Ion channel modulators

Abstract

This invention relates in part to fused heteroaryl compounds and compositions that can be used to prevent and / or treat diseases or conditions associated with abnormal function of voltage-gated sodium ion channels (e.g., abnormal late / continuous sodium current). Methods for treating diseases or conditions associated with abnormal function of sodium ion channels are also provided herein, including neurological disorders (e.g., Dravet syndrome, epilepsy), pain, and neuromuscular disorders.

Description

Prior Technology

[0001] Sodium ion (Na+) channels open transiently and inactivate rapidly, thereby generating a rapid Na+ current to initiate action potentials. Late or sustained sodium currents (INaL) are a sustained component of the rapid Na+ currents in cardiac myocytes and neurons. Many common neurological and cardiac conditions are associated with abnormal INaL enhancement, which contributes to the pathogenesis of both electrical and contractile dysfunction in mammals (e.g., see Pharmacol Ther (2008) 119:326-339). Therefore, pharmaceutical compounds that selectively modulate sodium channel activity (e.g., abnormal INaL) can be used to treat these disease states. Summary of the Invention

[0002] This article describes fused heteroaryl compounds and compositions that can be used to prevent and / or treat diseases, symptoms or conditions, such as those related to abnormal function of sodium ion channels (e.g., abnormal late sodium current (INaL)).

[0003] In one state, the present invention provides a form having [I] of the compound: ; Or a medicinally acceptable salt, in which X and Y are each independently CRd or N; R1 series Monocyclic C3-6 cycloalkyl or 4- to 7-membered monocyclic heterocyclic group, wherein such cycloalkyl and heterocyclic group are substituted by one or more Ra as appropriate; R2 refers to C1-4 haloalkyl, phenyl, or monocyclic C3-6 cycloalkyl groups, which may be substituted with one or more Rb groups as appropriate; R3 series hydrogen, C1-4 alkyl or C1-4 haloalkyl; R4 series hydrogen or C1-4 alkyl; R5-series halogens; R6 series C1-4 alkyl or C1-4 haloalkyl, wherein each of the C1-4 alkyl or C1-4 haloalkyl is substituted with ORc; t is 0, 1, or 2; Ra and Rb are each independently selected from halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy groups. Rc refers to C1-4 alkyl or C3-6 cycloalkyl groups substituted with C3-6 cycloalkyl or C1-4 alkoxy groups, depending on the situation; and Rd series hydrogen or C1-4 alkyl; The premise is that the compound is not a compound having the following formula: or Or a medicinally acceptable salt.

[0004] In some embodiments, the compound has formula Ia: ; Or a pharmaceutically acceptable salt, wherein the variables are as defined herein.

[0005] In some embodiments, the compound has the formula Ib: ; Or a pharmaceutically acceptable salt, wherein the variables are as defined herein.

[0006] In some embodiments, the compound has the formula [II]: ; Or a pharmaceutically acceptable salt, wherein the variables are as defined herein.

[0007] In some embodiments, the compound has the formula [III]: ; Or a pharmaceutically acceptable salt, wherein the variables are as defined herein.

[0008] In some embodiments, the compound has the formula [Ic]: ; Or a pharmaceutically acceptable salt, wherein the variables are as defined herein.

[0009] In another embodiment, the present invention provides a form having [Id] of compounds: ; Or a medicinally acceptable salt, in which R1 series Monocyclic C3-6 cycloalkyl or 4- to 7-membered monocyclic heterocyclic group, wherein such cycloalkyl and heterocyclic group are substituted by one or more Ra as appropriate; R2 refers to C1-4 haloalkyl, phenyl, or monocyclic C3-6 cycloalkyl groups, which may be substituted with one or more Rb groups as appropriate; R3 series hydrogen, C1-4 alkyl or C1-4 haloalkyl; R4 series hydrogen or C1-4 alkyl; R5-series halogens; R6 series C1-4 alkyl or C1-4 haloalkyl, wherein each of the C1-4 alkyl or C1-4 haloalkyl is substituted with ORc; t is 0, 1, or 2; Ra and Rb are each independently selected from halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; Rc refers to C1-4 alkyl or C3-6 cycloalkyl groups substituted with C3-6 cycloalkyl or C1-4 alkoxy groups, depending on the situation; and Rd series hydrogen or C1-4 alkyl.

[0010] In some embodiments, the compound has the formula [V]: ; Or a pharmaceutically acceptable salt, wherein the variables are as defined herein.

[0011] In some embodiments, the compound has the formula [VII]: ; Or a pharmaceutically acceptable salt, wherein the variables are as defined herein.

[0012] In some embodiments, the compound has the formula [VIII]: ; Or a pharmaceutically acceptable salt, wherein the variables are as defined herein.

[0013] In some embodiments, the compound has the formula [VIII]: ; Or a pharmaceutically acceptable salt, wherein the variables are as defined herein.

[0014] In another state, this paper provides crystalline compounds of the following formula: , The crystalline compound exhibits an X-ray powder diffraction pattern containing peaks at the following diffraction angles (2θ): 6.9±0.2, 16.5±0.2, and 20.8±0.2.

[0015] In another state, this paper provides crystalline compounds of the following formula: , The crystalline compound exhibits an X-ray powder diffraction pattern containing peaks at the following diffraction angles (2θ): 16.7±0.2, 19.0±0.2, and 20.4±0.2.

[0016] In another embodiment, the present invention provides a crystalline compound of the following formula: , The crystalline compound exhibits an X-ray powder diffraction pattern containing peaks at the following diffraction angles (2θ): 7.3±0.2, 14.5±0.2, and 21.9±0.2.

[0017] In another embodiment, the present invention provides a crystalline compound of the following formula: , The crystalline compound exhibits an X-ray powder diffraction pattern containing peaks at the following diffraction angles (2θ): 12.6±0.2, 15.8±0.2, and 18.6±0.2.

[0018] In another embodiment, the present invention provides a crystalline compound of the following formula: , The crystalline compound exhibits an X-ray powder diffraction pattern containing peaks at the following diffraction angles (2θ): 5.8±0.2, 19.7±0.2, and 21.0±0.2.

[0019] In another embodiment, the present invention provides a crystalline compound of the following formula: , The crystalline compound exhibits an X-ray powder diffraction pattern containing peaks at the following diffraction angles (2θ): 7.3±0.2, 16.6±0.2, and 18.4±0.2.

[0020] In another embodiment, the present invention provides a crystalline compound of the following formula: , The crystalline compound exhibits an X-ray powder diffraction pattern containing peaks at the following diffraction angles (2θ): 6.9±0.2, 16.4±0.2, and 19.5±0.2.

[0021] In another embodiment, the present invention provides a crystalline compound of the following formula: , The crystalline compound exhibits an X-ray powder diffraction pattern containing peaks at the following diffraction angles (2θ): 9.9±0.2, 19.8±0.2, and 23.7±0.2.

[0022] In another embodiment, the present invention provides a crystalline compound of the following formula: , The crystalline compound exhibits an X-ray powder diffraction pattern containing peaks at the following diffraction angles (2θ): 9.3±0.2, 18.8±0.2, and 21.4±0.2.

[0023] In another embodiment, this document provides pharmaceutical compositions comprising the compounds disclosed herein, or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers.

[0024] In another embodiment of the invention, a composition comprising the compounds disclosed herein (e.g., compounds of formula I, I', Ia, Ib, Ic, Id, II, III, V, VII, VIII, or IX) or their pharmaceutically acceptable salts and pharmaceutically acceptable carriers is provided.

[0025] This document also provides pharmaceutical compositions comprising the compounds disclosed herein (e.g., compounds of formula I, I', Ia, Ib, Ic, Id, II, III, V, VII, VIII, or IX) or their pharmaceutically acceptable salts and pharmaceutically acceptable carriers, for use in medicine.

[0026] In another embodiment, this document provides a method for treating an individual with a condition related to abnormal function of sodium ion channels, comprising administering to the individual a therapeutically effective amount of a compound disclosed herein (e.g., a compound of formula I, I', Ia, Ib, Ic, Id, II, III, V, VII, VIII, or IX) or a pharmaceutically acceptable salt thereof, or a composition or pharmaceutical composition disclosed herein.

[0027] In some embodiments, the condition is a neurological disorder or mental abnormality. In some embodiments, the condition is epilepsy or epilepsy syndrome. In some embodiments, the condition is hereditary epilepsy or hereditary epilepsy syndrome. In some embodiments, the condition is childhood epilepsy or childhood epilepsy syndrome. In some embodiments, the condition is epileptic encephalopathy. In some embodiments, epileptic encephalopathy is selected from the group consisting of: Dravet syndrome, infantile spasms, and Lennox-Gastaut syndrome.

[0028] In some embodiments, the condition is selected from the group consisting of: epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, or SCN8A mutations, early infantile epileptic encephalopathy, Delaware syndrome, Delaware syndrome with SCN1A mutation, generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infant epilepsy, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutation, cryptogenic partial epilepsy in children with SCN3A mutation, SCN8A epileptic encephalopathy, Rasmussen encephalitis, infantile malignant migratory partial epilepsy, autosomal dominant nocturnal frontal lobe epilepsy, sudden unexpected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy.

[0029] In another embodiment, this document provides a method for treating neurological disorders or mental abnormalities, wherein the method comprises administering to an individual in need a compound disclosed herein (e.g., a compound of formula I, I', Ia, Ib, Ic, Id, II, III, V, VII, VIII, or IX) or a pharmaceutically acceptable salt thereof, or a composition or pharmaceutical composition disclosed herein.

[0030] In another embodiment, the present invention provides a method for treating pain, wherein the method comprises administering to an individual in need a compound disclosed herein (e.g., a compound of formula I, I', Ia, Ib, Ic, Id, II, III, V, VII, VIII, or IX) or a pharmaceutically acceptable salt thereof, or a composition or pharmaceutical composition disclosed herein.

[0031] The present invention also provides compositions comprising compounds disclosed herein (e.g., compounds of formula I, I', Ia, Ib, Ic, Id, II, III, V, VII, VIII, or IX) or their pharmaceutically acceptable salts, or pharmaceutical compositions disclosed herein, or compositions disclosed herein, for the treatment of an individual with a condition related to abnormal function of sodium ion channels.

[0032] In some embodiments, the condition is a neurological disorder or mental abnormality. In some embodiments, the condition is pain. In some embodiments, the condition is epilepsy or epilepsy syndrome. In some embodiments, the condition is hereditary epilepsy or hereditary epilepsy syndrome. In some embodiments, the condition is childhood epilepsy or childhood epilepsy syndrome. In some embodiments, the condition is epileptic encephalopathy. In some embodiments, epileptic encephalopathy is selected from the group consisting of: Dravier syndrome, infantile spasms, and Regger syndrome.

[0033] In some embodiments, the condition is selected from the group consisting of: epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, Delaware syndrome, Delaware syndrome with SCN1A mutation, generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infant epilepsy, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutation, cryptogenic partial epilepsy in children with SCN3A mutation, SCN8A epileptic encephalopathy, Rasmussen encephalitis, infantile malignant migratory partial seizures, autosomal dominant nocturnal frontal lobe epilepsy, sudden unexpected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy.

[0034] In another embodiment, the present invention provides compositions comprising compounds disclosed herein (e.g., compounds of formula I, I', Ia, Ib, Ic, Id, II, III, V, VII, VIII, or IX) or their pharmaceutically acceptable salts, pharmaceutical compositions disclosed herein, or compositions disclosed herein for the treatment of neurological disorders or mental abnormalities.

[0035] Those skilled in the art will understand other objectives and advantages upon consideration of the subsequent implementation methods, examples and the scope of the patent application. Simple Explanation of the Diagram

[0036] [picture] [1A] shows the XRPD pattern of the raw material of compound 10. [picture] [1B] shows the DSC of compound 10. [picture] [2A] shows the XRPD pattern of the raw material of compound 62. [picture] [2B] shows the DSC of compound 62. [picture] [3A] shows the XRPD pattern of the raw material of compound 6B. [picture] [3B] shows the DSC of compound 6B. [picture] [4A] shows the XRPD pattern of the raw material of compound 56. [picture] [4B] shows the DSC of compound 56. [picture] [5A] shows the XRPD pattern of the raw material of compound 3. [picture] [5B] shows the DSC of compound 3. [picture] [6A] shows the XRPD pattern of the raw material of compound 11. [picture] [6B] shows the DSC of compound 11. [picture] [7A] shows the XRPD pattern of the raw material of compound 53. [picture] [7B] shows the DSC of compound 53. [picture] [8A] shows the XRPD pattern of the raw material of compound 59. [picture] [8B] shows the DSC of compound 59. [picture] [9A] shows the XRPD pattern of the raw material of compound 48. [picture] [9B] shows the DSC of compound 48. Implementation

[0037] Cross-reference to related applications This application claims priority and benefits to U.S. Provisional Patent Application No. 62 / 677,903, filed May 30, 2018, and No. 62 / 738,508, filed September 28, 2018, each of which is incorporated herein by reference in its entirety.

[0038] As generally described herein, the present invention provides compounds and compositions that can be used to prevent and / or treat the diseases, conditions, or illnesses described herein (e.g., diseases, conditions, or illnesses related to abnormal function of sodium ion channels (e.g., abnormal late sodium current (INaL))). Examples of diseases, conditions, or illnesses include neurological disorders (e.g., epilepsy or epilepsy syndrome, neurodevelopmental disorders, or neuromuscular disorders), mental disorders, pain, or gastrointestinal disorders.

[0039] [definition] [ ] Chemical definition The definitions of specific functional groups and chemical terms are elaborated in more detail below. Chemical elements are identified according to the periodic table, CAS edition, Handbook of Chemistry and Physics, 75th edition, inside cover, and specific functional groups are generally defined as described in this article. In addition, the general principles of organic chemistry, as well as specific functional parts and reactivity, are described in the following: Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd edition, Cambridge University Press, Cambridge, 1987.

[0040] The compounds described herein may contain one or more asymmetric centers, and therefore may exist in various isomeric forms (e.g., mirror-image isomers and / or non-mirror-image isomers). For example, the compounds described herein may exist as individual mirror-image isomers, non-mirror-image isomers, or geometric isomers, or as mixtures of stereoisomers (including racemic mixtures) and mixtures rich in one or more stereoisomers. The isomers may be separated from the mixture and form and crystallize chiral salts by methods known to those skilled in the art (including chiral high-performance liquid chromatography (HPLC)); or preferably, the isomers may be prepared by asymmetric synthesis. For example, see Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions, p. 268 (edited by EL Eliel, Univ. of Notre Dame Press, Notre Dame, IN 1972). This invention further covers the compounds described herein in the form of individual isomers substantially free of other isomers or in mixtures of various isomers.

[0041] As used herein, a pure mirror-isomer compound substantially does not contain any other mirror-isomers or stereoisomers of the compound (i.e., mirror-isomer excess). In other words, the "S" form of the compound substantially does not contain the "R" form of the compound, and therefore, is an "R" form of mirror-isomer excess. The terms "mirror-isomer pure" or "pure mirror-isomer" mean that the compound contains more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight, or more than 99.9% by weight. In some embodiments, the weight is based on the total weight of all mirror-isomers or stereoisomers of the compound.

[0042] In the compositions provided herein, the mirror-image isomeric pure compound may be present together with other active or inactive ingredients. For example, a pharmaceutical composition comprising a mirror-image isomeric pure R-compound may comprise, for example, about 90% excipients and about 10% mirror-image isomeric pure R-compound. In some embodiments, the mirror-image isomeric pure R-compound in these compositions may comprise, for example, at least about 95% by weight of R-compound and at most about 5% by weight of S-compound, based on the total weight of the compounds. For example, a pharmaceutical composition comprising a mirror-image isomeric pure S-compound may comprise, for example, about 90% excipients and about 10% mirror-image isomeric pure S-compound. In some embodiments, the mirror-image isomeric pure S-compound in these compositions may comprise, for example, at least about 95% by weight of S-compound and at most about 5% by weight of R-compound, based on the total weight of the compounds. In some embodiments, the active ingredient may be formulated with very little or no excipients or carriers.

[0043] The compounds described herein may also contain one or more isotopic substitutions. For example, H may be in any isotopic form, including 1H, 2H (D or deuterium), and 3H (T or tritium); C may be in any isotopic form, including 12C, 13C, and 14C; O may be in any isotopic form, including 16O and 18O; F may be in any isotopic form, including 18F and 19F; and so on.

[0044] The following terms are intended to have the meanings provided below and are used to understand the description and established scope of this invention. When the invention (which may include compounds and their pharmaceutically acceptable salts, pharmaceutical compositions containing such compounds, and methods of using such compounds and compositions) is described, the following terms (if present) shall have the following meanings unless otherwise indicated. It should also be understood that, when set forth herein, any portion defined below may be substituted with multiple substituents, and each definition is intended to include such substituted portion within its scope below. Unless otherwise stated, the term "substituted" shall be defined as set forth below. It should be further understood that, as used herein, the terms "group" and "radical" are considered interchangeable. The article "a" (and an) used herein refers to one or more (i.e., at least one) grammatical object of that article. For example, "analogue" means one or more analogues.

[0045] When listing a range of values, it is intended to encompass every value within that range and its subranges. For example, "C1-6 alkyl" is intended to encompass C1, C2, C3, C4, C5, C6, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl.

[0046] As used herein, "alkyl" refers to, for example, a straight-chain or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C1-20 alkyl"). In some embodiments, the alkyl group has 1 to 10 carbon atoms ("C1-10 alkyl"). In some embodiments, the alkyl group has 1 to 9 carbon atoms ("C1-9 alkyl"). In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C1-8 alkyl"). In some embodiments, the alkyl group has 1 to 7 carbon atoms ("C1-7 alkyl"). In some embodiments, the alkyl group has 1 to 6 carbon atoms ("C1-6 alkyl"). In some embodiments, the alkyl group has 1 to 5 carbon atoms ("C1-5 alkyl"). In some embodiments, the alkyl group has 1 to 4 carbon atoms ("C1-4 alkyl"). In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C1-3 alkyl"). In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C1-2 alkyl"). In some embodiments, the alkyl group has 1 carbon atom ("C1 alkyl"). Examples of C1-6 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, and the like.

[0047] As used herein, "alkenyl" refers to a straight-chain or branched hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds), and, where appropriate, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds) ("C2-20 alkenyl"). In some embodiments, the alkenyl group does not contain any triple bonds. In some embodiments, the alkenyl group has 2 to 10 carbon atoms ("C2-10 alkenyl"). In some embodiments, the alkenyl group has 2 to 9 carbon atoms ("C2-9 alkenyl"). In some embodiments, the alkenyl group has 2 to 8 carbon atoms ("C2-8 alkenyl"). In some embodiments, the alkenyl group has 2 to 7 carbon atoms ("C2-7 alkenyl"). In some embodiments, the alkenyl group has 2 to 6 carbon atoms ("C2-6 alkenyl"). In some embodiments, the alkenyl group has 2 to 5 carbon atoms ("C2-5 alkenyl"). In some embodiments, the alkenyl group has 2 to 4 carbon atoms ("C2-4 alkenyl"). In some embodiments, the alkenyl group has 2 to 3 carbon atoms ("C2-3 alkenyl"). In some embodiments, the alkenyl group has 2 carbon atoms ("C2 alkenyl"). One or more carbon-carbon double bonds may be located internally (e.g., in 2-butenyl) or terminally (e.g., in 1-butenyl). Examples of C2-4 alkenyl groups include vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-6 alkenyl groups include the C2-4 alkenyl groups mentioned above, as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl groups include heptenyl (C7), octenyl (C8), octetrinyl (C8), and the like.

[0048] As used herein, "alkynyl" refers to a straight-chain or branched hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds), and, where appropriate, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) ("C2-20 alkynyl"). In some embodiments, the alkynyl group does not contain any double bonds. In some embodiments, the alkynyl group has 2 to 10 carbon atoms ("C2-10 alkynyl"). In some embodiments, the alkynyl group has 2 to 9 carbon atoms ("C2-9 alkynyl"). In some embodiments, the alkynyl group has 2 to 8 carbon atoms ("C2-8 alkynyl"). In some embodiments, the alkynyl group has 2 to 7 carbon atoms ("C2-7 alkynyl"). In some embodiments, the alkynyl group has 2 to 6 carbon atoms ("C2-6 alkynyl"). In some embodiments, the alkynyl group has 2 to 5 carbon atoms ("C2-5 alkynyl"). In some embodiments, the alkynyl group has 2 to 4 carbon atoms ("C2-4 alkynyl"). In some embodiments, the alkynyl group has 2 to 3 carbon atoms ("C2-3 alkynyl"). In some embodiments, the alkynyl group has 2 carbon atoms ("C2 alkynyl"). One or more carbon-carbon triple bonds may be located internally (e.g., in the 2-butynyl group) or terminally (e.g., in the 1-butynyl group). Examples of C2-4 alkynyl groups include (but are not limited to) ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C2-6 alkynyl groups include the C2-4 alkynyl groups mentioned above, as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl groups include heptyynyl (C7), octyynyl (C8), and the like.

[0049] As used herein, "alkyl," "alkenyl," and "ynyl" refer to the divalent groups of alkyl, alkenyl, and ynyl groups, respectively. When a range or number of carbons is provided for a particular "alkyl," "alkenyl," or "ynyl," it should be understood that the range or number refers to the range or number of carbons in a straight-chain divalent carbon chain. "alkyl," "alkenyl," and "ynyl" may be substituted with one or more substituents as described herein or may not be substituted.

[0050] As used herein, "aryl" refers to a group ("C6-14 aryl") that provides a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system having 6-14 ring carbon atoms and 0 heteroatoms. In some embodiments, the aryl group has 6 ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl group has 10 ring carbon atoms ("C10 aryl"; e.g., naphthyl, e.g., 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms ("C14 aryl"; e.g., anthracene). "Aryl" also includes ring systems in which the aryl ring as defined above is fused with one or more carbocyclic or heterocyclic groups, wherein the group or connecting point is on the aryl ring, and in such cases, the number of carbon atoms continues to name the number of carbon atoms in the aryl ring system. Typical aryl groups include (but are not limited to) those derived from: ethenyl anthracene, acenaphthene, phenanthrene, anthracene, chamomile, benzene, Hexabenzobenzene, fluoranthene, fentanyl, hexabenzobenzene, hexalene, as-dicyclopentadienbenzene, s-dicyclopentadienbenzene, dihydroindene, indene, naphthalene, octabenzobenzene, octalene, oleophane, pent-2,4-diene, pentabenzobenzene, cyclopentadiene, dibenzophenanthrene, perylene, phenate, phenanthrene, pyrene, pyranthrene, rubicene, terphenyl and ternaphthalene. Specific aryl groups include phenyl, naphthyl, indene, and tetrahydronaphthyl.

[0051] As used herein, "heteroaryl" refers to a group that provides a 5-10 member monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 electrons shared in a ring array) having a ring carbon atom and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 member heteroaryl"). In heteroaryls containing one or more nitrogen atoms, the linkage may be a carbon or nitrogen atom, provided the valence allows. A heteroaryl bicyclic ring system may include one or more heteroatoms in one or two rings. "Heteroaryl" includes ring systems in which a heteroaryl as defined above is fused with one or more carbocyclic or heterocyclic groups, wherein the linkage is on the heteroaryl ring, and in such cases, the number of ring members continues to name the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl group, as defined above, is fused with one or more aryl groups, wherein the linkage is on an aryl or heteroaryl ring, and in such cases, the number of ring members is named the number of ring members in the fused (aryl / heteroaryl) ring system. Bicyclic heteroaryl groups are those in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like), and the linkage can be on either ring, i.e., a ring with a heteroatom (e.g., 2-indolyl) or a ring without a heteroatom (e.g., 5-indolyl).

[0052] In some embodiments, the heteroaryl group provides a 5-10 member aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 member heteroaryl"). In some embodiments, the heteroaryl group provides a 5-8 member aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 member heteroaryl"). In some embodiments, the heteroaryl group provides a 5-6 member aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 member heteroaryl"). In some embodiments, the 5-6 member heteroaryl group has 1-3 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 member heteroaryl group has 1-2 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 heteroaryl group has one cyclic heteroatom selected from nitrogen, oxygen, and sulfur.

[0053] Examples of 5-membered heteroaryl groups containing one heteroatom include (but are not limited to) pyrrole, furanyl, and thiophene. Examples of 5-membered heteroaryl groups containing two heteroatoms include (but are not limited to) imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Examples of 5-membered heteroaryl groups containing three heteroatoms include (but are not limited to) triazolyl, oxadiazolyl, and thiadiazolyl. Examples of 5-membered heteroaryl groups containing four heteroatoms include (but are not limited to) tetrazolyl. Examples of 6-membered heteroaryl groups containing one heteroatom include (but are not limited to) pyridinyl. Examples of 6-membered heteroaryl groups containing two heteroatoms include (but are not limited to) pyrazinyl, pyrimidinyl, and pyrazinyl. Examples of 6-membered heteroaryl groups containing three or four heteroatoms include (but are not limited to) triazinyl and tetraazinyl, respectively. Examples of 7-membered heteroaryl groups containing one heteroatom include (but are not limited to) aziryl, oxepinyl, and thiepinyl. Examples of 5,6-bicyclic heteroaryl groups include (but are not limited to) indole, isoyindolyl, indazole, benzotriazolyl, benzothiophene, isobenzothiophene, benzofuranyl, benzoisofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indazinyl, and purinyl. Examples of 6,6-bicyclic heteroaryl groups include (but are not limited to) naphthidyl, pteridyl, quinolinyl, isoquinolinyl, ... Linoyl, quinolinyl, phthalazinyl, and quinazolinyl.

[0054] Representative examples of heteroaryl groups include the following: Each Z is selected from carbonyl, N, NR65, O and S; and R65 is independently hydrogen, C1-8 alkyl, C3-10 carbocyclic, 4-10 heterocyclic, C6-C10 aryl and 5-10 heteroaryl.

[0055] As used herein, "carbocyclic group" or "carbocyclic" refers to a non-aromatic cyclic hydrocarbon group having 3 to 10 cyclic carbon atoms ("C3-10 carbocyclic group") and 0 heteroatoms in a non-aromatic ring system. In some embodiments, the carbocyclic group has 3 to 8 cyclic carbon atoms ("C3-8 carbocyclic group"). In some embodiments, the carbocyclic group has 3 to 7 cyclic carbon atoms ("C3-7 carbocyclic group"). In some embodiments, the carbocyclic group has 3 to 6 cyclic carbon atoms ("C3-6 carbocyclic group"). In some embodiments, the carbocyclic group has 5 to 10 cyclic carbon atoms ("C5-10 carbocyclic group"). Exemplary C3-6 carbocyclic groups include (but are not limited to) cyclopropyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3-8 carbon cyclogroups include (but are not limited to) the C3-6 carbon cyclogroups mentioned above, as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatetraenyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), and the like. Exemplary C3-10 carbon cyclogroups include (but are not limited to) the C3-8 carbon cyclogroups mentioned above, as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthyl (C10), spiro[4.5]decyl (C10), and the like. As illustrated in the examples above, in some embodiments, the carbocyclic group is a monocyclic (“monocyclic carbocyclic”) or contains a fused, bridged, or spirocyclic system, such as a bicyclic system (“bicyclic carbocyclic”), and may be saturated or partially unsaturated. “Carbocyclic” also includes ring systems in which the carbocyclic ring as defined above is fused with one or more aryl or heteroaryl groups, wherein the connection point is on the carbocyclic ring, and in such cases, the number of carbons continues to name the number of carbons in the carbocyclic ring system.

[0056] The term "cycloalkyl" refers to a monovalent saturated cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) hydrocarbon group with 3-12, 3-8, 4-8, or 4-6 carbon atoms, and is referred to herein as "C4-8 cycloalkyl" for example, derived from cycloalkanes. Exemplary cycloalkyl groups include (but are not limited to) cyclohexane, cyclopentane, cyclobutane, and cyclopropane.

[0057] As used herein, "C3-6 monocyclic cycloalkyl" or "monocyclic C3-6 cycloalkyl" refers to a saturated 3- to 7-membered monocyclic hydrocarbon ring system. 3- to 7-membered monocyclic cycloalkyl includes (but is not limited to) cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Where indicated as substituted or modified, the substituents on the cycloalkyl group (e.g., in the case of a substituted cycloalkyl group) may be present at any substituted position, including, for example, the position connecting to the cycloalkyl group.

[0058] As used herein, "heterocyclic group" or "heterocycle" refers to a group having a 3- to 10-membered non-aromatic ring system with a ring carbon atom and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 10-membered heterocyclic group"). In heterocyclic groups containing one or more nitrogen atoms, the bonding point can be a carbon or nitrogen atom, provided the valence allows. Heterocyclic groups can be monocyclic ("monocyclic heterocyclic group") or fused, bridged, or spirocyclic systems, such as bicyclic systems ("bicyclic heterocyclic group"), and can be saturated or partially unsaturated. A heterocyclic bicyclic system may include one or more heteroatoms in one or both rings. "Heterocyclic group" also includes ring systems in which a heterocyclic ring as defined above is fused with one or more carbocyclic groups, wherein the connection point is on the carbocyclic or heterocyclic ring; or ring systems in which a heterocyclic ring as defined above is fused with one or more aryl or heteroaryl groups, wherein the connection point is on the heterocyclic ring, and in such cases, the number of ring members continues to name the number of ring members in the heterocyclic ring system. The terms "heterocycle," "heterocyclic group," "heterocyclic ring," "heterocyclic moiety," and "heterocyclic group" are used interchangeably.

[0059] In some embodiments, the heterocyclic group is a 4-7 member non-aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("4-7 member heterocyclic group"). In some embodiments, the heterocyclic group is a 5-10 member non-aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("5-10 member heterocyclic group"). In some embodiments, the heterocyclic group is a 5-8 member non-aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 member heterocyclic group"). In some embodiments, the heterocyclic group is a 5-6 member non-aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 member heterocyclic group"). In some embodiments, the 5-6 member heterocyclic group has 1-3 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 member heterocyclic group has 1-2 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 member heterocyclic group has 1 cyclic heteroatom selected from nitrogen, oxygen, and sulfur.

[0060] Examples of 3-membered heterocyclic groups containing one heteroatom include (but are not limited to) azirropropyl, epoxyethyl, and thiohexacyclopropyl. Examples of 4-membered heterocyclic groups containing one heteroatom include (but are not limited to) azirrobutyl, oxadiazolyl, and thiohexacyclobutyl. Examples of 5-membered heterocyclic groups containing one heteroatom include (but are not limited to) tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidyl, dihydropyrroleyl, and pyrrole-2,5-dione. Examples of 5-membered heterocyclic groups containing two heteroatoms include (but are not limited to) dioxolanecycloyl, oxapentafluorothioalkyl, di-pentafluorothioalkyl, and oxazolidin-2-one. Examples of 5-membered heterocyclic groups containing three heteroatoms include (but are not limited to) triazolinyl, oxadiazolinyl, and thiadiazolinyl. Examples of 6-membered heterocyclic groups containing one heteroatom include (but are not limited to) hexahydropyridyl, tetrahydropyranyl, dihydropyridyl, and thiocanyl. Examples of 6-membered heterocyclic groups containing two heteroatoms include (but are not limited to) hexahydropyrazinyl, morpholinyl, dithiaalkyl, and dioxalyl. Examples of 6-membered heterocyclic groups containing two heteroatoms include (but are not limited to) triazine. Examples of 7-membered heterocyclic groups containing one heteroatom include (but are not limited to) azoheptanyl, oxecanyl, and thiocanyl. Examples of 8-membered heterocyclic groups containing one heteroatom include (but are not limited to) azocanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclic groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocycles) include (but are not limited to) indololinyl, isoindololinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinoneyl, and the like. Exemplary 6-membered heterocyclic groups fused to an aryl ring (also referred to herein as 6,6-bicyclic heterocycles) include (but are not limited to) tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0061] Examples of saturated or partially unsaturated heterocyclic groups include (but are not limited to) tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, pyrrolidyl, pyridoneyl, pyrroloneyl, hexahydropyridyl, oxazolidinyl, hexahydropyrazinyl, dioxoalkyl, dioxopentyl, morpholinyl, dihydrofuranyl, dihydropyranyl, dihydropyridyl, tetrahydropyridyl, dihydropyrimidinyl, oxoheterobutyl, azaheterobutyl, and tetrahydropyrimidinyl. If indicated as substituted or modified as appropriate, the substituents on the heterocyclic group (e.g., in the case of substituted heterocyclic groups) may be present at any substituted position, including (e.g.) the position connecting the heterocyclic group.

[0062] When used to describe a compound or a group present on a compound, "hetero" means that one or more carbon atoms in the compound or group are replaced by nitrogen, oxygen, or sulfur heteroatoms. Hetero can be any of the above-mentioned hydrocarbon groups, such as alkyl, such as heteroalkyl; carbocyclic, such as heterocyclic; aryl, such as heteroaryl; and those having 1 to 5, and specifically 1 to 3, heteroatoms.

[0063] As used in this article, "cyano" refers to -CN.

[0064] As used herein, the terms "halogen" and "halogen" refer to an atom selected from fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), and iodine (iodo, -I). In some embodiments, the halogen is fluorine or chlorine.

[0065] As used herein, the term "alkoxy" refers to an alkyl group (-O(alkyl)) that is attached to another part via an oxygen atom. Non-limiting examples include, for example, methoxy, ethoxy, propoxy, and butoxy.

[0066] "Haloalkoxy" refers to a haloalkyl group that is attached to another haloalkyl group via an oxygen atom, such as, but not limited to, -OCHCF2 or -OCF3. [ ]

[0067] The term "haloalkyl" includes mono-, poly-, and perhaloalkyl groups substituted with one or more halogen atoms, wherein the halogen is independently selected from fluorine, chlorine, bromine, and iodine. For the C1-4 haloalkyl group -O-C1-4 alkyl, the connecting point appears on the halogenated alkyl moiety.

[0068] As used in this article, "nitro" refers to -NO2.

[0069] As used in this article, "side radical" refers to -C=O.

[0070] Generally, the term "substituted" refers, regardless of whether it is preceded by the term "as the case may be," to a substituent on a group (e.g., a carbon or nitrogen atom) that has at least one hydrogen atom replaced by a permissible substituent, such that substitution produces a stable compound (e.g., a compound that does not spontaneously undergo transformation by, for example, rearrangement, cyclization, elimination, or other reactions). Unless otherwise indicated, a "substituted" group has substituents at one or more substituted positions, and when more than one position in any given structure is substituted, the substituents may be the same or different at each position.

[0071] Nitrogen atoms may be substituted or unsubstituted, as long as the valence allows, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Example nitrogen atom substituents include (but are not limited to) hydrogen, -OH, -ORaa, -N(Rcc)2, -CN, -C(=O)Raa, -C(=O)N(Rcc)2, -CO2Raa, -SO2Raa, -C(=NRbb)Raa, -C(=NRcc)ORaa, -C(=NRcc)N(Rcc)2, -SO2N(Rcc)2, -SO2Rcc, -SO2ORcc, -SORaa, -C(=S)N(Rcc)2, -C(=O)SRcc, -C(=S)SRcc, -P(=O)2Raa, -P(=O)(Ra a) 2, -P(=O)2N(Rcc)2, -P(=O)(NRcc)2, C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 carbocyclic, 3-14-membered heterocyclic, C6-14 aryl and 5-14-membered heteroaryl, or two Rcc groups attached to a nitrogen atom to form a 3-14-membered heterocyclic or 5-14-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4 or 5 Rdd groups, and wherein Raa, Rbb, Rcc and Rdd are as defined above.

[0072] These and other exemplary substituents are described in more detail in [Implementation Method] [Example] and [Scope of Patent Application] This invention is not intended to be limited in any way by the above-described exemplary list of substituents.

[0073] Other definitions As used herein, "pharmaceutically acceptable carrier" refers to a non-toxic carrier, adjuvant, or mediator that does not impair the pharmacological activity of the compound it is formulated with. Pharmaceutically acceptable carriers, adjuvants, or mediators that may be used in the compositions described herein include (but are not limited to) ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffers (e.g., phosphates), glycine, sorbic acid, potassium sorbate, mixtures of saturated vegetable fatty acid metaglycerides, water, salts, or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block copolymers, polyethylene glycol, and lanolin.

