Substituted pyridone compounds useful for the treatment of orthomyxovirus infections - Patents.com

Abstract

The present disclosure provides compounds of formula (I), as further described herein, as well as pharmaceutical compositions comprising such compounds, and methods of using the compounds and pharmaceutical compositions, for the treatment of certain viral disorders, including influenza. [Case 1] TIFF2024525915000567.tif2945

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 224,691, filed July 22, 2021, the contents of which are incorporated by reference herein in their entirety.

[0002] The present disclosure provides compounds that inhibit orthomyxovirus replication and are therefore useful in treating viral infections caused by orthomyxoviruses. The present disclosure further provides pharmaceutical compositions containing these compounds and methods of using these compounds to treat or prevent viral infections caused by orthomyxoviruses. [Background technology]

[0003] The orthomyxovirus family includes influenza A, influenza B, and influenza C (all of which can infect humans), as well as several other genera of viruses that do not commonly infect humans. Influenza infects millions of people worldwide each year and kills over 250,000. While the severity of "flu" can vary, it is usually life-threatening only in infants, the elderly, and people with underlying cardiac and pulmonary immunological disorders. However, influenza viruses are constantly adapting, often resulting in the emergence of new, more virulent strains. These new strains can cause pandemic outbreaks, such as the so-called Spanish flu (H1N1), which killed millions of people in 1918–1920 and was particularly virulent in healthy young adults. Immunization reduces the risk of infection, but it must be administered annually and is only effective against specific strains predicted to be prevalent in the upcoming influenza season. These predictions must be made several months before the start of the influenza season, and if predictions of strain spread are incorrect, immunization offers limited protection.

[0004] Currently available antiviral drugs for treating influenza target the M2 ion channel (amantadine and rimantadine), neuraminidase (e.g., oseltamivir), or endonuclease (baloxavir). To be effective, they must be administered early in the infection process, and resistance to both of these classes of antiviral drugs has been documented (at varying rates depending on the drug class). Thus, there remains a need for novel antiviral drugs effective against influenza.

[0005] Influenza nucleoprotein (NP) has emerged as a novel target for antiviral drug discovery. NP encapsidates viral RNA to form stable ribonucleoprotein (RNP) complexes. NP binds to the ribose-phosphate backbone of viral RNA, exposing the RNA bases to solvation and making them accessible to viral polymerase, conferring transcriptional competence to the RNP complex. Although the exact mechanism by which they act remains unclear, compounds that inhibit the proper assembly of NP and / or the RNP complex have been shown to have antiviral activity. (C. Cianci, et al., Antiviral Chemistry and Chemother., 23, 77-91 (2013)).

[0006] Influenza A virus (IAV) is the most important of these pathogens in humans, often accounting for the majority of severe cases of influenza during a typical influenza season. Importantly, all past influenza pandemics have been caused by IAV. Thus, there is a particular need for antiviral therapeutics that are effective in treating influenza A. The present disclosure provides novel compounds that inhibit the replication of orthomyxoviruses, specifically influenza A virus (IAV), influenza B virus (IBV), and influenza C virus, and thus may be useful in the treatment of influenza. Summary of the Invention

[0007] Provided herein are compounds that inhibit the replication of orthomyxoviruses, including influenza A, influenza B, and influenza C. Without being bound by theory, it is believed that these compounds achieve their antiviral effect by inhibiting the proper assembly of the NP or RNP complex.

[0008] In one aspect, the disclosure provides a compound of formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0009] [ka] [In the formula, R 1 , R 2 , R 3 and R 4 as described herein].

[0010] The compounds provided include compounds of formula (I), subgenus of formula (I), and all stereoisomers (including diastereoisomers and enantiomers), tautomers and isotopically enriched versions (including deuterium substitutions) thereof, as described herein, and pharmaceutically acceptable salts of these compounds.

[0011] The compounds of the present disclosure are inhibitors of influenza nucleoprotein function, as demonstrated by the data provided herein, and they inhibit influenza virus replication. Thus, these compounds are useful for treating or preventing orthomyxovirus infections in mammals susceptible to such infections, and are particularly useful for treating influenza virus infections in humans. These compounds are also useful for inhibiting the replication of orthomyxoviruses, including influenza viruses, in cells.

[0012] In another aspect, the present disclosure provides a pharmaceutical composition comprising the provided compound and at least one pharmaceutically acceptable carrier or excipient.In certain embodiments, such a pharmaceutical composition comprises the compound disclosed herein and two or more pharmaceutically acceptable carriers or excipients.In one embodiment of this aspect, such a pharmaceutical composition further comprises a therapeutically effective amount of at least one other antiviral agent.In one embodiment of this aspect, such a pharmaceutical composition further comprises a therapeutically effective amount of one or more therapeutically active co-medicines.

[0013] In another aspect, the disclosure provides a method of treating a subject infected with influenza A, B, or C, comprising administering to a subject in need of such treatment an effective amount of a provided compound.

[0014] In another aspect, the disclosure provides a method of treating a subject infected with influenza A, B, or C, comprising administering to a subject in need of such treatment an effective amount of a provided compound, alone or in combination with at least one other antiviral agent administered together or separately.

[0015] Another aspect of the disclosure is a method of inhibiting influenza virus nucleoprotein (NP), comprising contacting the NP with a provided compound.

[0016] Another aspect of the disclosure is a method of preventing or treating influenza, comprising administering to a subject a therapeutically effective amount of a provided compound.

[0017] Another aspect of the disclosure is a method of treating influenza, comprising administering to a subject in need thereof a therapeutically effective amount of a provided compound.

[0018] Another aspect of the present disclosure is the use of provided compounds in the manufacture of a medicament for the treatment or prevention of influenza.

[0019] Another aspect of the disclosure is the use of provided compounds in the manufacture of a medicament for the treatment or prevention of influenza A, B, or C.

[0020] Another aspect of the present disclosure is the use of provided compounds as a medicament for the treatment or prevention of influenza.

[0021] Another aspect of the present disclosure is the use of provided compounds as a medicament for the treatment or prevention of influenza A, B, or C.

[0022] Another aspect of the present disclosure is the use of provided compounds for the treatment or prevention of influenza.

[0023] Another aspect of the present disclosure is the use of provided compounds for the treatment or prevention of influenza A, B, or C. DETAILED DESCRIPTION OF THE INVENTION

[0024] definition For purposes of interpreting this specification, the following definitions shall apply, and where appropriate, terms used in the singular shall also include the plural. Terms used in the specification have the following meanings unless the context clearly indicates otherwise:

[0025] The term "alkyl," as used herein, refers to a fully saturated branched or straight chain hydrocarbon. In certain embodiments, an alkyl group can be referred to as a "C1-C2 alkyl," a "C1-C3 alkyl," a "C1-C4 alkyl," a "C1-C5 alkyl," a "C1-C6 alkyl," a "C1-C7 alkyl," a "C1-C8 alkyl," a "C1-C9 alkyl," or a "C1-C 10 alkyl" and "C1-C2 alkyl", "C1-C3 alkyl", "C1-C4 alkyl", "C1-C5 alkyl", "C1-C6 alkyl", "C1-C7 alkyl", "C1-C8 alkyl", "C1-C9 alkyl" or "C1-C 10The term "alkyl," as used herein, refers to an alkyl group containing at least 1 and at most 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, respectively. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.

[0026] The term "alkylene," as used herein, refers to a saturated, branched or straight-chain divalent hydrocarbon group derived from an alkyl group, as defined herein. In certain embodiments, an alkylene group is defined as "C1-C3 alkylene," "C1-C4 alkylene," "C1-C5 alkylene," "C1-C6 alkylene," "C1-C7 alkylene," "C1-C8 alkylene," "C1-C9 alkylene," or "C1-C 10 The terms "C1-C3 alkylene," "C1-C4 alkylene," "C1-C5 alkylene," "C1-C6 alkylene," "C1-C7 alkylene," and "C1-C8 alkylene," as used herein, refer to alkylene groups containing at least 1, and at most 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, respectively. Non-limiting examples of alkylene groups, as used herein, include methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, sec-butylene, t-butylene, n-pentylene, isopentylene, hexylene, heptylene, octylene, nonylene, decylene, and the like.

[0027] The term "alkoxy," as used herein, refers to -O-alkyl or -alkyl-O-, where "alkyl" is as defined herein. In certain embodiments, an alkoxy group is defined as "C1-C2 alkoxy," "C1-C3 alkoxy," "C1-C4 alkoxy," "C1-C5 alkoxy," "C1-C6 alkoxy," "C1-C7 alkoxy," "C1-C8 alkoxy," "C1-C9 alkoxy," or "C1-C 10 alkoxy", and includes "C1-C3 alkoxy", "C1-C4 alkoxy", "C1-C5 alkoxy", "C1-C6 alkoxy", "C1-C7 alkoxy", "C1-C8 alkoxy", "C1-C9 alkoxy" and "C 10 The term "alkoxy," as used herein, means -O-C1-C2 alkyl, -O-C1-C3 alkyl, -O-C1-C4 alkyl, -O-C1-C5 alkyl, -O-C1-C6 alkyl, -O-C1-C7 alkyl, -O-C1-C8 alkyl, -O-C1-C9 alkyl or -O-C1-C 10 Non-limiting examples of "alkoxy" groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, hexoxy, heptoxy, octoxy, nonoxy, and decoxy.

[0028] The term "C3-C8 cycloalkyl," as used herein, refers to a fully saturated, monocyclic hydrocarbon ring system having from 3 to 8 carbon atoms as ring members. Non-limiting examples of such "C3-C8 cycloalkyl" groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups.

[0029] The term "halo" or "halogen," as used herein, refers to fluoro (F), chloro (Cl), bromo (Br) or iodo (I).

[0030] The term "haloalkyl," as used herein, refers to an alkyl group, as defined herein, in which at least one of the alkyl's hydrogen atoms has been replaced with a halo group (as defined herein). A haloalkyl can be a monohaloalkyl, dihaloalkyl, trihaloalkyl, or polyhaloalkyl, including a perhaloalkyl. A monohaloalkyl can have one iodo, bromo, chloro, or fluoro within the alkyl group. Dihaloalkyl and polyhaloalkyl groups can have two or more of the same halo atoms or a combination of different halo groups within the alkyl. Typically, a polyhaloalkyl contains up to six, or four, or three, or two halo groups. Non-limiting examples of haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. Perhaloalkyl refers to an alkyl in which all hydrogen atoms have been replaced with halo atoms, e.g., trifluoromethyl. Preferred haloalkyl groups, unless otherwise specified, include monofluoro-, difluoro-, and trifluoro-substituted methyl and ethyl groups, e.g., CF, CHF, CHF, CHCHF, and CHCF.

[0031] The term "C1-C8 haloalkyl," as used herein, refers to a respective "C1-C8 alkyl," as defined herein, in which at least one of the hydrogen atoms has been replaced with a halo group (as defined herein). A C1-C6 haloalkyl group can be a mono-C1-C6 haloalkyl, where such a C1-C8 haloalkyl group has one iodo, one bromo, one chloro, or one fluoro. Furthermore, a C1-C6 haloalkyl group can be a di-C1-C8 haloalkyl, where such a C1-C8 haloalkyl group can have two halo atoms independently selected from iodo, bromo, chloro, or fluoro. Furthermore, a C1-C8 haloalkyl group can be a poly-C1-C8 haloalkyl, where such a C1-C8 haloalkyl group can have two or more of the same halo atoms or a combination of two or more different halo atoms. Such a poly C1-C8 haloalkyl can be a perhalo C1-C8 haloalkyl, in which all hydrogen atoms of each C1-C8 alkyl are replaced with halo atoms, which can be the same or a combination of different halo atoms. Non-limiting examples of "C1-C8 haloalkyl" groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl.

[0032] The term "haloalkoxy," as used herein, refers to an -O-haloalkyl group in which at least one hydrogen atom in the alkyl group of the alkoxy is replaced with a halo group (as defined herein). The haloalkoxy can be a monohaloalkoxy, dihaloalkoxy, trihaloalkoxy, or polyhaloalkoxy, including perhaloalkoxy. The monohaloalkoxy can have one iodo, bromo, chloro, or fluoro in the alkyl group. The dihaloalkoxy and polyhaloalkoxy groups can have two or more of the same halo atoms or a combination of different halo groups in the alkyl. Typically, a polyhaloalkoxy contains up to six, or four, or three, or two halo groups. Non-limiting examples of haloalkoxy include fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, pentafluoroethoxy, heptafluoropropoxy, difluorochloromethoxy, dichlorofluoromethoxy, difluoroethoxy, difluoropropoxy, dichloroethoxy and dichloropropoxy. Perhaloalkoxy refers to an alkoxy in which all hydrogen atoms are replaced with halo atoms, such as trifluoromethoxy. Preferred haloalkoxy groups, unless otherwise specified, include monofluoro-, difluoro- and trifluoro-substituted methoxy and ethoxy groups, such as -OCF3, -OCHF2, -OCH2F, -OCH2CHF2 and -OCH2CF3.

[0033] The term "C1-C8 haloalkoxy," as used herein, refers to an -O-C1-C8 haloalkyl group in which at least one of the hydrogen atoms of the "C1-C8 alkyl" of the "C1-C8 alkoxy" is replaced with a halo group (as defined herein). The C1-C8 haloalkoxy group may be a mono-C1-C6 haloalkoxy, where such a C1-C8 haloalkoxy group has one iodo, one bromo, one chloro, or one fluoro. Furthermore, the C1-C8 haloalkoxy group may be a di-C1-C8 haloalkoxy, where such a C1-C8 haloalkoxy group has two halo atoms independently selected from iodo, bromo, chloro, or fluoro. Furthermore, a C1-C8 haloalkoxy group can be a polyC1-C8 haloalkoxy, where such a C1-C8 haloalkoxy group can have two or more of the same halo atoms or a combination of two or more different halo atoms. Such a polyC1-C8 haloalkoxy can be a perhaloC1-C8 haloalkoxy, where all hydrogen atoms of each C1-C8 alkoxy are replaced with halo atoms, and the halo atoms can be the same or a combination of different halo atoms. Non-limiting examples of "C1-C8 haloalkoxy" groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, pentafluoroethoxy, heptafluoropropoxy, difluorochloromethoxy, dichlorofluoromethoxy, fluoroethoxy, difluoroethoxy, trifluoroethoxy, difluoropropoxy, dichloroethoxy, and dichloropropoxy.

[0034] The term "5- to 6-membered heteroaryl" as used herein includes N, NR 7 , O and S (wherein R 7(wherein R is as defined herein) refers to an aromatic, 5- or 6-membered system having 1 to 3 ring members independently selected from: (wherein R is as defined herein). Non-limiting examples of such 5-membered heteroaryl groups, as used herein, include furyl, imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, pyrrolyl, pyrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, pyridyl, pyridazinyl, pyrazinyl, and pyrimidinyl.

[0035] The term "9- to 10-membered heteroaryl" as used herein includes N, NR 7 , N + O - , O and S (wherein R 7 (wherein R is as defined herein) refers to an aromatic 9- or 10-membered fused bicyclic ring system having 1 to 4 ring members independently selected from the group consisting of benzo[c][1,2,5]oxadiazolyl, tetrazolo[1,5-a]pyridinyl, imidazo[1,2-a]pyridinyl, benzo[c][1,2,5]oxadiazolyl, tetrazolo[1,5-a]pyridinyl, imidazo[4, 5-b]pyridinyl, triazolo[4,3-a]pyrimidinyl, thieno[2,3-b]furanyl, 1H-pyrazolo[4,3-d]oxazolyl, imidazo[2,1-b]thiazolyl, pyrazino[2,3-d]pyridazinyl, imidazo[1,2-b][1,2,4]triazinyl, benzoxazolyl, benzimidazolyl, imidazopyridinyl, and benzothiazolyl. In certain embodiments, such bicyclic heteroaryl groups are 1H-benzo[d]imidazolyl or 1H-imidazo[4,5-c]pyridinyl.

[0036] The terms "heteroatom" or "heteroatom," as used herein, refer to a nitrogen (N), oxygen (O), or sulfur (S) atom.

[0037] The term "4-8 monocyclic heterocycloalkyl" as used herein refers to a cycloalkyl group, as defined herein, wherein 1-3 of the carbon atoms in the ring structure are selected from the group consisting of N, NH, NR 7 , O, S, C=O and S(=O)2 (wherein R 7 (wherein R is as defined herein). In particular, a 4-8 monocyclic heterocycloalkyl is a fully saturated, monocyclic hydrocarbon ring structure having 4 to 8 ring members, 1 to 3 of which are N, NH, NR 7 , O, S, C=O and S(=O)2 (wherein R 7are as defined herein. Non-limiting examples of heterocycloalkyl groups, as used herein, include oxazepanyl, oxomorpholinyl, dioxidethiomorpholinyl, dioxanyl, dioxepanyl, oxopyrrolidinyl, oxooxazolidinyl, azetidinyl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, oxetanyl, oxetan-2-yl, oxetan-3-yl, oxetan-4-yl, thietanyl, thietan-2-yl, thietan-3-yl, thietan-4-yl, pyrrolidinyl, pyrrolidin-1-yl, pyrrolidine -2-yl, pyrrolidin-3-yl, pyrrolidin-4-yl, pyrrolidin-5-yl, tetrahydrofuranyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrofuran-4-yl, tetrahydrofuran-5-yl, tetrahydrothienyl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, tetrahydrothien-4-yl, tetrahydrothien-5-yl, piperidinyl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperidin-5-yl, Piperidin-6-yl, tetrahydropyranyl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, tetrahydropyran-5-yl, tetrahydropyran-6-yl, tetrahydrothiopyranyl, tetrahydrothiopyran-2-yl, tetrahydrothiopyran-3-yl, tetrahydrothiopyran-4-yl, tetrahydrothiopyran-5-yl, tetrahydrothiopyran-6-yl, piperazinyl, piperazin-1-yl, piperazin-2-yl, piperazin-3-yl, piperazin-4-yl yl, piperazin-5-yl, piperazin-6-yl, morpholinyl, morpholin-2-yl, morpholin-3-yl, morpholin-4-yl, morpholin-5-yl, morpholin-6-yl, thiomorpholinyl, thiomorpholin-2-yl, thiomorpholin-3-yl, thiomorpholin-4-yl, thiomorpholin-5-yl, thiomorpholin-6-yl, oxathianily, oxathian-2-yl, oxathian-3-yl, oxathian-5-yl, oxathian-6-yl, dithianyl, dithian-2-yl, dithian-3-yl,Dithian-5-yl, dithian-6-yl, dioxolanyl, dioxolan-2-yl, dioxolan-4-yl, dioxolan-5-yl, thioxanyl, thioxan-2-yl, thioxan-3-yl, thioxan-4-yl, thioxan-5-yl, dithiolanyl, dithiolan-2-yl, dithiolan-4-yl, dithiolan-5-yl, pyrazolidinyl, pyrazolidin-1-yl, pyrazolidin-2-yl, pyrazolidin-3-yl, pyrazolidin-4-yl, pyrazolidin-5-yl, 2-azabicyclo[4.2.0]octanyl, octahydro-1H-cyclopenta[b]pyridine, and decahydroquinoline.

[0038] The term "9- to 12-membered heterocyclyl group" as used herein means N, NH, NR 7 , O or -S- (wherein R 7 Heterocyclyl refers to a 9- to 12-membered partially saturated hydrocarbon ring system having 1 to 4 ring members independently selected from N, NR, NR(s), and NR(s), which may be a monocyclic, fused bicyclic, or fused tricyclic ring system. A heterocyclic group may be attached to another group at a nitrogen or carbon atom. In certain embodiments, heterocyclyl is selected from N, NR(s), and NR(s). 7 , O and S (wherein R 7 and R, R, and R can be 9- to 12-membered fused bicyclic heterocyclyl ring structures having 1 to 4 ring members independently selected from: (where R, R, and R are as defined herein). Non-limiting examples of heterocyclyl groups, as used herein, include benzo[d][1,3]dioxolyl, benzo[b][1,4]dioxepinyl, tetrahydrobenzo[d]isoxazolyl, dihydrobenzofuranyl, tetrahydropyrano[3,4-c]pyrazolyl, chromanyl, and 6,7-dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]oxazinyl.

[0039] As used herein, the terms "optical isomer" or "stereoisomer" refer to any of the various stereoisomeric configurations that may exist for a given compound of the present disclosure, including geometric isomers. It is understood that substituents may be attached at chiral centers of carbon atoms. The term "chiral" refers to molecules possessing the property of not being superimposable on their mirror-image partners, while the term "achiral" refers to molecules that are superimposable on their mirror-image partners. Thus, the present disclosure includes enantiomers, diastereomers, or racemates of compounds. "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. This term is used to designate a racemic mixture where appropriate. "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms and are not mirror images of each other. Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog "RS" system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified as either R or S. Resolved compounds of unknown absolute configuration can be designated as (+) or (-) depending on the direction (dextrorotatory or levorotatory) they rotate plane-polarized light at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers or axes and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined in terms of absolute stereochemistry as (R)- or (S)-.

[0040] As used herein, the term "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drug stabilizers, binders, excipients, disintegrating agents, lubricants, sweeteners, flavoring agents, dyes, and the like, and combinations thereof, known to those of skill in the art for use in pharmaceutical compositions for administration to human subjects (see, e.g., Remington: The Science and Practice of Pharmacy, 22nd ed.). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated.

[0041] As used herein, the term "therapeutically effective amount" of a compound refers to an amount of a compound of the present disclosure that elicits a biological or medical response in a subject, e.g., an amount that is sufficient to reduce one or more symptoms, alleviate a condition, slow or delay disease progression, or prevent disease, etc. In one non-limiting embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the present disclosure that, when administered to a subject, is effective to reduce one or more symptoms associated with influenza virus infection, or shorten the duration of the symptomatic stage of influenza virus infection, or slow the progression of influenza virus infection, or reduce or stop the worsening of an underlying condition due to influenza virus infection.

[0042] In another non-limiting embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the present disclosure that, when administered to a cell, or tissue, or non-cellular biological material, or medium, is effective to cause a statistically significant decrease in the rate of replication or proliferation of an orthomyxovirus strain.

[0043] As used herein, the term "subject" refers to an animal. Typically, the subject is a human.

[0044] As used herein, the terms "inhibit," "inhibition," or "inhibiting" refer to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant reduction in the baseline activity of a biological activity or process.

[0045] As used herein, the terms "treat," "treating," or "treatment" of any disease or disorder refer, in one embodiment, to ameliorating the disease or disorder (i.e., slowing, stopping, or reducing the occurrence of the disease or at least one of its clinical symptoms). In another embodiment, "treat," "treating," or "treatment" refers to alleviating or ameliorating at least one physical parameter, including those that may not be discernible by the patient. In yet another embodiment, "treat," "treating," or "treatment" refers to modulating the disease or disorder physically (e.g., stabilization of discernible symptoms), physiologically (e.g., stabilization of physical parameters), or both. In yet another embodiment, "treat," "treating," or "treatment" refers to preventing or delaying the onset or progression of the disease or disorder.

[0046] As used herein, a subject is "in need of" a treatment if such subject would benefit biologically, medically, or in quality of life from such treatment.

[0047] As used herein, the terms "a," "an," "the," and similar terms as used in the context of this disclosure (particularly in the context of the claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0048] The names of the compounds provided herein were obtained using ChemDraw Professional version 17.1 (PerkinElmer Inc.).

[0049] Unless otherwise specified, the term "compounds of the invention," "compounds of the disclosure," or "compounds provided herein" refers to compounds of Formula (I) and its sub-formulas, such as Formula (II), Formula (III), Formula (IV), Formula (V), Formula (Va), Formula (Vb), Formula (Vc), Formula (V-a1), Formula (V-a2), Formula (V-b1), Formula (V-b2), Formula (V-b3), Formula (V-b4), Formula (V-c1), Formula (V-c2). , Formula (V-c3), Formula (V-c4), Formula (V-d1), Formula (V-d2), Formula (V-d3), Formula (V-d4), Formula (V-e1), Formula (V-e2), Formula (V-e3) and Formula (V-e4), as well as pharmaceutically acceptable salts, stereoisomers (including diastereoisomers and enantiomers), rotamers, tautomers and isotopically labeled compounds (including deuterium substitutions), and inherently formed moieties.

[0050] compound The present disclosure provides compounds having the structure of formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0051] [ka] [In the formula, R 1 is H or halo, R 2 is -C1-C8 haloalkyl, R 3 is L1R 5 or L2R 6 and R 4 is halo, CN, C1-C8 alkyl, C1-C8 alkoxy or C3-C8 cycloalkyl; L1 is a bond, -CH2-, or -(CH2) m -, -OCH2-, -O-, -CH2O-, -O(CH2) m -, -CH2OCH2-, -CH(R 7 )-, -OCH(R 7 )-, -CH(R 10 )-, -OCH(R 10 )-, -CF2-, -CF2CH2-, -OCF2-, -OCH2C(=O)-, -OCH2C(=O)NH-, -OCH2CH(OH)CH2-, -CH2OCH2C(R7)2-, -C(R 7 )2-, -OC(R 7 )2-, -OCH(R 10 )CH2-, -NH- or -NH(CH2) m -; and L2 is a bond, -CH2-, -(CH2) m -, -OCH2-, -CH2O-, -O(CH2) m -, -CH2OCH2-, -CH(R 7 )-, -OCH(R 7 )-, -CH(R 10 )-, -OCH(R 10 )-, -C(R 7 )2-, -OC(R 7 )2-, -CF2-, -CF2CH2-, -OCF2-, -OCH2C(=O)NH-, -OCH2CH(OH)CH2-, -CH2OCH2C(R7)2-, -NH(CH2) m -, -OCH(R 10 )CH2- or -OCH2C(=O)-; and L3 is a bond, -CH2-, -(CH2) m -, -OCH2-, -O-, -NH-, -NH(CH2) m -, -OCH2C(=O)-, -OCH2C(=O)NH-, -OCH2CH(OH)CH2-, -CH2OCH2-, -CH2O-, -O(CH2) m -, -CH(R 7 )-, -OCH(R 7 )-, -CH(R 10 )-, -OCH(R 10)-, -CH2OCH2C(R7)2-, -CF2-, -CF2CH2-, -OCF2-, -C(R 7 )2-, -OC(R 7 )2-, or -OCH(R 10 )CH2-; and L4 is a bond, -CH2-, -(CH2) m -, -C(R 7 )2-, -OC(R 7 )2, -CF2-, -OCH2-, -O(CH2) m -, -CH2O-, -CH2OCH2-, -CH2OCH2C(R7)2-, -NH(CH2) m -, -OCH2C(=O)-, -OCH2C(=O)NH-, -OCH2CH(OH)CH2-, -CF2CH2-, -OCF2-, -CH(R 10 )-, -OCH(R 10 )-, -OCH(R 7 )-, -OC(R 7 )2-, -CH(R 7 )-, or -OCH(R 10 )CH2; and R 5 teeth, i)R 9 phenyl substituted with 0 to 3 groups independently selected from ii)R 9 C3-C8 cycloalkyl substituted with 0 to 3 groups independently selected from iii)R 9 substituted with 0 to 3 groups independently selected from N, NR 7 a 4-8 membered monocyclic heterocycloalkyl group having 1 to 3 ring members independently selected from O, S, C=O, or S(=O)2; iv) R 9 substituted with 0 to 3 groups independently selected from N, NR 7 a 9- to 12-membered heterocyclyl group having 1 to 4 ring members independently selected from , O, or S; v)R 9 substituted with 0 to 3 groups independently selected from N, NR 7a 7-8 membered bridged bicyclic heterocycloalkyl group having 1-2 ring members independently selected from O, S, C=O, or S(=O)2; vi)R 9 substituted with 0 to 3 groups independently selected from N, NR 7 a fused 6-8 membered bicyclic heterocycloalkyl group having 1-2 ring members independently selected from O, S, C=O, or S(=O)2; vii)R 9 substituted with 0 to 3 groups independently selected from N, NR 7 , 5-6 membered heteroaryl having 1-3 ring members independently selected from O or S; and viii)R 9 substituted with 0 to 3 groups independently selected from N, NR 7 , N + O - 9-10 membered heteroaryl having 1-4 ring members independently selected from , O, or S; is selected from the group consisting of R 6 -CN, -OH, -NR 7 R 8 , -NR 7 C(=O)R 8 , -NR 7 S(=O)2R 8 , -C(=O)NR 7 R 8 , -S(=O)2R 8 , halo, C1-C8 haloalkoxy, C1-C8 alkoxy, -C1-C8 alkyl or -C2-C8 alkylene; Each R 7 are independently selected from H or -C1-C8 alkyl; R 8 is H or -C1-C8 alkyl, Each R 9 is -C1-C8 alkyl, -C1-C8 alkoxy, C1-C8 haloalkyl, spiro-linked C3-C8 cycloalkyl, R 10 , -OH, CN, halo, -C(=O)R 7 , -NR 7 R8 , -C(=O)NR 7 R 8 , -NR 7 C(=O)R 8 , -NR 7 C(=O)OR 8 , -C(=O)OR 8 , -NR 7 S(=O)2R 8 , -S(=O)2R 8 , -S(=O)2R 10 , NO2, CN, L3R 11 , L4R 12 or N, NR 7 spiro-linked 4-8 membered monocyclic heterocycloalkyl groups having 1-2 ring members independently selected from , O, or S; R 10 is C3-C8 cycloalkyl, or N, NR 7 , O, or S; or N, NR 7 , O, or S; Each R 11 teeth, i)R 13 phenyl substituted with 0 to 3 groups independently selected from ii)R 13 C3-C8 cycloalkyl substituted with 0 to 3 groups independently selected from iii)R 13 substituted with 0 to 3 groups independently selected from N, NR 7 a 4-8 membered monocyclic heterocycloalkyl group having 1 to 3 ring members independently selected from O, S, C=O, or S(=O)2; iv) R 13 substituted with 0 to 3 groups independently selected from N, NR 7 9-12 membered heterocyclyl having 1-4 ring members independently selected from , O, or S; v)R 13 substituted with 0 to 3 groups independently selected from N, NR7 a 7-8 membered bridged bicyclic heterocycloalkyl group having 1-2 ring members independently selected from O, S, C=O, or S(=O)2; vi)R 13 substituted with 0 to 3 groups independently selected from N, NR 7 a fused 6-8 membered bicyclic heterocycloalkyl group having 1-2 ring members independently selected from O, S, C=O, or S(=O)2; vii)R 13 substituted with 0 to 3 groups independently selected from N, NR 7 , 5-6 membered heteroaryl having 1-3 ring members independently selected from O or S; and viii)R 13 substituted with 0 to 3 groups independently selected from N, NR 7 , N + O - 9-10 membered heteroaryl having 1-4 ring members independently selected from , O, or S; are independently selected from the group consisting of Each R 12 are -CN, -CD3, -OCD3, -OH, -NR 7 R 8 , -NR 7 C(=O)R 8 , -NR 7 S(=O)2R 8 , -C(=O)NR 7 R 8 , -S(=O)2R 8 , -S(=O)2R 10 , halo, C1-C8 haloalkoxy, C1-C8 alkoxy, C1-C8 haloalkyl or -C1-C8 alkyl; Each R 13 is -C1-C8 alkyl, spiro-linked C3-C8 cycloalkyl, -C1-C8 alkoxy, -OH, halo, -C(=O)R 7 , -NR 7 R 8 , -C(=O)NR 7 R 8 , -NR 7 C(=O)R8 , -NR 7 S(=O)2R 8 , -S(=O)2R 8 , NO2, CN, or C1-C8 haloalkyl; each m is independently selected from 1, 2, 3, or 4; each n is independently selected from 0, 1, 2, or 3; each p is independently selected from 0, 1, 2, or 3].

[0052] Various embodiments are described herein. It should be recognized that the features specified in each embodiment may be combined with other specified features to provide further embodiments. The following listed embodiments are representative of aspects of the present disclosure.

[0053] Embodiment 1. A compound having the structure of formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0054] [ka] [In the formula, R 1 is H or halo, R 2 is -C1-C8 haloalkyl, R 3 is L1R 5 or L2R 6 and R 4 is halo, CN, C1-C8 alkyl, C1-C8 alkoxy or C3-C8 cycloalkyl; L1 is a bond, -CH2-, -(CH2) m -, -OCH2-, -O-, -CH2O-, -O(CH2) m -, -CH2OCH2-, -CH(R 7 )-, -OCH(R 7 )-, -CH(R 10 )-, -OCH(R 10)-, -CF2-, -CF2CH2-, -OCF2-, -OCH2C(=O)-, -OCH2C(=O)NH-, -OCH2CH(OH)CH2-, -CH2OCH2C(R7)2-, -C(R 7 )2-, -OC(R 7 )2-, -OCH(R 10 )CH2-, -NH- or -NH(CH2) m -; and L2 is a bond, -CH2-, -(CH2) m -, -OCH2-, -CH2O-, -O(CH2) m -, -CH2OCH2-, -CH(R 7 )-, -OCH(R 7 )-, -CH(R 10 )-, -OCH(R 10 )-, -C(R 7 )2-, -OC(R 7 )2-, -CF2-, -CF2CH2-, -OCF2-, -OCH2C(=O)NH-, -OCH2CH(OH)CH2-, -CH2OCH2C(R7)2-, -NH(CH2) m -, -OCH(R 10 )CH2- or -OCH2C(=O)-; and L3 is a bond, -CH2-, -(CH2) m -, -OCH2-, -O-, -NH-, -NH(CH2) m -, -OCH2C(=O)-, -OCH2C(=O)NH-, -OCH2CH(OH)CH2-, -CH2OCH2-, -CH2O-, -O(CH2) m -, -CH(R 7 )-, -OCH(R 7 )-, -CH(R 10 )-, -OCH(R 10 )-, -CH2OCH2C(R7)2-, -CF2-, -CF2CH2-, -OCF2-, -C(R 7 )2-, -OC(R 7 )2-, or -OCH(R 10 )CH2-; and L4 is a bond, -CH2-, -(CH2) m -, -C(R7 )2-, -OC(R 7 )2, -CF2-, -OCH2-, -O(CH2) m -, -CH2O-, -CH2OCH2-, -CH2OCH2C(R7)2-, -NH(CH2) m -, -OCH2C(=O)-, -OCH2C(=O)NH-, -OCH2CH(OH)CH2-, -CF2CH2-, -OCF2-, -CH(R 10 )-, -OCH(R 10 )-, -OCH(R 7 )-, -OC(R 7 )2-, -CH(R 7 )-, or -OCH(R 10 )CH2; and R 5 teeth, i)R 9 phenyl substituted with 0 to 3 groups independently selected from ii)R 9 C3-C8 cycloalkyl substituted with 0 to 3 groups independently selected from iii)R 9 substituted with 0 to 3 groups independently selected from N, NR 7 a 4-8 membered monocyclic heterocycloalkyl group having 1 to 3 ring members independently selected from O, S, C=O, or S(=O)2; iv) R 9 substituted with 0 to 3 groups independently selected from N, NR 7 a 9- to 12-membered heterocyclyl group having 1 to 4 ring members independently selected from , O, or S; v)R 9 substituted with 0 to 3 groups independently selected from N, NR 7 a 7-8 membered bridged bicyclic heterocycloalkyl group having 1-2 ring members independently selected from O, S, C=O, or S(=O)2; vi)R 9 substituted with 0 to 3 groups independently selected from N, NR 7a fused 6-8 membered bicyclic heterocycloalkyl group having 1-2 ring members independently selected from O, S, C=O, or S(=O)2; vii)R 9 N, NR substituted with 0 to 3 groups independently selected from 7 , 5-6 membered heteroaryl having 1-3 ring members independently selected from O or S; and viii)R 9 substituted with 0 to 3 groups independently selected from N, NR 7 , N + O - 9-10 membered heteroaryl having 1-4 ring members independently selected from , O, or S; is selected from the group consisting of R 6 -CN, -OH, -NR 7 R 8 , -NR 7 C(=O)R 8 , -NR 7 S(=O)2R 8 , -C(=O)NR 7 R 8 , -S(=O)2R 8 , halo, C1-C8 haloalkoxy, C1-C8 alkoxy, -C1-C8 alkyl or -C2-C8 alkylene; Each R 7 are independently selected from H or -C1-C8 alkyl; R 8 is H or -C1-C8 alkyl, Each R 9 is -C1-C8 alkyl, -C1-C8 alkoxy, C1-C8 haloalkyl, spiro-linked C3-C8 cycloalkyl, R 10 , -OH, CN, halo, -C(=O)R 7 , -NR 7 R 8 , -C(=O)NR 7 R 8 , -NR 7 C(=O)R 8 , -NR 7 C(=O)OR 8 , -C(=O)OR8 , -NR 7 S(=O)2R 8 , -S(=O)2R 8 , -S(=O)2R 10 , NO2, CN, L3R 11 , L4R 12 or N, NR 7 spiro-linked 4-8 membered monocyclic heterocycloalkyl groups having 1-2 ring members independently selected from , O, or S; R 10 is C3-C8 cycloalkyl, or N, NR 7 , O, or S; or N, NR 7 , O, or S; Each R 11 teeth, i)R 13 phenyl substituted with 0 to 3 groups independently selected from ii)R 13 C3-C8 cycloalkyl substituted with 0-3 groups independently selected from: iii)R 13 substituted with 0 to 3 groups independently selected from N, NR 7 a 4-8 membered monocyclic heterocycloalkyl group having 1 to 3 ring members independently selected from O, S, C=O, or S(=O)2; iv) R 13 substituted with 0 to 3 groups independently selected from N, NR 7 9-12 membered heterocyclyl having 1-4 ring members independently selected from , O, or S; v)R 13 substituted with 0 to 3 groups independently selected from N, NR 7 a 7-8 membered bridged bicyclic heterocycloalkyl group having 1-2 ring members independently selected from O, S, C=O, or S(=O)2; vi)R 13 substituted with 0 to 3 groups independently selected from N, NR7 a fused 6-8 membered bicyclic heterocycloalkyl group having 1-2 ring members independently selected from O, S, C=O, or S(=O)2; vii)R 13 substituted with 0 to 3 groups independently selected from N, NR 7 , 5-6 membered heteroaryl having 1-3 ring members independently selected from O or S and viii)R 13 substituted with 0 to 3 groups independently selected from N, NR 7 , N + O - 9-10 membered heteroaryl having 1-4 ring members independently selected from , O, or S; are independently selected from the group consisting of Each R 12 are -CN, -CD3, -OCD3, -OH, -NR 7 R 8 , -NR 7 C(=O)R 8 , -NR 7 S(=O)2R 8 , -C(=O)NR 7 R 8 , -S(=O)2R 8 , -S(=O)2R 10 , halo, C1-C8 haloalkoxy, C1-C8 alkoxy, C1-C8 haloalkyl or -C1-C8 alkyl; Each R 13 is -C1-C8 alkyl, spiro-linked C3-C8 cycloalkyl, -C1-C8 alkoxy, -OH, halo, -C(=O)R 7 , -NR 7 R 8 , -C(=O)NR 7 R 8 , -NR 7 C(=O)R 8 , -NR 7 S(=O)2R 8 , -S(=O)2R 8 , NO2, CN, or C1-C8 haloalkyl; each m is independently selected from 1, 2, 3, or 4; each n is independently selected from 0, 1, 2, or 3; each p is independently selected from 0, 1, 2, or 3].

