-3a (140 mg, 0.58 mmol), HATU [148893-10-1] (199 mg, 0.52 mmol), and DIPEA [7087-68-5] (0.37 mL, 2.1 mmol) in DMF (2.9 mL) at 0 °C under N 2 . The mixture was stirred at room temperature for 16 h. Saturated aqueous NaHCO 3 was then added, and the mixture was extracted with DCM. The organic layer was washed with brine, separated, dried (MgSO 4 ), filtered, and the solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica, MeOH in DCM from 0 / 100 to 2 / 98). The desired fractions were collected and concentrated in vacuo to give compound 19ab (127 mg, 48%) as a white solid.

[1021] 1H NMR(400MHz,DMSO)δ9.16(dd,J=2.3,1.1Hz,1H),8.51(d,J=2.4Hz,1H),8.48(t,J=6.0Hz,1 H),7.57(d,J=8.2Hz,2H),7.37(d,J=8.3Hz,2H),4.54(d,J=5.8Hz,2H),4.11-4.03(m,1H), 3.79(td,J=12.0,4.7Hz,1H),3.09-2.98(m,4H),2.75(dd,J=17.0,12.5Hz,1H),2.34(d,J= 0.4Hz, 3H), 2.33-2.23 (m, 4H), 1.94 (ddd, J=24.6, 11.7, 5.6Hz, 1H), 1.28 (t, J=7.5Hz, 3H).

[1022] Synthesis of compound 20ab

[1023] [ka]

[1024] Intermediate I-27 (126 mg, 0.34 mmol) was added to a solution of intermediate II-3a (120 mg, 0.41 mmol), HATU [148893-10-1] (194 mg, 0.51 mmol), and DIPEA [7087-68-5] (0.42 mL, 2.39 mmol) in DMF (5 mL) at room temperature. The mixture was stirred at room temperature for 16 h. Saturated aqueous NaHCO3 was then added, and the mixture was extracted with EtOAc (3 times). The combined organic layers were dried (MgSO4), filtered, and the solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica, MeOH in DCM from 0 / 100 to 100 / 0). The desired fractions were collected and concentrated in vacuo, and the residue was repurified by reverse phase (Phenomenex Gemini C18 30 × 100 mm 5 μm column, 59% [25 mM NH4HCO3]-41% [ACN:MeOH (1:1)] to 17% [25 mM NH4HCO3]-83% [ACN:MeOH (1:1)]). The desired fractions were collected and concentrated in vacuo to give compound 20ab (85 mg, 51%) as a white solid.

[1025] 1H NMR (400MHz, DMSO) δ9.18-9.11(m,1H),8.53-8.45(m,2H),7.73(d,J=8.2Hz,2H),7.38(d,J=8. 2Hz,2H),6.52(s,1H),4.54(d,J=5.9Hz,2H),4.30(dd,J=12.9,3.6Hz,1H),4.11(td,J=12.3,4 .8Hz,1H),3.13(dd,J=15.9,4.0Hz,1H),3.02(q,J=7.5Hz,3H),2.79(dd,J=15.8,11.2Hz,1H), 2.34(s,3H),2.27(dd,J=13.3,2.2Hz,1H),2.04(qd,J=11.8,5.7Hz,1H),1.28(t,J=7.5Hz,3H).

[1026] Synthesis of compound 21ab

[1027]

change

[1028] Intermediate I-32 (59 mg, 0.15 mmol) was added to a solution of intermediate II-3a (63 mg, 0.22), HATU [148893-10-1] (88 mg, 0.23 mmol), and DIPEA [7087-68-5] (0.19 mL, 1.08 mmol) in DMF (3 mL) at room temperature. The mixture was stirred at room temperature for 16 h. Saturated aqueous NaHCO3 was then added, and the mixture was extracted with EtOAc (3 times). The combined organic layers were dried (MgSO4), filtered, and the solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica, MeOH in DCM from 0 / 100 to 100 / 0). The desired fractions were collected and concentrated in vacuo, and the residue was repurified by reverse phase (Phenomenex Gemini C18 30 × 100 mm 5 μm column, 70% [0.1% HCOOH]-30% [ACN:MeOH (1:1)] to 27% [0.1% HCOOH]-73% [ACN:MeOH (1:1)]). The desired fractions were collected and concentrated in vacuo to give compound 21ab (25 mg, 32%) as a white solid.

[1029] 1H NMR(400MHz,DMSO)δ9.19-9.13(m,1H),8.51(d,J=2.4Hz,1H),8.50-8.47(m,1H) ,7.59(d,J=8.2Hz,2H),7.41(d,J=8.2Hz,2H),4.56(d,J=5.8Hz,2H),4.31-4.22( m,1H),4.07(td,J=12.3,4.6Hz,1H),3.08-2.96(m,4H),2.72-2.60(m,1H),2.34( s,3H),2.30-2.22(m,1H),2.08(s,3H),2.06-1.93(m,1H),1.28(t,J=7.5Hz,3H).

[1030] Synthesis of compound 22ab

[1031] [ka]

[1032] HATU [148893-10-1] (434 mg, 1.14 mmol) was added to a mixture of intermediate I-37 (200 mg, 0.57 mmol), intermediate II-3a (140 mg, 0.68 mmol), and DIPEA [7087-68-5] (0.58 mL, 3.42 mmol) in DMF (10 mL) at room temperature. The mixture was stirred at room temperature for 16 h, then 1 M aqueous NaCO solution was added, and the mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried (MgSO), filtered, and the solvent was evaporated in vacuo. The crude product was repurified by flash column chromatography (silica, 0 / 100 to 100 / 0 EtOAc in heptane). The desired fractions were collected and concentrated in vacuo, and the residue was repurified by reverse phase (Phenomenex Gemini C18 100 × 30 mm 5 μm column, 81% [0.1% HCOOH]-19% [ACN:MeOH (1:1)] to 45% [0.1% HCOOH]-55% [ACN:MeOH (1:1)]). The desired fractions were collected and concentrated in vacuo to give compound 22ab as a white solid (122 mg, 42%).

[1033] 1H NMR(400MHz,DMSO)δ9.33(s,1H),8.68(s,1H),8.67(d,J=8.6Hz,1H),8.11(t,J=7.8Hz,1 H),7.46(d,J=9.8Hz,2H),4.75(d,J=5.8Hz,2H),4.51(dd,J=12.7,3.9Hz,1H),4.35(td,J =12.1,4.8Hz,1H),3.40-3.31(m,2H),3.20(q,J=7.5Hz,2H),3.10(dd,J=17.6,12.2Hz,1 H),2.66(s,3H),2.47(s,1H),2.29(ddd,J=23.7,11.2,5.2Hz,1H),1.46(t,J=7.5Hz,3H).

[1034] Synthesis of compound 23ab

[1035] [ka]

[1036] HATU [148893-10-1] (0.44 g, 1.16 mmol) was added to a mixture of intermediate I-42 (0.2 g, 0.58 mmol), intermediate II-3a (0.18 g, 0.89 mmol), and DIPEA [7087-68-5] (0.59 mL, 3.47 mmol) in DMF (5 mL) at room temperature. The mixture was stirred at room temperature for 16 h. Then, saturated aqueous NaHCO3 was added, and the mixture was extracted with DCM. The organic layer was separated, washed with brine, dried (MgSO4), filtered, and the solvent was evaporated in vacuo. The crude product was washed with toluene and triturated with DCM. The precipitate was collected, the mother liquor was concentrated in vacuo, and the residue was repurified by flash column chromatography (silica, 0 / 100 to 100 / 0 EtOAc in heptane). The desired fractions were collected and concentrated in vacuo, and the residue was repurified by reverse phase (Phenomenex Gemini C18 100 × 30 mm 5 μm column, 70% [25 mM NH4HCO3]-30% [ACN:MeOH (1:1)] to 27% [25 mM NH4HCO3]-73% [ACN:MeOH (1:1)]). The desired fractions were collected and concentrated in vacuo, and the resulting solid was combined with the previously obtained solid to give compound 23ab (108 mg, 37%) as a white solid.

[1037] 1H NMR(400MHz,DMSO)δ9.15(s,1H),8.51(s,2H),7.87(d,J=7.8Hz,1H),7.27(d,J=8.7Hz,2H ),4.54(d,J=5.7Hz,2H),4.34(dd,J=12.3,4.2Hz,1H),4.18(td,J=12.0,4.6Hz,1H),3.20 (d,J=13.4Hz,2H),3.03(dd,J=14.9,7.5Hz,2H),2.93(dd,J=17.3,12.1Hz,1H),2.58(s,3 H),2.34(s,3H),2.31(s,1H),2.13(ddd,J=24.9,12.2,5.9Hz,1H),1.29(t,J=7.4Hz,3H).

[1038] Synthesis of compound 24ab

[1039] [ka]

[1040] Intermediate II-3a (173 mg, 0.49 mmol) was added to a solution of intermediate I-47 (173 mg, 0.64 mmol), HATU [148893-10-1] (282 mg, 0.74 mmol), and DIPEA [7087-68-5] (0.60 mL, 3.46 mmol) in DMF (5 mL). The reaction mixture was stirred at room temperature for 16 h, diluted with saturated aqueous NaHCO3, and extracted with EtOAc (twice). The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (silica, DCM / MeOH (9:1), 0 / 100 to 30 / 70) in DCM. The desired fractions were collected and concentrated in vacuo to give compound 24ab (149 mg, 62%) as a white solid.

[1041] 1H NMR(400MHz,DMSO)δ9.16(s,1H),8.51(s,2H),7.95(d,J=7.9Hz,2H),7.45(d,J=7.9Hz,2H),4.57(s,2H),4.51-4.42(m,1H),4.19(t,J=11.2Hz,1H), 3.44-3.35(m,1H),3.17(s,1H),3.08-2.99(m,2H),2.98-2.89(m,1H),2.3 4(s,3H),2.25(d,J=11.8Hz,1H),2.09-1.95(m,1H),1.28(t,J=7.4Hz,3H).

[1042] Synthesis of compound 25ab

[1043] [ka]

[1044] Intermediate I-51 (120 mg, 0.34 mmol) was added to a solution of intermediate II-3a (151 mg, 0.52 mmol), HATU [148893-10-1] (194 mg, 0.51 mmol), and DIPEA [7087-68-5] (0.42 mL, 2.38 mmol) in DMF (3 mL). The reaction mixture was stirred at room temperature for 16 h, diluted with saturated aqueous NaHCO3, and extracted with EtOAc (3 times). The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (silica, DCM / MeOH (9:1), 0 / 100 to 100 / 0) in DCM. The desired fractions were collected and concentrated in vacuo to give compound 25ab (89 mg, 55%) as a beige solid.

[1045] 1H NMR(400MHz,DMSO)δ9.20-9.12(m,1H),8.56-8.45(m,2H),7.95(d,J=8.2Hz,2H),7.4 4(d,J=8.2Hz,2H),6.20(td,J=56.2,4.1Hz,1H),4.57(d,J=5.9Hz,2H),4.35-4.26(m, 1H),4.13(td,J=12.1,4.9Hz,1H),3.10-2.97(m,3H),2.85-2.73(m,1H),2.70-2.56( m,1H),2.34(s,3H),2.20(d,J=13.5Hz,1H),2.02-1.88(m,1H),1.28(t,J=7.5Hz,3H).

[1046] Synthesis of compound 26ab

[1047] [ka]

[1048] HATU [148893-10-1] (523 mg, 1.37 mmol) was added to a mixture of intermediate I-56 (202 mg, 0.68 mmol), intermediate II-3a (239 mg, 1.16 mmol), and DIPEA [7087-68-5] (0.7 mL, 4.1 mmol) in DMF (5 mL) at room temperature. The mixture was stirred at room temperature for 18 hours. Then, saturated aqueous NaHCO3 was added, and the mixture was extracted with DCM. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica, MeOH in DCM 0 / 100 to 10 / 90). The desired fractions were collected and concentrated in vacuo. The residue was dissolved in a 95 / 5 mixture of DCM and methanol, and the solution was extracted with saturated aqueous NaHCO3. The organic layer was separated, dried (MgSO), filtered, and the solvent was evaporated in vacuo. The residue was triturated with DIPE / DCM (9:1) and DIPE / DCM (1:1) and dried in vacuo to give compound 26ab (179 mg, 58%) as a white solid.

[1049] 1H NMR(300MHz,DMSO)δ8.35(s,2H),8.00(d,J=8.2Hz,2H),7.55(d,J=8.2Hz,2H),4.28-3 .99(m,4H),3.95(d,J=3.9Hz,1H),3.33(s,3H),3.15-2.91(m,2H),2.34-2.09(m,2H).

[1050] Synthesis of Compound 27ab and Compound 28ab

[1051] [ka]

[1052] Intermediate I-60 (154 mg, 0.45 mmol) was added to a solution of intermediate II-3a (575 mg, 1.96 mmol), HATU [148893-10-1] (803 mg, 2.11 mmol), and DIPEA [7087-68-5] (1.71 mL, 9.86 mmol) in DMF (4 mL). The reaction mixture was stirred at room temperature for 16 h, diluted with saturated aqueous NaHCO3, and extracted with EtOAc (3 times). The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (silica, in DCM, DCM / MeOH (9:1), 0 / 100 to 100 / 0). The desired fractions were collected and concentrated in vacuo, and the residue was purified by reverse-phase HPLC (Phenomenex Gemini C18 30 × 100 mm 5 μm column, 72% [0.1% HCOOH]-28% [ACN:MeOH (1:1)] to 36% [0.1% HCOOH]-64% [ACN:MeOH (1:1)]). The desired fractions were collected and concentrated to give compounds 27ab (28 mg, 14%) and 28ab (84 mg, 40%) as white solids.

[1053] Compound 27ab 1H NMR(400MHz,DMSO)δ 9.19-9.12(m,1H),8.55-8.46(m,2H),7.94(d,J=8.3Hz,2H),7.43(d,J=8.3Hz,2 H),4.57(d,J=5.9Hz,2H),4.30-4.18(m,1H),4.10-3.99(m,1H),3.08-2.96(m,3H ),2.71-2.59(m,1H),2.34(d,J=0.6Hz,3H),2.20-2.08(m,1H),2.01-1.84(m,1H) ,1.28(t,J=7.5Hz,4H),0.81-0.71(m,1H),0.51-0.41(m,2H),0.28-0.15(m,2H).

[1054] Compound 28ab 1H NMR(400MHz,DMSO)δ9.16(dd,J=2.4,1.1Hz,1H),8.54-8.46(m,2H),7.94(d,J=8.3Hz, 2H),7.43(d,J=8.3Hz,2H),4.57(d,J=5.8Hz,2H),4.27-4.16(m,1H),4.12-4.00(m,1H) ,3.07-2.95(m,3H),2.46-2.40(m,1H),2.34(d,J=0.6Hz,3H),2.16-2.05(m,1H),1.97( s, 1H), 1.80-1.66 (m, 1H), 1.45-1.34 (m, 4H), 1.28 (t, J=7.5Hz, 3H), 0.98-0.85 (m, 3H).

[1055] Synthesis of compound 29ab

[1056] [ka]

[1057] Intermediate I-64 (92 mg, 0.32 mmol) was added to a solution of intermediate II-3a (85 mg, 0.27 mmol), HATU [148893-10-1] (103 mg, 0.27 mmol), and DIPEA [7087-68-5] (0.33 mL, 1.88 mmol) in DMF (3 mL). The reaction mixture was stirred at room temperature for 16 hours, diluted with saturated aqueous NaHCO3, and extracted with DCM (3 times). The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. The crude product was washed with water and triturated with n-pentane and DCM to give compound 29ab (77 mg, 66%) as a pale brown solid.

[1058] 1H NMR(400MHz,DMSO)δ9.16(s,1H),8.50(dd,J=7.6,4.1Hz,2H),7.94(d,J=8.2Hz,2H),7.44(d,J=8.2Hz,2H),5.21(d,J=3.4Hz,1H),4.57(d,J=5.8H) z,2H),4.26(s,1H),4.17(t,J=6.2Hz,2H),3.09-2.97(m,3H),2.79(dd,J =17.0,4.9Hz,1H),2.34(s,3H),2.18-1.98(m,2H),1.27(q,J=7.8Hz,3H).