[0074] As used herein, "medically acceptable salts" refers to salts that, to the extent of reasonable medical judgment, are suitable for contact with human and lower animal tissues without causing excessive toxicity, irritation, allergic reactions, and the like, and for which there is a proportionate reasonable benefit / risk ratio. Medically acceptable salts are well-known in the industry. For example, Berge et al. in J. Pharmaceutical Sciences (…

[1977] Pharmaceutically acceptable salts are described in detail in 66:1-19. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or with organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid) or by using other methods employed in the industry (e.g., ion exchange) and amine groups. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucono-p-ethylhexanoate, glyceryl phosphate, gluconate, hemisulfate, heptanate, hexanoate, hydroiodate, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, neopentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Pharmaceutically acceptable salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N+(C1-4 alkyl)4 salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Where appropriate, other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations, which are formed using relative ions such as halide, hydroxide, carboxyl, sulfate, phosphate, nitrate, low-carbon alkyl sulfonate, and aryl sulfonate. [ ]

[0075] As used herein, the term "individual" is intended to include (but is not limited to) humans (i.e., males or females of any age group, e.g., pediatric individuals (e.g., infants, children, adolescents) or adult individuals (e.g., young adults, middle-aged adults, or older adults)) and / or non-human animals (e.g., mammals, such as primates (e.g., cynomolgus monkeys, macaques), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs). In some embodiments, the individual is human. In some embodiments, the individual is a non-human animal. The terms "human," "patient," and "individual" are used interchangeably herein.

[0076] Disease, symptoms, and condition can be used interchangeably in this article.

[0077] As used herein and unless otherwise stated, the terms “treat, treating, and treatment” encompass actions that occur when an individual has a specified disease, condition, or illness, which reduce the severity of the disease, condition, or illness, or delay or slow the progression of the disease, condition, or illness (“therapeutic treatment”), and also encompass actions that occur before an individual begins to have a specified disease, condition, or illness (“preventive treatment”).

[0078] As used herein, the “effective amount” of a compound means an amount sufficient to elicit the desired biological response. As will be understood by those skilled in the art, the effective amount of the compounds of this invention can vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the individual’s age, health status, and condition. Effective amounts cover both therapeutic and preventative treatment.

[0079] As used herein and unless otherwise stated, a "therapeuticly effective amount" of a compound is an amount sufficient to provide therapeutic benefit in the treatment of a disease, symptom, or condition, or to delay or minimize one or more symptoms associated with the disease, symptom, or condition. A therapeutically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other therapies, that provides therapeutic benefit in the treatment of a disease, symptom, or condition. The term "therapeuticly effective amount" may also encompass amounts that improve overall therapy, reduce or prevent symptoms or causes of a disease or condition, or enhance the therapeutic efficacy of another therapeutic agent.

[0080] [Compound] [ ] In one embodiment, the present invention provides a compound having formula I: ; Or a medicinally acceptable salt, in which X and Y are each independently CRd or N; R1 series Monocyclic C3-6 cycloalkyl or 4- to 7-membered monocyclic heterocyclic group, wherein such cycloalkyl and heterocyclic group are substituted by one or more Ra as appropriate; R2 refers to C1-4 haloalkyl, phenyl, or monocyclic C3-6 cycloalkyl groups, which may be substituted with one or more Rb groups as appropriate; R3 series hydrogen, C1-4 alkyl or C1-4 haloalkyl; R4 series hydrogen or C1-4 alkyl; R5-series halogens; R6 series C1-4 alkyl or C1-4 haloalkyl, wherein each of the C1-4 alkyl or C1-4 haloalkyl is substituted with ORc; t is 0, 1, or 2; Ra and Rb are each independently selected from halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy groups. Rc refers to C1-4 alkyl or C3-6 cycloalkyl groups substituted with C3-6 cycloalkyl or C1-4 alkoxy groups, depending on the situation; and Rd series hydrogen or C1-4 alkyl; The premise is that the compound is not a compound having the following formula: or Or a medicinally acceptable salt. In one state, the present invention provides a form having [I'] compounds: ; Or a medicinally acceptable salt, in which X and Y are each independently CRd or N; R1 series Monocyclic C3-6 cycloalkyl or 4- to 7-membered monocyclic heterocyclic group, wherein such cycloalkyl and heterocyclic group are substituted by one or more Ra as appropriate; R2 refers to C1-4 haloalkyl, phenyl, or monocyclic C3-6 cycloalkyl groups, which may be substituted with one or more Rb groups as appropriate; R3 series hydrogen, C1-4 alkyl or C1-4 haloalkyl; R4 series hydrogen or C1-4 alkyl; R5-series halogens; R6 series C1-4 alkyl or C1-4 haloalkyl, wherein each of the C1-4 alkyl or C1-4 haloalkyl is substituted with ORc; t is 0, 1, or 2; Ra and Rb are each independently selected from halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy groups. Rc refers to C1-4 alkyl or C3-6 cycloalkyl groups substituted with C3-6 cycloalkyl or C1-4 alkoxy groups, depending on the situation; and Rd series hydrogen or C1-4 alkyl; Or a medicinally acceptable salt. In some embodiments, the compound has formula Ia: ; Or a pharmaceutically acceptable salt, wherein the variables are as defined herein. In some embodiments, the compound has the formula Ib: ; Or a pharmaceutically acceptable salt, wherein the variables are as defined herein. In some embodiments, the compound has the formula [II]: ; Or a pharmaceutically acceptable salt, wherein the variables are as defined herein. In some embodiments, the compound has the formula [III]: ; Or a pharmaceutically acceptable salt, wherein the variables are as defined herein. In some embodiments, the compound has the formula [Ic]: ; Or a pharmaceutically acceptable salt, wherein the variables are as defined herein. In another embodiment, the present invention provides a form having [Id] of compounds: ; Or a medicinally acceptable salt, in which R1 series Monocyclic C3-6 cycloalkyl or 4- to 7-membered monocyclic heterocyclic group, wherein such cycloalkyl and heterocyclic group are substituted by one or more Ra as appropriate; R2 refers to C1-4 haloalkyl, phenyl, or monocyclic C3-6 cycloalkyl groups, which may be substituted with one or more Rb groups as appropriate; R3 series hydrogen, C1-4 alkyl or C1-4 haloalkyl; R4 series hydrogen or C1-4 alkyl; R5-series halogens; R6 series C1-4 alkyl or C1-4 haloalkyl, wherein each of the C1-4 alkyl or C1-4 haloalkyl is substituted with ORc; t is 0, 1, or 2; Ra and Rb are each independently selected from halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; Rc refers to C1-4 alkyl or C3-6 cycloalkyl groups substituted with C3-6 cycloalkyl or C1-4 alkoxy groups, depending on the situation; and Rd series hydrogen or C1-4 alkyl. In some embodiments, the compound has the formula [V]: ; Or a pharmaceutically acceptable salt, wherein the variables are as defined herein. In some embodiments, the compound has the formula [VII]: ; Or a pharmaceutically acceptable salt, wherein the variables are as defined herein. In some embodiments, the compound has the formula [VIII]: ; Or a pharmaceutically acceptable salt, wherein the variables are as defined herein. In some embodiments, the compound has the formula [VIII]: ; Or a pharmaceutically acceptable salt, wherein the variables are as defined herein. In some embodiments, R1 series . In some embodiments, R1 is a cyclobutyl group substituted with one or more Ra groups, depending on the situation. In some embodiments, R2 is a C1-4 haloalkyl group. In some embodiments, R2 is a CF3 group. In some embodiments, R2 is a phenyl group. In one embodiment, R3 is a C1-4 alkyl group and R4 is H or a C1-4 alkyl group. In some embodiments, R3 and R4 are each a C1-4 alkyl group. In some embodiments, R3 and R4 are each methyl groups. In some embodiments, R3 is methyl and R4 is hydrogen. In some embodiments, R3 and R4 are each hydrogen. In some embodiments, R6-CF2-ORc. In some embodiments, Rc is a C1-4 alkyl group that is substituted with a cyclopropyl group, as appropriate. In some embodiments, Rc is a cyclopropyl group. In some embodiments, R6-based -C(F2)OCH2CH(CH3)2, -C(F2)OCH3, -C(F2)OCH2CH3, -C(F2)OCH(CH3)2, or -C(F2)OCH2C3H5. In some embodiments, R6-based -CH2-ORc. In some embodiments, Rc is a C1-4 alkyl group. In some embodiments, R6-series -CH2OCH3, -CH2OCH2CH3, or -CH2OCH2CH(CH3)2. In some embodiments, Ra is a C1-4 haloalkyl group. In some embodiments, Ra is a CF3 group. In some embodiments, Ra is a fluorine group. In some embodiments, t is 1. In some embodiments, t is 0. In some embodiments, Rd is a methyl group. In some embodiments, Rd is a hydrogen group. In some embodiments, the compound is selected from the group consisting of: and Or, or a medicinally acceptable salt. In some embodiments, the compound is selected from the group consisting of: and or its medically acceptable salt, and In another embodiment, the present invention provides a crystalline compound of the following formula: , The crystalline compound exhibits an X-ray powder diffraction pattern containing peaks at the following diffraction angles (2θ): 6.9±0.2, 16.5±0.2, and 20.8±0.2.

[0081] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern containing peaks at the following diffraction angles (2θ): 6.9±0.2, 13.9±0.2, 16.5±0.2, 19.5±0.2, and 20.8±0.2.

[0082] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 6.9±0.2, 11.2±0.2, 13.9±0.2, 16.5±0.2, 17.4±0.2, 18.1±0.2, 19.1±0.2, 19.5±0.2, and 20.8±0.2.

[0083] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern substantially the same as that shown in FIG2A.

[0084] In some embodiments, the crystalline compound has a melting initiation point of about 140°C, as determined by differential scanning calorimetry.

[0085] In some embodiments, the crystalline compound has a differential scanning calorimetry curve that is substantially the same as that shown in FIG2B.

[0086] In another state, this paper provides crystalline compounds of the following formula: , The crystalline compound exhibits an X-ray powder diffraction pattern containing peaks at the following diffraction angles (2θ): 16.7±0.2, 19.0±0.2, and 20.4±0.2.

[0087] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern containing peaks at the following diffraction angles (2θ): 7.2±0.2, 14.4±0.2, 16.7±0.2, 19.0±0.2, 20.4±0.2, and 25.7±0.2.

[0088] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 7.2±0.2, 14.4±0.2, 16.7±0.2, 17.9±0.2, 19.0±0.2, 20.4±0.2, 20.8±0.2, 23.2±0.2, 25.7±0.2, and 28.0±0.2.

[0089] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern substantially the same as that shown in FIG3A.

[0090] In some embodiments, the crystalline compound has a melting initiation point of about 68°C, as determined by differential scanning calorimetry.

[0091] In some embodiments, the crystalline compound has a differential scanning calorimetry curve that is substantially the same as that shown in FIG3B.

[0092] In another embodiment, the present invention provides a crystalline compound of the following formula: , The crystalline compound exhibits an X-ray powder diffraction pattern containing peaks at the following diffraction angles (2θ): 7.3±0.2, 14.5±0.2, and 21.9±0.2.

[0093] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern containing peaks at the following diffraction angles (2θ): 7.3±0.2, 14.5±0.2, 17.9±0.2, 19.0±0.2, and 21.9±0.2.

[0094] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 7.3±0.2, 13.7±0.2, 14.5±0.2, 17.9±0.2, 19.0±0.2, 20.3±0.2, 21.9±0.2, 24.7±0.2, and 25.4±0.2.

[0095] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern substantially the same as that shown in FIG4A.

[0096] In some embodiments, the crystalline compound has a melting initiation point of about 136°C, as determined by differential scanning calorimetry.

[0097] In some embodiments, the crystalline compound has a differential scanning calorimetry curve that is substantially the same as that shown in FIG4B.

[0098] In another state, this paper provides crystalline compounds of the following formula: , The crystalline compound exhibits an X-ray powder diffraction pattern containing peaks at the following diffraction angles (2θ): 12.6±0.2, 15.8±0.2, and 18.6±0.2.

[0099] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern containing peaks at the following diffraction angles (2θ): 10.7±0.2, 12.3±0.2, 12.6±0.2, 15.8±0.2, 18.6±0.2, and 22.6±0.2.

[0100] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 10.7±0.2, 12.3±0.2, 12.6±0.2, 14.9±0.2, 15.8±0.2, 16.6±0.2, 16.8±0.2, 18.6±0.2, 21.0±0.2, and 22.6±0.2.

[0101] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern substantially the same as that shown in FIG5A.

[0102] In some embodiments, the crystalline compound has a melting initiation point of about 107°C, as determined by differential scanning calorimetry.

[0103] In some embodiments, the crystalline compound has a differential scanning calorimetry curve that is substantially the same as that shown in FIG5B.

[0104] In another state, this paper provides crystalline compounds of the following formula: , The crystalline compound exhibits an X-ray powder diffraction pattern containing peaks at the following diffraction angles (2θ): 5.8±0.2, 19.7±0.2, and 21.0±0.2.

[0105] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern containing peaks at the following diffraction angles (2θ): 5.8±0.2, 14.5±0.2, 15.3±0.2, 19.7±0.2, 21.0±0.2, and 24.2±0.2.

[0106] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 5.8±0.2, 11.6±0.2, 12.0±0.2, 14.5±0.2, 15.3±0.2, 19.1±0.2, 19.7±0.2, 21.0±0.2, 22.4±0.2, and 24.2±0.2.

[0107] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern substantially the same as that shown in FIG6A.

[0108] In some embodiments, the crystalline compound has a melting initiation point of about 94°C, as determined by differential scanning calorimetry.

[0109] In some embodiments, the crystalline compound has a differential scanning calorimetry curve that is substantially the same as that shown in FIG6B.

[0110] In another embodiment, the present invention provides a crystalline compound of the following formula: , The crystalline compound exhibits an X-ray powder diffraction pattern containing peaks at the following diffraction angles (2θ): 7.3±0.2, 16.6±0.2, and 18.4±0.2.

[0111] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern containing peaks at the following diffraction angles (2θ): 7.3±0.2, 13.8±0.2, 16.6±0.2, 18.4±0.2, 20.3±0.2, and 24.3±0.2.

[0112] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 7.3±0.2, 10.8±0.2, 13.8±0.2, 16.6±0.2, 17.8±0.2, 18.4±0.2, 19.5±0.2, 20.3±0.2, 21.2±0.2, and 24.3±0.2.

[0113] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern substantially the same as that shown in FIG7A.

[0114] In some embodiments, the crystalline compound has a melting initiation point of about 103°C, as determined by differential scanning calorimetry.

[0115] In some embodiments, the crystalline compound has a differential scanning calorimetry curve that is substantially the same as that shown in FIG7B.

[0116] In another embodiment, the present invention provides a crystalline compound of the following formula: , The crystalline compound exhibits an X-ray powder diffraction pattern containing peaks at the following diffraction angles (2θ): 6.9±0.2, 16.4±0.2, and 19.5±0.2.

[0117] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern containing peaks at the following diffraction angles (2θ): 6.9±0.2, 16.4±0.2, 17.4±0.2, 18.0±0.2, 19.5±0.2, and 20.8±0.2.

[0118] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern containing peaks at the following diffraction angles (2θ): 6.9±0.2, 11.2±0.2, 13.6±0.2, 13.9±0.2, 16.4±0.2, 17.4±0.2, 18.0±0.2, 19.5±0.2, and 20.8±0.2.

[0119] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern substantially the same as that shown in FIG8A.

[0120] In some embodiments, the crystalline compound has a melting initiation point of about 133°C, as determined by differential scanning calorimetry.

[0121] In some embodiments, the crystalline compound has a differential scanning calorimetry curve that is substantially the same as that shown in FIG8B.

[0122] In another embodiment, the present invention provides a crystalline compound of the following formula: , The crystalline compound exhibits an X-ray powder diffraction pattern containing peaks at the following diffraction angles (2θ): 9.9±0.2, 19.8±0.2, and 23.7±0.2.

[0123] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern containing peaks at the following diffraction angles (2θ): 9.9±0.2, 12.3±0.2, 14.1±0.2, 19.8±0.2, 20.7±0.2, and 23.7±0.2.

[0124] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 7.3±0.2, 9.9±0.2, 12.3±0.2, 14.1±0.2, 16.5±0.2, 17.2±0.2, 19.8±0.2, 20.7±0.2, 23.7±0.2, 24.8±0.2, 27.7±0.2, and 29.1±0.2.

[0125] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern substantially the same as that shown in FIG9A.

[0126] In some embodiments, the crystalline compound has a melting initiation point of about 111°C, as determined by differential scanning calorimetry.

[0127] In some embodiments, the crystalline compound has a differential scanning calorimetry curve that is substantially the same as that shown in FIG9B.

[0128] In another state, this paper provides crystalline compounds of the following formula: , The crystalline compound exhibits an X-ray powder diffraction pattern containing peaks at the following diffraction angles (2θ): 9.3±0.2, 18.8±0.2, and 21.4±0.2.

[0129] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern containing peaks at the following diffraction angles (2θ): 9.3±0.2, 16.1±0.2, 18.8±0.2, 21.1±0.2, 21.4±0.2, and 21.6±0.2.

[0130] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 9.3±0.2, 16.1±0.2, 18.8±0.2, 21.1±0.2, 21.4±0.2, 21.6±0.2, 22.6±0.2, 23.9±0.2, 26.0±0.2, and 26.4±0.2.

[0131] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern substantially the same as that shown in FIG1A.

[0132] In some embodiments, the crystalline compound has a melting initiation point of about 122°C, as determined by differential scanning calorimetry.

[0133] In some embodiments, the crystalline compound has a differential scanning calorimetry curve that is substantially the same as that shown in FIG1B.

[0134] In some embodiments, the X-ray powder diffraction pattern is obtained using Cu Kα radiation.

[0135] [Pharmaceutical Compositions and Routes of Administration] [ ] The compounds provided according to the present invention are typically administered in the form of pharmaceutical compositions. Therefore, the present invention provides pharmaceutical compositions comprising one or more of the said compounds as active ingredients, or pharmaceutically acceptable salts or esters thereof, and one or more pharmaceutically acceptable excipients, carriers (including inert solid diluents and fillers), diluents (including sterile aqueous solutions and various organic solvents), permeation enhancers, solubilizers, and adjuvants. The pharmaceutical compositions may be administered alone or in combination with other therapeutic agents. These compositions are prepared in a manner well known in the pharmaceutical art (e.g., see Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa, 17th edition (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd edition (edited by GS Banker and CT Rhodes).

[0136] Pharmaceutical compositions can be administered in single or multiple doses via any of the acceptable modes of administration of agents with similar effects (e.g., as described in their patents and patent applications incorporated herein by reference, including rectal, buccal, intranasal and percutaneous routes, intra-arterial injection, intravenous, intraperitoneal, non-intestinal, intramuscular, subcutaneous, oral, topical, inhalation form, or via a cylindrical polymer impregnated or coated (e.g., a stent) or (e.g.) inserted into an artery).

[0137] One mode of administration is non-enteral, specifically by injection. Forms in which the novel compositions of the present invention can be incorporated for administration by injection include aqueous solutions or oil suspensions or emulsions with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextran, or sterile aqueous solutions and similar pharmaceutical mediators. Aqueous solutions in saline are also commonly used for injection, but are preferred in the context of this invention. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol and such (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be used. Appropriate flowability can be maintained, for example, by using coatings (e.g., lecithin), by maintaining the desired particle size (in the case of dispersions), and by using surfactants. Microbial action can be prevented by various antibacterial and antifungal agents (e.g., parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and such).

[0138] The sterile injectable solution is prepared by incorporating the required amount of the compound of the invention into a suitable solvent having the various other components listed above, followed by filtration and sterilization as needed. Typically, dispersions are prepared by incorporating various sterilized active ingredients into a sterile medium containing a basic dispersion medium and other desired components from those listed above. In the case of preparing sterile powders for sterile injectable solutions, preferred methods are vacuum drying and freeze-drying techniques, which can produce a powder containing the active ingredient plus any desired additional components from a pre-sterilely filtered solution.

[0139] Oral administration is another route of administration of the compound according to the present invention. Administration may be via capsules or enteric-coated tablets or the like. In the preparation of pharmaceutical compositions comprising at least one of the compounds described herein, the active ingredient is typically diluted and / or encapsulated in a carrier, which may be in the form of capsules, pouches, paper or other containers, by means of an excipient. When the excipient is used as a diluent, it may be in the form of a solid, semi-solid or liquid material (as described above), which serves as a mordant, carrier or medium for the active ingredient. Thus, the composition may be in the form of tablets, pills, powders, rhomboid tablets, pouches, capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (in solid form or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions and sterile packaged powders.

[0140] Some examples of suitable excipients include lactose, glucose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth gum, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulation may also include: lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifiers and suspending agents; preservatives such as methyl benzoate and propyl hydroxy benzoate; sweeteners; and flavoring agents.

[0141] The compositions of the present invention can be formulated using procedures known in the art to provide rapid, sustained, or delayed release of the active ingredient upon administration to a patient. Controlled-release drug delivery systems administered orally include osmotic pump systems and reservoirs containing polymer coatings or dissolution systems for drug-polymer matrix formulations. Examples of controlled-release systems are given in U.S. Patents 3,845,770, 4,326,525, 4,902,514, and 5,616,345. Another formulation used in the methods of the present invention employs a percutaneous delivery device (“patch”). These percutaneous patches can be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of percutaneous patches for delivering pharmaceuticals are well known in the art. See, for example, U.S. Patents 5,023,252, 4,992,445, and 5,001,139. These patches can be configured for continuous, pulsed, or on-demand delivery of pharmaceutical agents.

[0142] The composition is preferably formulated into a unit dosage form. The term "unit dosage form" refers to a physical discrete unit suitable for use as a unit dose for human individuals and other mammals, each unit containing a predetermined amount of active substance calculated to produce the desired therapeutic effect and suitable pharmaceutical excipients (e.g., tablets, capsules, ampoules). The compound is generally administered in a pharmaceutically effective amount. Preferably, for oral administration, each dose unit contains 1 mg to 2 g of the compound described herein, and for non-enteral administration, it preferably contains 0.1 to 700 mg of the compound described herein. However, it should be understood that the actual amount of the compound administered will be determined by the physician based on relevant factors including: the condition to be treated, the chosen route of administration, the compound actually administered and its relative activity, the individual patient's age, weight and response, the severity of the patient's symptoms, and so on.

[0143] To prepare solid compositions (e.g., tablets), the main active ingredient is mixed with a pharmaceutical excipient to form a solid preform composition containing a homogeneous mixture of the compounds of the present invention. When referring to such preformed compositions as homogeneous, it means that the active ingredient is uniformly dispersed throughout the composition so that the composition can be easily further divided into equal effective unit dosage forms, such as tablets, pills, and capsules.

[0144] The tablets or pills of this invention can be coated or otherwise compounded to provide a dosage form with the advantage of prolonged action, or to protect against the acidic conditions of the stomach. For example, the tablets or pills may comprise an internal dose component and an external dose component, the latter being a coating of the former. The two components may be separated by an enteric coating layer to resist disintegration in the stomach and allow the internal component to pass intact into the duodenum or to delay release. Such enteric coatings or coatings may be made of a variety of materials, including a large amount of polymeric acids and mixtures of polymeric acids with materials such as shellac, hexadecyl alcohol, and cellulose acetate.

[0145] Compositions for inhalation or inhalation include solutions, suspensions, and powders in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof. These liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. Preferably, these compositions are administered via oral or nasal inhalation to achieve local or systemic effects. Preferably, compositions in pharmaceutically acceptable solvents can be nebulized using an inert gas. The nebulized solution can be inhaled directly from a nebulizer or the nebulizer can be attached to a face mask or intermittent positive pressure ventilation machine. Solutions, suspensions, or powder compositions can preferably be administered orally or nasally from a device that delivers the preparation in a suitable manner.

[0146] In some embodiments, a pharmaceutical composition comprising the disclosed compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0147] [How to use] [ ] The compounds and compositions described herein are generally used to modulate the activity of sodium channels and to treat conditions associated with abnormal function of sodium ion channels (e.g., abnormal late sodium (INaL) currents). In some embodiments, the compounds provided by this invention are effective in treating epilepsy or epileptic syndrome, neurodevelopmental disorders, pain, or neuromuscular disorders. The provided compounds, their pharmaceutically acceptable salts, or compositions may modulate all sodium ion channels or may specifically target only one or more sodium ion channels, such as NaV 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, and / or 1.9.

[0148] In typical embodiments, the present invention is intended to cover the compounds disclosed herein, and pharmaceutically acceptable salts, pharmaceutically acceptable esters, tautomers, polymorphs, and prodrugs of such compounds. In some embodiments, the present invention includes pharmaceutically acceptable addition salts, pharmaceutically acceptable esters, solvates (e.g., hydrates) of addition salts, tautomers, polymorphs, mirror isomers, mixtures of mirror isomers, stereoisomers, or mixtures of stereoisomers (pure or in racemic or non-racemic mixture form) of the compounds described herein (e.g., compounds of formulas I, I', Ia, Ib, Ic, Id, II, III, V, VII, VIII, or IX).

[0149] Epilepsy and Epilepsy Syndrome The compounds described herein may be used to treat epilepsy and epilepsy syndrome. Epilepsy is a CNS disorder caused by the disruption of nerve cell activity in the brain, resulting in seizures or unusual behaviors, sensations, and sometimes periods of loss of consciousness. Seizure symptoms vary widely during a seizure, ranging from a few seconds of simple blank staring to repetitive twitching of the arms or legs.

[0150] Epilepsy can involve generalized tonic-clonic seizures or focal tonic-clonic seizures. In generalized tonic-clonic seizures, all areas of the brain are involved. A person experiencing a generalized tonic-clonic seizure may cry out or make some noise, freeze for several seconds to a minute, followed by rhythmic movements of the arms and legs. The eyes are usually open, and the person may appear not to be breathing and may actually turn blue. Recovery of consciousness is gradual, and the person may be confused for several minutes to several hours. There are six main types of generalized tonic-clonic seizures: tonic-clonic, tonic, clonic, myoclonic, absence, and atonic seizures. In focal tonic-clonic seizures, only parts of the brain are involved, and therefore only parts of the body are affected. Symptoms can vary depending on the part of the brain with abnormal activity.

[0151] Epilepsy as described in this article includes generalized, focal, complex focal, tonic-clonic, clonic, tonic, refractory seizures, status epilepticus, absence seizures, febrile seizures, or temporal lobe epilepsy.

[0152] The compounds described herein (e.g., compounds of formulas I, I', Ia, Ib, Ic, Id, II, III, V, VII, VIII, or IX) may be used to treat epileptic syndromes. Severe syndromes characterized by diffuse brain dysfunction, at least partially caused by a particular form of epilepsy, are also known as epileptic encephalopathy. These epileptic encephalopathy syndromes are associated with treatment-resistant, frequent seizures and severe cognitive impairment (e.g., West syndrome).

[0153] In some embodiments, epilepsy syndromes include epileptic encephalopathy such as Drave syndrome, Angelman syndrome, CDKL5 syndrome, frontal lobe epilepsy, infantile spasms, West syndrome, juvenile myoclonic epilepsy, Landau-Kleffner syndrome, Legg syndrome, Ohtahara syndrome, PCDH19 epilepsy, or Glut1 deficiency.

[0154] In some embodiments, epilepsy or epilepsy syndrome refers to hereditary epilepsy or hereditary epilepsy syndrome. In some embodiments, epilepsy or epilepsy syndrome includes epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, or SCN8A mutations, early infantile epileptic encephalopathy, Delaware syndrome, Delaware syndrome with SCN1A mutation, generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infant epilepsy, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutation, cryptogenic partial epilepsy in children with SCN3A mutation, SCN8A epileptic encephalopathy, Rasmussen encephalitis, infantile malignant migratory partial seizures, autosomal dominant nocturnal frontal lobe epilepsy, sudden unexpected death from epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, or KCNT1 epileptic encephalopathy.

[0155] In some embodiments, the methods described herein further include identifying patients with epilepsy or epileptic syndromes (e.g., epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, Dravire syndrome, Dravire syndrome with SCN1A mutations, generalized epilepsy with febrile seizures, refractory childhood epilepsy) before administering the compounds described herein (e.g., compounds of formula I, I', Ia, Ib, Ic, Id, II, III, V, VII, VIII, or IX). Individual methods for epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infant epilepsy, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutation, cryptogenic partial epilepsy in children with SCN3A mutation, SCN8A epileptic encephalopathy, Rasmussen's encephalitis, malignant migratory partial epilepsy in infants, autosomal dominant nocturnal frontal lobe epilepsy, sudden unexpected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, or KCNT1 epileptic encephalopathy.

[0156] In one embodiment, the present invention is characterized by a method of treating epilepsy or epileptic syndromes (e.g., epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, Dravir syndrome, Dravir syndrome with SCN1A mutation, generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infant epilepsy, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutation, cryptogenic partial epilepsy in children with SCN3A mutation, SCN8A epileptic encephalopathy, Rasmussen encephalitis, infantile malignant migratory partial epilepsy, autosomal dominant nocturnal frontal lobe epilepsy, sudden unexpected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, or KCNT1 epileptic encephalopathy), comprising administering a compound of formula (I) to an individual in need: ; Or a pharmaceutically acceptable salt, wherein the variables are as defined herein.

[0157] The compounds of this invention (e.g., compounds of formula I, I', Ia, Ib, Ic, Id, II, III, V, VII, VIII, or IX) can also be used to treat epileptic encephalopathy in individuals who have mutations in one or more of the following: ALDH7A1, ALG13, ARHGEF9, ARX, ASAH1, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLN8, CNTNAP2, CPA6, CSTB, DEPDC5, DNM1, EEF1A2, EPM2A, EPM2B, GABRA1, GABRB3, GABRG2, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, HCN1, IER3IP1, KCNA2, KCN B1, KCNC1, KCNMA1, KCNQ2, KCNQ3, KCNT1, KCTD7, LGI1, MEF2C, NHLRC1, PCDH19, PLCB1, PNKP, PNPO, PRICKLE1, PRICKLE2, PRRT2, RELN, SCARB2, SCN1A, SCN1B, SCN2A, SC N8A, SCN9A, SIAT9, SIK1, SLC13A5, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SNIP1, SPTAN1, SRPX2, ST3GAL3, STRADA, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, and WWOX.

[0158] In some embodiments, the methods described herein further include identifying individuals with mutations in one or more of the following prior to administration of the compounds described herein (e.g., compounds of formula I, I', Ia, Ib, Ic, Id, II, III, V, VII, VIII, or IX): ALDH7A1, ALG13, ARHGEF9, ARX, ASAH1, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLN8, CNTNAP2, CPA6, CSTB, DEPDC5, DNM1, EEF1A2, EPM2A, EPM2B, GABRA1, GABRB3, GABRG2, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, HCN1, IER3IP1, KC NA2, KCNB1, KCNC1, KCNMA1, KCNQ2, KCNQ3, KCNT1, KCTD7, LGI1, MEF2C, NHLRC1, PCDH19, PLCB1, PNKP, PNPO, PRICKLE1, PRICKLE2, PRRT2, RELN, SCARB2, SCN1A, SCN1B, SCN2A , SCN8A, SCN9A, SIAT9, SIK1, SLC13A5, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SNIP1, SPTAN1, SRPX2, ST3GAL3, STRADA, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24 and WWOX.

[0159] Neurodevelopmental disorders The compounds described herein may be used to treat neurodevelopmental disorders. In some embodiments, the neurodevelopmental disorder includes autism, autism with epilepsy, tuberous sclerosis, split X syndrome, Rett syndrome, Angelman syndrome, Dup15q syndrome, 22q13.3 deletion syndrome, Prader-Willi syndrome, soft palate-heart-face syndrome, Smith-Lemli-Opitz syndrome, or a neurodevelopmental disorder with epilepsy. In some embodiments, the methods described herein further include identifying individuals with neurodevelopmental disorders (e.g., autism, autism with epilepsy, tuberous sclerosis, X splitting syndrome, Rett syndrome, Angelman syndrome, Dup15q syndrome, 22q13.3 deletion syndrome, Predwell syndrome, soft palate-heart-face syndrome, Smith-Lanley-Obis syndrome, or neurodevelopmental disorders with epilepsy) before administering the compounds described herein (e.g., compounds of formula I, I', Ia, Ib, Ic, Id, II, III, V, VII, VIII, or IX).

[0160] In one embodiment, the present invention is characterized by a method for treating neurodevelopmental disorders (e.g., autism, autism with epilepsy, tuberous sclerosis, X-linked schizoid syndrome, Rett syndrome, Angelman syndrome, Dup15q syndrome, 22q13.3 deletion syndrome, Predwell syndrome, soft palate-heart-face syndrome, Smith-Lanley-Obis syndrome, or neurodevelopmental disorders with epilepsy), comprising administering a compound of formula (I) to an individual in need: ; Or a pharmaceutically acceptable salt, wherein the variables are as defined herein.

[0161] pain The compounds described herein can be used to treat pain. In some embodiments, pain includes neuropathic pain, trigeminal neuralgia, migraine, hemiplegic migraine, familial hemiplegic migraine, type 3 familial hemiplegic migraine, cluster headache, cerebellar ataxia, or related headache conditions. In some embodiments, the methods described herein further include identifying an individual suffering from pain (e.g., neuropathic pain, trigeminal neuralgia, migraine, hemiplegic migraine, familial hemiplegic migraine, type 3 familial hemiplegic migraine, cluster headache, cerebellar ataxia, or related headache conditions) before administering the compounds described herein (e.g., compounds of formula I, I', Ia, Ib, Ic, Id, II, III, V, VII, VIII, or IX).

[0162] In one embodiment, the present invention is characterized by a method for treating pain (e.g., neuropathic pain, trigeminal neuralgia, migraine, hemiplegic migraine, familial hemiplegic migraine, type 3 familial hemiplegic migraine, cluster headache, cerebellar ataxia, or related headache symptoms), comprising administering a compound of formula (I) to an individual in need: ; Or a pharmaceutically acceptable salt, wherein the variables are as defined herein.

[0163] Neuromuscular diseases The compounds described herein can be used to treat neuromuscular disorders. In some embodiments, neuromuscular disorders include amyotrophic lateral sclerosis (ALS), multiple sclerosis, myotonia, congenital paramyotonia, potassium-induced myotonia, periodic paralysis, periodic hyperkalemic paralysis, periodic hypokalemic paralysis, or laryngospasm with an SCN4A mutation. In some embodiments, the methods described herein further include identifying individuals with neuromuscular disorders (e.g., ALS, multiple sclerosis, myotonia, congenital paramyotonia, potassium-induced myotonia, periodic paralysis, periodic hyperkalemic paralysis, periodic hypokalemic paralysis, or laryngospasm with an SCN4A mutation) before administering the compounds described herein (e.g., compounds of formula I, I', Ia, Ib, Ic, Id, II, III, V, VII, VIII, or IX).

[0164] In one embodiment, the present invention is characterized by a method for treating neuromuscular disorders (e.g., amyotrophic lateral sclerosis, multiple sclerosis, myotonia, congenital paramyotonia, potassium-induced myotonia, periodic paralysis, periodic hyperkalemic paralysis, periodic hypokalemic paralysis, or laryngospasm with an SCN4A mutation), comprising administering a compound of formula (I) to an individual in need: ; Or a pharmaceutically acceptable salt, wherein the variables are as defined herein.

[0165] Other symptoms In some embodiments, the compounds of the present invention (e.g., compounds of formula I, I', Ia, Ib, Ic, Id, II, III, V, VII, VIII, or IX) may have suitable pharmacokinetic properties such that they are active with respect to the central and / or peripheral nervous systems. In some embodiments, the compounds provided herein are intended for the treatment of cardiovascular diseases, such as atrial and ventricular arrhythmias, including atrial fibrillation, Prinzmetal (variant) angina, stable angina, unstable angina, ischemic and reperfusion injury of the heart, kidneys, liver, and brain, exercise-induced angina, pulmonary hypertension, congestive heart disease (including diastolic and systolic heart failure), recurrent ischemia, cerebral ischemia, stroke, renal ischemia, organ transplant-related ischemia, acute coronary syndrome, peripheral artery disease, intermittent claudication, and myocardial infarction. In some embodiments, the compounds provided herein may be used to treat diseases affecting the neuromuscular system that result in pruritus, seizures, or paralysis, or to treat diabetes or decreased insulin sensitivity and diabetes-related disease states (e.g., diabetic peripheral neuropathy). In some embodiments, the disclosed method includes administering a pharmaceutical composition.