[0055] Embodiment 2. The compound of embodiment 1 having the structure of formula (II), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0056] [ka] [In the formula, R 1 , R 2 , R 3 and R 4 as described herein].

[0057] Embodiment 3. R 1 is H, R 2 is -C1-C8 haloalkyl, R 3 L1R 5 or L2R 6 and R 4 is halo, CN, C1-C8 alkyl, C1-C8 alkoxy, or C3-C8 cycloalkyl; L1 is -CH2-, -OCH2-, -O-, -CH2O-, -O(CH2) m -, -CH(R 7 )-, -OCH(R 7 )-, -CH(R 10 )-, -OCH(R 10 )-, -CF2CH2-, -OCF2-, -OCH2C(=O)-, -OCH2C(=O)NH-, or -OCH2CH(OH)CH2-; L2 is a bond, -CH2-, -OCH2-, -O(CH2) m -, -CH(R 7 )-, -OCH(R 10 )-, -OCH(R 10 )CH2- or -OCH2C(=O)-, L3 is a bond, -CH2-, -OCH2-, -O-, -NH-, or -NH(CH2) m -, -CH2OCH2- or -CH2O-, L4 is CH2-, -(CH2) m -, -C(R 7 )2-, -CF2-, -OCH2-, -O(CH2) m -, -CH2O-, -CH2OCH2-, -CH2OCH2C(R7)2- or -NH(CH2) m - and R 5 but, i)R 9 phenyl substituted with 0 to 3 groups independently selected from ii)R 9 C3-C8 cycloalkyl substituted with 0 to 3 groups independently selected from iii)R 9 substituted with 0 to 3 groups independently selected from N, NR 7 a 4-8 membered monocyclic heterocycloalkyl group having 1 to 3 ring members independently selected from O, S, C=O, or S(=O)2; iv) R 9 substituted with 0 to 3 groups independently selected from N, NR 7 a 9- to 12-membered heterocyclyl group having 1 to 4 ring members independently selected from , O, or S; v)R 9 substituted with 0 to 3 groups independently selected from N, NR 7 a 7-8 membered bridged bicyclic heterocycloalkyl group having 1-2 ring members independently selected from O or S; vi)R 9 substituted with 0 to 3 groups independently selected from N, NR 7 a 6-8 membered fused bicyclic heterocycloalkyl group having 1-2 ring members independently selected from O or S; vii)R 9 substituted with 0 to 3 groups independently selected from N, NR 7, 5-6 membered heteroaryl having 1-3 ring members independently selected from O or S and viii)R 9 substituted with 0 to 3 groups independently selected from N, NR 7 , N + O - 9-10 membered heteroaryl having 1-4 ring members independently selected from , O, or S; is selected from the group consisting of R 6 -CN, -OH, -NR 7 R 8 , -NR 7 C(=O)R 8 , -NR 7 S(=O)2R 8 , -C(=O)NR 7 R 8 , -S(=O)2R 8 , halo, C1-C8 haloalkoxy, C1-C8 alkoxy, -C1-C8 alkyl or -C2-C8 alkylene; Each R 7 are independently selected from H or -C1-C8 alkyl; R 8 is H or -C1-C8 alkyl, Each R 9 is -C1-C8 alkyl, -C1-C8 alkoxy, C1-C8 haloalkyl, spiro-linked C3-C8 cycloalkyl, R 10 , -OH, CN, halo, -C(=O)R 7 , -NR 7 R 8 , -C(=O)NR 7 R 8 , -NR 7 C(=O)R 8 , -C(=O)OR 8 , -NR 7 S(=O)2R 8 , -S(=O)2R 8 , -S(=O)2R 10 , NO2, CN, L3R 11 , L4R 12 or N, NR 7spiro-linked 4-8 membered monocyclic heterocycloalkyl groups having 1-2 ring members independently selected from , O, or S; R 10 is C3-C8 cycloalkyl, or N, NR 7 , O, or S; or N, NR 7 , O, or S; Each R 11 but, i)R 13 phenyl substituted with 0 to 3 groups independently selected from ii)R 13 C3-C8 cycloalkyl substituted with 0 to 3 groups independently selected from iii)R 13 substituted with 0 to 3 groups independently selected from N, NR 7 a 4-8 membered monocyclic heterocycloalkyl group having 1-3 ring members independently selected from O or S; and iv) R 13 substituted with 0 to 3 groups independently selected from N, NR 7 , 5-6 membered heteroaryl having 1-3 ring members independently selected from O or S are independently selected from the group consisting of Each R 12 -CN, -CD3, -OCD3, -OH, -NR 7 R 8 , -NR 7 C(=O)R 8 , -NR 7 S(=O)2R 8 , -C(=O)NR 7 R 8 , -S(=O)2R 8 , -S(=O)2R 10 , halo, C1-C8 haloalkoxy, C1-C8 haloalkyl, -C1-C8 alkyl or C1-C8-alkoxy; Each R13 are independently selected from -C1-C8 alkyl, -C1-C8-alkoxy, -OH or halo; each m is independently selected from 1, 2, or 3; The compound of embodiment 1 or embodiment 2, wherein each p is independently selected from 0 or 1.

[0058] Embodiment 4. The compound of any one of embodiments 1 to 3 having formula (III): or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0059] [ka]

[0060] Embodiment 5. The compound of any one of embodiments 1 to 4 having formula (IV), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0061] [ka]

[0062] Embodiment 6. R 5 but, i)R 9 phenyl substituted with 0 to 3 groups independently selected from ii) Each is R 9 cyclopropyl, cyclobutyl, or cyclohexyl, each substituted with 0 to 3 groups independently selected from iii) Each is R 9 morpholinyl, pyrrolidinyl, thiomorpholinyl, oxetanyl, oxazepanyl, azetidinyl, pyrrolidinyl, piperidinyl, oxomorpholinyl, dioxidethiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl, dioxanyl, dioxepanyl, oxopyrrolidinyl, or oxooxazolidinyl, each of which is substituted with 0 to 3 groups independently selected from iv) Each is R9 benzo[d][1,3]dioxolyl, benzo[b][1,4]dioxepinyl, tetrahydrobenzo[d]isoxazolyl, dihydrobenzofuranyl, tetrahydropyrano[3,4-c]pyrazolyl, chromanyl, or 6,7-dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]oxazinyl, each of which is substituted by 0 to 3 groups independently selected from v) Each is R 9 8-oxa-3-azabicyclo[3.2.1]octanyl, oxabicyclo[2.2.1]heptanyl, or 3,8-dioxabicyclo[3.2.1]octanyl, each of which is substituted with 0 to 3 groups independently selected from vi) Each is R 9 3-azabicyclo[3.1.0]hexanyl or 2,5-dioxabicyclo[4.1.0]heptanyl, each substituted with 0 to 3 groups independently selected from vii) Each is R 9 oxazolyl, isoxazolyl, pyrazolyl, thiophenyl, thiazolyl, thiadiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl, each substituted by 0 to 3 groups independently selected from and viii) Each is R 9 benzo[c][1,2,5]oxadiazolyl, indazolyl, tetrazolo[1,5-a]pyridinyl, imidazo[1,2-a]pyridinyl, imidazo[4,5-b]pyridinyl, triazolo[4,3-a]pyrimidinyl, quinoxalinyl, quinolinyl, or isoquinolinyl, each of which is substituted with 0 to 3 groups independently selected from 6. The compound of any one of embodiments 1 to 5, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

[0063] Embodiment 7. 7. The compound of any one of embodiments 1 to 6, having formula (V), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0064] [ka]

[0065] Embodiment 8. The compound of any one of embodiments 1 to 7 having formula (Va), formula (Vb) or formula (Vc), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0066] [ka]

[0067] Embodiment 9. The compound according to any one of embodiments 1 to 8 having the formula (V-a1) or (V-a2), or a pharmaceutically acceptable salt thereof.

[0068] [ka]

[0069] Embodiment 10. Each R 9 Methyl, ethyl, isopropyl, neopentyl, methoxy, ethoxy, propoxy, isopropoxy, -CH2F, -CHF2, -CF3, R 10 , -OH, CN, F, Cl, Br, -C(=O)CH3, -NH2, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, -NH(CH2)6CH3, -N(CH3)2, -C(=O)NH2, -C(=O)N(CH3)2, -C(=O)NHCH3, -NHC( =O)CH3, -NHC(=O)OC(CH3)3, -C(=O)OC(CH3)3, -NHS(=O)2CH3, -S(=O)2CH3, -S(=O)2CH(CH3)2, -S(=O)2CH2CH(CH3)2, -S(=O)2-cyclopropyl, NO2, CN, L3R 11 , L4R 12, cyclopropyl, cyclopentyl, spiro-linked cyclopropyl, spiro-linked oxetanyl, spiro-linked dioxepanyl, or spiro-linked tetrahydrofuranyl.

[0070] Embodiment 11. Each R 9 is -C1-C8 alkyl, -C1-C8 alkoxy, halo, C1-C8 haloalkyl, spiro-linked C3-C8 cycloalkyl, R 10 , L3R 11 , L4R 12 or N, NR 7 , O, or S.

[0071] Embodiment 12. Each R 9 Methyl, F, methoxy, -CH2F, -CHF2, L3R 11 , L4R 12 , —C(═O)N(CH3)2, cyclopropyl, cyclopentyl, spiro-linked cyclopropyl, spiro-linked oxetanyl, spiro-linked dioxepanyl, or spiro-linked tetrahydrofuranyl.

[0072] Embodiment 13. Each R 9 But methyl, L3R 11 or L4R 12 13. The compound of any one of embodiments 1-12, independently selected from:

[0073] Embodiment 14. Each R 9 but methyl or L3R 11 are independently selected from L3 is a bond, -CH2-, -OCH2-, -O-, -NH-, -NH(CH2) m -, -CH2OCH2-, -CH2O-, -O(CH2) m -, -CH(R 7)-, -OCH(R 7 )-, -CH(R 10 )-, -CF2CH2-, -C(R 7 )2-, or -OC(R 7 )2- and R 11 However, each has 0 to 2 R 13 phenyl, tetrahydrofuranyl, cyclobutyl, cyclopropyl, cyclopentyl, oxetanyl, azetidinyl, pyrrolyl, or pyrazolyl, each substituted with a group; Each R 13 is independently selected from F, OH, methoxy, or methyl.

[0074] Embodiment 15. Each R 9 but methyl or L3R 11 are independently selected from L3 is a bond, -CH2, -OCH2-, -O-, -NH-, -NHCH2-, -CH2OCH2- or -CH2O-; R 11 However, each has 0 to 2 R 13 phenyl, tetrahydrofuranyl, cyclobutyl, cyclopropyl, cyclopentyl, oxetanyl, azetidinyl, pyrrolyl, or pyrazolyl, each substituted with a group; Each R 13 is independently selected from F, OH, methoxy, or methyl.

[0075] Embodiment 16. Each R 9 but methyl or L4R 12 are independently selected from L4 is -OCH2CH2-, -NHCH2CH2-, -CH2-, -CH2O-, -CH2CH2-, -C(CH3)2-, -C(CH2CH3)2-, -CF2-, -CH2OCH2-, -CH2OCH2CH2- or -CH2OCH2C(CH3)2-; R 1214. The compound of any one of embodiments 1-13, wherein is OH, CN, CD3, OCD3, F, Cl, -OCH2F, -OCHF2, OCF3, OCH2CH2F, OCH2CHF2, OCH2CHF3, -CH2F, CHF2, CF3, -CH2CH2F, -CH2CHF2, -CH2CHF3, methoxy, ethoxy, isopropoxy, CN, methyl, ethyl, isopropyl, -S(=O)2CH3, -S(=O)2-cyclopropyl, or -N(CH3)2.

[0076] Embodiment 17. 14. The compound of any one of embodiments 1 to 13 having formula (V-b1), formula (V-b2), formula (V-b3) or formula (V-b4), or a pharmaceutically acceptable salt thereof.

[0077] [ka]

[0078] Embodiment 18. The compound of any one of embodiments 1 to 13 having formula (V-c1), formula (V-c2), formula (V-c3) or formula (V-c4), or a pharmaceutically acceptable salt thereof.

[0079] [ka]

[0080] Embodiment 19. L4 is -OCH2CH2-, -NHCH2CH2-, -CH2-, -CH2O-, -CH2CH2-, -C(CH3)2-, -C(CH2CH3)2-, -CF2-, -CH2OCH2-, -CH2OCH2CH2- or -CH2OCH2C(CH3)2-; R 1219. The compound of any one of embodiments 1-18, wherein is OH, CN, CD3, OCD3, F, Cl, -OCH2F, -OCHF2, OCF3, OCH2CH2F, OCH2CHF2, OCH2CHF3, -CH2F, CHF2, CF3, -CH2CH2F, -CH2CHF2, -CH2CHF3, methoxy, ethoxy, isopropoxy, CN, methyl, ethyl, isopropyl, -S(=O)2CH3, -S(=O)2-cyclopropyl, or -N(CH3)2.

[0081] Embodiment 20. L4 is a bond, -CH2-, -(CH2) m -, -C(R 7 )2-, -CF2-, -OCH2-, -O(CH2) m The compound of any one of embodiments 1-19, wherein the compound is -, -CH2O-, -CH2OCH2-, or -CH2OCH2C(R7)2-.

[0082] Embodiment 21. The compound of any one of embodiments 1 to 20, wherein L4 is a bond, -CH2-, -(CH2)2-, -C(CH3)2-, -C(CH2CH3)2-, -CF2-, -CH2O-, -CH2OCH2-, -CH2OCH2C(CH3)2-, or -CH2OCH2CH2-.

[0083] Embodiment 22. The compound of any one of embodiments 1-21, wherein L4 is -CH2-, or -CH2O-.

[0084] Embodiment 23. 23. The compound of any one of embodiments 1 to 22 having formula (V-d1), formula (V-d2), formula (V-d3) or formula (V-d4), or a pharmaceutically acceptable salt thereof.

[0085] [ka]

[0086] Embodiment 24.14. The compound of any one of embodiments 1-13 having formula (V-e1), formula (V-e2), formula (V-e3) or formula (V-e4), or a pharmaceutically acceptable salt thereof.

[0087] [ka]

[0088] Embodiment 25. R 12 The compound of any one of embodiments 1-24, wherein is CN, CD3, OCD3, OH, N(CH3)2, -S(O)2CH3, -S(O)2-cyclopropyl, F, Cl, -OCHF2, -OCHF2, OCF3, CH2F, CHF2, CF3, -methyl, methoxy, ethoxy, or isopropoxy.

[0089] Embodiment 26. R 12 The compound of any one of embodiments 1-25, wherein is methoxy, ethoxy, or isopropoxy.

[0090] Embodiment 27. 5-(4-(morpholinomethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(hydroxymethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-hydroxyphenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(benzyloxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-(pyrrolidin-1-ylmethyl)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-phenoxyphenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(3-aminophenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(3-cyanophenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(3-hydroxyphenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(3-Formamidophenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(methylsulfonamido)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(difluoromethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(methoxymethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(3-fluoro-4-methoxyphenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(methoxymethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-phenyl-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-isopropoxyphenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(3-chloro-4-methoxyphenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(methylcarbamoyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(cyanomethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(3-(dimethylamino)propoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(3-(cyanomethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(3-(morpholinomethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(m-tolyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(3-(hydroxymethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(p-tolyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3-methylmorpholino)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-(thiomorpholinomethyl)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2-methylmorpholino)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((7-oxa-4-azaspiro[2.5]octan-4-yl)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-((3-(pyridin-3-yl)morpholino)methyl)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(1-morpholinoethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1,4-oxazepan-4-yl)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6R)-2,6-dimethylmorpholino)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(3-fluoro-4-(morpholinomethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(1-hydroxyethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3-methoxyazetidin-1-yl)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2,2-dimethylmorpholino)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; (S)-5-(4-((3-methoxypyrrolidin-1-yl)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; (R)-5-(4-((3-methoxypyrrolidin-1-yl)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(2-fluoro-4-(morpholinomethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(3-methyl-4-(morpholinomethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-(piperidin-1-ylmethyl)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((dimethylamino)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-((3-oxomorpholino)methyl)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1,1-dioxidothiomorpholino)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(morpholino(oxazol-5-yl)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(methylsulfonamidomethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-((tetrahydro-2H-pyran-4-yl)methyl)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(2-(1,4-dioxan-2-yl)-1,1-difluoroethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1-acetylpiperidin-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3-aminobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(cyclohexylmethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4-methoxybenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4-(dimethylcarbamoyl)benzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3-methoxybenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3-(methylcarbamoyl)benzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3-(methylsulfonamido)benzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3-carbamoylbenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-((3-(propylamino)benzyl)oxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3-(dimethylcarbamoyl)benzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3-acetamidobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4-(methylcarbamoyl)benzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-(pyridin-4-ylmethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(benzo[c][1,2,5]oxadiazol-5-ylmethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-(pyridin-3-ylmethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-(pyridin-2-ylmethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(benzo[c][1,2,5]oxadiazol-4-ylmethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3-(methylsulfonyl)benzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4-cyanobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3-cyanobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-6-(trifluoromethyl)-5-(4-((3-(trifluoromethyl)benzyl)oxy)phenyl)-1,2-dihydropyridine-3-carboxamide; (R or S)-2-oxo-5-(4-(1-(pyridin-3-yl)ethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-(pyrimidin-5-ylmethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1-methylpiperidin-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-(pyridazin-4-ylmethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1H-indazol-6-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1H-indol-6-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-6-(trifluoromethyl)-5-(4-((4-(trifluoromethyl)benzyl)oxy)phenyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-((5-oxopyrrolidin-3-yl)methoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2-cyanobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-(tetrazolo[1,5-a]pyridin-7-ylmethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(imidazo[1,2-a]pyridin-7-ylmethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1-methylpiperidin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4-fluoro-3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 6-((4-(5-carbamoyl-6-oxo-2-(trifluoromethyl)-1,6-dihydropyridin-3-yl)phenoxy)methyl)benzo[c][1,2,5]oxadiazole 1-oxide; (R or S)-2-oxo-5-(4-(1-(pyrimidin-5-yl)ethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; (R or S)-5-(4-(1-(3-cyanophenyl)ethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((5-cyanopyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(1-(benzo[c][1,2,5]oxadiazol-5-yl)ethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-((tetrahydro-2H-pyran-3-yl)methoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-([1,2,4]triazolo[4,3-a]pyrimidin-6-ylmethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((5-chloro-2-fluoropyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((5-chloropyridin-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2-methoxypyridin-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2-chloro-5-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-(thiophen-3-ylmethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-6-(trifluoromethyl)-5-(4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3,4-difluorobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4-methoxy-3,5-dimethylpyridin-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3-fluoropyridin-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-(thiophen-2-ylmethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2,5-difluorobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4-chloropyridin-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2,4-dimethylthiazol-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2-chloropyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-((5-(propylamino)pyridin-3-yl)methoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-(pyrimidin-2-ylmethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2-morpholinopyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-(pyrazin-2-ylmethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; (R or S)-5-(4-(1-(5-cyanopyridin-3-yl)ethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1-methyl-1H-pyrazol-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4-methoxypyridin-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-morpholinopyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2-fluoropyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((5-fluoro-2-methoxypyridin-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-(quinoxalin-6-ylmethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1-methyl-1H-indazol-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4-(methylsulfonyl)benzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-(thiazol-5-ylmethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4,6-dimethylpyridin-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2-methoxypyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(isoquinolin-7-ylmethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-(quinolin-7-ylmethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3-fluoropyridin-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4,6-dimethylpyrimidin-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1-methyl-1H-imidazol-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2-morpholinopyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-(thiazol-2-ylmethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3,4-dimethoxypyridin-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1-methyl-1H-indazol-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((5-methoxypyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2,6-dimethylpyridin-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-chlorobenzo[d][1,3]dioxol-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2-hydroxypyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2-(oxetan-3-ylmethoxy)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2-(2-hydroxyethoxy)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-((2-propoxypyrimidin-5-yl)methoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-((2-((tetrahydrofuran-3-yl)oxy)pyrimidin-5-yl)methoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2-(cyclopentyloxy)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2-(oxetan-2-ylmethoxy)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-((2-((tetrahydrofuran-3-yl)methoxy)pyrimidin-5-yl)methoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2-(methylamino)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2-(cyclopentylamino)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2-(dimethylamino)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2-((cyclopropylmethyl)amino)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2-((2-hydroxyethyl)amino)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2-(cyclopropylamino)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2-(heptylamino)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2-(oxetan-3-ylamino)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-((2-((tetrahydrofuran-3-yl)amino)pyrimidin-5-yl)methoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-(cyclopentylamino)pyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-((cyclopropylmethyl)amino)pyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-(3,3-difluoroazetidin-1-yl)pyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-(3-methoxyazetidin-1-yl)pyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2-cyclopropylpyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2-(cyclopentylmethyl)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2-neopentylpyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4-(cyclopentylamino)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3-(cyclopropylmethyl)-3H-imidazo[4,5-b]pyridin-6-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-chloropyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-((pyridin-3-yloxy)methyl)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((5-(furan-3-yl)pyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((5-morpholinopyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-((5-(tetrahydrofuran-3-yl)pyridin-3-yl)methoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((5-(3-hydroxyoxetan-3-yl)pyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((5-(3-fluorooxetan-3-yl)pyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-((3-(pyridin-3-yl)oxetan-3-yl)oxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(cyclopropyl(pyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-((1-(pyridin-3-yl)pent-4-en-1-yl)oxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(2-methoxy-1-(pyridin-3-yl)ethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(2-hydroxy-1-(pyrazin-2-yl)ethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4-acetylmorpholin-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(morpholin-2-ylmethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; tert-butyl 2-((4-(5-carbamoyl-6-oxo-2-(trifluoromethyl)-1,6-dihydropyridin-3-yl)phenoxy)methyl)morpholine-4-carboxylate, 5-(4-((4-(isopropylsulfonyl)morpholin-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4-(2,2-difluoroethyl)morpholin-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4-(2-methoxyethyl)morpholin-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4-(cyclopropylmethyl)morpholin-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1,4-oxazepan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4-(oxetan-3-yl)-1,4-oxazepan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4-(isopropylsulfonyl)-1,4-oxazepan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4-(isobutylsulfonyl)-1,4-oxazepan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(2-morpholino-2-oxoethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(2-(butylamino)-2-oxoethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-(2-oxo-2-(pyridin-3-ylamino)ethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4-methoxytetrahydro-2H-pyran-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,5S)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2,8-dioxa-5-azaspiro[3.5]nonan-6-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((5-methyl-2,8-dioxa-5-azaspiro[3.5]nonan-6-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-6-(trifluoromethyl)-5-(4-((4,5,5-trimethylmorpholin-3-yl)methoxy)phenyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((5S)-4,5-dimethylmorpholin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((3S,5S)-5-cyclopropyl-4-methylmorpholin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((3R,5S)-5-cyclopropyl-4-methylmorpholin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((5S)-5-isopropyl-4-methylmorpholin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((5-bromopyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((5-chloropyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-(pyridazin-3-ylmethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-(pyrimidin-4-ylmethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-chloropyrazin-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1-ethyl-1H-pyrazol-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1-(2-methoxyethyl)-1H-pyrazol-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1-methyl-1H-pyrazol-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1-ethyl-1H-pyrazol-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(isoxazol-3-ylmethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((5-methylisoxazol-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(oxetan-2-ylmethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3-fluorooxetan-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3-methyloxetan-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3-ethyloxetan-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3-(cyanomethyl)oxetan-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2-oxaspiro[3.3]heptan-6-yl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-((tetrahydrofuran-3-yl)methoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-((tetrahydrofuran-2-yl)methoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3-methyl-2-oxooxazolidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3-ethyl-2-oxooxazolidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3-methyl-2-oxooxazolidin-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-((tetrahydro-2H-pyran-2-yl)methoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1,4-dioxan-2-yl)methoxy)-3-fluorophenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1,4-dioxan-2-yl)methoxy)-3-chlorophenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1,4-dioxan-2-yl)methoxy)-3-cyanophenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1,4-dioxan-2-yl)methoxy)-3-methylphenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1,4-dioxan-2-yl)methoxy)-3-cyclopropylphenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1,4-dioxan-2-yl)methoxy)-3-methoxyphenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1,4-dioxan-2-yl)methoxy)-2-fluorophenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(morpholin-3-ylmethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4-methylmorpholin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4-cyclopropylmorpholin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4-ethylmorpholin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-((5-oxomorpholin-3-yl)methoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4-methyl-5-oxomorpholin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1-(methylsulfonyl)cyclopropyl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1-(cyclopropylsulfonyl)cyclopropyl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(2-methoxyethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(2-hydroxyethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(2-(methylsulfonyl)ethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-(2-(2-oxooxazolidin-3-yl)ethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(2-(1H-imidazol-1-yl)ethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(2-morpholinoethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(2-hydroxy-3-morpholinopropoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1,3-dimethyl-1H-pyrazol-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3-ethyl-1-methyl-1H-pyrazol-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-6-(trifluoromethyl)-5-(4-((1,3,4-trimethyl-1H-pyrazol-5-yl)methoxy)phenyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1-(cyclopropylmethyl)-1H-pyrazol-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(oxazol-4-ylmethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(oxazol-5-ylmethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((5-cyclopropylisoxazol-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((5-methylisoxazol-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((5-methyl-3-(pyridin-4-yl)isoxazol-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2-methylthiazol-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4-methylthiazol-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4-methyl-1,2,3-thiadiazol-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4-methylpyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4-cyclopropylpyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4-methoxypyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4-ethoxypyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((5-methylpyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((5-cyclopropylpyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4-isopropoxypyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4-methylpyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4-cyclopropylpyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-methylpyrazin-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-cyclopropylpyrazin-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(imidazo[1,2-a]pyridin-2-ylmethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(imidazo[1,2-a]pyridin-3-ylmethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-((4,5,6,7-tetrahydrobenzo[d]isoxazol-3-yl)methoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2,3-dihydrobenzofuran-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1-methyl-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2-methyl-2,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1-isopropyl-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2-isopropyl-2,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(chroman-2-ylmethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; tert-butyl 3-((4-(5-carbamoyl-6-oxo-2-(trifluoromethyl)-1,6-dihydropyridin-3-yl)phenoxy)methyl)azetidine-1-carboxylate, tert-butyl ((1r,3r)-3-((4-(5-carbamoyl-6-oxo-2-(trifluoromethyl)-1,6-dihydropyridin-3-yl)phenoxy)methyl)cyclobutyl)carbamate, (S)-5-(4-((5,5-dimethyltetrahydrofuran-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; tert-butyl 6-((4-(5-carbamoyl-6-oxo-2-(trifluoromethyl)-1,6-dihydropyridin-3-yl)phenoxy)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate, tert-butyl 3-((4-(5-carbamoyl-6-oxo-2-(trifluoromethyl)-1,6-dihydropyridin-3-yl)phenoxy)methyl)pyrrolidine-1-carboxylate, tert-butyl 3-((4-(5-carbamoyl-6-oxo-2-(trifluoromethyl)-1,6-dihydropyridin-3-yl)phenoxy)methyl)-4-methylpyrrolidine-1-carboxylate, 5-(4-((1-benzyl-3-cyanopyrrolidin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; tert-butyl (2S,4R)-2-((4-(5-carbamoyl-6-oxo-2-(trifluoromethyl)-1,6-dihydropyridin-3-yl)phenoxy)methyl)-4-fluoropyrrolidine-1-carboxylate, tert-butyl (2S,4S)-2-((4-(5-carbamoyl-6-oxo-2-(trifluoromethyl)-1,6-dihydropyridin-3-yl)phenoxy)methyl)-4-fluoropyrrolidine-1-carboxylate, 5-(4-((3-isopropyl-2-oxooxazolidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3-(cyclopropylmethyl)-2-oxooxazolidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3-ethyl-2-oxooxazolidin-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3-isopropyl-2-oxooxazolidin-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3-(cyclopropylmethyl)-2-oxooxazolidin-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((7-oxabicyclo[2.2.1]heptan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3,8-dioxabicyclo[3.2.1]octan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1,4-dioxepan-6-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-methyl-1,4-dioxepan-6-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((5-methyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2R,6R)-6-cyclopropyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2R,6S)-6-cyclopropyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2R,6R)-6-methyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6R)-6-methyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6S)-6-methyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2R,6S)-6-methyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-cyclopentyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4,7-dioxaspiro[2.5]octan-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((5,5-difluorotetrahydro-2H-pyran-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4,7-dioxaspiro[2.5]octan-6-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((5,5-dimethyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((5-(fluoromethyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((5-(difluoromethyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-(difluoromethyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-(fluoromethyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-(1-methoxycyclopropyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-(2-hydroxypropan-2-yl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-(1-methylcyclopropyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-(1,1-difluoroethyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-(ethoxymethyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-((cyclopropylmethoxy)methyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-(((1-fluorocyclopropyl)methoxy)methyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-((3,3-difluorocyclobutoxy)methyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-((2,2-difluoroethoxy)methyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-((2-methoxy-2-methylpropoxy)methyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-((6-((trifluoromethoxy)methyl)-1,4-dioxan-2-yl)methoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-((1H-pyrrol-1-yl)methyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-((1H-pyrazol-1-yl)methyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-(((3-methyloxetan-3-yl)oxy)methyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3-cyclopropyl-6,7-dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]oxazin-6-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3-cyclopropyl-6,7-dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]oxazin-7-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-(2-methoxypropan-2-yl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-(3-fluoropentan-3-yl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-(hydroxymethyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-((3-fluoroazetidin-1-yl)methyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-((3,3-difluoroazetidin-1-yl)methyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-((3-methoxyazetidin-1-yl)methyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2-fluoro-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1,4-dioxan-2-yl)difluoromethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((1S,3R,6R)-7,7-difluoro-2,5-dioxabicyclo[4.1.0]heptan-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; Also known as 5-(4-((cis-7,7-difluoro-2,5-dioxabicyclo[4.1.0]heptan-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((1R,3R,6S)-7,7-difluoro-2,5-dioxabicyclo[4.1.0]heptan-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; Also known as 5-(4-((trans-7,7-difluoro-2,5-dioxabicyclo[4.1.0]heptan-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-(methoxymethyl)-5-methyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((1S,3S,6R)-7,7-difluoro-1-methyl-2,5-dioxabicyclo[4.1.0]heptan-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((1R,3S,6S)-7,7-difluoro-1-methyl-2,5-dioxabicyclo[4.1.0]heptan-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((1R,3R,6S)-7,7-difluoro-1-methyl-2,5-dioxabicyclo[4.1.0]heptan-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((1S,3R,6R)-7,7-difluoro-1-methyl-2,5-dioxabicyclo[4.1.0]heptan-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6S)-6-(methoxymethyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6R)-6-(methoxymethyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2R,6R)-6-(methoxymethyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2R,6S)-6-(methoxymethyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6R)-6-(isopropoxymethyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6S)-6-(isopropoxymethyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6S)-6-cyclopropyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6S)-6-(methoxymethyl)-6-methyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6R)-6-(methoxymethyl)-6-methyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2R,6R)-6-(methoxymethyl)-6-methyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2R,6S)-6-(methoxymethyl)-6-methyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6R)-6-(dimethylcarbamoyl)-6-methyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6S)-6-((methoxy-d3)methyl)-6-methyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6S)-6-(cyanomethyl)-6-methyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6R)-6-methyl-6-((methylsulfonyl)methyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6R)-6-((cyclopropylsulfonyl)methyl)-6-methyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; (S)-5-(4-((6,6-bis(methoxymethyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; (S)-5-(4-((2,5,8-trioxaspiro[3.5]nonan-6-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; (S)-5-(4-((1,4,8,11-tetraoxaspiro[5.6]dodecan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6S)-6-(fluoromethyl)-6-(methoxymethyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6S)-6-(chloromethyl)-6-(methoxymethyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6S)-6-(fluoromethyl)-6-methyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6R)-6-(fluoromethyl)-6-methyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6R)-6-((3-fluoroazetidin-1-yl)methyl)-6-methyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6R)-6-((3,3-difluoroazetidin-1-yl)methyl)-6-methyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6S)-6-((dimethylamino)methyl)-6-methyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6R)-6-((dimethylamino)methyl)-6-methyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6R)-6-((difluoromethoxy)methyl)-6-methyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6S)-6-(2-methoxyethyl)-6-methyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6R)-6-methyl-6-((oxetan-3-yloxy)methyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6S)-6-(ethoxymethyl)-6-methyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6R)-6-methyl-6-(((3-methyloxetan-3-yl)oxy)methyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6S)-6-((2-methoxyethoxy)methyl)-6-methyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6R)-6-((2,2-difluoroethoxy)methyl)-6-methyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6R)-6-methyl-6-((2,2,2-trifluoroethoxy)methyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6S)-6-(hydroxymethyl)-6-methyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6S)-6-(2,2-difluoroethyl)-6-methyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6S)-6-(2-fluoroethyl)-6-methyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6R)-6-((2-fluoroethoxy)methyl)-6-methyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6R)-6-cyclopropyl-6-methyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6R)-6-cyclopropyl-6-(methoxymethyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6S)-6-cyclopropyl-6-(methoxymethyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide, and / or 5-(4-(((5R,7S)-2,6,9-trioxaspiro[4.5]decan-7-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide The compound of embodiment 1 selected from:

[0091] Embodiment 28. R 3 L1R 5 The compound of any one of the above embodiments, wherein

[0092] Embodiment 29. R 3 is L2R 6 The compound of any one of the above embodiments, wherein

[0093] Embodiment 30. R 4 The compound of any one of the preceding embodiments, wherein is halo, CN, C1-C8 alkyl, C1-C8 alkoxy, or C3-C8 cycloalkyl.

[0094] Embodiment 31. R 4 The compound of any one of the above embodiments, wherein is halo.

[0095] Embodiment 32. R 4 The compound of any one of the above embodiments, wherein is CN.

[0096] Embodiment 33. R 4 The compound of any one of the preceding embodiments, wherein is C1-C8 alkyl.

[0097] Embodiment 34. R 4 The compound of any one of the preceding embodiments, wherein is C1-C8 alkoxy.

[0098] Embodiment 35. R 4 The compound of any one of the preceding embodiments, wherein is C3-C8 cycloalkyl.

[0099] Embodiment 36. L1 is a bond, -CH2-, or -(CH2) m -, -OCH2-, -O-, -CH2O-, -O(CH2) m -, -CH2OCH2-, -CH(R 7 )-, -OCH(R 7 )-, -CH(R 10 )-, -OCH(R 10)-, -CF2-, -CF2CH2-, -OCF2-, -OCH2C(=O)-, -OCH2C(=O)NH-, -OCH2CH(OH)CH2-, -CH2OCH2C(R7)2-, -C(R 7 )2-, -OC(R 7 )2-, -OCH(R 10 )CH2-, -NH- or -NH(CH2) m The compound of any one of the above embodiments, wherein

[0100] Embodiment 37. L1 is -CH2-, -OCH2-, -O-, -CH2O-, -O(CH2) m -, -CH(R 7 )-, -OCH(R 7 )-, -CH(R 10 )-, -OCH(R 10 )—, —CF2CH2—, —OCF2—, —OCH2C(═O)—, —OCH2C(═O)NH—, or —OCH2CH(OH)CH2—.

[0101] Embodiment 38. The compound of any one of the preceding embodiments, wherein L1 is -CH2-, -OCH2-, -O-, or -CH2O-.

[0102] Embodiment 39. L2 is a bond, -CH2-, -(CH2) m -, -OCH2-, -O-, -CH2O-, -O(CH2) m -, -CH2OCH2-, -CH(R 7 )-, -OCH(R 7 )-, -CH(R 10 )-, -OCH(R 10 )-, -CF2-, -CF2CH2-, -OCF2-, -OCH2C(=O)-, -OCH2C(=O)NH-, -OCH2CH(OH)CH2-, -CH2OCH2C(R7)2-, -C(R 7 )2-, -OC(R 7 )2-, -OCH(R 10 )CH2-, -NH- or -NH(CH2) mThe compound of any one of the above embodiments, wherein

[0103] Embodiment 40. L2 is a bond, -CH2-, -OCH2-, -O(CH2) m -, -CH(R 7 )-, -OCH(R 10 )-, -OCH(R 10 )CH2- or -OCH2C(=O)-.