[1059] Synthesis of compound 30ab

[1060] [ka]

[1061] Intermediate I-68 (199 mg, 0.41 mmol) was added to a solution of intermediate II-3a (134 mg, 0.49 mmol), HATU [148893-10-1] (156 mg, 0.41 mmol), and DIPEA [7087-68-5] (0.5 mL, 2.85 mmol) in DMF (3 mL). The reaction mixture was stirred at room temperature for 16 h, diluted with saturated aqueous NaHCO3, and extracted with DCM (3 times). The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (silica, DCM / MeOH (9:1), 0 / 100 to 100 / 0) in DCM. The desired fractions were collected and concentrated in vacuo to give compound 30ab (83 mg, 40%) as a yellow solid.

[1062] 1H NMR(400MHz,DMSO)δ9.16(d,J=1.0Hz,1H),8.50(dd,J=7.1,4.2Hz,2H),7.94(d,J=8.2Hz,2H), 7.44(d,J=8.2Hz,2H),4.57(d,J=5.8Hz,2H),4.22-4.03(m,3H),3.70-3.56(m,2H),3.43(t,J=4 .7Hz,2H),3.22(s,3H),3.10(dd,J=17.1,4.2Hz,1H),3.02(q,J=7.5Hz,2H),2.93(dd,J=17.1,4 .4Hz,1H),2.34(s,3H),2.29-2.20(m,1H),2.15(dt,J=13.4,6.6Hz,1H),1.28(t,J=7.5Hz,3H).

[1063] Synthesis of compound 31ab

[1064]

change

[1065] DMF (10 mL) was added to intermediate II-3a (0.19 g, 0.67 mmol) at room temperature, and the mixture was stirred for 10 minutes. Next, HATU [7087-68-5] (0.58 mL, 3.33 mmol) was added to the mixture at room temperature, and the mixture was stirred for another 10 minutes at room temperature. Next, HATU [148893-10-1] (0.26 g, 0.69 mmol) was added to the mixture at room temperature, and the mixture was stirred for another 10 minutes at room temperature. Finally, intermediate I-73a (0.21 g, 0.42 mmol) was added to the mixture, and the reaction mixture was stirred for another 18 hours at room temperature. The mixture was diluted with saturated aqueous NaHCO3 and then extracted with DCM (3 times). The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. Excess DMF was distilled off with toluene (100 mL x 3). The residue was dissolved in DCM, and the organic phase was washed with saturated aqueous NaHCO3. The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (silica, 0 / 100 to 5 / 95 MeOH in DCM). The desired fractions were collected and concentrated in vacuo. The solid was triturated with diethyl ether and a few drops of DCM and dried in vacuo to give compound 31ab (128 mg, 72%) as a white solid.

[1066] 1H NMR(400MHz,DMSO)δ9.16(dd,J=2.3,1.1Hz,1H),8.50(dd,J=7.4,4.2Hz,2H),7.94(d,J=8.2Hz,2H),7.44(d,J=8.2Hz,2H),4.57(d,J=5.9Hz,2H) ),4.13(t,J=6.0Hz,2H),3.02(q,J=7.5Hz,2H),2.85(t,J=6.3Hz,2H),2 .34(s,3H),2.05-1.98(m,2H),1.94-1.85(m,2H),1.28(t,J=7.5Hz,3H).

[1067] Synthesis of compound 32ab

[1068] [ka]

[1069] Compound 32ab was prepared (116 mg, 59%) following a procedure similar to that used to synthesize compound 31ab using intermediate I-73b (150 mg, 0.45 mmol) as the starting material.

[1070] 1H NMR(400MHz,DMSO)δ9.17(dd,J=2.3,1.1Hz,1H),8.51(dd,J=9.1,4.2Hz,2H),7.94(t,J=7.8Hz,1H),7.28(d,J=9.8Hz,2H),4.57(d,J=5.9Hz,2H) ),4.15(t,J=6.0Hz,2H),3.03(q,J=7.5Hz,2H),2.86(t,J=6.3Hz,2H),2 .34(s,3H),2.07-1.98(m,2H),1.96-1.85(m,2H),1.29(t,J=7.5Hz,3H).

[1071] Synthesis of compound 33ab

[1072] [ka]

[1073] Intermediate I-75 (100 mg, 0.26 mmol) was added to a solution of intermediate II-3a (110 mg, 0.39 mmol), HATU [148893-10-1] (100 mg, 0.26 mmol), and DIPEA [7087-68-5] (0.32 mL, 1.82 mmol) in DMF (3 mL). The reaction mixture was stirred at room temperature for 16 h, diluted with saturated aqueous NaHCO3, and extracted with DCM (3 times). The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (silica, MeOH in DCM from 0 / 100 to 100 / 0). The desired fractions were collected and concentrated in vacuo, and the residue was repurified by reverse-phase HPLC (Phenomenex Gemini C18 30 × 100 mm 5 μm column, 70% [25 mM NH4HCO3]-30% [ACN:MeOH (1:1)] to 27% [25 mM NH4HCO3]-73% [ACN:MeOH (1:1)]). The desired fractions were collected and concentrated in vacuo to give compound 33ab (10 mg, 7%) as a yellow solid.

[1074] 1H NMR(400MHz,DMSO)δ9.16(dd,J=2.3,1.1Hz,1H),8.51(dd,J=6.6,4.2Hz,2H),7.95(d,J=8 .3Hz,2H),7.45(d,J=8.3Hz,2H),5.25-5.19(m,1H),4.57(d,J=5.9Hz,2H),4.31(dt,J=11. 2,5.5Hz,1H),4.25-4.15(m,1H),3.36(dd,J=17.4,4.4Hz,1H),3.17(dd,J=17.3,4.9Hz,1H ),3.02(q,J=7.5Hz,2H),2.40(dd,J=11.3,5.6Hz,2H),2.34(s,3H),1.28(t,J=7.5Hz,3H).

[1075] Synthesis of compound 34ab

[1076] [ka]

[1077] Intermediate I-10 (202 mg, 0.52 mmol) was added to a solution of intermediate II-8a (200 mg, 0.73 mmol), HATU [148893-10-1] (297 mg, 0.78 mmol), and DIPEA [7087-68-5] (0.64 mL, 3.65 mmol) in DMF (10 mL). The reaction mixture was stirred at room temperature for 16 h, diluted with saturated aqueous NaHCO3, and extracted with DCM. The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (silica, MeOH in DCM from 0 / 100 to 30 / 70). The desired fractions were collected and concentrated in vacuo to give compound 34ab (177 mg, 69%) as a beige solid.

[1078] 1H NMR(400MHz,DMSO)δ9.18(d,J=7.0Hz,1H),8.42(t,J=5.9Hz,1H),7.69(d,J=8.2Hz,2 H),7.52(s,1H),7.33(d,J=8.2Hz,2H),7.05(d,J=7.1Hz,1H),4.51(d,J=5.8Hz,2H),4 .20-4.11(m,1H),4.05-3.90(m,1H),3.12-3.04(m,2H),2.99(q,J=7.5Hz,2H),2.83-2 .72(m,1H),2.54(s,3H),2.27-2.18(m,1H),2.01-1.85(m,1H),1.26(t,J=7.5Hz,3H).

[1079] Synthesis of compound 35ab

[1080] [ka]

[1081] HATU [148893-10-1] (440 mg, 1.15 mmol) was added to a mixture of I-16 (160 mg, 0.57 mmol), II-8c (180 mg, 0.86 mmol), and DIPEA [7087-68-5] (0.6 ml, 3.53 mmol) in DMF (6 ml), and the mixture was stirred at room temperature for 20 hours. The mixture was washed with 1 M aqueous NaHCO3 and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated in vacuo. Excess DMF was distilled off with toluene (100 ml × 3). The residue was dissolved in DCM, and the organic phase was washed with saturated aqueous NaHCO3. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated in vacuo. The crude product was triturated with DCM:DIPE 1:1 to give a white solid. The solid was dried in vacuo and purified by flash column chromatography (silica, 0 / 100 to 10 / 90 MeOH in DCM). The desired fractions were collected and concentrated in vacuo, and the residue was triturated with 1:1 DCM:DIPE to give compound 35ab (50 mg, 22%) as a white solid.

[1082] 1H NMR(400MHz,DMSO)δ9.03(dd,J=7.4,6.2Hz,1H),8.45(t,J=5.9Hz,1H),7.94(d,J=8.2Hz,2H),7.49(dd, J=9.8,2.6Hz,1H),7.43(d,J=8.3Hz,2H),7.06(td,J=7.7,2.7Hz,1H),4.56(d,J=5.9Hz,2H),4.22(ddd,J =12.6,5.6,2.9Hz,1H),4.13-4.02(m,1H),3.29(s,1H),3.05-2.92(m,3H),2.09(d,J=5.4Hz,1H),2.05(d d,J=13.7,2.7Hz,1H),1.74(dtd,J=13.4,10.8,5.8Hz,1H),1.27(t,J=7.5Hz,3H),1.10(d,J=6.6Hz,3H).

[1083] Synthesis of compound 36ab

[1084] [ka]

[1085] HATU [148893-10-1] (229 mg, 0.6 mmol) and DIPEA [7087-68-5] (0.56 mL, 3.22 mmol) were added to a solution of intermediate II-6a (202 mg, 0.74 mmol) in DMF (5 mL) at room temperature. The mixture was stirred for 10 minutes, and then intermediate I-81 (171 mg, 0.46 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. Saturated aqueous NaHCO3 was then added, and the mixture was extracted with EtOAc (3 times). The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. Excess DMF was distilled off with toluene (10 mL x 3). The solid was dissolved in DCM and extracted with saturated aqueous NaHCO3. The organic phase was separated, dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (silica, DCM / MeOH 9:1, 0 / 100 to 30 / 70 in DCM). The desired fractions were collected and concentrated in vacuo. The residue was repurified by reverse-phase HPLC (Phenomenex Gemini, C18 30x100 mm 5 μm, 95% [0.1% HCOOH] - 5% [ACN:MeOH (1:1)] - 63% [0.1% HCOOH] - 37% [ACN:MeOH (1:1)]). The desired fractions were collected and concentrated in vacuo to give compound 36ab as a white solid (41 mg, yield: 17%).

[1086] 1H NMR(400MHz,DMSO)δ9.30(t,J=5.8Hz,1H),8.57(d,J=7.0Hz,1H),8.49(d,J=1.6H z,1H),7.85-7.73(m,3H),7.66(s,1H),7.59-7.52(m,1H),7.20(td,J=6.9,1.0Hz, 1H),4.56(d,J=5.6Hz,2H),4.27-4.16(m,1H),4.00(td,J=12.3,4.5Hz,1H),3.17- 3.04(m,2H),2.80(dd,J=17.4,12.6Hz,1H),2.29-2.19(m,1H),2.04-1.89(m,1H).

[1087] Synthesis of the final compound Method A: Coupling reaction between carboxylic acid derivatives and amine derivatives General Procedure HATU [CAS148893-10-1] (1.5-2.5 equiv.) was added to a mixture of the carboxylic acid intermediate (1.4-4 equiv.) and DIPEA (5-7 equiv.) in DMF. The amine intermediate (1 equiv.) was added, and the reaction mixture was stirred at room temperature for 18 h. The mixture was washed with NaHCO3 solution (saturated aqueous solution) and extracted with the appropriate solvent (DCM or EtOAc). The combined organic extracts were dried (anhydrous MgSO4), filtered, and the solvent was removed in vacuo.

[1088] The crude product was purified to give the desired compound.

[1089] The purification techniques used were flash column chromatography (silica, eluent: DCM / MeOH (9:1) in DCM, MeOH in DCM or EtOAc in heptane), reverse phase chromatography or preparative HPLC. If necessary, other purification techniques, such as trituration (DIPE, DCM, EtO), may also be used.

[1090] It will be appreciated that several purification techniques may be used to obtain the desired compounds in high purity.

[1091] The following compounds were obtained by Method A: Synthesis of compound 37

[1092] [ka]

[1093] Compound 37 was synthesized from intermediates II-3a and I-138 and obtained as an off-white solid (37.5 mg, 21%). 1H NMR(400MHz,DMSO)δ9.21(s,1H),8.52(d,J=2.4Hz,1H),8.49(d,J=5.8Hz,1H),8.23(d,J=8.1Hz ,1H),7.34(d,J=8.1Hz,1H),4.65(d,J=5.7Hz,2H),4.37(dd,J=12.5,3.9Hz,1H),4.21(td,J=11 .7,4.5Hz,1H),3.22(d,J=12.6Hz,2H),3.09(q,J=7.5Hz,2H),2.95(dd,J=17.7,12.3Hz,1H),2. 81(s,3H),2.34(s,3H),2.33(s,1H),2.13(dtd,J=17.2,11.3,5.7Hz,1H),1.33(t,J=7.5Hz,3H).

[1094] Synthesis of compound 38

[1095]

change

[1096] Compound 38, intermediate II-3a and I-139 were synthesized and a white solid was obtained (41.7 mg, 24%). 1 H NMR(400MHz,DMSO)δ9.21(d,J=1.1Hz,1H),8.96(s,1H),8.52(d,J=2.5Hz,1H),8.52-8.49(m, 1H),7.34(s,1H),4.65(d,J=5.8Hz,2H),4.37(dd,J=12.8,3.7Hz,1H),4.21(td,J=12.2,4.8Hz ,1H),3.27-3.18(m,2H),3.07(q,J=7.5Hz,2H),2.96(dd,J=17.8,12.3Hz,1H),2.60(s,3H),2 .34(s,3H),2.32(d,J=2.0Hz,1H),2.13(dtd,J=16.9,11.3,5.5Hz,1H),1.32(t,J=7.5Hz,3H).

[1097] Synthesis of compound 39

[1098]

change

[1099] Compound 39 was synthesized from intermediate II-3a and I-146 and obtained as a white solid (7.6 mg, 11%). 1 H NMR(400MHz,DMSO)δ9.21(dd,J=2.2,1.1Hz,1H),9.10(d,J=1.8Hz,1H),8.52(t,J =4.7Hz,2H),8.29(dd,J=8.2,2.2Hz,1H),7.50(d,J=8.2Hz,1H),4.69(d,J=5.8Hz, 2H),4.42-4.30(m,1H),4.27-4.13(m,1H),3.26-3.16(m,2H),3.07(q,J=7.5Hz,2H ),3.00-2.90(m,1H),2.38-2.31(m,4H),2.22-2.06(m,1H),1.32(t,J=7.5Hz,3H).

[1100] Synthesis of compound 40

[1101] [ka]

[1102] Compound 40 was synthesized from intermediates II-8a and I-146 and obtained as a white solid (48.8 mg, 29%). 1 H NMR(400MHz,DMSO)δ9.20(d,J=7.0Hz,1H),8.46(t,J=6.0Hz,1H),7.94(t,J=7.8Hz,1H ),7.29(d,J=9.8Hz,2H),7.06(d,J=7.1Hz,1H),4.57(d,J=5.9Hz,2H),4.42-4.26(m,1 H),4.18(td,J=12.0,4.8Hz,1H),3.18(d,J=4.1Hz,2H),3.02(q,J=7.5Hz,2H),2.98-2 .88(m,1H),2.55(s,3H),2.41-2.21(m,1H),2.21-1.95(m,1H),1.28(t,J=7.5Hz,3H).

[1103] Synthesis of compound 41

[1104] [ka]

[1105] Compound 41 was synthesized from intermediate II-3a and I-144 and obtained as a white solid (21.3 mg, 49%). 1 H NMR(400MHz,DMSO)δ9.21(dd,J=2.3,1.1Hz,1H),8.63(s,1H),8.53(d,J=2.4Hz,1H),8.20(d,J=8.8Hz,1H),7.81(d,J=8.8Hz,1H),4.89(s,2H), 4.47-4.20(m,2H),3.29-3.15(m,3H),3.06(q,J=7.5Hz,2H),3.04-2.94 (m,1H),2.34(d,J=0.7Hz,3H),2.22-2.09(m,1H),1.31(t,J=7.5Hz,3H).

[1106] Synthesis of compound 42

[1107] [ka]

[1108] Compound 42 was synthesized from intermediates II-6a and I-145 and obtained as a beige solid (67.2 mg, 33%). 1 H NMR(400MHz,DMSO)δ9.36(t,J=5.7Hz,1H),8.65(d,J=1.8Hz,1H),8.59(d,J=7.0Hz,1H),8.02( d,J=8.1Hz,1H),7.88(dd,J=8.1,2.2Hz,1H),7.80(d,J=9.1Hz,1H),7.60-7.54(m,1H),7.21(td ,J=6.9,1.0Hz,1H),4.63(d,J=5.6Hz,2H),4.36(dd,J=12.8,3.6Hz,1H),4.21(td,J=12.2,4.9 Hz,1H),3.25-3.15(m,2H),3.01-2.89(m,1H),2.34-2.30(m,1H),2.13(qd,J=11.6,5.8Hz,1H).