[0166] In some embodiments, this document provides a method for treating neurological disorders or mental abnormalities, wherein the method comprises administering to an individual in need a compound disclosed herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition disclosed herein.

[0167] [Combination therapy] [ ] The compounds or compositions described herein (e.g., for modulating sodium ion channels, such as late sodium (INaL) currents) may be administered in combination with another agent or therapy. Individuals who wish to administer the compounds disclosed herein may suffer from a disease, condition, or illness, or symptoms thereof, that would benefit from treatment with another agent or therapy. Such diseases or illnesses may be associated with epilepsy or epileptic syndrome, neurodevelopmental disorders, pain, or neuromuscular disorders.

[0168] Antiepileptic drugs Antiepileptic drugs include brivaracetam, carbamazepine, clobazam, clonazepam, diazepam, divalproex, eslicarbazepine, ethosuximide, ezogabine, felbamate, gabapentin, lacosamide, lamotrigine, and levetiracetam. (levetiracetam), lorazepam, oxcarbezepine, permpanel, phenobarbital, phenytoin, pregabalin, primidone, rufinamide, tigabine, topiramate, valproic acid, vigabatrin, zonisamide, and cannabidiol.

[0169] Cardiovascular combination therapy Cardiovascular-related diseases or conditions that may benefit from the combination of the sodium channel blocker of this invention with other therapeutic agents include (but are not limited to) angina pectoris (including stable angina, unstable angina (UA), exercise-induced angina, variant angina), arrhythmia, intermittent claudication, myocardial infarction (including non-STE myocardial infarction (NSTEMI)), pulmonary hypertension (including pulmonary hypertension), heart failure (including congestive (or chronic) heart failure and diastolic heart failure and heart failure with preserved ejection fraction (diastolic dysfunction), acute heart failure) or recurrent ischemia.

[0170] Suitable therapeutic agents for treating cardiovascular diseases or conditions include antianginal agents, heart failure agents, antithrombotic agents, antiarrhythmic agents, antihypertensive agents, and lipid-lowering agents.

[0171] The co-administration of the sodium channel blocker of this invention with a therapeutic agent suitable for treating cardiovascular conditions allows for enhancement of the standard care currently received by the patient.

[0172] Antianginal drugs Antianginal drugs include beta-blockers, calcium channel blockers, and nitrates. Beta-blockers reduce the heart's oxygen demand by decreasing the workload on the heart, thereby reducing heart rate and the number of intense cardiac contractions. Examples of β-blockers include acebutolol (Sectral), atenolol (Tenormin), betaxolol (Kerlone), bisoprolol / hydrochlorothiazide (Ziac), bisoprolol (Zebeta), carteolol (Cartrol), esmolol (Brevibloc), labetalol (Normodyne, Trandate), metoprolol (Lopressor, Toprol XL), nadolol (Corgard), propranolol (Inderal), sotalol (Betapace), and timolol (Blocadren).

[0173] Nitrates dilate arteries and veins by increasing coronary blood flow and lowering blood pressure. Examples of nitrates include nitroglycerin, nitrate patches, isosorbide dinitrate, and isosorbide 5-mononitrate.

[0174] Calcium channel blockers prevent the normal inflow of calcium into the cells of the heart and blood vessels, thereby causing vasodilation and increasing the supply of blood and oxygen to the heart. Examples of calcium channel blockers include amlodipine (Norvasc, Lotrel), bepridil (Vascor), diltiazem (Cardizem, Tiazac), felodipine (Plendil), nifedipine (Adalat, Procardia), nimodipine (Nimotop), nisoldipine (Sular), verapamil (Calan, Isoptin, Verelan), and nicardipine.

[0175] Heart failure medication Medications used to treat heart failure include diuretics, ACE inhibitors, vasodilators, and cardiac glycosides. Diuretics eliminate excess fluid from tissues and circulation, thereby alleviating many symptoms of heart failure. Examples of diuretics include hydrochlorothiazide, metolazone (Zaroxolyn), furosemide (Lasix), bumetanide (Bumex), spironolactone (Aldactone), and eplerenone (Inspra).

[0176] Angiotensin-converting enzyme (ACE) inhibitors reduce the workload on the heart by dilating blood vessels and reducing resistance to blood flow. Examples of ACE inhibitors include benazepril (Lotensin), captopril (Capoten), enalapril (Vasotec), fosinopril (Monopril), lisinopril (Prinivil, Zestril), moexipril (Univasc), perindopril (Aceon), quinapril (Accupril), ramipril (Altace), and trandolapril (Mavik).

[0177] Vasodilators reduce pressure on blood vessels by relaxing and dilating them. Examples of vasodilators include hydralazine, diazoxide, prazosin, clonidine, and methyldopa. ACE inhibitors, nitrates, potassium channel activators, and calcium channel blockers are also used as vasodilators.

[0178] Cardiac glycosides are compounds that increase the contractility of the heart. These compounds enhance the heart's pumping ability and improve irregular heartbeats. Examples of cardiac glycosides include digitalis, digoxin, and digitoxin.

[0179] Antithrombotic agents Antithrombotic agents inhibit the blood's ability to clot. There are three main types of antithrombotic agents: platelet inhibitors, anticoagulants, and thrombolytics.

[0180] Platelet inhibitors suppress platelet clot activity, thereby reducing clots in arteries. Examples of platelet inhibitors include acetylsalicylic acid (aspirin), ticlopidine, clopidogrel (plavix), dipyridamole, cilostazol, persantine, sulfinpyrazone, indomethacin, and glycoprotein IIb / IIIa inhibitors, such as abciximab, tirofiban, and eptifibatide (integrelin). Beta-blockers and calcium channel blockers also have platelet-inhibiting effects.

[0181] Anticoagulants prevent blood clots from growing and prevent the formation of new clots. Examples of anticoagulants include bivalirudin (Angiomax), warfarin (Coumadin), unclassified heparin, low molecular weight heparin, danaparoid, lepirudin, and argatroban.

[0182] Thrombolytic agents are used to break down existing blood clots. Examples of thrombolytic agents include streptococcal kinase, urokinase, tenecteplase (TNK), and tissue plasminogen activator (t-PA).

[0183] Antiarrhythmic agents Antiarrhythmic agents are used to treat disorders of heart rate and rhythm. Examples of antiarrhythmic agents include amiodarone, dronedarone, quinidine, procainamide, lidocaine, and propafenone. Cardiac glycosides and beta-blockers are also used as antiarrhythmic agents.

[0184] Given the recently discovered synergistic effects of the sodium channel blocker ranolazine, amiodarone, and dronedarone, the combination of amiodarone and dronedarone is particularly interesting.

[0185] Antihypertensive drugs Antihypertensive drugs are used to treat hypertension, a condition in which blood pressure is consistently higher than normal. Hypertension is associated with many forms of cardiovascular disease, including congestive heart failure, atherosclerosis, and blood clot formation. Examples of antihypertensive agents include alpha-1-adrenergic antagonists such as prazosin (Minipress), doxazosin mesylate (Cardura), prazosin hydrochloride (Minipress), prazosin, polythiazide (Minizide), and terazosin hydrochloride (Hytrin); beta-adrenergic antagonists such as propranolol (Inderal), naldolol (Corgard), timolol (Blocadren), metoprolol (Lopressor), and indrolol (Visken); and central alpha-adrenergic receptor agonists such as caffeine hydrochloride (Catapres), caffeine hydrochloride, chlorthalidone (Clorpres, Combipres), guanabenz acetate (Wytensin), and guanfacine hydrochloride. (Tenex), methyldopa (Aldomet), methyldopa and chlorothiazide (Aldoclor), methyldopa and hydrochlorothiazide (Aldoril); combination α / β-adrenergic antagonists, such as labetalol (Normodyne, Trandate) and carvedilol (Coreg); adrenergic neuronal blocking agents, such as guanethidine (ismelin) and serpasil; central nervous system antihypertensive agents, such as caffeine (Catapres), methyldopa (Aldomet), and guanethidine (Wytensin); antiangiogenic peptide II agents; ACE inhibitors, such as perindopril (Aceon), captopril (Capoten), enalapril (Vasotec), and lisinopril (Prinivil, Zestril); angiotensin-II receptor antagonists, such as candesartan (Atacand) and eprosartan. (Teveten), Irbesartan (Avapro), Losartan (Cozaar), Telmisartan (Micardis), Valsartan (Diovan);Calcium channel blockers, such as verapamil (Calan, Isoptin), diltiazem (Cardizem), and nifedipine (Adalat, Procardia); diuretics; direct vasodilators, such as nitroprusside (Nipride), hyperstat IV, apresoline, minoxidil (Loniten), and verapamil; and potassium channel activators, such as aprikaline (aprikalim), bimakalim, cromakalim, emakalim, nicorandil, and pinacidil.

[0186] lipid-lowering agents Lipid-lowering agents are used to reduce the amount of cholesterol or fatty acids present in the blood. Examples of lipid-lowering agents include bezafibrate (Bezalip), ciprofibrate (Modalim), and statins such as atorvastatin (Lipitor), fluvastatin (Lescol), lovastatin (Mevacor, Altocor), mevastatin, pitavastatin (Livalo, Pitava), pravastatin (Lipostat), rosuvastatin (Crestor), and simvastatin (Zocor).

[0187] In this invention, patients presenting with acute coronary artery disease events often have secondary medical conditions, such as one or more of metabolic disorders, lung disease, peripheral vascular disease, or gastrointestinal disease. These patients may benefit from combination therapy comprising administering ranolazine to the patient in combination with at least one therapeutic agent.

[0188] Combination therapy for lung diseases Lung diseases refer to any disease or condition related to the lungs. Examples of lung diseases include (but are not limited to) asthma, chronic obstructive pulmonary disease (COPD), bronchitis, and emphysema.

[0189] Examples of therapeutic agents used to treat lung conditions include bronchodilators, including β2 agonists and anti-parasympathetic drugs, corticosteroids, and electrolyte supplements. Specific examples of therapeutic agents used to treat lung conditions include adrenaline, terbutaline (Brethaire, Bricanyl), albuterol (Proventil), salmeterol (Serevent, Serevent Diskus), theophylline, ipratropium bromide (Atrovent), tiotropium (Spiriva), methylprednisolone (Solu-Medrol, Medrol), magnesium, and potassium.

[0190] Metabolic Disorder Combination Therapy Examples of metabolic disorders include (but are not limited to) diabetes (including type 1 and type 2 diabetes), metabolic syndrome, dyslipidemia, obesity, glucose intolerance, hypertension, elevated serum cholesterol, and elevated triglycerides.

[0191] Examples of therapeutic agents used to treat metabolic disorders include antihypertensive agents and lipid-lowering agents, as described in the "Cardiovascular Combination Therapy" section above. Additional therapeutic agents used to treat metabolic disorders include insulin, sulfonylureas, biguanides, alpha-glucosidase inhibitors, and incretin mimics.

[0192] Combination therapy for peripheral vascular diseases Peripheral vascular diseases are conditions related to blood vessels (arteries and veins) located outside the heart and brain, including (for example) peripheral artery disease (PAD), which occurs when arteries supplying blood to internal organs, arms, and legs are completely or partially blocked due to atherosclerosis.

[0193] Combination therapy for gastrointestinal diseases Gastrointestinal disorders refer to diseases and conditions related to the gastrointestinal tract. Examples of gastrointestinal disorders include gastroesophageal reflux disease (GERD), inflammatory bowel disease (IBD), gastroenteritis, gastritis, peptic ulcer disease, and pancreatitis.

[0194] Examples of therapeutic agents used to treat gastrointestinal disorders include proton pump inhibitors such as pantoprazole (Protonix), lansoprazole (Prevacid), esomeprazole (Nexium), omeprazole (Prilosec), and rabeprazole; H2 blockers such as cimetidine (Tagamet), ranitidine (Zantac), famotidine (Pepcid), and nizatidine (Axid); prostaglandins such as misoprostol (Cytotec); sucralfate; and antacids.

[0195] Combination therapy of antibiotics, analgesics, antidepressants, and anti-anxiety drugs Patients presenting with acute coronary events may demonstrate benefit from treatment with a combination of ranolazine or antibiotics, analgesics, antidepressants, and anxiolytics.

[0196] antibiotic Antibiotics are therapeutic agents that kill microorganisms (including bacteria and fungi) or stop their growth. Examples of antibiotics include β-lactam antibiotics, including penicillin (amoxicillin), and cephalosporins such as cefazolin, cefuroxime, cefadroxil (Duricef), cephalexin (Keflex), cephradine (Velosef), cefaclor (Ceclor), cefuroxime axtel (Ceftin), cefprozil (Cefzil), loracarbef (Lorabid), cefixime (Suprax), cefpodoxime proxetil (Vantin), and ceftibuten. (Cedax), cefdinir (Omnicef), ceftriaxone (Rocephin), carbapenem, and monobactam; tetracyclines, such as tetracycline; macrocyclic lactone antibiotics, such as erythromycin; aminoglycosides, such as gentamicin, tobramycin, and amikacin; quinolinones, such as ciprofloxacin; cyclic peptides, such as vancomycin, streptogramin, and polymyxin; lincosamides, such as clindamycin; oxazolidinones, such as linezolid; and sulfonamide antibiotics, such as sulfisoxazole.

[0197] Painkillers Analgesics are therapeutic agents used to relieve pain. Examples of analgesics include opiates and morphine analogues, such as fentanyl and morphine; paracetamol; NSAIDs and COX-2 inhibitors. Given the ability of the sodium channel blocker of the present invention to treat neuropathic pain by inhibiting NaV 1.7 and 1.8 sodium channels, combinations with analgesics are particularly envisioned. See U.S. Patent Application Publication 20090203707.

[0198] Antidepressants and anti-anxiety drugs Antidepressants and anti-anxiety medications include those used to treat anxiety disorders, depression, and the like, as well as those used as sedatives and tranquilizers. Examples of antidepressants and anti-anxiety medications include benzodiazepines, such as diazepam, lorazepam, and midazolam; benzodiazepines; barbiturates; glutethimide; chloral hydrate; meprobamate; sertraline (Zoloft, Lustral, Apo-Sertral, Asentra, Gladem, Serlift, Stimuroton); escitalopram (Lexapro, Cipralex); fluoxetine (Prozac, Sarafem, Fluxtin, Fontex, Prodep, Fludep, Lovan); venlafaxine (Effexor XR, Efexor); and citalopram. (Celexa, Cipramine, Talohexane); paroxetine (Paxil, Seroxat, Aropax); trazodone (Desyrel); amitriptyline (Elavil); and bupropion (Wellbutrin, Zyban). Antidepressants and anti-anxiety medications may include neuroactive steroids and ketamine, as well as related NMDA receptor antagonists.

[0199] Therefore, one embodiment of the present invention provides a composition comprising the sodium channel blocker of the present invention and at least one therapeutic agent. In alternative embodiments, the composition comprises the sodium channel blocker of the present invention and at least two therapeutic agents. In other alternative embodiments, the composition comprises the sodium channel blocker of the present invention and at least three therapeutic agents, the sodium channel blocker of the present invention and at least four therapeutic agents, or the sodium channel blocker of the present invention and at least five therapeutic agents.

[0200] The combination therapy method includes the co-administration of a single formulation containing the sodium channel blocker and therapeutic agent or drug of the present invention, the substantially simultaneous administration of one or more formulations containing the sodium channel blocker and therapeutic agent or drug of the present invention, and the sequential administration of the sodium channel blocker and therapeutic agent or drug of the present invention in any order, wherein preferably, there is a time period during which the sodium channel blocker and therapeutic agent or drug of the present invention exert their therapeutic effects simultaneously.

[0201] [Example] [ ] The following representative examples are intended to help illustrate the present invention, and are not intended and should not be construed as limiting the scope of the present invention.

[0202] The compounds described herein can be prepared from readily available starting materials using the following general methods and procedures. It should be understood that although typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, other process conditions may be used unless otherwise specified. Optimal reaction conditions may vary depending on the specific reactants or solvents used, but these conditions can be determined by a person skilled in this technique through routine optimization.

[0203] Furthermore, as those skilled in this art will understand, protecting groups may be necessary to prevent certain functional groups from undergoing undesirable reactions. The selection of suitable protecting groups for specific functional groups and the appropriate conditions for protection and deprotection is well-known in the field. For example, TW Greene and PGM Wuts' *Protecting Groups in Organic Synthesis* (2nd edition, Wiley, New York, 1991) and the references cited herein describe numerous protecting groups and their introduction and removal.

[0204] The compounds described herein can be separated and purified using known standard procedures. These procedures include recrystallization, filtration, rapid chromatography, grinding, high-performance liquid chromatography (HPLC), or supercritical fluid chromatography (SFC). Note that rapid chromatography can be performed manually or via an automated system. The compounds described herein can be characterized using known standard procedures, such as nuclear magnetic resonance (NMR) spectroscopy or liquid chromatography-mass spectrometry (LCMS). NMR chemical shifts are reported in parts per million (ppm) and are produced using methods familiar to those skilled in the art.

[0205] Typical general methods for analytical LCMS include Method A (Ultimate C18 (2.1 mm × 30 mm, 3 µm); A = H2O (0.04% TFA) and B = CH3CN (0.02% TFA); 50 °C; 1.2 mL / min; 10-80% B over 0.9 min, then 80% B held for 0.6 min) and Method B (Chromolith Flash RP-18-capped C18 (2 mm × 25 mm); A = H2O (0.04% TFA) and B = CH3CN (0.02% TFA); 50 °C; 1.5 mL / min; 5-95% B over 0.7 min, then 95% B held for 0.4 min).

[0206] [List of Abbreviations] [ ] Pd(dppf)Cl2 [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride Pd(t-Bu3P)2 bis(tri-tert-butylphosphine)palladium(0) Pd(OAc)₂ Palladium(II) acetate SPhos 2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl Et3N Triethylamine AgOTf Silver Trifluoromethanesulfonate DMF N,N-dimethylformamide MeOH (methanol) EtOH (ethanol) i-Pr2O diisopropyl ether THF Tetrahydrofuran DCM dichloromethane AcN or MeCN acetonitrile EA or EtOAc (ethyl acetate) PE petroleum ether DMSO (dimethyl sulfoxide) AcOH (acetic acid) NBS N-bromosuccinimide NaOMe (sodium methoxide) EtONa sodium ethanol TsOH p-Toluenesulfonic acid DEA N,N-diethylaniline DIPEA N,N-Diisopropylethylamine TFA (trifluoroacetic acid) KOAc potassium acetate T3P propanephosphonic anhydride

[0207] [Example] [1] [:] [3-[] [Cyclopropylmethoxy] [(] [Difluoride] [)] [methyl] []-6-[5-] [fluorine] [-6-(2,2,2-] [Trifluoroethoxy] [)-3-] [Pyridyl] []-[1,2,4]] [Triazo] [[4,3-a]] [Pyridine] [ ] [B] [Synthesis:] 2,2,2-trifluoroethanol (7.36 g, 73.56 mmol) was slowly added to a suspension of NaH (2.94 g, 73.56 mmol) in THF (50 mL) at 20 °C, and the mixture was stirred for 1 hour. Then, 5-chloro-2,3-difluoropyridine (10 g, 66.88 mmol) was added, and the mixture was stirred at 20 °C for another 4 hours. The mixture was quenched with saturated NH4Cl (50 mL) and extracted with EtOAc (100 mL × 2). The combined organic phases were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to obtain an oily solution. [B] (15000 mg, 65.34 mmol). [ 1 ] [H NMR] (400MHz, CDCl3) δH = 7.83 (d, 1H), 7.38 (dd, 1H), 4.73 (q, 2H). [A3] [The synthesis:] will A mixture of [B] (8 g, 34.85 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborpine-2-yl)-1,3,2-dioxaborpine (26.55 g, 104.55 mmol), K3PO4 (14.79 g, 69.7 mmol), SPhos (4.29 g, 10.45 mmol), and Pd(OAc)2 (782.4 mg, 3.48 mmol) in 1,4-dioxane (250 mL) was stirred at 85 °C for 16 hours. After cooling to room temperature, the mixture was filtered through diatomaceous earth and precipitated with EtOAc (50 mL × 2). The filtrate was concentrated and diluted with EtOAc (200 mL), washed with water (100 mL × 2) and brine (100 mL), dried over Na2SO4, filtered, and concentrated to produce a crude product. This crude product was then purified by rapid chromatography on silica gel (EtOAc in PE = 0 to 10% to 40%) to obtain an oily product (3 g, 4.6021 mmol). [ 1 ] [H NMR] (400MHz, CDCl3) δH = 8.26 (d, 1H), 7.72 (dd, 1H), 4.87 (q, 2H), 1.35 (s, 12H). [LCMS] Rt = 0.94 min. Using method B, MS ESI calculated value C13H17BF4NO3 [M+H]+ 322.1, experimental value 322.3. [A2] [Synthesis:] NaH (212.41 mg, 5.31 mmol) was added to a mixture of cyclopropylmethanol (382.93 mg, 5.31 mmol) and THF (10 mL), and the mixture was stirred at 20 °C for 0.5 h. Then, 6-bromo-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyridine (300 mg, 1.06 mmol) was added to the mixture, and the mixture was stirred at 20 °C for 2 h. The reaction mixture was quenched with saturated NH4Cl (10 mL), and the mixture was extracted with EtOAc (10 mL × 2). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated to yield the crude product. The crude product was purified by rapid chromatography on silicone (EtOAc in PE = 10% to 40%), resulting in a solid product (240 mg, 0.73 mmol). [LCMS] Rt = 2.29 min in 4 min chromatography. [Compound] [1] [Synthesis:] A mixture of 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborpinecyclo-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (111.02 mg, 0.35 mmol), Pd(dppf)Cl2 (34.5 mg, 0.05 mmol), 6-bromo-3-[cyclopropylmethoxy(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyridine (100 mg, 0.31 mmol) and K2CO3 (86.89 mg, 0.63 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was stirred at 90 °C under N2 for 16 hours. After cooling to room temperature, the mixture was filtered through diatomaceous earth and dissolved with EtOAc (10 mL × 2). The filtrate was then concentrated to produce a crude product. The crude product was purified by Prep-HPLC (Waters Xbridge 150 mm × 25 mm 5 µm) using A = H2O (10 mM NH4HCO3) and B = CH3CN (50-70% B) over 7 minutes to produce a solid product (100.49 mg, 0.23 mmol). [ 1 ] [H NMR] (400MHz, DMSO-d6) δH = 8.75 (s, 1H), 8.46 (d, 1H), 8.34 (dd, 11.2 Hz, 1H), 8.14 - 8.09 (m, 1H), 7.97 (dd, 1H), 5.18 (q, 2H), 4.09 (d, 2H), 1.31 - 1.21 (m, 1H), 0.61 - 0.55 (m, 2H), 0.43 - 0.37 (m, 2H). [LCMS] In 2.0 min chromatography, Rt = 1.31 min, MS ESI calculated value C18H15F6N4O2 [M+H]+ 433.1, experimental value 433.0.

[0208] [Example] [2] [:] [3-[] [Difluoride] [(] [Isobutyroxy] [)] [methyl] []-6-[5-] [fluorine] [-6-(2,2,2-] [Trifluoroethoxy] [)-3-] [Pyridyl] []-[1,2,4]] [Triazo] [[4,3-a]] [Pyridine] [ ] [A4] [Synthesis:] NaH (212.41 mg, 5.31 mmol) was added to a mixture of 2-methylprop-1-ol (393.6 mg, 5.31 mmol) and THF (10 mL), and the mixture was stirred at 20 °C for 0.5 h. Then, 6-bromo-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyridine (300 mg, 1.06 mmol) was added to the mixture, and the mixture was stirred at 20 °C for 2 h. The reaction mixture was quenched with saturated NH4Cl (10 mL), and the mixture was extracted with EtOAc (20 mL × 2). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated to yield the crude product. The crude product was purified by rapid chromatography on silicone (EtOAc in PE = 10% to 40%), resulting in a solid product (100 mg, 0.30 mmol). [LCMS] In 1.5 min chromatography, Rt = 0.86 min, MS ESI calculated value C11H13BrF2N3O [M+H+2]+ 320.0, experimental value 320.2. [Compound] [2] [Synthesis:] A mixture of 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborpinecyclo-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (110.33 mg, 0.34 mmol), Pd(dppf)Cl2 (34.28 mg, 0.05 mmol), 6-bromo-3-[difluoro(isobutoxy)methyl]-[1,2,4]triazolo[4,3-a]pyridine (100 mg, 0.31 mmol) and K2CO3 (86.35 mg, 0.62 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was stirred at 90 °C under N2 for 16 hours. After cooling to room temperature, the mixture was filtered through diatomaceous earth and dissolved with EtOAc (10 mL × 2). The filtrate was then concentrated to produce a crude product. The crude product was purified by Prep-HPLC (Waters Xbridge 150 mm × 25 mm 5 µm) using A = H2O (10 mM NH4HCO3) and B = CH3CN (50-70% B) over 8 minutes to produce a solid product (53.41 mg, 0.12 mmol). [ 1 ] [H NMR] (400MHz, DMSO-d6) δH = 8.70 (s, 1H), 8.44 (d, 1H), 8.33 (dd, 1H), 8.12 (dd, 1H), 7.96 (dd, 1H), 5.18 (q, 2H), 4.02 (d, 2H), 2.09 - 1.98 (m, 1H), 0.96 (d, 6H). [LCMS] In 2.0 min chromatography, Rt = 1.34 min, MS ESI calculated value C18H17F6N4O2 [M+H]+ 435.1, experimental value 435.1.

[0209] [Example] [3] [:] [3-[] [Ethoxy] [(] [Difluoride] [)] [methyl] []-6-[5-] [fluorine] [-6-(2,2,2-] [Trifluoroethoxy] [)-3-] [Pyridyl] []-[1,2,4]] [Triazo] [[4,3-a]] [Pyridine] [ ] [A5] [Synthesis]: A mixture of 6-bromo-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyridine (300 mg, 1.06 mmol) and EtONa (361.37 mg, 5.31 mmol) in ethanol (10 mL) was stirred at 80 °C for 24 hours. After cooling to room temperature, the reaction mixture was quenched with saturated NH4Cl (10 mL), and the mixture was extracted with EtOAc (20 mL × 2). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated to produce a crude product. The crude product was purified by rapid chromatography on silicone (EtOAc in PE = 10% to 40%) to produce a solid product (70 mg, 0.17 mmol). [LCMS] In 4 min chromatography, Rt = 1.97 min, MS ESI calculated value C9H9BrF2N3O [M+H+2]+ 294.0, experimental value 293.8. [Compound] [3] [Synthesis:] A mixture of 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborpinecyclo-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (84.65 mg, 0.26 mmol), Pd(dppf)Cl2 (26.3 mg, 0.04 mmol), 6-bromo-3-[ethoxy(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyridine (70 mg, 0.24 mmol), and K2CO3 (66.25 mg, 0.48 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was stirred at 90 °C under N2 for 16 hours. After cooling to room temperature, the mixture was filtered through diatomaceous earth, precipitated with EtOAc (10 mL × 2), and the filtrate was concentrated to produce the crude product. The crude product was purified by Prep-HPLC (Waters Xbridge 150 mm × 25 mm 5 µm) A = H2O (10 mM NH4HCO3) and B = CH3CN; 42-62% B) within 8 minutes to produce a solid product (44.33 mg, 0.11 mmol). [ 1 ] [H NMR] (400MHz, DMSO-d6) δH = 8.73 (s, 1H), 8.46 (d, 1H), 8.35 (br d, 1H), 8.11 (d, 1H), 7.96 (d, 1H), 5.18 (q, 2H), 4.29 (q, 2H), 1.36 (t, 3H) [LCMS] In 2.0 min chromatography, Rt = 1.25 min, MS ESI calculated value C16H13F6N4O2 [M+H]+ 407.1, experimental value 407.0.

[0210] [Example] [4] [:] [3-[] [Difluoride] [(] [Isopropoxy] [)] [methyl] []-6-[5-] [fluorine] [-6-(2,2,2-] [Trifluoroethoxy] [)-3-] [Pyridyl] []-[1,2,4]] [Triazo] [[4,3-a]] [Pyridine] [ ] [A6] [Synthesis:] NaH (127.45 mg, 3.19 mmol) was added to a mixture of propan-2-ol (319.15 mg, 5.31 mmol) and THF (10 mL), and the mixture was stirred at 20 °C for 0.5 h. Then, 6-bromo-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyridine (300 mg, 1.06 mmol) was added to the mixture, and the mixture was stirred at 20 °C for 2 h. The reaction mixture was quenched with saturated NH4Cl (10 mL), and the mixture was extracted with EtOAc (10 mL × 2). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated to yield the crude product. The crude product was purified by rapid chromatography on silicone (EtOAc in PE = 10% to 40%), resulting in a solid product (240 mg, 0.72 mmol). [LCMS] In 4 min chromatography, Rt = 2.18 min, MS ESI calculated value C10H11BrF2N3O [M+H+2]+ 306.0, experimental value 305.9. [ ] [Compound] [4] [Synthesis:] A mixture of 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborpinecyclo-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (115.38 mg, 0.36 mmol), Pd(dppf)Cl2 (35.85 mg, 0.05 mmol), 6-bromo-3-[difluoro(isopropoxy)methyl]-[1,2,4]triazolo[4,3-a]pyridine (100 mg, 0.33 mmol) and K2CO3 (90.3 mg, 0.65 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was stirred at 90 °C under N2 for 16 hours. After cooling to room temperature, the mixture was filtered through diatomaceous earth and dissolved with EtOAc (10 mL × 2). The filtrate was then concentrated to produce a crude product. The crude product was purified by Prep-HPLC (Waters Xbridge 150 mm × 25 mm 5 µm) using A = H2O (10 mM NH4HCO3) and B = CH3CN (45-65% B) over 8 minutes to produce a solid product (80.25 mg, 0.19 mmol). [ 1 ] [H NMR] (400MHz, DMSO-d6) δH = 8.60 (s, 1H), 8.43 (d, 1H), 8.32 (dd, 1H), 8.11 (d, 1H), 7.95 (dd, 1H), 5.17 (q, 2H), 4.90 (spt, 1H), 1.41 (d, 6H). [LCMS] In 2.0 min chromatography, Rt = 1.29 min, MS ESI calculated value C17H15F6N4O2 [M+H]+ 421.1, experimental value 421.0.

[0211] [Example] [5] [:] [3-[] [Difluoride] [(] [Methoxy] [)] [methyl] []-6-[5-] [fluorine] [-6-(2,2,2-] [Trifluoride] [-1,1-] [Dimethyl] [-] [Ethoxy] [)-3-] [Pyridyl] []-[1,2,4]] [Triazo] [[4,3-b]] [Tarazine] [ ] [ ] [A7] [Synthesis:] 2-Chloro-2,2-difluoroacetic acid (2-chloro-2,2-difluoroacetyl) ester (5.55 g, 22.83 mmol) was added to a mixture of (6-chloro-3-yl)hydrazine (3 g, 20.75 mmol) in toluene (40 mL). The reaction mixture was stirred at 110 °C for 4 hours. After cooling to room temperature, the reaction mixture was concentrated. The residue was diluted with saturated NaHCO3 (50 mL), and the mixture was extracted with EtOAc (50 mL × 2). The combined organic phases were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated to yield a crude solid product. [ 1 ] [H NMR] (400MHz, DMSO-d6) δH = 8.67 (d, 1H), 7.78 (d, 1H). [A9] [Synthesis:] A mixture of 6-chloro-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-b]pyrazine (200 mg, 0.84 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)pyridine (350.58 mg, 1 mmol), Pd(t-Bu3P)2 (64.15 mg, 0.13 mmol) and K3PO4 (532.95 mg, 2.51 mmol) in 1,4-dioxane (2 mL) and water (0.20 mL) was stirred at 80 °C for 16 hours. After cooling to room temperature, the suspension was diluted with 10 mL of EtOAc, filtered through a silica gel filter, and precipitated with 20 mL of EtOAc. The combined filtrates were concentrated to obtain the crude product. The crude product was purified by rapid chromatography on silica gel (EtOAc in PE = 20% to 50% to 80%) to produce a solid product (260 mg, 0.50 mmol). [LCMS] In 1.5 min chromatography, Rt = 0.96 min, MS ESI calculated value C15H11ClF6N5O [M+H]+ 426.1, experimental value 425.9. [Compound] [5] [Synthesis] AgOTf (905.31 mg, 3.52 mmol) and MeOH (8 mL, 0.35 mmol) were added to a mixture of 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyrazine (150 mg, 0.35 mmol) in MeCN (1 mL). The mixture was stirred at 90 °C for 10 days. After cooling to room temperature, the mixture was concentrated to obtain a residue. The residue was diluted with water (30 mL) and extracted with EtOAc (30 mL × 2). The combined organic phases were washed with water (20 mL × 2) and brine (30 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated to obtain a crude product. The crude product was purified by Prep-HPLC (Waters Xbridge (150 mm × 25 mm, 5 µm), A = H2O (0.05% NH4OH) and B = CH3CN; 57-87% B within 9 minutes) to produce a solid product. [ 1 ] [H NMR] (CDCl3, 400MHz) δH = 8.55 (d, 1H), 8.29 (d, 1H), 8.09 (dd, 1H), 7.65 (d, 1H), 3.94 (s, 3H), 1.90 (s, 6H). [LCMS] In 2.0 min chromatography, Rt = 1.32 min, MS ESI calculated value C16H14F6N5O2 [M+H]+422.1, experimental value 422.0.

[0212] [Example] [6] [:] [3-[] [Difluoride] [(] [Methoxy] [)] [methyl] []-6-[5-] [fluorine] [-6-[(1S)-2,2,2-] [Trifluoride] [-1-] [methyl] [-] [Ethoxy] []-3-] [Pyridyl] []-[1,2,4]] [Triazo] [[4,3-a]] [Pyridine] [ ] [ ] A mixture of 6-bromo-3-[difluoro(methoxy)methyl]-[1,2,4]triazolo[4,3-a]pyridine (100 mg, 360 µmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (144.62 mg, 430 µmol), K₂CO₃ (99.41 mg, 720 µmol), and Pd(dppf)Cl₂ (39.47 mg, 50 µmol) in 1,4-dioxane (5 mL) and water (500 µL) was stirred at 80 °C under N₂ for 12 hours. After cooling to room temperature, the mixture was diluted with H₂O (10 mL) and extracted with EtOAc (20 mL × 2). The combined organic phases were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated to produce a crude product. The crude product was purified by Prep-HPLC (Boston Prime C18 (150 x 30 mm, 5 µm), A = H2O (0.05% NH4OH) and B = CH3CN; 53-83% B within 8 minutes) to produce a solid product. [ 1 ] [H NMR] (400MHz, DMSO-d6) δH = 8.73 (s, 1H), 8.45 (d, 1H), 8.33 (dd, 1H), 8.10 (d, 1H), 7.94 (d, 1H), 6.01 (spt, 1H), 3.89 (s, 3H), 1.54 (d, 3H). [LCMS] In 2.0 min chromatography, Rt = 1.27 min, MS ESI calculated value C18H13F6N4O2 [M+H]+ 407.09, experimental value 406.9.

[0213] [Example] [7] [:] [3-[] [Difluoride] [(] [Methoxy] [)] [methyl] []-6-[5-] [fluorine] [-6-[(1R)-2,2,2-] [Trifluoride] [-1-] [methyl] [-] [Ethoxy] []-3-] [Pyridyl] []-[1,2,4]] [Triazo] [[4,3-a]] [Pyridine] [ ] [ ] A mixture of 6-bromo-3-[difluoro(methoxy)methyl]-[1,2,4]triazolo[4,3-a]pyridine (100 mg, 360 µmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (144.62 mg, 430 µmol), K₂CO₃ (99.41 mg, 720 µmol), and Pd(dppf)Cl₂ (39.47 mg, 50 µmol) in 1,4-dioxane (5 mL) and water (500 µL) was stirred at 80 °C under N₂ for 12 hours. After cooling to room temperature, the mixture was diluted with H₂O (10 mL) and extracted with EtOAc (20 mL × 2). The combined organic phases were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated to produce a crude product. The crude product was purified by Prep-HPLC (Boston Prime C18 (150 mm × 30 mm, 5 µm), A = H2O (0.05% NH4OH) and B = CH3CN; 53-83% B within 8 minutes) to produce a solid product. [ 1 ] [H-NMR] (400MHz, DMSO-d6) δH = 8.74 (s, 1H), 8.46 (d, 1H), 8.35 (dd, 1H), 8.11 (d, 1H), 7.95 (dd, 1H), 6.02 (spt, 1H), 3.95 - 3.82 (m, 3H), 1.55 (d, 3H). [LCMS] In 2.0 min chromatography, Rt = 1.27 min, MS ESI calculated value C18H13F6N4O2 [M+H]+ 407.1, experimental value 406.9.