[0104] Embodiment 41. The compound according to any one of the preceding embodiments, wherein L2 is a bond, -CH2- or -OCH2-.

[0105] Embodiment 42. L3 is a bond, -CH2-, -(CH2) m -, -OCH2-, -O-, -CH2O-, -O(CH2) m -, -CH2OCH2-, -CH(R 7 )-, -OCH(R 7 )-, -CH(R 10 )-, -OCH(R 10 )-, -CF2-, -CF2CH2-, -OCF2-, -OCH2C(=O)-, -OCH2C(=O)NH-, -OCH2CH(OH)CH2-, -CH2OCH2C(R7)2-, -C(R 7 )2-, -OC(R 7 )2-, -OCH(R 10 )CH2-, -NH- or -NH(CH2) m The compound of any one of the above embodiments, wherein

[0106] Embodiment 43. L3 is a bond, -CH2-, -OCH2-, -O-, -NH-, or -NH(CH2) m The compound of any one of the above embodiments, wherein the aryl group is -, -CH2OCH2-, or -CH2O-.

[0107] Embodiment 44.The compound according to any one of the preceding embodiments, wherein L3 is a bond, -CH2-, -OCH2-, -CH2OCH2- or -CH2O-.

[0108] Embodiment 45. L4 is a bond, -CH2-, -(CH2) m -, -OCH2-, -O-, -CH2O-, -O(CH2) m -, -CH2OCH2-, -CH(R 7 )-, -OCH(R 7 )-, -CH(R 10 )-, -OCH(R 10 )-, -CF2-, -CF2CH2-, -OCF2-, -OCH2C(=O)-, -OCH2C(=O)NH-, -OCH2CH(OH)CH2-, -CH2OCH2C(R7)2-, -C(R 7 )2-, -OC(R 7 )2-, -OCH(R 10 )CH2-, -NH- or -NH(CH2) m The compound of any one of the above embodiments, wherein

[0109] Embodiment 46. L4 is -CH2-, -(CH2) m -, -C(R 7 )2-, -CF2-, -OCH2-, -O(CH2) m -, -CH2O-, -CH2OCH2-, -CH2OCH2C(R7)2- or -NH(CH2) m The compound of any one of the above embodiments, wherein

[0110] Embodiment 47. L4 is a bond, -CH2-, -(CH2) m -, -C(R 7 )2-, -CF2-, -OCH2-, -O(CH2) m The compound according to any one of the above embodiments, wherein the compound is -, -CH2O-, -CH2OCH2-, or -CH2OCH2C(R7)2-.

[0111] Embodiment 48.The compound according to any one of the preceding embodiments, wherein L4 is a bond, -CH2-, -(CH2)2-, -C(CH3)2-, -C(CH2CH3)2-, -CF2-, -CH2O-, -CH2OCH2-, -CH2OCH2C(CH3)2- or -CH2OCH2CH2-.

[0112] Embodiment 49. The compound of any one of the preceding embodiments, wherein L4 is -CH2-, or -CH2O-.

[0113] Embodiment 50. R 5 But R 9 The compound of any one of the preceding embodiments, wherein the compound is phenyl substituted with 0 to 3 groups independently selected from:

[0114] Embodiment 51. R 5 But R 9 The compound of any one of the preceding embodiments, wherein the aryl group is C3-C8 cycloalkyl, substituted with 0-3 groups independently selected from:

[0115] Embodiment 52. R 5 But R 9 substituted with 0 to 3 groups independently selected from N, NR 7 , O, S, C═O, or S(═O)2.

[0116] Embodiment 53. R 5 But R 9 substituted with 0 to 3 groups independently selected from N, NR 7 , O, or S.

[0117] Embodiment 54. R 5 But R 9substituted with 0 to 3 groups independently selected from N, NR 7 , O, S, C=O, or S(=O)2.

[0118] Embodiment 55. R 5 But R 9 substituted with 0 to 3 groups independently selected from N, NR 7 , O, S, C=O, or S(=O)2.

[0119] Embodiment 56. R 5 But R 9 substituted with 0 to 3 groups independently selected from N, NR 7 , O or S.

[0120] Embodiment 57. R 5 But R 9 substituted with 0 to 3 groups independently selected from N, NR 7 , N + O - , O, or S.

[0121] Embodiment 58. R 6 -CN, -OH, -NR 7 R 8 , -NR 7 C(=O)R 8 , -NR 7 S(=O)2R 8 , -C(=O)NR 7 R 8 , -S(=O)2R 8, halo, C1-C8 haloalkoxy, C1-C8-alkoxy, -C1-C8 alkyl or -C2-C8 alkylene.

[0122] Embodiment 59. R 9 The compound of any one of the preceding embodiments, wherein is -C1-C8 alkyl.

[0123] Embodiment 60. Each R 9 is -C1-C8 alkyl, -C1-C8 alkoxy, C1-C8 haloalkyl, spiro-linked C3-C8 cycloalkyl, R 10 , -OH, CN, halo, -C(=O)R 7 , -NR 7 R 8 , -C(=O)NR 7 R 8 , -NR 7 C(=O)R 8 , -NR 7 C(=O)OR 8 , -C(=O)OR 8 , -NR 7 S(=O)2R 8 , -S(=O)2R 8 , -S(=O)2R 10 , NO2, CN, L3R 11 , L4R 12 or N, NR 7 , O, or S.

[0124] Embodiment 61. Each R 9 is -C1-C8 alkyl, -C1-C8 alkoxy, C1-C8 haloalkyl, spiro-linked C3-C8 cycloalkyl, R 10 , -OH, CN, Halo, L4R 12 , or N, NR 7, O, or S.

[0125] Embodiment 62. Each R 9 But -R 10 or L4R 12 The compound of any one of the above embodiments, independently selected from:

[0126] Embodiment 63. R 10 is C3-C8 cycloalkyl, or N, NR 7 , O, or S; or N, NR 7 , O, or S.

[0127] Embodiment 64. R 10 The compound of any one of the preceding embodiments, wherein is C3-C8 cycloalkyl.

[0128] Embodiment 65. R 10 But N, NR 7 , O or S.

[0129] Embodiment 66. R 10 But N, NR 7 , O, or S.

[0130] Embodiment 67. R 11 But R 13The compound of any one of the preceding embodiments, wherein the compound is phenyl substituted with 0 to 3 groups independently selected from:

[0131] Embodiment 68. R 11 But R 13 The compound of any one of the preceding embodiments, wherein the aryl group is C3-C8 cycloalkyl substituted with 0-3 groups independently selected from:

[0132] Embodiment 69. R 11 But R 13 substituted with 0 to 3 groups independently selected from N, NR 7 , O, S, C═O, or S(═O)2.

[0133] Embodiment 70. R 11 But R 13 substituted with 0 to 3 groups independently selected from N, NR 7 , O, or S.

[0134] Embodiment 71. R 11 But R 13 substituted with 0 to 3 groups independently selected from N, NR 7 , O, S, C=O, or S(=O)2.

[0135] Embodiment 72. R 11 But R 13 substituted with 0 to 3 groups independently selected from N, NR 7, O, S, C=O, or S(=O)2.

[0136] Embodiment 73. R 11 But R 13 substituted with 0 to 3 groups independently selected from N, NR 7 , O or S.

[0137] Embodiment 74. R 11 But R 13 substituted with 0 to 3 groups independently selected from N, NR 7 , N + O - , O, or S.

[0138] Embodiment 75. Each R 12 -CN, -CD3, -OCD3, -OH, -NR 7 R 8 , -NR 7 C(=O)R 8 , -NR 7 S(=O)2R 8 , -C(=O)NR 7 R 8 , -S(=O)2R 8 , -S(=O)2R 10 , halo, C1-C8 haloalkoxy, C1-C8-alkoxy, C1-C8 haloalkyl, or -C1-C8 alkyl.

[0139] Embodiment 76. Each R 12 -CN, -OH, -NR 7 R 8 , -NR 7 C(=O)R 8 , -NR7 S(=O)2R 8 , -C(=O)NR 7 R 8 , -S(=O)2R 8 , -S(=O)2R 10 , halo, C1-C8 haloalkoxy, C1-C8-alkoxy, C1-C8 haloalkyl, or -C1-C8 alkyl.

[0140] Embodiment 77. Each R 13 -C1-C8 alkyl, spiro-linked C3-C8 cycloalkyl, -C1-C8 alkoxy, -OH, halo, -C(=O)R 7 , -NR 7 R 8 , -C(=O)NR 7 R 8 , -NR 7 C(=O)R 8 , -NR 7 S(=O)2R 8 , -S(=O)2R 8 , NO2, CN, or C1-C8 haloalkyl.

[0141] Embodiment 78. Each R 13 is independently selected from -C1-C8 alkyl, -C1-C8-alkoxy, -OH, or halo.

[0142] Embodiment 79. The compound of any one of the above embodiments, wherein each m is independently selected from 1, 2, 3, or 4.

[0143] Embodiment 80. The compound of any one of the above embodiments, wherein each n is independently selected from 0, 1, 2, or 3.

[0144] Embodiment 81. The compound of any one of the above embodiments, wherein each p is independently selected from 0, 1, 2, or 3.

[0145] Embodiment 82. The compound of any one of the above embodiments, wherein m is independently selected from 1, 2, or 3.

[0146] Embodiment 83. The compound of any one of the above embodiments, wherein each n is 0.

[0147] Embodiment 84. The compound of any one of the above embodiments, wherein each p is independently selected from 0 and 1.

[0148] Embodiment 85. Each R 7 is independently selected from H or -C1-C8 alkyl.

[0149] Embodiment 86. Each R 7 is H.

[0150] Embodiment 87. Each R 7 The compound of any one of the preceding embodiments, wherein is -C1-C8 alkyl.

[0151] Embodiment 88. R 8 The compound of any one of the preceding embodiments, wherein is H or -C1-C8 alkyl.

[0152] Embodiment 89. R 8 is H.

[0153] General synthetic procedure The compounds provided can be prepared by organic synthesis methods known to those skilled in the art, with reference to the following general synthetic schemes of the reactions below, and more specifically in the Examples.

[0154] All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents, and catalysts utilized to synthesize the compounds provided are either commercially available or can be produced by organic synthesis methods known to those skilled in the art (Houben-Weyl 4th Ed. 1952, Methods of Organic Synthesis, Thieme, Volume 21).

[0155] Within the scope of this text, unless the context suggests otherwise, only readily removable groups that are not components of a particular desired end product of the compound provided are designated as "protecting groups." The protection of functional groups by such protecting groups, the protecting groups themselves, and their cleavage reactions can be found, for example, in standard reference works, such as Science of Synthesis: Houben-Weyl Methods of Molecular Transformation. Georg Thieme Verlag, Stuttgart, Germany. 2005. 41627 pp. (URL: http: / / www.science-of-synthesis.com (Electronic Version, 48 Volumes)); J. F. W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973; T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999; in "The Peptides"; Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1981; in "Methoden der Organischen Chemie" (Methods of Organic Synthesis); Chemistry), Houben Weyl, 4th edition, Volume 15 / I, Georg Thieme Verlag, Stuttgart 1974, H.-D. Jakubke and H.Protecting groups are described in Jeschkeit, "Aminosauren, Peptide, Proteine" (Amino acids, Peptides, Proteins), Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982, and in Jochen Lehmann, "Chemie der Kohlenhydrate: Monosaccharide und Derivate" (Chemistry of Carbohydrates: Monosaccharides and Derivatives), Georg Thieme Verlag, Stuttgart 1974. A characteristic of protecting groups is that they can be easily removed (i.e., without causing undesired secondary reactions), for example, by solvolysis, reduction, photolysis, or alternatively under physiological conditions (e.g., by enzymatic cleavage).

[0156] The present disclosure further provides processes for producing the compounds of formula (I) disclosed herein, and any variants of the processes of the invention, in which intermediate products available at any stage thereof are used as starting materials to carry out the remaining steps, or in which starting materials are formed in situ under the reaction conditions, or in which reaction components are used in the form of their salts or optically pure materials.

[0157] The compounds and intermediates provided can also be converted into each other according to general methods known to those skilled in the art.

[0158] Methods for synthesizing compounds of Formula (I) are shown in Schemes A-G and are illustrated by the Examples herein. Scheme A depicts an approach for preparing compounds where R can be a variety of groups and linkages. This begins with the formation of a 2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate compound, as shown in Schemes B-G, where the 3-carboxylate is protected with a suitable removable protecting group that can be converted to an amide, and the 5-position of the ring has a suitable leaving group that can be readily condensed with an appropriately substituted phenylborate to give either the provided compound or a compound with a linkage suitable for further manipulation.

[0159] [ka]

[0160] Thus, Schemes B-G depict methods for producing compounds of formula (I), where R is a variously substituted aminomethyl group, a substituted methoxy group, and more specifically, a racemic or chiral substituted-1,4-dioxan-2-yl)methoxy group, respectively.

[0161] [ka]

[0162] [ka]

[0163] [ka]

[0164] [ka]

[0165] [ka]

[0166] [ka]

[0167] Using these synthetic schemes and examples provided, one of ordinary skill in the art can prepare compounds of formula (I).

[0168] Depending on the selection of starting materials and synthetic procedures, compounds can exist in one of the possible isomeric forms or as mixtures thereof, e.g., as pure optical isomers, or as isomeric mixtures, e.g., as racemic and diastereomeric mixtures, depending on the number of asymmetric carbon atoms. The present disclosure includes all such possible isomers, including racemic mixtures, diastereomeric mixtures, and optically pure forms. Optically active (R)- and (S)-isomers may be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. If a compound contains a double bond, the substituent may be in the E- or Z-configuration unless otherwise specified. If a compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans-configuration unless otherwise specified. All tautomeric forms are also intended to be included.

[0169] Any asymmetric atom (e.g., carbon, etc.) of the provided compound(s) can be present in racemic or enantiomerically enriched, e.g., (R)-, (S)-, or (R,S)-configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess of either the (R)- or (S)-configuration. That is, for optically active compounds, it is often preferable to use one enantiomer to the substantial exclusion of the other enantiomer. Thus, enantiomeric purity of at least 95% is usually preferred. Substituents at atoms with unsaturated double bonds can exist in cis-(Z)- or trans-(E)-form, where possible.

[0170] Thus, as used herein, the compounds provided may be in the form of one of these possible isomers, rotamers, atropisomers, tautomers, or mixtures thereof, such as substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (enantiomers), racemates, or mixtures thereof. "Substantially pure" or "substantially free of other isomers," as used herein, means that the product contains less than 5%, preferably less than 2%, of other isomers, based on the amount by weight of the preferred isomer.

[0171] The resulting mixture of isomers can usually be separated on the basis of the physical chemical differences of the constituent substances into pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and / or fractional crystallization.

[0172] Racemic final products or intermediates can usually be resolved into their optical antipodes by known methods, for example, by separating their diastereomeric salts obtained with optically active acids or bases and liberating the optically active acidic or basic compounds. Thus, in particular, basic moieties can be used to resolve provided compounds into their optical antipodes, for example, by fractional crystallization of salts formed with optically active acids, such as tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, di-O,O'-p-toluoyltartaric acid, mandelic acid, malic acid, or camphor 10-sulfonic acid. Racemic products can also be resolved by chiral chromatography, for example, high-performance liquid chromatography (HPLC) using a chiral stationary phase.

[0173] In many cases, the provided compounds are capable of forming acid and / or base salts due to the presence of amino and / or carboxyl groups or groups similar thereto. As used herein, the term "salt(s)" refers to acid addition salts or base addition salts of the provided compounds. "Salt" specifically includes "pharmaceutically acceptable salts." The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the provided compounds and are usually not biologically or otherwise unsuitable.

[0174] Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids, e.g., acetate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, chloride / hydrochloride, chlorotheophylline, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide / iodide, isethionate, lactate, The salt may be lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methylsulfate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, polygalacturonate, propionate, stearate, succinate, sulfosalicylate, tartrate, tosylate, or trifluoroacetate. Lists of additional suitable salts can be found, for example, in "Remington's Pharmaceutical Sciences", 20th ed., Mack Publishing Company, Easton, Pa., (1985), and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0175] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0176] Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, etc. Pharmaceutically acceptable base addition salts can be formed with inorganic or organic bases and can have either inorganic or organic counterions.

[0177] Inorganic counterions for such base salts include, for example, ammonium salts and metals from columns I-XII of the Periodic Table. In certain embodiments, the counterion is selected from sodium, potassium, ammonium, alkylammonium having one to four C1-C4 alkyl groups, calcium, magnesium, iron, silver, zinc, or copper. Particularly suitable salts include ammonium, potassium, sodium, calcium, or magnesium salts.

[0178] Organic bases from which salts can be derived include, for example, primary, secondary, or tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, etc. Suitable organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, or tromethamine.

[0179] The pharmaceutically acceptable salts of the present disclosure can be synthesized from basic or acidic moieties by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid form of these compounds with a stoichiometric amount of an appropriate base (e.g., hydroxide, carbonate, bicarbonate, etc. of Na, Ca, Mg, or K), or by reacting the free base form of these compounds with a stoichiometric amount of an appropriate acid. Such reactions are usually carried out in water or an organic solvent, or a mixture of the two. Generally, where feasible, the use of non-aqueous media such as ether, ethyl acetate, tetrahydrofuran, toluene, chloroform, dichloromethane, methanol, ethanol, isopropanol, or acetonitrile is desirable.

[0180] Any formula given herein is also intended to represent unlabeled forms (i.e., compounds in which all atoms are present at natural isotopic abundance and are not isotopically enriched) as well as isotopically enriched or labeled forms of the compounds. Isotopically enriched or labeled compounds have a structure as shown in the formula given herein, except that at least one atom of the compound is replaced with an atom having an atomic mass or mass number different from the naturally occurring atomic mass or atomic mass distribution. Examples of isotopes that can be incorporated into enriched or labeled compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, or chlorine, e.g., 2 H, 3 H, 11 C. 13 C. 14 C. 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl, or 125 I. The present disclosure provides various isotopically labeled compounds as defined herein, e.g., radioactive isotopes, e.g., 3 H and 14 C, or non-radioactive isotopes, e.g. 2 H and 13 These isotopically labeled compounds include compounds in which C is present at levels significantly above the natural abundance for these isotopes. 14 C), reaction kinetic experiments (e.g., 2 H or 3 H), detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or in radiotherapy of patients. 18F-labeled compounds may be particularly desirable for PET or SPECT experiments. Isotopically labeled compounds of formula (I) may generally be prepared by conventional techniques known to those skilled in the art, or by methods analogous to those described in the accompanying Examples, using appropriate isotopically labeled reagents in place of the otherwise utilized non-labeled reagents.

[0181] Additionally, heavier isotopes, especially deuterium (i.e. 2 Substitution with heavier isotopes (H or D) can result in certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dose requirements, or improved therapeutic index. The concentration of such heavier isotopes, specifically deuterium, can be defined by an isotopic enrichment factor. The term "isotopic enrichment factor," as used herein, means the ratio between the abundance of an isotope and the natural abundance of the specified isotope. When a substituent in a provided compound is deuterium as designated, such compounds have an isotopic enrichment factor of at least 3500 (52.5% deuterium bonding for each designated deuterium atom), an isotopic enrichment factor of at least 4000 (60% deuterium bonding), an isotopic enrichment factor of at least 4500 (67.5% deuterium bonding), an isotopic enrichment factor of at least 5000 (75% deuterium bonding), or an isotopic enrichment factor of at least 6000 (67.5% deuterium bonding). , an isotopic enrichment factor of at least 5500 (82.5% deuterium bonded), an isotopic enrichment factor of at least 6000 (90% deuterium bonded), an isotopic enrichment factor of at least 6333.3 (95% deuterium bonded), an isotopic enrichment factor of at least 6466.7 (97% deuterium bonded), an isotopic enrichment factor of at least 6600 (99% deuterium bonded), or an isotopic enrichment factor of at least 6633.3 (99.5% deuterium bonded).

[0182] Furthermore, the provided compounds, including their salts, can also be obtained in the form of their hydrates, or can include other solvents used in their crystallization. The provided compounds can inherently or by design form solvates with pharmaceutically acceptable solvents (including water). Thus, the present disclosure encompasses both solvated and non-solvated forms. The term "solvate" refers to a molecular complex of the provided compounds (including their pharmaceutically acceptable salts) with one or more solvent molecules. Such solvent molecules are commonly used in the pharmaceutical field and are known to be harmless to recipients, such as water, ethanol, etc. The term "hydrate" refers to a complex in which the solvent molecule is water.

[0183] Pharmaceutically acceptable solvates in accordance with the present disclosure include those in which the solvent of crystallization may be isotopically substituted, e.g., D2O, d 6 - acetone, d 6 -Includes solvates with DMSO, as well as non-concentrated solvents.

[0184] The compounds disclosed herein, i.e., compounds of Formula (I) containing groups capable of acting as donors and / or acceptors for hydrogen bonds, may be capable of forming co-crystals with suitable co-crystal formers. These co-crystals can be prepared from compounds of Formula (I) by known co-crystal formation procedures. Such procedures include grinding, heating, co-sublimating, co-melting, or contacting a compound of Formula (I) with a co-crystal former in solution under crystallization conditions, and isolating and thereby forming a co-crystal. Suitable co-crystal formers include those described in WO 2004 / 078163. Accordingly, the present disclosure further provides co-crystals comprising compounds of Formula (I).

[0185] The present disclosure further provides additional compounds that, upon conversion in the body of a subject, produce any of the compounds discussed above. These additional compounds are prodrug forms of the compounds discussed above. As used herein, the term "prodrug" refers to a precursor compound that, after administration to a subject, releases a biologically active compound in vivo through some chemical or physiological process (e.g., upon reaching a physiological pH or through enzymatic action, the prodrug is converted into the biologically active compound). The prodrug itself may lack or possess the desired biological activity.

[0186] Pharmaceutical Compositions and Routes of Administration In another aspect, the present disclosure provides a pharmaceutical composition comprising a provided compound, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises at least two pharmaceutically acceptable excipients or carriers. Pharmaceutically acceptable carriers and other excipients are known to those skilled in the art and can be selected, for example, from carriers and excipients used in approved (registered) formulated therapeutic agents administered via similar administration routes. Pharmaceutical compositions can be formulated for a specific administration route, such as oral administration, parenteral administration, rectal administration, etc. In addition, the provided pharmaceutical compositions can be made in solid form (including, without limitation, capsules, tablets, pills, granules, powders, or suppositories) or liquid form (including, without limitation, solutions, suspensions, or emulsions). The pharmaceutical compositions can be subjected to conventional pharmaceutical processes, such as sterilization, and / or can contain conventional inert diluents, lubricants, or buffers, as well as adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers, and / or buffers.

[0187] In one embodiment, provided compounds are formulated for oral delivery. Typically, these pharmaceutical compositions are tablets or gelatin capsules containing the active ingredient (at least one compound of Formula (I)) together with one or more excipients selected from the following: a) diluents, such as lactose, glucose, sucrose, mannitol, sorbitol, cellulose and / or glycine; b) lubricants, such as silica, talcum, stearic acid, its magnesium or calcium salts and / or polyethylene glycol, and also for tablets, c) binders, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, if desired; d) disintegrating agents, such as starch, agar, alginic acid or its sodium salt, or effervescent mixtures, and / or e) Absorbents, colorants, flavorings and / or sweetening agents.

[0188] Tablets may be film coated or enteric coated according to methods known in the art.

[0189] Compositions suitable for oral administration contain an effective amount of the compound provided in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions can contain one or more agents selected from sweeteners, flavoring agents, coloring agents, and / or preservatives to provide pharmaceutically elegant and palatable preparations. Tablets can contain the active ingredient mixed with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients can be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as starch, gelatin, or acacia; and / or lubricants such as magnesium stearate, stearic acid, or talc. Tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained effect over a longer period of time.For example, time-delay materials such as glyceryl monostearate or glyceryl distearate can be used.The preparation for oral use can be presented as a hard gelatin capsule, in which active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate or kaolin, or as a soft gelatin capsule, in which active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.

[0190] Certain injectable compositions are aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions. The compositions may be sterilized and / or contain adjuvants, such as preservatives, stabilizers, wetting agents or emulsifiers, dissolution promoters, salts for adjusting osmotic pressure, and / or buffers. In addition, these compositions may also contain other therapeutically valuable substances. The compositions are prepared according to conventional mixing, granulating, or coating methods, respectively, and contain about 0.1-75% of the active ingredient, or about 1-50% of the active ingredient.

[0191] The composition suitable for transdermal application comprises an effective amount of the compound provided and a suitable carrier.The carrier suitable for transdermal delivery comprises a pharmacologically acceptable absorbent solvent to aid passage through the host's skin.For example, transdermal device is in the form of a bandage, comprising a backing member, a reservoir containing the compound, optionally with a carrier, optionally with a rate-controlling barrier for delivering the compound to the host's skin at a controlled and predetermined rate over a long period of time, and with a means for fixing the device to the skin.

[0192] Compositions suitable for topical application, for example, topical application to the skin and eyes, include aqueous solutions, suspensions, ointments, creams, gels, or sprayable formulations, such as sprayable formulations for delivery by aerosol. Such local delivery systems can be associated with inhalation or intranasal application, which may be suitable for use in treating influenza, and may contain, for example, solubilizers, stabilizers, tonicity enhancers, buffers, and / or preservatives. They can be conveniently delivered in the form of dry powder from a dry powder inhaler (alone, as a mixture, for example, as a dry blend with lactose, or as component particles mixed with, for example, phospholipids), or as an aerosol spray presentation from a pressurized container, pump, spray, atomizer, or nebulizer, with or without the use of a suitable propellant.

[0193] The present disclosure further provides anhydrous pharmaceutical compositions and dosage forms comprising the provided compounds as active ingredients, as water can facilitate the degradation of some compounds.

[0194] The anhydrous pharmaceutical compositions and dosage forms disclosed herein can be prepared using anhydrous or low-moisture ingredients and low-moisture or low-humidity conditions.The anhydrous pharmaceutical compositions can be prepared and stored so that their anhydrous nature is maintained.Therefore, the anhydrous compositions are packaged using materials known to prevent exposure to water so that they can be included in suitable prescription kits.Suitable packaging examples include, but are not limited to, hermetically sealed foils, plastics, unit-dose containers (e.g., vials), blister packs, and / or strip packs.

[0195] The present disclosure further provides pharmaceutical compositions and dosage forms that include one or more agents that reduce the decomposition rate of a provided compound as an active ingredient. Such agents, referred to herein as "stabilizers," include, but are not limited to, antioxidants, such as ascorbic acid, pH buffers, and / or salt buffers.

[0196] The provided pharmaceutical compositions or combinations may be in unit dosage forms containing about 1-1000 mg of active ingredient(s), or about 1-500 mg, or about 1-250 mg, or about 1-150 mg, or about 0.5-100 mg, or about 1-50 mg of active ingredient for a human subject weighing about 50-70 kg. The therapeutically effective dose of the compounds, pharmaceutical compositions, or combinations thereof depends on the species, weight, age, and individual condition of the subject, and the disorder or disease being treated, or its severity. A physician, clinician, or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients required to prevent, treat, or inhibit the progression of the disorder or disease.

[0197] The aforementioned dosage characteristics can be demonstrated in vitro and in vivo tests, preferably using mammals, such as mice, rats, dogs, monkeys, or their isolated organs, tissues, and preparations. The provided compounds can be applied in vitro in the form of solutions, for example, aqueous solutions, and in vivo enterally, parenterally, advantageously intravenously, for example, as a suspension or in aqueous solution. The in vitro dosage is about 10 -3 Molar ~ 10 -9 The molar concentration may range between 0.1 and 0.5.

[0198] Pharmacology and Usefulness The compounds of Formula (I), in free or salt form, exhibit valuable pharmacological properties. For example, these compounds inhibit or prevent orthomyxovirus replication, as shown by the test data provided in the next section, and are therefore suitable for use as therapeutics or research chemicals, e.g., as tool compounds for studying the replication of orthomyxoviruses, particularly influenza A, influenza B, or influenza C. Accordingly, the compounds disclosed herein are useful for treating infections caused by orthomyxoviruses, particularly influenza A, influenza B, or influenza C, in human subjects. In some embodiments, the subject being treated is a human having or at risk of contracting an influenza virus infection, particularly influenza A, influenza B, or influenza C. For example, subjects with pre-existing conditions, such as asthma or COPD, which may be significantly exacerbated by influenza infection, can be treated with provided methods or compounds before they exhibit symptoms of influenza infection, particularly influenza A, influenza B, or influenza C, especially if the subjects are at risk for influenza due to, for example, close proximity to a person, such as a family member, who has or appears to have influenza. In other embodiments, subjects for treatment with provided methods and compositions are subjects who have been diagnosed with symptoms consistent with influenza infection, particularly influenza A, influenza B, or influenza C. In other embodiments, a subject can be a human who has been tested with known diagnostic methods, such as a Rapid Influenza Diagnostic Test (RIDT) or Reverse Transcriptase PCR (RT-PCR), to detect the presence of influenza virus and find out they have been infected with influenza, regardless of the presence of typical influenza symptoms.

[0199] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein is intended merely to further elucidate the disclosure and does not pose a limitation on the scope of the embodiments or otherwise claimed.

[0200] In another aspect, the present disclosure provides methods of treating a subject infected with influenza A, B, or C, comprising administering to a subject in need of such treatment an effective amount of a compound of Formula (I) or any subgenus or species thereof, or a pharmaceutical composition comprising such a compound or composition, as described herein. The subject can be a mammal, preferably a human, although the provided compounds and methods are also suitable for treating other species suffering from influenza A, influenza B, or influenza C, or other orthomyxoviruses. The present disclosure includes compounds of Formula (I) and subgenus of Formula (I) described herein, and includes all stereoisomers (including diastereoisomers and enantiomers), as well as tautomers and isotopically enriched versions (including deuterium substitutions) thereof, and pharmaceutically acceptable salts of these compounds, except where a particular isomer is explicitly described.

[0201] In further embodiments, the present disclosure provides for the use of a compound of Formula (I) or any of the embodiments within Formula (I) described herein in therapy. In particular, the compounds are suitable for use in treating subjects having, or at particular high risk for, an orthomyxovirus infection, particularly influenza A, influenza B, or influenza C.

[0202] In another embodiment, the present disclosure provides a method of treating a disease caused by an orthomyxovirus, comprising administering a therapeutically effective amount of a compound of Formula (I) or any of the embodiments within the scope of Formula (I) described herein to a subject in need of such treatment. In some embodiments, the compound of Formula (I) is administered orally. In further embodiments, the disease is selected from influenza A, influenza B, and influenza C. The method generally comprises administering to a subject in need of such treatment an effective amount of a compound described herein, or a pharmaceutical composition containing an effective amount of such a compound. The compound can be administered by any suitable method, e.g., a method described herein, and administration can be repeated at intervals that can be selected by the treating physician. In some embodiments, the compound or pharmaceutical composition is administered orally.

[0203] Thus, as a further embodiment, the disclosure provides the use of a compound of Formula (I) or any of the embodiments of such a compound described herein for the manufacture of a medicament. In certain embodiments, the medicament is for the treatment of an orthomyxovirus infection, particularly influenza A, influenza B, or influenza C.

[0204] A further embodiment of the disclosure provides the use of a compound of formula (I) or any of the embodiments of such a compound described herein for the manufacture of a medicament for the treatment of influenza. A further embodiment of the disclosure provides the use of a compound of formula (I) or any of the embodiments of such a compound described herein for the manufacture of a medicament for the treatment of influenza A, influenza B, or influenza C.

[0205] Additionally, the present disclosure provides for the use of a compound of Formula (I) for treating a viral infection caused by an orthomyxovirus, particularly influenza, which may be influenza A, influenza B, or influenza C. In a further embodiment, the present disclosure provides for the use of a compound of Formula (I) for treating influenza. In a further embodiment, the present disclosure provides for the use of a compound of Formula (I) for treating influenza A, influenza B, or influenza C.

[0206] Combination treatment The compounds disclosed herein can be administered simultaneously with, before, or after one or more co-therapeutic agents(s). The provided compounds can be administered separately from the co-medication(s) or in the same pharmaceutical composition as the co-medication(s), by the same or different administration route. Suitable co-medication agents for use with the provided compounds include antiviral agents active against influenza viruses, such as neuraminidase inhibitors, including oseltamivir, peramivir, zanamivir, and laninamivir, including laninamivir octanoate, and adamantanes, such as amantadine and rimantadine. Additional concomitant medications for use in these methods include M2 ​​protein inhibitors, polymerase inhibitors, PB2 inhibitors, favipiravir, fludase, ADS-8902, beraprost, Neugene®, ribavirin, CAS Reg. No. 1422050-75-6, VX-787, Flu Mist Quadrivalent®, Fluarix® Quadrivalent, Fluzone® Quadrivalent, Flucelvax®, or FluBlok®.

[0207] In one embodiment, the disclosure provides an article of manufacture comprising a compound of Formula (I) and at least one other co-therapeutic agent as a combined preparation for simultaneous, separate, or sequential use in therapy. In one embodiment, the therapy is treatment of a viral infection caused by an orthomyxovirus, particularly influenza A, influenza B, or influenza C. Articles of manufacture provided as combined preparations include compositions comprising a compound of Formula (I) and at least one other co-therapeutic agent(s) together in the same pharmaceutical composition, or compositions comprising a compound of Formula (I) and at least one other co-therapeutic agent(s) in separate forms, for example, in the form of a kit, for use in treating a subject in the methods described herein.

[0208] In one embodiment, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I) and another co-therapeutic agent(s). Suitable co-medications include, for example, neuraminidase inhibitors with antiviral activity against influenza viruses, including oseltamivir, peramivir, zanamivir, and laninamivir, and adamantanes, such as amantadine and rimantadine. If necessary, the pharmaceutical composition can include a pharmaceutically acceptable carrier as described above.

[0209] In one embodiment, the present disclosure provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains a compound of Formula (I). The other pharmaceutical composition may also contain one of the appropriate concomitant medications. In one embodiment, the kit comprises a means for separately retaining the compositions, such as a container, a divided bottle, or a divided foil packet. An example of such a kit is a blister pack, such as those commonly used for packaging tablets, capsules, etc.

[0210] The kits disclosed herein can be used to administer different dosage forms, e.g., oral and parenteral dosage forms, to administer separate compositions at different dosage intervals, or to titrate separate compositions against one another. To aid in compliance, the kits provided typically include instructions for administration.

[0211] In the combination therapies disclosed herein, the provided compound and co-therapeutic agent can be manufactured and / or formulated by the same or different manufacturers. Furthermore, the provided compound and co-therapeutic agent can be combined together in the combination therapy: (i) before the combination product is delivered to the physician (e.g., in the case of a kit containing the provided compound and another therapeutic agent); (ii) by the physician (or under the physician's guidance) immediately prior to administration; or (iii) by the patient themselves, for example, during sequential administration of the provided compound and co-therapeutic agent.

[0212] Thus, the present disclosure provides the use of a compound of Formula (I) for treating a viral infection caused by an orthomyxovirus, particularly influenza (which may be influenza A, influenza B, or influenza C), wherein the medicament is prepared for administration with a co-therapeutic agent. Typically, in methods using the provided compounds, the influenza serotype is not identified prior to treatment. The present disclosure also provides the use of a co-therapeutic agent for treating a disease or condition, wherein the medicament is administered with a compound of Formula (I).

[0213] The present disclosure also provides a compound of Formula (I) for use in a method of treating a viral infection caused by an orthomyxovirus, particularly influenza A, influenza B, or influenza C, wherein the compound is prepared for administration with a co-therapeutic agent. The present disclosure also provides another co-therapeutic agent for use in a method of treating a viral infection caused by an orthomyxovirus, particularly influenza, for example, influenza A, influenza B, or influenza C, wherein the co-therapeutic agent is prepared for administration with a compound of Formula (I). The present disclosure also provides a compound of Formula (I) for use in a method of treating a viral infection caused by an orthomyxovirus, particularly influenza A, influenza B, or influenza C, wherein the compound is administered with a co-therapeutic agent. The present disclosure also provides a co-therapeutic agent for use in a method of treating a viral infection caused by an orthomyxovirus, particularly influenza A, influenza B, or influenza C, wherein the co-therapeutic agent is administered with a compound of Formula (I).

[0214] The present disclosure also provides for the use of a compound of Formula (I) to treat a viral infection caused by an orthomyxovirus, particularly influenza, e.g., influenza A, influenza B, or influenza C, where the patient has previously (e.g., within 24 hours) been treated with another therapeutic agent. The present disclosure also provides for the use of another therapeutic agent to treat a viral infection caused by an orthomyxovirus, particularly influenza A, influenza B, or influenza C, where the patient has previously (e.g., within 24 hours) been treated with a compound of Formula (I).

[0215] In one embodiment, the co-therapeutic agent is selected from antiviral agents said to be useful in treating infections caused by influenza viruses, e.g., neuraminidase inhibitors, including, e.g., oseltamivir, peramivir, zanamivir, and / or laninamivir, and adamantanes, e.g., amantadine and / or rimantadine. [Example]

[0216] The following examples are intended for illustrative purposes only and should not be construed as limiting the scope of the embodiments. Temperatures are given in degrees Celsius. Unless otherwise noted, all evaporations are carried out under reduced pressure, typically between about 15 mmHg and 100 mmHg (about 20-133 mbar). The structures of final products, intermediates, and starting materials are confirmed by standard analytical methods, e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR, and NMR. Abbreviations used are conventional in the art.