[1109] Synthesis of compound 43

[1110] [ka]

[1111] Compound 43 was synthesized from intermediate II-3a and I-145 and obtained as a white solid (66.9 mg, 35%). 1 H NMR(400MHz,DMSO)δ9.16(s,1H),8.65(d,J=1.6Hz,1H),8.54(d,J=6.0Hz,1H),8.52(d,J=2.4Hz,1H), 8.01(d,J=8.1Hz,1H),7.88(dd,J=8.1,2.2Hz,1H),4.60(d,J=5.8Hz,2H),4.36(dd,J=13.1,3.9Hz,1H ),4.25-4.15(m,1H),3.22(s,1H),3.18(d,J=4.9Hz,1H),3.02(q,J=7.5Hz,2H),2.94(dd,J=17.6,12. 2Hz,1H), 2.34(s,3H),2.33-2.31(m,1H),2.13(ddd,J=17.0,11.0,5.4Hz,1H),1.28(t,J=7.5Hz,3H).

[1112] Synthesis of compound 44

[1113] [ka]

[1114] Compound 44 was synthesized from intermediates II-3a and I-122 and obtained as a white solid (117 mg, 47%). 1H NMR(400MHz,DMSO)δ9.16(dd,J=2.3,1.1Hz,1H),8.52(d,J=2.3Hz,1H),8.50(d,J=5.9Hz,1H),7.15(s ,1H),7.10(d,J=10.7Hz,1H),4.54(d,J=5.8Hz,2H),4.35(dd,J=12.7,3.6Hz,1H),4.20(td,J=12.0,4. 5Hz,1H),3.23(s,1H),3.18(d,J=4.1Hz,1H),3.04(q,J=7.5Hz,2H),2.94(dd,J=16.5,10.6Hz,1H),2. 34(s,3H),2.33-2.27(m,1H),2.25(s,3H),2.14(ddd,J=24.6,11.4,5.7Hz,1H),1.29(t,J=7.5Hz,3H).

[1115] Synthesis of compound 45

[1116]

change

[1117] Compound 45, intermediate II-3a and I-141 were synthesized and a white solid was obtained (50.1 mg, 59%). 1 H NMR(400MHz,DMSO)δ9.18(dd,J=2.3,1.1Hz,1H),8.55(s,1H),8.52(q,J=4.7Hz,2 H),7.82(d,J=11.4Hz,1H),4.64(d,J=5.8Hz,2H),4.37(dd,J=11.7,4.7Hz,1H),4. 26-4.17(m,1H),3.25-3.17(m,2H),3.03(q,J=7.5Hz,2H),2.96(dd,J=17.5,12.0H z,1H),2.33(d,J=5.5Hz,4H),2.15(tt,J=11.6,5.8Hz,1H),1.29(t,J=7.5Hz,3H).

[1118] Synthesis of compound 46

[1119]

change

[1120] Compound 46 was synthesized from intermediate II-3a and I-143 and obtained as a white solid (125.8 mg, 57%). 1 H NMR(400MHz,DMSO)δ9.16(dd,J=2.4,1.1Hz,1H),8.56-8.51(m,J=8.1,4.1Hz,2H),8.49(s,1 H),7.70(s,1H),4.57(d,J=5.8Hz,2H),4.36(dd,J=13.0,3.5Hz,1H),4.20(tt,J=12.1,6.1Hz ,1H),3.30(s,3H),3.26-3.15(m,J=12.1Hz,2H),3.03(q,J=7.5Hz,2H),2.95(dd,J=17.3,12. 0Hz,1H), 2.34(d,J=0.7Hz,3H),2.33-2.30(m,1H),2.20-2.08(m,1H),1.29(t,J=7.5Hz,3H).

[1121] Synthesis of compound 47

[1122] [ka]

[1123] Compound 47 was synthesized from intermediates II-6a and I-147 and obtained as a white solid (20.5 mg, 10%). 1 H NMR(400MHz,DMSO)δ9.36(t,J=5.8Hz,1H),8.62(d,J=7.0Hz,1H),8.55(s,1H),7 .83-7.78(m,2H),7.60-7.55(m,1H),7.21(td,J=6.9,1.1Hz,1H),4.67(d,J=5.4 Hz,2H),4.38(dd,J=12.6,3.5Hz,1H),4.26-4.18(m,1H),3.26-3.18(m,2H),2.9 7(dd,J=17.6,12.3Hz,1H),2.34(d,J=10.9Hz,1H),2.15(qd,J=11.5,5.8Hz,1H).

[1124] Synthesis of compound 48

[1125] [ka]

[1126] Compound 48 was synthesized from intermediate II8b and I-88 and obtained as a white solid (1.28 g, 63%). 1 H NMR(400MHz,DMSO)δ8.97(d,J=3.1Hz,1H),8.52(d,J=3.1Hz,1H),8.47(t,J=5.9Hz,1H) ,7.96(d,J=8.3Hz,2H),7.45(d,J=8.3Hz,2H),4.58(d,J=5.7Hz,2H),4.38-4.27(m,1H), 4.17(td,J=12.1,4.8Hz,1H),3.86(s,3H),3.26-3.13(m,2H),3.03(q,J=7.5Hz,2H),2.9 2(dd,J=17.6,12.1Hz,1H),2.37-2.25(m,1H),2.19-2.03(m,1H),1.28(t,J=7.5Hz,3H).

[1127] Synthesis of compound 49

[1128] [ka]

[1129] Compound 49 was synthesized from intermediate II8b and I-87 and obtained as a white solid (1.10 g, 55%). 1H NMR(400MHz,DMSO)δ8.97(d,J=3.1Hz,1H),8.52(d,J=3.1Hz,1H),8.48(t,J=5.9Hz,1H),7 .96(d,J=8.3Hz,2H),7.45(d,J=8.3Hz,2H),4.58(d,J=5.9Hz,2H),4.37-4.26(m,1H),4.17 (td,J=12.0,4.8Hz,1H),3.86(s,3H),3.18(dd,J=9.5,8.3Hz,2H),3.03(q,J=7.5Hz,2H),2 .92(dd,J=17.6,12.1Hz,1H),2.38-2.26(m,1H),2.17-2.04(m,1H),1.28(t,J=7.5Hz,3H).

[1130] Synthesis of compound 50

[1131]

change

[1132] Compound 50を, intermediate II-101 and I-87 were synthesized, and the solid color of the compound was obtained (225 mg, 86%). 1 H NMR(400MHz,DMSO)δ9.08-9.04(m,1H),8.47(t,J=5.7Hz,1H),7.95(d,J=8.2Hz,2H),7.69(dd,J =9.8,5.4Hz,1H),7.53-7.47(m,1H),7.45(d,J=8.3Hz,2H),4.58(d,J=5.6Hz,2H),4.33(dd,J=1 2.7,3.7Hz,1H),4.17(td,J=12.0,4.8Hz,1H),3.23-3.15(m,2H),3.02(q,J=7.5Hz,2H),2.93(d d,J=17.5,12.1Hz,1H),2.32(dd,J=10.9,2.1Hz,1H),2.18-2.05(m,1H),1.27(t,J=7.5Hz,3H).

[1133] Synthesis of compound 51

[1134]

change

[1135] Compound 51 was synthesized from intermediates II-98 and I-87 and obtained as a white solid (264 mg, 97%). 1 H NMR(400MHz,DMSO)δ9.16(d,J=2.4Hz,1H),8.54-8.48(m,2H),7.95(d,J=8.3H z,2H),7.45(d,J=8.3Hz,2H),4.57(d,J=5.9Hz,2H),4.37-4.28(m,1H),4.17(t d,J=12.0,4.9Hz,1H),3.23-3.15(m,2H),3.02(q,J=7.5Hz,2H),2.92(dd,J=1 7.6,12.2Hz,1H),2.32-2.28(m,1H),2.17-2.05(m,1H),1.28(t,J=7.5Hz,3H).

[1136] Synthesis of compound 52

[1137] [ka]

[1138] Compound 52 was synthesized from intermediates II-101 and I-88 and obtained as a white solid (239 mg, 92%). 1 H NMR(400MHz,DMSO)δ9.07(dd,J=5.1,2.3Hz,1H),8.47(s,1H),7.96(d,J=8.2Hz,2H),7.70(dd,J= 9.8,5.3Hz,1H),7.53-7.47(m,1H),7.45(d,J=8.2Hz,2H),4.58(d,J=3.7Hz,2H),4.33(dd,J=12.8 ,3.5Hz,1H),4.17(td,J=12.2,4.7Hz,1H),3.24-3.16(m,2H),3.02(q,J=7.5Hz,2H),2.93(dd,J= 17.3,11.9Hz,1H),2.35-2.28(m,1H),2.12(ddd,J=24.5,11.5,5.7Hz,1H),1.28(t,J=7.5Hz,3H).

[1139] Synthesis of compound 53

[1140] [ka]

[1141] Compound 53 was synthesized from intermediates II-96 and I-88 and obtained as a yellow solid (22.1 mg, 12%). 1 H NMR (400 MHz, DMSO) δ 9.33 (t, J = 5.8 Hz, 1H), 9.05 (dd, J = 7.0, 2.0 Hz, 1H), 8.85 (dd, J = 4.1, 2.0 Hz, 1H), 7.98 (d, J = 8.3 Hz, 2H), 7.47 (d, J = 8.3 Hz, 2H), 7.36 (dd, J = 7.0, 4.1 Hz, 1H), 4.61 (d, J = 5.7 Hz, 2H), 4.37-4.31 (m, 1H), 4.23-4.14 (m, 1H), 3.25-3.15 (m, 3H), 2.99-2.89 (m, 1H), 2.19-2.06 (m, 1H). 1H overlapped with the solvent signal.

[1142] Synthesis of compound 54

[1143] [ka]

[1144] Compound 54 was synthesized from intermediates II-36 and I-88 and obtained as a pale yellow solid (61.9 mg, 32.5%). 1H NMR(400MHz,DMSO)δ9.14(t,J=6.0Hz,1H),7.94(d,J=8.3Hz,2H),7.38(d,J=8.3Hz,2H), 4.48(d,J=5.9Hz,2H),4.33(dd,J=12.8,3.5Hz,1H),4.17(td,J=12.0,4.8Hz,1H),3.93(t ,J=5.8Hz,2H),3.24-3.14(m,2H),2.93(dd,J=17.5,12.1Hz,1H),2.78(t,J=6.3Hz,2H),2 .34-2.28(m,1H),2.12(qd,J=11.5,5.8Hz,1H),1.91(d,J=4.2Hz,2H),1.88-1.79(m,2H).

[1145] Synthesis of compound 55

[1146]

change

[1147] Compound 55, intermediate II8b and I-88 were synthesized and a white solid was obtained (126.1 mg, 66%). 1 H NMR (400MHz, DMSO) δ8.99(dt,J=7.0,1.0Hz,1H),8.43(t,J=5.9Hz,1H),7.96(d,J=8.3Hz,2H),7. 64-7.57(m,1H),7.45(d,J=8.3Hz,2H),7.41-7.33(m,1H),7.01(td,J=6.9,1.2Hz,1H),4.58(d,J= 5.9Hz,2H),4.37-4.27(m,1H),4.17(td,J=11.9,4.7Hz,1H),3.26-3.12(m,2H),3.01(q,J=7.5Hz ,2H),2.93(dd,J=17.7,12.2Hz,1H),2.36-2.27(m,1H),2.19-2.05(m,1H),1.28(t,J=7.5Hz,3H).

[1148] Synthesis of compound 56

[1149]

change

[1150] Compound 56を, intermediate II-17a and I-88 were synthesized and a white solid was obtained (130 mg, 66%). 1 H NMR(400MHz,DMSO)δ8.33(t,J=5.6Hz,1H),7.94(d,J=8.3Hz,2H),7.38(d,J=8.3Hz,2H),4 .46(d,J=6.0Hz,2H),4.37-4.27(m,1H),4.17(td,J=12.0,4.8Hz,1H),4.01(t,J=5.8Hz,2 H),3.26-3.12(m,2H),2.92(dd,J=17.6,12.1Hz,1H),2.73(t,J=6.2Hz,2H),2.65(q,J=7. 5Hz,2H),2.37-2.27(m,1H),2.18-2.05(m,1H),1.93-1.75(m,4H),1.11(t,J=7.5Hz,3H).

[1151] Synthesis of compound 57

[1152]

change

[1153] Compound 57を, intermediate II-102 and I-87 were synthesized and a white solid was obtained (158 mg, 81%). 1 H NMR(400MHz,DMSO)δ8.99(d,J=6.9Hz,1H),8.45(t,J=5.9Hz,1H),7.95(d,J=8.3Hz,2H),7.60(d, J=9.0Hz,1H),7.45(d,J=8.3Hz,2H),7.40-7.35(m,1H),7.01(td,J=6.9,1.2Hz,1H),4.57(d,J=5 .8Hz,2H),4.33(dd,J=13.0,3.4Hz,1H),4.22-4.11(m,1H),3.25-3.15(m,2H),3.01(q,J=7.5Hz, 2H),2.93(dd,J=17.6,12.2Hz,1H),2.36-2.27(m,1H),2.18-2.05(m,1H),1.27(t,J=7.5Hz,3H).

[1154] Synthesis of compound 58

[1155] [ka]

[1156] Compound 58 was synthesized from intermediates II-36 and I-87 and obtained as a beige solid (95 mg, 42%). 1 H NMR(400MHz,DMSO)δ9.14(t,J=6.0Hz,1H),7.94(d,J=8.3Hz,2H),7.38(d,J=8.3Hz,2H), 4.48(d,J=5.9Hz,2H),4.33(dd,J=12.9,3.5Hz,1H),4.17(td,J=12.1,4.8Hz,1H),3.93(t ,J=5.8Hz,2H),3.26-3.12(m,2H),2.93(dd,J=18.0,12.3Hz,1H),2.78(t,J=6.3Hz,2H),2 .32-2.28(m,1H),2.12(qd,J=11.6,5.9Hz,1H),1.91(d,J=4.4Hz,2H),1.88-1.79(m,2H).

[1157] Synthesis of compound 59

[1158] [ka]

[1159] Compound 59 was synthesized from intermediates II-104 and I-88 and obtained as a white solid (85.9 mg, 56%). 1H NMR(400MHz,DMSO)δ9.16(d,J=2.4Hz,1H),8.59(d,J=2.5Hz,1H),8.52(t,J=6.0Hz,1H),7.96(d ,J=8.3Hz,2H),7.46(d,J=8.3Hz,2H),4.58(d,J=5.9Hz,2H),4.34(dd,J=12.8,4.1Hz,1H),4.23- 4.13(m,1H),3.24-3.14(m,2H),3.04(q,J=7.5Hz,2H),2.93(dd,J=17.8,12.5Hz,1H),2.72(q,J =7.2Hz,2H),2.33-2.29(m,1H),2.18-2.06(m,1H),1.29(t,J=7.5Hz,3H),1.24(t,J=7.5Hz,3H).

[1160] Synthesis of compound 60

[1161]

change

[1162] Compound 60, intermediate II-17b and I-87 were synthesized and a pale yellow solid was obtained (287 mg, 36%). 1 H NMR(400MHz,DMSO)δ9.06(s,1H),8.83(d,J=6.9Hz,1H),7.96(d,J=8.3Hz,2H),7.76(d,J= 9.1Hz,1H),7.53(ddd,J=9.1,6.8,1.2Hz,1H),7.47(d,J=8.3Hz,2H),7.36(t,J=53.9Hz,1H ),7.17(td,J=6.9,1.1Hz,1H),4.59(s,2H),4.37-4.28(m,1H),4.17(td,J=12.0,4.8Hz,1H ),3.25-3.15(m,2H),2.93(dd,J=17.7,12.2Hz,1H),2.36-2.28(m,1H),2.18-2.04(m,1H).