[0214] [Example] [8] [:] [3-[] [Cyclopropylmethoxy] [(] [Difluoride] [)] [methyl] []-6-[5-] [fluorine] [-6-(2,2,2-] [Trifluoroethoxy] [)-3-] [Pyridyl] []-[1,2,4]] [Triazo] [[4,3-a]] [Pyrazine] [ ] A mixture of 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine (300 mg, 0.75 mmol) and AgOTf (1938.39 mg, 7.54 mmol) in cyclopropylmethanol (15 mL, 0.75 mmol) and CH3CN (15 mL) was stirred at 90 °C for 14 days. After cooling to room temperature, the reaction mixture was diluted with EtOAc (40 mL) and saturated NaCl (40 mL) was added to the mixture. The mixture was filtered through diatomaceous earth and precipitated with EtOAc (20 mL × 2). The filtrate was concentrated to produce a crude product. The crude product was purified by Prep-TLC (EtOAc : PE = 1 : 1) to produce an impure product. The impure product was purified by Prep-HPLC (Waters Xbridge 150 mm × 25 mm 5 µm) A = H2O (10 mM NH4HCO3) and B = CH3CN; within 8 minutes, the impurity product was 48-68% B), thus producing a solid product. [ 1 ] [H-NMR] (CDCl3, 400MHz) δH = 9.52 (d, 1H), 8.57 (d, 1H), 8.50 (d, 1H), 8.07 (dd, 1H), 4.93 (q, 2H), 4.13 (d, 2H), 1.40 - 1.30 (m, 1H), 0.79 - 0.73 (m, 2H), 0.49 - 0.42 (m, 2H). [LCMS] In 2.0 min chromatography, Rt = 1.33 min, MS ESI calculated value C17H14F6N5O2 [M+H]+ 434.1, experimental value 434.0.

[0215] [Example] [9] [:] [3-[] [Cyclopropylmethoxy] [(] [Difluoride] [)] [methyl] []-6-[5-] [fluorine] [-6-(2,2,2-] [Trifluoroethoxy] [)-3-] [Pyridyl] []-[1,2,4]] [Triazo] [[4,3-a]] [Pyrazine] [ ] [A19] [Synthesis] [:] A mixture of Pd(dppf)Cl2 (15.13 g, 20.68 mmol), Cs2CO3 (269.49 g, 827.17 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (141.18 g, 439.69 mmol) and 2-bromo-5-chloropyrazine (80 g, 413.59 mmol) in 1,4-dioxane (1 L) and water (150 mL) was stirred at 35 °C for 2 hours under N2. After cooling to room temperature, water (300 mL) was added to the mixture, and the mixture was filtered through diatomaceous earth. After separation, the organic phase was washed with brine (300 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to produce a crude product. The crude product was redissolved in EA / PE = 1 / 3 (500 mL) and then filtered through a silicone mat. The cake was washed with EA / PE = 1 / 3 (500 mL). The combined organic phases were concentrated to produce an oily residue. PE (500 mL) was slowly added to the oily residue, yielding some solids. The solids were collected and dried in an oven to produce a solid product (100 g, 242.4 mmol, 58% yield). [LCMS] In 2.0 min chromatography, Rt = 1.28 min, 10-80 AB, MS ESI calculated value C11H7ClF4N3O [M+H]+ 308.0, experimental value 307.9. [A20] [Synthesis] A mixture of 2-chloro-5-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]pyrazine (140 g, 339.36 mmol) and hydrazine hydrate (169.88 g, 3393.6 mmol) in MeCN (1.4 L) was stirred at 100 °C for 16 hours. After cooling to room temperature, the mixture was slowly poured into water (4.5 L). Some solids were observed and collected by filtration. The cake was washed with water (500 mL × 2). The solids were redissolved in EtOAc (3 L), washed with brine (500 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated to produce a crude solid product (100 g, 329.8 mmol, 97% yield). [LCMS] In 1.5 min chromatography, Rt = 0.74 min, 5-95 AB, MS ESI calculated value C11H10F4N5O [M+H]+ 304.1, experimental value 303.9. [A13] [Synthesis] Add one drop of DMF and (COCl)₂ (50.5 mL, 596.81 mmol) to a solution of 2-bromo-2,2-difluoro-acetic acid (87 g, 497.34 mmol) in THF (1 L). Stir the resulting mixture at 20 °C for 1 hour. Use the resulting solution directly in the next step. Add [5-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]pyrazin-2-yl]hydrazine (100 g, 329.79 mmol) to a solution of 2-bromo-2,2-difluoro-acetyl chloride (95.66 g, 494.69 mmol) in THF (1 L). Stir the resulting mixture at 20 °C for 2 hours. Add water (1 L) to the solution and extract with EtOAc (1 L × 2). The combined organic phases were washed with brine (500 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated to produce a crude solid product (150 g, 326.0 mmol, 98% yield, a mixture of mono- and di-alkylated products). [LCMS] In 1.5 min chromatography at 5-95 AB, Rt = 0.92 min, MS ESI C13H9BrF6N5O2 [M+H]+ calculated value 460.1, experimental value 459.8. [A14] [Synthesis] A solution of 2-bromo-2,2-difluoro-N'-[5-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]pyrazin-2-yl]acetylhydrazine (150 g, 325.99 mmol) and TsOH (16.84 g, 97.8 mmol) in toluene (1.5 L) was stirred at 130 °C for 16 hours. After cooling to room temperature, the mixture was poured into water (2 L) and extracted with EtOAc (2 L × 2). The combined organic phases were washed with brine (1 L × 2), dried over anhydrous Na2SO4, filtered, and concentrated to yield a crude product. The crude product was purified by rapid chromatography on silica gel (EtOAc in PE = 0% to 15% to 30%) to yield an oily product (80 g, 181.0 mmol, 55% yield). [ 1 ] [H NMR] (CDCl3, 400MHz) δH = 9.60 (d, 1H), 8.55 (d, 1H), 8.45 (s, 1H), 8.09 (dd, 1H), 4.93 (q, 2H). [Compound]

[10] [Synthesis:] A mixture of 3-[bromo(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine (76 g, 171.9 mmol) and AgBF4 (66.93 g, 343.81 mmol) in ethanol (760 mL) was stirred at 60 °C for 1 hour. After cooling to room temperature, the mixture was poured into a saturated aqueous solution of NaCl (1 L) and EtOAc (2 L). The mixture was filtered through diatomaceous earth. After separation, the aqueous layer was extracted with (500 mL × 2). The combined organic phases were washed with brine (500 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated to produce a crude product. The crude product was purified by rapid column chromatography on silicone (EtOAc in PE = 0% to 30% to 50%) and then ground with EtOH (50 mL) to produce a solid product (44.45 g, 109.01 mmol, 63% yield). [ 1 ] [H NMR] (CDCl3 400MHz) δH = 9.52 (d, 1H), 8.49 (dd, 2H), 8.07 (dd, 1H), 4.93 (q, 2H), 4.37 (q, 2H), 1.51 (t, 3H). [LCMS] In 2.0 min chromatography at 10-80 AB, Rt = 1.25 min, MS ESI C15H12F6N5O2 [M+H]+ calculated value 408.1, experimental value 408.0.

[0216] [Example]

[10] [:] [3-[] [Difluoride] [(] [Methoxy] [)] [methyl] []-6-[5-] [fluorine] [-6-[1-(] [Trifluoromethyl] [)] [Cyclobutoxy] []-3-] [Pyridyl] []-[1,2,4]] [Triazo] [[4,3-a]] [Pyrazine] [ ] A mixture of 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[1-(trifluoromethyl)cyclobutoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine (1.4 g, 3.2 mmol) and AgOTf (8.22 g, 31.98 mmol) in a mixed solvent of methanol (14 mL) and DMF (14 mL) was stirred at 90 °C for 24 hours. After cooling to room temperature, the reaction mixture was treated with brine (40 mL) and the precipitate was filtered off. The filtrate was extracted with EtOAc (40 mL × 2). The combined organic phases were washed with brine (20 mL), dried over Na2SO4, and concentrated to produce a crude product. The crude product was purified by Prep-HPLC (Waters Xbridge (150 mm × 25 mm 5 µm) A = H2O (10 mM NH4HCO3) and B = CH3CN; 57-67% B within 8 minutes) to yield the product (240 mg). Another batch was prepared at 1.2 g. [A24] was started, and approximately 110 mg of product was obtained by Prep-HPLC (Boston Prime C18 (150 mm × 30 mm, 5 µm) A = H2O (0.05% NH4OH) and B = CH3CN; 50-80% B within 9 minutes). The two batches of product were combined and lyophilized to produce a solid product. [ 1 ] [H NMR] (CDCl3, 400 MHz) δH = 9.51 (d, 1H), 8.49 (d, 1H), 8.47 (d, 1H), 8.05 (dd, 1H), 3.98 (s, 3H), 2.98 - 2.86 (m, 2H), 2.81 - 2.72 (m, 2H), 2.11 - 1.93 (m, 2H). [LCMS] In 2 min chromatography, Rt = 1.30 min, 10-80 AB, MS ESI calculated value C17H14F6N5O2 [M+H]+ 434.1, experimental value 433.9.

[0217] [Example]

[11] [:] [3-[] [Difluoride] [(] [Methoxy] [)] [methyl] []-6-[5-] [fluorine] [-6-[(1S)-2,2,2-] [Trifluoride] [-1-] [methyl] [-] [Ethoxy] []-3-] [Pyridyl] []-[1,2,4]] [Triazo] [[4,3-b]] [Tarazine] [ ] [A25] [Synthesis:] A mixture of 6-chloro-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-b]pyrazine (120 mg, 0.50 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (201.9 mg, 0.60 mmol), K3PO4 (319.74 mg, 1.51 mmol), Pd(t-Bu3P)2 (25.66 mg, 0.05 mmol) in 1,4-dioxane (12 mL) and H2O (4 mL) was stirred at 90 °C for 16 hours. After cooling to room temperature, the reaction mixture was concentrated, diluted with water (20 mL), and extracted with ethyl acetate alkylene (20 mL × 2). The combined organic phase was washed with brine (40 mL), dried over Na₂SO₄, and concentrated to produce a residue. The residue was purified by rapid chromatography on silicone (EtOAc in PE = 0% to 60%) to produce a solid product (120 mg, 0.29 mmol). [ 1 ] [H-NMR] (CDCl3, 400MHz) δH = 8.57 (d, 1 H), 8.35 (d, 1 H), 8.15 (dd, 1 H), 7.74 (d, 1 H), 5.93 (m, 1 H) 1.61 (d, 3 H). [Compound]

[12] [Synthesis:] A mixture of AgOTf (599.15 mg, 2.33 mmol) and 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyrazine (120 mg, 0.29 mmol) in methanol (6 mL) was stirred at 90 °C for 120 hours. After cooling to room temperature, the reaction mixture was treated with brine (20 mL) and the precipitate was filtered off. The filtrate was concentrated, diluted with water (20 mL), and extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with brine (40 mL), dried over Na2SO4, and concentrated to produce the residue. The residue was purified by prep-HPLC (Boston Prime C18 150 x 30 mm 5 µm) A = H2O (0.05 % NH4OH) and B = CH3CN; 52-82 % B) within 8 minutes to produce the product (5.12 mg, 13 µmol). [ 1 ] [H-NMR] (CDCl3, 400MHz) δH = 8.55 (d, 1 H), 8.30 (d, 1 H), 8.14 (dd, 1 H), 7.66 (d, 1 H), 5.92 (m, 1 H), 3.94 (s, 3 H), 1.61 (d, 3 H). [LCMS] In 2.0 min chromatography, Rt = 1.28 min, MS ESI calculated value C15H12F6N5O2 [M+H]+ 408.1, experimental value 408.0.

[0218] [Example]

[12] [:] [3-[] [Difluoride] [(] [Methoxy] [)] [methyl] []-6-[5-] [fluorine] [-6-[(1R)-2,2,2-] [Trifluoride] [-1-] [methyl] [-] [Ethoxy] []-3-] [Pyridyl] []-[1,2,4]] [Triazo] [[4,3-b]] [Tarazine] [ ] [A26] [Synthesis:] A mixture of 6-chloro-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-b]pyrazine (120 mg, 0.50 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (201.9 mg, 0.60 mmol), K3PO4 (319.74 mg, 1.51 mmol), Pd(t-Bu3P)2 (25.66 mg, 0.05 mmol) in 1,4-dioxane (12 mL) and H2O (4 mL) was stirred at 90 °C for 16 hours. After cooling to room temperature, the reaction mixture was concentrated to remove the solvent, diluted with water (20 mL), and extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with brine (40 mL), dried over Na2SO4, and concentrated to produce a crude product. The crude product was purified by rapid chromatography on silica gel (EtOAc in PE = 0% to 60%) to produce a solid product (140 mg, 0.34 mmol). [ 1 ] [H-NMR](CDCl3, 400MHz) δH = 8.57 (d, 1 H), 8.35 (d, 1 H), 8.14 (dd, 1 H), 7.74 (d, 1 H), 5.93 (m, 1 H), 1.61 (d, 3 H). [Compound]

[13] [Synthesis:] A mixture of 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyrazine (140 mg, 0.34 mmol) and AgOTf (699 mg, 2.72 mmol) in methanol (8 mL) was stirred at 90 °C for 120 hours. After cooling to room temperature, the reaction mixture was treated with brine (20 mL) and the precipitate was filtered off. The filtrate was concentrated and diluted with water (20 mL), and then extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with brine (40 mL), dried over Na2SO4, and concentrated to produce a residue. The residue was purified by Prep-HPLC (Boston Prime C18 150 x 30 mm 5µm) A = H2O (0.05 % NH4OH) and B = CH3CN; 52-82 % B) within 8 minutes to produce the product (5 mg, 12.2 µmol). [ 1 ] [H-NMR] (CDCl3, 400MHz) δH = 8.55 (d, 1 H), 8.30 (d, 1 H), 8.14 (dd, 1 H), 7.66 (d, 1 H), 5.92 (m, 1 H), 3.94 (s, 3 H), 1.61 (d, 3 H). [LCMS] In 2.0 min chromatography, Rt = 1.26 min, MS ESI calculated value C15H12F6N5O2 [M+H]+ 408.1, experimental value 408.0.

[0219] [Example]

[13] [:] [3-[] [Cyclopropylmethoxy] [(] [Difluoride] [)] [methyl] []-6-[5-] [fluorine] [-6-(2,2,2-] [Trifluoroethoxy] [)-3-] [Pyridyl] []-[1,2,4]] [Triazo] [[4,3-b]] [Tarazine] [ ] [ ] [A27] [Synthesis:] A mixture of 6-chloro-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-b]pyrazine (500 mg, 2.09 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (2015.06 mg, 6.28 mmol), Pd(t-Bu3P)2 (160.37 mg, 0.31 mmol) and K3PO4 (888.25 mg, 4.18 mmol) in 1,4-dioxane (15 mL) and water (1.5 mL) was stirred at 90 °C under N2 for 16 hours. The mixture was filtered through diatomaceous earth and dissolved with EtOAc (10 mL × 2), and the filtrate was concentrated to produce a crude product. The crude product was purified by rapid chromatography on silica gel (EtOAc in PE = 20% to 60%) to produce a solid product (900 mg, 1.90 mmol). [LCMS] In 1.5 min chromatography, Rt = 0.85 min, MS ESI calculated value C13H7ClF6N5O [M+H]+ 398.0, experimental value 398.0. [Compound]

[14] [Synthesis:] A mixture of 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyrazine (200 mg, 0.50 mmol) and AgOTf (1292.26 mg, 5.03 mmol) in cyclopropylmethanol (10 mL, 0.50 mmol) and CH3CN (10 mL) was stirred at 90 °C for 13 days. After cooling to room temperature, the reaction mixture was diluted with EtOAc (40 mL) and brine (40 mL). The mixture was filtered through diatomaceous earth, precipitated with EtOAc (20 mL × 2), and the filtrate was concentrated to produce the crude product. The crude product was purified by Prep-HPLC (Boston Prime C18 150 mm × 30 mm 5 µm) A = H2O (0.05% NH4OH v / v) and B = CH3CN; 58-88% B) over 8 minutes, resulting in an impure product. The impure product was then ground with n-hexane / i-Pr2O (v / v = 1:1, 2 mL) to produce a solid product (9.82 mg, 22.2 µmol). [ 1 ] [H NMR] (DMSO-d6, 400MHz) δH = 8.83 (d, 1H), 8.67 (d, 1H), 8.45 (dd, 1H), 8.21 (d, 1H), 5.22 (q, 2H), 4.03 (d, 2H), 1.26 - 1.18 (m, 1H), 0.62 - 0.54 (m, 2H), 0.43 - 0.33 (m, 2H). [LCMS] In 4.0 min chromatography, Rt = 2.87 min, MS ESI calculated value C17H14F6N5O2 [M+H]+ 434.1, experimental value 434.0.

[0220] [Example]

[14] [:] [3-[] [Difluoride] [(] [Methoxy] [)] [methyl] []-6-[5-] [fluorine] [-6-(2,2,2-] [Trifluoride] [-1,1-] [Dimethyl] [-] [Ethoxy] [)-3-] [Pyridyl] []-[1,2,4]] [Triazo] [[4,3-a]] [Pyrazine] [ ] [A29] Synthesis: A solution of [5-[5-fluoro-6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridyl]pyrazin-2-yl]hydrazine (300 mg, 0.91 mmol) and 2-chloro-2,2-difluoroacetic acid (2-chloro-2,2-difluoro-acetyl) ester (660.02 mg, 2.72 mmol) in toluene (30 mL) was stirred at 110 °C for 72 hours. After cooling to room temperature, the mixture was concentrated to produce a residue. Water (50 mL) was added to the residue, and the mixture was extracted with EtOAc (50 mL × 2). The combined organic phases were washed with water (50 mL) and brine (50 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated to produce a crude product. The crude product was purified by rapid column chromatography on silicone (EtOAc in PE = 0% to 10% to 20%), resulting in a solid product (150 mg, 346.3 µmol). [LCMS] In 4.0 min chromatography, Rt = 3.06 min, MS ESI calculated value C15H11ClF6N5O [M+H]+426.0, experimental value 426.0. [Compound]

[15] [Synthesis] AgOTf (1.81 g, 7.05 mmol) was added to a solution of 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine (150 mg, 0.35 mmol) in methanol (5 mL) and MeCN (5 mL). The resulting mixture was stirred in a sealed tube under N2 at 90 °C for 5 days. The mixture was cooled to room temperature and then brine (20 mL) and EtOAc (30 mL) were added, and the mixture was filtered. After separating the filtrate, the organic phase was washed with water (20 mL × 2) and brine (20 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated to produce the crude product. The crude product was purified by Prep-TLC (PE: EtOAc = 4:1) to produce a solid product (14.23 mg, 33.2 mmol). [ 1 ] [H NMR] (CDCl3, 400MHz) δH= 9.52 (d, 1H), 8.51 (d, 1H), 8.45 (d, 1H), 8.02 (dd, 1H), 3.98 (s, 3H), 1.89 (s, 6H). [LCMS] In 2.0 min chromatography, Rt = 1.33 min, MS ESI calculated value C16H14F6N5O2 [M+H]+422.1, experimental value 422.0.

[0221] [Example]

[15] [:] [3-[] [Ethoxy] [(] [Difluoride] [)] [methyl] []-6-[5-] [fluorine] [-6-(2,2,2-] [Trifluoroethoxy] [)-3-] [Pyridyl] []-[1,2,4]] [Triazo] [[4,3-b]] [Tarazine] [ ] A mixture of 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyrazine (200 mg, 0.50 mmol) and AgOTf (1292.26 mg, 5.03 mmol) in ethanol (10 mL, 0.50 mmol) and CH3CN (10 mL) was stirred at 90 °C for 13 days. After cooling to room temperature, the reaction mixture was diluted with EtOAc (40 mL) and brine (40 mL). The mixture was filtered through diatomaceous earth, precipitated with EtOAc (20 mL × 2), and the filtrate was concentrated to produce a crude product. The crude product was purified by Prep-TLC (EtOAc : DCM : PE = 1 : 1 : 1) to produce an impure product. The impure product was ground from hexane / CH2Cl2 (v / v = 1 : 2, 6 mL) to produce a solid product (15.95 mg, 39.2 mmol). [ 1 ] [H NMR] (DMSO-d6, 400MHz) δH = 8.81 (d, 1H), 8.68 (d, 1H), 8.43 (dd, 1H), 8.21 (d, 1H), 5.22 (q, 2H), 4.24 (q, 2H), 1.36 (t, 3H). [LCMS] In 2.0 min chromatography, Rt = 1.26 min, MS ESI calculated value C15H12F6N5O2 [M+H]+ 408.1, experimental value 408.0. [ ]

[0222] [Example]

[16] [:] [3-[] [Difluoride] [(] [Methoxy] [)] [methyl] []-6-[5-] [fluorine] [-6-[1-(] [Trifluoromethyl] [)] [Cyclobutoxy] []-3-] [Pyridyl] []-[1,2,4]] [Triazo] [[4,3-b]] [Tarazine] [ ] [A7-a] [Synthesis:] 2-Chloro-2,2-difluoroacetic acid (2-chloro-2,2-difluoroacetyl) ester (7.56 g, 31.13 mmol) was added to a mixture of (6-chloro-3-yl)hydrazine (3.0 g, 20.75 mmol) in toluene (40 mL). The reaction mixture was stirred at 110 °C for 4 hours. After cooling to room temperature, the reaction mixture was concentrated. The residue was diluted with saturated NaHCO3 (50 mL), and the mixture was extracted with EtOAc (50 mL × 2). The combined organic phases were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated to yield a crude product as a solid (4700 mg, 19.66 mmol). [ 1 ] [H NMR] (400MHZ, CDCl3) δH = 7.35 (d, 1H), 8.23 ​​(d, 1H). [A30] [Synthesis:] A mixture of 6-chloro-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-b]pyrazine (150 mg, 0.63 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)-2-[1-(trifluoromethyl)cyclobutoxy]pyridine (362.64 mg, 1 mmol), K3PO4 (399.65 mg, 1.88 mmol), bis(tri-tert-butylphosphine)palladium(0) (64.15 mg, 0.1300 mmol) in 1,4-dioxane (12 mL) and water (4 mL) was stirred at 80 °C for 16 hours. New spots were observed by TLC (Rf = 0.45, UV), and no starting material remained (Rf = 0.8, UV). After cooling to room temperature, the reaction mixture was concentrated to remove the solvent, diluted with water (20 mL), and extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with brine (40 mL), dried over Na₂SO₄, and concentrated to yield a crude product. The crude product was purified by rapid chromatography on silicone (EtOAc in PE = 0% to 60%) to yield a solid product (120 mg, 0.27 mmol). [ 1 ] [H NMR] (CDCl3, 400MHz) δH = 8.57 (d, 1H), 8.33 (d, 1H), 8.15 - 8.06 (m, 1H), 7.73 (d, 1H), 2.82 - 2.96 (m, 2H), 2.78 - 2.81 (m, 2H), 2.00 - 2.08 (m, 2H). [Compound]

[17] [Synthesis] A mixture of 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[1-(trifluoromethyl)cyclobutoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyrazine (120 mg, 0.27 mmol) and silver trifluoromethanesulfonate (0.7 g, 2.74 mmol) in a mixed solvent of methanol (12 mL) and MeCN (4 mL) was stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was treated with brine (20 mL) and the precipitate was filtered off. The filtrate was concentrated to remove the solvent, diluted with water (20 mL), and extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with brine (40 mL), dried over Na2SO4, and concentrated to produce a residue. The crude product was purified by prep-HPLC (Boston Prime C18 150 x 30 mm 5 µm) A = H2O (0.05% NH4OH) and B = ACN; 52-82% B) within 8 minutes to produce a solid product (27.93 mg, 64.5 µmol). [ 1 ] [H NMR] (CDCl3, 400 MHz) δH = 8.54 (d, 1H), 8.28 (d, 1H), 8.11 (dd, 1H), 7.64 (d, 1H), 3.93 (s, 3H), 2.82 - 2.96 (m, 2H), 2.76 - 2.81 (m, 2H), 1.57 - 2.07 (m, 2H). [LCMS] In 2.0 min chromatography, Rt = 1.32 min, MS ESI calculated value C17H14F6N5O2 [M+H]+ 434.1, experimental value 434.0.

[0223] [Example]

[17] [:] [3-[] [Difluoride] [(] [Methoxy] [)] [methyl] []-6-[5-] [fluorine] [-6-[1-(] [Trifluoromethyl] [)] [Cyclobutoxy] []-3-] [Pyridyl] []-[1,2,4]] [Triazo] [[4,3-a]] [Pyridine] [ ] [ ] [A1] [Synthesis:] A mixture of (5-bromo-2-pyridyl)hydrazine (2.6 g, 13.83 mmol) and 2-chloro-2,2-difluoroacetic acid (2-chloro-2,2-difluoroacetyl) ester (5.04 g, 20.74 mmol) in toluene (100 mL) was stirred at 10 °C for 1 hour, and then the mixture was heated to 120 °C and stirred for 36 hours. After cooling to room temperature, the reaction mixture was quenched with saturated NaHCO3 (50 mL), and the mixture was extracted with EtOAc (50 mL × 2). The organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to produce a crude product. The crude product was purified by rapid chromatography on silicone (EtOAc in PE = 0% to 20% to 30%) to produce a solid product (3900 mg, 13.81 mmol). [ 1 ] [H NMR] (400MHz, CDCl3) δH = 8.42 (s, 1H), 7.84 (d, 1H), 7.53 (dd, 1H). [LCMS] In 7.0 min chromatography, Rt = 3.19 min, MS ESI calculated value C7H4BrClF2N3 [M+H+2]+ 283.9, experimental value 283.6. [A15] [Synthesis] A mixture of 6-bromo-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyridine (1 g, 3.54 mmol) and NaOMe (956.21 mg, 17.7 mmol) in methanol (20 mL) was stirred at 80 °C for 24 hours. After cooling to room temperature, the reaction mixture was quenched with saturated NH4Cl (50 mL), and the mixture was extracted with EtOAc (50 mL × 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to produce a crude product. The crude product was purified by rapid chromatography on silicone (EtOAc in PE = 0% to 30% to 40%) to produce a solid product (380 mg, 127.56 µmol). [ 1 ] [H-NMR] (CDCl3, 400MHz) δH = 8.43 (s, 1H), 7.77 (d, 1H), 7.47 - 7.41 (m, 1H), 3.92 (s, 3H). [LCMS] In 7.0 min chromatography, Rt = 2.95 min, MS ESI calculated value C8H7BrF2N3O [M+H+2]+ 280.0, experimental value 279.7. [Compound]

[18] [Synthesis] A mixture of 6-bromo-3-[difluoro(methoxy)methyl]-[1,2,4]triazolo[4,3-a]pyridine (100 mg, 0.36 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborpinecyclo-2-yl)-2-[1-(trifluoromethyl)cyclobutoxy]pyridine (155.86 mg, 0.43 mmol), K₂CO₃ (99.41 mg, 0.72 mmol), and Pd(dppf)Cl₂ (39.47 mg, 0.05 mmol) in 1,4-dioxane (5 mL) and water (0.50 mL) was stirred at 80 °C for 12 hours. After cooling to room temperature, the mixture was diluted with H₂O (10 mL) and extracted with EtOAc (20 mL × 2). The combined organic phases were washed with water (30 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated to produce a crude product. The crude product was purified by Prep-HPLC (Boston Prime C18 (150 x 30 mm, 5 µm), A = H2O (0.05% NH4OH) and B = CH3CN; 58-88% B over 8 minutes) to produce a solid product (66.89 mg, 15.47 µmol). [ 1 ] [H NMR] (DMSO-d6, 400MHz) δH = 8.75 (s, 1H), 8.46 (d, 1H), 8.33 (dd, 1H), 8.10 (d, 1H), 7.96 (dd, 1H), 3.89 (s, 3H), 2.97 - 2.85 (m, 2H), 2.72 - 2.62 (m, 2H), 2.07 - 1.95 (m, 1H), 1.93 - 1.81 (m, 1H). [LCMS] In 2.0 min chromatography, Rt = 1.32 min, MS ESI calculated value C18H15F6N4O2 [M+H]+ 433.1, experimental value 432.9.

[0224] [Example]

[18] [:] [3-[] [Cyclopropylmethoxy] [(] [Difluoride] [)] [methyl] []-6-[5-] [fluorine] [-6-[(1S)-2,2,2-] [Trifluoride] [-1-] [methyl] [-] [Ethoxy] []-3-] [Pyridyl] []-[1,2,4]] [Triazo] [[4,3-a]] Synthesis of pyridine [ ] A mixture of 6-bromo-3-[cyclopropylmethoxy(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyridine (65 mg, 200 µmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborphanecyclo-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (82.16 mg, 250 µmol), K2CO3 (56.48 mg, 410 µmol), and Pd(dppf)Cl2 (22.43 mg, 30 µmol) in 1,4-dioxane (5 mL) and water (0.50 mL) was stirred at 80 °C under N2 for 12 hours. After cooling to room temperature, the mixture was diluted with H2O (10 mL) and extracted with EtOAc (20 mL × 2). The combined organic phases were washed with water (20 mL) and brine (30 mL), dried over Na2SO4, filtered, and concentrated to produce a crude product. The crude product was purified by Prep-HPLC (Boston Prime C18 (150 x 30 mm, 5 µm) A = H2O (0.05% NH4OH) and B = CH3CN; 62-92% B within 8 minutes) to produce a solid product (43.42 mg, 97.3 µmol, 48% yield). [ 1 ] [H NMR] (DMSO-d6, 400MHz) δH = 8.74 (s, 1H), 8.44 (d, 1H), 8.32 (dd, 1H), 8.11 (dd, 1H), 7.95 (dd, 1H), 6.02 (spt, 1H), 4.09 (d, 2H), 1.54 (d, 3H), 1.32 - 1.21 (m, 1H), 0.62 - 0.52 (m, 2H), 0.44 - 0.33 (m, 2H). [LCMS] In 2.0 min chromatography, Rt = 1.37 min, 10-80 AB, MS ESI calculated value C19H17F6N4O2 [M+H]+ 447.1, experimental value 447.0.

[0225] [Example]

[19] [:] [3-[] [Difluoride] [(] [Isopropoxy] [)] [methyl] []-6-[5-] [fluorine] [-6-[(1S)-2,2,2-] [Trifluoride] [-1-] [methyl] [-] [Ethoxy] []-3-] [Pyridyl] []-[1,2,4]] [Triazo] [[4,3-a]] [Pyridine] [ ] [ ] A mixture of 6-bromo-3-[difluoro(isopropoxy)methyl]-[1,2,4]triazolo[4,3-a]pyridine (70 mg, 230 µmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (91.96 mg, 270 µmol), K₂CO₃ (63.21 mg, 460 µmol), and Pd(dppf)Cl₂ (25.1 mg, 30 µmol) in 1,4-dioxane (5 mL) and water (0.50 mL) was stirred at 80 °C under N₂ for 12 hours. After cooling to room temperature, the mixture was diluted with H₂O (10 mL) and extracted with EtOAc (20 mL × 2). The combined organic phases were washed with water (20 mL) and brine (30 mL), dried over Na2SO4, filtered, and concentrated to produce a crude product. The crude product was purified by Prep-HPLC (Boston Prime C18 (150 x 30 mm, 5 µm), A = H2O (0.05% NH4OH) and B = CH3CN; 60-90% B within 8 minutes) to produce a solid product (33.94 mg, 78.1 µmol, 34% yield). 1H NMR (DMSO-d6, 400MHz) δH = 8.61 (s, 1H), 8.43 (d, 1H), 8.31 (dd, 1H), 8.11 (dd, 1H), 7.95 (dd, 1H), 6.02 (spt, 1H), 4.90 (spt, 1H), 1.54 (d, 3H), 1.41 (d, 6H). [LCMS] In 2.0 min chromatography, Rt = 1.35 min, 10-80 AB, MS ESI calculated value C18H17F6N4O2 [M+H]+ 435.1, experimental value 435.0.

[0226] [Example]

[20] [:] [3-[] [Difluoride] [(] [Isopropoxy] [)] [methyl] []-6-[5-] [fluorine] [-6-[(1R)-2,2,2-] [Trifluoride] [-1-] [methyl] [-] [Ethoxy] []-3-] [Pyridyl] []-[1,2,4]] [Triazo] [[4,3-a]] [Pyridine] [ ] [ ] A mixture of 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (84.29 mg, 0.25 mmol), Pd(dppf)Cl2 (25.1 mg, 0.03 mmol), 6-bromo-3-[difluoro(isopropoxy)methyl]-[1,2,4]triazolo[4,3-a]pyridine (70 mg, 0.23 mmol) and K2CO3 (63.21 mg, 0.46 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was stirred at 90 °C under N2 for 16 hours. After cooling to room temperature, the mixture was filtered through diatomaceous earth and dissolved with EtOAc (10 mL × 2). The filtrate was then concentrated to produce a crude product. The crude product was purified by Prep-HPLC (Boston Prime C18 (150 mm × 30 mm 5 µm) A = H2O (0.05% ammonia hydroxide v / v) and B = CH3CN; 60-90% B within 8 minutes) to produce a solid product (24.78 mg, 57.1 µmol, 25% yield). [ 1 ] [H NMR] (DMSO-d6, 400MHz) δH = 8.61 (s, 1H), 8.43 (d, 1H), 8.32 (dd, 1H), 8.12 (d, 1H), 7.95 (dd, 1H), 6.03 (spt, 1H), 4.95 - 4.85 (m, 1H), 1.54 (d, 3H), 1.41 (d, 6H). [LCMS] In 2.0 min chromatography, Rt = 1.37 min, 10-80 AB, MS ESI calculated value C18H17F6N4O2 [M+H]+ 435.1, experimental value 435.1.

[0227] [Example] [twenty one] [:] [3-[] [Difluoride] [(] [Isobutyroxy] [)] [methyl] []-6-[5-] [fluorine] [-6-[(1S)-2,2,2-] [Trifluoride] [-1-] [methyl] [-] [Ethoxy] []-3-] [Pyridyl] []-[1,2,4]] [Triazo] [[4,3-a]] [Pyridine] [ ] [ ] [A1-a] [Synthesis:] A mixture of (5-bromo-2-pyridyl)hydrazine (5 g, 26.59 mmol) and 2-chloro-2,2-difluoroacetic acid (2-chloro-2,2-difluoroacetyl) ester (9690.21 mg, 39.89 mmol) in toluene (200 mL) was stirred at 10 °C for 1 hour, and then heated at 120 °C for 36 hours. After cooling to room temperature, the reaction mixture was quenched with saturated NaHCO3 (200 mL), and then extracted with EtOAc (80 mL × 2). The organic layer was washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated to yield the crude product. The crude product was purified by rapid chromatography on silicone (EtOAc in PE = 0% to 5% to 20%), resulting in a solid product (5700 mg, 20.18 mmol, 76% yield). [ 1 ] [H NMR] (CDCl3, 400MHz) δH = 8.43 (s, 1H), 7.84 (dd, 1H), 7.54 (dd, 1H). [ ] [A4-a] [Synthesis:] NaH (708.04 mg, 17.7 mmol) was added to a mixture of 2-methylprop-1-ol (1312 mg, 17.7 mmol) in THF (40 mL), and the mixture was stirred at 20 °C for 0.5 h. Then, 6-bromo-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyridine (1000 mg, 3.54 mmol) was added to the mixture, and the mixture was stirred at 20 °C for 2 h. The reaction mixture was quenched with saturated NH4Cl (40 mL), and the mixture was extracted with EtOAc (30 mL × 2). The combined organic phases were washed with brine (70 mL), dried over Na2SO4, filtered, and concentrated to yield the crude product. The crude product was purified by rapid chromatography on silicone (EtOAc in PE = 10% to 40%), resulting in an oily product (750 mg, 2.34 mmol, 66% yield). [ 1 ] [H NMR] (CDCl3, 400MHz) δH = 8.44 (s, 1H), 7.77 (d, 1H), 7.44 (dd, 1H), 4.00 (d, 2H), 2.16 - 2.06 (m, 1H), 1.04 (d, 6H). [Compound] [twenty two] [Synthesis:] A mixture of 6-bromo-3-[difluoro(isobutoxy)methyl]-[1,2,4]triazolo[4,3-a]pyridine (100 mg, 310 µmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (125.61 mg, 370 µmol), K2CO3 (86.35 mg, 620 µmol), and Pd(dppf)Cl2 (34.28 mg, 50 µmol) in 1,4-dioxane (5 mL) and water (0.50 mL) was stirred at 80 °C under N2 for 12 hours. After cooling to room temperature, the mixture was diluted with H2O (10 mL) and extracted with EtOAc (20 mL × 2). The combined organic phases were washed with water (20 mL) and brine (30 mL), dried over Na2SO4, filtered, and concentrated to produce a crude product. The crude product was purified by Prep-HPLC (Boston Prime C18 (150 x 30 mm, 5 µm), A = H2O (0.05% NH4OH) and B = CH3CN; 65-95% B over 8 minutes) to produce a solid product (47.11 mg, 105.1 µmol, 34% yield). [ 1 ] [H NMR] (DMSO-d6, 400MHz) δH = 8.70 (s, 1H), 8.43 (d, 1H), 8.31 (dd, 1H), 8.11 (dd, 1H), 7.95 (dd, 1H), 6.02 (spt, 1H), 4.01 (d, 2H), 2.10 - 1.95 (m, 1H), 1.54 (d, 3H), 0.96 (d, 6H). [LCMS] In 2.0 min chromatography, Rt = 1.41 min, 10-80 AB, MS ESI calculated value C19H19F6N4O2 [M+H]+ 449.1, experimental value 449.1.