[0217] All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents, and catalysts utilized to synthesize the provided compounds are either commercially available or can be produced by organic synthesis methods known to those skilled in the art (Houben-Weyl 4th Ed. 1952, Methods of Organic Synthesis, Thieme, Volume 21). Additionally, the provided compounds can be produced by organic synthesis methods known to those skilled in the art in light of the following examples.

[0218] Abbreviation ATP adenosine 5'-triphosphate Bn Benzyl BOC tertiary butyl carboxylate br Wide BSA Bovine serum albumin d doublet dd Double of doublets DCM dichloromethane DEAD Diethyl azodicarboxylate DBAD Di-tert-butyl azodicarboxylate DIBAL-H Diisobutylaluminum hydride DIEA Diethylisopropylamine DME 1,4-dimethoxyethane DMF N,N-dimethylformamide DMSO dimethyl sulfoxide DTT Dithiothreitol EDTA Ethylenediaminetetraacetic acid ESI electrospray ionization EtOAc or EA ethyl acetate FCC flash column chromatography h time HBTU 1-[bis(dimethylamino)methylene]-1H-benzotriazolium hexafluorophosphate(1-)3-oxide HOBt 1-hydroxy-7-azabenzotriazole HPLC High Performance Liquid Chromatography IR Infrared Spectroscopy LCMS Liquid Chromatography and Mass Spectrometry MeOH Methanol MS mass spectrometry MW Microwave m multiplet min mL milliliter m / z mass-to-charge ratio NBS N-Bromosuccinimide NCS N-chlorosuccinimide NMP N-methylpyrrolidinone NMR nuclear magnetic resonance ppm parts per million PyBOP Benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate rac racemic rt room temperature s singlet SEM (2-(trimethylsilyl)ethoxy)methyl t triplet TBDMS t-butyldimethylsilyl TBDPS t-butyldiphenylsilyl TFA trifluoroacetic acid THF tetrahydrofuran Tris·HCl Aminotris(hydroxymethyl)methane hydrochloride

[0219] Synthesis of representative compounds [Example 1] 5-(4-(morpholinomethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (1)

[0220] [ka]

[0221] Step 1: To a solution of ethoxyethene (100 g, 1.389 mol) in DCM (1.0 L) was added 2,2,2-trifluoroacetic anhydride (306 g, 1.457 mol) and DMAP (10 g, 81.9 mmol) in sequence at -10 °C. The mixture was then stirred at 25 °C for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 1:0 to 30:1) to give (E)-4-ethoxy-1,1,1-trifluorobut-3-en-2-one. 1 H NMR: (CDCl3, 400 MHz), δ= 7.92 (d, J=12.30 Hz, 1 H) 5.87 (d, J=12.30 Hz, 1 H) 4.12 - 4.17 (q, 2 H) 1.43 (t, J=7.09 Hz, 3H).

[0222] Step 2: To a solution of (E)-4-ethoxy-1,1,1-trifluorobut-3-en-2-one (Step 1) (50 g, 298 mmol) and NaOEt (40 g, 596 mmol) in EtOH (500 mL) was added ethyl 3-amino-3-oxopropanoate (43 g, 358 mmol) at 25 °C. The mixture was then stirred at 80 °C for 16 h. The reaction mixture was poured into water (1.0 L) and then extracted with EA (500 mL × 2). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated to give the crude product. The residue was purified by column chromatography (PE:EA = 10:1 to 1:1) to give ethyl 2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate. 1 H NMR (400MHz, chloroform-d) δ= 8.31 (d, J=6.8 Hz, 1H), 7.23 (d, J=6.8 Hz, 1H), 4.42 (m, 2H), 1.36 (t, J=6.4 Hz, 3H); LCMS: Rt 0.702 min, MS m / z 236.0 (M+H).

[0223] Step 3: To a solution of ethyl 2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate (10 g, 42.6 mmol) in DMF (50 mL) was added NBS (9.1 g, 51.1 mmol) at 25 °C. The mixture was stirred at 25 °C for 1 h. The mixture was washed with HO (100 mL) and extracted with EA (100 mL × 2). The combined organic layer was dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by column chromatography (PE / EA = 10 / 1) to give ethyl 5-bromo-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate. 1 H NMR (400MHz, DMSO-d6) δ= 8.43 (s, 1H), 4.33-4.28 (m, 2H), 1.30 (t, J=8 Hz, 3H) LCMS: Rt 0.864 min, MS m / z 314.0 (M+H).

[0224] Step 4: A solution of ethyl 5-bromo-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate (5 g, 16.0 mmol) in NH / MeOH (50 mL) was stirred in an autoclave under 0.8 MPa at 60° C. for 16 h. The reaction mixture was concentrated to give 5-bromo-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide, which was used in the next step without further purification. 1 H NMR: (DMSO, 400 MHz), δ= 10.41 (s, 1H), 8.09 (s, 1H), 7.22 (s, 2H); LCMS: Rt 0.665 min, MS m / z 286.9 (M+H).

[0225] Step 5: 5-Bromo-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (100 mg, 0.35 mmol), (4-(morpholinomethyl)phenyl)boronic acid (117 mg, 0.529 mmol), and PdCl(dppf)-CHCl adduct (28.7 mg, 0.035 mmol) were added to a microwave vial with a stir bar and then purged with nitrogen. 1,4-Dioxane (1170 μl) was then added, followed by sodium carbonate (2.0 M in water) (877 μl, 1.754 mmol). The vial was sealed and heated in a microwave at 100 °C for 60 min. The mixture was poured into water (5 mL) and extracted with EA (5 mL × 2). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by preparative HPLC under acidic conditions (MeCN / water with TFA) to give 5-(4-(morpholinomethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (1). 1H NMR: (400 MHz, DMSO-d6) δ 8.58 (s, 1H), 8.28 (s, 1H), 8.11 (s, 1H), 7.44 - 7.36 (m, 2H), 7.35 - 7.27 (m, 2H), 3.60 (t, J = 4.7 Hz, 4H), 2.40 (t, J = 4.7 Hz, 4H). LCMS: Rt = 0.43 min, m / z = 382.3 (M+H).

[0226] [Example 2] 5-(4-(hydroxymethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (2)

[0227] [ka] 5-(4-(hydroxymethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (2) was synthesized using a procedure similar to that used to synthesize 5-(4-(morpholinomethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (1), except that (4-(morpholinomethyl)phenyl)boronic acid was replaced with (4-(hydroxymethyl)phenyl)boronic acid. 1 H NMR: (400 MHz, DMSO-d6) δ 9.55 (bs, 1H), 8.06 (s, 1H), 7.62 (t, J = 9.8 Hz, 1H), 7.43 - 7.30 (m, 2H), 7.24 (d, J = 7.9 Hz, 2H), 7.17 - 6.92 (m, 1H), 5.22 (t, J = 6.0 Hz, 1H), 4.54 (d, J = 4.8 Hz, 2H). LCMS: Rt = 0.50 min, m / z = 313.1 (M+H).

[0228] [Example 3] 5-(4-hydroxyphenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (3)

[0229] [ka] 5-(4-Hydroxyphenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (3) was synthesized using a procedure similar to that used to synthesize 5-(4-(morpholinomethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (1), except that (4-(morpholinomethyl)phenyl)boronic acid was replaced with (4-hydroxyphenyl)boronic acid. 1 H NMR: (400 MHz, DMSO-d6) δ 9.83 (s, 1H), 9.03 - 8.69 (m, 1H), 8.24 (s, 1H), 8.10 - 7.97 (m, 1H), 7.12 (d, J=8.4Hz, 2H), 6.86 (d, J=8.4 Hz, 1H). LCMS: Rt = 0.68 min, m / z = 299.0 (M+H).

[0230] [Example 4] 5-(4-(benzyloxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (4)

[0231] [ka] 5-(4-(benzyloxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (4) was synthesized using a procedure similar to that used to synthesize 5-(4-(morpholinomethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (1), except that (4-(morpholinomethyl)phenyl)boronic acid was replaced with (4-(benzyloxy)phenyl)boronic acid.1 H NMR: (400 MHz, DMSO-d6) δ 8.59 (s, 1H), 8.43-8.41 (d, J=8, 1H), 8.25 (s, 1H), 8.11 (s, 2H), 8.50-8.47 (m, 3H), 7.43-7.41 (m, 2H), 7.39-7.34 (m, 1H), 7.28-7.26 (m, 2H), 7.10-7.08 (m, 2H), 5.10 (s, 2H). LCMS: Rt = 0.86 min, m / z = 389.2 (M+H).

[0232] [Example 5] 2-Oxo-5-(4-(pyrrolidin-1-ylmethyl)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (5)

[0233] [ka] 2-oxo-5-(4-(pyrrolidin-1-ylmethyl)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (5) was synthesized using a procedure similar to that used to synthesize 5-(4-(morpholinomethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (1), except that (4-(morpholinomethyl)phenyl)boronic acid was replaced with (4-(pyrrolidin-1-ylmethyl)phenyl)boronic acid. 1 H NMR: (400 MHz, DMSO-d6) δ 9.86 (br, s, 1H), 7.99 (s, 1H), 7.45 (d, J=8.0 2H), 7.28 (d, J=8.0 2H), 4.03 (s, 2H), 2.89 (m, 4H), 1.84 (m, 4H). LCMS: Rt = 0.53 min, m / z = 366.2 (M+H).

[0234] [Example 6] 2-Oxo-5-(4-phenoxyphenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (6)

[0235] [ka] 2-Oxo-5-(4-phenoxyphenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (6) was synthesized using a procedure similar to that used to synthesize 5-(4-(morpholinomethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (1), except that (4-(morpholinomethyl)phenyl)boronic acid was replaced with (4-phenoxyphenyl)boronic acid. 1 H NMR: (400 MHz, DMSO-d6) δ 8.46 (s, 1H), 8.30 (s, 1H), 8.15 (s, 1H), 7.42 (d, J=8.0Hz, 2H), 7.36 (d, J=8.0 Hz, 2H), 7.19 (t, J=7.2Hz, 1H), 7.07 (d, J=8.4 Hz, 4H). LCMS: Rt = 0.85 min, m / z = 375.2 (M+H).

[0236] [Example 7] 5-(3-aminophenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (7)

[0237] [ka] 5-(3-Aminophenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (7) was synthesized using a procedure similar to that used to synthesize 5-(4-(morpholinomethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (1), except that (4-(morpholinomethyl)phenyl)boronic acid was replaced with (3-aminophenyl)boronic acid.1 H NMR: (400 MHz, DMSO-d6) δ 8.17 (s, 1H), 7.05 (t, J=7.8 Hz, 1H), 6.58 (d, J=7.9 Hz, 1H), 6.51 - 6.46 (m, 1H), 6.45 - 6.38 (m, 1H). LCMS: Rt = 0.61 min, m / z = 298.1 (M+H).

[0238] [Example 8] 5-(3-cyanophenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (8)

[0239] [ka] 5-(3-cyanophenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (8) was synthesized using a procedure similar to that used to synthesize 5-(4-(morpholinomethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (1), except that (4-(morpholinomethyl)phenyl)boronic acid was replaced with (3-cyanophenyl)boronic acid. 1 H NMR: (400 MHz, DMSO-d6) δ 13.93 - 13.72 (m, 1H), 8.51 - 8.40 (m, 1H), 8.33 (s, 1H), 8.27 - 8.21 (m, 1H), 7.99 - 7.88 (m, 2H), 7.72 (s, 2H). LCMS: Rt = 0.68 min, m / z = 308.2 (M+H).

[0240] [Example 9] 5-(3-hydroxyphenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (9)

[0241] [ka] 5-(3-Hydroxyphenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (9) was synthesized using a procedure similar to that used to synthesize 5-(4-(morpholinomethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (1), except that (4-(morpholinomethyl)phenyl)boronic acid was replaced with (3-hydroxyphenyl)boronic acid. 1 H NMR: (400 MHz, DMSO-d6) δ 13.81 - 13.62 (m, 1H), 9.66 (s, 1H), 8.48 (s, 1H), 8.29 (s, 1H), 8.20 (s, 1H), 7.26 (t, J=7.8 Hz, 1H), 6.85 (s, 1H), 6.79 - 6.66 (m, 2H). LCMS: Rt = 0.59 min, m / z = 299.2 (M+H).

[0242] [Example 10] 5-(3-Formamidophenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (10)

[0243] [ka] 5-(3-Formamidophenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (10) was synthesized using a procedure similar to that used to synthesize 5-(4-(morpholinomethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (1), except that (4-(morpholinomethyl)phenyl)boronic acid was replaced with (3-formamidophenyl)boronic acid. 1H NMR: (400 MHz, DMSO-d6) δ 10.44 - 10.33 (m, 1H), 8.57 - 8.38 (m, 2H), 8.31 (m, 2H), 8.21 (s., 1H), 7.64 (s, 2H), 7.49 - 7.36 (m, 1H), 7.10 - 7.04 (m, 1H). LCMS: Rt = 0.58 min, m / z = 326.0 (M+H).

[0244] [Example 11] 5-(4-(methylsulfonamido)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (11)

[0245] [ka] 5-(4-(Methylsulfonamido)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (11) was synthesized using a procedure similar to that used to synthesize 5-(4-(morpholinomethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (1), except that (4-(morpholinomethyl)phenyl)boronic acid was replaced with (4-(methylsulfonamido)phenyl)boronic acid. LCMS: Rt=0.61 min, m / z=376.1 (M+H).

[0246] [Example 12] 5-(4-(difluoromethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (12)

[0247] [ka] 5-(4-(Difluoromethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (12) was synthesized using a procedure similar to that used to synthesize 5-(4-(morpholinomethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (1), except that (4-(morpholinomethyl)phenyl)boronic acid was replaced with (4-(difluoromethoxy)phenyl)boronic acid. LCMS: Rt = 0.77 min, m / z = 349.0 (M+H).

[0248] [Example 13] 5-(4-(methoxymethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (13)

[0249] [ka] 5-(4-(Methoxymethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (13) was synthesized using a procedure similar to that used to synthesize 5-(4-(morpholinomethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (1), except that (4-(morpholinomethyl)phenyl)boronic acid was replaced with (4-(methoxymethoxy)phenyl)boronic acid. LCMS: Rt = 2.94 min, m / z = 343.0 (M+H).

[0250] [Example 14] 5-(3-fluoro-4-methoxyphenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (14)

[0251] [ka] 5-(3-Fluoro-4-methoxyphenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (14) was synthesized using a procedure similar to that used to synthesize 5-(4-(morpholinomethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (1), except that (4-(morpholinomethyl)phenyl)boronic acid was replaced with (3-fluoro-4-methoxyphenyl)boronic acid. LCMS: Rt = 2.02 min, m / z = 329.0 (M−H).

[0252] [Example 15] 5-(4-(methoxymethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (15)

[0253] [ka] 5-(4-(Methoxymethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (15) was synthesized using a procedure similar to that used to synthesize 5-(4-(morpholinomethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (1), except that (4-(morpholinomethyl)phenyl)boronic acid was replaced with (4-(methoxymethyl)phenyl)boronic acid. LCMS: Rt = 2.91 min, m / z = 327.0 (M+H).

[0254] [Example 16] 2-Oxo-5-phenyl-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (16)

[0255] [ka] 2-Oxo-5-phenyl-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (16) was synthesized using a procedure similar to that used to synthesize 5-(4-(morpholinomethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (1), except that (4-(morpholinomethyl)phenyl)boronic acid was replaced with phenylboronic acid. LCMS: Rt = 0.96 min, m / z = 283.5 (M+H).

[0256] [Example 17] 5-(4-Isopropoxyphenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (17)

[0257] [ka] 5-(4-Isopropoxyphenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (17) was synthesized using a procedure similar to that used to synthesize 5-(4-(morpholinomethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (1), except that (4-(morpholinomethyl)phenyl)boronic acid was replaced with (4-isopropoxyphenyl)boronic acid. LCMS: Rt = 3.20 min, m / z = 339.0 (M−H).

[0258] [Example 18] 5-(3-chloro-4-methoxyphenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (18)

[0259] [ka] 5-(3-chloro-4-methoxyphenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (18) was synthesized using a procedure similar to that used to synthesize 5-(4-(morpholinomethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (1), except that (4-(morpholinomethyl)phenyl)boronic acid was replaced with (3-chloro-4-methoxyphenyl)boronic acid. LCMS: Rt = 2.08 min, m / z = 345.0 (M−H).

[0260] [Example 19] 5-(4-(methylcarbamoyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (19)

[0261] [ka] 5-(4-(methylcarbamoyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (19) was synthesized using a procedure similar to that used to synthesize 5-(4-(morpholinomethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (1), except that (4-(morpholinomethyl)phenyl)boronic acid was replaced with (4-(methylcarbamoyl)phenyl)boronic acid. LCMS: Rt = 2.40 min, m / z = 340.0 (M+H).

[0262] [Example 20] 5-(4-(cyanomethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (20)

[0263] [ka] 5-(4-(cyanomethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (20) was synthesized using a procedure similar to that used to synthesize 5-(4-(morpholinomethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (1), except that (4-(morpholinomethyl)phenyl)boronic acid was replaced with (4-(cyanomethyl)phenyl)boronic acid. LCMS: Rt = 2.80 min, m / z = 322.0 (M+H).

[0264] [Example 21] 5-(4-(3-(dimethylamino)propoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (21)

[0265] [ka] 5-(4-(3-(dimethylamino)propoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (21) was synthesized using a procedure similar to that used to synthesize 5-(4-(morpholinomethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (1), except that (4-(morpholinomethyl)phenyl)boronic acid was replaced with (4-(3-(dimethylamino)propoxy)phenyl)boronic acid. LCMS: Rt=2.13 min, m / z=384.0 (M+H).

[0266] [Example 22] 5-(3-(cyanomethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (22)

[0267] [ka] 5-(3-(cyanomethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (22) was synthesized using a procedure similar to that used to synthesize 5-(4-(morpholinomethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (1), except that (4-(morpholinomethyl)phenyl)boronic acid was replaced with (3-(cyanomethyl)phenyl)boronic acid. LCMS: Rt = 2.77 min, m / z = 320.0 (M−H).

[0268] [Example 23] 5-(3-(morpholinomethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (23)

[0269] [ka] 5-(3-(morpholinomethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (23) was synthesized using a procedure similar to that used to synthesize 5-(4-(morpholinomethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (1), except that (4-(morpholinomethyl)phenyl)boronic acid was replaced with (3-(morpholinomethyl)phenyl)boronic acid. LCMS: Rt = 1.95 min, m / z = 380.0 (M−H).

[0270] [Example 24] 2-Oxo-5-(m-tolyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (24)

[0271] [ka] 2-Oxo-5-(m-tolyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (24) was synthesized using a procedure similar to that used to synthesize 5-(4-(morpholinomethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (1), except that (4-(morpholinomethyl)phenyl)boronic acid was replaced with m-tolylboronic acid. LCMS: Rt = 3.04 min, m / z = 295.2 (M−H).

[0272] [Example 25] 5-(3-(hydroxymethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (25)

[0273] [ka] 5-(3-(hydroxymethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (25) was synthesized using a procedure similar to that used to synthesize 5-(4-(morpholinomethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (1), except that (4-(morpholinomethyl)phenyl)boronic acid was replaced with (3-(hydroxymethyl)phenyl)boronic acid. LCMS: Rt = 1.17 min, m / z = 311.0 (M−H).

[0274] [Example 26] 2-Oxo-5-(p-tolyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (26)

[0275] [ka] 2-Oxo-5-(p-tolyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (26) was synthesized using a procedure similar to that used to synthesize 5-(4-(morpholinomethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (1), except that (4-(morpholinomethyl)phenyl)boronic acid was replaced with p-tolylboronic acid. LCMS: Rt = 3.02 min, m / z = 295.0 (M−H).

[0276] [Example 27] 5-(4-((3-methylmorpholino)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (27)

[0277] [ka]

[0278] Step 1: To a solution of 5-bromo-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (see Example 1) (3.0 g, 10.5 mmol) in dioxane (10 mL) and HO (2 mL) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (2.9 g, 12.6 mmol), NaCO (2.2 g, 21.0 mmol), and Pd(dppf)Cl-CHCl adduct (0.4 g, 0.5 mmol) at 25 °C under N. The mixture was stirred at 100 °C for 12 h. The mixture was washed with HO (10 mL) and extracted with EA (10 mL × 2). The combined organic layer was dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by preparative HPLC under acidic conditions (MeCN / water with TFA) to give 5-(4-formylphenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide. 1H NMR: (400MHz, DMSO) δ = 10.07 (s, 1H), 8.43 (br, s, 1H), 8.32 (s, 1H), 8.20 (br, s, 1H), 8.01 (d, J=8.0 Hz, 2H), 7.61 (d, J=8.0 Hz, 2H). LCMS: Rt = 0.66 min, m / z = 311.0 (M+H).

[0279] Step 2: To a solution of 5-(4-formylphenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (200 mg, 0.64 mmol) in MeOH (5 mL) was added 3-methylmorpholine (130 mg, 1.29 mmol) and CHCOOH (40 mg, 0.32 mmol) at 25 °C. The mixture was stirred at 25 °C for 1 h. Then NaBHCN (120 mg, 1.92 mmol) was added at 0 °C. The mixture was stirred at 25 °C for 11 h. The mixture was washed with HO (10 mL) and extracted with EA (10 mL × 2). The combined organic layer was dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by preparative HPLC under basic conditions ("basic" method using MeCN / water containing (NH.sub.3·H.sub.2O)) to give 5-(4-((3-methylmorpholino)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (27). 1 H NMR (400MHz, DMSO) δ = 7.88 (s, 1H), 7.30 (d, J=8.0, 2H), 7.18 (d, J=8.0, 2H), 4.02(d, J=13.2, 1H), 3.64 (m, 2H), 3.61- 3.60(m, 2H), 3.33 (s, 1H), 3.16-3.12 (m,2H), 2.49-2.48 (m, 2H). 2.10-2.07(m, 1H), 1.02-1.00 (d, J=6.4, 3H). LCMS: Rt = 0.92 min, m / z = 396.1 (M+H).

[0280] [Example 28] 2-Oxo-5-(4-(thiomorpholinomethyl)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (28)

[0281] [ka] 2-Oxo-5-(4-(thiomorpholinomethyl)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (28) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-methylmorpholino)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (27), except that 3-methylmorpholine was replaced with thiomorpholine. 1 H NMR (400MHz, DMSO) δ = 8.01 (s, 1H), 7.46 (br s, 1H), 7.32 (d, J=8.0 Hz, 2H), 7.22 (d, J=8.0 Hz, 2H), 3.53 (s, 2H), 2.63-2.61 (m, 8H), LCMS: Rt = 0.99 min, m / z = 398.1 (M+H).

[0282] [Example 29] 5-(4-((2-methylmorpholino)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (29)

[0283] [ka] 5-(4-((2-methylmorpholino)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (29) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-methylmorpholino)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (27), except that 3-methylmorpholine was replaced with 2-methylmorpholine. 1H NMR (400MHz, DMSO) δ = 7.86 (s, 1H), 7.29 (d, J=8.0,2H), 7.18 (d, J=8.0,2H), 3.73 (m, 1H), 3.51(m, 2H), 3.46 (s, 2H), 2.70 (m, 1H), 2.67 (m, 1H), 2.49-2.48 (m, 1H), 2.02-2.01(m, 1H), 1.71 (t, J=10.8, 1H), 1.02-1.01(d, J=6.0, 3H). LCMS: Rt = 0.78 min, m / z = 396.1 (M+H).

[0284] [Example 30] 5-(4-((7-oxa-4-azaspiro[2.5]octan-4-yl)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (30)

[0285] [ka] 5-(4-((7-oxa-4-azaspiro[2.5]octan-4-yl)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (30) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-methylmorpholino)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (27), except that 3-methylmorpholine was replaced with 7-oxa-4-azaspiro[2.5]octane. 1H NMR (400MHz, DMSO) δ = 9.15 (br. s, 1H), 8.19 (s, 1H), 8.14 (s, 1H), 7.84 (s, 1H), 7.33 (d, J=8.0 Hz, 2H), 7.23 (d, J=8.0 Hz, 2H), 3.84 (s, 2H), 3.67 - 3.65 (m, 2H), 3.55 (br. s., 2H), 2.69 - 2.67 (m, 2H), 0.69 - 0.67 (m, 2H), 0.50 - 0.48 (m, 2H). LCMS: Rt = 0.65 min, m / z = 408.1 (M+H).

[0286] [Example 31] 5-(4-(((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (31)

[0287] [ka] 5-(4-(((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (31) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-methylmorpholino)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (27), except that 3-methylmorpholine was replaced with (1R,5S)-8-oxa-3-azabicyclo[3.2.1]octane. 1H NMR (400MHz, DMSO) δ = 7.82 (s, 1H), 7.28 (d, J=8.0 Hz, 2H), 7.16 (d, J=8.0 Hz, 2H), 7.05 - 6.94 (m, 1H), 4.21 (d, J=2.0 Hz, 2H), 3.46 (s, 2H), 2.54 (s, 1H), 2.20 (d, J=9.4 Hz, 2H), 1.90 (d, J=6.4 Hz, 2H), 1.76 - 1.69 (m, 2H). LCMS: Rt = 1.09 min, m / z = 408.0 (M+H).

[0288] [Example 32] 2-Oxo-5-(4-((3-(pyridin-3-yl)morpholino)methyl)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (32)

[0289] [ka] 2-Oxo-5-(4-((3-(pyridin-3-yl)morpholino)methyl)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (32) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-methylmorpholino)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (27), except that 3-methylmorpholine was replaced with 3-(pyridin-3-yl)morpholine. 1H NMR (400MHz, DMSO) δ = 8.71 (s, 1H), 8.54 - 8.53 (m, 1H), 8.16 (s, 1H), 7.96 - 7.94 (m, 1H), 7.45 - 7.42 (m, 1H), 7.33-7.24 (m, 4H), 3.84 - 3.82 (m, 1H), 3.73 - 3.71 (m, 1H), 3.65 - 3.56 (m, 2H), 3.54 - 3.48 (m, 1H), 3.37 (br. s., 1H), 3.07 - 3.00 (m, 1H), 2.74 - 2.66 (m, 1H), 2.33 - 2.26(m, 1H). LCMS: Rt = 0.70 min, m / z = 459.1 (M+H).

[0290] [Example 33] 5-(4-(1-morpholinoethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (33)

[0291] [ka] 5-(4-(1-Morpholinoethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (33) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-methylmorpholino)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (27), except that 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde was replaced with 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethan-1-one and 3-methylmorpholine was replaced with morpholine. 1H NMR (400MHz, DMSO) δ = 9.15 (s, 1H),8.15 (s, 1H), 7.82 (s, 1H),7.35 (d, J=8.0 Hz, 1H), 7.25 (d, J=8.0 Hz, 1H), 3.75-3.55 (m, 5H), 2.40-2.30(m, 2H), 2.29-2.26 (m., 2H), 1.31-1.25 (m, 3H). LCMS: Rt = 0.53 min, m / z = 396.3 (M+H).

[0292] [Example 34] 5-(4-((1,4-oxazepan-4-yl)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (34)

[0293] [ka] 5-(4-((1,4-oxazepan-4-yl)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (34) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-methylmorpholino)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (27), except that 3-methylmorpholine was replaced with 1,4-oxazepane. 1 H NMR (400MHz, DMSO) δ = 10.24 (br, s, 1H), 7.92 (s, 1H), 7.34 (d, J=8.0 Hz, 2H), 7.25 (br. s., 1H), 7.20 (d, J=8.0 Hz, 2H), 3.71 (m, 2H), 3.67 (s, 2H), 3.63 - 3.61 (m, 2H), 2.66 - 2.62 (m, 4H), 1.84 - 1.81 (m, 2H). LCMS: Rt = 1.00 min, m / z = 396.3 (M+H).

[0294] [Example 35] 5-(4-(((2S,6R)-2,6-dimethylmorpholino)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (35)

[0295] [ka] 5-(4-(((2S,6R)-2,6-dimethylmorpholino)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (35) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-methylmorpholino)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (27), except that 3-methylmorpholine was replaced with (2S,6R)-2,6-dimethylmorpholine. 1 H NMR (400MHz, DMSO) δ = 8.82 - 8.68 (m, 1H), 8.26 (s, 1H), 8.05 (s, 1H), 7.43 - 7.36 (m, 2H), 7.34 - 7.24 (m, 2H), 3.61 - 3.59 (m, 2H), 3.53 (s, 2H), 2.71 (d, J=10.4 Hz, 2H), 1.71 (t, J=10.7 Hz, 2H), 1.04 (d, J=6.3 Hz, 6H). LCMS: Rt = 0.98 min, m / z = 410.2 (M+H).

[0296] [Example 36] 5-(3-fluoro-4-(morpholinomethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (36)

[0297] [ka] 5-(3-Fluoro-4-(morpholinomethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (36) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-methylmorpholino)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (27), except that 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde was replaced with 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde and 3-methylmorpholine was replaced with morpholine. 1 H NMR (400MHz, DMSO) δ = 8.39 (s, 1H), 8.30 (s, 1H), 8.18 (s, 1H), 7.68 (t, J=8.0 Hz, 1H), 7.42 (d, J=8.0Hz, 1H), 7.33 (d, J=8.0 Hz, 1H), 4.40 (s., 2H), 3.79 (m., 5H), 3.19 (bs., 3H). LCMS: Rt = 0.59 min, m / z = 400.3 (M+H).

[0298] [Example 37] 5-(4-(1-hydroxyethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (37)

[0299] [ka] 5-(4-(1-hydroxyethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (37) was synthesized using a procedure similar to that used in step 1 of the procedure for synthesizing 5-(4-((3-methylmorpholino)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (27), except that 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde was replaced with 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethan-1-ol. 1 H NMR (400MHz, DMSO) δ = 8.47 (s, 1H), 8.30 (s, 1H), 8.18(s, 1H), 7.44 (d, J=8.0 Hz, 2H), 7.31 (d, J=8.0 Hz, 2H), 5.26 (s, 1H), 4.79 (d, J=6.4 Hz, 1H), 1.37 (d, J=6.4 Hz, 3H). LCMS: Rt = 0.64 min, m / z = 327.0 (M+H).

[0300] [Example 38] 5-(4-((3-methoxyazetidin-1-yl)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (38)

[0301] [ka] 5-(4-((3-Methoxyazetidin-1-yl)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (38) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-methylmorpholino)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (27), except that 3-methylmorpholine was replaced with 3-methoxyazetidine. 1H NMR (400MHz, DMSO) δ = 9.42 (s, 1H), 8.09 (s, 1H), 7.69 (s, 1H), 7.39 (d, J=7.8 Hz, 2H), 7.27 (d, J=7.8 Hz, 2H), 4.12 - 4.06 (m, 1H), 3.90 (s, 2H), 3.77 (s, 2H), 3.28 - 3.24 (m, 2H), 3.20 - 3.17. LCMS: Rt = 0. 48 min, m / z = 382.1 (M+H).

[0302] [Example 39] 5-(4-((2,2-dimethylmorpholino)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (39)

[0303] [ka] 5-(4-((2,2-dimethylmorpholino)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (39) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-methylmorpholino)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (27), except that 3-methylmorpholine was replaced with 2,2-dimethylmorpholine. 1 H NMR (400MHz, DMSO) δ = 8.43 (s, 1H), 8.31 (s, 1H), 8.18 (s, 1H), 7.62 (d, J=8.0Hz, 2H), 7.47 (d, J=8.0Hz, 2H), 4.38 (br. s, 4H), 3.17 - 2.91 (m, 4H), 1.26 (br. s, 6H). LCMS: Rt = 0. 88 min, m / z = 410.2 (M+H).

[0304] [Example 40] (S)-5-(4-((3-methoxypyrrolidin-1-yl)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (40)

[0305] [ka] (S)-5-(4-((3-methoxypyrrolidin-1-yl)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (40) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-methylmorpholino)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (27), except that 3-methylmorpholine was replaced with (S)-3-methoxypyrrolidine. 1 H NMR (400MHz, DMSO) δ = 9.64 - 9.33 (m, 1H), 8.09 (s, 1H), 7.66 (s, 1H), 7.38 (d, J=8.0 Hz, 2H), 7.26 (d, J=7.9 Hz, 2H), 3.99 - 3.88 (m, 1H), 3.74 (s, 2H), 3.17 (s, 3H), 2.90 - 2.78 (m, 1H), 2.75 - 2.67 (m, 1H), 2.60 (d, J=7.9 Hz, 2H), 2.08 - 1.99 (m, 1H), 1.81 - 1.66 (m, 1H). LCMS: Rt = 0. 52 minutes, m / z = 396.1 (M+H).

[0306] [Example 41] (R)-5-(4-((3-methoxypyrrolidin-1-yl)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (41)

[0307] [ka] (R)-5-(4-((3-methoxypyrrolidin-1-yl)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (41) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-methylmorpholino)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (27), except that 3-methylmorpholine was replaced with (R)-3-methoxypyrrolidine. 1 H NMR (400MHz, DMSO) δ = 10.59 (s, 1H), 7.85 (s, 1H), 7.29(d, J=8.0 Hz, 2H), 7.18 (d, J=7.6 Hz, 2H), 7.08(br. s., 1H), 3.90-3.89(m, 1H), 3.33 (s, 2H), 2.52(s, 3H), 2.51-2.50 (m, 1H), 2.50-2.48(m,1H), 2.48-2.47(m, 2H), 2.44-2.00 (m, 1H), 1.99-1.66 (m, 1H). LCMS: Rt = 0. 51 min, m / z = 396.2 (M+H).

[0308] [Example 42] 5-(2-fluoro-4-(morpholinomethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (42)

[0309] [ka] 5-(2-Fluoro-4-(morpholinomethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (42) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-methylmorpholino)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (27), except that 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde was replaced with 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde and 3-methylmorpholine was replaced with morpholine. 1 H NMR (400MHz, DMSO) δ = 8.33 (s, 1H), 8.29 (s, 1H), 8.22 - 8.10 (m, 1H), 7.63 - 7.40 (m, 3H), 4.34 (s, 2H), 3.79 (s, 4H), 3.13 (s, 5H). LCMS: Rt = 0. 49 min, m / z = 400.3 (M+H).

[0310] [Example 43] 5-(3-methyl-4-(morpholinomethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (43)

[0311] [ka] 5-(3-Methyl-4-(morpholinomethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (43) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-methylmorpholino)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (27), except that 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde was replaced with 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde and 3-methylmorpholine was replaced with morpholine. 1 H NMR (400MHz, DMSO) δ = 8.40 (s, 1H), 8.27 (s, 1H), 8.16 (s, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.36 - 7.23 (m, 2H), 4.36 (s, 2H), 4.01 - 3.66 (m, 4H), 3.22 (s, 4H), 2.46 (s, 3H). LCMS: Rt = 0. 51 min, m / z = 396.1 (M+H).

[0312] [Example 44] 2-Oxo-5-(4-(piperidin-1-ylmethyl)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (44)

[0313] [ka] 2-Oxo-5-(4-(piperidin-1-ylmethyl)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (44) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-methylmorpholino)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (27), except that 3-methylmorpholine was replaced with piperidine. 1H NMR (400MHz, DMSO) δ = 7.87 (s, 1H), 7.27(d, J=8.0, 2H), 7.16 (d, J=8.0, 2H), 3.52 (s, 2H), 2.49(m, 4H),1.53 (m, 4H), 1.40 (m, 2H). LCMS: Rt = 1.03 min, m / z = 380.2 (M+H).

[0314] [Example 45] 5-(4-((dimethylamino)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (45)

[0315] [ka] 5-(4-((dimethylamino)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (45) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-methylmorpholino)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (27), except that 3-methylmorpholine was replaced with dimethylamine. 1 H NMR (400MHz, DMSO) δ = 10.59 (s, 1H), 7.85 (s, 1H), 7.28 - 7.16 (m, 4H), 7.06(s, 1H), 3.45 (s, 2H), 2.19 (s, 6H). LCMS: Rt = 0.40 min, m / z = 340.2 (M+H).

[0316] [Example 46] 2-Oxo-5-(4-((3-oxomorpholino)methyl)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (46)

[0317] [ka] 2-Oxo-5-(4-((3-oxomorpholino)methyl)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (46) was synthesized using a procedure similar to that used in step 1 of the procedure for synthesizing 5-(4-((3-methylmorpholino)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (27), except that 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde was replaced with 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholin-3-one. 1 H NMR (400MHz, DMSO) δ = 8.46 (s, 1H), 8.31 (s, 1H), 8.19 (s, 1H), 7.36 (s, 4H), 4.62 (s, 2H), 4.15 (s, 2H), 3.86 (t, J=5.1 Hz, 2H), 3.32 - 3.29 (m, 2H). LCMS: Rt = 0.59 min, m / z = 396.0 (M+H). 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholin-3-one was obtained using the following procedure:

[0318] [ka] To a solution of morpholin-3-one (40 mg, 0.78 mmol) in THF (2 mL) was added NaH (12 mg, 0.98 mmol) at 0 °C. The mixture was then stirred at 25 °C for 1 h. 2-(4-(bromomethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (200 mg, 0.68 mmol) was then added, and the mixture was stirred at 25 °C for 15 h. The reaction mixture was poured into water (10 mL), and the resulting mixture was extracted with EA (10 mL × 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to give 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholin-3-one. The crude product was used directly without purification. TLC: PE:EA = 1:1, Rf = 0.2. LCMS: Rt=0.78 min, m / z=318.1(M+H).