[1163] Synthesis of compound 61

[1164]

change

[1165] Compound 61 was synthesized from intermediates II-17b and I-88 and obtained as a beige solid (376 mg, 47%). 1 H NMR(400MHz,DMSO)δ9.05(t,J=5.6Hz,1H),8.82(d,J=7.0Hz,1H),7.96(d,J=8.3Hz,2H),7.76(dd ,J=9.1,1.0Hz,1H),7.53(ddd,J=9.1,6.8,1.2Hz,1H),7.47(d,J=8.3Hz,2H),7.35(t,J=53.8Hz, 1H),7.17(td,J=6.9,1.2Hz,1H),4.59(d,J=5.6Hz,2H),4.40-4.27(m,1H),4.17(td,J=12.1,4.9 Hz,1H),3.24-3.16(m,2H),2.93(dd,J=17.7,12.2Hz,1H),2.38-2.26(m,1H),2.21-2.03(m,1H).

[1166] Synthesis of compound 62

[1167] [ka]

[1168] Compound 62 was synthesized from intermediates II-104 and I-87 and obtained as a white solid (69.7 mg, 44%). 1H NMR (400MHz, DMSO) δ9.15(d,J=2.4Hz,1H),8.58(d,J=2.5Hz,1H),8.51(t,J=5.7Hz,1H),7.95(d,J =8.3Hz,2H),7.45(d,J=8.3Hz,2H),4.57(d,J=5.9Hz,2H),4.33(dd,J=12.8,3.7Hz,1H),4.21-4.1 2(m,1H),3.23-3.15(m,2H),3.03(q,J=7.5Hz,2H),2.93(dd,J=17.7,12.1Hz,1H),2.74-2.68(m,2 H),2.36-2.27(m,1H),2.11(qd,J=11.5,5.8Hz,1H),1.28(t,J=7.5Hz,3H),1.23(t,J=7.5Hz,3H).

[1169] Synthesis of compound 63

[1170]

change

[1171] Compound 63, intermediate II-19 and I-88 were synthesized and a white solid was obtained (115 mg, 51%). 1 H NMR(400MHz,DMSO)δ9.44(s,1H),8.65(t,J=5.8Hz,1H),7.97(d,J=8.3Hz,2H),7.84 (d,J=9.4Hz,1H),7.66(dd,J=9.4,1.9Hz,1H),7.47(d,J=8.3Hz,2H),4.60(d,J=5.9 Hz,2H),4.37-4.30(m,1H),4.24-4.13(m,1H),3.25-3.16(m,2H),3.06(q,J=7.5Hz, 2H),2.98-2.88(m,1H),2.33-2.28(m,1H),2.17-2.07(m,1H),1.30(t,J=7.5Hz,3H).

[1172] Synthesis of compound 64

[1173]

change

[1174] Compound 64 was synthesized from intermediates II-19 and I-87 and obtained as a white solid (82.4 mg, 55%). 1 H NMR(400MHz,DMSO)δ9.43(s,1H),8.64(t,J=5.9Hz,1H),7.96(d,J=8.3Hz,2H),7.83(d,J =9.4Hz,1H),7.65(dd,J=9.4,1.9Hz,1H),7.46(d,J=8.3Hz,2H),4.59(d,J=5.9Hz,2H),4 .37-4.29(m,1H),4.17(td,J=12.1,4.9Hz,1H),3.24-3.14(m,2H),3.09-3.00(m,2H),2. 93(dd,J=17.7,12.2Hz,1H),2.36-2.26(m,1H),2.18-2.05(m,1H),1.29(t,J=7.5Hz,3H).

[1175] Synthesis of compound 65

[1176] [ka]

[1177] Compound 65 was synthesized from intermediates II-32 and II-104 and obtained as a white solid (108.3 mg, 54%). 1H NMR (400MHz, DMSO) δ8.25(t,J=6.1Hz,1H),7.94(d,J=8.2Hz,2H),7.38(d,J=8.2Hz,2H),4.45(d,J=5.9Hz,2H),4.32 (dd,J=12.8,3.7Hz,1H),4.23-4.11(m,2H),3.46(dd,J=12.7,10.7Hz,1H),3.27-3.12(m,2H),2.92(dd,J=17.6,12.1 Hz,1H),2.79(ddd,J=17.0,5.5,2.8Hz,1H),2.73-2.59(m,3H),2.32(dd,J=10.8,2.2Hz,1H),2.18-2.05(m,1H),1.98 (d,J=5.6Hz,1H),1.87(d,J=12.1Hz,1H),1.46(qd,J=11.5,5.8Hz,1H),1.10(t,J=7.5Hz,3H),1.02(d,J=6.6Hz,3H).

[1178] Synthesis of compound 66

[1179]

change

[1180] Compound 66, intermediates II-35 and I-88 were synthesized and a solid color was obtained (126.7 mg, 69%). 1 H NMR (400MHz, DMSO) δ8.26(t,J=6.0Hz,1H),7.93(d,J=8.2Hz,2H),7.38(d,J=8.3Hz,2H),4.45(d,J=6.0Hz ,2H),4.32(dd,J=12.9,3.6Hz,1H),4.22-4.11(m,2H),3.91-3.80(m,1H),3.23-3.13(m,2H),2.92(dd,J= 17.6,12.1Hz,1H),2.84(dd,J=16.4,4.9Hz,1H),2.64(dt,J=8.3,6.8Hz,2H),2.35-2.23(m,2H),2.18-2. 05(m,1H),2.00-1.89(m,2H),1.53(qd,J=11.3,5.6Hz,1H),1.10(t,J=7.5Hz,3H),1.04(d,J=6.5Hz,3H).

[1181] Synthesis of compound 67

[1182] [ka]

[1183] Compound 67 was synthesized from intermediates II-34 and I-87 and obtained as a white solid (123 mg, 64%). 1 H NMR(400MHz,DMSO)δ8.25(t,J=6.0Hz,1H),7.94(d,J=8.2Hz,2H),7.38(d,J=8.3Hz,2H),4. 46(d,J=6.0Hz,2H),4.38-4.29(m,1H),4.22-4.13(m,2H),3.93-3.82(m,1H),3.24-3.14(m, 2H),2.98-2.88(m,1H),2.88-2.80(m,1H),2.68-2.61(m,2H),2.38-2.24(m,2H),2.19-2.05 (m,1H),2.01-1.87(m,2H),1.59-1.46(m,1H),1.11(t,J=7.5Hz,3H),1.05(d,J=6.5Hz,3H).

[1184] Synthesis of compound 68

[1185] [ka]

[1186] Compound 68 was synthesized from intermediates II-35 and I-87 and obtained as a white solid (121.2 mg, 64%). 1HNMR(400MHz,DMSO)δ8.25(t,J=6.0Hz,1H),7.93(d,J=8.3Hz,2H),7.38(d,J=8.3Hz,2H),4. 45(d,J=6.0Hz,2H),4.36-4.28(m,1H),4.22-4.12(m,2H),3.91-3.82(m,1H),3.25-3.13(m, 2H),2.99-2.88(m,1H),2.87-2.79(m,1H),2.69-2.60(m,2H),2.37-2.23(m,2H),2.18-2.04 (m,1H),2.01-1.87(m,2H),1.58-1.47(m,1H),1.10(t,J=7.5Hz,3H),1.04(d,J=6.5Hz,3H).

[1187] Synthesis of compound 69

[1188]

change

[1189] Compound 69を, intermediate II-33 and I-87 were synthesized, and a solid color of the color was obtained (89 mg, 45%). 1 H NMR (400MHz, DMSO) δ8.26(t,J=6.0Hz,1H),7.94(d,J=8.3Hz,2H),7.38(d,J=8.3Hz,2H),4.52-4.39(m,2H),4.32(dd, J=12.8,3.7Hz,1H),4.23-4.10(m,2H),3.46(dd,J=12.8,10.6Hz,1H),3.24-3.12(m,2H),2.98-2.86(m,1H),2.80(dd d,J=17.0,5.5,2.9Hz,1H),2.73-2.60(m,3H),2.32(dd,J=10.7,2.1Hz,1H),2.11(qd,J=11.5,5.9Hz,1H),2.00(dd,J =14.2,6.3Hz,1H),1.87(d,J=11.8Hz,1H),1.46(qd,J=11.5,5.8Hz,1H),1.11(t,J=7.5Hz,3H),1.02(d,J=6.6Hz,3H).

[1190] Synthesis of compound 70

[1191] [ka]

[1192] Compound 70 was synthesized from intermediates II-34 and I-88 and obtained as a white solid (118.6 mg, 61%). 1 H NMR(400MHz,DMSO)δ8.26(t,J=5.8Hz,1H),7.93(d,J=8.3Hz,2H),7.38(d,J=8.3Hz,2H),4.45(d,J= 6.0Hz,2H),4.36-4.26(m,1H),4.21-4.13(m,2H),3.87(td,J=13.0,4.5Hz,1H),3.25-3.14(m,2H),2 .92(dd,J=17.6,12.1Hz,1H),2.84(dd,J=16.2,5.1Hz,1H),2.68-2.60(m,2H),2.36-2.25(m,2H),2. 18-2.04(m,1H),2.00-1.90(m,2H),1.59-1.46(m,1H),1.11(t,J=7.5Hz,3H),1.04(d,J=6.5Hz,3H).

[1193] Synthesis of compound 71

[1194] [ka]

[1195] Compound 71 was synthesized from intermediates II-32 and I-88 and obtained as a white solid (79.5 mg, 37%). 1H NMR (400MHz, DMSO) δ8.29-8.24(m,1H),7.94(d,J=8.2Hz,2H),7.39(d,J=8.3Hz,2H),4.46(d,J=5.9Hz,2H),4.37 -4.29(m,1H),4.22-4.14(m,2H),3.47(dd,J=12.8,10.7Hz,1H),3.24-3.16(m,2H),2.93(dd,J=17.5,12.2Hz,1H ),2.80(ddd,J=16.9,5.5,2.8Hz,1H),2.74-2.61(m,3H),2.37-2.29(m,1H),2.12(qd,J=11.4,5.7Hz,1H),2.03- 1.94(m,1H),1.88(d,J=11.7Hz,1H),1.46(qd,J=11.6,5.7Hz,1H),1.11(t,J=7.5Hz,3H),1.03(d,J=6.6Hz,3H).

[1196] Synthesis of compound 72

[1197]

change

[1198] Compound 72を, intermediate II-33 and I-88 were synthesized and a solid color was obtained (101.4 mg, 59%). 1H NMR(400MHz,DMSO)δ8.27-8.22(m,1H),7.94(d,J=8.2Hz,2H),7.38(d,J=8.3Hz,2H),4.45(d,J=5.9Hz,2H),4.32( dd,J=12.9,3.5Hz,1H),4.21-4.12(m,2H),3.46(dd,J=12.8,10.7Hz,1H),3.23-3.14(m,2H),2.92(dd,J=17.6,12 .1Hz,1H),2.80(ddd,J=17.0,5.4,2.8Hz,1H),2.72-2.60(m,3H),2.32(dd,J=10.8,2.1Hz,1H),2.18-2.05(m,1H) ,2.03-1.92(m,1H),1.88(dd,J=11.3,2.5Hz,1H),1.52-1.40(m,1H),1.11(t,J=7.5Hz,3H),1.02(d,J=6.6Hz,3H).

[1199] Synthesis of compounds 73 and 74

[1200] [ka]

[1201] Isomers 73 and 74 were synthesized from intermediates II-83 and I-37 and separated by SFC (Jasco SFC prep system, i-cellulose column (Phenomenex) 250 * After 30 nm, 5 mm particle size, 100 ml / min, CO2 (50%) / EtOH (50%) / diethylamine (0.1%), 30 °C, 150 bar, isocratic mode, 73 (R * ) (111.4 mg, 35%) and 74 (S * ) (109.5 mg, 34%) was obtained as a beige solid.

[1202] 73: 11H NMR (400 MHz, DMSO) δ 9.34 (dd, J = 6.9, 2.0 Hz, 1H), 8.62 (dd, J = 4.2, 2.0 Hz, 1H), 8.57 (t, J = 6.0 Hz, 1H), 7.95 (t, J = 7.8 Hz, 1H), 7.30 (d, J = 9.3 Hz, 2H), 7.17 (dd, J = 6.9, 4.2 Hz, 1H), 4.59 (d, J = 5.9 Hz, 2H), 4.40 - 4.28 (m, 1H), 4.24 - 4.11 (m, 1H), 3.26 - 3.14 (m, 2H), 3.06 (q, J = 7.5 Hz, 2H), 2.94 (dd, J = 17.7, 12.3 Hz, 1H), 2.37 - 2.27 (m, 1H), 2.19 - 2.06 (m, 1H), 1.30 (t, J = 7.5 Hz, 3H).

[1203] 74: 1 1H NMR (400 MHz, DMSO) δ 9.34 (dd, J = 6.9, 2.0 Hz, 1H), 8.62 (dd, J = 4.2, 2.0 Hz, 1H), 8.55 (t, J = 6.0 Hz, 1H), 7.95 (t, J = 7.8 Hz, 1H), 7.30 (d, J = 9.4 Hz, 2H), 7.17 (dd, J = 6.9, 4.2 Hz, 1H), 4.59 (d, J = 5.9 Hz, 2H), 4.42 - 4.28 (m, 1H), 4.18 (td, J = 12.0, 4.7 Hz, 1H), 3.27 - 3.14 (m, 2H), 3.05 (q, J = 7.5 Hz, 2H), 2.94 (dd, J = 17.7, 12.3 Hz, 1H), 2.37 - 2.27 (m, 1H), 2.19 - 2.05 (m, 1H), 1.30 (t, J = 7.5 Hz, 3H).

[1204] Synthesis of Compound 75

[1205]

Chem.

[1206] Compound 75 was synthesized from intermediates II-82 and I-87 and obtained as a white solid (150.1 mg, 65.6%). 1H NMR (400 MHz, DMSO) δ 7.93 (d, J = 8.2 Hz, 2H), 7.84 (t, J = 6.0 Hz, 1H), 7.37 (d, J = 8.3 Hz, 2H), 4.48-4.37 (m, 2H), 4.35-4.29 (m, 1H), 4.21-4.05 (m, 2H), 3.96-3.88 (m, 1H), 3.23-3.15 (m, 2H), 3.05 (dd, J = 16.6, 4 .5Hz,1H),2.97-2.87(m,1H),2.70(q,J=7.5Hz,2H),2.47-2.41(m,1H),2.35-2.28(m,1H),2.11(qd,J =11.5,5.9Hz,1H),2.00-1.86(m,2H),1.68-1.56(m,1H),1.10(t,J=7.5Hz,3H),1.06(d,J=6.5Hz,3H).

[1207] Synthesis of compounds 76 and 77

[1208] [ka]

[1209] Isomers 76 and 77 were synthesized from intermediates II-17a and I-6 and separated by SFC (Jasco SFC prep system, i-cellulose column (Phenomenex) 250 * After 30 nm, 5 mm particle size, 100 ml / min, CO2 (50%) / EtOH (50%) / diethylamine (0.1%), 30 °C, 150 bar in isocratic mode, 76 (R * ) (64.8 mg, 24%) and 77 (S * ) (70.5 mg, 26%) was obtained as a white solid.

[1210] 76: 11H NMR (400 MHz, DMSO) δ 8.28 (t, J = 6.0 Hz, 1H), 7.93 (dd, J = 9.8, 6.1 Hz, 1H), 7.22 (dd, J = 9.4, 4.8 Hz, 2H), 4.46 (d, J = 6.0 Hz, 2H), 4.35 (dd, J = 12.8, 3.7 Hz, 1H), 4.18 (td, J = 12.1, 4.9 Hz, 1H), 3.99 (t, J = 5.8 Hz, 2H), 3.25 - 3.14 (m, 2H), 2.94 (dd, J = 17.6, 12.1 Hz, 1H), 2.71 (dd, J = 11.4, 5.3 Hz, 2H), 2.66 (q, J = 7.5 Hz, 2H), 2.32 (ddd, J = 8.7, 4.8, 2.3 Hz, 1H), 2.19 - 2.07 (m, 1H), 1.90 - 1.71 (m, 4H), 1.11 (t, J = 7.5 Hz, 3H).