[0228] [Example] [twenty two] [:] [3-[] [Difluoride] [(] [Isobutyroxy] [)] [methyl] []-6-[5-] [fluorine] [-6-[(1R)-2,2,2-] [Trifluoride] [-1-] [methyl] [-] [Ethoxy] []-3-] [Pyridyl] []-[1,2,4]] [Triazo] [[4,3-a]] [Pyridine] [ ] A mixture of 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (115.14 mg, 0.34 mmol), Pd(dppf)Cl2 (34.28 mg, 0.05 mmol), 6-bromo-3-[difluoro(isobutoxy)methyl]-[1,2,4]triazolo[4,3-a]pyridine (100 mg, 0.31 mmol) and K2CO3 (86.35 mg, 0.62 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was stirred at 90 °C under N2 for 16 hours. After cooling to room temperature, the mixture was filtered through diatomaceous earth and precipitated with EtOAc (10 mL × 2). The filtrate was then concentrated to produce a crude product. The crude product was purified by Prep-HPLC (Boston Prime C18 150 mm × 30 mm 5 µm) A = H2O (0.05% ammonia hydroxide v / v) and B = CH3CN (61-91% B) within 8 minutes to produce a solid product (68.11 mg, 0.15 mmol, 48% yield). [ 1 ] [H NMR] (DMSO-d6, 400MHz) δH = 8.70 (s, 1H), 8.43 (d, 1H), 8.31 (dd, 1H), 8.15 - 8.09 (m, 1H), 7.95 (dd, 1H), 6.08 - 5.96 (m, 1H), 4.02 (d, 2H), 2.09 - 1.96 (m, 1H), 1.54 (d, 3H), 0.96 (d, 6H). [LCMS] In 2.0 min chromatography, Rt = 1.42 min, 10-80 ABMS ESI calculated value C19H19F6N4O2 [M+H]+ 449.1, experimental value 449.1.

[0229] [Example] [twenty three] [:] [3-[] [Difluoride] [(] [Methoxy] [)] [methyl] []-6-[5-] [fluorine] [-6-(2,2,2-] [Trifluoride] [-1,1-] [Dimethyl] [-] [Ethoxy] [)-3-] [Pyridyl] []-[1,2,4]] [Triazo] [[4,3-a]] [Pyridine] [ ] [ ] [A15-a] [Synthesis] A mixture of 6-bromo-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyridine (1000 mg, 3.54 mmol) and NaOMe (956.21 mg, 17.7 mmol) in methanol (20 mL) was stirred at 80 °C for 24 hours. After cooling to room temperature, the reaction mixture was quenched with saturated NH4Cl (50 mL), and then extracted with EtOAc (50 mL × 2). The organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to produce a crude product. The crude product was purified by rapid chromatography on silicone (EtOAc in PE = 0% to 30% to 40%) to produce an oily product (230 mg, 754.3 µmol, 21% yield). [LCMS] In 1.5 min chromatography, Rt = 1.41 min, 5-95 AB, MS ESI calculated value C8H8BrF2N3O [M+H+2]+ 280.0, experimental value 279.9. [Compound] [twenty four] [Synthesis:] A mixture of 6-bromo-3-[difluoro(methoxy)methyl]-[1,2,4]triazolo[4,3-a]pyridine (70 mg, 250 µmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)pyridine (105.47 mg, 300 µmol), K2CO3 (69.59 mg, 500 µmol), and Pd(dppf)Cl2 (27.63 mg, 40 µmol) in 1,4-dioxane (5 mL) and water (0.50 mL) was stirred at 80 °C under N2 for 12 hours. After cooling to room temperature, the mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL × 2). The combined organic phases were washed with water (30 mL) and brine (30 mL), dried over Na2SO4, filtered, and concentrated to produce a crude product. The crude product was purified by Prep-HPLC (Boston Prime C18 (150 x 30 mm, 5 µm), A = H2O (0.05% NH4OH) and B = CH3CN; 56-86% B over 8 min) to produce a solid product (22.72 mg, 54.1 µmol, 21% yield). [ 1 ] [H NMR] (DMSO-d6, 400MHz) δH = 8.75 (s, 1H), 8.47 (d, 1H), 8.31 (dd, 1H), 8.14 - 8.05 (m, 1H), 7.95 (dd, 1H), 3.89 (s, 3H), 1.82 (s, 6H). [LCMS] In 2.0 min chromatography, Rt = 1.31 min, 10-80 AB, MS ESI calculated value C17H15F6N4O2 [M+H]+ 421.1, experimental value 421.1.

[0230] [Example] [twenty four] [:] [3-[] [Cyclopropylmethoxy] [(] [Difluoride] [)] [methyl] []-6-[5-] [fluorine] [-6-[(1R)-2,2,2-] [Trifluoride] [-1-] [methyl] [-] [Ethoxy] []-3-] [Pyridyl] []-[1,2,4]] [Triazo] [[4,3-a]] [Pyridine] [ ] [ ] A mixture of 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborpinecyclo-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (69.52 mg, 0.21 mmol), Pd(dppf)Cl2 (20.7 mg, 0.03 mmol), 6-bromo-3-[cyclopropylmethoxy(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyridine (60 mg, 0.19 mmol) and K2CO3 (52.14 mg, 0.38 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was stirred at 90 °C under N2 for 16 hours. After cooling to room temperature, the mixture was filtered through diatomaceous earth and dissolved with EtOAc (10 mL × 2). The filtrate was then concentrated to produce a crude product. The crude product was purified by Prep-HPLC (Boston Prime C18 150 mm × 30 mm 5 µm) A = H2O (0.05% ammonia hydroxide v / v) and B = CH3CN (60-90% B) over 8 minutes to produce a solid product (51.82 mg, 0.12 mmol, 62% yield). [ 1 ] [H NMR] (DMSO-d6, 400MHz) δH = 8.74 (s, 1H), 8.45 (d, 1H), 8.32 (dd, 1H), 8.11 (dd, 1H), 7.96 (dd, 1H), 6.02 (spt, 1H), 4.09 (d, 2H), 1.54 (d, 3H), 1.32 - 1.21 (m, 1H), 0.62 - 0.54 (m, 2H), 0.43 - 0.36 (m, 2H). [LCMS] In 2.0 min chromatography, Rt = 1.39 min, 10-80 ABMS ESI calculated value C19H17F6N4O2 [M+H]+ 447.1, experimental value 447.1.

[0231] [Example]

[25] [:] [3-[] [Ethoxy] [(] [Difluoride] [)] [methyl] []-6-[5-] [fluorine] [-6-[(1R)-2,2,2-] [Trifluoride] [-1-] [methyl] [-] [Ethoxy] []-3-] [Pyridyl] []-[1,2,4]] [Triazo] [[4,3-a]] [Pyrazine] A mixture of 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine (500 mg, 1.21 mmol) and AgOTf (3120.55 mg, 12.15 mmol) in ethanol (7 mL) and MeCN (7 mL) was stirred at 90 °C for 5 days. The mixture was cooled to room temperature, and then EtOAc (20 mL) and brine (50 mL) were added to the mixture, followed by filtration through diatomaceous earth to obtain a suspension. The layers were separated, and the aqueous phase was extracted with EtOAc (50 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated to produce a crude product. The crude product was purified by rapid chromatography over silicone (EtOAc in PE = 10% to 30% to 50%), and then ground with DCM (3 mL) and n-hexane (4 mL) to produce a solid product (31.35 mg, 74 µmol, 6% yield). [ 1 ] [H NMR] (CDCl3, 400MHz) δH = 9.52 (d, 1H), 8.48 (dd, 2H), 8.04 (dd, 1H), 5.95 - 5.87 (m, 1H), 4.37 (q, 2H), 1.60 (d, 3H), 1.51 (t, 3H). [LCMS] In 2 min chromatography, Rt = 1.35 min, 10-80 AB, MS ESI calculated value C16H14F6N5O2 [M+H]+ 422.1, experimental value 422.1.

[0232] [Example]

[26] [:] [6-[5-] [fluorine] [-6-(2,2,2-] [Trifluoride] [-1,1-] [Dimethyl] [-] [Ethoxy] [)-3-] [Pyridyl] []-3-(] [Methoxymethyl] [)-[1,2,4]] [Triazo] [[4,3-b]] [Tarazine] [ ] A mixture of 6-chloro-3-(methoxymethyl)-[1,2,4]triazolo[4,3-b]pyrazine (100 mg, 0.5 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboranecyclo-2-yl)-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)pyridine (210.94 mg, 0.6 mmol), K3PO4 (213.79 mg, 1.01 mmol), and Pd(t-Bu3P)2 (38.6 mg, 0.08 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was stirred at 80 °C under N2 for 16 hours. After cooling to room temperature, the mixture was diluted with H2O (10 mL) and extracted with EtOAc (20 mL × 2). The combined organic phase was washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered and concentrated to produce a crude product. The crude product was purified by Prep-HPLC (Boston Prime C18 (150 mm × 30 mm, 5 µm; mobile phase: [water (0.05% NH4OH)-ACN]; B%: 40-70%, 9 min) to produce a solid product (47.66 mg, 0.12 mmol, 25% yield). [ 1 ] [H NMR] (CDCl3, 400MHz) δH = 8.54 (d, 1H), 8.24 (d, 1H), 8.09 (dd, 1H), 7.57 (d, 1H), 5.11 (s, 2H), 3.53 (s, 3H), 1.90 (s, 6H). [LCMS] In 2.0 min chromatography, Rt = 1.21 min, 10-80 AB, MS ESI calculated value C16H16F4N5O2 [M +H]+ 386.1, experimental value 386.0.

[0233] [Example]

[27] [:] [6-[5-] [fluorine] [-6-(2,2,2-] [Trifluoride] [-1,1-] [Dimethyl] [-] [Ethoxy] [)-3-] [Pyridyl] []-3-(] [Methoxymethyl] [)-[1,2,4]] [Triazo] [[4,3-a]] [Pyridine] [ ] [A33] [Synthesis] [:] 2-Methoxyacetyl chloride (5.4 g, 49.73 mmol) was added dropwise to a solution of (5-bromo-2-pyridyl)hydrazine (8.5 g, 45.21 mmol) in toluene (80 mL) at 25 °C. The solution was stirred at 25 °C for 30 min, and then refluxed at 120 °C for 48 h. After cooling to room temperature, the reaction mixture was concentrated to produce a residue. The residue was milled from DCM (100 mL) to give a solid product (3.0 g, 10.01 mmol, 22% yield). [ 1 ] [H NMR](MeOD-d4, 400MHz) δ [= ]9.15 (s, 1H), 8.19 - 8.32 (m, 1H), 8.11 - 7.96 (m, 1H), 5.09 (s, 2H), 3.49 (s, 3H). [Compound]

[28] [Synthesis] A mixture of 6-bromo-3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyridine (150 mg, 0.62 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborpinecyclo-2-yl)-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)pyridine (259.61 mg, 0.74 mmol), K₂CO₃ (171.29 mg, 1.24 mmol), and Pd(dppf)Cl₂ (68.01 mg, 0.09 mmol) in a mixed solvent of 1,4-dioxane (15 mL) and water (3 mL) was heated at 85 °C for 16 hours. After cooling to room temperature, the reaction mixture was concentrated and diluted with H₂O (20 mL), and then extracted with DCM (20 mL × 2). The combined organic phases were washed with brine (30 mL), dried over Na₂SO₄, filtered, and concentrated to yield a crude product. The crude product was purified using Prep-HPLC (YMC-Actus Triart C18 (100 mm × 30 mm, 5 µm) A = H₂O (0.05% HCl) and B = CH₃CN; 50–75% B over 8 minutes) to yield the product in CH₃CN / H₂O (approximately 150 mL). The solution was concentrated to remove most of the CH₃CN, alkalized to approximately pH 9 with NaHCO₃ (solid), and then extracted with DCM (50 mL × 3). The combined organic phases were concentrated to yield a solid product (121.16 mg, 0.32 mmol, 51% yield). [ 1 ] [H NMR] (CDCl3, 400MHz) δ = 8.34 (s, 1H), 8.16 (d, 1H), 7.89 (d, 1H), 7.60 (dd, 1H), 7.47 (dd, 1H), 5.08 (s, 2H), 3.42 (s, 3H), 1.87 (s, 6H). [LCMS] In 2.0 min chromatography, Rt = 1.25 min, 10-80 AB, MS ESI calculated value C17H17F4N4O2 [M+H]+ 385.1, experimental value 384.9.

[0234] [Example]

[28] [:] [6-[5-] [fluorine] [-6-(2,2,2-] [Trifluoroethoxy] [)-3-] [Pyridyl] []-3-(] [Methoxymethyl] [)-[1,2,4]] [Triazo] [[4,3-a]] [Pyridine] A mixture of 6-bromo-3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyridine (150 mg, 0.62 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborpinecyclo-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (238.75 mg, 0.74 mmol), K₂CO₃ (171.29 mg, 1.24 mmol), and Pd(dppf)Cl₂ (68.01 mg, 0.09 mmol) in a mixed solvent of 1,4-dioxane (15 mL) and water (3 mL) was stirred at 85 °C for 16 hours. After cooling to room temperature, the reaction mixture was concentrated and diluted with H₂O (20 mL), and then extracted with DCM (20 mL × 2). The combined organic phases were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to produce a crude product. The crude product was purified by Prep-HPLC (Boston Prime C18 (150 mm × 30 mm, 5 µm) A = H2O (0.05% NH4OH) and B = CH3CN; 40-70% B over 8 minutes) to produce a solid product (141.29 mg, 0.39 mmol, 64% yield). [ 1 ] [H NMR] (CDCl3, 400MHz) δ = 8.35 (s, 1H), 8.17 (d, 1H), 7.90 (d, 1H), 7.65 (dd, 1H), 7.47 (dd, 1H), 5.09 (s, 2H), 4.91 (q, 2H), 3.43 (s, 3H). [LCMS] In 2.0 min chromatography, Rt = 1.17 min, 10-80 AB, MS ESI calculated value C15H13F4N4O2 [M+H]+ 357.1, experimental value 356.9.

[0235] [Example]

[29] [:] [3-[] [Difluoride] [(] [Methoxy] [)] [methyl] []-6-[5-] [fluorine] [-6-(2,2,2-] [Trifluoroethoxy] [)-3-] [Pyridyl] []-[1,2,4]] [Triazo] [[4,3-a]] [Pyridine] [ ] A mixture of 6-bromo-3-[difluoro(methoxy)methyl]-[1,2,4]triazolo[4,3-a]pyridine (70 mg, 250 µmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborpinecyclo-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (97 mg, 300 µmol), K₂CO₃ (69.59 mg, 0.50 mmol), and Pd(dppf)Cl₂ (27.63 mg, 0.04 mmol) in 1,4-dioxane (5 mL) and water (0.50 mL) was stirred at 80 °C under N₂ for 12 hours. After cooling to room temperature, the mixture was diluted with H₂O (10 mL) and extracted with EtOAc (20 mL × 2). The combined organic phases were washed with water (10 mL) and brine (10 mL), dried over Na₂SO₄, filtered, and concentrated to produce a crude product. The crude product was first purified by Prep-HPLC (Boston Prime C18 (150 mm × 30 mm, 5 µm), A = H₂O (0.05% NH₄OH) and B = CH₃CN; 43-73% B over 8 min), and then by Prep-HPLC (Boston Green ODS (150 mm × 30 mm, 5 µm), A = H₂O (0.075% TFA) and B = CH₃CN; 49-63% B over 10 min). The combined fraction was concentrated to remove ACN, alkalized to pH 8 with saturated NaHCO₃, and the mixture was extracted with EtOAc (30 mL × 2). The combined organic phases were washed with brine (40 mL), dried over Na2SO4, filtered, and concentrated to produce a solid product (41.36 mg, 105.4 µmol, 42% yield). [ 1 ] [H NMR] (DMSO-d6, 400MHz) δH = 8.74 (s, 1H), 8.47 (d, 1H), 8.36 (dd, 1H), 8.11 (dd, 1H), 7.96 (dd, 1H), 5.18 (q, 2H), 3.89 (s, 3H). [LCMS] In 2.0 min chromatography, Rt = 1.19 min, 10-80 AB, MS ESI calculated value C15H11F6N4O2 [M+H]+ 393.1, experimental value 393.0.

[0236] [Example]

[30] [:] [6-[5-] [fluorine] [-6-[(1R)-2,2,2-] [Trifluoride] [-1-] [methyl] [-] [Ethoxy] []-3-] [Pyridyl] []-3-(] [Methoxymethyl] [)-[1,2,4]] [Triazo] [[4,3-a]] [Pyrazine] [ ] [ ] A mixture of 6-chloro-3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyrazine (70 mg, 0.35 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboranecyclo-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (141.73 mg, 0.42 mmol), Cs2CO3 (229.66 mg, 0.70 mmol), Pd(dppf)Cl2 (38.68 mg, 0.05 mmol) in 1,4-dioxane (5 mL) and water (0.50 mL) was stirred at 70 °C under N2 for 5 hours. After cooling to room temperature, the mixture was diluted with H2O (20 mL) and extracted with EtOAc (30 mL × 2). The combined organic phase was washed with water (30 mL) and brine (30 mL), dried over Na2SO4, filtered, and concentrated to produce a crude product. The crude product was first purified by Prep-TLC (silicone, PE: EtOAc = 1:1). The product was further purified by Prep-HPLC (Boston Prime C18 (150 mm × 30 mm, 5 µm), A = H2O (0.05% NH4OH) and B = CH3CN; 38-68% B within 9 min) to produce a solid product (4.43 mg, 11.9 µmol, 3% yield). [ 1 ] [H NMR] (CDCl3, 400MHz) δH = 9.44 (d, 1H), 8.49 (dd, 1H), 8.47 (s, 1H), 8.05 (dd, 1H), 5.95 - 5.83 (m, 1H), 5.14 (s, 2H), 3.47 (s, 3H), 1.60 (d, 3H). [LCMS] In 2.0 min chromatography, Rt = 1.18 min, 10-80 AB, MS ESI calculated value C15H14F4N5O2 [M+H]+ 372.1, experimental value 371.9.

[0237] [Example]

[31] [:] [3-[] [Ethoxy] [(] [Difluoride] [)] [methyl] []-6-[5-] [fluorine] [-6-[(1S)-2,2,2-] [Trifluoride] [-1-] [methyl] [-] [Ethoxy] []-3-] [Pyridyl] []-[1,2,4]] [Triazo] [[4,3-a]] [Pyridine] [ ] [ ] A mixture of 6-bromo-3-[ethoxy(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyridine (100 mg, 0.34 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (137.67 mg, 0.41 mmol), K2CO3 (94.64 mg, 0.68 mmol), and Pd(dppf)Cl2 (37.58 mg, 0.05 mmol) in 1,4-dioxane (5 mL) and water (0.50 mL) was stirred at 80 °C under N2 for 12 hours. After cooling to room temperature, the mixture was diluted with H2O (10 mL) and extracted with EtOAc (20 mL × 2). The combined organic phases were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated to produce a crude product. The crude product was purified by Prep-HPLC (Boston Prime C18 (150 mm × 30 mm, 5 μm), A = H2O (0.05% NH4OH) and B = CH3CN; 60-90% B over 9 minutes) to produce a solid product (39.75 mg, 93.5 µmol, 27% yield). [ 1 ] [H NMR] (DMSO-d6, 400MHz) δH = 8.72 (s, 1H), 8.44 (d, 1H), 8.33 (dd, 1H), 8.10 (d, 1H), 7.94 (dd, 1H), 6.02 (spt, 1H), 4.29 (q,2H), 1.54 (d,3H), 1.36 (t,3H). [LCMS] In 2.0 min chromatography, Rt = 1.28 min, 10-80 ABMS ESI calculated value C17H15F6N4O2 [M+H]+ 421.1, experimental value 421.0.

[0238] [Example]

[32] [:] [3-[] [Ethoxy] [(] [Difluoride] [)] [methyl] []-6-[5-] [fluorine] [-6-[(1S)-2,2,2-] [Trifluoride] [-1-] [methyl] [-] [Ethoxy] []-3-] [Pyridyl] []-[1,2,4]] [Triazo] [[4,3-a]] [Pyrazine] [ ] A mixture of 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine (200 mg, 0.49 mmol) and AgOTf (1.25 g, 4.86 mmol) in ethanol (10 mL) and MeCN (10 mL) was stirred at 90 °C for 5 days. The mixture was then cooled to room temperature. EtOAc (50 mL) and brine (50 mL) were added to the mixture, and the mixture was filtered through diatomaceous earth. The filtrate was separated, and the aqueous layer was extracted with EtOAc (50 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated to produce a crude product. The crude product was purified by rapid chromatography over silicone (EtOAc in PE = 10% to 30% to 50%), and then ground in n-hexane (5 mL) to produce a solid product (41.27 mg, 98.0 µmol, 20% yield). [ 1 ] [H NMR] (CDCl3, 400MHz) δH = 9.52 (d, 1H), 8.50 - 8.45 (m, 2H), 8.04 (dd, 1H), 6.00 - 5.82 (m, 1H), 4.37 (q, 2H), 1.60 (d, 3H), 1.51 (t, 3H). [LCMS] In 2.0 min chromatography, Rt = 1.29 min, 10-80 AB, MS ESI calculated value C16H14F6N5O2 [M+H]+ 422.1, experimental value 422.0.

[0239] [Example]

[33] [:] [3-[] [Ethoxy] [(] [Difluoride] [)] [methyl] []-6-[5-] [fluorine] [-6-[(1R)-2,2,2-] [Trifluoride] [-1-] [methyl] [-] [Ethoxy] []-3-] [Pyridyl] []-[1,2,4]] [Triazo] [[4,3-a]] [Pyridine] [ ] A mixture of 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboropyrano-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (126.2 mg, 0.38 mmol), Pd(dppf)Cl2 (37.58 mg, 0.05 mmol), 6-bromo-3-[ethoxy(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyridine (100 mg, 0.34 mmol) and K2CO3 (94.64 mg, 0.68 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was stirred at 90 °C under N2 for 16 hours. After cooling to room temperature, the mixture was filtered through diatomaceous earth, dissolved with EtOAc (10 mL × 2), and the filtrate was concentrated to produce a crude product. The crude product was purified by Prep-HPLC (Boston Prime C18 (150 mm × 30 mm, 5 µm) A = H2O (0.05% NH4OH) and B = CH3CN; 45-75% B) within 9 minutes to produce a solid product (62.87 mg, 0.15 mmol, 43% yield). [1 ] [H NMR] (DMSO-d6, 400MHz) δH = 8.72 (s, 1H), 8.44 (d, 1H), 8.33 (dd, 1H), 8.14 - 8.06 (m, 1H), 7.94 (dd, 1H), 6.01 (spt, 1H), 4.28 (q, 2H), 1.54 (d, 3H), 1.36 (t, 3H). [LCMS] In 2.0 min chromatography, Rt = 1.26 min, 10-80 AB, MS ESI calculated value C17H15F6N4O2 [M+H]+ 421.1, experimental value 421.0.

[0240] [Example]

[34] [:] [6-[5-] [fluorine] [-6-(2,2,2-] [Trifluoroethoxy] [)-3-] [Pyridyl] []-3-(] [Methoxymethyl] [)-[1,2,4]] [Triazo] [[4,3-b]] [Tarazine] [ ] A mixture of 6-chloro-3-(methoxymethyl)-[1,2,4]triazolo[4,3-b]pyrazine (100 mg, 0.50 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborpine-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (194 mg, 0.60 mmol), K3PO4 (213.79 mg, 1.01 mmol), and Pd(t-Bu3P)2 (38.6 mg, 0.08 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was stirred at 80 °C under N2 for 3 hours. After cooling to room temperature, water (20 mL) and EtOAc (20 mL) were added to the mixture, and the mixture was filtered through diatomaceous earth. After separation, the organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to produce a crude product. The crude product was purified by Prep-HPLC (Boston Prime C18 (150 mm × 30 mm, 5 µm) A = H2O (0.05% NH4OH) and B = CH3CN; 33-63% B within 8 minutes) to produce a solid product (49 mg, 137.2 µmol, 27% yield). [ 1 ] [H NMR] (CDCl3, 400MHz) δH = 8.54 (d, 1H), 8.25 (d, 1H), 8.17 (dd, 1H), 7.58 (d, 1H), 5.11 (s, 2H), 4.94 (q, 2H), 3.54 (s, 3H). [LCMS] In 2.0 min chromatography, Rt = 1.08 min, 10-80 AB, MS ESI calculated value C14H12F4N5O2 [M+H]+ 358.1, experimental value 357.9.

[0241] [Example]

[35] [:] [3-[] [Cyclopropoxy] [(] [Difluoride] [)] [methyl] []-6-[5-] [fluorine] [-6-[(1R)-2,2,2-] [Trifluoride] [-1-] [methyl] [-] [Ethoxy] []-3-] [Pyridyl] []-[1,2,4]] [Triazo] [[4,3-a]] [Pyridine] [ ] A mixture of 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborpinecyclo-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (121.22 mg, 0.36 mmol), Pd(dppf)Cl2 (36.09 mg, 0.05 mmol), 6-bromo-3-[cyclopropoxy(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyridine (100 mg, 0.33 mmol) and K2CO3 (90.9 mg, 0.66 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was stirred at 90 °C under N2 for 16 hours. After cooling to room temperature, the mixture was filtered through diatomaceous earth and dissolved with EtOAc (10 mL × 2). The filtrate was then concentrated to produce a crude product. The crude product was purified by Prep-HPLC (Boston Prime C18 (150 mm × 30 mm, 5 µm) A = H2O (0.05% NH4OH) and B = CH3CN; 47-77% B within 9 minutes) to produce a solid product (54.98 mg, 0.13 mmol, 39% yield). [ 1 ] [H NMR] (DMSO-d6, 400MHz) δH = 8.65 (s, 1H), 8.44 (d, 1H), 8.33 (dd, 1H), 8.11 (d, 1H), 7.94 (dd, 1H), 6.07 - 5.97 (m, 1H), 4.25 - 4.15 (m, 1H), 1.54 (d, 3H), 0.95 - 0.86 (m, 2H), 0.77 - 0.69 (m, 2H). [LCMS] In 2.0 min chromatography, Rt = 1.33 min, 10-80 ABMS ESI calculated value C18H15F6N4O2 [M+H]+ 433.1, experimental value 433.1.

[0242] [Example]

[36] [:] [3-[] [Cyclopropoxy] [(] [Difluoride] [)] [methyl] []-6-[5-] [fluorine] [-6-[(1S)-2,2,2-] [Trifluoride] [-1-] [methyl] [-] [Ethoxy] []-3-] [Pyridyl] []-[1,2,4]] [Triazo] [[4,3-a]] [Pyridine] [A36] [Synthesis:] Potassium terbutoxide (476.69 mg, 4.25 mmol) was added to a mixture of cyclopropanol (246.74 mg, 4.25 mmol) and 6-bromo-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyridine (600 mg, 2.12 mmol) in DMF (10 mL). The reaction mixture was stirred at 20 °C for 2 hours. The reaction mixture was quenched with saturated NH4Cl (40 mL), and then extracted with EtOAc (50 mL × 2). The combined organic phases were washed with water (80 mL) and brine (80 mL), dried over Na2SO4, filtered, and concentrated to yield the crude product. The crude product was purified by rapid chromatography on silicone (EtOAc in PE = 0% to 20% to 40%), resulting in a solid product (270 mg, 0.89 mmol, 42% yield). [LCMS] In 7.0 min chromatography, Rt = 3.74 min, 0-60 ABMS ESI calculated value C10H9BrF2N3O [M+H+2]+ 306.0, experimental value 305.8. [Compound]

[37] [Synthesis] [:] A mixture of 6-bromo-3-[cyclopropoxy(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyridine (100 mg, 0.33 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (132.24 mg, 0.39 mmol), K2CO3 (90.9 mg, 0.66 mmol), and Pd(dppf)Cl2 (36.09 mg, 0.05 mmol) in 1,4-dioxane (5 mL) and water (0.50 mL) was stirred at 80 °C under N2 for 12 hours. After cooling to room temperature, the mixture was diluted with H2O (10 mL) and extracted with EtOAc (20 mL × 2). The combined organic phases were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated to produce a crude product. The crude product was purified by Prep-HPLC (Boston Prime C18 (150 mm × 30 mm, 5 µm), A = H2O (0.05% NH4OH) and B = CH3CN; 50-70% B over 9 minutes) to produce a solid product (35.99 mg, 83.2 µmol, 25% yield). [ 1 ] [H NMR] (DMSO-d6, 400MHz) δH = 8.65 (s, 1H), 8.44 (d, 1H), 8.33 (dd, 1H), 8.11 (dd, 1H), 7.94 (dd, 1H), 6.09 - 5.95 (m, 1H), 4.25 - 4.14 (m, 1H), 1.54 (d, 3H), 0.95 - 0.86 (m, 2H), 0.79 - 0.67 (m, 2H). [LCMS] In 2.0 min chromatography, Rt = 1.29 min, 10-80 AB, MS ESI calculated value C18H15F6N4O2 [M+H]+ 433.1, experimental value 433.0.

[0243] [Example]

[37] [:] [6-[5-] [fluorine] [-6-[(1, S , )-2,2,2-] [Trifluoride] [-1-] [methyl] [-] [Ethoxy] []-3-] [Pyridyl] []-3-(] [Methoxymethyl] [)-[1,2,4]] [Triazo] [[4,3-a]] [Pyrazine] [ ] [A37] [Synthesis:] 12N HCl (1.73 mL, 20.75 mmol) was added to a mixture of 1,1,2-trimethoxyethane (1.25 g, 10.38 mmol) and (5-chloropyrazine-2-yl)hydrazine (1 g, 6.92 mmol) in ethanol (20 mL), and the mixture was stirred at 20 °C for 20 h. Water (20 mL) was added to the mixture, and the mixture was alkalized to pH 9 with Na₂CO₃ (solid) and extracted with EtOAc (50 mL × 4). The combined organic phases were washed with brine (30 mL), dried over Na₂SO₄, filtered, and concentrated to produce a crude product. The crude product was ground from EtOAc / PE (2 / 10 mL) and dried in an oven to produce solid 5-chloro-N-(2-methoxyethyleneamino)pyrazine-2-amine (1050 mg, 3.73 mmol, 54% yield). [LCMS] In 1.5 min chromatography, Rt = 0.70 min, 5-95 AB, MS ESI calculated value C7H10ClN4O [M+H]+ 201.0, experimental value 201.0. [A38] [Synthesis] [:] A solution of NBS (1.24 g, 6.98 mmol) in DMF (7 mL) was added dropwise to a mixture of 5-chloro-N-(2-methoxyethyleneamino)pyrazin-2-amine (1 g, 4.98 mmol) in DMF (10 mL) over 0.5 hours, and the mixture was then stirred at 20 °C for 1 hour. The mixture was diluted with water H2O (50 mL) and extracted with EtOAc (50 mL × 4). The combined organic phases were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to produce a crude product as a solid (1000 mg, 3.58 mmol, 72% yield), which was used directly without any further purification. [LCMS] In 1.5 min chromatography, Rt = 0.80 min, 5-95 AB, MS ESI calculated value C7H9BrClN4O [M+H+2]+ 281.0, experimental value 280.9. [A34] [Synthesis] Et3N (0.99 mL, 7.16 mmol) was added to a mixture of N-(5-chloropyrazine-2-yl)-2-methoxy-ethanehydrazone bromide (1 g, 3.58 mmol) in toluene (15 mL), and the mixture was stirred at 20 °C for 1 hour. The mixture was diluted with H2O (30 mL) and extracted with EtOAc (50 mL × 2). The combined organic phases were washed with water (20 mL × 2) and brine (20 mL), dried over Na2SO4, filtered, and concentrated to yield a crude product. The crude product was purified by rapid chromatography on silicone (EtOAc in PE = 0% to 40% to 80%) to yield a solid product (380 mg, 1.87 mmol, 52% yield). [ 1 ] [H NMR] (CDCl3, 400MHz) δH= 9.21 (d, 1H), 8.28 (d, 1H), 5.07 (s, 2H), 3.45 (s, 3H). [LCMS] In 1.5 min chromatography, Rt = 0.30 min, 5-95 AB, MS ESI calculated value C7H8ClN4O [M+H]+ 199.0, experimental value 199.0. [Compound]

[38] [Synthesis] [:] A mixture of 6-chloro-3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyrazine (70 mg, 0.35 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (177.16 mg, 0.53 mmol), Pd(dppf)Cl2 (64.47 mg, 88.1 µmol), and Cs2CO3 (229.66 mg, 0.70 mmol) in 1,4-dioxane (8 mL) and water (0.80 mL) was stirred at 75 °C under N2 for 12 hours. After cooling to room temperature, the mixture was diluted with H2O (30 mL) and extracted with EtOAc (50 mL × 2). The combined organic phases were washed with water (20 mL × 2) and brine (20 mL), dried over Na2SO4, filtered, and concentrated to produce a crude product. The crude product was first purified by Prep-TLC (silicone, PE: EtOAc = 1:1) and then by Prep-HPLC [Boston Prime C18 (150 mm × 30 mm, 5 µm) A = H2O (0.05% NH4OH) and B = CH3CN; 38-68% B over 9 min] to produce a solid product (12.63 mg, 34.0 µmol, 10% yield). [ 1 ] [H NMR] (CDCl3, 400MHz) δH= 9.44 (d, 1H), 8.50 (d, 1H), 8.47 (d, 1H), 8.05 (dd, 1H), 5.97 - 5.84 (m, 1H), 5.14 (s, 2H), 3.47 (s, 3H), 1.60 (d, 3H). [LCMS] In 2.0 min chromatography, Rt = 1.17 min, 10-80 ABMS ESI calculated value C15H14F4N5O2 [M+H]+ 372.1, experimental value 371.9.

[0244] [Example]

[38] [:] [6-[5-] [fluorine] [-6-(2,2,2-] [Trifluoroethoxy] [)-3-] [Pyridyl] []-3-(] [Methoxymethyl] [)-[1,2,4]] [Triazo] [[4,3-a]] [Pyrazine] [ ] [ ] A mixture of 6-chloro-3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyrazine (70 mg, 0.35 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboranecyclo-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (169.75 mg, 0.53 mmol), Pd(dppf)Cl2 (64.47 mg, 88.1 µmol), and Cs2CO3 (229.66 mg, 0.70 mmol) in 1,4-dioxane (8 mL) and water (0.80 mL) was stirred at 75 °C under N2 for 12 hours. After cooling to room temperature, the mixture was diluted with H2O (20 mL) and extracted with EtOAc (30 mL × 2). The combined organic phase was washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated to produce a crude product. The crude product was purified by Prep-TLC (silicone, PE:EtOAc = 1:1) to produce a solid product (14.65 mg, 40.7 µmol, 12% yield). [ 1 ] [H NMR] (CDCl3, 400MHz) δH= 9.44 (d, H), 8.52 (d, 1H), 8.48 (d, 1H), 8.07 (dd, 1H), 5.14 (s, 2H), 4.92 (q, 2H), 3.47 (s, 3H). [LCMS] In 2.0 min chromatography, Rt = 1.19 min, 10-80 ABMS ESI calculated value C14H12F4N5O2 [M+H]+358.1, experimental value 357.9.