[0319] [Example 47] 5-(4-((1,1-dioxidothiomorpholino)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (47)

[0320] [ka] 5-(4-((1,1-dioxidethiomorpholino)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (47) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-methylmorpholino)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (27), except that 3-methylmorpholine was replaced with thiomorpholine 1,1-dioxide. 1H NMR (400MHz, DMSO) δ = 9.62 (br, s, 1H), 8.06 (s, 1H), 7.59 (br, s, 1H), 7.38 (d, J=8.0 Hz, 2H), 7.27 (d, J=8.0 Hz, 2H), 3.71 (s, 2H), 3.14 (m, 4H), 2.91 (m, 4H). LCMS: Rt = 1.1 min, m / z = 430.1 (M+H).

[0321] [Example 48] 5-(4-(morpholino(oxazol-5-yl)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (48)

[0322] [ka] 5-(4-(morpholino(oxazol-5-yl)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (48) was synthesized using a procedure similar to that used in step 1 of the procedure for synthesizing 5-(4-((3-methylmorpholino)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (27), except that 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde was replaced with 4-(oxazol-5-yl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl)morpholine. 1H NMR (400MHz, DMSO) δ = 10.89 - 10.74 (m, 1H), 8.33 (s, 1H), 7.79 (s, 1H), 7.40 (d, J=8.0 Hz, 2H), 7.21 (d, J=8.0 Hz, 2H), 7.17 (s, 1H), 6.98 (d, J=6.1 Hz, 1H), 4.72 (s, 1H), 3.59 (t, J=4.3 Hz, 4H), 2.41 - 2.26 (m, 4H). LCMS: Rt = 0.78 min, m / z = 449.2 (M+H). 4-(oxazol-5-yl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl)morpholine was obtained using the following procedure:

[0323] [ka]

[0324] Step 1: To a solution of (4-bromophenyl)(oxazol-5-yl)methanol (Science of Synthesis (2002), 11, 383-479) (400 mg, 1.9 mmol), TEA (500 mg, 3.8 mmol) in DCM (4 mL) was added MsCl (200 mg, 2.3 mmol) at 0 °C. The mixture was then stirred at 25 °C for 1 h to give crude (4-bromophenyl)(oxazol-5-yl)methyl methanesulfonate, which was used directly in the next step. TLC: PE:EA = 1:1 Rf = 0.7.

[0325] Step 2: A solution of (4-bromophenyl)(oxazol-5-yl)methyl methanesulfonate (400 mg, 1.2 mmol) in morpholine (4 mL) was stirred at 25 °C for 16 h. The reaction mixture was poured into water (10 mL), and the resulting mixture was extracted with EA (10 mL × 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product, which was purified by column chromatography (PE:EA = 3:1 to 1:1) to give 4-((4-bromophenyl)(oxazol-5-yl)methyl)morpholine. TLC: PE:EA = 1:1 Rf = 0.3. 1 H NMR: (CDCl3, 400 MHz), δ: 7.86 (s, 1H), 7.50 (d, J=8.4 Hz, 2H), 7.35 (d, J=8.4 Hz, 2H), 7.02 (s, 1H), 4.50 (s, 1H), 3.73 (t, J=4.6 Hz, 4H), 2.41 (m, 4H).

[0326] Step 3: To a solution of 4-((4-bromophenyl)(oxazol-5-yl)methyl)morpholine (200 mg, 1.0 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (500 mg, 2.0 mmol), and NaOAc (240 mg, 3.0 mmol) in dioxane (2 mL), Pd(dppf)Cl (26 mg, 0.05 mmol) was added, and the mixture was stirred at 100 °C for 16 h. The mixture was diluted with HO (10 mL), extracted with EA (5.0 mL × 3), dried over NaSO, filtered, and concentrated in vacuo to give 4-(oxazol-5-yl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl)morpholine. LCMS: Rt=1.20 min, m / z=371.1(M+H).

[0327] [Example 49] 5-(4-(methylsulfonamidomethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (49)

[0328] [ka] 5-(4-(Methylsulfonamidomethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (49) was synthesized using a procedure similar to that used in step 1 of the procedure for synthesizing 5-(4-((3-methylmorpholino)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (27), except that 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde was replaced with N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)methanesulfonamide. 1H NMR (400MHz, DMSO) δ = 8.46 (br, s, 1H), 8.29 (s, 1H), 8.18 (br, s, 1H), 7.64 (t, 1H), 7.46 (d, J=8.2 Hz, 2H), 7.36 (m, 2H), 4.24 (d, J=6.4 Hz, 2H), 2.88 (s, 3H). LCMS: Rt = 0.60 min, m / z = 390.0 (M+H).

[0329] [Example 50] 5-(4-((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (50)

[0330] [ka] 5-(4-((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (50) was synthesized using a procedure similar to that used in Step 1 of the procedure for synthesizing 5-(4-((3-methylmorpholino)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (27), except that 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde was replaced with 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)tetrahydro-2H-pyran-4-ol. TLC: PE:EA=1:1 Rf=0.1. LCMS: Rt = 0.622 min, [M+H] + = 397.1. 1H NMR (400MHz, DMSO) δ= 9.56-10.13 (m, 1H), 8.02 (s, 1H), 7.44-7.56 (m, 1H), 7.25 (d, J=7.6 Hz, 2H), 7.07-7.21 (m, 2H), 4.35-4.50 (m, 1H), 3.60 (d, J=6.6 Hz, 4H), 2.73 (s, 2H), 1.46-1.66 (m, 2H), 1.32 (d, J=13.2 Hz, 2H).

[0331] Using a method similar to step 3 in the preparation of 4-(oxazol-5-yl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl)morpholine, except replacing 4-((4-bromophenyl)(oxazol-5-yl)methyl)morpholine with 4-(4-bromobenzyl)tetrahydro-2H-pyran-4-ol, 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)tetrahydro-2H-pyran-4-ol was obtained. 4-(4-Bromobenzyl)tetrahydro-2H-pyran-4-ol was prepared using the following procedure:

[0332] [ka] To a mixture of Mg (1 g, 41 mmol) and 1,2-dibromoethane (10 mg, 0.1 mmol) in diethyl ether (20 mL), 1-bromo-4-(bromomethyl)benzene (1 g, 1 mmol) was added dropwise. The mixture was stirred at 0 °C for 1 h. Tetrahydro-4H-pyran-4-one (400 mg, 1.2 mmol) was then added at 0 °C. The mixture was then stirred at 25 °C for 15 h. The reaction mixture was poured into water (20 mL), and the resulting mixture was extracted with EA (20 mL × 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product. The crude product was purified by column chromatography (PE:EA = 5:1 to 1:1) to give 4-(4-bromobenzyl)tetrahydro-2H-pyran-4-ol. TLC: PE:EA = 1:1 Rf = 0.5. LCMS: Rt = 0.69 min, [M+H] + = 253.0, 1 H NMR (400MHz, DMSO) δ= 7.50 - 7.44 (m, 2H), 7.11 (d, J=8.4 Hz, 2H), 3.79 - 3.72 (m, 4H), 2.75 (s, 2H), 1.81 - 1.72 (m, 2H), 1.52 - 1.39 (m, 2H).

[0333] [Example 51] 5-(4-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (51)

[0334] [ka] 5-(4-((4-Fluorotetrahydro-2H-pyran-4-yl)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (51) was synthesized using a procedure similar to that used in Step 1 of the procedure for synthesizing 5-(4-((3-methylmorpholino)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (27), except that 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde was replaced with 2-(4-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. TLC: PE:EA=1:1 Rf=0.1. LCMS: Rt = 0.775 min, [M+H] + = 399.0. 1 H NMR (400MHz, DMSO) δ= 14.23 - 13.31 (m, 1H), 8.49 (s, 1H), 8.32 (s, 1H), 8.22 (s, 1H), 7.42 - 7.25 (m, 4H), 3.74 (m, 2H), 3.56 - 3.51 (m, 2H), 3.11 - 2.93 (m, 2H), 1.90 - 1.65 (m, 2H), 1.65 - 1.52 (m, 2H).

[0335] Using a method similar to step 3 in the preparation of 4-(oxazol-5-yl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl)morpholine, except replacing 4-((4-bromophenyl)(oxazol-5-yl)methyl)morpholine with 4-(4-bromobenzyl)-4-fluorotetrahydro-2H-pyran, 2-(4-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was obtained. 4-(4-Bromobenzyl)-4-fluorotetrahydro-2H-pyran was prepared using the following procedure:

[0336] [ka] To a solution of 4-(4-bromobenzyl)tetrahydro-2H-pyran-4-ol (500 mg, 2 mmol) in DCM (5 mL) was added DAST (300 mg, 2.2 mmol) at 0 °C. The mixture was then stirred at 0 °C for 1 h. The reaction mixture was poured into water (10 mL), and the resulting mixture was extracted with EA (10 mL × 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product. The crude product was purified by column chromatography (PE:EA = 10:1 to 3:1) to give 4-(4-bromobenzyl)-4-fluorotetrahydro-2H-pyran (300 mg, 1.2 mmol, 60% yield) as a colorless solid. TLC: PE:EA = 1:1 Rf = 0.6.

[0337] [Example 52] 2-Oxo-5-(4-((tetrahydro-2H-pyran-4-yl)methyl)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (52)

[0338] [ka]

[0339] Step 1. To a solution of diethyl (4-bromobenzyl)phosphonate (500 mg, 1 mmol) and tetrahydro-4H-pyran-4-one (200 mg, 1.2 mmol) in THF (5 mL) was added tBuOK (300 mg, 2 mmol). The mixture was then stirred at 25 °C for 16 h. The reaction mixture was poured into water (10 mL). The resulting mixture was extracted with EA (10 mL × 2). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated to give the crude product. The crude product was purified by column chromatography (5:1 to 3:1) to give 4-(4-bromobenzylidene)tetrahydro-2H-pyran. TLC: PE:EA = 1:1 Rf = 0.4. LCMS: Rt = 1.00 min, [M+H] + = 252.9. 1H NMR (400MHz, CDCl3) δ= 7.44 (d, J=8.4 Hz, 1H), 7.07 (d, J=8.4 Hz, 1H), 6.26 (s, 1H), 3.79 (t, J=5.4 Hz, 2H), 3.67 (t, J=5.4 Hz, 2H), 2.54 - 2.46 (m, 2H), 2.44 - 2.35 (m, 2H).

[0340] Step 2: To a solution of 4-(4-bromobenzylidene)tetrahydro-2H-pyran (300 mg, 1.0 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (500 mg, 2.0 mmol), and NaOAc (240 mg, 3.0 mmol) in dioxane (2 mL) was added Pd(dppf)Cl2 (26 mg, 0.05 mmol), and the mixture was stirred at 100 °C for 16 h to give 4,4,5,5-tetramethyl-2-(4-((tetrahydro-4H-pyran-4-ylidene)methyl)phenyl)-1,3,2-dioxaborolane, which was used directly in the next step. LCMS: Rt = 1.12 min, [M+H] + =301.1.

[0341] Step 3: To a solution of 5-bromo-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (200 mg, 0.70 mmol), 4,4,5,5-tetramethyl-2-(4-((tetrahydro-4H-pyran-4-ylidene)methyl)phenyl)-1,3,2-dioxaborolane (240 mg, 0.84 mmol), and NaCO (149 mg, 1.40 mmol) in dioxane:HO=9:1 (2 mL) was added Pd(dppf)Cl (26 mg, 0.04 mmol). The mixture was then stirred at 100 °C for 16 h. The reaction mixture was poured into water (10 mL) and extracted with EA (10 mL × 2). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated to give the crude product. The crude product was purified by preparative HPLC (TFA) to give 2-oxo-5-(4-((tetrahydro-4H-pyran-4-ylidene)methyl)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide. TLC: PE:EA=1:1 Rf=0.1. LCMS: Rt=0.87 min, [M+H] + =379.1.

[0342] Step 4: To a solution of 2-oxo-5-(4-((tetrahydro-4H-pyran-4-ylidene)methyl)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (50 mg, 0.13 mmol) in MeOH (2 mL) was added Pd / C (10 mg), and the mixture was stirred under a balloon of hydrogen gas at 25° C. for 16 hours. The reaction mixture was filtered and concentrated to give the crude product. The crude product was purified by preparative HPLC (TFA) to give 2-oxo-5-(4-((tetrahydro-2H-pyran-4-yl)methyl)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide. TLC: PE:EA=1:1 Rf=0.3. LCMS: Rt=0.75 min, [M+H] + = 381.0. 1H NMR (400MHz, DMSO) δ= 9.90 - 9.31 (m, 1H), 8.09 (s, 1H), 7.79 - 7.53 (m, 1H), 7.30 - 7.05 (m, 4H), 3.82 (d, J=11.2 Hz, 2H), 3.27 - 3.21 (m, 2H), 2.58 - 2.53 (m, 2H), 1.76 (t, J=7.2 Hz, 1H), 1.49 (d, J=11.0 Hz, 2H), 1.26 - 1.20 (m, 2H).

[0343] [Example 53] 5-(4-(2-(1,4-dioxan-2-yl)-1,1-difluoroethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (53)

[0344] [ka] 5-(4-(2-(1,4-Dioxan-2-yl)-1,1-difluoroethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (53) was synthesized using a procedure similar to that used in step 1 of the procedure for synthesizing 5-(4-((3-methylmorpholino)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (27), except that 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde was replaced with 2-(4-(2-(1,4-dioxan-2-yl)-1,1-difluoroethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0345] Using a method similar to step 3 in the preparation of 4-(oxazol-5-yl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl)morpholine, except replacing 4-((4-bromophenyl)(oxazol-5-yl)methyl)morpholine with 2-(2-(4-bromophenyl)-2,2-difluoroethyl)-1,4-dioxane, 2-(4-(2-(1,4-dioxan-2-yl)-1,1-difluoroethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was obtained. 2-(2-(4-bromophenyl)-2,2-difluoroethyl)-1,4-dioxane was prepared using the following procedure:

[0346] [ka]

[0347] Step 1: 2-(4-Bromophenyl)-1,3-dithiane (2.0 g, 7.27 mmol) in THF (30 mL) was cooled to -78 °C, and LDA (4.36 mL, 10.9 mmol) was added dropwise. The mixture was warmed to 0 °C, and then a solution of 2-(iodomethyl)-1,4-dioxane (1.82 g, 7.99 mmol) in THF (30 mL) was added dropwise at 0 °C. The mixture was then warmed to 25 °C and stirred for 3 h. The reaction mixture was poured into water (100 mL) and extracted with EA (100 mL × 2). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product. The crude product was purified by silica gel column (PE / EA=20 / 1 to 5 / 1) to give 2-((2-(4-bromophenyl)-1,3-dithian-2-yl)methyl)-1,4-dioxane. TLC: PE / EA=5 / 1, Rf=0.60. LCMS: Rt=1.02, [M+H] + = 375 / 377. 1H NMR (400MHz, CDCl3) δ = 7.84 (d, J=8.0 Hz, 2H), 7.51 (d, J=8.0 Hz, 2H), 3.69 - 3.42 (m, 6H), 3.16 (m, 1H), 2.75 - 2.62 (m, 4H), 2.18 (m, 1H), 1.99 - 1.91 (m, 2H), 1.89 (m, 1H).

[0348] Step 2: Triethylamine trihydrofluoride (2.15 g, 13.32 mmol, EtN-3HF) was added to a mixture of 2-((2-(4-bromophenyl)-1,3-dithian-2-yl)methyl)-1,4-dioxane (1.0 g, 2.66 mmol) in DCM (50 ml) at −78 °C. Then 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (3.81 g, 13.32 mmol) in DCM (50 ml) was added over 30 min. The mixture was stirred at 25 °C for 3.5 h. The solution was quenched with NaOH (1 N, 50 mL) and extracted with DCM (50 ml × 3). The separated organic layer was dried over NaSO, filtered, and concentrated in vacuo. The crude product was purified by reverse phase column chromatography (FA) to give 2-(2-(4-bromophenyl)-2,2-difluoroethyl)-1,4-dioxane. TLC: PE / EA=5:1, Rf=0.5. LCMS: Rt=5.979 min, M + = 306 / 308. 1 H NMR (400 MHz, chloroform-d) δ = 7.59 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 3.84 - 3.55 (m, 6H), 3.34 (m, 1H), 2.44 - 2.28 (m, 1H), 2.23 - 2.06 (m, 1H).

[0349] [Example 54] 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54)

[0350] [ka]

[0351] Step 1: To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (3.0 g, 13.6 mmol) in THF (30 mL) was added NaH (1.1 g, 27.2 mmol) at 0 °C, and the mixture was stirred at 0 °C for 0.5 h. Then 1-(bromomethyl)-3-nitrobenzene (3.5 g, 16.4 mmol) was added to the above mixture at 25 °C. The mixture was washed with HO (100 mL) and extracted with EA (100 mL × 2). The combined organic layer was dried over anhydrous NaSO, filtered, and concentrated to give crude 4,4,5,5-tetramethyl-2-(4-((3-nitrobenzyl)oxy)phenyl)-1,3,2-dioxaborolane. The residue was used in the next step without purification. LCMS: Rt=0.99 min, m / z=356.2(M+H).

[0352] Step 2: To a solution of 5-bromo-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (4.0 g, 14.1 mmol) in dioxane (200 mL) and HO (20 mL) under N was added 4,4,5,5-tetramethyl-2-(4-((3-nitrobenzyl)oxy)phenyl)-1,3,2-dioxaborolane (5.0 g, 14.1 mmol), NaCO (3.0 g, 28.2 mmol), and PdCl(dppf)-CHCl (500 mg, 0.7 mmol) at 25 °C under N. The mixture was stirred at 100 °C for 12 h. The mixture was washed with HO (100 mL) and extracted with EA (200 mL × 2). The combined organic layer was dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by column chromatography (PE / EA=1 / 1) to give 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54). 1H NMR (400MHz, DMSO) δ = 13.65 (br. s., 1H), 8.51 - 8.42 (m, 1H), 8.37 - 8.33 (m, 1H), 8.30 - 8.26 (m, 1H), 8.24 - 8.14 (m, 2H), 7.97 - 7.92 (m, 1H), 7.75 - 7.69 (m, 1H), 7.30 (d, J=8.5 Hz, 2H), 7.14 (d, J=8.7 Hz, 2H), 5.33 (s, 2H). LCMS: Rt = 0.85 min, m / z = 434.2 (M+H).

[0353] [Example 55] 5-(4-((1-acetylpiperidin-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (55)

[0354] [ka]

[0355] Step 1: To a solution of 1-(4-(hydroxymethyl)piperidin-1-yl)ethan-1-one (200 mg, 1.3 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (250 mg, 1.4 mmol), and PPh3 (600 mg, 2.6 mmol) in THF (5 mL) was added DTBAD (500 mg, 2.6 mmol) at 0° C. The mixture was then stirred at 25° C. for 16 h. The reaction mixture was poured into water (20 mL) and then extracted with EA (20 mL × 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to give crude 1-(4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)piperidin-1-yl)ethan-1-one, which was used directly in the next step. TLC: PE / EA=1:1, Rf=0.6. LCMS: Rt=1.60 min, m / z=360.2 (M+H).

[0356] Step 2: To a solution of 5-bromo-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (200 mg, 0.70 mmol), 1-(4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)piperidin-1-yl)ethan-1-one (320 mg, 0.84 mmol), NaCO (149 mg, 1.40 mmol) in dioxane (2 mL) and HO (0.2 mL) was added PdCl(dppf)-CHCl (26 mg, 0.04 mmol) under N, and the mixture was stirred at 100 °C for 16 h. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL × 2). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated to give the crude product, which was purified by preparative HPLC under acidic conditions (MeCN / water with TFA) to give 5-(4-((1-acetylpiperidin-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (55). 1 H NMR (400MHz, DMSO) δ = 8.70 - 8.48 (m, 1H), 8.25 (s, 1H), 8.17 - 8.07 (m, 1H), 7.26 (d, J=8.6 Hz, 2H), 7.02 (d, J=8.8 Hz, 2H), 4.54 - 4.34 (m, 1H), 4.01 - 3.81 (m, 3H), 3.13 - 3.00 (m, 1H), 2.61 - 2.54 (m, 1H), 2.01 (s, 4H), 1.81 (s, 2H), 1.37 - 1.08 (m, 2H). LCMS: Rt = 0.73 min, m / z = 438.1 (M+H).

[0357] [Example 56] 2-Oxo-5-(4-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (56)

[0358] [ka] 2-Oxo-5-(4-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (56) was synthesized using a procedure similar to that used to synthesize 5-(4-((1-acetylpiperidin-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (55), except that 1-(4-(hydroxymethyl)piperidin-1-yl)ethan-1-one was replaced with (tetrahydro-2H-pyran-4-yl)methanol. 1 H NMR (400MHz, DMSO) δ = 13.62 (s, 1H), 8.46 (s, 1H), 8.27 (s, 1H), 8.18 (s, 1H), 7.26 (d, J=8.0 Hz, 2H), 7.02 (d, J=8.0 Hz, 2H), 3.88 (d, J=8.0 Hz, 4H), 3.33 - 3.28 (m, 2H), 2.06 - 1.95 (m, 1H), 1.69 (m, 2H), 1.34 (m, 2H). LCMS: Rt = 0.79 min, m / z = 397.1 (M+H).

[0359] [Example 57] 5-(4-((3-aminobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (57)

[0360] [ka] 5-(4-((3-aminobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (57) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 3-(bromomethyl)aniline. 1 H NMR (400MHz, DMSO) δ = 7.96 (s, 1H), 7.42 (brs, 1H), 7.18-7.15 (d, J=12Hz, 2H), 7.03 - 6.98 (m, 3H), 6.65 (s, 1H), 6.64 - 6.58 (d, J=24Hz, 1H), 6.57-6.51(d, J=24Hz, 1H), 4.96 (s, 2H). LCMS: Rt = 0.66 min, m / z = 404.2 (M+H).

[0361] [Example 58] 5-(4-(cyclohexylmethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (58)

[0362] [ka] 5-(4-(cyclohexylmethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (58) was synthesized using a procedure similar to that used to synthesize 5-(4-((1-acetylpiperidin-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (55), except that 1-(4-(hydroxymethyl)piperidin-1-yl)ethan-1-one was replaced with cyclohexylmethanol. 1H NMR (400MHz, DMSO) δ = 12.70 (s, 1H), 7.66 (s, 1H), 7.42 (s, 1H), 7.31 (s, 1H), 6.40 (d, J=8.0 Hz, 2H), 6.15 (d, J=8.0 Hz, 2H), 2.97 (d, J=4.0 Hz, 2H), 1.02 - 0.74 (m, 6H), 0.49 - 0.28 (m, 3H), 0.26 - 0.12 (m, 2H). LCMS: Rt = 0.94 min, m / z = 395.1 (M+H).

[0363] [Example 59] 5-(4-((4-methoxybenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (59)

[0364] [ka] 5-(4-((4-Methoxybenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (59) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 1-(bromomethyl)-4-methoxybenzene. 1 H NMR (400MHz, DMSO) δ = 8.66 - 8.49 (m, 1H), 8.26 (s, 1H), 8.14 (s, 1H), 7.42 (d, J=8.0 Hz, 2H), 7.27 (d, J=8.0 Hz, 2H), 7.09 (d, J=8.0 Hz, 2H), 6.97 (d, J=8.0 Hz, 2H), 5.07 (s, 2H), 3.77 (s, 3H). LCMS: Rt = 0.82 min, m / z = 419.3 (M+H).

[0365] [Example 60] 5-(4-((4-(dimethylcarbamoyl)benzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (60)

[0366] [ka] 5-(4-((4-(dimethylcarbamoyl)benzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (60) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 4-(bromomethyl)-N,N-dimethylbenzamide. 1 H NMR (400MHz, DMSO) δ = 8.58 - 8.40 (m, 1H), 8.29 (s, 1H), 8.24 - 8.16 (m, 1H), 7.54 (d, J=8.0 Hz, 2H), 7.49 - 7.41 (m, 2H), 7.30 (d, LCMS: Rt = 0.76 min, m / z = 460.1 (M+H).

[0367] [Example 61] 5-(4-((3-methoxybenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (61)

[0368] [ka] 5-(4-((3-Methoxybenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (61) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 1-(bromomethyl)-3-methoxybenzene. 1 H NMR (400MHz, DMSO) δ = 8.52 - 8.35 (m, 1H), 8.24 (s, 1H), 8.17 - 8.04 (m, 1H), 7.67 - 7.48 (m, 1H), 7.40 - 7.23 (m, 2H), 7.18 - 7.01 (m, 4H), 6.98 - 6.85 (m, 1H), 5.13 (s, 2H), 3.77 (s, 3H). LCMS: Rt = 0.89 min, m / z = 419.3 (M+H).

[0369] [Example 62] 5-(4-((3-(methylcarbamoyl)benzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (62)

[0370] [ka] 5-(4-((3-(methylcarbamoyl)benzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (62) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 3-(bromomethyl)-N-methylbenzamide. 1H NMR (400MHz, DMSO) δ = 8.60 - 8.45 (m, 1H), 8.29 (s, 1H), 8.23 ​​- 8.15 (m, 1H), 7.96 (s, 1H), 7.89 - 7.77 (m, 1H), 7.69 - 7.59 (m, 1H), 7.50 (s, 1H), 7.30 (d, J=8.0 Hz, 2H), 7.12 (d, J=8.0 Hz, 2H), 5.22 (s, 2H), 2.79 (d, J=4.0 Hz, 3H). LCMS: Rt = 0.17 min, m / z = 446.1 (M+H).

[0371] [Example 63] 2-Oxo-5-(4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (63)

[0372] [ka] 2-Oxo-5-(4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (63) was synthesized using a procedure similar to that used to synthesize 5-(4-((1-acetylpiperidin-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (55), except that 1-(4-(hydroxymethyl)piperidin-1-yl)ethan-1-one was replaced with tetrahydro-2H-pyran-4-ol. 1 H NMR (400MHz, DMSO) δ = 8.79 (s, 1H), 8.23 ​​(s, 1H), 8.07 (s, 1H), 7.26 (d, J=8.8 Hz, 2H), 7.07 (d, J=8.4 Hz, 2H), 4.65-4.60 (m, 1H), 3.89-3.85 (m, 2H), 3.53 - 3.47 (m, 2H), 2.01-1.64 (m, 2H), 1.62-1.58 (m, 2H). LCMS: Rt = 0.78 min, m / z = 383.0 (M+H).

[0373] [Example 64] 5-(4-((3-(methylsulfonamido)benzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (64)

[0374] [ka] 5-(4-((3-(methylsulfonamido)benzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (64) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with N-(3-(bromomethyl)phenyl)methanesulfonamide.1 H NMR (400MHz, DMSO) δ = 9.83 (s, 1H), 8.47 (br, s, 1H), 8.27 (s, 1H), 8.18 (br, s, 1H), 7.36 (m, 1H), 7.31 (m, 1H), 7.21(m, 2H), 7.20(m, 2H), 7.10(m, 2H), 5.14(s, 2H), 2.99(s, 3H). LCMS: Rt = 0.72 min, m / z = 482.0 (M+H).

[0375] [Example 65] 5-(4-((3-carbamoylbenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (65)

[0376] [ka] 5-(4-((3-carbamoylbenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (65) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 3-(bromomethyl)benzamide. 1 H NMR (400MHz, DMSO) δ = 8.00 (s, 3H), 7.85 (d, J=8.0 Hz, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.55 - 7.45 (m, 1H), 7.41 (s, 1H), 7.20 (d, J=8.0 Hz, 2H), 7.06 (d, J=8.0 Hz, 2H), 5.18 (s, 2H). LCMS: Rt = 0.78 min, m / z = 432.1 (M+H).

[0377] [Example 66] 2-Oxo-5-(4-((3-(propylamino)benzyl)oxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (66)

[0378] [ka] 2-Oxo-5-(4-((3-(propylamino)benzyl)oxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (66) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 3-(bromomethyl)-N-propylaniline. 1 H NMR (400MHz, DMSO) δ = 8.46 (br s, 1H), 8.28 (s, 1H), 8.20 (br s, 1H), 7.27 (d, J=8.0 Hz, 2H), 7.17 (t, J=7.7 Hz, 1H), 7.08 (d, J=8.0 Hz,, 2H), 6.81 (br s, 1H), 6.76 - 6.66 (m, 2H), 3.02 (t, J=7.2 Hz, 2H), 1.58 - 1.53 (m, 2H), 0.94 (t, J=7.4 Hz, 3H). LCMS: Rt = 0.74 min, m / z = 446.3 (M+H).

[0379] [Example 67] 5-(4-((3-(dimethylcarbamoyl)benzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (67)

[0380] [ka] 5-(4-((3-(dimethylcarbamoyl)benzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (67) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 3-(bromomethyl)-N,N-dimethylbenzamide. 1 H NMR (400MHz, DMSO) δ = 7.54 (s, 1H), 7.51 - 7.45 (m, 3H), 7.40 - 7.34 (m, 1H), 7.17 (d, J=8.0 Hz, 2H), 7.04 (d, J=8.0 Hz, 2H), 5.27 - 5.14 (m, 2H), 3.04 - 2.97 (m, 3H), 2.89 (s, 3H). LCMS: Rt = 0.84 min, m / z = 460.0 (M+H).

[0381] [Example 68] 5-(4-((3-acetamidobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (68)

[0382] [ka] 5-(4-((3-acetamidobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (68) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with N-(3-(bromomethyl)phenyl)acetamide. 1H NMR (400MHz, DMSO) δ = 10.01 (s, 1H), 8.48 (br s, 1H), 8.29 (s, 1H), 8.21 (br s, 1H), 7.71 (s, 1H), 7.55 (m, 1H), 7.35 - 7.32 (m, 1H), 7.29 (d, J=8.8 Hz, 2H), 7.14 (m, 1H), 7.10 (d, J=8.8 Hz, 2H), 5.13 (s, 2H), 2.05 (s, 3H). LCMS: Rt = 0.75 min, m / z = 446.3 (M+H).

[0383] [Example 69] 5-(4-((4-(methylcarbamoyl)benzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (69)

[0384] [ka] 5-(4-((4-(methylcarbamoyl)benzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (69) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 4-(bromomethyl)-N-methylbenzamide. 1 H NMR (400MHz, DMSO) δ = 8.57 - 8.42 (m, 1H), 8.32 - 8.24 (m, 1H), 8.21 - 8.12 (m, 1H), 7.87 (d, J=8.2 Hz, 2H), 7.56 (d, J=8.2 Hz, 2H), 7.29 (d, J=8.6 Hz, 2H), 7.11 (d, J=8.6 Hz, 2H), 5.23 (s, 2H), 2.79 (m, 3H). LCMS: Rt = 0.67 min, m / z = 446.1 (M+H).

[0385] [Example 70] 2-Oxo-5-(4-(pyridin-4-ylmethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (70)

[0386] [ka] 2-Oxo-5-(4-(pyridin-4-ylmethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (70) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 4-(bromomethyl)pyridine. 1 H NMR (400MHz, MeOD) δ = 8.57 (d, J=6.0 Hz, 2H), 8.13 (s, 1H), 7.59 (d, J=8.8Hz, 2H), 7.25 (d, J=8.8 Hz, 2H), 7.07 (d, J=8.8 Hz, 2H), 5.25 (s, 2H). LCMS: Rt = 0.77 min, m / z = 390.0 (M+H).

[0387] [Example 71] 5-(4-(benzo[c][1,2,5]oxadiazol-5-ylmethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (71)

[0388] [ka] 5-(4-(benzo[c][1,2,5]oxadiazol-5-ylmethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (71) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 5-(bromomethyl)benzo[c][1,2,5]oxadiazole. 1 H NMR (400MHz, DMSO) δ = 13.93 - 13.31 (m, 1H), 8.48 (s, 1H), 8.29 (s, 1H), 8.18 (s, 1H), 8.15 - 8.08 (m, 2H), 7.69 (d, J=9.5 Hz, 1H), 7.33 (d, J=8.4 Hz, 2H), 7.19 (d, J=8.4 Hz, 2H), 5.34 (s, 2H). LCMS: Rt = 0.83 min, m / z = 431.0 (M+H).

[0389] [Example 72] 2-Oxo-5-(4-(pyridin-3-ylmethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (72)

[0390] [ka] 2-Oxo-5-(4-(pyridin-3-ylmethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (72) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 3-(bromomethyl)pyridine. 1H NMR (400MHz, MeOD) δ= 8.71 (s, 1H), 8.57 (d, J=4.0 Hz, 1H), 8.08 (s., 1H), 7.92 (d, J=8.0 Hz, 1H), 7.51 - 7.39 (m, 1H), 7.24 (d, J=8.0 Hz, 2H), 7.10 (s., 2H), 5.20 (s, 2H). LCMS: Rt = 0.77 min, m / z = 390.0 (M+H).

[0391] [Example 73] 2-Oxo-5-(4-(pyridin-2-ylmethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (73)

[0392] [ka] 2-Oxo-5-(4-(pyridin-2-ylmethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (73) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 2-(bromomethyl)pyridine. 1 H NMR (400MHz, DMSO) δ= 8.65 - 8.55 (m, 1H), 8.04 (s, 1H), 7.90 - 7.82 (m, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.37 (m, 1H), 7.22 (d, J=8.0 Hz, 2H), 7.07 (d, J=8.0 Hz, 2H), 5.22 (s, 2H). LCMS: Rt = 0.84 min, m / z = 390.0 (M+H).

[0393] [Example 74] 5-(4-(benzo[c][1,2,5]oxadiazol-4-ylmethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (74)

[0394] [ka] 5-(4-(benzo[c][1,2,5]oxadiazol-4-ylmethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (74) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 4-(bromomethyl)benzo[c][1,2,5]oxadiazole. 1 H NMR (400MHz, DMSO) δ= 13.76 - 13.59 (m, 1H), 8.58 - 8.43 (m, 1H), 8.30 (s, 1H), 8.19 (s, 1H), 8.06 (d, J=8.0 Hz, 1H), 7.76 - 7.71 (m, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.32 (d, J=8.0 Hz, 2H), 7.19 (d, J=8.0 Hz, 2H), 5.70 - 5.48 (m, 2H). LCMS: Rt = 0.85 min, m / z = 431.1 (M+H).

[0395] [Example 75] 5-(4-((3-(methylsulfonyl)benzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (75)

[0396] [ka] 5-(4-((3-(methylsulfonyl)benzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (75) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 1-(bromomethyl)-3-(methylsulfonyl)benzene. 1 H NMR (400MHz, DMSO) δ= 13.66 (s, 1H), 8.48 (s, 1H), 8.30 (s, 1H), 8.20 (s, 1H), 8.06 (s, 1H), 7.94 (s, 1H), 7.85 (s, 1H), 7.74(s, 1H), 7.32 (d, J=8.0Hz, 2H), 7.15 (d, J=8.0Hz, 2H), 5.30 (s, 2H), 3.26 (s, 3H). LCMS: Rt = 0.76 min, m / z = 467.2 (M+H).

[0397] [Example 76] 5-(4-((2-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (76)

[0398] [ka] 5-(4-((2-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (76) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 1-(bromomethyl)-2-nitrobenzene. 1H NMR (400MHz, DMSO) δ= 10.37( brs, 1H), 8.15 (d, J=8.2 Hz, 1H), 7.90 (br. s., 1H), 7.85 - 7.82 (m, 2H), 7.66 - 7.62 (m, 1H), 7.18 (d, J=8.0 Hz, 2H), 7.03 (d, J=8.3 Hz, 2H), 5.49 (s, 2H). LCMS: Rt = 0.85 min, m / z = 434.2 (M+H).

[0399] [Example 77] 5-(4-((4-cyanobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (77)

[0400] [ka] 5-(4-((4-cyanobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (77) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 4-(bromomethyl)benzonitrile. 1 H NMR (400MHz, DMSO) δ= 13.65 (br,s, 1H), 8.49 (s., 1H), 8.27 (s, 1H), 8.19 (s, 1H), 7.91 (d, J=8.0 Hz, 2H), 7.69 (d, J=8.0 Hz, 2H), 7.31 (d, J=8.0 Hz, 2H), 7.12 (d, J=8.0 Hz, 2H), 5.29 (s, 2H). LCMS: Rt = 1.02 min, m / z = 414.0 (M+H).

[0401] [Example 78] 5-(4-((3-cyanobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (78)

[0402] [ka] 5-(4-((3-cyanobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (78) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 3-(bromomethyl)benzonitrile. 1 H NMR (400MHz, DMSO) δ= 13.78 - 13.42 (m, 1H), 8.49 ( s., 1H), 8.29 (s, 1H), 8.20 (s., 1H), 7.96 (s, 1H), 7.84 (d, J=8.0 Hz, 2H), 7.71 - 7.54 (m, 1H), 7.30 (d, J=8.0 Hz, 2H), 7.13 (d, J=8.0 Hz, 2H), 5.23 (s, 2H). LCMS: Rt = 0.82 min, m / z = 414.1 (M+H).

[0403] [Example 79] 2-Oxo-6-(trifluoromethyl)-5-(4-((3-(trifluoromethyl)benzyl)oxy)phenyl)-1,2-dihydropyridine-3-carboxamide (79)

[0404] [ka] 2-Oxo-6-(trifluoromethyl)-5-(4-((3-(trifluoromethyl)benzyl)oxy)phenyl)-1,2-dihydropyridine-3-carboxamide (79) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 1-(bromomethyl)-3-(trifluoromethyl)benzene. 1 H NMR (400MHz, DMSO) δ= 13.66 (br,s, 1H), 8.48 (s, 1H), 8.28 (s, 1H), 8.21 (s, 1H), 7.85 (s, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.72 (m, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.31 (d, J=8.0 Hz, 2H), 7.13 (d, J=8.0 Hz, 2H), 5.28 (s, 2H). LCMS: Rt = 0.91 min, m / z = 457.1 (M+H).