[1211] 77: 1 1H NMR (400 MHz, DMSO) δ 8.28 (t, J = 6.0 Hz, 1H), 7.94 (dd, J = 10.2, 5.8 Hz, 1H), 7.23 (dd, J = 9.4, 4.9 Hz, 2H), 4.47 (d, J = 6.0 Hz, 2H), 4.35 (dd, J = 12.8, 3.6 Hz, 1H), 4.19 (td, J = 12.0, 4.8 Hz, 1H), 4.00 (t, J = 5.8 Hz, 2H), 3.28 - 3.12 (m, 2H), 2.94 (dd, J = 17.6, 12.2 Hz, 1H), 2.72 (t, J = 6.2 Hz, 2H), 2.66 (q, J = 7.5 Hz, 2H), 2.33 (ddd, J = 8.8, 4.8, 2.5 Hz, 1H), 2.13 (ddd, J = 24.9, 11.5, 5.8 Hz, 1H), 1.83 (dd, J = 25.1, 4.6 Hz, 4H), 1.12 (t, J = 7.5 Hz, 3H).

[1212] Synthesis of Compounds 78 and 79

[1213] [[ID=!4]]

Chem.

[1214] Isomers 78 and 79 were synthesized from intermediates I-37 and II-85 and separated by SFC (Jasco SFC prep system, amylose column (Regis Technologies) 250 * After 78 (R * )(76mg, 20%) and 79(S * ) (62.6 mg, 16%) was obtained as a white solid.

[1215] 78: 1 H NMR(400MHz,DMSO)δ9.00(d,J=6.9Hz,1H),8.45(t,J=5.9Hz,1H),7.95(t,J=8.0Hz,1H),7.61(d, J=9.0Hz,1H),7.41-7.36(m,1H),7.31(s,1H),7.28(d,J=3.1Hz,1H),7.02(td,J=6.9,1.2Hz,1H) ,4.58(d,J=5.9Hz,2H),4.39-4.30(m,1H),4.18(td,J=11.8,4.5Hz,1H),3.25-3.15(m,2H),3.02 (q,J=7.5Hz,2H),2.98-2.89(m,1H),2.36-2.29(m,1H),2.18-2.07(m,1H),1.28(t,J=7.5Hz,3H).

[1216] 79: 1H NMR(400MHz,DMSO)δ9.00(d,J=7.0Hz,1H),8.45(t,J=6.0Hz,1H),7.95(t,J=8.0Hz,1H),7.61(d ,J=9.0Hz,1H),7.39(dd,J=7.9,6.6Hz,1H),7.31(s,1H),7.28(d,J=3.4Hz,1H),7.03-6.99(m,1 H),4.58(d,J=6.2Hz,2H),4.34(d,J=11.6Hz,1H),4.23-4.14(m,1H),3.24-3.17(m,2H),3.03(t ,J=7.5Hz,2H),2.98-2.88(m,1H),2.35-2.28(m,1H),2.20-2.05(m,1H),1.28(t,J=7.5Hz,3H).

[1217] Synthesis of compound 80

[1218]

change

[1219] Compound 80を, intermediate I-87(R) and II-37 were synthesized and a white solid was obtained (123.3 mg, 60%). 1 H NMR(400MHz,DMSO)δ8.82(t,J=5.8Hz,1H),7.94(d,J=8.2Hz,2H),7.39(d,J=8.2Hz,2H), 6.95(t,J=54.3Hz,1H),4.48(d,J=5.9Hz,2H),4.36-4.29(m,1H),4.23-4.12(m,1H),4.04 (t,J=5.5Hz,2H),3.23-3.14(m,2H),2.93(dd,J=17.7,12.0Hz,1H),2.79(t,J=6.3Hz,2H ),2.32(d,J=7.6Hz,1H),2.19-2.05(m,1H),1.90(d,J=4.9Hz,2H),1.83(d,J=4.7Hz,2H).

[1220] Synthesis of Compound 81

[1221]

change

[1222] Compound 81 was synthesized from intermediates I-87(S) and II-81 and obtained as a pale yellow oil (134.1 mg, 73%). 1 H NMR(400MHz,DMSO)δ7.93(d,J=8.3Hz,2H),7.83(t,J=6.0Hz,1H),7.37(d,J=8.3Hz,2H),4.49-4.37(m,2H),4.36-4.27( m,1H),4.18(dd,J=11.6,4.8Hz,1H),4.10(dtd,J=10.7,8.2,5.2Hz,1H),3.97-3.86(m,1H),3.26-3.13(m,2H),3.05(dd, J=16.5,4.4Hz,1H),2.97-2.87(m,1H),2.74-2.66(m,2H),2.48-2.40(m,1H),2.37-2.27(m,1H),2.19-2.05(m,1H),1.98 (t,J=12.7Hz,1H),1.93-1.83(m,1H),1.62(ddd,J=24.1,11.3,5.7Hz,1H),1.10(t,J=7.5Hz,3H),1.06(d,J=6.5Hz,3H).

[1223] Synthesis of compound 82

[1224] [ka]

[1225] Compound 82 was synthesized from intermediates I-87(R) and II-82 and obtained as a pale yellow solid (134.1 mg, 73%). 1HNMR(400MHz,DMSO)δ7.93(d,J=8.2Hz,2H),7.83(t,J=6.0Hz,1H),7.37(d,J=8.3Hz,2H),4.43(d,J =4.4Hz,2H),4.36-4.28(m,1H),4.22-4.06(m,2H),3.98-3.87(m,1H),3.24-3.14(m,2H),3.05(dd, J=16.7,4.2Hz,1H),2.92(dd,J=17.6,12.1Hz,1H),2.70(q,J=7.5Hz,2H),2.48-2.41(m,1H),2.32( dd,J=11.1,2.1Hz,1H),2.19-2.05(m,1H),2.01-1.84(m,2H),1.69-1.55(m,1H),1.13-1.02(m,6H).

[1226] Synthesis of compound 83

[1227] [ka]

[1228] Compound 83 was synthesized from intermediates I-87(R) and II-81 and obtained as a pale yellow solid (134.1 mg, 73%). 1H NMR (400MHz, DMSO) δ7.93(d,J=8.3Hz,2H),7.83(t,J=6.0Hz,1H),7.37(d,J=8.3Hz,2H),4.49-4.37(m,2H),4.32(dd,J=12.8,3. 7Hz,1H),4.17(td,J=12.1,5.0Hz,1H),4.09(ddd,J=12.8,5.4,2.7Hz,1H),3.97-3.87(m,1H),3.25-3.13(m,2H),3.05(dd,J=16. 6,4.4Hz,1H),2.97-2.86(m,1H),2.70(q,J=7.5Hz,2H),2.48-2.40(m,1H),2.32(dd,J=11.1,2.1Hz,1H),2.11(qd,J=11.5,5.9H z,1H),1.97(d,J=16.3Hz,1H),1.91(d,J=5.6Hz,1H),1.62(qd,J=11.3,5.7Hz,1H),1.10(t,J=7.5Hz,3H),1.06(d,J=6.5Hz,3H).

[1229] Synthesis of compound 84

[1230]

change

[1231] Compound 84を, intermediates I-87(S) and II-88 were synthesized and a white solid was obtained (17.1 mg, 27%). 1 H NMR(400MHz,DMSO)δ9.54(d,J=2.3Hz,1H),8.83(d,J=2.6Hz,1H),8.65(t,J=5.8Hz,1H),7 .95(d,J=8.3Hz,2H),7.46(d,J=8.3Hz,2H),4.59(d,J=5.8Hz,2H),4.33(dd,J=12.9,3.6Hz ,1H),4.17(td,J=11.9,4.8Hz,1H),3.24-3.15(m,2H),3.08(q,J=7.5Hz,2H),2.92(dd,J= 17.7,12.3Hz,1H),2.32(dd,J=10.7,2.0Hz,1H),2.17-2.07(m,1H),1.30(t,J=7.5Hz,3H).

[1232] Synthesis of compound 85

[1233] [ka]

[1234] Compound 85 was synthesized from intermediates I-87(R) and II-88 and obtained as a white solid (20.7 mg, 26%). 1 H NMR(400MHz,DMSO)δ9.54(d,J=2.7Hz,1H),8.83(d,J=2.8Hz,1H),8.65(t,J=5.9Hz,1 H),7.95(d,J=8.2Hz,2H),7.46(d,J=8.2Hz,2H),4.59(d,J=5.9Hz,2H),4.36-4.29(m ,1H),4.17(td,J=12.1,4.7Hz,1H),3.23-3.15(m,2H),3.08(q,J=7.5Hz,2H),2.92(d d,J=17.7,12.2Hz,1H),2.36-2.28(m,1H),2.18-2.05(m,1H),1.30(t,J=7.5Hz,3H).

[1235] Synthesis of compounds 86 and 87

[1236] [ka]

[1237] Isomers 86 and 87 were synthesized from intermediates I-37 and II-85 and separated by SFC (Jasco SFC prep system, i-cellulose column (Regis Technologies) 250 * After elution (30 mm, 5 mm particle size, 40 ml / min, CO (50%) / EtOH (50%) / diethylamine (0.1%), 30 °C, 120 bar, isocratic mode) 86(R) (83.9 mg, 33%) and 87(S) (82.4 mg, 33%) were obtained as beige solids.

[1238] 86: 1H NMR(400MHz,DMSO)δ9.32(dd,J=6.9,2.0Hz,1H),8.62(dd,J=4.2,2.0Hz,1H),8.54(t,J=5.9Hz,1H ),7.87(d,J=7.8Hz,1H),7.27(d,J=8.8Hz,2H),7.16(dd,J=6.9,4.2Hz,1H),4.55(d,J=5.9Hz,2H) ,4.41-4.29(m,1H),4.18(td,J=12.1,4.9Hz,1H),3.26-3.14(m,2H),3.05(q,J=7.5Hz,2H),2.93( dd,J=17.4,12.0Hz,1H),2.58(s,3H),2.36-2.27(m,1H),2.20-2.06(m,1H),1.30(t,J=7.5Hz,3H).

[1239] 87: 1 H NMR(400MHz,DMSO)δ9.32(dd,J=6.9,2.0Hz,1H),8.62(dd,J=4.2,2.0Hz,1H),8.54(t,J=6.0Hz,1H ),7.87(d,J=7.8Hz,1H),7.27(d,J=8.8Hz,2H),7.17(dd,J=6.9,4.2Hz,1H),4.55(d,J=5.9Hz,2H) ,4.39-4.28(m,1H),4.18(td,J=12.0,4.8Hz,1H),3.26-3.14(m,2H),3.05(q,J=7.5Hz,2H),2.93( dd,J=17.4,12.0Hz,1H),2.58(s,3H),2.38-2.28(m,1H),2.20-2.07(m,1H),1.30(t,J=7.5Hz,3H).

[1240] Synthesis of compound 88

[1241]

change

[1242] Compound 88を, intermediate I-132 and II-3a were synthesized and a white solid was obtained (75.4 mg, 39%). 1H NMR(400MHz,DMSO)δ9.14(s,1H),8.51(d,J=2.3Hz,1H),8.46(t,J=5.9Hz,1H),7.68(d,J=8.1Hz,2H),7.42(s,1H),7.32(d,J=8.1Hz,2H),4.5 1(d,J=5.8Hz,2H),3.95(t,J=5.7Hz,2H),3.00(q,J=7.5Hz,2H),2.74(t,J=6.2Hz,2H),2.34(s,3H),1.95-1.80(m,4H),1.27(t,J=7.5Hz,3H).

[1243] Synthesis of compound 89

[1244]

change

[1245] Compound 89を, intermediate I-131 and II-3a were synthesized and a white solid was obtained (64.1 mg, 37%). 1 H NMR(400MHz,DMSO-d6)δ9.15(dd,J=2.1,1.0Hz,1H),8.51(d,J=2.4Hz,1H),8.47(t,J=6.0Hz,1H),7.68(d ,J=8.2Hz,2H),7.44(s,1H),7.32(d,J=8.2Hz,2H),4.51(d,J=5.9Hz,2H),4.05(ddd,J=12.5,5.4,2.7Hz, 1H),3.89(td,J=11.7,4.6Hz,1H),3.01(q,J=7.5Hz,2H),2.88(dd,J=17.2,5.6Hz,1H),2.33(d,J=5.0Hz, 4H),2.07-1.90(m,2H),1.60(dtd,J=13.7,11.3,5.8Hz,1H),1.27(t,J=7.5Hz,3H),1.07(d,J=6.5Hz,3H).

[1246] Synthesis of compound 90

[1247]

change

[1248] Compound 90を, intermediate II-110 and II-8e were synthesized and a white solid was obtained (94.5 mg, 21%). 1 H NMR(400MHz,DMSO)δ9.35(s,1H),8.49(t,J=5.9Hz,1H),7.69(d,J=8.2Hz,2H),7.52 (s,1H),7.33(d,J=8.2Hz,2H),4.51(d,J=5.8Hz,2H),4.23-4.10(m,1H),3.98(td,J= 12.1,4.4Hz,1H),3.11-3.04(m,2H),3.01(q,J=7.5Hz,2H),2.77(dd,J=17.3,12.7Hz ,1H),2.61(s,3H),2.23(d,J=11.2Hz,1H),2.01-1.88(m,1H),1.27(t,J=7.5Hz,3H).

[1249] Synthesis of Compound 91

[1250]

change

[1251] Compound 91, intermediate I-131 and II-8a were synthesized and a white solid was obtained (120 mg, 53%). 1 H NMR (400MHz, DMSO) δ9.18(d,J=7.0Hz,1H),8.41(t,J=5.9Hz,1H),7.67(d,J=8.2Hz,2H),7.43(s,1H),7. 31(d,J=8.2Hz,2H),7.05(d,J=7.1Hz,1H),4.50(d,J=5.8Hz,2H),4.05(ddd,J=12.4,5.4,2.8Hz,1H),3. 88(td,J=11.9,4.7Hz,1H),2.99(q,J=7.5Hz,2H),2.87(dd,J=16.4,4.9Hz,1H),2.54(s,3H),2.32(dd,J =16.3,10.3Hz,1H),2.05-1.90(m,2H),1.67-1.52(m,1H),1.26(t,J=7.5Hz,3H),1.07(d,J=6.5Hz,3H).

[1252] Synthesis of Compound 92

[1253] [ka]

[1254] Compound 92 was synthesized from intermediates I-16 and II-8a and obtained as a white solid (90.1 mg, 41%). 1 H NMR(400MHz,DMSO)δ9.20(d,J=7.0Hz,1H),8.45(t,J=5.8Hz,1H),7.93(d,J=8.2Hz ,2H),7.43(d,J=8.2Hz,2H),7.05(d,J=7.1Hz,1H),4.56(d,J=5.8Hz,2H),4.27-4. 17(m,1H),4.15-3.96(m,1H),3.05-2.93(m,3H),2.55(s,3H),2.47-2.40(m,1H),2 .15-1.99(m,2H),1.81-1.67(m,1H),1.27(t,J=7.5Hz,3H),1.10(d,J=6.6Hz,3H).

[1255] Synthesis of compounds 93 and 94

[1256] [ka]

[1257] Isomers 93 and 94 were synthesized from intermediates I-16 and II-3a and separated by SFC (Jasco SFC prep system, amylose column (Phenomenex) 250 * After isocratic mixing (30 mm, 5 mm particle size, CO2 (50%) / EtOH (50%) / diethylamine (0.1%)), compound 93 (R * ) (542 mg, 39%) and Intermediate 94 (S * ) (543 mg, 40%) was obtained as a beige solid.

[1258] 93: 1H NMR(400MHz,DMSO)δ9.16(s,1H),8.51(d,J=2.3Hz,1H),8.51-8.48(m,1H),7.94(d,J=8 .2Hz,2H),7.43(d,J=8.2Hz,2H),4.57(d,J=5.6Hz,2H),4.22(ddd,J=12.5,5.6,2.8Hz,1 H),4.15-4.02(m,1H),3.06-2.99(m,2H),2.99-2.94(m,1H),2.48-2.40(m,1H),2.34(s, 3H),2.14-1.96(m,2H),1.82-1.66(m,1H),1.28(t,J=7.5Hz,3H),1.10(d,J=6.6Hz,3H).

[1259] 94: 1 H NMR(400MHz,DMSO)δ9.16(d,J=1.2Hz,1H),8.51(d,J=2.4Hz,1H),8.51-8.48(m,1H),7.94( d,J=8.2Hz,2H),7.43(d,J=8.2Hz,2H),4.57(d,J=5.6Hz,2H),4.22(ddd,J=12.7,5.9,3.0Hz ,1H),4.13-4.02(m,1H),3.02(q,J=7.5Hz,2H),3.00-2.93(m,1H),2.45-2.39(m,1H),2.34 (s,3H),2.12-1.93(m,2H),1.82-1.67(m,1H),1.28(t,J=7.5Hz,3H),1.10(d,J=6.5Hz,3H).