[0245] [Example]

[39] [:] [6-[5-] [fluorine] [-6-[(1R)-2,2,2-] [Trifluoride] [-1-] [methyl] [-] [Ethoxy] []-3-] [Pyridyl] []-3-(] [Methoxymethyl] [)-[1,2,4]] [Triazo] [[4,3-a]] [Pyridine] [ ] A mixture of 6-bromo-3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyridine (200 mg, 0.83 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (332.23 mg, 0.99 mmol), K₂CO₃ (228.38 mg, 1.65 mmol), Pd(dppf)Cl₂ (90.68 mg, 0.12 mmol) in 1,4-dioxane (15 mL) and water (5 mL) was stirred at 85 °C for 16 hours. After cooling to room temperature, the reaction mixture was concentrated and diluted with H₂O (20 mL), and then extracted with DCM (20 mL × 2). The combined organic phases were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to produce a crude product. The crude product was purified using Prep-HPLC (Boston Prime C18 (150 mm × 30 mm 5 µm) A = H2O (0.05% NH4OH) and B = CH3CN; 35-65% B over 9 minutes) to produce a solid product (104.44 mg, 0.28 mmol, 34% yield). [ 1 ] [H NMR] (DMSO-d6, 400 MHz) δH = 8.85 (s, 1H), 8.49 (d, 1H), 8.35 (dd, 1H), 7.89 - 8.05 (m, 1H), 7.77 - 7.88 (m, 1H), 6.05 - 5.87 (m, 1H), 5.02 (s, 2H), 3.35 (s, 3H), 1.55 (d, 3H). [LCMS] In 2.0 min chromatography, Rt = 1.150 min, 10-80 AB, MS ESI calculated value C16H15F4N4O2 [M+H]+ 371.1, experimental value 371.1.

[0246] [Example]

[40] [:] [3-[] [Ethoxy] [(] [Difluoride] [)] [methyl] []-6-[5-] [fluorine] [-6-[(1S)-2,2,2-] [Trifluoride] [-1-] [methyl] [-] [Ethoxy] []-3-] [Pyridyl] []-[1,2,4]] [Triazo] [[4,3-b]] [Tarazine] A mixture of 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyrazine (300 mg, 0.73 mmol) and AgOTf (1872.33 mg, 7.29 mmol) in ethanol (10 mL) and MeCN (10 mL) was stirred at 90 °C for 9 days. After cooling to room temperature, the reaction mixture was diluted with EtOAc (60 mL) and added together with the mixture and brine (20 mL). The mixture was filtered through diatomaceous earth and extracted with EtOAc (50 mL × 2). The combined organic layer was washed with water (50 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated to produce a crude product. The crude product was purified by rapid chromatography over silicone (EtOAc in PE = 0% to 70%). The product was then ground with n-hexane (1 mL) and i-Pr2O (1 mL) to produce a solid product (28.86 mg, 67.3 µmol, 9% yield). [ 1 ] [H NMR] (CDCl3, 400MHz) δH = 8.54 (d, 1H), 8.29 (d, 1H), 8.13 (dd, 1H), 7.65 (d, 1H), 5.92 (spt, 1H), 4.33 (q, 2H), 1.61 (d, 3H), 1.48 (t, 3H). [LCMS] In 2.0 min chromatography, Rt = 1.27 min, 10-80 AB, MS ESI calculated value C16H14F6N5O2 [M+H]+ 422.1, experimental value 422.0.

[0247] [Example]

[41] [:] [3-[] [Ethoxy] [(] [Difluoride] [)] [methyl] []-6-[5-] [fluorine] [-6-[(1R)-2,2,2-] [Trifluoride] [-1-] [methyl] [-] [Ethoxy] []-3-] [Pyridyl] []-[1,2,4]] [Triazo] [[4,3-b]] [Tarazine] [ ] [A26-a] [Synthesis:] A mixture of 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (1.54 g, 4.6 mmol), 6-chloro-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-b]pyrazine (1 g, 4.18 mmol), Pd(t-Bu3P)2 (320.73 mg, 0.63 mmol) and K3PO4 (1.78 g, 8.37 mmol) in 1,4-dioxane (20 mL) and water (4 mL) was stirred at 80 °C under N2 for 16 hours. After cooling to room temperature, the mixture was filtered through diatomaceous earth and precipitated with EtOAc (20 mL × 2). The filtrate was then concentrated to produce a crude product. The crude product was purified by rapid chromatography on silica gel (EtOAc in PE = 30% to 60%) to produce a solid product (1000 mg, 2.12 mmol, 51% yield). [LCMS] In 1.5 min chromatography, Rt = 0.93 min, 5-95 AB, MS ESI calculated value C14H9ClF6N5O [M+H]+ 412.0, experimental value 412.1. [Compound]

[42] [Synthesis] A mixture of 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyrazine (300 mg, 0.73 mmol) and AgOTf (1872.33 mg, 7.29 mmol) in ethanol (10 mL, 0.73 mmol) and CH3CN (10 mL) was stirred at 90 °C for 8 days. After cooling to room temperature, the reactants were diluted with EtOAc (40 mL), and the mixture was added to saturated NaCl (40 mL). The mixture was filtered through diatomaceous earth, precipitated with EtOAc (20 mL × 2), and the filtrate was concentrated to produce a crude product. The crude product was purified by rapid chromatography on silicone (EtOAc in PE = 0% to 50% to 100%). The product was further purified by Prep-HPLC (Boston Prime C18 (150 mm × 30 mm 5 µm) A = H2O (0.05% NH4OH v / v) and B = CH3CN; 51-81% B within 9 min) to produce a solid product (8.12 mg, 19.3 µmol, 3% yield). [ 1 ] [H NMR] (CDCl3, 400MHz) δH = 8.54 (d, 1H), 8.30 (d, 1H), 8.13 (dd, 1H), 7.66 (d, 1H), 5.96 - 5.88 (m, 1H), 4.33 (q, 2H), 1.62 (s, 3H), 1.48 (t, 3H). [LCMS] In 2.0 min chromatography, Rt = 1.29 min, 10-80 AB, MS ESI calculated value C16H14F6N5O2 [M+H]+ 422.1, experimental value 422.0.

[0248] [Example]

[42] [:] [6-[5-] [fluorine] [-6-[(1S)-2,2,2-] [Trifluoride] [-1-] [methyl] [-] [Ethoxy] []-3-] [Pyridyl] []-3-(] [Methoxymethyl] [)-[1,2,4]] [Triazo] [[4,3-a]] [Pyridine] [ ] A mixture of 6-bromo-3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyridine (100 mg, 0.41 mmol), Pd(dppf)Cl2 (45.34 mg, 0.06 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborpinecyclo-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (166.12 mg, 0.50 mmol) and K2CO3 (114.19 mg, 0.83 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was stirred at 80 °C under N2 for 16 hours. After cooling to room temperature, the mixture was filtered through diatomaceous earth and precipitated with EtOAc (10 mL × 2). The filtrate was then concentrated to produce a crude product. The crude product was purified by rapid chromatography on silica gel (EtOAc in PE = 50% to 100%). The product was then ground in hexane / DCM (5:1, 10 mL) to produce a solid product (46.5 mg, 0.13 mmol, 30% yield). [ 1 ] [H NMR] (DMSO-d6, 400MHz) δH = 8.84 (s, 1H), 8.49 (d, 1H), 8.35 (dd, 1H), 7.97 - 7.90 (m, 1H), 7.87 - 7.80 (m, 1H), 6.01 (spt, 1H), 5.01 (s, 2H), 3.34 (s, 3H), 1.54 (d, 3H). [LCMS] In 2.0 min chromatography, Rt = 1.13 min, 10-80 AB, MS ESI calculated value C16H15F4N4O2 [M+H]+ 371.1, experimental value 370.9.

[0249] [Example]

[43] [:] [6-[5-] [fluorine] [-6-[(1S)-2,2,2-] [Trifluoride] [-1-] [methyl] [-] [Ethoxy] []-3-] [Pyridyl] []-3-(] [Methoxymethyl] [)-[1,2,4]] [Triazo] [[4,3-b]] [Tarazine] [ ] A mixture of 6-chloro-3-(methoxymethyl)-[1,2,4]triazolo[4,3-b]pyrazine (100 mg, 0.50 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboranecyclo-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (202.47 mg, 0.60 mmol), K3PO4 (213.79 mg, 1.01 mmol), and Pd(t-Bu3P)2 (38.6 mg, 0.08 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was stirred at 80 °C under N2 for 3 hours. After cooling to room temperature, water (20 mL) and EtOAc (20 mL) were added to the mixture, and the mixture was filtered through diatomaceous earth. After separation, the organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to produce a crude product. The crude product was purified by Prep-HPLC (Boston Prime C18 (150 mm × 30 mm, 5 µm) A = H2O (0.05% NH4OH) and B = CH3CN; 33-63% B within 8 minutes) to produce a solid product (38 mg, 102.3 µmol, 20% yield). [ 1 ] [H NMR] (CDCl3, 400MHz) δH = 8.53 (d, 1H), 8.25 (d, 1H), 8.14 (dd, 1H), 7.57 (d, 1H), 5.98 - 5.85 (m, 1H), 5.11 (s, 2H), 3.54 (s, 3H), 1.61 (d, 3H). [LCMS] In 2.0 min chromatography, Rt = 1.13 min, 10-80 AB, MS ESI calculated value C15H14F4N5O2 [M+H]+ 372.1, experimental value 371.9.

[0250] [Example]

[44] [:] [3-[] [Difluoride] [(] [Isobutyroxy] [)] [methyl] []-6-[5-] [fluorine] [-6-[(1S)-2,2,2-] [Trifluoride] [-1-] [methyl] [-] [Ethoxy] []-3-] [Pyridyl] []-[1,2,4]] [Triazo] [[4,3-a]] [Pyrazine] [ ] A mixture of 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine (200 mg, 0.49 mmol) and AgOTf (1.25 g, 4.86 mmol) in isobutyl alcohol (10 mL) and MeCN (10 mL) was stirred at 90 °C for 7 days. EtOAc (50 mL) and brine (50 mL) were added to the mixture, and some solids were observed. The mixture was filtered through diatomaceous earth. The filtrate was separated, and the aqueous layer was extracted with EtOAc (50 mL). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and concentrated to produce a crude product. The crude product was purified by rapid chromatography on silicone (EtOAc in PE = 10% to 30% to 50%), resulting in an oily product (80 mg). The impure product (80 mg, 0.18 mmol) was purified and concentrated by Prep-HPLC (Boston Green ODS (150 mm × 30 mm, 5 µm) A = H2O (0.075% TFA) and B = CH3CN; 66-96% B over 8 min) to produce a residue. A saturated aqueous solution of NaHCO3 (10 mL) was added to the residue, and the mixture was extracted with EtOAc (15 mL × 2). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to produce a solid product (55.97 mg, 124.6 µmol, 70% yield). [ 1 ] [H NMR] (CDCl3 + D2O, 400MHz) δH = 9.52 (d, 1H), 8.53 - 8.43 (m, 2H), 8.04 (dd, 1H), 5.98 - 5.84 (m, 1H), 4.06 (d, 2H), 2.21 - 2.06 (m, 1H), 1.60 (d, 3H), 1.08 (d, 6H). [LCMS] In 2.0 min chromatography, Rt = 1.37 min, 10-80 AB, MS ESI calculated value C18H18F6N5O2 [M+H]+ 450.1, experimental value 450.0.

[0251] [Example]

[45] [:] [6-[5-] [fluorine] [-6-[(1R)-2,2,2-] [Trifluoride] [-1-] [methyl] [-] [Ethoxy] []-3-] [Pyridyl] []-3-(] [Methoxymethyl] [)-[1,2,4]] [Triazo] [[4,3-b]] [Tarazine] [A32] [Synthesis:] 2-Methoxyacetyl chloride (2.48 g, 22.83 mmol) was added dropwise to a solution of (6-chloropyrazine-3-yl)hydrazine (3 g, 20.75 mmol) in toluene (80 mL) at 25 °C. The solution was stirred at 25 °C for 30 min and refluxed at 120 °C for 24 h. After cooling to room temperature, the mixture was diluted with H₂O (40 mL) and extracted with EtOAc (40 mL × 2). The combined organic phases were washed with brine (40 mL), dried over Na₂SO₄, filtered, and concentrated to yield a crude product. The crude product was ground from i-Pr₂O (10 mL) to yield a solid product (1500 mg, 7.31 mmol, 35% yield). [LCMS] In 1.5 min chromatography, Rt = 0.43 min, 5-95 AB, MS ESI calculated value C7H8ClN4O[M+H]+ 198.0, experimental value 199.0. [Compound]

[46] [Synthesis:] A mixture of 6-chloro-3-(methoxymethyl)-[1,2,4]triazolo[4,3-b]pyrazine (100 mg, 0.5 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (202.47 mg, 0.6 mmol), K3PO4 (213.79 mg, 1.01 mmol), Pd(t-Bu3P)2 (38.6 mg, 0.08 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was stirred at 80 °C under N2 for 12 hours. After cooling to room temperature, the mixture was diluted with H2O (10 mL) and extracted with EtOAc (20 mL × 2). The combined organic phases were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated to produce a crude product. The crude product was purified by Prep-HPLC (column: Boston Prime (150 mm × 30 mm, 5 µm; mobile phase: A = H2O (0.05% NH4OH); B = CH3CN, 35-65% B over 9 min) to produce a solid product (43.29 mg, 0.12 mmol, 23% yield). [ 1 ] [H NMR] (CDCl3, 400MHz) δH = 8.53 (d, 1H), 8.25 (d, 1H), 8.14 (dd, 1H), 7.57 (d, 1H), 5.98 - 5.85 (m, 1H), 5.11 (s, 2H), 3.54 (s, 3H), 1.61 (d, 3H). [LCMS] In 2.0 min chromatography, Rt = 1.17 min, 10-80 AB, MS ESI calculated value C15H14F4N5O2 [M +H]+ 372.1, experimental value 372.1.

[0252] [Example]

[46] [:] [3-[] [Difluoride] [(] [Isobutyroxy] [)] [methyl] []-6-[5-] [fluorine] [-6-[(1S)-2,2,2-] [Trifluoride] [-1-] [methyl] [-] [Ethoxy] []-3-] [Pyridyl] []-[1,2,4]] [Triazo] [[4,3-b]] [Tarazine] [ ] A mixture of 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyrazine (300 mg, 0.73 mmol) and AgOTf (1872.33 mg, 7.29 mmol) in 2-methylprop-1-ol (10 mL, 0.73 mmol) and MeCN (10 mL) was stirred at 90 °C for 9 days. After cooling to room temperature, the reaction mixture was diluted with EtOAc (60 mL) and brine (20 mL), filtered through diatomaceous earth, and extracted with EtOAc (50 mL × 2). The combined organic layer was washed with water (50 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated to produce a crude product. The crude product was purified by rapid chromatography over silicone (EtOAc in PE = 0% to 70%). The separated product was further purified by Prep-HPLC (Boston Prime C18 (150 mm × 30 mm, 5 µm), A = H2O (0.05% NH4OH) and B = CH3CN; 60-90% B within 9 minutes) to produce a solid product (7.42 mg, 16.5 µmol, 2% yield). [ 1 ] [H NMR] (CDCl3, 400MHz) δH = 8.54 (d, 1H), 8.30 (d, 1H), 8.14 (dd, 1H), 7.66 (d, 1H), 5.98 - 5.85 (m, 1H), 4.01 (d, 2H), 2.15 - 2.01 (m, 1H), 1.61 (d, 3H), 1.05 (d, 6H). [LCMS] In 2.0 min chromatography, Rt = 1.39 min, 10-80 AB, MS ESI calculated value C18H18F6N5O2 [M+H]+ 450.1, experimental value 450.1.

[0253] [Example]

[47] [:] [3-[] [Ethoxy] [(] [Difluoride] [)] [methyl] []-6-[5-] [fluorine] [-6-[(1S)-2,2,2-] [Trifluoride] [-1-] [methyl] [-] [Ethoxy] []-3-] [Pyridyl] []-[1,2,4]] [Triazo] [[4,3-b]] [Tarazine] [ ] [ ] A mixture of 6-chloro-3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyrazine (150 mg, 0.76 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborpinecyclo-2-yl)-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)pyridine (527.36 mg, 1.51 mmol), Cs₂CO₃ (738.18 mg, 2.27 mmol), Pd(dppf)Cl₂ (110.52 mg, 0.15 mmol) in 1,4-dioxane (8 mL) and water (0.80 mL) was stirred at 75 °C under N₂ for 9 hours. After cooling to room temperature, the mixture was diluted with H₂O (20 mL) and extracted with EtOAc (30 mL × 2). The combined organic phases were washed with water (30 mL × 1) and brine (30 mL), dried over Na2SO4, filtered, and concentrated to produce a crude product. The crude product was purified by Prep-HPLC (Boston Prime C18 (150 mm × 30 mm, 5 µm), A = H2O (0.05% NH4OH) and B = CH3CN; 49-59% B within 9 minutes) to produce a solid product (90.56 mg, 235 µmol, 31% yield). [ 1 ] [H NMR] (CDCl3, 400MHz) δH = 9.43 (s, 1H), 8.57 - 8.40 (m, 2H), 8.01 (d, 1H), 5.13 (s, 2H), 3.46 (s, 3H), 1.88 (s, 6H). [LCMS] In 2.0 min chromatography, Rt = 1.24 min, 10⁻⁸ AB, MS ESI calculated value C₁₆H₁₆F₄N₅O₂ [M+H]⁺ 386.1, experimental value 386.1.

[0254] [Example]

[48] [:] [3-[] [Difluoride] [(] [Isobutyroxy] [)] [methyl] []-6-[5-] [fluorine] [-6-[(1R)-2,2,2-] [Trifluoride] [-1-] [methyl] [-] [Ethoxy] []-3-] [Pyridyl] []-[1,2,4]] [Triazo] [[4,3-b]] [Tarazine] A mixture of 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyrazine (500 mg, 1.21 mmol) and AgOTf (3120.6 mg, 12.15 mmol) in 2-methylprop-1-ol (10 mL, 1.21 mmol) and CH3CN (10 mL) was stirred at 90 °C for 8 days. After cooling to room temperature, the reaction mixture was diluted with EtOAc (40 mL) and added together with the mixture and brine (40 mL). The mixture was filtered through diatomaceous earth and precipitated with EtOAc (20 mL × 2). The filtrate was then concentrated to produce a crude product. The crude product was purified by rapid chromatography over silicone (EtOAc in PE = 0% to 50% to 100%), resulting in an impure product. The impure product was then purified by Prep-HPLC (Waters Xbridge 150 mm × 25 mm, 5 µm) using A = H₂O (10 mM NH₄HCO₃) and B = CH₃CN, within 8 minutes, yielding a solid product (53.85 mg, 0.12 mmol, 10% yield). [ 1 ] [H NMR] (CDCl3, 400MHz) δH = 8.54 (d, 1H), 8.30 (d, 1H), 8.13 (dd, 1H), 7.66 (d, 1H), 5.92 (spt, 1H), 4.01 (d, 2H), 2.16 - 2.04 (m, 1H), 1.61 (d, 3H), 1.05 (d, 6H). [LCMS] In 2.0 min chromatography, Rt = 1.42 min, 10-80 AB, MS ESI calculated value C18H18F6N5O2 [M+H]+ 450.1, experimental value 450.1.

[0255] [Example]

[49] [:] [3-(] [Ethoxymethyl] [)-6-[5-] [fluorine] [-6-[(1S)-2,2,2-] [Trifluoride] [-1-] [methyl] [-] [Ethoxy] []-3-] [Pyridyl] []-[1,2,4]] [Triazo] [[4,3-a]] [Pyrazine] [ ] [A40] Synthesis: A mixture of [5-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]pyrazin-2-yl]hydrazine (200 mg, 0.63 mmol), DIPEA (0.33 mL, 1.89 mmol), and 2-ethoxyacetyl chloride (92.71 mg, 0.76 mmol) in CH2Cl2 (10 mL) was stirred at 25 °C for 16 hours. The mixture was concentrated to a residue, which was then redissolved in EtOAc (20 mL), washed with water (10 mL × 2) and brine (10 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated to produce a solid product (150 mg, 0.13 mmol, 20% yield). [LCMS] In 1.5 min chromatography, Rt = 0.84 min, 5-95 AB, MS ESI calculated value C16H18F4N5O3 [M+H]+ 404.1, experimental value 404.2. [Compound]

[50] [Synthesis:] A mixture of 2-ethoxy-N'-[5-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]pyrazin-2-yl]acetylhydrazine (150 mg, 0.37 mmol) in acetic acid (15 mL) was stirred at 120 °C for 4 days. After cooling to room temperature, the mixture was concentrated to produce a solid. The solid was redissolved in EtOAc (20 mL), alkalized to pH 9 with saturated Na2CO3, washed with water (10 mL × 2) and brine (10 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated to produce a crude product. The crude product was purified by Prep-HPLC (Boston Prime C18 150 mm × 30 mm 5 µm) A = H2O (0.05% ammonia hydroxide) and B = CH3CN; 45-75% B) within 9 minutes to produce a solid product (48.08 mg, 0.12 mmol, 34% yield). [ 1 ] [H NMR] (DMSO-d6, 400MHz) δH = 9.55 (d, 1H), 9.15 (d, 1H), 8.77 (d, 1H), 8.49 (dd, 1H), 6.08 - 5.98 (m, 1H), 5.08 (s, 2H), 3.61 (q, 2H), 1.55 (d, 3H), 1.15 (t, 3H). [LCMS] In 2.0 min chromatography, Rt = 1.23 min, 10-80 AB, MS ESI calculated value C16H16F4N5O2 [M+H]+ 386.1, experimental value 386.0.

[0256] [Example]

[50] [:] [3-[] [Cyclopropoxy] [(] [Difluoride] [)] [methyl] []-6-[5-] [fluorine] [-6-[(1R)-2,2,2-] [Trifluoride] [-1-] [methyl] [-] [Ethoxy] []-3-] [Pyridyl] []-[1,2,4]] [Triazo] [[4,3-a]] [Pyrazine] [ ] Potassium terbutoxide (54.51 mg, 0.49 mmol) was added dropwise to a mixture of cyclopropanol (28.22 mg, 0.49 mmol), 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine (100 mg, 0.24 mmol) in DMF (2 mL). The reaction mixture was stirred at 20 °C for 2 hours. The reaction mixture was quenched with saturated NH4Cl (10 mL) and extracted with (10 mL × 2) extractants. The combined organic phases were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated to yield the crude product. The crude product was purified by Prep-HPLC (Waters Xbridge (150 mm × 25 mm, 5 µm) A = H2O (10 mM NH4HCO3) and B = CH3CN; 57-67% B within 8 minutes) to produce an oily product (3.98 mg, 0.01 mmol, 4% yield). [ 1 ] [H NMR] (CD3CN, 400 MHz) δH = 9.46 (s, 1H), 8.67 - 8.56 (m, 2H), 8.20 (dd, 1H), 6.01 - 5.92 (m, 1H), 4.21 - 4.14 (m, 1H), 1.58 (d, 3H), 1.00 - 0.91 (m, 2H), 0.81 - 0.73 (m, 2H). [LCMS] In 2 min chromatography, Rt = 1.31 min, 10-80 AB, MS ESI calculated value C17H14F6N5O2 [M+H]+ 434.1, experimental value 433.9.

[0257] [Example]

[51] [:] [3-(] [Ethoxymethyl] [)-6-[5-] [fluorine] [-6-[(1R)-2,2,2-] [Trifluoride] [-1-] [methyl] [-] [Ethoxy] []-3-] [Pyridyl] []-[1,2,4]] [Triazo] [[4,3-a]] [Pyrazine] [ ] [A41] [Synthesis:] A mixture of (5-chloropyrazine-2-yl)hydrazine (500 mg, 3.46 mmol) and 2-ethoxyacetyl chloride (551.03 mg, 4.5 mmol) in toluene (7 mL) was stirred at 20 °C for 2 hours, then heated to 130 °C and maintained for 3 days. Most of the toluene was then removed, and acetic acid (40 mL) was added, followed by stirring at 120 °C for 16 hours. After cooling to room temperature, the mixture was concentrated to produce a residue. The residue was redissolved in EtOAc (40 mL), alkalized to pH approximately 9 with saturated Na₂CO₃, washed with water (20 mL × 2) and brine (20 mL × 2), dried over anhydrous Na₂SO₄, filtered, and concentrated to produce a crude product. The crude product was purified by rapid chromatography on silicone (EtOAc in PE = 40% to 70%), resulting in a solid product (240 mg, 1.11 mmol, 32% yield). [LCMS] In 1.5 min chromatography, Rt = 0.60 min, 5-95 AB, MS ESI calculated value C8H10ClN4O [M+H]+ 213.0, experimental value 213.0. [Compound]

[52] [Synthesis:] A mixture of 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (453.86 mg, 1.35 mmol), Cs2CO3 (1103.16 mg, 3.39 mmol), 6-chloro-3-(ethoxymethyl)-[1,2,4]triazolo[4,3-a]pyrazine (240 mg, 1.13 mmol), and Pd(dppf)Cl2 (123.88 mg, 0.17 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was stirred at 75°C under N2 for 16 hours. After cooling to room temperature, the mixture was filtered through diatomaceous earth and dissolved with EtOAc (10 mL × 2). The filtrate was then concentrated to produce a crude product. The crude product was purified by rapid chromatography on silica gel (EtOAc in PE = 30% to 60% to 100%), resulting in an impurity. The impurity was purified by Prep-HPLC (Waters Xbridge 150 mm × 25 mm, 5 µm) A = H2O (10 mM NH4HCO3) and B = CH3CN; 40-70% B) within 8 minutes to produce a solid product (37.8 mg, 98.1 µmol, 9% yield). [ 1 ] [H NMR] (DMSO-d6, 400MHz) δH = 9.56 (d, 1H), 9.15 (d, 1H), 8.77 (d, H), 8.49 (dd, 1H), 6.09 - 5.97 (m, 1H), 5.08 (s, 2H), 3.61 (q, 2H), 1.55 (d, 3H), 1.14 (t, 3H). [LCMS] In 2.0 min chromatography, Rt = 1.24 min, 10-80 AB, MS ESI calculated value C16H16F4N5O2 [M+H]+ 386.1, experimental value 386.1.

[0258] [Example]

[52] [:] [3-[] [Difluoride] [(] [Methoxy] [)] [methyl] []-6-[5-] [fluorine] [-6-(2,2,2-] [Trifluoroethoxy] [)-3-] [Pyridyl] []-[1,2,4]] [Triazo] [[4,3-a]] [Pyrazine] [ ] [ ] [A19-a] [Synthesis] A mixture of 2-bromo-5-chloropyrazine (3 g, 15.51 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborpinecyclo-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (4.98 g, 15.51 mmol), Cs₂CO₃ (10.11 g, 31.02 mmol), and Pd(dppf)Cl₂ (1.7 g, 2.33 mmol) in 1,4-dioxane (50 mL) and water (5 mL) was stirred at 55 °C under N₂ for 5 hours. The reaction mixture was cooled to room temperature and concentrated to produce a residue. Water (50 mL) and EtOAc (50 mL) were added to the residue, and the mixture was then filtered. After separation, the organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated to produce a crude product. The crude product was purified by rapid chromatography on silicone (EtOAc in PE = 0% to 5% to 10%) to produce a solid product (3700 mg, 10.69 mmol, 69% yield). [ 1 ] [H NMR] (DMSO-d6, 400MHz) δH =9.19 (d, 1H), 8.88 (d, 1H), 8.80 (d, 1H), 8.49 (dd, 1H), 5.18 (q, 2H). [LCMS] In 1.5 min chromatography, Rt = 0.93 min, 5-95 AB, MS ESI calculated value C11H7ClF4N3O [M+H]+ 308.0, experimental value 308.0. [ ] [A20-a] [Synthesis:] Hydrazine (3.85 g, 120.27 mmol) was added to a mixture of 2-chloro-5-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]pyrazine (3.7 g, 12.03 mmol) in MeCN (50 mL), and the mixture was stirred at 90 °C for 16 h. The reaction mixture was cooled to room temperature and concentrated to produce a residue. Water (30 mL) was added to the residue and the residue was extracted with EtOAc (30 mL × 2). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated to produce a crude product as a solid (3500 mg, 9.60 mmol, 80% yield). [ 1 ] [H NMR] (DMSO-d6, 400MHz) δH = 8.62 (d, 1H), 8.58 (d, 1H), 8.30 - 8.24 (m, 2H), 8.19 (d, 1H), 5.12 (q, 2H), 4.36 (s, 2H). [LCMS] In 1.5 min chromatography, Rt = 0.73 min, 5-95 AB, MS ESI calculated value C11H10F4N5O [M+1H]+ 304.1, experimental value 304.0. [A18] [Synthesis] A solution of [5-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]pyrazin-2-yl]hydrazine (3 g, 9.89 mmol) and 2-chloro-2,2-difluoroacetic acid (2-chloro-2,2-difluoroacetyl) ester (7.21 g, 29.68 mmol) in toluene (60 mL) was stirred at 110 °C for 96 hours. Molecular sieves (3 g) were then added to the mixture, and the mixture was stirred at 130 °C for another 16 hours. After cooling to room temperature, the mixture was concentrated to obtain a residue. Water (20 mL) was added to the residue, and the mixture was extracted with EtOAc (30 mL × 2). The combined organic phases were washed with water (20 mL) and brine (20 mL × 2), dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain a crude product. The crude product was purified by rapid column chromatography on silicone (EtOAc in PE = 0% to 10% to 20%), resulting in an oily product (1300 mg, 3.24 mmol, 33% yield). [LCMS] In 4 min chromatography, Rt = 2.63 min, 10-80 AB, MS ESI calculated value C13H7ClF6N5O [M+H]+ 398.0, experimental value 397.9. [Compound]

[53] [Synthesis:] A mixture of 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine (600 mg, 1.51 mmol) and AgOTf (3.88 g, 15.09 mmol) in methanol (12 mL) and DMF (4 mL) was stirred at 90 °C for 48 hours. After cooling to room temperature, the reaction mixture was treated with brine (20 mL) and the precipitate was filtered off. The filtrate was concentrated and diluted with water (20 mL), and then extracted with EtOAc (20 mL × 3). The combined organic phases were washed with brine (20 mL), dried over Na2SO4, and concentrated to produce the crude product. The crude product was purified by rapid chromatography on silicone (EtOAc in PE = 0% to 10% to 30%), resulting in a solid product (247.53 mg, 0.63 mmol, 42% yield). [ 1 ] [H NMR] (CDCl3, 400MHz) δH = 9.52 (d, 1H), 8.52 (d, 1H), 8.46 (d, 1H), 8.07 (dd, 1H), 4.93 (q, 2H), 3.98 (s, 3H). [LCMS] In 1.5 min chromatography, Rt = 1.23 min, 5-95 AB, MS ESI calculated value C14H10F6N5O2 [M+H]+ 394.1, experimental value 394.0.

[0259] [Example]

[53] [:] [3-[] [Difluoride] [(] [Methoxy] [)] [methyl] []-6-[6-(2,2,2-] [Trifluoride] [-1,1-] [Dimethyl] [-] [Ethoxy] [)-3-] [Pyridyl] []-[1,2,4]] [Triazo] [[4,3-a]] [Pyrazine] [ ] A mixture of 3-[chloro(difluoro)methyl]-6-[6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine (1.9 g, 4.66 mmol) and AgOTf (11.97 g, 46.59 mmol) in DMF (15 mL) and methanol (15 mL) was stirred at 90 °C for 96 hours. After cooling to room temperature, the reaction mixture was treated with brine (50 mL) and the precipitate was filtered off. The filtrate was concentrated and diluted with water (40 mL), and then extracted with EtOAc (50 mL × 2). The combined organic phases were washed with brine (50 mL), dried over Na2SO4, and concentrated to obtain a crude product. The crude product was purified by rapid chromatography on silica gel (EtOAc in PE = 0% to 40%) to obtain the product (170 mg). Another 88 mg product was obtained from another batch. The three batches of product were combined and lyophilized to produce a solid product (193.0 mg, 0.48 mmol). [ 1 ] [H NMR] (400MHz, CDCl3) δ = 9.52 (d, 1H), 8.72 (d, 1H), 8.43 (s, 1H), 8.19 (dd, 1H), 6.94 (d, 1H), 3.98 (s, 3H), 1.87 ppm (s, 6H). [LCMS] In 2.0 min chromatography, Rt = 1.235 min, 10-80 AB, MS ESI calculated value C16H15F5N5O2 [M+H]+ 404.1, experimental value 403.9. [ ]

[0260] [Example]

[54] [:] [3-[] [chlorine] [(] [Difluoride] [)] [methyl] []-6-[6-[1-(] [Trifluoromethyl] [)] [Ring Ding] [Oxygen group] []-3-] [Pyridyl] []-[1,2,4]] [Triazo] [[4,3-a]] [Pyrazine] [ ] [A54] [Synthesis] [:] NaH (1.86 g, 46.4 mmol) was added to a solution of 1-(trifluoromethyl)cyclobutanol (5 g, 35.69 mmol) in THF (300 mL) for 20 min at 0 °C, and the mixture was stirred at 0 °C for 30 min. Then, 5-bromo-2-fluoropyridine (8.48 g, 48.18 mmol) was added to the mixture, and the mixture was stirred at 30 °C for 3 h. The mixture was quenched with saturated NH4Cl (50 mL), and then extracted with EtOAc (50 mL). The combined organic phases were washed with brine (50 mL × 3), dried over Na2SO4, filtered, and concentrated to produce an oily crude product (4.8 g, 15.49 mmol, 43% yield). [LCMS] In 1.5 min chromatography, Rt = 0.99 min, 5-95 AB, MS ESI calculated value C10H10BrF3NO[M+H]+ 295.9, experimental value 296.0. [A55] [Synthesis] A mixture of 5-bromo-2-[1-(trifluoromethyl)cyclobutoxy]pyridine (2.5 g, 8.44 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborpine-2-yl)-1,3,2-dioxaborpine (3.22 g, 12.67 mmol), KOAc (1.66 g, 16.89 mmol), and Pd(dppf)Cl2 (432.48 mg, 0.59 mmol) in 1,4-dioxane (50 mL) was stirred at 90 °C under N2 for 12 hours. After cooling to room temperature, the mixture was concentrated to obtain a residue. The residue was diluted with H2O (40 mL), and the mixture was extracted with EtOAc (40 mL × 2). The combined organic phases were washed with water (40 mL) and brine (40 mL), dried over Na2SO4, filtered, and concentrated to produce a crude product. The crude product was purified by rapid chromatography on silicone (EtOAc in PE = 0% to 1%) to produce an oily crude product (2.65 g, 3.92 mmol, 46% yield). [ 1 ] [H NMR] (CDCl3, 400MHz) δH = 8.54 (d, 1H), 7.95 (dd, 1H), 6.74 (d, 1H), 2.99 - 2.81 (m, 2H), 2.75 - 2.53 (m, 2H), 2.13 - 1.78 (m, 2H), 1.34 (s, 12H). [A56] [Synthesis] A mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborpine-2-yl)-2-[1-(trifluoromethyl)cyclobutoxy]pyridine (2.1 g, 6.12 mmol), 2-bromo-5-chloro-pyrazine (1.18 g, 6.12 mmol), Pd(dppf)Cl2 (671.68 mg, 0.92 mmol), and Cs2CO3 (3.99 g, 12.24 mmol) in 1,4-dioxane (20 mL) and water (2 mL) was stirred at 60 °C under N2 for 6 hours. After cooling to room temperature, the mixture was concentrated to obtain a residue. The residue was diluted with H2O (20 mL) and the mixture was extracted with EtOAc (20 mL × 2). The combined organic phases were washed with water (20 mL) and brine (40 mL), dried over Na2SO4, filtered, and concentrated to produce a crude product. The crude product was purified by rapid chromatography on silicone (EtOAc in PE = 0% to 1% to 10%) to produce an oily product (1.5 g, 4.263 mmol, 70% yield). [ 1 ] [H NMR] (CDCl3, 400MHz) δH = 8.80 - 8.72 (m, 2H), 8.63 (d, 1H), 8.25 (dd, 1H), 6.91 (d, 1H), 3.01 - 2.83 (m, 2H), 2.78 - 2.62 (m, 2H), 2.18 - 1.84 (m, 2H). [ ] [A57] [Synthesis:] A mixture of 2-chloro-5-[6-[1-(trifluoromethyl)cyclobutoxy]-3-pyridyl]pyrazine (1.2 g, 3.64 mmol) and hydrazine (1.17 g, 36.4 mmol) in MeCN (20 mL) was heated to 90 °C and stirred for 16 hours. After cooling to room temperature, the reaction mixture was concentrated, diluted with H2O (30 mL), and extracted with EtOAc (30 mL × 2). The combined organic phases were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to give a crude product as a solid (950 mg, 2.48 mmol, 68% yield). [LCMS] In 2.0 min chromatography, Rt = 0.99 min, 10-80 AB, MS ESI calculated value C14H15F3N5O [M +H]+ 326.1, experimental value 326.0. [A58] [Synthesis] A mixture of [5-[6-[1-(trifluoromethyl)cyclobutoxy]-3-pyridyl]pyrazin-2-yl]hydrazine (1.13 g, 3.47 mmol), 4A molecular sieve (1 g, 3.47 mmol), and 2-chloro-2,2-difluoroacetic acid (2-chloro-2,2-difluoroacetyl) ester (1.69 g, 6.95 mmol) in toluene (15 mL) was heated to 130 °C and stirred for 16 hours. After cooling to room temperature, the reaction mixture was filtered, diluted with H2O (50 mL), and extracted with EtOAc (50 mL × 2). The combined organic phases were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to yield a crude product in solid form (820 mg, 1.13 mmol, 33% yield). [LCMS] In 2.0 min chromatography, Rt = 1.38 min, 10-80 AB, MS ESI calculated value C16H12ClF5N5O [M +H]+ 420.1, experimental value 420.0. [Compound]

[57] [Synthesis] A mixture of 3-[chloro(difluoro)methyl]-6-[6-[1-(trifluoromethyl)cyclobutoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine (600 mg, 1.43 mmol) and AgOTf (4.4 g, 17.15 mmol) in DMF (6 mL) and methanol (6 mL, 1.43 mmol) was stirred at 90 °C for 16 hours. After cooling to room temperature, the reaction mixture was quenched with saturated NaCl (30 mL) and extracted with EtOAc (30 mL × 2). The organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by rapid chromatography on silicone (EtOAc in PE = 0% to 40% to 70%), resulting in a solid product (194.76 mg, 0.47 mmol, 33% yield). [ 1 ] [H NMR] (CDCl3, 400MHz) δH = 9.52 (d, 1H), 8.72 (d, 1H), 8.44 (d, 1H), 8.23 ​​(dd, 1H), 7.0 - 6.89 (m, 1H), 3.97 (s, 3H), 3.00 - 2.85 (m, 2H), 2.80 - 2.63 (m, 2H), 2.13 - 1.89 (m, 2H). [LCMS] In 2.0 min chromatography, Rt = 1.33 min, 10-80 AB, MS ESI calculated value C17H15F5N5O2 [M +H]+ 416.1, experimental value 416.1.