[0405] [Example 80] (R or S)-2-oxo-5-(4-(1-(pyridin-3-yl)ethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; (SFC peak 1, chiral) (80)

[0406] [ka] (R or S)-2-oxo-5-(4-(1-(pyridin-3-yl)ethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (SFC peak 1, chiral) (80) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 3-(1-bromoethyl)pyridine. The racemic mixture was separated by chiral SFC followed by elution on a Chiralcel-OD-H 20 × 250 mm semi-preparative column using a mobile phase of methanol (5–40%) + DEA (0.05%) in CO2 and a flow rate of 60–100 mL / min ("Chiral HPLC" conditions herein). 1 H NMR (400MHz, DMSO) δ= 14.09 - 13.22 (m, 1H), 8.92 - 8.63 (m, 2H), 8.50 (d, J=4.8 Hz, 1H), 8.19 (s, 1H), 8.04 (s, 1H), 7.85 (d, J=7.9 Hz, 1H), 7.40 (d J=7.8 Hz, 1H), 7.20 (d, J=8.5 Hz, 2H), 7.01 (d, J=8.7 Hz, 2H), 5.68 (m, 1H), 1.61 (d, J=6.4 Hz, 3H). LCMS: Rt = 0.89 min, m / z = 404.1 (M+H). SFC: Rt = 2.33 min, ee 92%.

[0407] [Example 81] (R or S)-2-oxo-5-(4-(1-(pyridin-3-yl)ethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; (SFC peak 2, chiral) (81)

[0408] [ka] (R or S)-2-oxo-5-(4-(1-(pyridin-3-yl)ethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (SFC peak 1, chiral) (81) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 3-(1-bromoethyl)pyridine. 1 H NMR (400MHz, DMSO) δ= 9.08 - 8.79 (m, 1H), 8.68 (d, J=1.9 Hz, 1H), 8.50 (d, J=4.8 Hz, 1H), 8.15 (s, 1H), 7.95 (s, 1H), 7.85 (d, J=7.9 Hz, 1H), 7.40 (d J=8.1 Hz, 1H), 7.18 (d, J=8.7 Hz, 2H), 7.00 (d, J=8.8 Hz, 2H), 5.67 (m, 1H), 1.61 (d, J=6.4 Hz, 3H). LCMS: Rt = 0.89 min, m / z = 404.1 (M+H). SFC: Rt = 2.48 min, ee 82%.

[0409] [Example 82] 2-Oxo-5-(4-(pyrimidin-5-ylmethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (82)

[0410] [ka] 2-Oxo-5-(4-(pyrimidin-5-ylmethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (82) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 5-(bromomethyl)pyrimidine. 1 H NMR (400MHz, DMSO) δ= 10.84 - 10.38 (m, 1H), 9.20 (s, 1H), 8.96 (s, 2H), 7.84 (s, 1H), 7.23 - 7.10 (m, 4H), 7.05 (d, J=8.7 Hz, 2H), 5.21 (s, 2H). LCMS: Rt = 0.57 min, m / z = 413.1 (M+H).

[0411] [Example 83] 5-(4-((1-methylpiperidin-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (83)

[0412] [ka] 5-(4-((1-methylpiperidin-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (83) was synthesized using a procedure similar to that used to synthesize 5-(4-((1-acetylpiperidin-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (55), except that 1-(4-(hydroxymethyl)piperidin-1-yl)ethan-1-one was replaced with (1-methylpiperidin-4-yl)methanol. 1H NMR (400MHz, DMSO) δ= 10.60 (d, J=5.1 Hz, 1H), 7.83 (s, 1H), 7.16 - 7.07 (m, 3H), 6.91 (d, J=8.7 Hz, 2H), 3.85 (d, J=5.8 Hz, 2H), 3.02 - 2.91 (m, 2H), 2.32 (s, 3H), 2.17 (s, 2H), 1.89 - 1.72 (m, 3H), 1.40 (d, J=10.8 Hz, 2H). LCMS: Rt = 0.87 min, m / z = 410.2 (M+H).

[0413] [Example 84] 2-Oxo-5-(4-(pyridazin-4-ylmethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (84)

[0414] [ka] 2-Oxo-5-(4-(pyridazin-4-ylmethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (84) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 4-(bromomethyl)pyridazine. 1 H NMR (400MHz, DMSO) δ= 9.34 (s, 1H), 9.26 (d, J=4.0 Hz, 1H), 8.20 (s, 1H), 8.08 (br. s., 1H), 7.77 (s, 1H), 7.71 (br. s., 1H), 7.26 (d, J=8.0 Hz, 2H), 7.11 (d, J=8.0 Hz, 2H), 5.30 (s, 2H). LCMS: Rt = 0.65 min, m / z = 391.2 (M+H).

[0415] [Example 85] 5-(4-((1H-indazol-6-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (85)

[0416] [ka] 5-(4-((1H-indazol-6-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (85) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 6-(bromomethyl)-1H-indazole. 1 H NMR (400MHz, DMSO) δ= 8.50 (br. s., 1H), 8.28 (s, 1H), 8.08 (s, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.65 (s, 1H), 7.29 (d, J=8.0 Hz, 2H), 7.22 (d, J=8.0 Hz, 1H), 7.14 (d, J=8.0 Hz, 2H), 5.31 (s, 2H). LCMS: Rt = 0.76 min, m / z = 429.2 (M+H).

[0417] [Example 86] 5-(4-((1H-indol-6-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (86)

[0418] [ka] 5-(4-((1H-indol-6-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (86) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 6-(bromomethyl)-1H-indole. 1 H NMR (400MHz, DMSO) δ= 11.14 (s, 1H), 8.49 (br,s, 1H), 8.27 (s, 1H), 8.17 (br,s, 1H), 7.56 (m, 1H), 7.54 (m, 1H), 7.36 (m, 1H), 7.28 (m, 2H), 7.12 (m, 2H), 6.43 (br. s., 1H), 5.24 (s, 2H). LCMS: Rt = 0.82 min, m / z = 428.3 (M+H).

[0419] [Example 87] 2-Oxo-6-(trifluoromethyl)-5-(4-((4-(trifluoromethyl)benzyl)oxy)phenyl)-1,2-dihydropyridine-3-carboxamide (87)

[0420] [ka] 2-Oxo-6-(trifluoromethyl)-5-(4-((4-(trifluoromethyl)benzyl)oxy)phenyl)-1,2-dihydropyridine-3-carboxamide (87) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 1-(bromomethyl)-4-(trifluoromethyl)benzene. 1H NMR (400MHz, DMSO) δ= 13.65 (br,s, 1H), 8.46 (br,s, 1H), 8.27 (s, 1H), 8.17 (s, 1H), 7.96 (m, 2H), 7.71 (m, 2H), 7.30 (d, J=8.0 Hz, 2H), 7.12 (d, J=8.0 Hz, 2H), 5.28 (s, 2H). LCMS: Rt = 0.91 min, m / z = 457.1 (M+H).

[0421] [Example 88] 2-Oxo-5-(4-((5-oxopyrrolidin-3-yl)methoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (88)

[0422] [ka] 2-Oxo-5-(4-((5-oxopyrrolidin-3-yl)methoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (88) was synthesized using a procedure similar to that used to synthesize 5-(4-((1-acetylpiperidin-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (55), except that 1-(4-(hydroxymethyl)piperidin-1-yl)ethan-1-one was replaced with 4-(hydroxymethyl)pyrrolidin-2-one. 1H NMR (400MHz, DMSO) δ= 13.80 - 13.42 (m, 1H), 8.47 (s, 1H), 8.28 (s, 1H), 8.17 (s, 1H), 7.59 (s, 1H), 7.28 (d, J=8.4 Hz, 2H), 7.04 (d, J=8.8 Hz, 2H), 4.06 - 3.97 (m, 2H), 3.48 - 3.40 (m, 1H), 3.13 (d, J=9.6 Hz, 1H), 2.86 (s, 1H), 2.38 - 2.32 (m, 1H), 2.06 (d, J=16.8 Hz, 1H). LCMS: Rt = 0.65 min, m / z = 379.1 (M+H).

[0423] [Example 89] 5-(4-((2-cyanobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (89)

[0424] [ka] 5-(4-((2-cyanobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (89) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 2-(bromomethyl)benzonitrile. 1H NMR (400MHz, DMSO) δ= 13.67 (br,s, 1H), 8.53 (br,s, 1H), 8.28 (s., 1H), 8.20 (m, 1H), 7.95 (d, J=8.0 Hz, 1H), 7.77 (s., 2H), 7.60 (s., 1H), 7.32 (d, J=8.0 Hz, 2H), 7.16 (d, J=8.0 Hz, 2H), 5.31 (s., 2H). LCMS: Rt = 0.81 min, m / z = 414.0 (M+H).

[0425] [Example 90] 2-Oxo-5-(4-(tetrazolo[1,5-a]pyridin-7-ylmethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (90)

[0426] [ka] 2-Oxo-5-(4-(tetrazolo[1,5-a]pyridin-7-ylmethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (90) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 7-(bromomethyl)tetrazolo[1,5-a]pyridine. 1 H NMR (400MHz, DMSO) δ= 13.86 - 13.59 (m, 1H), 14.05 - 13.38 (m, 1H), 9.36 (d, J=7.2 Hz, 1H), 8.48 (s, 1H), 8.29 (s, 2H), 8.19 (s, 1H), 7.53 (d, J=7.0 Hz, 1H), 7.33 (d, J=8.6 Hz, 2H), 7.19 (d, J=8.8 Hz, 2H), 5.42 (s, 2H). LCMS: Rt = 0.68 min, m / z = 431.0 (M+H).

[0427] [Example 91] 5-(4-(imidazo[1,2-a]pyridin-7-ylmethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (91)

[0428] [ka] 5-(4-(imidazo[1,2-a]pyridin-7-ylmethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (91) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 7-(bromomethyl)imidazo[1,2-a]pyridine. 1 H NMR (400MHz, DMSO) δ= 8.57 (d, J=4.0 Hz, 1H), 8.29 (br. s., 2H), 7.96 (s, 1H), 7.89 (br. s., 1H), 7.66 (br. s., 1H), 7.58 (s, 1H), 7.18 (d, J=8.0 Hz, 2H), 7.06 (d, J=8.0 Hz, 2H), 7.00 - 6.98 (m, 1H), 5.19 (s, 2H). LCMS: Rt = 0.61 min, m / z = 429.3 (M+H).

[0429] [Example 92] 5-(4-((1-methylpiperidin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (92)

[0430] [ka] 5-(4-((1-methylpiperidin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (92) was synthesized using a procedure similar to that used to synthesize 5-(4-((1-acetylpiperidin-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (55), except that 1-(4-(hydroxymethyl)piperidin-1-yl)ethan-1-one was replaced with 3-(bromomethyl)-1-methylpiperidine. 1 H NMR (400MHz, DMSO) δ= 10.77 (s, 1H), 7.81 (s, 1H), 7.11 (d, J=7.2 Hz, 2H), 7.04 (s, 1H), 6.91 (d, J=7.2 Hz, 2H), 3.85 (d, J=8.0 Hz, 2H), 2.84 (d, J=8.2 Hz, 1H), 2.64 (s, 1H), 2.18 (s, 3H), 2.06 - 1.87 (m, 2H), 1.85 - 1.70 (m, 2H), 1.64 (s, 1H), 1.51 (d, J=10.2 Hz, 1H), 1.08 (d, J=8.6 Hz, 1H). LCMS: Rt = 0.86 min, m / z = 410.0 (M+H).

[0431] [Example 93] 5-(4-((4-fluoro-3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (93)

[0432] [ka] 5-(4-((4-Fluoro-3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (93) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 4-(bromomethyl)-1-fluoro-2-nitrobenzene. 1 H NMR (400MHz, DMSO) δ= 13.80 - 13.54 (m, 1H), 8.47 (s, 1H), 8.33 - 8.27 (m, 2H), 8.20 (s, 1H), 7.95 (d, J=8.6 Hz, 1H), 7.67 (d, J=11.4 Hz, 1H), 7.31 (d, J=8.6 Hz, 2H), 7.14 (d, J=8.8 Hz, 2H), 5.27 (s, 2H). LCMS: Rt = 0.91 min, m / z = 452.0 (M+H).

[0433] [Example 94] 6-((4-(5-carbamoyl-6-oxo-2-(trifluoromethyl)-1,6-dihydropyridin-3-yl)phenoxy)methyl)benzo[c][1,2,5]oxadiazole 1-oxide (94)

[0434] [ka] To a solution of 5-(4-((4-fluoro-3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (93) (100 mg, 0.22 mmol) was added sodium azide (43 mg, 0.66 mmol) in NMP (2.2 mL), and the mixture was stirred at 60 °C for 18 h. The reaction mixture was poured into water (10 mL), extracted with EA (3 mL × 5), dried over Na SO , filtered, and concentrated. The crude product was purified by preparative HPLC under acidic conditions (MeCN / water with TFA) to give 6-((4-(5-carbamoyl-6-oxo-2-(trifluoromethyl)-1,6-dihydropyridin-3-yl)phenoxy)methyl)benzo[c][1,2,5]oxadiazole 1-oxide. 1 H NMR (400MHz, DMSO) δ= 13.70 (br s, 1H), 8.47 (s, 1H), 8.29 (s, 1H), 8.20 (s, 1H), 7.95 - 7.45 (m, 3H), 7.32 (d, J=8.4 Hz, 2H), 7.16 (d, J=8.4 Hz, 2H), 5.24 (s, 2H). LCMS: Rt = 0.80 min, m / z = 447.1 (M+H).

[0435] [Example 95] (R or S)-2-oxo-5-(4-(1-(pyrimidin-5-yl)ethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; (SFC peak 1, chiral) (95)

[0436] [ka] (R or S)-2-oxo-5-(4-(1-(pyrimidin-5-yl)ethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (SFC peak 1, chiral) (95) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 5-(1-bromoethyl)pyrimidine. 1 H NMR (400MHz, DMSO) δ= 10.93 - 10.62 (m, 1H), 9.13 (s, 1H), 8.91 (s, 2H), 7.84 - 7.70 (m, 1H), 7.09 (d, J=8.0 Hz, 2H), 6.96 (d, J=8.2 Hz, 2H), 5.74 - 5.63 (m, 1H), 1.64 (m, 3H). LCMS: Rt = 0.66 min, m / z = 405.1 (M+H). SFC: Rt = 2.21 min, ee 91%.

[0437] [Example 96] (R or S)-2-oxo-5-(4-(1-(pyrimidin-5-yl)ethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; (SFC peak 2, chiral) (96)

[0438] [ka] (R or S)-2-oxo-5-(4-(1-(pyrimidin-5-yl)ethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (SFC peak 2, chiral) (96) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 5-(1-bromoethyl)pyrimidine. 1 H NMR (400MHz, DMSO) δ= 9.19 (s, 1H), 8.97 (s, 2H), 8.58 - 8.50 (m, 1H), 8.32 (s, 1H), 8.28 - 8.22 (m, 1H), 7.47 - 7.36 (m, 1H), 7.30 (d, J=8.8 Hz, 2H), 7.14 - 7.11 (m, 2H), 5.84 - 5.77 (m, 1H), 1.72 (m, 3H). LCMS: Rt = 0.66 min, m / z = 405.1 (M+H). SFC: Rt = 2.33 min, ee 89%.

[0439] [Example 97] (R or S)-5-(4-(1-(3-cyanophenyl)ethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; (SFC peak 1, chiral) (97)

[0440] [ka] (R or S)-5-(4-(1-(3-cyanophenyl)ethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (SFC peak 1, chiral) (97) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 3-(1-bromoethyl)benzonitrile. 1 H NMR (400MHz, DMSO) δ= 13.81 - 13.59 (m, 1H), 8.90 - 8.55 (m, 1H), 8.20 (s, 1H), 8.12 - 8.05 (m, 1H), 7.93 (s, 1H), 7.83 - 7.73 (m, 2H), 7.64 - 7.56 (m, 1H), 7.20 (d, J=8.0 Hz, 2H), 7.00 (d, J=8.0 Hz, 2H), 5.66 (d, J=4.0 Hz, 1H), 1.60 (s, 3H). LCMS: Rt = 1.00 min, m / z = 428.0 (M+H). SFC: Rt = 2.78 minutes, ee 92%.

[0441] [Example 98] (R or S)-5-(4-(1-(3-cyanophenyl)ethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; (SFC peak 2, chiral) (98)

[0442] [ka] (R or S)-5-(4-(1-(3-cyanophenyl)ethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (SFC peak 2, chiral) (98) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 3-(1-bromoethyl)benzonitrile. 1 H NMR (400MHz, DMSO) δ= 7.98 - 7.94 (m, 1H), 7.93 (s, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.78 - 7.74 (m, 1H), 7.62 - 7.56 (m, 1H), 7.16 - 7.09 (m, 2H), 6.98 - 6.91 (m, 2H), 5.79 - 5.54 (m, 1H), 1.58 (d, J=4.0 Hz, 3H). LCMS: Rt = 1.00 min, m / z = 428.0 (M+H). SFC: Rt = 2.98 min, ee 97%.

[0443] [Example 99] 5-(4-((5-cyanopyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (99)

[0444] [ka] 5-(4-((5-cyanopyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (99) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 5-(bromomethyl)nicotinonitrile. 1 H NMR (400MHz, DMSO) δ= 8.95 (d, J=2.0 Hz, 1H), 8.91 (d, J=1.6 Hz, 1H), 8.39 (s, 1H), 8.35 (s, 1H), 8.27 (s, 1H), 7.31(d, J=8.8 Hz, 2H), 7.14 (d, J=8.4 Hz, 2H), 5.29 (s, 2H). LCMS: Rt = 0.74 min, m / z = 415.1 (M+H).

[0445] [Example 100] (R or S)-5-(4-(1-(benzo[c][1,2,5]oxadiazol-5-yl)ethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; (SFC peak 1, chiral) (100)

[0446] [ka] (R or S)-5-(4-(1-(benzo[c][1,2,5]oxadiazol-5-yl)ethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (SFC peak 1, chiral) (100) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 5-(1-bromoethyl)benzo[c][1,2,5]oxadiazole. 1 H NMR (400MHz, MeOD) δ= 8.40 (s, 1H), 8.22 (s, 1H), 8.00 - 7.88 (m, 2H), 7.66 (d, J=10.2 Hz, 1H), 7.22 (d, J=8.6 Hz, 2H), 7.05 (d, LCMS: Rt = 0.85 min, m / z = 445.1 (M+H). SFC: Rt = 2.15 min, ee 80%,.

[0447] [Example 101] (R or S)-5-(4-(1-(benzo[c][1,2,5]oxadiazol-5-yl)ethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; (SFC peak 2, chiral) (101)

[0448] [ka] (R or S)-5-(4-(1-(benzo[c][1,2,5]oxadiazol-5-yl)ethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (SFC peak 2, chiral) (101) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 5-(1-bromoethyl)benzo[c][1,2,5]oxadiazole. 1 H NMR (400MHz, MeOD) δ= 8.22 (s, 1H), 7.95 (s, 1H), 7.93-7.92 (m, 2H), 7.67 - 7.64 (m, 1H), 7.22 (d, J=8.4 Hz, 2H), 7.05 (d, J=8.4 Hz, 2H), 5.65 (d, J=6.0 Hz, 1H), 1.72 (d, J=6.4 Hz, 3H). LCMS: Rt = 0.85 min, m / z = 445.1 (M+H). SFC: Rt = 2.32 min, ee 91%.

[0449] [Example 102] 2-Oxo-5-(4-((tetrahydro-2H-pyran-3-yl)methoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (102)

[0450] [ka] 2-Oxo-5-(4-((tetrahydro-2H-pyran-3-yl)methoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (102) was synthesized using a procedure similar to that used to synthesize 5-(4-((1-acetylpiperidin-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (55), except that 1-(4-(hydroxymethyl)piperidin-1-yl)ethan-1-one was replaced with (tetrahydro-2H-pyran-3-yl)methanol. 1 H NMR (500MHz, DMSO) δ= 8.45 (br s, 1H), 8.22 (s, 1H), 8.05 (br s, 1H), 7.25 (d, J = 8.5 Hz, 2H), 7.01 (d, J = 8.6 Hz, 2H), 3.90 (t, J = 5.8 Hz, 3H), 3.76 (d, J = 11.2 Hz, 1H), 2.02 (s, 1H), 1.87 (d, J = 12.9 Hz, 1H), 1.69 - 1.46 (m, 2H), 1.42 (dd, J = 16.7, 6.6 Hz, 2H). LCMS: Rt = 0.72 min, m / z = 397.2 (M+H).

[0451] [Example 103] 5-(4-([1,2,4]triazolo[4,3-a]pyrimidin-6-ylmethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (103)

[0452] [ka] 5-(4-([1,2,4]triazolo[4,3-a]pyrimidin-6-ylmethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (103) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 6-(bromomethyl)-[1,2,4]triazolo[4,3-a]pyrimidine. 1 H NMR (500MHz, DMSO) δ= 9.61 (s, 1H), 9.08 (s, 1H), 8.72 (s, 1H), 8.33 (s, 2H), 7.86 (s, 1H), 7.30 (s, 1H), 7.19 (d, J=8.0 Hz, 2H), 7.10 (d, J=8.0 Hz, 2H), 5.29 (s, 2H). LCMS: Rt = 0.70 min, m / z = 431.2 (M+H).

[0453] [Example 104] 5-(4-((5-chloro-2-fluoropyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (104)

[0454] [ka] 5-(4-((5-chloro-2-fluoropyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (104) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 3-(bromomethyl)-5-chloro-2-fluoropyridine. LCMS: Rt=3.23 min, m / z=442.0 (M+H).

[0455] [Example 105] 5-(4-((5-chloropyridin-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (105)

[0456] [ka] 5-(4-((5-chloropyridin-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (105) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 2-(bromomethyl)-5-chloropyridine. LCMS: Rt=3.10 min, m / z=424.0 (M+H).

[0457] [Example 106] 5-(4-((2-methoxypyridin-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (106)

[0458] [ka] 5-(4-((2-Methoxypyridin-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (106) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 4-(bromomethyl)-2-methoxypyridine. LCMS: Rt=2.90 min, m / z=420.0 (M+H).

[0459] [Example 107] 5-(4-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (107)

[0460] [ka] 5-(4-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (107) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 4-(bromomethyl)-3,5-dimethylisoxazole. LCMS: Rt=2.90 min, m / z=408.0 (M+H).

[0461] [Example 108] 5-(4-((2-chloro-5-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (108)

[0462] [ka] 5-(4-((2-chloro-5-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (108) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 2-(bromomethyl)-1-chloro-4-nitrobenzene. LCMS: Rt=3.35 min, m / z=468.0 (M+H).

[0463] [Example 109] 5-(4-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (109)

[0464] [ka]

[0089] 5-(4-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (109) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 4-(bromomethyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole. LCMS: Rt = 3.07 min, m / z = 461.1 (M+H).

[0465] [Example 110] 2-Oxo-5-(4-(thiophen-3-ylmethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (110)

[0466] [ka] 2-Oxo-5-(4-(thiophen-3-ylmethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (110) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 3-(bromomethyl)thiophene. LCMS: Rt=3.18 min, m / z=295.0 (M+H).

[0467] [Example 111] 2-Oxo-6-(trifluoromethyl)-5-(4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)-1,2-dihydropyridine-3-carboxamide (111)

[0468] [ka]

[0089] 2-oxo-6-(trifluoromethyl)-5-(4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)-1,2-dihydropyridine-3-carboxamide (111) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 5-(bromomethyl)-2-(trifluoromethyl)pyridine. LCMS: Rt = 3.21 min, m / z = 458.1 (M+H).

[0469] [Example 112] 5-(4-((3,4-difluorobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (112)

[0470] [ka] 5-(4-((3,4-Difluorobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (112) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 4-(bromomethyl)-1,2-difluorobenzene. LCMS: Rt=3.34 min, m / z=425.0 (M+H).

[0471] [Example 113] 5-(4-((4-methoxy-3,5-dimethylpyridin-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (113)

[0472] [ka]

[0089] 5-(4-((4-Methoxy-3,5-dimethylpyridin-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (113) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 2-(bromomethyl)-4-methoxy-3,5-dimethylpyridine. LCMS: Rt = 2.39 min, m / z = 448.0 (M+H).

[0473] [Example 114] 5-(4-((3-fluoropyridin-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (114)

[0474] [ka] 5-(4-((3-fluoropyridin-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (114) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 2-(bromomethyl)-3-fluoropyridine. LCMS: Rt=2.82 min, m / z=408.0 (M+H).

[0475] [Example 115] 2-Oxo-5-(4-(thiophen-2-ylmethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (115)

[0476] [ka]

[0113] 2-Oxo-5-(4-(thiophen-2-ylmethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (115) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 2-(bromomethyl)thiophene. LCMS: Rt = 3.18 min, m / z = 395.0 (M+H).

[0477] [Example 116] 5-(4-((2,5-difluorobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (116)

[0478] [ka] 5-(4-((2,5-difluorobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (116) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 2-(bromomethyl)-1,4-difluorobenzene. LCMS: Rt=3.32 min, m / z=425.0 (M+H).

[0479] [Example 117] 5-(4-((4-chloropyridin-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (117)

[0480] [ka] 5-(4-((4-chloropyridin-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (117) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 2-(bromomethyl)-4-chloropyridine. LCMS: Rt=3.01 min, m / z=424.0 (M+H).

[0481] [Example 118] 5-(4-((2,4-dimethylthiazol-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (118)

[0482] [ka] 5-(4-((2,4-dimethylthiazol-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (118) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 5-(bromomethyl)-2,4-dimethylthiazole. LCMS: Rt=2.75 min, m / z=424.1 (M+H).

[0483] [Example 119] 5-(4-((2-chloropyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (119)

[0484] [ka] 5-(4-((2-chloropyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (119) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 3-(bromomethyl)-2-chloropyridine. LCMS: Rt=3.02 min, m / z=424.0 (M+H).

[0485] [Example 120] 2-Oxo-5-(4-((5-(propylamino)pyridin-3-yl)methoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (120)

[0486] [ka] 2-Oxo-5-(4-((5-(propylamino)pyridin-3-yl)methoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (120) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 5-(bromomethyl)-N-propylpyridin-3-amine. 1 H NMR (400MHz, DMSO) δ= 10.72 (s, 1H), 7.92 (d, J=2.4 Hz, 1H), 7.83 (d, J=10.8 Hz, 2H), 7.14 (d, J=8.4 Hz, 2H), 7.05 - 6.93 (m, 4H), 5.94 (s, 1H), 5.04 (s, 2H), 3.88 (s, 1H), 3.00 (q, J=6.7 Hz, 2H), 1.65 - 1.49 (m, 2H), 0.94 (m, 3H). LCMS: Rt = 0.93 min, m / z = 447.0 (M+H).

[0487] [Example 121] 2-Oxo-5-(4-(pyrimidin-2-ylmethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (121)

[0488] [ka] 2-Oxo-5-(4-(pyrimidin-2-ylmethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (121) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 2-(bromomethyl)pyrimidine. 1 H NMR (400MHz, DMSO) δ= 8.86 (d, J=5.2 Hz, 2H), 8.85 (s, 1H), 8.25 (s, 1H), 8.14 (s, 1H), 7.49 (t, J=4.8 Hz, 1H), 7.25 (d, J=8.4 Hz, 2H), 7.06 (d, J=8.4 Hz, 2H), 5.33 (s, 2H). LCMS: Rt = 0.63 min, m / z = 391.0 (M+H).

[0489] [Example 122] 5-(4-((2-morpholinopyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (122)

[0490] [ka] 5-(4-((2-morpholinopyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (122) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 4-(5-(bromomethyl)pyrimidin-2-yl)morpholine. 1H NMR (400MHz, DMSO) δ= 9.84 (m, 1H), 8.53 (s, 2H), 8.26 (s, 1H), 7.98 (s, 1H), 7.47 (br s, 1H), 7.19 (d, J=8.4 Hz, 2H), 7.04 (d, J=8.4 Hz, 2H), 4.98 (s, 2H), 3.80 (m, 4H), 3.67 (m, 4H). LCMS: Rt = 0.72 min, m / z = 476.1 (M+H).

[0491] [Example 123] 2-Oxo-5-(4-(pyrazin-2-ylmethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (123)

[0492] [ka] 2-Oxo-5-(4-(pyrazin-2-ylmethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (123) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 2-(bromomethyl)pyrazine. 1 H NMR (400MHz, DMSO) δ= 10.79 (br s, 1H), 8.86 (m, 1H), 8.82 (s, 1H), 8.72 - 8.67 (m, 1H), 8.67 - 8.62 (m, 1H), 7.80 (s, 1H), 7.75 (m, 1H), 7.16 (d, J=8.8 Hz, 2H), 7.06 (d, J=8.8 Hz, 2H), 5.28 (s, 2H). LCMS: Rt = 0.65 min, m / z = 391.1 (M+H).

[0493] [Example 124] (R or S)-5-(4-(1-(5-cyanopyridin-3-yl)ethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; (SFC peak 1, chiral) (124)

[0494] [ka] (R or S)-5-(4-(1-(5-cyanopyridin-3-yl)ethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; (SFC peak 1, chiral) (124) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 5-(1-bromoethyl)nicotinonitrile. 1 H NMR (400MHz, DMSO) δ= 9.33 - 9.09 (m, 1H), 8.96 (d, J=1.8 Hz, 2H), 8.42 (t, J=2.0 Hz, 1H), 8.10 (s, 1H), 7.82 (s, 1H), 7.19 (d, J=8.0 Hz, 2H), 7.02 (d, J=8.0 Hz, 2H), 5.73 (d, J=8.0Hz, 1H), 1.63 (d, J=8.0 Hz, 3H), 1.68 - 1.58 (m, 1H). LCMS: Rt = 0.91 min, m / z = 429.1 (M+H). SFC: Rt = 2.29 minutes, ee 100%.

[0495] [Example 125] (R or S)-5-(4-(1-(5-cyanopyridin-3-yl)ethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; (SFC peak 2, chiral) (125)

[0496] [ka] (R or S)-5-(4-(1-(5-cyanopyridin-3-yl)ethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; (SFC peak 2, chiral) (125) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 5-(1-bromoethyl)nicotinonitrile. 1 H NMR (400MHz, DMSO) δ= 9.17 (s, 1H), 8.96 (d, J=1.6 Hz, 2H), 8.42 (s, 1H), 8.11 (s, 1H), 7.83 (s, 1H), 7.19 (d, J=8.0 Hz, 2H), 7.02 (d, J=8.0 Hz, 2H), 5.74 (d, J=6.0 Hz, 1H), 1.63 (d, J=6.4 Hz, 3H). LCMS: Rt = 0.91 min, m / z = 429.1 (M+H). SFC: Rt = 3.29 min, ee 92%.

[0497] [Example 126] 5-(4-((1-methyl-1H-pyrazol-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (126)

[0498] [ka] 5-(4-((1-methyl-1H-pyrazol-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (126) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 5-(bromomethyl)-1-methyl-1H-pyrazole. 1 H NMR (400MHz, DMSO) δ= 13.64 (s, 1H), 8.46 (s, 1H), 8.28 (s, 1H), 8.17 (s, 1H), 7.39(d, J=1.6 Hz, 1H), 7.30 (d, J=8.4 Hz, 2H), 7.15 (d, J=8.8 Hz, 2H), 6.40(d, J=1.6 Hz, 1H), 5.23 (s, 2H), 3.85 (s, 3H). LCMS: Rt = 0.66 min, m / z = 393.1 (M+H).

[0499] [Example 127] 5-(4-((4-methoxypyridin-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (127)

[0500] [ka] 5-(4-((4-methoxypyridin-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (127) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 2-(bromomethyl)-4-methoxypyridine. LCMS: Rt=2.29 min, m / z=420.1 (M+H).

[0501] [Example 128] 5-(4-((6-morpholinopyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (128)

[0502] [ka] 5-(4-((6-morpholinopyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (128) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 4-(5-(bromomethyl)pyridin-2-yl)morpholine. LCMS: Rt=2.34 min, m / z=475.2 (M+H).

[0503] [Example 129] 5-(4-((2-fluoropyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (129)

[0504] [ka] 5-(4-((2-fluoropyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (129) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 3-(bromomethyl)-2-fluoropyridine. LCMS: Rt=2.94 min, m / z=408.1 (M+H).

[0505] [Example 130] 5-(4-((5-fluoro-2-methoxypyridin-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (130)

[0506] [ka] 5-(4-((5-Fluoro-2-methoxypyridin-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (130) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 4-(bromomethyl)-5-fluoro-2-methoxypyridine. LCMS: Rt=3.16 min, m / z=438.1 (M+H).

[0507] [Example 131] 2-Oxo-5-(4-(quinoxalin-6-ylmethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (131)

[0508] [ka] 2-Oxo-5-(4-(quinoxalin-6-ylmethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (131) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 6-(bromomethyl)quinoxaline. LCMS: Rt=2.93 min, m / z=441.1 (M+H).

[0509] [Example 132] 5-(4-((1-methyl-1H-indazol-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (132)

[0510] [ka] 5-(4-((1-methyl-1H-indazol-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (132) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 4-(bromomethyl)-1-methyl-1H-indazole. LCMS: Rt=3.06 min, m / z=443.1 (M+H).

[0511] [Example 133] 5-(4-((4-(methylsulfonyl)benzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (133)

[0512] [ka]

[0111] 5-(4-((4-(methylsulfonyl)benzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (133) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 1-(bromomethyl)-4-(methylsulfonyl)benzene. LCMS: Rt = 2.85 min, m / z = 467.1 (M+H).

[0513] [Example 134] 2-Oxo-5-(4-(thiazol-5-ylmethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (134)

[0514] [ka] 2-Oxo-5-(4-(thiazol-5-ylmethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (134) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 5-(bromomethyl)thiazole. LCMS: Rt=2.71 min, m / z=396.1 (M+H).

[0515] [Example 135] 5-(4-((4,6-dimethylpyridin-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (135)

[0516] [ka] 5-(4-((4,6-dimethylpyridin-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (135) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 2-(bromomethyl)-4,6-dimethylpyridine. LCMS: Rt=2.30 min, m / z=418.2 (M+H).

[0517] [Example 136] 5-(4-((2-methoxypyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (136)

[0518] [ka] 5-(4-((2-Methoxypyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (136) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 3-(bromomethyl)-2-methoxypyridine. LCMS: Rt=3.08 min, m / z=420.1 (M+H).

[0519] [Example 137] 5-(4-(isoquinolin-7-ylmethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (137)

[0520] [ka] 5-(4-(isoquinolin-7-ylmethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (137) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 7-(bromomethyl)isoquinoline. LCMS: Rt=2.45 min, m / z=440.1 (M+H).

[0521] [Example 138] 2-Oxo-5-(4-(quinolin-7-ylmethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (138)

[0522] [ka] 2-Oxo-5-(4-(quinolin-7-ylmethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (138) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 7-(bromomethyl)quinoline. LCMS: Rt=2.44 min, m / z=440.1 (M+H).

[0523] [Example 139] 5-(4-((3-fluoropyridin-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (139)

[0524] [ka] 5-(4-((3-fluoropyridin-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (139) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 4-(bromomethyl)-3-fluoropyridine. LCMS: Rt=2.76 min, m / z=408.1 (M+H).

[0525] [Example 140] 5-(4-((4,6-dimethylpyrimidin-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (140)

[0526] [ka]

[0111] 5-(4-((4,6-dimethylpyrimidin-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (140) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 2-(bromomethyl)-4,6-dimethylpyrimidine. LCMS: Rt = 2.67 min, m / z = 419.1 (M+H).

[0527] [Example 141] 5-(4-((1-methyl-1H-imidazol-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (141)

[0528] [ka] 5-(4-((1-methyl-1H-imidazol-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (141) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 2-(bromomethyl)-1-methyl-1H-imidazole. LCMS: Rt=2.10 min, m / z=393.1 (M+H).

[0529] [Example 142] 5-(4-((2-morpholinopyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (142)

[0530] [ka] 5-(4-((2-morpholinopyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (142) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 4-(3-(bromomethyl)pyridin-2-yl)morpholine. LCMS: Rt=2.56 min, m / z=475.1 (M+H).

[0531] [Example 143] 2-Oxo-5-(4-(thiazol-2-ylmethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (143)

[0532] [ka] 2-Oxo-5-(4-(thiazol-2-ylmethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (143) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 2-(bromomethyl)thiazole. LCMS: Rt=2.82 min, m / z=396.1 (M+H).

[0533] [Example 144] 5-(4-((3,4-dimethoxypyridin-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (144)

[0534] [ka] 5-(4-((3,4-Dimethoxypyridin-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (144) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 2-(bromomethyl)-3,4-dimethoxypyridine. LCMS: Rt=2.31 min, m / z=450.1 (M+H).

[0535] [Example 145] 5-(4-((1-methyl-1H-indazol-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (145)

[0536] [ka]

[0111] 5-(4-((1-methyl-1H-indazol-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (145) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 5-(bromomethyl)-1-methyl-1H-indazole. LCMS: Rt = 3.06 min, m / z = 443.1 (M+H).