[1260] Synthesis of Compound 95

[1261]

change

[1262] Compound 95, intermediate I-86 and II-3a were synthesized and a white solid was obtained (63.7 mg, 51%). 1H NMR(400MHz,DMSO)δ9.15(d,J=1.2Hz,1H),8.51(d,J=2.4Hz,1H),8.47(t,J=5 .9Hz,1H),7.72(d,J=8.2Hz,2H),7.37(d,J=8.2Hz,2H),6.41(s,1H),4.54(d, J=5.9Hz,2H),4.07(t,J=6.1Hz,2H),3.01(q,J=7.5Hz,2H),2.76(t,J=6.3Hz, 2H),2.34(s,3H),2.01-1.94(m,2H),1.84-1.74(m,2H),1.28(t,J=7.5Hz,3H).

[1263] Synthesis of Compound 96

[1264]

change

[1265] Compound 96, intermediate I-89 and II-3a were synthesized and a white solid was obtained (21.4 mg, 20%). 1 H NMR (400MHz, DMSO) δ9.16(dd,J=2.2,1.1Hz,1H),8.50(dd,J=9.8,4.2Hz,2H),7.95(d,J=8.2Hz,2H),7.45(d,J=8.2Hz,2H),5.49-5.28(m,1H ),4.57(d,J=5.9Hz,2H),4.38-4.09(m,2H),3.29-3.15(m,2H),3.02(q,J=7.5Hz,2H),2.46-2.22(m,2H),2.34(s,3H),1.28(t,J=7.5Hz,3H).

[1266] Synthesis of compound 97

[1267]

change

[1268] Compound 97, intermediate I-16 and II-3a were synthesized and a white solid was obtained (115 mg, 41%). 1H NMR (400MHz, DMSO) δ9.17(d,J=1.1Hz,1H),8.52(d,J=2.4Hz,1H),8.49(t,J=5.9Hz,1H),7.94( t,J=7.8Hz,1H),7.28(d,J=6.5Hz,1H),7.27(s,1H),4.58(d,J=5.9Hz,2H),4.24(ddd,J=12.6, 5.6,2.9Hz,1H),4.16-4.03(m,1H),3.08-2.93(m,3H),2.48-2.42(m,1H),2.34(s,3H),2.20-2 .01(m,2H),1.75(dtd,J=13.4,10.8,5.8Hz,1H),1.29(t,J=7.5Hz,3H),1.10(d,J=6.6Hz,3H).

[1269] Synthesis of compound 98

[1270]

change

[1271] Compound 98, intermediate I-126 and II-3a were synthesized and a white solid was obtained (213 mg, 58%). 1 H NMR(400MHz,DMSO)δ9.16(s,1H),8.50(dd,J=10.7,4.2Hz,2H),7.94(d,J=8.2Hz,2H),7 .44(d,J=8.2Hz,2H),4.57(d,J=5.9Hz,2H),4.22-4.07(m,2H),4.07-4.00(m,1H),3.64 -3.47(m,2H),3.10(dd,J=17.1,4.3Hz,1H),3.02(q,J=7.5Hz,2H),2.92(dd,J=17.1,4. 6Hz,1H),2.34(s,3H),2.27-2.11(m,2H),1.28(t,J=7.5Hz,3H),1.11(t,J=7.0Hz,3H).

[1272] Synthesis of compound 99

[1273]

change

[1274] Compound 99 was synthesized from intermediates I-51 and II-8a and obtained as a beige solid (85 mg, 66%). 1 H NMR(400MHz,DMSO)δ9.20(d,J=7.0Hz,1H),8.46(t,J=5.8Hz,1H),7.93(s,2H),7.44(d,J=8.1 Hz,2H),7.05(d,J=7.1Hz,1H),6.20(td,J=56.3,3.9Hz,1H),4.56(d,J=5.7Hz,2H),4.40-4.2 4(m,1H),4.13(td,J=12.1,4.8Hz,1H),3.09-2.95(m,3H),2.79(dd,J=16.7,10.8Hz,1H),2.7 1-2.58(m,1H),2.55(s,3H),2.20(d,J=11.9Hz,1H),2.03-1.83(m,1H),1.27(t,J=7.5Hz,3H).

[1275] Synthesis of Compound 100

[1276] [ka]

[1277] Compound 100 was synthesized from intermediates I-81 and II-94 and obtained as a yellow solid (78.3 mg, 46%). 1 H NMR(400MHz,DMSO)δ9.06(dd,J=2.3,1.1Hz,1H),8.56(t,J=5.9Hz,1H),8.50(d,J=2.4Hz,1H), 7.70(d,J=8.2Hz,2H),7.54(s,1H),7.34(d,J=8.3Hz,2H),4.52(d,J=5.9Hz,2H),4.16(dd,J=1 2.6,3.5Hz,1H),3.98(td,J=12.2,4.6Hz,1H),3.65-3.50(m,1H),3.19-3.01(m,2H),2.78(dd, J=17.3,12.6Hz,1H),2.33(s,3H),2.28-2.19(m,1H),2.06-1.86(m,1H),1.28(d,J=6.7Hz,6H).

[1278] Synthesis of Compound 101

[1279] [ka]

[1280] Compound 101 was synthesized from intermediates I-135 and II-6a and obtained as a beige solid (47.2 mg, 23%). 1 H NMR(400MHz,DMSO)δ9.33(t,J=5.6Hz,1H),8.60(d,J=7.0Hz,1H),8.43(s,1H),7.8 0(d,J=9.1Hz,1H),7.69-7.63(m,2H),7.57(ddd,J=9.1,6.8,1.2Hz,1H),7.21(td,J =6.9,1.1Hz,1H),4.61(d,J=5.5Hz,2H),4.29-4.19(m,1H),4.06-3.95(m,1H),3.15 -3.06(m,2H),2.81(dd,J=17.4,12.8Hz,1H),2.30-2.20(m,1H),2.06-1.89(m,1H).

[1281] Synthesis of Compound 102

[1282] [ka]

[1283] Compound 102 was synthesized from intermediates I-120 and II-3a and obtained as a pale orange-yellow solid (105.1 mg, 57%). 1H NMR(400MHz,DMSO)δ9.16(dd,J=2.4,1.1Hz,1H),8.54-8.47(m,2H),7.94(d,J=8.3Hz,2H),7.43(d ,J=8.3Hz,2H),4.57(d,J=5.9Hz,2H),4.23(ddd,J=12.7,5.5,3.0Hz,1H),4.08(td,J=11.7,4.7Hz, 1H),3.38(dq,J=6.0,2.9Hz,2H),3.29(s,3H),3.06-2.93(m,3H),2.60-2.53(m,1H),2.33(dd,J=6. 1,1.3Hz,3H),2.31-2.24(m,1H),2.13(d,J=13.4Hz,1H),1.85-1.72(m,1H),1.27(q,J=7.1Hz,3H).

[1284] Synthesis of Compounds 103, 104, and 105

[1285] [ka]

[1286] Racemic compound 103 was synthesized from intermediates I-133 and II-3a and obtained as a white solid (128 mg, 80%).

[1287] The isomers were separated by SFC (Jasco SFC prep system, i-cellulose column (Phenomenex) 250 * 30 mm, 5 mm particle size, 100 ml / min, CO2 (40%) / MeOH (60%) / diethylamine (0.1%), isocratic mode at 30 °C and 120 bar), Compound 104 ( * R) and Compound 105( * S) was obtained as a white solid.

[1288] 103: 1H NMR(400MHz,DMSO)δ9.16(dd,J=2.3,1.1Hz,1H),8.54-8.46(m,2H),7.95(d,J=8.3Hz,2H),7.44(d,J=8.3Hz,2H),4.57(d,J=5.8Hz,2H),4.30(dd,J=12.7,3.5Hz,1H),4.12(td,J=12.0,4.6Hz,1H),3.09(dd,J=16.6,4.0Hz,1H),3.02(q,J=7.5Hz,2H),2.79(dd,J=16.5,11.5Hz,1H),2.69-2.64(m,1H),2.34(s,3H),2.29-2.21(m,1H),2.02-1.90(m,1H),1.71(t,J=19.5Hz,3H),1.28(t,J=7.5Hz,3H)。

[1289] 104: 1 H NMR(400MHz,DMSO)δ9.16(dd,J=2.3,1.1Hz,1H),8.51(dd,J=7.0,4.2Hz,2H),7.95(d,J=8.3Hz,2H),7.44(d,J=8.3Hz,2H),4.57(d,J=5.9Hz,2H),4.30(dd,J=12.6,3.8Hz,1H),4.12(td,J=12.1,4.6Hz,1H),3.09(dd,J=16.5,4.1Hz,1H),3.01(t,J=7.5Hz,2H),2.79(dd,J=16.5,11.4Hz,1H),2.71-2.60(m,1H),2.33(d,J=5.5Hz,3H),2.25(dd,J=13.5,2.1Hz,1H),1.96(ddd,J=25.1,11.7,5.7Hz,1H),1.71(t,J=19.5Hz,3H),1.28(t,J=7.5Hz,3H)。

[1290] 105: 1H NMR(400MHz,DMSO)δ9.16(dd,J=2.4,1.1Hz,1H),8.51(dd,J=6.9,4.2Hz,2H),7.98-7.91(m,2H),7.44(d,J= 8.3Hz,2H),4.57(d,J=5.9Hz,2H),4.34-4.25(m,1H),4.12(td,J=12.1,4.6Hz,1H),3.09(dd,J=16.6,3.9Hz ,1H),3.01(t,J=7.5Hz,2H),2.79(dd,J=16.5,11.3Hz,1H),2.71-2.59(m,1H),2.34(t,J=2.7Hz,3H),2.25( dd,J=13.5,2.3Hz,1H),1.96(ddd,J=25.2,11.7,5.7Hz,1H),1.71(t,J=19.5Hz,3H),1.28(t,J=7.5Hz,3H).

[1291] Synthesis of compound 106

[1292]

change

[1293] Compound 106を, intermediate I-121 and II-3a were synthesized, and the solid color of the compound was obtained (96.2 mg, 48%). 1 H NMR (400MHz, DMSO) δ9.17(s,1H),8.52(s,2H),7.94(t,J=7.7Hz,1H),7.29(d,J=9. 6Hz,2H),4.58(s,2H),4.37-4.28(m,1H),4.19-4.07(m,1H),3.15-3.07(m,1H),3.0 3(dd,J=14.8,7.4Hz,2H),2.87-2.74(m,1H),2.74-2.60(m,1H),2.34(s,3H),2.26( d,J=11.6Hz,1H),2.06-1.91(m,1H),1.71(t,J=19.5Hz,3H),1.29(t,J=7.4Hz,3H).

[1294] Synthesis of compound 107

[1295]

change

[1296] Compound 107 was synthesized from intermediates I-56 and II-3a and obtained as an orange-yellow solid (87.2 mg, 43%). 1 H NMR(400MHz,DMSO)δ9.21-9.10(m,1H),8.54-8.48(m,2H),7.93(t,J=7.8Hz,1 H),7.28(d,J=9.8Hz,2H),4.58(d,J=5.5Hz,2H),4.25-4.06(m,2H),3.99-3.9 0(m,1H),3.32(s,3H),3.10(dd,J=17.2,4.2Hz,1H),3.03(dd,J=15.0,7.5Hz, 2H), 3.00-2.94 (m, 1H), 2.34 (s, 3H), 2.30-2.12 (m, 2H), 1.29 (t, J=7.5Hz, 3H).

[1297] Synthesis of Compounds 108 and 109

[1298] [ka]

[1299] Compounds 108 and 109 were synthesized from intermediates I-133 and II-3a. The crude mixture was purified to give compound 108 (CF2) as a white solid (21.4 mg, 40%) and compound 109 (Et) as a yellow solid (12.1 mg, 25%).

[1300] 108: 1H NMR(400MHz,DMSO)δ9.16(s,1H),8.52(d,J=2.2Hz,1H),8.47(t,J=5.8Hz,1H),7.70(d,J=8.1Hz, 2H),7.49(s,1H),7.34(d,J=8.1Hz,2H),4.52(d,J=5.7Hz,2H),4.15(dd,J=12.4,3.9Hz,1H),3.9 3(dt,J=12.2,6.1Hz,1H),3.01(dt,J=12.5,6.2Hz,3H),2.71-2.60(m,1H),2.58-2.54(m,1H),2. 35(s,3H),2.18(d,J=12.0Hz,1H),1.87-1.76(m,1H),1.70(t,J=19.5Hz,3H),1.34-1.26(m,3H).

[1301] 109: 1 H NMR(400MHz,DMSO)δ9.15(dd,J=2.4,1.1Hz,1H),8.51(d,J=2.4Hz,1H),8.46(t,J=6.0Hz,1H),7.68(d,J=8.2Hz, 2H),7.43(s,1H),7.32(d,J=8.3Hz,2H),4.51(d,J=5.8Hz,2H),4.06(ddd,J=12.4,5.5,3.0Hz,1H),3.87(td,J=11 .9,4.6Hz,1H),3.01(q,J=7.5Hz,2H),2.91(dd,J=16.5,3.9Hz,1H),2.34(t,J=1.8Hz,4H),1.77(s,1H),1.58(ddd ,J=23.9,11.0,5.4Hz,1H),1.46-1.36(m,2H),1.27(t,J=7.5Hz,3H),1.04(d,J=6.1Hz,1H),0.95(t,J=7.4Hz,3H.

[1302] Synthesis of compound 110

[1303]

change

[1304] Compound 110を, intermediate I-100b and II-3a were synthesized and a white solid was obtained (76.2 mg, 39%).1 H NMR (400 MHz, DMSO) δ 9.17 (s, 1H), 8.55-8.48 (m, 2H), 7.95 (d, J = 8.2 Hz, 2H), 7.45 (d, J = 8.2 Hz, 2H), 4.58 (d, J = 5.8 Hz, 2H), 4.31-4.22 (m, 1H), 4.18-4.08 (m, 1H), 3.13-2.99 (m, 3H), 2.74-2.65 (m, 1H), 2.40 (s, 1H), 2.35 (s, 3H), 2.19 (d, J = 12.9 Hz, 1H), 1.98-1.85 (m, 1H), 1.29 (t, J = 7.5 Hz, 3H). The CH2 signal overlapped with the DMSO signal. The purity was confirmed by HSQC.

[1305] Synthesis of Compound 111

[1306] [ka]

[1307] Compound 111 was synthesized from intermediates I-151a(R) and II-8b and obtained as a white solid (90.2 mg, 65%). 1 H NMR(400MHz,DMSO)δ8.95(d,J=2.8Hz,1H),8.52(d,J=2.8Hz,1H),8.44(t,J=5.6Hz,1H),7. 70(d,J=8.0Hz,2H),7.52(s,1H),7.34(d,J=8.0Hz,2H),4.53(d,J=5.4Hz,2H),4.21-4.12(m ,1H),3.98(td,J=12.1,4.3Hz,1H),3.86(s,3H),3.12-3.06(m,2H),3.05-2.97(m,2H),2.77 (dd,J=17.2,12.7Hz,1H),2.23(d,J=12.0Hz,1H),2.02-1.88(m,1H),1.27(t,J=7.4Hz,3H).

[1308] Synthesis of Compound 112

[1309] [ka]

[1310] Compound 112 was synthesized from intermediates II-8b and I-151b(S) and obtained as a white solid (45.1 mg, 33%). 1 H NMR(400MHz,DMSO)δ8.95(d,J=3.1Hz,1H),8.52(d,J=3.1Hz,1H),8.44(t,J=6.0Hz,1H ),7.69(d,J=8.2Hz,2H),7.52(s,1H),7.34(d,J=8.3Hz,2H),4.53(d,J=5.9Hz,2H),4.1 9-4.13(m,1H),3.98(td,J=12.4,4.9Hz,1H),3.86(s,3H),3.12-2.95(m,4H),2.77(dd, J=17.4,12.9Hz,1H),2.23(d,J=11.1Hz,1H),2.00-1.88(m,1H),1.27(t,J=7.5Hz,3H).