[0261] [Example]

[56] [:] [3-[] [Difluoride] [(] [Methoxy] [)] [methyl] []-6-[5-] [fluorine] [-6-[(1S)-2,2,2-] [Trifluoride] [-1-] [methyl] [-] [Ethoxy] []-3-] [Pyridyl] []-5-] [methyl] [-[1,2,4]] [Triazo] [[4,3-a]] [Pyrazine] [ ] [A59] [Synthesis:] A mixture of 2-bromo-5-chloro-3-methylpyrazine (900 mg, 4.34 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (1.31 g, 3.9 mmol), Pd(dppf)Cl2 (0.48 g, 0.65 mmol), and Cs2CO3 (2.83 g, 8.68 mmol) in 1,4-dioxane (40 mL) and water (8 mL) was stirred at 50 °C under N2 for 5 hours. The mixture was cooled to room temperature, diluted with EtOAc (30 mL), filtered through silica gel, precipitated with EtOAc (20 mL), and the filtrate was concentrated to produce the crude product. The product was purified by rapid chromatography on silicone (EtOAc in PE = 0% to 3%), resulting in a solid product (1100 mg, 2.83 mmol, 65% yield). [LCMS] In 1.5 min chromatography, Rt = 1.41 min, 10-80 AB, MS ESI calculated value C13H11ClF4N3O [M+H]+ 336.0, experimental value 336.0. [A60] [Synthesis] A mixture of 5-chloro-2-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-3-methyl-pyrazine (1.1 g, 3.28 mmol) and hydrazine (1.05 g, 32.83 mmol) in MeCN (20 mL) was heated to 90 °C and stirred for 16 hours. After cooling to room temperature, the reaction mixture was concentrated. The mixture was diluted with H₂O (20 mL) and extracted with EtOAc (20 mL × 2). The combined organic phases were washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated to yield a crude product. The crude product was ground from PE (5 mL) to yield a solid product (800 mg, 2.41 mmol, 68% yield). The crude product was used in the next step without further purification. [LCMS] In 1.5 min chromatography, Rt = 0.75 min, 5-95 AB, MS ESI calculated value C13H14F4N5O [M+H]+ 332.1, experimental value 332.1. [A61] [Synthesis] [:] A mixture of [5-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-6-methyl-pyrazin-2-yl]hydrazine (500 mg, 1.51 mmol) in toluene (10 mL) was supplemented with 2-chloro-2,2-difluoroacetic acid (2-chloro-2,2-difluoro-acetyl) ester (366.68 mg, 1.51 mmol) and 4A molecular sieve (1 g). The reaction mixture was stirred at 110 °C for 5 days. After cooling to room temperature, the reaction mixture was concentrated. The residue was diluted with NaHCO3 (30 mL), and the mixture was extracted with EtOAc (30 mL × 2). The combined organic phases were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated to obtain the residue. The residue was purified by rapid column chromatography on silicone (EtOAc in PE = 0% to 20%), resulting in a solid product (105 mg, 0.16 mmol, 11% yield). [LCMS] In 1.5 min chromatography, Rt = 0.92 min, 5-95 AB, MS ESI calculated value C15H11ClF6N5O [M+H]+426.0, experimental value 426.2. [Compound]

[58] [Synthesis:] A mixture of 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-5-methyl-[1,2,4]triazolo[4,3-a]pyrazine (105 mg, 0.25 mmol) and AgOTf (633.7 mg, 2.47 mmol) in a mixed solvent of methanol (1 mL) and DMF (1 mL) was stirred at 90 °C for 48 hours. After cooling to room temperature, the reaction mixture was treated with brine (15 mL) and the precipitate was filtered off. The filtrate was extracted with EtOAc (15 mL × 2). The combined organic phases were dried over Na2SO4 and concentrated to produce a crude product. The crude product was purified by rapid chromatography on silicone (EtOAc in PE = 0% to 30% to 50%). The crude product was then ground with DCM (0.5 mL) and n-hexane (0.5 mL) to produce the product (2.05 mg, 4.90 µmol, 2% yield). [ 1 ] [H NMR] (CDCl3, 400MHz) δH = 9.39 (s, 1H), 8.11 (d, 1H), 7.69 (dd, 1H), 5.94 - 5.86 (m, 1H), 3.92 (s, 3H), 2.88 (s, 3H), 1.60 (d, 3H). [LCMS] In 2 min chromatography, Rt = 1.24 min, 10-80 AB, MS ESI calculated value C16H14F6N5O2 [M+H]+ 422.1, experimental value 422.0.

[0262] [Example]

[57] [:] [3-[] [Difluoride] [(] [Methoxy] [)] [methyl] []-6-[6-[(1S)-2,2,2-] [Trifluoride] [-1-] [methyl] [-] [Ethoxy] []-3-] [Pyridyl] []-[1,2,4]] [Triazo] [[4,3-a]] [Pyrazine] [ ] [A62] [Synthesis:] LiAlH4 (0.5 g, 13.2 mmol) was added to a mixture of (2S)-2-(trifluoromethyl)ethylene oxide (3 g, 26.77 mmol) in THF (25 mL) for 30 minutes at 0 °C under N2. The mixture was then stirred at 20 °C for 2 hours. After cooling to 0 °C, the mixture was quenched with water (0.9 g) and stirred at 35 °C for 30 minutes. The mixture was filtered through diatomaceous earth, precipitated with THF (20 mL × 2), and the organic phase was washed with brine (20 mL × 2) and dried over Na2SO4. Filtration yielded a crude product (2S)-1,1,1-trifluoroprop-2-ol (3 g, 26.3 mmol, 98% yield) in solution in THF, which was used directly without any further purification. [A63] [Synthesis:] NaH (0.8 g, 19.94 mmol) was added to a solution of (2S)-1,1,1-trifluoroprop-2-ol in THF (50 mL) for 20 minutes at 0 °C, and the mixture was stirred at 0 °C for 40 minutes. Then, 5-bromo-2-fluoropyridine (2.7 g, 15.34 mmol) was added to the mixture, and the mixture was stirred at 50 °C for 2 hours. The mixture was quenched with saturated NH4Cl (40 mL), extracted with EtOAc (60 mL), and the combined organic phases were washed with brine (40 mL × 2), dried over Na2SO4, filtered, and concentrated to produce an oily crude product (3.48 g, 9.29 mmol, 61% yield). [LCMS] In 1.5 min chromatography, Rt = 0.95 min, 5-95 AB, MS ESI calculated value C8H8BrF3NO [M+H]+ 270.0, experimental value 269.9. [A64] [Synthesis:] A mixture of 5-bromo-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (3.48 g, 12.89 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborpine-2-yl)-1,3,2-dioxaborpine (4.91 g, 19.33 mmol), KOAc (2.53 g, 25.77 mmol), and Pd(dppf)Cl2 (1.13 g, 1.55 mmol) in 1,4-dioxane (35 mL) was stirred at 85 °C under N2 for 12 hours. After cooling to room temperature, the mixture was concentrated to obtain a residue. The residue was diluted with H2O (30 mL), and the mixture was extracted with EtOAc (40 mL × 2). The combined organic phases were washed with water (40 mL) and brine (40 mL), dried over Na2SO4, filtered, and concentrated to produce a crude product. The crude product was purified by rapid chromatography on silicone (EtOAc in PE = 0% to 1%) to produce an oily product (3 g, 5.72 mmol, 44% yield). [ 1 ] [H NMR] (DMSO-d6, 400MHz) δH = 8.42 (d, 1H), 7.96 (dd, 1H), 6.93 (d, 1H), 6.00 - 5.93 (m, 1H), 1.45 (d, 3H), 1.30 (s, 12H). [LCMS] In 1.5 min chromatography, Rt = 1.02 min, 5-95 AB, MS ESI calculated value C14H20BF3NO3 [M+H]+ 318.1, experimental value 318.1. [A65] [Synthesis:] A mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborpine-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (600 mg, 1.89 mmol), 2-bromo-5-chloro-pyrazine (329.39 mg, 1.7 mmol), Pd(dppf)Cl2 (207.67 mg, 0.28 mmol), and Cs2CO3 (1232.88 mg, 3.78 mmol) in 1,4-dioxane (15 mL) and water (1.5 mL) was stirred at 60 °C under N2 for 5 hours. After cooling to room temperature, the mixture was concentrated to obtain a residue. The residue was diluted with H2O (20 mL) and the mixture was extracted with EtOAc (30 mL × 2). The combined organic phases were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated to produce a crude product. The crude product was purified by rapid chromatography on silicone (EtOAc in PE = 0% to 3%) to produce an oily product (350 mg, 1.15 mmol, 61% yield). [LCMS] In 1.5 min chromatography, Rt = 0.95 min, 5-95 AB, MS ESI calculated value C12H10ClF3N3O [M+H]+ 304.0, experimental value 304.1. [A66] [Synthesis:] A mixture of 2-chloro-5-[6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]pyrazine (351.14 mg, 1.16 mmol) and hydrazine (741.21 mg, 23.13 mmol) in CH3CN (5 mL) was stirred at 90 °C for 16 hours. After cooling to room temperature, the reaction mixture was quenched with saturated NH4Cl (30 mL), and the mixture was extracted with EtOAc (20 mL × 2). The combined organic phases were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to yield a crude solid product (350 mg, 1.05 mmol, 91% yield). [LCMS] In 1.5 min chromatography, Rt = 0.74 min, 5-95 AB, MS ESI calculated value C12H13F3N5O [M+H]+ 300.1, experimental value 300.1. [A67] [Synthesis:] A mixture of [5-[6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]pyrazin-2-yl]hydrazine (350 mg, 1.17 mmol), 2-chloro-2,2-difluoroacetic acid (2-chloro-2,2-difluoro-acetyl) ester (852.42 mg, 3.51 mmol) and 4A molecular sieve (500 mg, 1.17 mmol) in toluene (8 mL) was stirred at 120 °C for 2 days. After cooling to room temperature, the reaction mixture was quenched with saturated NaHCO3 (20 mL), and the mixture was extracted with EtOAc (20 mL × 2). The combined organic phases were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered and concentrated to produce a solid product (420 mg, 1.01 mmol, 86% yield). [LCMS] In 1.5 min chromatography, Rt = 0.92 min, 5-95 ABMS ESI calculated value C14H10ClF5N5O [M+H]+ 394.0, experimental value 394.1. [Compound]

[59] [Synthesis:] A mixture of 3-[chloro(difluoro)methyl]-6-[6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine (420 mg, 1.07 mmol) and AgOTf (3289.25 mg, 12.8 mmol) in DMF (6 mL) and methanol (6 mL, 1.07 mmol) was stirred at 90 °C for 24 hours. After cooling to room temperature, the reactants were diluted with EtOAc (30 mL) and quenched with saturated NaCl (30 mL). The mixture was filtered through diatomaceous earth and precipitated with EtOAc (10 mL). The filtrate was washed with water (30 mL) and brine (30 mL), dried over Na2SO4, filtered, and concentrated to produce the crude product. The crude product was purified by rapid chromatography on silicone (EtOAc in PE = 0% to 15% to 30%), resulting in an impure product. The impure product was then ground in hexane / DCM (2:1, 6 mL) to produce a solid product (118.39 mg, 0.30 mmol, 29% yield). [ 1 ] [H NMR] (CD3CN, 400MHz) δH = 9.46 (d, 1H), 8.81 (d, 1H), 8.66 (d, 1H), 8.35 (dd, 1H), 6.99 (d, 1H), 5.99 - 5.88 (m, 1H), 3.94 (s, 3H), 1.53 (d, 3H). [LCMS] In 2.0 min chromatography, Rt = 1.28 min, 10-80 AB, MS ESI calculated value C15H13F5N5O2 [M+H]+ 390.1, experimental value 390.0.

[0263] [Example]

[58] [:] [3-[] [Difluoride] [(] [Methoxy] [)] [methyl] []-6-[5-] [fluorine] [-6-[(1R)-2,2,2-] [Trifluoride] [-1-] [methyl] [-] [Ethoxy] []-3-] [Pyridyl] []-5-] [methyl] [-[1,2,4]] [Triazo] [[4,3-a]] [Pyrazine] [ ] [A68] [Synthesis:] A mixture of 2-bromo-5-chloro-3-methylpyrazine (900 mg, 4.34 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (1.31 g, 3.9 mmol), Pd(dppf)Cl2 (0.48 g, 0.65 mmol), and Cs2CO3 (2.83 g, 8.68 mmol) in 1,4-dioxane (40 mL) and water (8 mL) was stirred at 55 °C under N2 for 16 hours. The mixture was cooled to room temperature, diluted with EtOAc (50 mL), filtered through silica gel, dissolved and concentrated with EtOAc (20 mL), and the crude product was obtained. The product was purified by rapid chromatography on silicone (EtOAc in PE = 0% to 20%), resulting in a colorless oily product (930 mg, 2.62 mmol, 60% yield). [LCMS] In 1.5 min chromatography, Rt = 0.95 min, 5-95 AB, MS ESI calculated value C13H11ClF4N3O [M+H]+ 336.0, experimental value 336.1. [A69] [Synthesis:] A mixture of hydrazine (1775.89 mg, 55.41 mmol) and 5-chloro-2-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-3-methyl-pyrazine (930 mg, 2.77 mmol) in CH3CN (10 mL) was stirred at 90 °C for 16 hours. After cooling to room temperature, the reaction mixture was quenched with saturated NH4Cl (30 mL), and the mixture was extracted with EtOAc (40 mL × 2). The combined organic phases were washed with water (30 mL) and brine (30 mL), dried over Na2SO4, filtered, and concentrated to yield a crude solid product (980 mg, 2.45 mmol, 89% yield). [LCMS] In 1.5 min chromatography, Rt = 0.75 min, 5-95 AB, MS ESI calculated value C13H14F4N5O [M+H]+ 332.1, experimental value 332.2. [A70] Synthesis: A mixture of [5-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-6-methyl-pyrazin-2-yl]hydrazine (600 mg, 1.81 mmol), 2-chloro-2,2-difluoroacetic acid (2-chloro-2,2-difluoro-acetyl) ester (1320.05 mg, 5.43 mmol) and 4A molecular sieve (600 mg, 1.81 mmol) in toluene (10 mL) was stirred at 120 °C for 5 days. After cooling to room temperature, the reaction mixture was quenched with saturated NaHCO3 (20 mL), and the mixture was extracted with EtOAc (20 mL × 2). The combined organic phases were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated to produce the crude product. The crude product was purified by rapid chromatography on silicone (EtOAc in PE = 0% to 40%), resulting in a solid product (140 mg, 0.22 mmol, 12% yield). [LCMS] In 1.5 min chromatography, Rt = 0.92 min, 5-95 AB, MS ESI calculated value C15H11ClF6N5O [M+H]+ 426.0, experimental value 426.1. [Compound]

[60] [Synthesis:] A mixture of 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-5-methyl-[1,2,4]triazolo[4,3-a]pyrazine (140 mg, 0.33 mmol) and AgOTf (1267.44 mg, 4.93 mmol) in DMF (2 mL) and methanol (2 mL, 0.33 mmol) was stirred at 90 °C for 2 days. After cooling to room temperature, the reactants were diluted with EtOAc (10 mL) and saturated NaCl (10 mL), and the mixture was filtered through diatomaceous earth and precipitated with EtOAc (10 mL). The combined organic phases were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated to produce the crude product. The crude product was purified by Prep-TLC (silicone, PE: EtOAc = 2:1), resulting in an impure product. The impure product was then ground in hexane / DCM (2:1, 3 mL) to produce a solid product (11.92 mg, 28.3 µmol, 9% yield). [ 1 ] [H NMR] (CDCl3, 400MHz) δH = 9.39 (s, 1H), 8.11 (d, 1H), 7.69 (dd, 1H), 5.96 - 5.85 (m, 1H), 3.92 (s, 3H), 2.88 (s, 3H), 1.60 (d, 3H). [LCMS] In 2.0 min chromatography, Rt = 1.28 min, 10-80 AB, MS ESI calculated value C16H14F6N5O2 [M+H]+ 422.1, experimental value 422.2. [ ]

[0264] [Example]

[59] [:] [3-[] [Difluoride] [(] [Methoxy] [)] [methyl] []-6-[5-] [fluorine] [-6-(2,2,2-] [Trifluoroethoxy] [)-3-] [Pyridyl] []-5-] [methyl] [-[1,2,4]] [Triazo] [[4,3-a]] [Pyrazine] [ ] [A71] [Synthesis:] NBS (34.35 g, 192.98 mmol) was added to a solution of 5-chloropyrazine-2-amine (25 g, 192.98 mmol) in DCM (250 mL). The resulting mixture was stirred at 40 °C for 1 hour. After cooling to room temperature and concentration, water (200 mL) was added, resulting in a residue, which was extracted with EtOAc (150 mL × 2). The combined organic phases were washed with brine (150 mL), dried over Na2SO4, filtered, and concentrated to yield a crude product. The crude product was purified by column chromatography on silicone (EtOAc in PE = 0% to 15% to 30%) to yield a solid product (31 g, 148.72 mmol, 77% yield). [ 1 ] [H NMR] (DMSO-d6, 400MHz) δH = 8.09 (s, 1H), 6.96 (s, 2H). [A72] [Synthesis] [:] 3-Bromo-5-chloro-pyrazin-2-amine (31 g, 148.72 mmol), Pd(dppf)Cl2 (16.32 g, 22.31 mmol), methyl A mixture of acid (13.35 g, 223.09 mmol) and Cs₂CO₃ (96.91 g, 297.45 mmol) in water (30 mL) and 1,4-dioxane (300 mL) was stirred at 90 °C for 16 hours. After cooling to room temperature, the mixture was concentrated to produce a residue. Water (100 mL) was added to the residue, and the mixture was extracted with EtOAc (100 mL × 2). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to produce a crude product. The crude product was purified by rapid chromatography on silicone (EtOAc in PE = 20% to 40% to 60% to 80%) to produce a solid product (13 g, 90.548 mmol, 61% yield). [ 1 ] [H NMR] (DMSO-d6, 400MHz) δH = 7.83 (s, 1H), 6.40 (s, 2H), 2.26 (s, 3H). [A73] [Synthesis] A mixture of 5-chloro-3-methylpyrazine-2-amine (3 g, 20.9 mmol), isopentyl nitrite (3.67 g, 31.34 mmol), and CuBr (3 g, 20.9 mmol) in MeCN (30 mL) was stirred at 50 °C for 12 hours. The mixture was diluted with H₂O (30 mL) and extracted with EtOAc (70 mL × 2). The combined organic phases were washed with water (30 mL × 2) and brine (30 mL), dried over Na₂SO₄, and concentrated to produce a crude product. The crude product was purified by rapid column chromatography on silicone (DCM in PE = 0% to 2%) to produce an oily product (1.2 g, 5.78 mmol, 28% yield). [ 1 ] [H NMR] (CDCl3, 400MHz) δH = 8.22 (s, 1H), 2.68 (s, 3H). [LCMS] In 2.0 min chromatography, Rt = 1.10 min, 10-80 AB, MS ESI calculated value C5H5BrClN2 [M+H]+ 208.9, experimental value 208.7. [A74] [Synthesis] A mixture of 2-bromo-5-chloro-3-methylpyrazine (1.2 g, 5.78 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborpinecyclo-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (1.3 g, 4.05 mmol), Cs₂CO₃ (3.77 g, 11.57 mmol), and Pd(dppf)Cl₂ (634.85 mg, 0.87 mmol) in 1,4-dioxane (30 mL) and water (3 mL) was stirred at 60 °C under N₂ for 16 hours. After cooling to room temperature, water (30 mL) and EtOAc (50 mL) were added to the mixture, and the mixture was filtered through diatomaceous earth. After separation of the filtrate, the organic phase was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated to produce a crude product. The crude product was purified by rapid column chromatography on silicone (EtOAc in PE = 0% to 1% to 2%) to produce a solid product (580 mg, 1.71 mmol, 30% yield). [ 1 ] [H NMR] (CDCl3, 400MHz) δH = 8.52 (s, 1H), 8.19 (d, 1H), 7.73 (dd, 1H), 4.91 (q, 2H), 2.69 (s, 3H). [LCMS] In 1.5 min chromatography, Rt = 0.93 min, 5-95 AB, MS ESI calculated value C12H9ClF4N3O [M+H]+ 322.0, experimental value 322.0. [A75] [Synthesis] A solution of 5-chloro-2-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-3-methyl-pyrazine (640 mg, 1.89 mmol) and hydrazine (605.42 mg, 18.89 mmol) in MeCN (20 mL) was stirred at 90 °C for 16 hours. After cooling to room temperature, the mixture was concentrated, water (20 mL) was added, and the mixture was extracted with EtOAc (20 mL × 3). The combined organic phases were washed with brine (20 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated to produce a crude product in solid form (530 mg, 1.30 mmol, 69% yield). [ 1 ] [H NMR] (DMSO-d6, 400MHz) δH = 8.18 (d, 1H), 8.08 (s, 1H), 8.06 (s, 1H), 7.97 (dd, 1H), 5.13 (q, 2H), 4.32 (br s, 2H), 2.41 (s, 3H). [LCMS] In 1.5 min chromatography, Rt = 0.72 min, 5-95 AB, MS ESI calculated value C12H12F4N5O [M+H]+ 318.1, experimental value 318.1. [A76] Synthesis: A solution of [5-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-6-methyl-pyrazin-2-yl]hydrazine (530 mg, 1.67 mmol), 2-chloro-2,2-difluoroacetic acid (2-chloro-2,2-difluoroacetyl) ester (1.22 g, 5.01 mmol), and 4A molecular sieve (3 g) in toluene (30 mL) was stirred at 120 °C for 6 days. After cooling to room temperature, the mixture was concentrated to produce a residue. Water (50 mL) was added to the residue, and then it was extracted with EtOAc (50 mL × 2). The combined organic phases were washed with water (50 mL) and brine (50 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated to produce a crude product. The crude product was purified by rapid column chromatography on silicone (EtOAc in PE = 0% to 15% to 30%), resulting in an oily product (180 mg, 426.2 µmol, 26% yield). [LCMS] In 7.0 min chromatography, Rt = 3.64 min, 10-80 AB, MS ESI calculated value C14H9ClF6N5O [M+H]+ 412.0, experimental value 412.1. [Compound]

[61] [Synthesis] A solution of 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-5-methyl-[1,2,4]triazolo[4,3-a]pyrazine (180 mg, 0.44 mmol) and AgOTf (1.69 g, 6.56 mmol) in methanol (5 mL) and DMF (5 mL) was stirred at 90 °C under N2 for 16 hours. After cooling to room temperature, saturated NaCl (50 mL) and EtOAc (50 mL) were added to the mixture, and the mixture was filtered through diatomaceous earth. After separation, the organic phase was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated to produce the crude product. The crude product was purified by rapid column chromatography on silicone (EtOAc in PE = 0% to 15% to 30%), resulting in a solid product (38.62 mg, 94.1 µmol, 22% yield). [ 1 ] [H NMR] (CDCl3, 400MHz) δH = 9.39 (s, 1H), 8.12 (d, 1H), 7.71 (dd, 1H), 4.93 (q, 2H), 3.92 (s, 3H), 2.88 (s, 3H). [LCMS] In 2.0 min chromatography, Rt = 1.20 min, 10-80 AB, MS ESI calculated value C15H12F6N5O2 [M+H]+ 408.1, experimental value 407.9.

[0265] [Example]

[60] [:] [3-[] [Difluoride] [(] [Methoxy] [)] [methyl] []-6-[6-[(1R)-2,2,2-] [Trifluoride] [-1-] [methyl] [-] [Ethoxy] []-3-] [Pyridyl] []-[1,2,4]] [Triazo] [[4,3-a]] [Pyrazine] [ ] AgBF4 (2.58 g, 13.24 mmol) was added to a suspension of 3-[bromo(difluoro)methyl]-6-[6-[racemic-(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine (2.9 g, 6.62 mmol) in methanol (30 mL) at 25 °C under N2. The mixture was protected from light and stirred at 60 °C for 1 hour. The solution was added to saturated NaCl (30 mL) and filtered. The filtrate was extracted with EtOAc (20 mL × 2). The combined organic phases were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by rapid column chromatography on silicone (EtOAc in PE = 0% to 10% to 20%), resulting in a solid product (1.96 g, ee = 92.28%). [Analytical] [SFC]: Analysis by SFC (Chiralpak OJ-3 150×4.6 mm ID, 3 μm mobile phase: A: CO2, B: ethanol (0.05% DEA); gradient: from 5% to 40% B in 5 min and from 40% to 5% B in 0.5 min, holding at 5% B for 1.5 min; flow rate: 2.5 mL / min, column temperature: 35℃) showed two peaks at 2.71 min and 2.96 min. The product was separated by SFC (DAICEL CHIRALCEL OJ (250 mm × 50 mm, 10 mm); A = CO2 and B = 0.1% NH3H2O ​​EtOH; 35℃; 200 mL / min; 25% B; 8 min run; 100 injections, Rt of peak 1 = 4.2 min and Rt of peak 2 = 4.7 min), resulting in a solid product (1415.6 mg, 3.64 mmol, 55% yield). [ 1 ] [H NMR] (400MHz, CD3CN) δH = 9.45 (d, 1H), 8.80 (d, 1H), 8.66 (d, 1H), 8.35 (dd, 1H), 6.99 (d, 1H), 5.97 - 5.90 (m, 1H), 3.94 (s, 3H), 1.53 (d, 3H). [LCMS] In 2.0 min chromatography, Rt = 1.27 min, 10-80 AB, MS ESI calculated value C15H13F5N5O2 [M+H]+ 389.1, experimental value 390.0.

[0266] [Example]

[61] [:] [3-[] [Cyclopropoxy] [(] [Difluoride] [)] [methyl] []-6-[5-] [fluorine] [-6-[(1S)-2,2,2-] [Trifluoride] [-1-] [methyl] [-] [Ethoxy] []-3-] [Pyridyl] []-[1,2,4]] [Triazo] [[4,3-a]] [Pyrazine] [ ] Potassium terbutoxide (163.54 mg, 1.46 mmol) was added to a mixture of cyclopropanol (84.65 mg, 1.46 mmol), 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine (300 mg, 0.73 mmol) in DMF (5 mL). The reaction mixture was stirred at 20 °C for 1 hour. The mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL × 2). The combined organic phases were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated to produce a crude product. The crude product was purified by rapid chromatography on silicone (EtOAc in PE = 0% to 30%), resulting in an impure product. The impure product was ground from hexane / DCM (2:1, 3 mL) to produce the product (33.18 mg, 76.6 µmol, 11% yield). [ 1 ] [H NMR] (CDCl3, 400MHz) δH = 9.52 (d, 1H), 8.49 (d, 1H), 8.43 (d, 1H), 8.05 (dd, 1H), 5.96 - 5.86 (m, 1H), 4.21 - 4.16 (m, 1H), 1.61 (d, 3H), 1.04 - 0.99 (m, 2H), 0.87 - 0.81 (m, 2H). [LCMS] Rt = 1.34 min, 10⁻⁸ AB in 2.0 min chromatography. MS ESI calculated value C17H14F6N5O₂ [M+H]+ 434.1, experimental value 434.1.

[0267] [Example]

[62] [:] [6-(6-)] [Benzyloxy] [-5-] [fluorine] [-3-] [Pyridyl] [)-3-[] [Ethoxy] [(] [Difluoride] [)] [methyl] []-[1,2,4]] [Triazo] [[4,3-, a , ]] [Pyrazine] [A84] [Synthesis:] NaH (7 g, 175 mmol) was added fractionally to a solution of phenylmethanol (10.5 g, 97.1 mmol) in THF (100 mL) at 0 °C for 0.5 h. After addition, the mixture was stirred at 20 °C for 1 h. Then, 5-bromo-2,3-difluoropyridine (18.83 g, 97.1 mmol) was added to the mixture. The resulting mixture was stirred at 20 °C for 3 h. The mixture was poured into a saturated NH4Cl solution (100 mL) and extracted with EtOAc (100 mL × 2). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated to yield an oily crude product (27 g, 89.52 mmol). [A85] [Synthesis:] A mixture of 2-benzyloxy-5-bromo-3-fluoropyridine (27 g, 95.71 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborpine-2-yl)-1,3,2-dioxaborpine (29.16 g, 114.85 mmol), KOAc (18.79 g, 191.41 mmol), and Pd(dppf)Cl2 (10.5 g, 14.36 mmol) in 1,4-dioxane (300 mL) was stirred at 90 °C under N2 for 16 hours. After cooling to room temperature, the mixture was filtered through diatomaceous earth and the filtrate was concentrated. The crude product was purified by rapid chromatography on silicone (PE) to produce a solid product (20 g, 60.75 mmol, 63% yield). [ 1 ] [H NMR] (400MHz, CDCl3) δH = 8.30 (d, 1H), 7.66 (dd, 1H), 7.50 (d, 2H), 7.41 - 7.31 (m, 3H), 5.52 (s, 2H), 1.35 (s, 12H). [A86] [Synthesis:] A mixture of 2-bromo-5-chloropyrazine (4 g, 20.68 mmol), 2-benzyloxy-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborpine-2-yl)pyridine (6.81 g, 20.68 mmol), Cs₂CO₃ (13.47 g, 41.36 mmol), and Pd(dppf)Cl₂ (2.27 g, 3.1 mmol) in 1,4-dioxane (30 mL) and water (3 mL) was stirred at 50 °C under N₂ for 16 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated. Water (50 mL) was added and the aqueous layer was extracted with EtOAc (50 mL × 2). The combined organic layers were washed with brine (50 mL), dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by rapid chromatography on silicone (EtOAc in PE = 0% to 15% to 30%), resulting in a solid product (5.5 g, 17.42 mmol, 84% yield). [ 1 ] [H NMR] (400MHz, DMSO-d6) δH = 9.15 (s, 1H), 8.85 (s, 1H), 8.77 (s, 1H), 8.37 (d, 1H), 7.52 - 7.46 (m, 2H), 7.44 - 7.32 (m, 3H), 5.51 (s, 2H). [A87] [Synthesis:] A mixture of 2-(6-benzyloxy-5-fluoro-3-pyridyl)-5-chloro-pyrazine (4.2 g, 13.3 mmol) and hydrazine (4.26 g, 133.03 mmol) in MeCN (20 mL) was stirred at 90 °C for 16 hours. After cooling to room temperature, the solution was concentrated under reduced pressure. Water (30 mL) was added and the aqueous layer was extracted with EtOAc (30 mL × 2). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated to yield a crude solid product (4 g, 7.38 mmol). [LCMS] In 1.5 min chromatography, Rt = 0.76 min, 5-95 AB, MS ESI calculated value C16H15FN5O [M+H]+ 312.1, experimental value 311.9. [A88] [Synthesis:] To a solution of 2-bromo-2,2-difluoroacetyl chloride (1.65 g, 8.53 mmol) in THF (30 mL), [5-(6-benzyloxy-5-fluoro-3-pyridyl)pyrazin-2-yl]hydrazine (2 g, 6.42 mmol) was added. The mixture was stirred at 20 °C for 1 hour. Water (30 mL) was added and the aqueous layer was extracted with EtOAc (30 mL × 2). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to yield a crude solid product (900 mg, 1.92 mmol). [ 1 ] [H NMR] (400MHz, DMSO-d6) δH = 11.40 (s, 1H), 9.52 (s, 1H), 8.78 (d, 1H), 8.63 (d, 1H), 8.24 (dd, 1H), 8.14 (d, 1H), 7.49 (d, 2H), 7.43 - 7.32 (m, 3H), 5.49 (s, 2H). [A89] [Synthesis:] 2-Methoxypyridine (230.74 mg, 2.11 mmol) and Tf₂O (0.19 mL, 1.15 mmol) were added to a mixture of N'-[5-(6-benzyloxy-5-fluoro-3-pyridyl)pyrazin-2-yl]-2-bromo-2,2-difluoroacetylhydrazine (450 mg, 0.96 mmol) in DCM (9 mL). The mixture was stirred at 20 °C for 16 hours. Water (50 mL) was added and the aqueous layer was extracted with EtOAc (50 mL × 2). The combined organic phases were washed with saturated NaHCO₃ solution (30 mL) and brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was purified by rapid chromatography on silicone (EtOAc in PE = 0% to 30% to 50%), resulting in a solid product (240 mg, 533.1 µmol, 55% yield). [ 1 ] [H NMR] (400MHz, CDCl3) δH = 9.57 (d, 1H), 8.55 (d, 1H), 8.41 (s, 1H), 8.01 (dd, 1H), 7.52 (d, 2H), 7.44 - 7.32 (m, 3H), 5.57 (s, 2H). [Compound]

[64] [Synthesis:] A mixture of 6-(6-benzyloxy-5-fluoro-3-pyridyl)-3-[bromo(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyrazine (240 mg, 0.53 mmol) and AgBF4 (207.55 mg, 1.07 mmol) in ethanol (5 mL) was stirred in the dark at 60 °C for 1 hour. After cooling to room temperature, the mixture was filtered through diatomaceous earth and the filtrate was concentrated. The crude product was purified by rapid chromatography on silica gel (EtOAc in PE = 0% to 30% to 50%) to produce a solid product (31.09 mg, 74.8 µmol, 14% yield). [ 1 ] [H NMR] (400MHz, CDCl3) δH = 9.51 (d, 1H), 8.50 (d, 1H), 8.46 (s, 1H), 8.00 (dd, 1H), 7.55-7.48 (m, 2H), 7.44 - 7.33 (m, 3H), 5.56 (s, 2H), 4.37 (q, 2H), 1.51 (t, 3H). [LCMS] In 2.0 min chromatography, Rt = 1.38 min, 10-80 AB, MS ESI calculated value C20H17F3N5O2 [M+H]+ 416.1, experimental value 416.0.