[0537] [Example 146] 5-(4-((5-methoxypyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (146)

[0538] [ka] 5-(4-((5-methoxypyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (146) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 3-(bromomethyl)-5-methoxypyridine. LCMS: Rt=2.37 min, m / z=420.1 (M+H).

[0539] [Example 147] 5-(4-((2,6-dimethylpyridin-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (147)

[0540] [ka]

[0111] 5-(4-((2,6-dimethylpyridin-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (147) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 4-(bromomethyl)-2,6-dimethylpyridine. LCMS: Rt = 2.32 min, m / z = 418.1 (M+H).

[0541] [Example 148] 5-(4-((6-chlorobenzo[d][1,3]dioxol-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (148)

[0542] [ka]

[0111] 5-(4-((6-chlorobenzo[d][1,3]dioxol-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (148) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 5-(bromomethyl)-6-chlorobenzo[d][1,3]dioxole. LCMS: Rt=3.03 min, m / z=467.1 (M+H).

[0543] [Example 149] 5-(4-((3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (149)

[0544] [ka]

[0082] 5-(4-((3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (149) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 7-(bromomethyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)methoxy)phenyl). LCMS: Rt = 1.80 min, m / z = 461.1 (M+H).

[0545] [Example 150] 5-(4-((2-hydroxypyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (150)

[0546] [ka] To a solution of 5-(4-((2-chloropyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carbonitrile (50 mg, 0.12 mmol), acetaldoxime (14.5 mg, 0.25 mmol), and PPh (0.48 mg, 0.02 mmol) in EtOH (1 mL) and HO (0.5 mL) was added Pd(OAc) (2 mg, 0.01 mmol) at 25 °C. The mixture was stirred at 80 °C for 1 h. The reaction mixture was filtered and purified by preparative HPLC (acid) to give 5-(4-((2-hydroxypyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (150). 1 H NMR (400MHz, DMSO) δ= 10.18 (br s, 1H) 8.43 (s, 2H), 8.25 (s, 1H), 7.91 (s, 1H), 7.32 - 7.31 (m, 1H), 7.19 (d, J=8.4 Hz, 2H), 7.03 (d, J=8.4Hz, 2H), 4.88 (s, 2H). LCMS: Rt = 0.56 min, m / z = 406.9 (M+H).

[0547] A procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54) was used, except that 1-(bromomethyl)-3-nitrobenzene was replaced with 5-(bromomethyl)-2-chloropyrimidine and 5-bromo-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carbonitrile was replaced with 5-bromo-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54) to give 5-(4-((2-chloropyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carbonitrile. LCMS: Rt=0.80 min, m / z=406.8(M+H).

[0548] [Example 151] 5-(4-((2-(oxetan-3-ylmethoxy)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (151)

[0549] [ka]

[0550] Step 1: To a solution of oxetan-3-ylmethanol (163 mg, 1.84 mmol) in THF (1 mL) was added tBuONa (53 mg, 0.55 mmol), and the mixture was stirred at 25° C. for 15 minutes. Then, 5-(4-((2-chloropyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carbonitrile (150 mg, 0.37 mmol) in THF (1 mL) was added via syringe, and the mixture was stirred at 50° C. for 10 minutes under microwave irradiation. The reaction mixture was poured into water (10 mL) and extracted with chloroform / isopropanol = 3 / 1 (10 mL × 2). The organic layers were combined, dried over anhydrous Na2SO4, filtered, and concentrated to give crude 5-(4-((2-(oxetan-3-ylmethoxy)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carbonitrile, which was used in the next step without further purification. LCMS: Rt=0.90 min, m / z=459.1 [M+H].

[0551] Step 2: To a solution of 5-(4-((2-(oxetan-3-ylmethoxy)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carbonitrile (0.2 g, 0.44 mmol), acetaldoxime (52 mg, 0.87 mmol), and PPh (23 mg, 0.08 mmol) in a mixture of EtOH (3 mL) and HO (1 mL) under N at 25 °C, Pd(OAc) (10 mg, 0.04 mmol) was added. The mixture was heated to 80 °C and stirred for 3 h. The reaction mixture was filtered, concentrated, and purified by preparative HPLC (basic) to give 5-(4-((2-(oxetan-3-ylmethoxy)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (151). 1 H NMR (400 MHz, DMSO-d6) δ 10.75 (br. s, 1H), 8.74 (s, 2H), 7.80 (s, 1H), 7.16 (d, J = 8.8 Hz, 2H), 7.02 (d, J = 8.8 Hz, 2H), 5.08 (s, 2H), 4.72 (m, 2H), 4.55 (m, 2H), 4.45 (m, 2H); LCMS: Rt = 0.70 min, m / z = 477.1 [M+H].

[0552] [Example 152] 5-(4-((2-(2-hydroxyethoxy)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (152)

[0553] [ka] 5-(4-((2-(2-hydroxyethoxy)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (152) was synthesized using a procedure similar to that used to synthesize 5-(4-((2-(oxetan-3-ylmethoxy)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (151), except that oxetan-3-ylmethanol was replaced with ethane-1,2-diol. 1 H NMR (400 MHz, DMSO-d6) δ 9.61 (br., s, 1H), 8.73 (s, 2H), 8.24 (br., s, 1H), 8.02 (s, 1H), 7.57 (br., s, 1H), 7.22 ( d, J = 7.6 Hz, 2H), 7.08 (d, J = 7.6 Hz, 2H), 5.10 (s, 2H), 4.34 (s, 2H), 3.73 (s, 1H); LCMS: Rt = 0.69 min, m / z = 451.0 [M+H].

[0554] [Example 153] 2-Oxo-5-(4-((2-propoxypyrimidin-5-yl)methoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (153)

[0555] [ka] 2-Oxo-5-(4-((2-propoxypyrimidin-5-yl)methoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (153) was synthesized using a procedure similar to that used to synthesize 5-(4-((2-(oxetan-3-ylmethoxy)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (151), except that oxetan-3-ylmethanol was replaced with propan-1-ol.1 H NMR (400 MHz, DMSO-d6) δ 9.49 (br. s, 1H), 8.73 (s, 2H), 8.19 (s, 1H), 8.05 (s, 1H), 7.64 (br.s, 1H), 7.24 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 8.4 Hz, 2H), 5.10 (s, 2H), 4.29 (m, 2H), 1.77 (m, 2H), 0.99(m, 3H); LCMS: Rt = 0.80 min, m / z = 449.1 [M+H].

[0556] [Example 154] 2-Oxo-5-(4-((2-((tetrahydrofuran-3-yl)oxy)pyrimidin-5-yl)methoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (154)

[0557] [ka] 2-Oxo-5-(4-((2-((tetrahydrofuran-3-yl)oxy)pyrimidin-5-yl)methoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (154) was synthesized using a procedure similar to that used to synthesize 5-(4-((2-(oxetan-3-ylmethoxy)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (151), except that oxetan-3-ylmethanol was replaced with tetrahydrofuran-3-ol. 1H NMR (400 MHz, DMSO-d6) δ 8.75 (s, 2H), 8.22 (s, 1H), 8.02 (s, 1H), 7.29 (d, J = 8.4 Hz, 2H), 7.13 (d, J = 8.4 Hz, 2H), 5.52 (m, 1H), 5.13 (s, 2H), 3.94-3.79 (m, 4H), 2.27 (m, 1H), 2.06 (m, 1H); LCMS: Rt = 0.66 min, m / z = 477.1 [M+H].

[0558] [Example 155] 5-(4-((2-(cyclopentyloxy)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (155)

[0559] [ka] 5-(4-((2-(cyclopentyloxy)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (155) was synthesized using a procedure similar to that used to synthesize 5-(4-((2-(oxetan-3-ylmethoxy)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (151), except that oxetan-3-ylmethanol was replaced with cyclopentanol. 1 H NMR (400 MHz, DMSO-d6) δ 10.70 (br., s, 1H), 8.71 (s, 2H), 7.82 (s, 1H), 7.17 ( d, J = 8.4 Hz, 2H), 7.04( d, J = 8.8 Hz, 2H), 5.39 (m, 2H), 5.07 (s, 2H), 1.99 (m,2H), 1.76-1.71(m,4H), 1.61 (m,2H); LCMS: Rt = 0.91 min, m / z = 497.1 [M+H].

[0560] [Example 156] 5-(4-((2-(oxetan-2-ylmethoxy)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (156)

[0561] [ka] 5-(4-((2-(oxetan-2-ylmethoxy)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (156) was synthesized using a procedure similar to that used to synthesize 5-(4-((2-(oxetan-3-ylmethoxy)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (151), except that oxetan-3-ylmethanol was replaced with oxetan-2-ylmethanol. 1 H NMR (400 MHz, DMSO-d6) δ 10.75 (s, 1H), 8.74 (s, 2H), 7.80 (s, 1H), 7.16 (d, J = 8.8 Hz, 2H), 7.02 (d, J = 8.8 Hz, 2H), 5.08 (s, 2H), 4.72 (m, 2H), 4.55 (m, 2H), 4.45 (m, 2H); LCMS: Rt = 0.70 min, m / z = 477.1 [M+H].

[0562] [Example 157] 2-Oxo-5-(4-((2-((tetrahydrofuran-3-yl)methoxy)pyrimidin-5-yl)methoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (157)

[0563] [ka] 2-Oxo-5-(4-((2-((tetrahydrofuran-3-yl)methoxy)pyrimidin-5-yl)methoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (157) was synthesized using a procedure similar to that used to synthesize 5-(4-((2-(oxetan-3-ylmethoxy)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (151), except that oxetan-3-ylmethanol was replaced with (tetrahydrofuran-3-yl)methanol. 1 H NMR (400 MHz, DMSO-d6) δ 8.96 (br. s, 1H), 8.74 (s, 2H), 8.17 (br. s, 1H), 7.96 (s, 1H), 7.28 (d, J = 8.4 Hz, 2H), 7.11 (d, J = 8.4 Hz, LCMS: Rt = 0.68 min, m / z = 491.1 [M+H].

[0564] [Example 158] 5-(4-((2-(methylamino)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (158)

[0565] [ka]

[0566] Step 1: To a solution of 5-(4-((2-chloropyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carbonitrile (80 mg, 0.2 mmol) in DMF (1 mL) was added methanamine (8 mg, 0.24 mmol) and EtN (40 mg, 0.4 mmol) at 25 °C. The mixture was stirred at 50 °C for 12 h. The mixture was washed with HO (1 mL) and extracted with EA (1 mL × 2). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by reverse-phase preparative HPLC to give 5-(4-((2-(methylamino)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carbonitrile. LCMS: Rt=0.71 min, m / z=402.0[M+H].

[0567] Step 2: To a solution of 5-(4-((2-(methylamino)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carbonitrile (0.18 g, 0.44 mmol), acetaldoxime (52 mg, 0.87 mmol), and PPh (23 mg, 0.08 mmol) in a mixture of EtOH (3 mL) and HO (1 mL) under N at 25 °C, Pd(OAc) (10 mg, 0.04 mmol) was added. The mixture was heated to 80 °C and stirred for 3 h. The reaction mixture was filtered, concentrated, and purified by preparative HPLC (basic) to give 5-(4-((2-(methylamino)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (158). 1H NMR (400 MHz, DMSO-d6) δ 10.20 (br. s, 1H), 8.40 (s, 2H), 8.29 (br. s, 1H), 8.32 - 8.26 (m, 1H), 7.89 (s, 1H), 7.16 (d, J = 8.4 Hz, 2H), 7.01 (d, J = 8.4 Hz, 2H), 4.92 (s, 2H), 2.81 (d, J = 4.8 Hz, 3H); LCMS: Rt = 0.62 min, m / z = 420.1 [M+H].

[0568] [Example 159] 5-(4-((2-(cyclopentylamino)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (159)

[0569] [ka] 5-(4-((2-(cyclopentylamino)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (159) was synthesized using a procedure similar to that used to synthesize 5-(4-((2-(methylamino)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (158), except that methanamine was replaced with cyclopentanamine. 1 H NMR (400MHz, DMSO) δ= 8.41 (s, 2H), 8.39 (m, 1H), 7.31 (d, J=7.6 Hz, 1H), 7.25 (d, J=8.0 Hz, 2H), 7.07 (d, J=8.4 Hz, 2H), 4.93 (s, LCMS: Rt = 0.76 min, m / z = 474.0 (M+H).

[0570] [Example 160] 5-(4-((2-(dimethylamino)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (160)

[0571] [ka] 5-(4-((2-(dimethylamino)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (160) was synthesized using a procedure similar to that used to synthesize 5-(4-((2-(methylamino)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (158), except that methanamine was replaced with dimethylamine. 1 H NMR (400 MHz, DMSO-d6) δ 8.47 (s, 2H), 8.27 (m, 1H), 7.88 (s, 1H), 7.16 (d, J = 8.4 Hz, 2H), 7.01 (d, J = 8.4 Hz, 2H), 4.94 (s, 2H), 3.13 (s, 6H); LCMS: Rt = 0.75 min, m / z = 434.0 [M+H].

[0572] [Example 161] 5-(4-((2-((cyclopropylmethyl)amino)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (161)

[0573] [ka] 5-(4-((2-((cyclopropylmethyl)amino)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (161) was synthesized using a procedure similar to that used to synthesize 5-(4-((2-(methylamino)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (158), except that methanamine was replaced with cyclopropylmethanamine. 1 H NMR (400 MHz, DMSO-d6) δ 9.83 (br. s, 1H), 8.17 (br. s, 2H), 8.02 (s, 1H), 7.73 (br. s, 1H), 7.25 - 7.08 (m, 2H), 7.04 - 6.88 (m, 2H), 6.96 (d, J = 8.0 Hz, 1H), 6.81 (d, J = 8.0 Hz, 1H), 4.79 - 4.62 (m, 2H), 2.95 (s, 2H), 0.85 (s, 1H), 0.19 (d, J = 5.9 Hz, 2H), 0.00 (s, 2H); LCMS: Rt = 0.78 min, m / z = 460.0 [M+H].

[0574] [Example 162] 5-(4-((2-((2-hydroxyethyl)amino)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (162)

[0575] [ka] 5-(4-((2-((2-hydroxyethyl)amino)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (162) was synthesized using a procedure similar to that used to synthesize 5-(4-((2-(methylamino)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (158), except that methanamine was replaced with 2-aminoethan-1-ol. 1 H NMR (400 MHz, DMSO-d6) δ 8.40 (s, 2H), 8.07 (br. s, 1H), 7.66 (br. s, 1H), 7.23 (m, 1H), 7.16 (m, 2H), 4.93 (s, 2H), 4.68 (br.s, 1H), 3.51 (br.s, 2H), 3.38 (m, 2H); LCMS: Rt = 0.62 min, m / z = 450.1 [M+H].

[0576] [Example 163] 5-(4-((2-(cyclopropylamino)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (163)

[0577] [ka] Using a procedure similar to that used to synthesize 5-(4-((2-(methylamino)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (158), except that methanamine was replaced with cyclopropanamine, 5-(4-((2-(cyclopropylamino)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (163) was synthesized. LCMS: Rt=0.64 min, m / z=446.1 [M+H].

[0578] [Example 164] 5-(4-((2-(heptylamino)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (164)

[0579] [ka] Using a procedure similar to that used to synthesize 5-(4-((2-(methylamino)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (158), except that methanamine was replaced with heptan-1-amine, 5-(4-((2-(heptylamino)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (164) was synthesized. LCMS: Rt=0.96 min, m / z=504.4 [M+H].

[0580] [Example 165] 5-(4-((2-(oxetan-3-ylamino)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (165)

[0581] [ka] 5-(4-((2-(oxetan-3-ylamino)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (165) was synthesized using a procedure similar to that used to synthesize 5-(4-((2-(methylamino)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (158), except that methanamine was replaced with oxetan-3-amine. 1H NMR (400 MHz, DMSO-d6) δ = 10.54 (br. s, 1H), 8.42 (s, 2H), 8.03 (d, J = 5.8 Hz, 1H), 7.83 (s, 1H), 7.15 (d, J = 8.6 Hz, 2H), 7.00 (d, J = LCMS: Rt = 0.63 min, m / z = 462.1 [M+H].

[0582] [Example 166] 2-Oxo-5-(4-((2-((tetrahydrofuran-3-yl)amino)pyrimidin-5-yl)methoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (166)

[0583] [ka] 2-oxo-5-(4-((2-((tetrahydrofuran-3-yl)amino)pyrimidin-5-yl)methoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (166) was synthesized using a procedure similar to that used to synthesize 5-(4-((2-(methylamino)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (158), except that methanamine was replaced with tetrahydrofuran-3-amine. 1H NMR (400 MHz, DMSO-d6) δ= 8.42 (s, 2H), 7.94 (s, 1H), 7.53 (d, J = 6.4 Hz, 1H), 7.18 (d, J = 8.2 Hz, 2H), 7.03 (d, J = 8.8 Hz, 2H), 4.93 (s, 2H), 4.39 (d, J = 7.2 Hz, 1H), 3.91 - 3.82 (m, 3H), 3.76 - 3.67 (m, 2H), 3.55 (d, J = 8.6 Hz, 1H), 2.18 - 2.11 (m, 1H), 1.88 (t, J = 12.4 Hz, 1H); LCMS: Rt = 0.64 min, m / z = 476.1 [M+H].

[0584] [Example 167] 5-(4-((6-(cyclopentylamino)pyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (167)

[0585] [ka]

[0586] Step 1: (6-Fluoropyridin-3-yl)methanol (300 mg, 2.36 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (623 mg, 2.83 mmol), and triphenylphosphine (805 mg, 3.07 mmol) were added to an oven-dried 40 mL vial containing a stir bar, and the vial was sealed with a septa-top vial and purged with vacuum / N. THF (7.9 mL) was added, and the reaction was cooled to 0 °C. DEAD (448 μL, 2.83 mmol) was added dropwise, and the reaction mixture was allowed to warm to room temperature and then stirred overnight. The reaction mixture was concentrated in vacuo and purified by silica gel chromatography (ISCO, 0-40% EtOAc / heptane) to give 2-fluoro-5-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)pyridine. LCMS Rt=1.04 min, m / z=330.3 [M+H] + .

[0587] Step 2: To an oven-dried 4 mL vial containing a stir bar was added 2-fluoro-5-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)pyridine (39 mg, 0.08 mmol). The vial was sealed with a septa top cap and purged with vacuum / N (×3). DMSO (0.45 mL) and cyclopentanamine (0.16 mL, 1.66 mmol) were added and the reaction mixture was heated to 80 °C and stirred overnight. The reaction mixture was diluted with EA, washed with water and brine, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ISCO, 0-50% EA / heptane) to give N-cyclopentyl-5-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)pyridin-2-amine. LCMS t=1.03, m / z=395.3 [M+H].

[0588] Step 3: To a 4 mL vial containing a stir bar was added N-cyclopentyl-5-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)pyridin-2-amine (13 mg, 0.033 mmol), 5-bromo-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (11.28 mg, 0.040 mmol), potassium phosphate tripotassium (20.99 mg, 0.099 mmol), and (dtbpf)PdCl (2.149 mg, 3.30 μmol), and the reaction vial was sealed with a septa top cap and purged with vacuum / N (×3). Dioxane (247 μL) and water (82 μL) were added, and the reaction mixture was heated to 65 °C and stirred overnight. The reaction mixture was diluted with EtOAc, filtered, and concentrated in vacuo. The crude product was purified by preparative HPLC to give 5-(4-((6-(cyclopentylamino)pyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (167). 1 H NMR (500 MHz, DMSO-d6) δ 13.65 (br. s, 1H), 8.43 (br. s, 1H), 8.26 (s, 1H), 8.16 (br. s, 1H), 8.06 (d, J = 2.1 Hz, 1H), 7.87 (d, J = 9.3 Hz, 1H), 7.30 (d, J = 8.7 Hz, 2H), 7.10 (d, J = 8.7 Hz, 2H), 6.93 (br. s, 1H), 5.03 (s, 2H), 4.04 (dt, J = 10.8, 6.2 Hz, 1H), 1.99 (dq, J = 12.9, 6.6, 6.0 Hz, 2H), 1.74 - 1.65 (m, 2H), 1.63 - 1.47 (m, 4H). LCMS: Rt = 0.72 min, m / z = 473.3 [M+H].

[0589] [Example 168] 5-(4-((6-((cyclopropylmethyl)amino)pyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (168)

[0590] [ka] 5-(4-((6-((cyclopropylmethyl)amino)pyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (168) was synthesized using a procedure similar to that used to synthesize 5-(4-((6-(cyclopentylamino)pyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (167), except cyclopentanamine was replaced with cyclopropylmethanamine. 1 H NMR (500 MHz, DMSO-d6) δ 13.61 (br. s, 1H), 8.44 (br. s, 1H), 8.26 (s, 1H), 8.17 (br. s, 1H), 8.06 (d, J = 2.2 Hz, 1H), 7.87 (br. d, J = 9.1 Hz, 1H), 7.34 - 7.21 (m, 2H), 7.18 - 7.04 (m, 2H), 6.97 (br. s, 1H), 5.02 (s, 2H), 3.19 (dd, J = 7.1, 2.9 Hz, 2H), 1.16 - 1.05 (m, 1H), 0.64 - 0.39 (m, 2H), 0.28 (dt, J = 6.1, 4.3 Hz, 2H). LCMS:Rt = 0.67 min, m / z = 459.3 [M+H].

[0591] [Example 169] 5-(4-((6-(3,3-difluoroazetidin-1-yl)pyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (169)

[0592] [ka]

[0593] Step 1: The procedure described in Step 3 of Example 167 was used, except N-cyclopentyl-5-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)pyridin-2-amine was replaced with 2-fluoro-5-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)pyridine to give 5-(4-((6-fluoropyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide. LCMS: Rt=0.93 min, m / z=408.1 [M+H].

[0594] Step 2: To an oven-dried 4 mL vial was added 5-(4-((6-fluoropyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (20 mg, 0.029 mmol), 3,3-difluoroazetidine hydrochloride (7.63 mg, 0.059 mmol), and potassium carbonate (16.29 mg, 0.118 mmol), and the vial was sealed with a septa top cap and purged with vacuum / N (×3). DMSO (295 μl) was added, and the reaction mixture was heated to 120 °C and stirred overnight. The reaction mixture was diluted with DCM, filtered, and concentrated. The crude product was purified by preparative HPLC to give 5-(4-((6-(3,3-difluoroazetidin-1-yl)pyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (169). 1H NMR (500 MHz, DMSO-d6) δ 13.63 (br. s, 1H), 8.45 (br. s, 1H), 8.29 - 8.25 (m, 2H), 8.17 (br. s, 1H), 7.76 (dd, J = 8.5, 2.3 Hz, 1H), 7.30 - 7.23 (m, 2H), 7.13 - 7.04 (m, 2H), 6.64 (d, J = 8.5 Hz, 1H), 5.05 (s, 2H), 4.40 (t, J = 12.5 Hz, 4H); LCMS: Rt = 0.81 min, m / z = 481.1 [M+H].

[0595] [Example 170] 5-(4-((6-(3-methoxyazetidin-1-yl)pyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (170)

[0596] [ka] The title compound was prepared according to the procedure in Example 167 and synthesized using a procedure similar to that used to synthesize 5-(4-((6-(3,3-difluoroazetidin-1-yl)pyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (169), except difluoroazetidine hydrochloride was replaced with 3-methoxyazetidine hydrochloride. 1H NMR (500 MHz, DMSO-d6) δ 13.68 (br. s, 1H), 8.44 (br. s, 1H), 8.26 (s, 1H), 8.19 - 8.14 (m, 2H), 7.84 (br. s, 1H), 7.36 - 7.21 (m, 2H), 7.12 - 7.05 (m, 2H), 6.66 (s, 1H), 5.03 (s, 2H), 4.38 - 4.32 (m, 1H), 4.28 (t, J = 8.5 Hz, 2H), 3.90 (d, J = 8.5 Hz, 2H), 3.26 (s, 3H); LCMS: Rt = 0.72 min, m / z = 475.1 [M+H].

[0597] [Example 171] 5-(4-((2-cyclopropylpyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (171)

[0598] [ka] The procedures of Steps 1 and 3 in Example 167 were used, except that (6-fluoropyridin-3-yl)methanol was replaced with (2-cyclopropylpyrimidin-5-yl)methanol and N-cyclopentyl-5-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)pyridin-2-amine was replaced with 2-cyclopropyl-5-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)pyrimidine to give 5-(4-((2-cyclopropylpyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (171). LCMS: Rt=0.80 min, m / z=431.1 [M+H]. Notes: (2-cyclopropylpyrimidin-5-yl)methanol was obtained using the following procedure:

[0599] [ka]

[0600] Step 1: To an oven-dried, argon-cooled, 50 mL, two-neck flask equipped with a stir bar was added methyl 3,3-dimethoxypropanoate (0.71 mL, 5.0 mmol), methyl formate (0.74 mL, 12.0 mmol), and DME (10.0 mL). Sodium hydride (260 mg, 6.50 mmol) was added in one portion, and the reaction was heated to 50 °C for 1 h. The reaction mixture was then cooled to room temperature and stirred overnight. The resulting suspension was diluted with EtO, filtered, and evaporated to dryness in vacuo to give sodium 2-(dimethoxymethyl)-3-methoxy-3-oxoprop-1-en-1-oleate, which was used without further purification. LCMS Rt = 0.28 min, no ionization.

[0601] Step 2: To an oven-dried 4 mL vial containing a stir bar was added sodium 2-(dimethoxymethyl)-3-methoxy-3-oxoprop-1-en-1-olate (238 mg, 1.20 mmol) and cyclopropanecarboximidamide hydrochloride (121 mg, 1.00 mmol). The reaction vial was sealed with a septa top cap and purged with vacuum / N (×3). DMF (1.0 mL) was added and the reaction was heated to 120 °C for 1 h. The reaction was diluted with DCM and filtered through a plug of Celite®. Subsequent concentration in vacuo afforded methyl 2-cyclopropylpyrimidine-5-carboxylate, which was used in the next step without further purification. LCMS Rt = 0.57 min, m / z = 179.4 [M+H].

[0602] Step 3: To an oven-dried 20 mL vial containing a stir bar, methyl 2-cyclopropylpyrimidine-5-carboxylate (166 mg, 0.93 mmol) was added. The reaction vial was sealed with a septa-top cap and purged with vacuum / N₂ (x3) via a needle. THF (4.7 mL) was added, and the reaction was cooled to -78 °C. DIBAL-H (1.0 M in PhMe, 2.05 mL, 2.05 mmol) was then added dropwise, and the reaction mixture was allowed to warm slowly to room temperature overnight in a cooling bath. The reaction was quenched by the addition of an aqueous solution of Rochelle's salt, diluted with EA, and stirred vigorously for 30 min. The layers were separated, and the aqueous layer was extracted into EA. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. Purification by silica gel chromatography (ISCO, 50–100% EA / heptane) afforded (2-cyclopropylpyrimidin-5-yl)methanol. LCMS Rt=0.29 min, m / z=151.1[M+H].

[0603] [Example 172] 5-(4-((2-(cyclopentylmethyl)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (172)

[0604] [ka] The procedures of Step 1 and Step 3 in Example 167 were used, except that (6-fluoropyridin-3-yl)methanol was replaced with (2-(cyclopentylmethyl)pyrimidin-5-yl)methanol and N-cyclopentyl-5-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)pyridin-2-amine was replaced with 2-(cyclopentylmethyl)-5-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)pyrimidine to provide 5-(4-((2-(cyclopentylmethyl)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (172). LCMS: Rt=0.90 min, m / z=473.3[M+H].

[0605] [Example 173] 5-(4-((2-neopentylpyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (173)

[0606] [ka] The procedures of Step 1 and Step 3 in Example 167 were used, except that (6-fluoropyridin-3-yl)methanol was replaced with ((2-neopentylpyrimidin-5-yl)methanol and N-cyclopentyl-5-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)pyridin-2-amine was replaced with 2-neopentyl-5-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)pyrimidine to give 5-(4-((2-neopentylpyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (173). 1H NMR (500 MHz, DMSO-d6) δ 13.63 (br, s, 1H), 8.86 (s, 2H), 8.55 (br. s, 1H), 8.25 (s, 2H), 8.11 (br. s, 1H), 7.30 (d, J = 8.6 Hz, 2H), 7.18 - 7.09 (m, 2H), 5.19 (s, 2H), 2.79 (s, 2H), 0.96 (s, 9H). LCMS: Rt = 0.90 min, m / z = 473.3 [M+H].

[0607] [Example 174] 5-(4-((4-(cyclopentylamino)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (174)

[0608] [ka] 5-(4-((4-(cyclopentylamino)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (174). 1 H NMR (400 MHz, DMSO-d6) δ 10.55 (s, 1H), 8.44 (s, 1H), 8.31 (s, 1H), 8.17 (s, 1H), 7.84 (s, 1H), 7.17 (d, J = 8.6 Hz, 2H), 7.09 (s, 1H), 7.02 (d, J = 8.8 Hz, 2H), 6.77 (d, J = 7.2 Hz, 1H), 5.00 (s, 2H), 4.44 (d, J = 7.0 Hz, 1H), 1.95 (d, J = 6.2 Hz, 2H), 1.70 (s, 2H), 1.54 (s, 4H); LCMS: Rt = 0.64 min, m / z =474.1 [M+H].

[0609] N-cyclopentyl-5-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)pyrimidin-4-amine was obtained using the procedures in Step 1 and Step 3 in Example 167:

[0610] [ka] LCMS: Rt 0.821 min, m / z 396.1 [M+H]. (4-(cyclopentylamino)pyrimidin-5-yl)methanol was obtained using the following procedure:

[0611] [ka]

[0612] Step 1: To a solution of cyclopentanamine (456 mg, 5.36 mmol) in THF (10 mL) was added ethyl 4-chloropyrimidine-5-carboxylate (1.0 g, 5.36 mmol) followed by EtN (1.08 g, 10.7 mmol) at 0 °C. The mixture was then stirred at 25 °C for 3 h. The reaction mixture was poured into water (10 mL) and then extracted with EA (10 mL × 2). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated to give the crude product, which was purified by flash column chromatography to give ethyl 4-(cyclopentylamino)pyrimidine-5-carboxylate. TLC: PE / EA = 3 / 1, Rf = 0.2; 1 H NMR (400MHz, DMSO-d6) δ 8.66 (d, J = 7.0 Hz, 1H), 8.14 (d, J = 6.8 Hz, 1H), 4.49 - 4.36 (m, 1H), 4.30 (q, J = 7.2 Hz, 2H), 2.05 - 1.94 (m, 2H), 1.75 - 1.55 (m, 4H), 1.49 (td, J = 6.1, 12.1 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H).

[0613] Step 2: (4-(cyclopentylamino)pyrimidin-5-yl)methanol was obtained using the method of Step 3 in Example 171. LCMS: Rt 0.544 min, m / z 194.1 [M+H].

[0614] [Example 175] 5-(4-((3-(cyclopropylmethyl)-3H-imidazo[4,5-b]pyridin-6-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (175)

[0615] [ka] 5-(4-((3-(cyclopropylmethyl)-3H-imidazo[4,5-b]pyridin-6-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (175) was synthesized using a procedure similar to that used to synthesize 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (54), except that 1-(bromomethyl)-3-nitrobenzene was replaced with 6-bromo-3-(cyclopropylmethyl)-3H-imidazo[4,5-b]pyridine. 1 H NMR (400 MHz, DMSO-d6) δ 10.50 (br. s, 1H), 8.56 (s, 1H), 8.52 (d, J = 1.8 Hz, 1H), 8.29 (s, 1H), 8.20 (d, J = 1.8 Hz, 1H), 7.85 (d, J = 9.6 Hz, 1H), 7.17 (d, J = 7.6 Hz, 2H), 7.06 (d, J = 7.6 Hz, 2H), 5.27 (s, 2H), 4.17 (d, J = 7.4 Hz, 2H), 1.37 (m, 1H), 0.54 (m, 2H), 0.48 (m, 2H); LCMS: Rt = 0.67 min, m / z = 484.1 [M+H]. 6-Bromo-3-(cyclopropylmethyl)-3H-imidazo[4,5-b]pyridine was obtained using the following procedure:

[0616] [ka] To a solution of 6-bromo-3H-imidazo[4,5-b]pyridine (4.6 g, 23.2 mmol) and KCO (4.8 g, 34.9 mmol) in DMF (50 mL) was added (bromomethyl)cyclopropane (4.7 g, 34.9 mmol), and the reaction was stirred at 25 °C for 12 h. The mixture was washed with HO (200 mL) and extracted with ...

Claims

1. A compound of formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof 【Chemical 1】 [In the formula, R １ is H or halo, R ２ Ha-C １ ~C ８ is haloalkyl, R ３ Is L １ R ５ or L ２ R ６ and R ４ Halo, CN, C １ ~C ８ Alkyl, C １ ~C ８ Alkoxy or C ３ ~C ８ is cycloalkyl, L １ is a bond, -CH ２ -, -(CH ２ ) ｍ -, -OCH ２ -, -O-, -CH ２ O-, -O(CH ２ ) ｍ -, -CH ２ OCH ２ -, -CH(R ７ )-, -OCH(R ７ )-, -CH(R １０ )-, -OCH(R １０ )-, -CF ２ -, -CF ２ CH ２ -, -OCF ２ -, -OCH ２ C(=O)-, -OCH ２ C(=O)NH-, -OCH ２ CH(OH)CH ２ -, -CH ２ OCH ２ C(R ７ ) ２ -, -C(R ７ ) ２ -, -OC(R ７ ) ２ -, -OCH(R １０ )CH ２ -, -NH- or -NH(CH ２ ) ｍ -; and L ２ is a bond, -CH ２ -, -(CH ２ ) ｍ -, -OCH ２ -, -CH ２ O-, -O(CH ２ ) ｍ -, -CH ２ OCH ２ -, -CH(R ７ )-, -OCH(R ７ )-, -CH(R １０ )-, -OCH(R １０ )-, -C(R ７ ) ２ -, -OC(R ７ ) ２ -, -CF ２ -, -CF ２ CH ２ -, -OCF ２ -, -OCH ２ C(=O)NH-, -OCH ２ CH(OH)CH ２ -, -CH ２ OCH ２ C(R ７ ) ２ -, -NH(CH ２ ) ｍ -, -OCH(R １０ )CH ２ - or -OCH ２ C(=O)-; and L ３ is a bond, -CH ２ -, -(CH ２ ) ｍ -, -OCH ２ -, -O-, -NH-, -NH(CH ２ ) ｍ -, -OCH ２ C(=O)-, -OCH ２ C(=O)NH-, -OCH ２ CH(OH)CH ２ -, -CH ２ OCH ２ -, -CH ２ O-, -O(CH ２ ) ｍ -, -CH(R ７ )-, -OCH(R ７ )-, -CH(R １０ )-, -OCH(R １０ )-, -CH ２ OCH ２ C(R ７ ) ２ -, -CF ２ -, -CF ２ CH ２ -, -OCF ２ -, -C(R ７ ) ２ -, -OC(R ７ ) ２ -, or -OCH(R １０ )CH ２ -; and L ４ is a bond, -CH ２ -, -(CH ２ ) ｍ -, -C(R ７ ) ２ -, -OC(R ７ ) ２ , -CF ２ -, -OCH ２ -, -O(CH ２ ) ｍ -, -CH ２ O-, -CH ２ OCH ２ -, -CH ２ OCH[[ID=3,3]] ２ C(R ７ ) ２ -, -NH(CH ２ ) ｍ -, -OCH ２ C(=O)-, -OCH ２ C(=O)NH-, -OCH ２ CH(OH)CH ２ -, -CF ２ CH ２ -, -OCF ２ -, -CH(R １０ )-, -OCH(R １０ )-, -OCH(R ７ )-, -OC(R ７ ) ２ -, -CH(R ７ )-, or -OCH(R １０ )CH ２ ; and R ５ teeth, i) R ９ phenyl substituted with 0 to 3 groups independently selected from ii) R ９ C substituted with 0 to 3 groups independently selected from ３ ~C ８ cycloalkyl, iii) R ９ N, NR ７ , O, S, C=O or S(=O) ２ a 4-8 membered monocyclic heterocycloalkyl group having 1 to 3 ring members independently selected from iv) R ９ N, NR ７ a 9- to 12-membered heterocyclyl group having 1 to 4 ring members independently selected from , O, or S; v) R ９ N, NR ７ , O, S, C=O or S(=O) ２ a 7-8 membered bridged bicyclic heterocycloalkyl group having 1 to 2 ring members independently selected from vi) R ９ N, NR ７ , O, S, C=O or S(=O) ２ a fused 6-8 membered bicyclic heterocycloalkyl group having 1 to 2 ring members independently selected from vii) R ９ N, NR ７ , 5-6 membered heteroaryl having 1-3 ring members independently selected from O or S, and viii) R ９ N, NR ７ , N ＋ O － 9-10 membered heteroaryl having 1-4 ring members independently selected from , O, and S; is selected from the group consisting of R ６ is -CN, -OH, -NR ７ R ８ , -NR ７ C(=O)R ８ , -NR ７ S (= O) ２ R ８ , —C(═O)NR ７ R ８ , -S(=O) ２ R ８ , Haro, C １ ~C ８ Haloalkoxy, C １ ~C ８ -alkoxy, -C １ ~C ８ Alkyl or -C ２ -C ８ is alkylene, Each R ７ is H and -C １ ~C ８ independently selected from alkyl, R ８ is H or -C １ ~C ８ is alkyl, Each R ９ is -C １ ~C ８ Alkyl, -C １ ~C ８ -alkoxy, C １ ~C ８ Haloalkyl, spiro-bonded C ３ ~C ８ Cycloalkyl, R １０ , —OH, CN, halo, —C(═O)R ７ , -NR ７ R ８ , —C(═O)NR ７ R ８ , -NR ７ C(=O)R ８ , -NR ７ C(=O)OR ８ , -C(=O)OR ８ , -NR ７ S (= O) ２ R ８ , -S(=O) ２ R ８ , -S(=O) ２ R １０ , NO ２ , C.N., L. ３ R １１ , L ４ R １２ , and N, N.R. ７ , O, S; R １０ is C ３ ~C ８ cycloalkyl or N, NR ７ , O, or S; or N, NR ７ , O, or S; Each R １１ teeth, i) R １３ phenyl substituted with 0 to 3 groups independently selected from ii) R １３ C substituted with 0 to 3 groups independently selected from ３ ~C ８ cycloalkyl iii) R １３ N, NR ７ , O, S, C=O or S(=O) ２ a 4-8 membered monocyclic heterocycloalkyl group having 1 to 3 ring members independently selected from iv) R １３ N, NR ７ 9-12 membered heterocyclyl having 1 to 4 ring members independently selected from: , O, or S; v) R １３ N, NR ７ , O, S, C=O or S(=O) ２ a 7-8 membered bridged bicyclic heterocycloalkyl group having 1 to 2 ring members independently selected from vi) R １３ N, NR ７ , O, S, C=O or S(=O) ２ a fused 6-8 membered bicyclic heterocycloalkyl group having 1 to 2 ring members independently selected from vii) R １３ N, NR ７ , 5-6 membered heteroaryl having 1-3 ring members independently selected from O or S, and viii) R １３ N, NR ７ , N ＋ O － , O, or S; are independently selected from the group consisting of Each R １２ -CN, -CD ３ , -OCD ３ , —OH, —NR ７ R ８ , -NR ７ C(=O)R ８ , -NR ７ S (= O) ２ R ８ , —C(═O)NR ７ R ８ , -S(=O) ２ R ８ , -S(=O) ２ R １０ , Haro, C １ ~C ８ Haloalkoxy, C １ ~C ８ -alkoxy, C １ ~C ８ haloalkyl or -C １ ~C ８ independently selected from alkyl, Each R １３ is -C １ ~C ８ Alkyl, spiro bonded C ３ ~C ８ cycloalkyl, —C １ ~C ８ -alkoxy, -OH, halo, -C(=O)R ７ , -NR ７ R ８ , —C(═O)NR ７ R ８ , -NR ７ C(=O)R ８ , -NR ７ S (= O) ２ R ８ , -S(=O) ２ R ８ , NO ２ , CN or C １ ~C ８ haloalkyl; each m is independently selected from 1, 2, 3, or 4; each n is independently selected from 0, 1, 2, or 3; each p is independently selected from 0, 1, 2, or 3.