[1311] Synthesis of Compound 113

[1312] [ka]

[1313] Compound 113 was synthesized from intermediates I-151b(S) and II-8c and obtained as a pink solid (71.8 mg, 49%). 1H NMR(400MHz,DMSO)δ9.06-8.98(m,1H),8.42(t,J=6.0Hz,1H),7.69(d,J=8.3Hz,2H),7.52(d,J=7.9Hz,1 H),7.49(dd,J=9.8,2.3Hz,1H),7.33(d,J=8.3Hz,2H),7.06(td,J=7.6,2.7Hz,1H),4.51(d,J=5.9Hz,2H ),4.21-4.11(m,1H),3.98(td,J=12.1,4.6Hz,1H),3.14-3.03(m,2H),3.01-2.93(m,2H),2.78(dd,J=17 .4,12.7Hz,1H),2.23(dd,J=13.2,2.2Hz,1H),1.95(qd,J=11.8,5.5Hz,1H),1.26(td,J=7.5,3.1Hz,3H).

[1314] Synthesis of compound 114

[1315]

change

[1316] Compound 114を, intermediate I-151a (R) and II-8c were synthesized, and the solid color of the compound was obtained (63.9 mg, 48%). 1 H NMR(400MHz,DMSO)δ9.02(dd,J=7.4,6.2Hz,1H),8.42(t,J=5.9Hz,1H),7.69(d,J=8.2Hz,2H),7.5 2(s,1H),7.49(dd,J=9.9,2.4Hz,1H),7.33(d,J=8.3Hz,2H),7.06(td,J=7.6,2.7Hz,1H),4.51(d, J=5.7Hz,2H),4.21-4.10(m,1H),3.98(td,J=12.1,4.6Hz,1H),3.15-3.02(m,2H),2.97(q,J=7.5H z,2H),2.77(dd,J=17.3,12.6Hz,1H),2.28-2.19(m,1H),2.03-1.88(m,1H),1.26(t,J=7.5Hz,3H).

[1317] Synthesis of compound 115

[1318] [ka]

[1319] Compound 115 was synthesized from intermediates I-111 and II-3a and obtained as a pale orange-yellow solid (98.9 mg, 57%). 1 H NMR(400MHz,DMSO)δ9.16(dd,J=2.4,1.1Hz,1H),8.54-8.47(m,2H),7.94(d,J=8.3Hz,2 H),7.44(d,J=8.3Hz,2H),4.57(d,J=5.8Hz,2H),4.21-4.07(m,2H),3.29(s,3H),3.22( s,2H),3.02(q,J=7.5Hz,2H),2.78(d,J=17.1Hz,1H),2.63(d,J=17.0Hz,1H),2.34(s,3 H),1.99(dt,J=13.9,6.8Hz,1H),1.89-1.80(m,1H),1.28(t,J=7.5Hz,3H),1.00(s,3H).

[1320] Synthesis of Compound 116

[1321] [ka]

[1322] Compound 116 was synthesized from intermediates I-135 and II-3a and obtained as a white solid (61.3 mg, 33%). 1H NMR (400MHz, DMSO) δ9.15(dd,J=2.3,1.1Hz,1H),8.51(d,J=2.4Hz,1H),8.47(t,J=6.0Hz,1H),7.68(d ,J=8.2Hz,2H),7.50(s,1H),7.34(d,J=8.3Hz,2H),4.52(d,J=5.9Hz,2H),4.30(dd,J=12.4,5.2Hz,1H) ,4.03-3.94(m,1H),3.20(s,1H),3.01(q,J=7.5Hz,2H),2.97-2.88(m,1H),2.83(ddd,J=16.8,11.1,6 .0Hz,1H),2.34(s,3H),2.24-2.14(m,1H),1.92(ddd,J=24.3,11.3,5.8Hz,1H),1.27(t,J=7.5Hz,3H).

[1323] Synthesis of compound 117

[1324]

change

[1325] Compound 117を, intermediate I-130 and II-3a were synthesized and a white solid was obtained (102 mg, 65%). 1 H NMR(400MHz,DMSO)δ9.16(dd,J=2.3,1.1Hz,1H),8.51(d,J=2.4Hz,1H),8.48(s,1H),7.98(t ,J=8.2Hz,1H),7.43(d,J=4.3Hz,1H),7.26-7.18(m,2H),4.53(s,2H),4.27-4.17(m,1H),3. 99(td,J=12.2,4.5Hz,1H),3.17-3.06(m,2H),3.02(q,J=7.5Hz,2H),2.80(dd,J=17.4,12.7 Hz,1H),2.34(s,3H),2.28-2.20(m,1H),1.95(qd,J=11.9,5.6Hz,1H),1.28(t,J=7.5Hz,3H).

[1326] Synthesis of compound 118

[1327] [ka]

[1328] Compound 118 was synthesized from intermediates I-136 and II-3a and obtained as a white solid (78.8 mg, 24%). 1 H NMR(400MHz,DMSO)δ9.15(dd,J=2.3,1.1Hz,1H),8.51(d,J=2.4Hz,1H),8.47(t,J=5.9Hz,1H),7.68(d,J=8.2H) z,2H),7.44(s,1H),7.32(d,J=8.3Hz,2H),4.51(d,J=5.7Hz,2H),4.11-4.02(m,1H),3.95-3.83(m,1H),3.37-3 .33(m,2H),3.29(s,J=1.9Hz,3H),3.01(q,J=7.5Hz,2H),2.86(dd,J=16.5,4.3Hz,1H),2.41(dd,J=16.5,10.6 Hz,1H), 2.34(d,J=0.6Hz,3H),2.24-2.13(m,1H),2.08-1.97(m,1H),1.71-1.57(m,1H),1.27(t,J=7.5Hz,3H).

[1329] Synthesis of Compound 119

[1330] [ka]

[1331] Compound 119 was synthesized from intermediates I-73a and II-8b and obtained as a beige solid (96.6 mg, 48%). 1H NMR (400MHz, DMSO) δ8.97(d,J=2.9Hz,1H),8.52(d,J=2.9Hz,1H),8.47(s,1H),7.94(d,J=8.1Hz,2H),7.44(d,J=8.0Hz,2H),4.58(d,J=4.8Hz,2H ),4.13(t,J=5.8Hz,2H),3.86(s,3H),3.03(q,J=7.5Hz,2H),2.85(t,J= 6.2Hz,2H),2.06-1.97(m,2H),1.95-1.86(m,2H),1.28(t,J=7.5Hz,3H).

[1332] Synthesis of compound 120

[1333]

change

[1334] Compound 120, intermediate I-73a and II-101 were synthesized and a white solid was obtained (100.5 mg, 51%). 1 H NMR(400MHz,DMSO)δ9.04(dd,J=7.5,6.2Hz,1H),8.46(t,J=5.9Hz,1H),7.95(d,J =8.3Hz,2H),7.50(dd,J=9.8,2.6Hz,1H),7.44(d,J=8.3Hz,2H),7.07(td,J=7.6, 2.7Hz,1H),4.57(d,J=5.7Hz,2H),4.14(t,J=6.0Hz,2H),2.99(q,J=7.5Hz,2H),2 .86(t,J=6.3Hz,2H),2.06-1.99(m,2H),1.95-1.87(m,2H),1.27(t,J=7.5Hz,3H).

[1335] Synthesis of compound 121

[1336]

change

[1337] Compound 121を, intermediate I-129 and II-3a were synthesized and a white solid was obtained (87.1 mg, 38%).1 H NMR(400MHz,DMSO)δ9.14(s,1H),8.51(d,J=2.3Hz,1H),8.47(t,J=5.2Hz,1H),7.77(d,J=8.5Hz,1 H),7.31(s,1H),7.19(d,J=4.5Hz,2H),4.50(d,J=4.4Hz,2H),4.20(dd,J=12.5,3.8Hz,1H),4.00(t d,J=12.2,4.5Hz,1H),3.12-3.05(m,2H),3.02(q,J=7.5Hz,2H),2.79(dd,J=17.2,12.6Hz,1H),2.4 3(s,3H),2.34(s,3H),2.24(d,J=13.4Hz,1H),1.96(qd,J=11.9,5.4Hz,1H),1.28(t,J=7.5Hz,3H).

[1338] Synthesis of compound 122

[1339]

change

[1340] Compound 122を, intermediate I-142 and II-3a were synthesized and a white solid was obtained (78.6 mg, 42%). 1 H NMR(400MHz,DMSO)δ9.21(s,1H),8.84(s,1H),8.52(d,J=2.3Hz,1H),8.48(t,J=5.7H z,1H),7.46(s,1H),7.24(s,1H),4.61(d,J=5.7Hz,2H),4.22(dd,J=12.8,3.5Hz,1H), 4.02(td,J=12.3,4.5Hz,1H),3.21-2.98(m,4H),2.81(dd,J=17.2,12.6Hz,1H),2.44( s,3H),2.34(s,3H),2.25(d,J=11.3Hz,1H),2.05-1.90(m,1H),1.32(t,J=7.5Hz,3H).

[1341] Synthesis of compound 123

[1342]

change

[1343] Compound 123 was synthesized from intermediates I-143 and II-3a and obtained as a beige solid (47.2 mg, 26%). 1 H NMR(400MHz,DMSO)δ9.15(dd,J=2.4,1.1Hz,1H),8.51(d,J=2.4Hz,1H),8.48(t,J=5.9Hz,1H),8.3 6(d,J=1.9Hz,1H),7.58(s,1H),7.55(d,J=1.6Hz,1H),4.51(d,J=5.8Hz,2H),4.27-4.18(m,1H),4. 00(td,J=12.2,4.6Hz,1H),3.18-3.05(m,2H),3.01(q,J=7.5Hz,2H),2.80(dd,J=17.2,12.5Hz,1H ),2.61(s,3H),2.34(d,J=0.6Hz,3H),2.29-2.19(m,1H),2.03-1.88(m,1H),1.28(t,J=7.5Hz,3H).

[1344] Synthesis of compound 124

[1345] [ka]

[1346] Compound 124 was synthesized from intermediates I-96 and II-3a and obtained as a white solid (60.3 mg, 48%). 1H NMR(400MHz,DMSO)δ9.16(dd,J=2.3,1.1Hz,1H),8.51(d,J=2.4Hz,1H),8.47(t,J=5.9Hz,1 H),7.72(d,J=8.3Hz,2H),7.37(d,J=8.3Hz,2H),4.52(d,J=5.9Hz,2H),4.10-3.98(m,1H), 3.85(dd,J=12.0,4.6Hz,1H),3.81(s,3H),3.06-2.94(m,4H),2.73(dd,J=15.9,11.4Hz,1H ),2.34(s,J=6.1Hz,3H),2.26(d,J=11.4Hz,1H),1.99-1.84(m,1H),1.28(t,J=7.5Hz,3H).

[1347] Synthesis of compound 125

[1348]

change

[1349] Compound 125を, intermediate I-16 and II-3a were synthesized and a white solid was obtained (136.6 mg, 58%). 1 H NMR(400MHz,DMSO)δ9.16(s,1H),8.51(s,2H),7.94(d,J=7.6Hz,2H),7.43(d,J=7 .6Hz,2H),4.57(d,J=5.0Hz,2H),4.28-4.19(m,1H),3.69(t,J=11.0Hz,1H),3.02 (dd,J=14.6,7.2Hz,2H),2.88(dd,J=40.3,13.9Hz,2H),2.34(s,3H),2.20(s,1H) ,1.96(s,1H),1.60(d,J=6.8Hz,1H),1.28(t,J=7.3Hz,3H),1.08(d,J=6.4Hz,3H).

[1350] Synthesis of compounds 126 and 127

[1351]

change

[1352] Isomers 126 and 127 were synthesized from intermediates I-27 and II-84 and separated by SFC (Jasco SFC prep system, i-cellulose column (Phenomenex) 250 * After 30 mm, 5 mm particle size, 100 ml / min, CO2 (40%) / MeOH (60%) / diethylamine (0.1%), isocratic mode at 30 °C and 120 bar, 126 (R * ) (37.4 mg, yield: 24%) and compound 127 (S * ) (40.3 mg, yield: 26%) was obtained as a white solid.

[1353] 126: 1 H NMR(400MHz,DMSO)δ7.82(t,J=6.0Hz,1H),7.70(d,J=8.2Hz,2H),7.30(d,J=8.3Hz,2H),6.51(s,1H),4.4 0(d,J=6.0Hz,2H),4.34-4.25(m,1H),4.11(td,J=12.3,4.7Hz,1H),3.98(t,J=6.0Hz,2H),3.18-3.08(m, 1H),3.09-2.95(m,1H),2.89(t,J=6.3Hz,2H),2.79(dd,J=15.8,11.1Hz,1H),2.70(q,J=7.5Hz,2H),2.31 -2.22(m,1H),2.04(qd,J=11.8,5.7Hz,1H),1.96-1.86(m,2H),1.81-1.67(m,2H),1.11(t,J=7.5Hz,3H).

[1354] 127: 1H NMR (400MHz, DMSO) δ7.82(t,J=6.0Hz,1H),7.70(d,J=8.2Hz,2H),7.30(d,J=8.3Hz,2H),6.51(s,1H),4.40(d,J= 6.0Hz,2H),4.33-4.25(m,1H),4.11(td,J=12.3,4.8Hz,1H),3.98(t,J=6.0Hz,2H),3.13(dd,J=15.8,3.7Hz,1H) ,3.08-2.96(m,1H),2.88(t,J=6.3Hz,2H),2.79(dd,J=15.8,11.2Hz,1H),2.70(q,J=7.5Hz,2H),2.27(dd,J=13. 2,2.3Hz,1H),2.03(ddd,J=25.0,11.8,5.7Hz,1H),1.95-1.88(m,2H),1.80-1.72(m,2H),1.11(t,J=7.5Hz,3H).

[1355] Synthesis of compound 128

[1356]

change

[1357] Compound 128を, intermediates I-47 and II-17a were synthesized and a white solid was obtained (78.9 mg, 22%). 1 H NMR(400MHz,DMSO)δ8.25(t,J=6.0Hz,1H),7.93(d,J=8.2Hz,2H),7.38(d,J=8.3Hz,2H),4.4 5(d,J=6.0Hz,2H),4.36-4.28(m,1H),4.17(td,J=12.0,4.9Hz,1H),3.99(t,J=5.8Hz,2H),3 .18(dd,J=9.5,8.3Hz,2H),2.92(dd,J=17.6,12.2Hz,1H),2.71(t,J=6.3Hz,2H),2.64(q,J= 7.5Hz,2H),2.36-2.27(m,1H),2.18-2.03(m,1H),1.91-1.73(m,4H),1.10(t,J=7.5Hz,3H).

[1358] Synthesis of compound 129

[1359] [ka]

[1360] Compound 129 was synthesized from intermediates I-87(S) and II-65 and obtained as a white solid (22.4 mg, 18%). 1 H NMR(400MHz,DMSO)δ8.25(t,J=5.8Hz,1H),7.94(d,J=8.2Hz,2H),7.39(d,J=8.2Hz,2H),5.12(d,J=3.2Hz, 1H),4.46(d,J=6.0Hz,2H),4.37-4.30(m,1H),4.19(dd,J=11.9,4.9Hz,1H),4.15-4.05(m,2H),3.87(dd,J= 13.1,4.5Hz,1H),3.20(d,J=12.9Hz,1H),2.93(dd,J=17.5,12.1Hz,1H),2.81(dd,J=15.7,8.9Hz,1H),2.74 -2.61(m,4H),2.34(dt,J=3.8,1.9Hz,1H),2.18-2.06(m,1H),1.86(d,J=4.8Hz,2H),1.12(t,J=7.5Hz,3H).

[1361] Synthesis of Compound 130

[1362] [ka]

[1363] Compound 130 was synthesized from intermediates I-87(S) and II-66 and obtained as a white solid (69.2 mg, 65%). 1H NMR(400MHz,DMSO)δ8.36(s,1H),7.94(d,J=8.3Hz,2H),7.38(d,J=8.3Hz,2H),5.1 6(d,J=3.2Hz,1H),4.46(d,J=6.0Hz,2H),4.32(dd,J=11.3,4.2Hz,1H),4.21-4.05( m,3H),3.89(dd,J=13.2,4.1Hz,1H),3.24-3.14(m,2H),2.97-2.63(m,5H),2.36-2 .28(m,1H),2.18-2.05(m,1H),1.87(dd,J=11.4,5.9Hz,2H),1.12(t,J=7.5Hz,3H).