2. 10. The compound of claim 1 having the formula (II), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. 【Chemistry 2】

3. R １ is H, R ２ Ga-C １ ~C ８ is haloalkyl, R ３ L １ R ５ or L ２ R ６ and R ４ But, Haro, CN, C １ ~C ８ Alkyl, C １ ~C ８ Alkoxy or C ３ ~C ８ is cycloalkyl, L １ is -CH ２ -, -OCH ２ -, -O-, -CH ２ O-, -O(CH ２ ) ｍ -, -CH(R ７ )-, -OCH(R ７ )-, -CH(R １０ )-, -OCH(R １０ )-, -CF ２ CH ２ -, -OCF ２ -, -OCH ２ C(=O)-, -OCH ２ C(=O)NH-, or -OCH ２ CH(OH)CH ２ -, and L ２ is a bond, -CH ２ -, -OCH ２ -, -O(CH ２ ) ｍ -, -CH(R ７ ) -, -OCH(R １０ ) -, -OCH(R １０ ) CH ２ - or -OCH ２ C(═O)—, L ３ is a bond, -CH ２ -, -OCH ２ -, -O-, -NH-, -NH(CH ２ ) ｍ -, -CH ２ OCH ２ - or -CH ２ O-, L ４ But CH ２ -, -(CH ２ ) ｍ -, -C(R ７ ) ２ -, -CF ２ -, -OCH ２ -, -O(CH ２ ) ｍ -, -CH ２ O-, -CH ２ OCH ２ -, -CH ２ OCH ２ C (R ７ ) ２ - or -NH(CH ２ ) ｍ - and R ５ but, i) R ９ phenyl substituted with 0 to 3 groups independently selected from ii) R ９ C substituted with 0 to 3 groups independently selected from ３ ~C ８ cycloalkyl, iii) R ９ N, NR ７ , O, S, C=O or S(=O) ２ a 4-8 membered monocyclic heterocycloalkyl group having 1 to 3 ring members independently selected from iv) R ９ N, NR ７ a 9- to 12-membered heterocyclyl group having 1 to 4 ring members independently selected from , O, or S; v) R ９ N, NR ７ a 7-8 membered bridged bicyclic heterocycloalkyl group having 1-2 ring members independently selected from O or S; vi) R ９ N, NR ７ a fused 6-8 membered bicyclic heterocycloalkyl group having 1-2 ring members independently selected from O and S; vii) R ９ N, NR ７ , 5-6 membered heteroaryl having 1-3 ring members independently selected from O or S, and viii) R ９ N, NR ７ , N ＋ O － , O, or S; is selected from the group consisting of R ６ -CN, -OH, -NR ７ R ８ , -NR ７ C(=O)R ８ , -NR ７ S (= O) ２ R ８ , —C(═O)NR ７ R ８ , -S(=O) ２ R ８ , Haro, C １ ~C ８ Haloalkoxy, C １ ~C ８ -alkoxy, -C １ ~C ８ Alkyl or -C ２ -C ８ is alkylene, Each R ７ is H or -C １ ~C ８ independently selected from alkyl, R ８ is H or -C １ ~C ８ Alkyl; Each R ９ But, -C １ ~C ８ Alkyl, -C １ ~C ８ -alkoxy, C １ ~C ８ Haloalkyl, spiro-bonded C ３ ~C ８ Cycloalkyl, R １０ , —OH, CN, halo, —C(═O)R ７ , -NR ７ R ８ , —C(═O)NR ７ R ８ , -NR ７ C(=O)R ８ , -C(=O)OR ８ , -NR ７ S (= O) ２ R ８ , -S(=O) ２ R ８ , -S(=O) ２ R １０ , NO ２ , C.N., L. ３ R １１ , L ４ R １２ , and N, N.R. ７ , O, or S; R １０ But C ３ ~C ８ cycloalkyl or N, NR ７ , O, or S; or N, NR ７ , O, or S; Each R １１ but, i) R １３ phenyl substituted with 0 to 3 groups independently selected from ii) R １３ C substituted with 0 to 3 groups independently selected from ３ ~C ８ cycloalkyl, iii) R １３ N, NR ７ a 4-8 membered monocyclic heterocycloalkyl group having 1 to 3 ring members independently selected from O or S; and iv) R １３ N, NR ７ , 5-6 membered heteroaryl having 1-3 ring members independently selected from O or S; Each R １２ But, -CN, -CD ３ , -OCD ３ , —OH, —NR ７ R ８ , -NR ７ C(=O)R ８ , -NR ７ S (= O) ２ R ８ , —C(═O)NR ７ R ８ , -S(=O) ２ R ８ , -S(=O) ２ R １０ , Haro, C １ ~C ８ Haloalkoxy, C １ ~C ８ Haloalkyl, —C １ ~C ８ Alkyl or C １ ~C ８ -alkoxy; Each R １３ Ga-C １ ~C ８ Alkyl, -C １ ~C ８ -alkoxy, -OH or halo; each m is independently selected from 1, 2, or 3; 2. The compound of claim 1, wherein each p is independently selected from 0 or 1.

4. 10. The compound of claim 1 having the formula (III), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. 【Chemistry 3】

5. 10. The compound of claim 1 having formula (IV), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. 【Chemistry 4】

6. R ５ but, i) R ９ phenyl substituted with 0 to 3 groups independently selected from ii) each of which is R ９ cyclopropyl, cyclobutyl, or cyclohexyl, each substituted with 0 to 3 groups independently selected from iii) Each is R ９ morpholinyl, pyrrolidinyl, thiomorpholinyl, oxetanyl, oxazepanyl, azetidinyl, pyrrolidinyl, piperidinyl, oxomorpholinyl, dioxidethiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl, dioxanyl, dioxepanyl, oxopyrrolidinyl, or oxooxazolidinyl, each substituted with 0 to 3 groups independently selected from iv) each of which is R ９ benzo[d][1,3]dioxolyl, benzo[b][1,4]dioxepinyl, tetrahydrobenzo[d]isoxazolyl, dihydrobenzofuranyl, tetrahydropyrano[3,4-c]pyrazolyl, chromanyl, or 6,7-dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]oxazinyl, each of which is substituted by 0 to 3 groups independently selected from v) Each is R ９ 8-oxa-3-azabicyclo[3.2.1]octanyl, oxabicyclo[2.2.1]heptanyl, or 3,8-dioxabicyclo[3.2.1]octanyl, each of which is substituted with 0 to 3 groups independently selected from vi) each of which is R ９ 3-azabicyclo[3.1.0]hexanyl or 2,5-dioxabicyclo[4.1.0]heptanyl, each substituted with 0 to 3 groups independently selected from vii) each of which is R ９ oxazolyl, isoxazolyl, pyrazolyl, thiophenyl, thiazolyl, or thiadiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl, each substituted with 0 to 3 groups independently selected from viii) each of which is R ９ benzo[c][1,2,5]oxadiazolyl, indazolyl, tetrazolo[1,5-a]pyridinyl, imidazo[1,2-a]pyridinyl, imidazo[4,5-b]pyridinyl, triazolo[4,3-a]pyrimidinyl, quinoxalinyl, quinolinyl, or isoquinolinyl, each of which is substituted with 0 to 3 groups independently selected from 2. The compound of claim 1, selected from the group consisting of:

7. 10. The compound of claim 1 having the formula (V), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. 【Chemistry 5】

8. 2. The compound according to claim 1, having the formula (Va), (Vb), or (Vc), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. 【Chemistry 6】

9. 2. The compound according to claim 1, having the formula (V-a1) or (V-a2), or a pharmaceutically acceptable salt thereof: 【Chemistry 7】

10. Each R ９ methyl, ethyl, isopropyl, neopentyl, methoxy, ethoxy, propoxy, isopropoxy, -CH ２ F, -CHF ２ , -CF ３ , R １０ , -OH, CN, F, Cl, Br, -C(=O)CH ３ , -NH ２ , -NHCH ３ , -NHCH ２ CH ３ , -NHCH ２ CH ２ CH ３ , -NH(CH ２ ) ６ CH ３ , -N(CH ３ ) ２ , —C(═O)NH ２ , -C(=O)N(CH ３ ) ２ , -C(=O)NHCH ３ , -NHC(=O)CH ３ , -NHC(=O)OC(CH ３ ) ３ , -C(=O)OC(CH ３ ) ３ , -NHS(=O) ２ CH ３ , -S(=O) ２ CH ３ , -S(=O) ２ CH (CH ３ ) ２ , -S(=O) ２ CH ２ CH (CH ３ ) ２ , -S(=O) ２ -cyclopropyl, NO ２ , C.N., L. ３ R １１ , L ４ R １２ , cyclopropyl, cyclopentyl, spiro-linked cyclopropyl, spiro-linked oxetanyl, spiro-linked dioxepanyl, or spiro-linked tetrahydrofuranyl.

11. Each R ９ But, -C １ ~C ８ Alkyl, -C １ ~C ８ Alkoxy, Halo, C １ ~C ８ Haloalkyl, spiro-bonded C ３ ~C ８ Cycloalkyl, R １０ , L ３ R １１ , L ４ R １２ , or N, NR ７ , O, or S.

12. Each R ９ is methyl, F, methoxy, -CH ２ F, -CHF ２ , L ３ R １１ , L ４ R １２ , -C(=O)N(CH ３ ) ２ , cyclopropyl, cyclopentyl, spiro-linked cyclopropyl, spiro-linked oxetanyl, spiro-linked dioxepanyl, or spiro-linked tetrahydrofuranyl.

13. Each R ９ But methyl, L ３ R １１ or L ４ R １２ 2. The compound of claim 1, independently selected from:

14. Each R ９ is methyl or L ３ R １１ are independently selected from L ３ is a bond, -CH ２ -, -OCH ２ -, -O-, -NH-, -NH(CH ２ ) ｍ -, -CH ２ OCH ２ -, -CH ２ O-, -O(CH ２ ) ｍ -, -CH(R ７ ) -, -OCH(R ７ ) -, -CH(R １０ ) -, -CF ２ CH ２ -, -C(R ７ ) ２ -, or -OC(R ７ ) ２ - and R １１ However, each has 0 to 2 R １３ phenyl, tetrahydrofuranyl, cyclobutyl, cyclopropyl, cyclopentyl, oxetanyl, azetidinyl, pyrrolyl, or pyrazolyl, each substituted with a group; Each R １３ is independently selected from F, OH, methoxy, or methyl.

15. Each R ９ is methyl or L ３ R １１ are independently selected from L ３ is a bond, -CH ２ , -OCH ２ -, -O-, -NH-, -NHCH ２ -, -CH ２ OCH ２ - or -CH ２ O-, R １１ However, each has 0 to 2 R １３ phenyl, tetrahydrofuranyl, cyclobutyl, cyclopropyl, cyclopentyl, oxetanyl, azetidinyl, pyrrolyl, or pyrazolyl, each substituted with a group; Each R １３ is independently selected from F, OH, methoxy, or methyl.

16. Each R ９ is methyl or L ４ R １２ are independently selected from L ４ is -OCH ２ CH ２ -, -NHCH ２ CH ２ -, -CH ２ -, -CH ２ O-, -CH ２ CH ２ -, -C(CH ３ ) ２ -, -C(CH ２ CH ３ ) ２ -, -CF ２ -, -CH ２ OCH ２ -, -CH ２ OCH ２ CH ２ - or -CH ２ OCH ２ C(CH ３ ) ２ and R １２ But, OH, CN, CD ３ , OCD ３ , F, Cl, -OCH ２ F, -OCHF ２ , OCF ３ , OCH ２ CH ２ F, OCH ２ CHF ２ , OCH ２ CHF ３ , -CH ２ F, CHF ２ , C.F. ３ , -CH ２ CH ２ F, -CH ２ CHF ２ , -CH ２ CHF ３ , methoxy, ethoxy, isopropoxy, CN, methyl, ethyl, isopropyl, -S(=O) ２ CH ３ , -S(=O) ２ -cyclopropyl or -N(CH ３ ) ２ 2. The compound of claim 1, wherein:

17. The compound according to claim 1, having the formula (V-b1), (V-b2), (V-b3) or (V-b4), or a pharmaceutically acceptable salt thereof: 【Chemistry 8】

18. 2. The compound according to claim 1, having the formula (V-c1), (V-c2), (V-c3) or (V-c4), or a pharmaceutically acceptable salt thereof. 【Chemistry 9】

19. L ４ is -OCH ２ CH ２ -, -NHCH ２ CH ２ -, -CH ２ -, -CH ２ O-, -CH ２ CH ２ -, -C(CH ３ ) ２ -, -C(CH ２ CH ３ ) ２ -, -CF ２ -, -CH ２ OCH ２ -, -CH ２ OCH ２ CH ２ - or -CH ２ OCH ２ C(CH ３ ) ２ and R １２ But, OH, CN, CD ３ , OCD ３ , F, Cl, -OCH ２ F, -OCHF ２ , OCF ３ , OCH ２ CH ２ F, OCH ２ CHF ２ , OCH ２ CHF ３ , -CH ２ F, CHF ２ , C.F. ３ , -CH ２ CH ２ F, -CH ２ CHF ２ , -CH ２ CHF ３ , methoxy, ethoxy, isopropoxy, CN, methyl, ethyl, isopropyl, -S(=O) ２ CH ３ , -S(=O) ２ -cyclopropyl or -N(CH ３ ) ２ 2. The compound of claim 1, wherein:

20. L ４ is a bond, -CH ２ -, -(CH ２ ) ｍ -, -C(R ７ ) ２ -, -CF ２ -, -OCH ２ -, -O(CH ２ ) ｍ -, -CH ２ O-, -CH ２ OCH ２ - or -CH ２ OCH ２ C (R ７ ) ２ The compound of claim 1, wherein

21. L ４ is a bond, -CH ２ -, -(CH ２ ) ２ -, -C(CH ３ ) ２ -, -C(CH ２ CH ３ ) ２ -, -CF ２ -, -CH ２ O-, -CH ２ OCH ２ -, -CH ２ OCH ２ C(CH ３ ) ２ - or -CH ２ OCH ２ CH ２ The compound of claim 1, wherein

22. L ４ Ga-CH ２ - or -CH ２ The compound of claim 1, wherein the aryl group is O-.

23. 2. The compound according to claim 1, having the formula (V-d1), (V-d2), (V-d3) or (V-d4), or a pharmaceutically acceptable salt thereof. 【Chemistry 10】

24. 2. The compound according to claim 1, having the formula (V-e1), (V-e2), (V-e3) or (V-e4), or a pharmaceutically acceptable salt thereof. 【Chemistry 11】

25. R １２ But CN, CD ３ , OCD ３ , OH, N(CH ３ ) ２ , -S(O) ２ CH ３ , -S(O) ２ -cyclopropyl, F, Cl, -OCHF ２ , -OCHF ２ , OCF ３ , C.H. ２ F, CHF ２ , C.F. ３ , -methyl, methoxy, ethoxy or isopropoxy.

26. R １２ The compound of claim 1 , wherein is methoxy, ethoxy, or isopropoxy.

27. 5-(4-(morpholinomethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(hydroxymethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-hydroxyphenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(benzyloxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-(pyrrolidin-1-ylmethyl)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-phenoxyphenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(3-aminophenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(3-cyanophenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(3-hydroxyphenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(3-formamidophenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(methylsulfonamido)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(difluoromethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(methoxymethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(3-fluoro-4-methoxyphenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(methoxymethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-phenyl-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-isopropoxyphenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(3-chloro-4-methoxyphenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(methylcarbamoyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(cyanomethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(3-(dimethylamino)propoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(3-(cyanomethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(3-(morpholinomethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(m-tolyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(3-(hydroxymethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(p-tolyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3-methylmorpholino)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-(thiomorpholinomethyl)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2-methylmorpholino)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((7-oxa-4-azaspiro[2.5]octan-4-yl)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-((3-(pyridin-3-yl)morpholino)methyl)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(1-morpholinoethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1,4-oxazepan-4-yl)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6R)-2,6-dimethylmorpholino)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(3-fluoro-4-(morpholinomethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(1-hydroxyethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3-methoxyazetidin-1-yl)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2,2-dimethylmorpholino)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; (S)-5-(4-((3-methoxypyrrolidin-1-yl)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; (R)-5-(4-((3-methoxypyrrolidin-1-yl)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(2-fluoro-4-(morpholinomethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(3-methyl-4-(morpholinomethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-(piperidin-1-ylmethyl)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((dimethylamino)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-((3-oxomorpholino)methyl)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1,1-dioxidothiomorpholino)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(morpholino(oxazol-5-yl)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(methylsulfonamidomethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-((tetrahydro-2H-pyran-4-yl)methyl)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(2-(1,4-dioxan-2-yl)-1,1-difluoroethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1-acetylpiperidin-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3-aminobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(cyclohexylmethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4-methoxybenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4-(dimethylcarbamoyl)benzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3-methoxybenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3-(methylcarbamoyl)benzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3-(methylsulfonamido)benzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3-carbamoylbenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-((3-(propylamino)benzyl)oxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3-(dimethylcarbamoyl)benzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3-acetamidobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4-(methylcarbamoyl)benzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-(pyridin-4-ylmethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(benzo[c][1,2,5]oxadiazol-5-ylmethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-(pyridin-3-ylmethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-(pyridin-2-ylmethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(benzo[c][1,2,5]oxadiazol-4-ylmethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3-(methylsulfonyl)benzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4-cyanobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3-cyanobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-6-(trifluoromethyl)-5-(4-((3-(trifluoromethyl)benzyl)oxy)phenyl)-1,2-dihydropyridine-3-carboxamide; (R or S)-2-oxo-5-(4-(1-(pyridin-3-yl)ethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-(pyrimidin-5-ylmethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1-methylpiperidin-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-(pyridazin-4-ylmethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1H-indazol-6-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1H-indol-6-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-6-(trifluoromethyl)-5-(4-((4-(trifluoromethyl)benzyl)oxy)phenyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-((5-oxopyrrolidin-3-yl)methoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2-cyanobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-(tetrazolo[1,5-a]pyridin-7-ylmethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(imidazo[1,2-a]pyridin-7-ylmethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1-methylpiperidin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4-fluoro-3-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 6-((4-(5-carbamoyl-6-oxo-2-(trifluoromethyl)-1,6-dihydropyridin-3-yl)phenoxy)methyl)benzo[c][1,2,5]oxadiazole 1-oxide; (R or S)-2-oxo-5-(4-(1-(pyrimidin-5-yl)ethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; (R or S)-5-(4-(1-(3-cyanophenyl)ethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((5-cyanopyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(1-(benzo[c][1,2,5]oxadiazol-5-yl)ethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-((tetrahydro-2H-pyran-3-yl)methoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-([1,2,4]triazolo[4,3-a]pyrimidin-6-ylmethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((5-chloro-2-fluoropyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((5-chloropyridin-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2-methoxypyridin-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2-chloro-5-nitrobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-(thiophen-3-ylmethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-6-(trifluoromethyl)-5-(4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3,4-difluorobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4-methoxy-3,5-dimethylpyridin-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3-fluoropyridin-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-(thiophen-2-ylmethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2,5-difluorobenzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4-chloropyridin-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2,4-dimethylthiazol-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2-chloropyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-((5-(propylamino)pyridin-3-yl)methoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-(pyrimidin-2-ylmethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2-morpholinopyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-(pyrazin-2-ylmethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; (R or S)-5-(4-(1-(5-cyanopyridin-3-yl)ethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1-methyl-1H-pyrazol-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4-methoxypyridin-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-morpholinopyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2-fluoropyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((5-fluoro-2-methoxypyridin-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-(quinoxalin-6-ylmethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1-methyl-1H-indazol-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4-(methylsulfonyl)benzyl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-(thiazol-5-ylmethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4,6-dimethylpyridin-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2-methoxypyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(isoquinolin-7-ylmethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-(quinolin-7-ylmethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3-fluoropyridin-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4,6-dimethylpyrimidin-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1-methyl-1H-imidazol-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2-morpholinopyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-(thiazol-2-ylmethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3,4-dimethoxypyridin-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1-methyl-1H-indazol-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((5-methoxypyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2,6-dimethylpyridin-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-chlorobenzo[d][1,3]dioxol-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2-hydroxypyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2-(oxetan-3-ylmethoxy)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2-(2-hydroxyethoxy)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-((2-propoxypyrimidin-5-yl)methoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-((2-((tetrahydrofuran-3-yl)oxy)pyrimidin-5-yl)methoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2-(cyclopentyloxy)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2-(oxetan-2-ylmethoxy)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-((2-((tetrahydrofuran-3-yl)methoxy)pyrimidin-5-yl)methoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2-(methylamino)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2-(cyclopentylamino)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2-(dimethylamino)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2-((cyclopropylmethyl)amino)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2-((2-hydroxyethyl)amino)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2-(cyclopropylamino)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2-(heptylamino)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2-(oxetan-3-ylamino)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-((2-((tetrahydrofuran-3-yl)amino)pyrimidin-5-yl)methoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-(cyclopentylamino)pyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-((cyclopropylmethyl)amino)pyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-(3,3-difluoroazetidin-1-yl)pyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-(3-methoxyazetidin-1-yl)pyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2-cyclopropylpyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2-(cyclopentylmethyl)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2-neopentylpyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4-(cyclopentylamino)pyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3-(cyclopropylmethyl)-3H-imidazo[4,5-b]pyridin-6-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-chloropyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-((pyridin-3-yloxy)methyl)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((5-(furan-3-yl)pyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((5-morpholinopyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-((5-(tetrahydrofuran-3-yl)pyridin-3-yl)methoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((5-(3-hydroxyoxetan-3-yl)pyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((5-(3-fluorooxetan-3-yl)pyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-((3-(pyridin-3-yl)oxetan-3-yl)oxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(cyclopropyl(pyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-((1-(pyridin-3-yl)pent-4-en-1-yl)oxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(2-methoxy-1-(pyridin-3-yl)ethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(2-hydroxy-1-(pyrazin-2-yl)ethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4-acetylmorpholin-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(morpholin-2-ylmethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; tert-butyl 2-((4-5-carbamoyl-6-oxo-2-trifluoromethyl-1,6-dihydropyridin-3-yl)phenoxy)methyl)morpholine-4-carboxylate; 5-(4-((4-(isopropylsulfonyl)morpholin-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4-(2,2-difluoroethyl)morpholin-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4-(2-methoxyethyl)morpholin-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4-(cyclopropylmethyl)morpholin-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1,4-oxazepan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4-(oxetan-3-yl)-1,4-oxazepan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4-(isopropylsulfonyl)-1,4-oxazepan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4-(isobutylsulfonyl)-1,4-oxazepan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(2-morpholino-2-oxoethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(2-(butylamino)-2-oxoethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-(2-oxo-2-(pyridin-3-ylamino)ethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4-methoxytetrahydro-2H-pyran-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,5S)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2,8-dioxa-5-azaspiro[3.5]nonan-6-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((5-methyl-2,8-dioxa-5-azaspiro[3.5]nonan-6-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-6-(trifluoromethyl)-5-(4-((4,5,5-trimethylmorpholin-3-yl)methoxy)phenyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((5S)-4,5-dimethylmorpholin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((3S,5S)-5-cyclopropyl-4-methylmorpholin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((3R,5S)-5-cyclopropyl-4-methylmorpholin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((5S)-5-isopropyl-4-methylmorpholin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((5-bromopyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((5-chloropyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-(pyridazin-3-ylmethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-(pyrimidin-4-ylmethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-chloropyrazin-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1-ethyl-1H-pyrazol-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1-(2-methoxyethyl)-1H-pyrazol-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1-methyl-1H-pyrazol-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1-ethyl-1H-pyrazol-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(isoxazol-3-ylmethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((5-methylisoxazol-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(oxetan-2-ylmethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3-fluorooxetan-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3-methyloxetan-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3-ethyloxetan-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3-(cyanomethyl)oxetan-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2-oxaspiro[3.3]heptan-6-yl)oxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-((tetrahydrofuran-3-yl)methoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-((tetrahydrofuran-2-yl)methoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3-methyl-2-oxooxazolidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3-ethyl-2-oxooxazolidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3-methyl-2-oxooxazolidin-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-((tetrahydro-2H-pyran-2-yl)methoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1,4-dioxan-2-yl)methoxy)-3-fluorophenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1,4-dioxan-2-yl)methoxy)-3-chlorophenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1,4-dioxan-2-yl)methoxy)-3-cyanophenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1,4-dioxan-2-yl)methoxy)-3-methylphenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1,4-dioxan-2-yl)methoxy)-3-cyclopropylphenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1,4-dioxan-2-yl)methoxy)-3-methoxyphenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1,4-dioxan-2-yl)methoxy)-2-fluorophenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(morpholin-3-ylmethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4-methylmorpholin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4-cyclopropylmorpholin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4-ethylmorpholin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-((5-oxomorpholin-3-yl)methoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4-methyl-5-oxomorpholin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1-(methylsulfonyl)cyclopropyl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1-(cyclopropylsulfonyl)cyclopropyl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(2-methoxyethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(2-hydroxyethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(2-(methylsulfonyl)ethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-(2-(2-oxooxazolidin-3-yl)ethoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(2-(1H-imidazol-1-yl)ethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(2-morpholinoethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(2-hydroxy-3-morpholinopropoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1,3-dimethyl-1H-pyrazol-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3-ethyl-1-methyl-1H-pyrazol-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-6-(trifluoromethyl)-5-(4-((1,3,4-trimethyl-1H-pyrazol-5-yl)methoxy)phenyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1-(cyclopropylmethyl)-1H-pyrazol-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(oxazol-4-ylmethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(oxazol-5-ylmethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((5-cyclopropylisoxazol-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((5-methylisoxazol-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((5-methyl-3-(pyridin-4-yl)isoxazol-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2-methylthiazol-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4-methylthiazol-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4-methyl-1,2,3-thiadiazol-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4-methylpyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4-cyclopropylpyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4-methoxypyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4-ethoxypyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((5-methylpyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((5-cyclopropylpyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4-isopropoxypyridin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4-methylpyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4-cyclopropylpyrimidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-methylpyrazin-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-cyclopropylpyrazin-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(imidazo[1,2-a]pyridin-2-ylmethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(imidazo[1,2-a]pyridin-3-ylmethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-((4,5,6,7-tetrahydrobenzo[d]isoxazol-3-yl)methoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2,3-dihydrobenzofuran-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1-methyl-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2-methyl-2,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1-isopropyl-1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2-isopropyl-2,4,5,7-tetrahydropyrano[3,4-c]pyrazol-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(chroman-2-ylmethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; tert-butyl 3-((4-(5-carbamoyl-6-oxo-2-(trifluoromethyl)-1,6-dihydropyridin-3-yl)phenoxy)methyl)azetidine-1-carboxylate, tert-butyl((1r,3r)-3-((4-(5-carbamoyl-6-oxo-2-(trifluoromethyl)-1,6-dihydropyridin-3-yl)phenoxy)methyl)cyclobutyl)carbamate, (S)-5-(4-((5,5-dimethyltetrahydrofuran-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; tert-butyl 6-((4-(5-carbamoyl-6-oxo-2-(trifluoromethyl)-1,6-dihydropyridin-3-yl)phenoxy)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate, tert-butyl 3-((4-(5-carbamoyl-6-oxo-2-(trifluoromethyl)-1,6-dihydropyridin-3-yl)phenoxy)methyl)pyrrolidine-1-carboxylate, tert-butyl 3-((4-(5-carbamoyl-6-oxo-2-(trifluoromethyl)-1,6-dihydropyridin-3-yl)phenoxy)methyl)-4-methylpyrrolidine-1-carboxylate, 5-(4-((1-benzyl-3-cyanopyrrolidin-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; tert-butyl (2S,4R)-2-((4-(5-carbamoyl-6-oxo-2-(trifluoromethyl)-1,6-dihydropyridin-3-yl)phenoxy)methyl)-4-fluoropyrrolidine-1-carboxylate, tert-butyl (2S,4S)-2-((4-(5-carbamoyl-6-oxo-2-(trifluoromethyl)-1,6-dihydropyridin-3-yl)phenoxy)methyl)-4-fluoropyrrolidine-1-carboxylate, 5-(4-((3-isopropyl-2-oxooxazolidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3-(cyclopropylmethyl)-2-oxooxazolidin-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3-ethyl-2-oxooxazolidin-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3-isopropyl-2-oxooxazolidin-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3-(cyclopropylmethyl)-2-oxooxazolidin-4-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((7-oxabicyclo[2.2.1]heptan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3,8-dioxabicyclo[3.2.1]octan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1,4-dioxepan-6-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-methyl-1,4-dioxepan-6-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((5-methyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2R,6R)-6-cyclopropyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2R,6S)-6-cyclopropyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2R,6R)-6-methyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6R)-6-methyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6S)-6-methyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2R,6S)-6-methyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-cyclopentyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4,7-dioxaspiro[2.5]octan-5-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((5,5-difluorotetrahydro-2H-pyran-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((4,7-dioxaspiro[2.5]octan-6-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((5,5-dimethyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((5-(fluoromethyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((5-(difluoromethyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-(difluoromethyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-(fluoromethyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-(1-methoxycyclopropyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-(2-hydroxypropan-2-yl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-(1-methylcyclopropyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-(1,1-difluoroethyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-(ethoxymethyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-((cyclopropylmethoxy)methyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-(((1-fluorocyclopropyl)methoxy)methyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-((3,3-difluorocyclobutoxy)methyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-((2,2-difluoroethoxy)methyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-((2-methoxy-2-methylpropoxy)methyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 2-oxo-5-(4-((6-((trifluoromethoxy)methyl)-1,4-dioxan-2-yl)methoxy)phenyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-((1H-pyrrol-1-yl)methyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-((1H-pyrazol-1-yl)methyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-(((3-methyloxetan-3-yl)oxy)methyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3-cyclopropyl-6,7-dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]oxazin-6-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((3-cyclopropyl-6,7-dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]oxazin-7-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-(2-methoxypropan-2-yl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-(3-fluoropentan-3-yl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-(hydroxymethyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-((3-fluoroazetidin-1-yl)methyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-((3,3-difluoroazetidin-1-yl)methyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-((3-methoxyazetidin-1-yl)methyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((2-fluoro-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((1,4-dioxan-2-yl)difluoromethoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((1S,3R,6R)-7,7-difluoro-2,5-dioxabicyclo[4.1.0]heptan-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; Also known as 5-(4-((cis-7,7-difluoro-2,5-dioxabicyclo[4.1.0]heptan-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((1R,3R,6S)-7,7-difluoro-2,5-dioxabicyclo[4.1.0]heptan-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; Also known as 5-(4-((trans-7,7-difluoro-2,5-dioxabicyclo[4.1.0]heptan-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-((6-(methoxymethyl)-5-methyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((1S,3S,6R)-7,7-difluoro-1-methyl-2,5-dioxabicyclo[4.1.0]heptan-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((1R,3S,6S)-7,7-difluoro-1-methyl-2,5-dioxabicyclo[4.1.0]heptan-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((1R,3R,6S)-7,7-difluoro-1-methyl-2,5-dioxabicyclo[4.1.0]heptan-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((1S,3R,6R)-7,7-difluoro-1-methyl-2,5-dioxabicyclo[4.1.0]heptan-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6S)-6-(methoxymethyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6R)-6-(methoxymethyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2R,6R)-6-(methoxymethyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2R,6S)-6-(methoxymethyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6R)-6-(isopropoxymethyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6S)-6-(isopropoxymethyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6S)-6-cyclopropyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6S)-6-(methoxymethyl)-6-methyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6R)-6-(methoxymethyl)-6-methyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2R,6R)-6-(methoxymethyl)-6-methyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2R,6S)-6-(methoxymethyl)-6-methyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6R)-6-(dimethylcarbamoyl)-6-methyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6S)-6-((methoxy-d3)methyl)-6-methyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6S)-6-(cyanomethyl)-6-methyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6R)-6-methyl-6-((methylsulfonyl)methyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6R)-6-((cyclopropylsulfonyl)methyl)-6-methyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; (S)-5-(4-((6,6-bis(methoxymethyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; (S)-5-(4-((2,5,8-trioxaspiro[3.5]nonan-6-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; (S)-5-(4-((1,4,8,11-tetraoxaspiro[5.6]dodecan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6S)-6-(fluoromethyl)-6-(methoxymethyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6S)-6-(chloromethyl)-6-(methoxymethyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6S)-6-(fluoromethyl)-6-methyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6R)-6-(fluoromethyl)-6-methyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6R)-6-((3-fluoroazetidin-1-yl)methyl)-6-methyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6R)-6-((3,3-difluoroazetidin-1-yl)methyl)-6-methyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6S)-6-((dimethylamino)methyl)-6-methyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6R)-6-((dimethylamino)methyl)-6-methyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6R)-6-((difluoromethoxy)methyl)-6-methyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6S)-6-(2-methoxyethyl)-6-methyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6R)-6-methyl-6-((oxetan-3-yloxy)methyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6S)-6-(ethoxymethyl)-6-methyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6R)-6-methyl-6-(((3-methyloxetan-3-yl)oxy)methyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6S)-6-((2-methoxyethoxy)methyl)-6-methyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6R)-6-((2,2-difluoroethoxy)methyl)-6-methyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6R)-6-methyl-6-((2,2,2-trifluoroethoxy)methyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6S)-6-(hydroxymethyl)-6-methyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6S)-6-(2,2-difluoroethyl)-6-methyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6S)-6-(2-fluoroethyl)-6-methyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6R)-6-((2-fluoroethoxy)methyl)-6-methyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6R)-6-cyclopropyl-6-methyl-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6R)-6-cyclopropyl-6-(methoxymethyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide; 5-(4-(((2S,6S)-6-cyclopropyl-6-(methoxymethyl)-1,4-dioxan-2-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide, and / or The compound of claim 1, which is 5-(4-(((5R,7S)-2,6,9-trioxaspiro[4.5]decan-7-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide.

28. 30. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 27, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

29. 30. A method for inhibiting influenza virus nucleoprotein (NP), comprising contacting the NP with a compound of any one of claims 1 to 27, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

30. 1. A pharmaceutical composition for use in a method for preventing or treating influenza, comprising: The pharmaceutical composition comprises a compound according to any one of claims 1 to 27, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof; The method comprises administering to a subject a therapeutically effective amount of a compound of any one of claims 1 to 27, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

31. 28. A pharmaceutical composition comprising a compound according to any one of claims 1 to 27, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

32. A combination comprising a therapeutically effective amount of a compound according to any one of claims 1 to 27, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and one or more therapeutically active co-agents.

33. 1. A pharmaceutical composition for use in a method for treating influenza, comprising: The pharmaceutical composition comprises a compound according to any one of claims 1 to 27, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof; The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 27, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

34. 30. A compound according to any one of claims 1 to 27, a stereoisomer thereof or a pharmaceutically acceptable salt thereof for use in the treatment of influenza.

35. 30. Use of a compound according to any one of claims 1 to 27, a stereoisomer thereof or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of influenza.

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