[1364] Synthesis of compound 131

[1365]

change

[1366] Compound 131を, intermediates I-87(S) and II-67 were synthesized and a white solid was obtained (79.4 mg, 63%). 1 H NMR (400MHz, DMSO) δ8.28(t,J=5.9Hz,1H),7.93(d,J=8.3Hz,2H),7.38(d,J=8.3Hz,2H),5.06( d,J=3.4Hz,1H),4.46(d,J=6.0Hz,2H),4.38-4.27(m,1H),4.18(dd,J=11.7,4.9Hz,1H),4.15- 4.07(m,1H),4.07-4.00(m,2H),3.24-3.12(m,2H),3.00-2.85(m,2H),2.69-2.59(m,3H),2.37 -2.25(m,1H),2.18-2.05(m,1H),2.00-1.91(m,1H),1.92-1.81(m,1H),1.11(t,J=7.5Hz,3H).

[1367] Synthesis of compound 132

[1368]

change

[1369] Compound 132 was synthesized from intermediates I-87(S) and II-68 and obtained as an orange-yellow solid (43 mg, 43%). 1 H NMR(400MHz,DMSO)δ8.31(s,1H),7.94(d,J=8.3Hz,2H),7.38(d,J=8.3Hz,2H),5.08(d ,J=3.3Hz,1H),4.46(d,J=5.9Hz,2H),4.32(dd,J=12.8,3.6Hz,1H),4.22-4.13(m,1H), 4.13-3.97(m,3H),3.24-3.14(m,2H),2.99-2.86(m,2H),2.71-2.56(m,3H),2.38-2.27 (m,1H),2.11(ddd,J=24.7,11.5,5.8Hz,1H),2.01-1.82(m,2H),1.11(t,J=7.5Hz,3H).

[1370] Synthesis of compound 133

[1371] [ka]

[1372] Compound 133 was synthesized from intermediates I-160 and II-102 and obtained as a white solid (53.4 mg, 52%). 1H NMR(400MHz,DMSO)δ8.99(dt,J=7.0,1.1Hz,1H),8.45(t,J=6.0Hz,1H),7.96(d,J=8.3Hz,2H),7.61(dt,J=9.0,1.1 Hz,1H),7.45(d,J=8.4Hz,2H),7.39(ddd,J=8.9,6.8,1.3Hz,1H),4.58(d,J=5.9Hz,2H),4.38-4.21(m,1H),4.12(td ,J=12.3,4.8Hz,1H),3.10(dd,J=16.6,3.9Hz,1H),3.01(q,J=7.5Hz,2H),2.80(dd,J=16.5,11.4Hz,1H),2.73-2.5 7(m,1H),2.26(dd,J=13.4,2.0Hz,1H),1.96(tt,J=18.9,6.5Hz,1H),1.72(t,J=19.5Hz,3H),1.28(t,J=7.5Hz,3H).

[1373] Synthesis of compound 134

[1374]

change

[1375] Compound 134を, intermediate I-160 and II-17a were synthesized and a white solid was obtained (50 mg, 49%). 1 H NMR (400MHz, DMSO) δ8.25(t,J=6.0Hz,1H),7.93(d,J=8.3Hz,2H),7.37(d,J=8.3Hz,2H),4.45(d,J=6.0Hz ,2H),4.34-4.27(m,1H),4.11(td,J=12.1,4.7Hz,1H),3.99(t,J=5.8Hz,2H),3.09(dd,J=16.6,3.9Hz,1H ),2.79(dd,J=16.4,11.4Hz,1H),2.71(t,J=6.3Hz,2H),2.64(q,J=7.5Hz,3H),2.25(dd,J=13.4,2.1Hz,1 H),1.96(ddd,J=25.2,11.8,5.8Hz,1H),1.89-1.77(m,4H),1.71(t,J=19.5Hz,3H),1.10(t,J=7.5Hz,3H).

[1376] Synthesis of compound 135

[1377] [ka]

[1378] Compound 135 was synthesized from intermediates I-87(S) and II-70 and obtained as a white solid (39 mg, 29%). 1 ...

Claims

1. Formula (IA) 【Chemistry 1】 During the ceremony, A is a six-membered ring which may be aromatic or non-aromatic; B is a 5-membered aromatic ring; X ａ and X ｂ one of which represents N and the other represents C; X １ But, =N-, -CH ２ -, or =C(R １０ａ )-, X ２ , X ３ , X ４ , X ５ and X ６ are each independently ═N— or ═C(R １０ｂ )-, R １ Or R ２ are each independently hydrogen, halo, -R ６ｃ , -O-R ６ｄ , —C(═O)—R ６ｅ , -C(=O)-N(R ６ ) (R ７ ), —CN and —N(R ６ａ ) R ６ｂ represents a substituent selected from R ３ is H, halo (e.g., Cl, F), and halo (e.g., F) and —O—C １－３ -C (linear, branched, or cyclic) optionally substituted with one or more substituents selected from alkyl １－３ represents a substituent selected from alkyl, R ４ But H, F, -C １－３ Alkyl and —O—C １－３ represents a substituent selected from alkyl, R ５ H, -OH, -R ８ａ , —C(═O)—R ８ｂ , -SO ２ -R ９ , and −N(R １１ａ ) R １１ｂ represents one or more substituents selected from R ６ and R ７ are independently H and —C １－３ alkyl, R ６ａ and R ６ｂ However, independently, H, C １－６ represents alkyl, or R ６ａ and R ６ｂ are linked together to form a 3- to 6-membered ring, R ６ｃ and R ６ｄ are independently hydrogen, halo (e.g., F), —O—CH ３ , phenyl, —N(R ６ａ ) R ６ｂ -C optionally substituted by one or more substituents selected from １－４ represents alkyl, R ６ｅ But, -C １－３ is alkyl, R ８ａ But -CN, -C １－４ Alkyl (linear, branched, or cyclic, said alkyl group optionally substituted with one or more substituents selected from halo, e.g., —CF ３ , -CHF ２ , -CF ２ CH ３ (forming halo and —O—CH ３ optionally substituted by one or more substituents selected from １－３ represents alkyl, R ８ｂ is hydrogen or —C (optionally substituted with one or more fluoro atoms) １－３ is alkyl, R ９ is halo (e.g., F) and —O—CH ３ -C optionally substituted by one or more substituents selected from １－４ represents alkyl, R １０ａ and R １０ｂ are independently H, halo (per se, fluoro, -CN, -R １２ａ , -OR １２ｂ , -N(R １２ｃ ) R １２ｄ and / or -C(O)N(R １２ｅ ) R １２ｆ C optionally substituted with one or more (e.g., one) substituent(s) selected from １－４ alkyl, or (per se, fluoro, -R １２ｇ , -OR １２ｈ and / or -N(R １２ｉ ) R １２ｊ and optionally substituted by one or more (e.g., one) substituent(s) selected from １－４ represents alkyl, R １１ａ and R １１ｂ are independently hydrogen, C (optionally substituted with one or more fluoro atoms), １－３ Alkyl or -S(O) ２ R ６ｃ (Here, R ６ｃ is defined above), R １２ａ , R １２ｂ , R １２ｃ , R １２ｄ , R １２ｅ , R １２ｆ , R １２ｇ , R １２ｈ , R １２ｉ and R １２ｊ are independently hydrogen or C (optionally substituted with one or more fluoro atoms); １－３ represents alkyl] or a pharmaceutically acceptable salt thereof.

2. Formula (I) 【Chemistry 2】 [In the formula, A is a six-membered ring which may be aromatic or non-aromatic; X １ But, =N-, -CH ２ -, or =C(R １０ａ )-, X ２ , X ３ , X ４ , X ５ and X ６ are each independently ═N— or ═C(R １０ｂ )-, R １ Or R ２ are each independently hydrogen, halo (e.g., Cl, F), —R ６ｃ , -O-R ６ｄ , —C(═O)—R ６ｅ , -C(=O)-N(R ６ ) (R ７ ), —CN and —N(R ６ａ ) R ６ｂ represents a substituent selected from R ３ is H, halo (e.g., Cl, F), and halo (e.g., F) and —O—C １－３ -C (linear, branched, or cyclic) optionally substituted with one or more substituents selected from alkyl １－３ represents a substituent selected from alkyl, R ４ But H, F, -C １－３ Alkyl and —O—C １－３ represents a substituent selected from alkyl, R ５ H, -OH, -R ８ａ , —C(═O)—R ８ｂ , -SO ２ -R ９ , and −N(R １１ａ ) R １１ｂ represents one or more substituents selected from R ６ and R ７ are independently H and —C １－３ alkyl, R ６ａ and R ６ｂ However, independently, H, C １－６ represents alkyl, or R ６ａ and R ６ｂ are linked together to form a 3- to 6-membered ring, R ６ｃ and R ６ｄ are independently hydrogen, or halo (e.g., F), —O—CH ３ , phenyl, —N(R ６ａ ) R ６ｂ -C optionally substituted by one or more substituents selected from １－４ represents alkyl, R ６ｅ But, -C １－３ is alkyl, R ８ａ But -CN, -C １－４ Alkyl (linear, branched, or cyclic, said alkyl optionally substituted with one or more substituents selected from halo, e.g., —CF ３ , -CHF ２ , -CF ２ CH ３ (forming halo and —O—CH ３ optionally substituted by one or more substituents selected from １－３ represents alkyl, R ８ｂ is hydrogen or —C (optionally substituted with one or more fluoro atoms); １－３ is alkyl, R ９ is halo (e.g., F) and —O—CH ３ -C optionally substituted by one or more substituents selected from １－４ represents alkyl, R １０ａ and R １０ｂ are independently H, halo (per se, fluoro, -CN, -R １２ａ , -OR １２ｂ , -N(R １２ｃ ) R １２ｄ and / or -C(O)N(R １２ｅ ) R １２ｆ C optionally substituted with one or more (e.g., one) substituent(s) selected from １－４ alkyl, or (per se, fluoro, -R １２ｇ , -OR １２ｈ and / or -N(R １２ｉ ) R １２ｊ and optionally substituted by one or more (e.g., one) substituent(s) selected from １－４ represents alkyl, R １１ａ and R １１ｂ are independently hydrogen, C (optionally substituted with one or more fluoro atoms), １－３ Alkyl or -S(O) ２ R ６ｃ (Here, R ６ｃ is defined above), R １２ａ , R １２ｂ , R １２ｃ , R １２ｄ , R １２ｅ , R １２ｆ , R １２ｇ , R １２ｈ , R １２ｉ and R １２ｊ are independently hydrogen or C (optionally substituted with one or more fluoro atoms); １－３ represents alkyl] or a pharmaceutically acceptable salt thereof.

3. Ring A is aromatic; X １ represents ═N— or ═CH—; R １ and R ２ are each independently hydrogen, —CH ３ , -F, -Cl, -OCH ３ , -NH ２ , -CH ２ NH ２ 3. A compound according to claim 1 or claim 2, wherein the compound represents a substituent selected from:

4. R ３ H, -CF ３ , -CHF ２ , -CH ３ , -CH ２ CH ３ 3. A compound according to claim 1 or 2, wherein the substituent is selected from:

5. Ring C is 【Transformation 3】 is selected from In the formula, R ４ But H, F, -C １－３ Alkyl and —O—C １－３ 3. A compound according to claim 1 or 2, wherein the substituents are selected from alkyl.

6. Ring D is 【Chemistry 4】 is selected from During the ceremony, R ５ H, -OH, -R ８ａ , —C(═O)—R ８ｂ , -SO ２ -R ９ , or -N(R １１ａ ) R １１ｂ represents one or more substituents selected from R １０ｂ H, halo (itself, fluoro, -CN, -R １２ａ , -OR １２ｂ , -N(R １２ｃ ) R １２ｄ and / or -C(O)N(R １２ｅ ) R １２ｆ C optionally substituted with one or more (e.g., one) substituent(s) selected from １－４ alkyl, or (by itself, fluoro, -R １２ｇ , -OR １２ｈ and / or -N(R １２ｉ ) R １２ｊ and optionally substituted by one or more (e.g., one) substituent(s) selected from １－４ 3. A compound according to claim 1 or 2, which represents alkyl.

7. R ５ is H, -CH ３ , -CH ２ CH ３ , -CH ２ CH ２ CH ３ , cyclopropyl, —OH, —OCH ３ , -OCF ３ , -OCH ２ CH ２ OCH ３ , -CF ３ , -CHF ２ , -CF ２ CH ３ , -NH ２ , -NH(SO ２ )CF ３ , -N(CH ３ ) (SO ２ )CF ３ , and -SO ２ CF ３ 3. The compound according to claim 1 or 2, wherein

8. Ring D is 【Transformation 5】 is selected from In the formula, R ５ is H, -CH ３ , -CH ２ CH ３ , -CH ２ CH ２ CH ３ , cyclopropyl, —OH, —OCH ３ , -OCF ３ , -OCH ２ CH ２ OCH ３ , -CF ３ , -CHF ２ , -CF ２ CH ３ , -NH ２ , -NH(SO ２ )CF ３ , -N(CH ３ ) (SO ２ )CF ３ , and -SO ２ CF ３ 3. The compound according to claim 1 or 2, wherein

9. Formula (IX) 【Transformation 6】 [In the formula, X １ represents ═N— or ═CH—; X ２ , X ５ and X ６ are each independently ═N—, ═CH—, or ═C(CH ３ )-, R １ and R ２ are each independently hydrogen, —CH ３ , -F, -Cl, -OCH ３ , -NH ２ , -CH ２ NH ２ represents a substituent selected from R ３ H, -CF ３ , -CHF ２ , -CH ３ , -CH ２ CH ３ represents a substituent selected from, and cyclopropyl; R ４ is H, F, and -CH ３ represents a substituent selected from R ５ is H, -CH ３ , -CH ２ CH ３ , -CH ２ CH ２ CH ３ , cyclopropyl, —OH, —OCH ３ , -OCF ３ , -OCH ２ CH ２ OCH ３ , -CF ３ , -CHF ２ , -CF ２ CH ３ , -NH ２ , -NH(SO ２ )CF ３ , -N(CH ３ ) (SO ２ )CF ３ , or -SO ２ CF ３ represents 3. The compound of claim 1 or 2, wherein:

10. Formula (IB) 【Transformation 7】 wherein all variables are as defined in claim 1 or as defined in claim 2. A compound.

11. 11. The compound of claim 10, wherein the bicycle comprising ring A and ring B represents any one of the following: 【Transformation 8】

12. R １ and R ２ and both represent hydrogen.

13. R ３ But C １－３ 11. A compound according to claim 10, which represents alkyl (e.g. ethyl).

14. 11. The compound of claim 10, wherein Ring C is unsubstituted phenyl, i.e., represents formula (XXX). 【Chemistry 9】

15. 11. The compound according to claim 10, wherein ring D represents formula (XXXI) or formula (XXXII). 【Chemistry 10】

16. R ５ C optionally substituted by one or more fluoro atoms １－３ Alkyl (e.g., CF ３ 11. The compound of claim 10, wherein

17. 3. A compound according to claim 1 or 2 for use as a pharmaceutical.

18. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 1 or 2 as an active ingredient.

19. 3. A compound according to claim 1 or 2 for use in the treatment of a mycobacterial infection (e.g. tuberculosis).

20. 10. Use of a compound according to claim 1 or 2 for the manufacture of a medicament for the treatment of mycobacterial infections (e.g. tuberculosis).

21. 10. A pharmaceutical composition for the treatment of mycobacterial infections (e.g., tuberculosis), comprising a compound according to claim 1 or 2.

22. 10. A pharmaceutical composition comprising: (a) a compound according to claim 1 or 2; and (b) in combination with one or more other anti-mycobacterial (e.g., anti-tuberculosis) agents.

23. A product containing (a) a compound of claim 1 or 2 and (b) one or more other antimycobacterial (e.g., antituberculosis) agents as a combined preparation for simultaneous, separate or sequential use in the treatment of bacterial infections.

24. A process for preparing a compound of formula (IA) according to claim 1 or a compound of formula (I) according to claim 2, said process comprising: (i) Formula (XL) or (X) 【Chemistry 11】 wherein the variables are as defined in claim 1. with a compound of formula (XI) 【Chemistry 12】 wherein the variables are as defined in claim 1. reacting a compound of or (ii) Formula (XLI) or (XII) 【Chemistry 13】 wherein the variables are as defined in claim 1 and R １３ represents a suitable group, e.g., a suitable leaving group). The compound Formula (XIII) 【Chemistry 14】 [In the formula, R ４ is as defined in claim 1, and R １４ represents a suitable group, e.g., a suitable leaving group. a compound of formula (I)

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