[0268] [Example]

[63] [:] [3-[] [Difluoride] [(] [Methoxy] [)] [methyl] []-6-[5-] [fluorine] [-6-(2,2,2-] [Trifluoroethoxy] [)-3-] [Pyridyl] []-7-] [methyl] [-[1,2,4]] [Triazo] [[4,3-, b , ]] [Tarazine] [A100] [Synthesis:] A mixture of 3-[bromo(difluoro)methyl]-6-chloro-7-methyl-[1,2,4]triazolo[4,3-b]pyrazine (900 mg, 3.03 mmol) and AgBF4 (1.17 g, 6.05 mmol) in methanol (10 mL) was stirred in the dark at 60 °C for 1 hour. After cooling to room temperature, brine (50 mL) and EtOAc (50 mL) were added to the mixture, and the mixture was filtered through diatomaceous earth. The organic phase was separated, washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by rapid chromatography on silica gel (EtOAc in PE = 0% to 30% to 50%) to produce a solid product (180 mg, 724.0 µmol, 23% yield). [ 1 ] [H NMR] (400MHz, CDCl3) δH = 7.99 (s, 1H), 3.90 (s, 3H), 2.53 (s, 3H). [LCMS] In 1.5 min chromatography, Rt = 0.78 min, 5-95 AB, MS ESI calculated value C8H8ClF2N4O [M+H]+ 249.0, experimental value 248.9. [Compound]

[65] [Synthesis] A mixture of 6-chloro-3-[difluoro(methoxy)methyl]-7-methyl-[1,2,4]triazolo[4,3-b]pyrazine (100 mg, 0.40 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborpinecyclo-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (193.72 mg, 0.60 mmol), K3PO4 (170.78 mg, 0.80 mmol), and Pd(t-Bu3P)2 (30.83 mg, 0.06 mmol) in 1,4-dioxane (5 mL) and water (0.50 mL) was stirred at 80 °C under N2 for 3 hours. After cooling to room temperature, water (20 mL) was added to the mixture, and the aqueous layer was extracted with EtOAc (20 mL × 2). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by rapid chromatography on silicone (EtOAc in PE = 0% to 30% to 50%) to produce a solid product (64.84 mg, 158.9 µmol, 39% yield). [ 1 ] [H NMR] (400MHz, CDCl3) δH = 8.20 (d, 1H), 8.06 (s, 1H), 7.69 (dd, 1H), 4.94 (q, 2H), 3.88 (s, 3H), 2.48 (s, 3H). [LCMS] In 2.0 min chromatography, Rt = 1.18 min, 10-80 AB, MS ESI calculated value C15H12F6N5O2 [M+H]+ 408.1, experimental value 408.0.

[0269] [Example]

[64] [:] [3-[] [Difluoride] [(] [Methoxy] [)] [methyl] []-6-[5-] [fluorine] [-6-[(1R)-2,2,2-] [Trifluoride] [-1-] [methyl] [-] [Ethoxy] []-3-] [Pyridyl] []-7-] [methyl] [-[1,2,4]] [Triazo] [[4,3-, b , ]] [Tarazine] [ ] A mixture of 3-fluoro-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborpine-2-yl)pyridine (121.31 mg, 0.36 mmol), 6-chloro-3-[difluoro(methoxy)methyl]-7-methyl-[1,2,4]triazolo[4,3-b]pyrazine (75 mg, 0.3 mmol), Pd(t-Bu3P)2 (23.13 mg, 0.05 mmol), and K3PO4 (128.09 mg, 0.6 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was stirred at 80 °C for 3 hours. After cooling to room temperature, the mixture was concentrated and diluted with H2O (20 mL). The aqueous layer was extracted with EtOAc (20 mL × 2). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by rapid chromatography on silica gel (EtOAc 100%) to produce a solid product (70.46 mg, 0.17 mmol, 55% yield). [ 1 ] [H NMR] (400MHz, CDCl3) δH = 8.18 (d, 1H), 8.06 (d, 1H), 7.67 (dd, 1H), 5.97 - 5.86 (m, 1H), 3.88 (s, 3H), 2.49 (s, 3H), 1.61 (d, 3H). [LCMS] In 2 min chromatography, Rt = 1.24 min, 10-80 AB, MS ESI calculated value C16H14F6N5O2 [M+H]+ 422.1, experimental value 422.0.

[0270] [Example]

[65] [:] [3-[] [Ethoxy] [(] [Difluoride] [)] [methyl] []-6-[5-] [fluorine] [-6-[(1S)-2,2,2-] [Trifluoride] [-1-] [methyl] [-] [Ethoxy] []-3-] [Pyridyl] []-5-] [methyl] [-[1,2,4]] [Triazo] [[4,3-, a , ]] [Pyrazine] A mixture of 3-[bromo(difluoro)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-5-methyl-[1,2,4]triazolo[4,3-a]pyrazine (100 mg, 0.21 mmol) and AgBF4 (82.81 mg, 0.43 mmol) in ethanol (1 mL) was stirred in the dark at 60 °C for 1 hour. After cooling to room temperature, EtOAc (30 mL) and saturated NaCl aqueous solution (30 mL) were added to the mixture. The mixture was filtered through diatomaceous earth, and the filtrate phases were separated. The aqueous phase was extracted with EtOAc (20 mL). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was purified by rapid chromatography over silicone (EtOAc in PE = 0% to 30% to 50%), yielding a solid impurity (55 mg). The impurity was then ground with EtOH (1 mL) to produce a solid product (19.57 mg, 21% yield). [ 1 ] [H NMR] (400MHz, CDCl3) δH = 9.39 (s, 1H), 8.11 (d, 1H), 7.69 (dd, 1H), 5.96 - 5.85 (m, 1H), 4.32 (q,2H), 2.90 (s, 3H), 1.60 (d, 3H), 1.45 (t, 3H). [LCMS] In 2.0 min chromatography, Rt = 1.34 min, 10-80 AB, MS ESI calculated value C17H16F6N5O2 [M+H]+ 436.1, experimental value 436.0.

[0271] [Example]

[66] [:] [3-[] [Difluoride] [(] [Methoxy] [)] [methyl] []-6-[5-] [fluorine] [-6-[(1S)-2,2,2-] [Trifluoride] [-1-] [methyl] [-] [Ethoxy] []-3-] [Pyridyl] []-7-] [methyl] [-[1,2,4]] [Triazo] [[4,3-, b , ]] [Tarazine] [A103] [Synthesis:] A mixture of 3,6-dichloro-4-methyl-pyrazine (14 g, 85.89 mmol) and N₂H₄·H₂O (4.29 g, 85.89 mmol) in ethanol (200 mL) was stirred at 70 °C for 30 hours. After cooling to room temperature, the suspension was filtered. The filter cake was washed with EtOH (50 mL × 3) and dried in an oven to produce two regioisomers ( [A103]、 The product was a solid (8 g, 50.45 mmol, 58% yield) in the form of a mixture of [A103-2] and in a ratio of about 1:1 (as determined by 1H NMR). [A99] [Synthesis:] A mixture of 6-chloro-5-methyl-pyrazin-3-amine (2.0 g, 13.93 mmol), (6-chloro-4-methyl-pyrazin-3-yl)hydrazine, and 2-bromo-2,2-difluoroacetyl chloride (5.4 g, 27.86 mmol) in toluene (80 mL) was stirred at 120 °C for 16 hours. After cooling to room temperature, the mixture was concentrated, and the residue was diluted with H₂O (50 mL). The mixture was extracted with EtOAc (100 mL × 2). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was purified by rapid chromatography on silicone (EtOAc in PE = 20% to 40% to 60%), yielding a solid product. [A99] (400 mg, 1.34 mmol, 10% yield) and [A99-2] (600 mg, 2.01 mmol, 14% yield). [A99] [ 1 [H NMR] [(]400MHz, CDCl3) δH = 8.08 (s, 1H), 2.58 (s, 3H). [A99-2, 1 [H NMR] [(]400MHz, CDCl3) δH = 7.14 (s, 1H), 2.81 (s, 3H). [A100-a] [Synthesis:] A mixture of 3-[bromo(difluoro)methyl]-6-chloro-7-methyl-[1,2,4]triazolo[4,3-b]pyrazine (400 mg, 1.34 mmol) and AgBF4 (523.5 mg, 2.69 mmol) in methanol (5 mL) was stirred in the dark at 55 °C for 12 hours. After cooling to room temperature, saturated aqueous NaCl solution (30 mL) and EtOAc (30 mL) were added. The mixture was filtered through diatomaceous earth and the filtrate was extracted with EtOAc (30 mL). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by rapid chromatography on silica gel (EtOAc in PE = 0% to 30% to 50%) to produce a solid product (230 mg, 0.93 mmol, 68% yield). [ 1 ] [H NMR] [(]400MHz, CDCl3) δH = 7.98 (d, 1H), 3.89 (s, 3H), 2.53 (s, 3H). [LCMS] In 1.5 min chromatography, Rt = 0.73 min, 10-80 AB, MS ESI calculated value C8H8ClF2N4O [M+H]+ 249.0, experimental value 248.8. [Compound]

[68] [Synthesis:] A mixture of 6-chloro-3-[difluoro(methoxy)methyl]-7-methyl-[1,2,4]triazolo[4,3-b]pyrazine (70 mg, 0.28 mmol), 3-fluoro-2-(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborpine-2-yl)pyridine (113.22 mg, 0.34 mmol), K3PO4 (119.55 mg, 0.56 mmol), and Pd(t-Bu3P)2 (21.58 mg, 0.04 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was stirred at 80 °C under N2 for 3 hours. After cooling to room temperature, the mixture was filtered through diatomaceous earth and the filtrate was concentrated. Water (20 mL) was added and the mixture was extracted with EtOAc (20 mL × 2). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by prep-TLC (silicone, EtOAc) to obtain a solid product (65 mg, 154.3 µmol, 54% yield). [ 1 ] [H NMR] (400MHz, CDCl3) δH = 8.18 (d, 1H), 8.06 (d, 1H), 7.67 (dd, 1H), 5.96 - 5.87 (m, 1H), 3.88 (s, 3H), 2.49 (s, 3H), 1.61 (d, 3H). [LCMS] In 2.0 min chromatography, Rt = 1.31 min, 10-80 AB, MS ESI calculated value C16H14F6N5O2 [M+H]+ 422.1, experimental value 422.2.

[0272] [Example]

[67] [:] [6-[5-] [fluorine] [-6-(2,2,2-] [Trifluoride] [-1,1-] [Dimethyl] [-] [Ethoxy] [)-3-] [Pyridyl] []-3-(] [Methoxymethyl] [)-7-] [methyl] [-[1,2,4]] [Triazo] [[4,3-, b , ]] [Tarazine] [ ] A mixture of 6-chloro-3-(methoxymethyl)-7-methyl-[1,2,4]triazolo[4,3-b]pyrazine (80 mg, 0.38 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborpinecyclo-2-yl)-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)pyridine (197.03 mg, 0.56 mmol), K3PO4 (159.74 mg, 0.75 mmol) and Pd(t-Bu3P)2 (28.84 mg, 0.06 mmol) in 1,4-dioxane (5 mL) and H2O (0.5 mL) was stirred at 80 °C under N2 for 3 hours. After cooling to 25°C, the mixture was filtered through diatomaceous earth and the filtrate was concentrated. Water (20 mL) was added and the mixture was extracted with EtOAc (20 mL × 2). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by prep-HPLC (Waters XBridge BEH C18 (150 mm × 25 mm, 5 μm) A = H2O (0.075% NH4HCO3) and B = CH3CN; 50-60% B) within 9.5 min, yielding a solid product (21.64 mg, 0.05 mmol, 14% yield). [ 1 ] [H NMR] (400 MHz, CDCl3) δH = 8.15 (d, 1H), 8.00 (d, 1H), 7.62 (dd, 1H), 5.04 (s, 2H), 3.48 (s, 3H), 2.45 (s, 3H), 1.90 (s, 6H). Chromatography was performed in 2.0 min. [LCMS]Rt = 1.28 min, 10-80AB, MS ESI calculated value C17H18F4N5O2 [M+H]+ 400.1, experimental value 400.1.

[0273] [Example]

[68] [:] [6-[5-] [fluorine] [-6-[(1S)-2,2,2-] [Trifluoride] [-1-] [methyl] [-] [Ethoxy] []-3-] [Pyridyl] []-3-(] [Methoxymethyl] [)-7-] [methyl] [-[1,2,4]] [Triazo] [[4,3-, b , ]] [Tarazine] A mixture of 6-chloro-3-(methoxymethyl)-7-methyl-[1,2,4]triazolo[4,3-b]pyrazine (70 mg, 0.33 mmol), 3-fluoro-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridine (132.38 mg, 0.40 mmol), K3PO4 (139.78 mg, 0.66 mmol) and Pd(t-Bu3P)2 (25.24 mg, 0.05 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was stirred at 80 °C under N2 for 3 hours. After cooling to 25°C, the mixture was filtered through diatomaceous earth and the filtrate was concentrated. Water (20 mL) was added and the aqueous layer was extracted with EtOAc (20 mL × 2). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was purified by rapid chromatography on silica gel (EtOAc in PE = 10% to 20%) to produce a solid product (33.02 mg, 0.09 mmol, 26% yield). [ 1 ] [H NMR] (400MHz, CDCl3) δH = 8.16 (d, 1H), 8.00 (d, 1H), 7.65 (dd, 1H), 5.96 - 5.86 (m, 1H), 5.04 (s, 2H), 3.49 (s, 3H), 2.46 (s, 3H), 1.61 (d, 3H). [LCMS] In 2.0 min chromatography, Rt = 1.24 min, 10-80 AB, MS ESI calculated value C16H16F4N5O2 [M+H]+ 386.1, experimental value 385.9.

[0274] [Example]

[69] [:] [6-[5-] [fluorine] [-6-(2,2,2-] [Trifluoroethoxy] [)-3-] [Pyridyl] []-3-(] [Methoxymethyl] [)-7-] [methyl] [-[1,2,4]] [Triazo] [[4,3-, b , ]] [Tarazine] [ ] [A105] [Synthesis:] The corresponding pinacol ester was dissolved in MeCN and an aqueous HCl solution was added. The mixture was stirred at room temperature for 2 hours and then concentrated to produce A105, which was used crudely. [Compound]

[71] [Synthesis:] 6-chloro-3-(methoxymethyl)-7-methyl-[1,2,4]triazolo[4,3-b]pyrazine (70 mg, 0.33 mmol), [5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl] A mixture of acid (94.39 mg, 0.40 mmol), K3PO4 (139.78 mg, 0.66 mmol), and Pd(t-Bu3P)2 (25.24 mg, 0.05 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was stirred at 80 °C under N2 for 3 hours. After cooling to room temperature, the mixture was filtered through diatomaceous earth and the filtrate was concentrated. Water (20 mL) was added and the aqueous layer was extracted with EtOAc (20 mL × 2). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by prep-TLC (diatomaceous earth, EtOAc) to obtain a solid product (9.8 mg, 0.03 mmol, 8% yield). [ 1 ] [H NMR] (400MHz, CDCl3) δH = 8.17 (d, 1H), 8.01 (s, 1H), 7.68 (dd, 1H), 5.04 (s, 2H), 4.93 (q, 2H), 3.49 (s, 3H), 2.45 (s, 3H). [LCMS] In 2.0 min chromatography, Rt = 1.19 min, 10-80 AB, MS ESI calculated value C15H14F4N5O2 [M+H]+ 372.1, experimental value 372.0.

[0275] [Example]

[70] [:] [6-[5-] [fluorine] [-6-[(1R)-2,2,2-] [Trifluoride] [-1-] [methyl] [-] [Ethoxy] []-3-] [Pyridyl] []-3-(] [Methoxymethyl] [)-7-] [methyl] [-[1,2,4]] [Triazo] [[4,3-, b, ]] [Tarazine] [A104] [Synthesis:] 2-Methoxyacetyl chloride (2737.12 mg, 25.22 mmol) was added to a solution of (6-chloro-5-methyl-pyrazin-3-yl)hydrazine and (6-chloro-4-methyl-pyrazin-3-yl)hydrazine (2 g, 12.61 mol) in toluene (30 mL) at 25 °C. The mixture was heated to 120 °C and stirred for 16 hours. After cooling to room temperature, the mixture was concentrated, and the residue was diluted with H2O (30 mL). The mixture was extracted with EtOAc (50 mL × 2). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified three times by rapid silica gel chromatography (EtOAc) to produce a solid. [A104] (250 mg, 1.17 mmol, 9% yield) and [A104-2] (500 mg, 2.35 mmol, 19% yield). [ 1 ] [H NMR] (400MHz, CDCl3) δH = 7.94 (d, 1H), 5.02 (s, 2H), 3.50 (s, 3H), 2.51 (s, 3H). [Compound]

[72] [Synthesis] A mixture of 6-chloro-3-(methoxymethyl)-7-methyl-[1,2,4]triazolo[4,3-b]pyrazine (60 mg, 0.28 mmol), 3-fluoro-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborpine-2-yl)pyridine (113.47 mg, 0.34 mmol), K3PO4 (119.81 mg, 0.56 mmol), and Pd(t-Bu3P)2 (21.63 mg, 0.04 mmol) in 1,4-dioxane (5 mL) and H2O (0.5 mL) was stirred at 80 °C under N2 for 1 hour. After cooling to room temperature, the mixture was filtered through diatomaceous earth and the filtrate was concentrated. Water (20 mL) was added and the mixture was extracted with EtOAc (20 mL × 2). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by prep-TLC (silicone, EtOAc) to yield a solid product (23.22 mg, 59.2 µmol, 21% yield). [ 1 ] [H NMR] (400MHz, CDCl3) δH = 8.16 (d, 1H), 8.01 (s, 1H), 7.65 (dd, 1H), 5.96 - 5.85 (m, 1H), 5.04 (s, 2H), 3.49 (s, 3H), 2.45 (s, 3H), 1.61 (d, 3H). [LCMS] In 2.0 min chromatography, Rt = 1.24 min, 10-80 AB, MS ESI calculated value C16H16F4N5O2 [M+H]+ 386.1, experimental value 386.1.

[0276] [Example]

[71] [:] [3-(] [Difluoride] [(] [Methoxy] [)] [methyl] [)-6-(6-(3,3-] [Difluorocyclobutoxy] [)] [Pyridine] [-3-] [base] [)-[1,2,4]] [Triazo] [[4,3-, a , ]] [Pyrazine] [ ] [A107] [Synthesis:] Water (3.0 mL) and Cs₂CO₃ (2.73 g, 8.37 mmol) were added to a stirred solution of 6-chloro-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyrazine (1.0 g, 4.18 mmol) and 2-(3,3-difluorocyclobutoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborpinecyclo-2-yl)pyridine (1.43 g, 4.6 mmol) in 1,4-dioxane (27.0 mL). Pd(dppf)Cl₂·DCM (0.34 g, 0.42 mmol) was added to the reaction mixture under a nitrogen atmosphere and the mixture was heated at 80 °C for 16 hours. The reaction mixture was cooled to room temperature, filtered through diatomaceous earth, and concentrated under reduced pressure. The crude product was purified by column chromatography on silicone with 25% ethyl acetate / PE to obtain the product (430 mg, 1.11 mmol, 26% yield). [LCMS]: 388.1 (M+H), Rt 2.4 min, Column: ZORBAX XDB C-18 (50 X 4.6 mm), 3.5 µm, Mobile phase: A: 0.1% HCOOH in water: ACN (95:5), B: ACN; Flow rate: 1.5 mL / min. [ ] [Compound]

[73] [Synthesis] [:] Cs₂CO₃ (515 mg, 1.58 mmol) and methanol (0.21 mL, 5.2 mmol) were added to a stirred solution of 3-(chlorodifluoromethyl)-6-(6-(3,3-difluorocyclobutoxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine (100 mg, 0.26 mmol) in MeCN (4.5 mL). The reaction mixture was stirred for 1 h at room temperature. The reaction mixture was treated with water (20.0 mL) and extracted with ethyl acetate (2 × 20 mL). The organic layer was washed with brine (15 mL), dried over anhydrous Na₂SO₄ and concentrated. The crude compound was purified by preparative HPLC to give a solid (32 mg, 0.08 mmol, 32% yield). Prep-HPLC method: Rt = 16.1; column: XBridge C8 (150 X 19 mm), 5.0 µm; mobile phase: 0.1% TFA / acetonitrile in water; flow rate: 15.0 mL / min. [HPLC]: Rt 4.49 min, column: XBridge C8 (50 X 4.6) mm, 3.5 µm, mobile phase: A: 0.1% TFA in water, B: 0.1% TFA in ACN; flow rate: 2.0 mL / min. [LCMS: ]384.1 (M+H), Rt 2.22 min, Column: ZORBAX XDB C-18 (50 X 4.6 mm), 3.5 µm, Mobile phase: A: 0.1% HCOOH in water: ACN (95:5), B: ACN; Flow rate: 1.5 mL / min. [ 1 ] [H NMR](400 MHz, CD3OD): []δ 9.54 (d, 1H), 8.86 (d, 1H), 8.78 (s, 1H), 8.39 (dd, 1H), 6.99 (d, 1H), 5.25-5.22 (m, 1H), 3.99 (s, 3H), 3.23-3.13 (m, 2H), 2.82-2.70 (m, 2H).

[0277] [Example]

[72] [:] [3-(] [Cyclopropoxydifluoromethyl] [)-6-(6-(2,2,2-] [Trifluoroethoxy] [)] [Pyridine] [-3-] [base] [)-[1,2,4]] [Triazo] [[4,3-, a , ]] [Pyrazine] [ ] Synthesis of A109: NaH (60%, in mineral oil, 1.25 g, 31.25 mmol) was added aliquots into a stirred solution of 2,2,2-trifluoroethanol (3.12 g, 31.25 mmol) in THF (25 mL) at 0 °C. The reaction mixture was slowly heated to room temperature and stirred for 15 min. 5-Bromo-2-fluoropyridine (5.0 g, 28.41 mmol) was added dropwise to the reaction mixture and stirred for 2 h. The reaction mixture was cooled to 10 °C and treated with ice water (50 mL). The reaction mixture was extracted with ethyl acetate (2 × 60 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na₂SO₄, and concentrated. The crude compound was purified by column chromatography on silicone rubber containing 5% ethyl acetate / PE to give the product (5.0 g, 19.5 mmol, 68% yield). [LCMS:] 256.0 (M+H) and 258 (M+2+H), Rt 2.59 min, column: ZORBAX XDB C-18 (50 X 4.6 mm), 3.5 µm, mobile phase: A: 0.1% HCOOH in water: ACN (95:5), B: ACN; flow rate: 1.5 mL / min. [ ] [A110] [Synthesis:] Potassium acetate (3.83 g, 39.0 mmol) was added to a stirred solution of 5-bromo-2-(2,2,2-trifluoroethoxy)pyridine (5.0 g, 19.53 mmol) and bis(pinacol)diboron (6.45 g, 25.39 mmol) in 1,4-dioxane (50.0 mL). Pd(dppf)Cl2·DCM (1.59 g, 1.95 mmol) was added to the reaction mixture under a nitrogen atmosphere, and the mixture was heated at 80 °C for 12 hours. The reaction mixture was cooled to room temperature, filtered through diatomaceous earth, and concentrated under reduced pressure. The crude compound was purified by column chromatography on silica gel containing 5% ethyl acetate / PE to give the product (4.32 g, 14.3 mmol, 73% yield). [LCMS: ]304.1 (M+H), Rt 2.85 min, Column: ZORBAX XDB C-18 (50 X 4.6 mm), 3.5 µm, Mobile phase: A: 0.1% HCOOH in water: ACN (95:5), B: ACN; Flow rate: 1.5 mL / min. [ ] [A112] [Synthesis:] Water (2.5 mL) and Cs₂CO₃ (3.22 g, 9.9 mmol) were added to a stirred solution of 6-chloro-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyrazine (1.3 g, 5.44 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (1.5 g, 4.95 mmol) in 1,4-dioxane (25.0 mL). Pd(dppf)Cl₂·DCM (0.4 g, 0.49 mmol) was added to the reaction mixture under a nitrogen atmosphere and the mixture was heated at 80 °C for 12 hours. The reaction mixture was cooled to room temperature, filtered through diatomaceous earth, and concentrated under reduced pressure. The crude product was purified by column chromatography on silicone with 30% ethyl acetate / PE to obtain the product (500 mg, 1.3 mmol, 26% yield). [LCMS]: 380.0 (M+H), Rt 2.45 min, column: ZORBAX XDB C-18 (50 X 4.6 mm), 3.5 µm, mobile phase: A: 0.1% HCOOH in water: ACN (95:5), B: ACN; flow rate: 1.5 mL / min. [ ] [Compound]

[74] [Synthesis:] Cs₂CO₃ (514 mg, 1.58 mmol) and cyclopropanol (0.21 mL, 3.29 mmol) were added to a stirred solution of 3-(chlorodifluoromethyl)-6-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine (100 mg, 0.26 mmol) in MeCN (10 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was treated with water (15.0 mL) and extracted with ethyl acetate (2 × 20 mL). The organic layer was washed with brine (15 mL), dried over anhydrous Na₂SO₄, and concentrated. The crude compound was purified by preparative HPLC to give a solid (10 mg, 0.024 mmol, 9% yield). Prep-HPLC method: Rt = 14.2; column: XBridge C8 (150 X 19 mm), 5.0 µm; mobile phase: 0.1% TFA / acetonitrile in water; flow rate: 15.0 mL / min. [HPLC]: Rt 5.01 min, column: XBridge C8 (50 X 4.6) mm, 3.5 µm, mobile phase: A: 0.1% TFA in water, B: 0.1% TFA in ACN; flow rate: 2.0 mL / min. [LCMS]: 402.1 (M+H), Rt 2.30 min, Column: XBridge C8 (50 X 4.6 mm), 3.5 µm, Mobile phase: A: 0.1% TFA in water : ACN (95:5), B: 0.1% TFA in ACN; Flow rate: 1.5 mL / min [。] [ 1 ] [H NMR] (400 MHz, CD3OD): δ 9.55 (d, 1H), 8.89 (d, 1H), 8.75 (s, 1H), 8.43 (dd, 1H), 7.09 (d, 1H), 4.98 (q, 2H), 4.26-4.23 (m, 1H), 0.99 (m, 2H), 0.85-0.81 (m, 2H).

[0278] [Example]

[73] [:] [3-(] [Cyclopropoxydifluoromethyl] [)-6-(5-] [fluorine] [-6-(2,2,2-] [Trifluoroethoxy] [)] [Pyridine] [-3-] [base] [)-[1,2,4]] [Triazo] [[4,3-, a , ]] [Pyrazine] [ ] [A113] [Synthesis:] NaH (60%, in mineral oil, 2.26 g, 56.71 mmol) was added aliquots into a stirred solution of 2,2,2-trifluoroethanol (5.67 g, 56.71 mmol) in THF (200 mL) at 0 °C. The reaction mixture was stirred for 15 min and 5-bromo-2,3-difluoropyridine (10.0 g, 51.55 mmol) was added dropwise. The reaction mixture was slowly heated to room temperature and stirred for 2 h. The reaction mixture was cooled to 10 °C and treated with ice water (100 mL). The reaction mixture was extracted with ethyl acetate (2 × 100 mL). The organic layer was washed with brine (80 mL), dried over anhydrous Na₂SO₄, and concentrated. The crude compound was purified by column chromatography on silicone with 2% ethyl acetate / PE to give the product (10.5 g, 38.1 mmol, 73% yield). [LCMS]: 273.9 (M+H) and 276.0 (M+2+H), Rt 2.53 min, column: ZORBAX XDB C-18 (50 X 4.6 mm), 3.5 µm, mobile phase: A: 0.1% HCOOH in water: ACN (95:5), B: ACN; flow rate: 1.5 mL / min. [ ] [A3-a] [Synthesis:] Potassium acetate (2.15 g, 21.9 mmol) was added to a stirred solution of 5-bromo-3-fluoro-2-(2,2,2-trifluoroethoxy)pyridine (3.0 g, 10.95 mmol) and bis(pinacol)diboron (3.61 g, 14.23 mmol) in 1,4-dioxane (30.0 mL). Pd(dppf)Cl2·DCM (0.89 g, 1.09 mmol) was added to the reaction mixture under a nitrogen atmosphere, and the mixture was heated at 80 °C for 12 h. The reaction mixture was cooled to room temperature, filtered through diatomaceous earth, and concentrated under reduced pressure. The crude compound was purified by column chromatography on silica gel containing 15% ethyl acetate / PE to give the product (2.0 g, 6.2 mmol, 56% yield). [LCMS]: 322.1 (M+H), Rt 2.97 min, column: Atlantis dC18 (50 X 4.6 mm), 5 µm, mobile phase: A: 0.1% HCOOH in water: ACN (95:5), B: ACN; flow rate: 1.5 mL / min. [ ] [A18-a] [Synthesis:] Water (4.0 mL) and K₂CO₃ (2.31 g, 16.74 mmol) were added to a stirred solution of 6-chloro-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyrazine (2.0 g, 8.37 mmol) and 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (2.96 g, 9.2 mmol) in 1,4-dioxane (26.0 mL). PdCl₂(PPh₃)₂ (0.59 g, 0.84 mmol) was added to the reaction mixture under a nitrogen atmosphere and the mixture was heated at 90 °C for 12 hours. The reaction mixture was cooled to room temperature, filtered through diatomaceous earth, and concentrated under reduced pressure. The crude product was purified by column chromatography using 30% ethyl acetate / PE silicone tubing to obtain the product (1.35 g, 3.4 mmol, 40% yield). [LCMS]: 398.0 (M+H), Rt 2.51 min, column: Atlantis dC-18 (50 X 4.6 mm), 3.5 µm, mobile phase: A: 0.1% HCOOH in water: ACN (95:5), B: ACN; flow rate: 1.5 mL / min. ¹H NMR (400 MHz, DMSO-d6): δ 9.77 (d, ¹H), 9.14 (s, ¹H), 8.84 (d, ¹H), 8.66 (dd, ¹H), 5.20 (q, 2H). [Compound]

[75] [Synthesis:] Cs₂CO₃ (737 mg, 2.26 mmol) and cyclopropanol (0.48 mL, 7.54 mmol) were added to a stirred solution of 3-(chlorodifluoromethyl)-6-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine (150.0 mg, 0.38 mmol) in MeCN (8.0 mL). The reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was treated with water (15.0 mL) and extracted with ethyl acetate (2 × 20 mL). The organic layer was washed with brine (15 mL), dried over anhydrous Na₂SO₄, and concentrated. The crude compound was purified by preparative HPLC to give a solid (15 mg, 0.035 mmol, 9% yield). Preparative HPLC method: Rt 14.8; Column: XBridge C-18 (150 X 19 mm), 5.0 µm; Mobile phase: 0.1% TFA in water / acetonitrile; Flow rate: 15.0 mL / min. [HPLC]: Rt 5.16 min, column: XBridge C8 (50 X 4.6) mm, 3.5 µm, mobile phase: A: 0.1% TFA in water, B: 0.1% TFA in ACN; flow rate: 2.0 mL / min. [LCMS]: 420.0 (M+H), Rt 2.64 min, column: Atlantis dC18 (50 X 4.6 mm), 3.5 µm, mobile phase: A: 0.1% HCOOH in water, B: ACN; flow rate: 1.5 mL / min. [ 1 ] [H NMR ](400 MHz, DMSO-d6): δ 9.71 (d, 1H), 8.93 (d, 1H), 8.78 (d, 1H), 8.56 (dd, 1H), 5.19 (q, 2H), 4.24-4.20 (m, 1H), 0.96-0.92 (m, 2H), 0.77-0.72 (m, 2H).

[0279] [Example]

[74] [:] [3-(] [Difluoride] [(] [Methoxy] [)] [methyl] [)-6-(6-(3,3-] [Difluorocyclobutoxy] [)-5-] [Fluoropyridine] [-3-] [base] [)-[1,2,4]] [Triazo] [[4,3-, a , ]] [Pyrazine] [ ] [A115] [Synthesis:] Chlorodifluoroacetic anhydride (6.54 mL, 37.39 mmol) was added to a stirred solution of 2-chloro-5-hydrazinopyrazine (5.0 g, 33.99 mmol) in toluene (50 mL) at 0 °C. The reaction mixture was heated at 110 °C for 1 hour. The reaction mixture was cooled to room temperature and concentrated. The crude reaction mixture was treated with water (50 mL) and extracted with ethyl acetate (2 × 50 mL). The organic layer was washed with brine (30 mL), dried over Na₂SO₄, and concentrated to a solid (6 g). This solid was used in the next step without further purification. [A111] [Synthesis:] Trifluoromethanesulfonic anhydride (4.73 mL, 28.01 mmol) and 2-methoxypyridine (4.91 mL, 46.69 mmol) were added to a stirred solution of 2-chloro-N'-(5-chloropyrazin-2-yl)-2,2-difluoroacetylhydrazine (6.0 mg, 23.34 mmol) in DCM (120 mL) at 0 °C. The reaction mixture was slowly heated to room temperature and stirred for 2 hours. The reaction mixture was treated with 10% sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (2 × 50 mL). The organic layer was washed with brine (50 mL), dried over Na2SO4, and concentrated. The crude product was purified by column chromatography on silicone with 15% EtOAc / PE to give a solid product (4.0 g, 16.5 mmol, 71% yield). [LCMS]: 239.0 (M+H), Rt 1.66 min, column: ZORBAX XDB C-18 (50 X 4.6 mm), 3.5 µm, mobile phase: A: 0.1% HCOOH in water: ACN (95:5), B: ACN; flow rate: 1.5 mL / min. [ ] [A116] [Synthesis:] NaH (60%, in mineral oil, 204 mg, 5.09 mmol) was added aliquots to a stirred solution of 3,3-difluorocyclobutanol (500 mg, 4.63 mmol) in THF (10 mL) at 0 °C. The reaction mixture was slowly heated to room temperature and stirred for 15 min. Then, 5-bromo-2,3-difluoropyridine (0.9 g, 4.63 mmol) was added dropwise to the reaction mixture and stirred for 4 h. The reaction mixture was cooled to 10 °C and treated with ice water (30 mL). The reaction mixture was extracted with ethyl acetate (2 × 30 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na₂SO₄, and concentrated. The crude compound was purified by column chromatography on silicone with 10% ethyl acetate / PE to give the product (1.0 g, 3.57 mmol, 77% yield). [LCMS]: 282.0 (M+H) and 284.0 (M+2+H), Rt 2.66 min, column: ZORBAX XDB C-18 (50 X 4.6 mm), 3.5 µm, mobile phase: A: 0.1% HCOOH in water: ACN (95:5), B: ACN; flow rate: 1.5 mL / min. [ ] [A117] [Synthesis:] Potassium acetate (0.77 g, 7.83 mmol) was added to a stirred solution of 5-bromo-2-(3,3-difluorocyclobutoxy)-3-fluoropyridine (1.1 g, 3.91 mmol) and bis(pinacol)diboron (1.29 g, 5.09 mmol) in 1,4-dioxane (20.0 mL). Pd(dppf)Cl2·DCM (0.32 g, 0.39 mmol) was added to the reaction mixture under a nitrogen atmosphere, and the mixture was heated at 90 °C for 16 h. The reaction mixture was cooled to room temperature, filtered through diatomaceous earth, and concentrated under reduced pressure. The crude compound was purified by column chromatography on silica gel containing 5% ethyl acetate / PE to give the product (1.2 g, 3.6 mmol, 93% yield). [LCMS]: 330.1 (M+H), Rt 2.97 min, column: ZORBAX XDB C-18 (50 X 4.6 mm), 3.5 µm, mobile phase: A: 0.1% HCOOH in water: ACN (95:5), B: ACN; flow rate: 1.5 mL / min. [ ] [A118] [Synthesis:] Water (3.0 mL) and Cs₂CO₃ (2.31 g, 7.13 mmol) were added to a stirred solution of 6-chloro-3-(chlorodifluoromethyl)-[1,2,4]triazolo[4,3-a]pyrazine (0.91 g, 3.83 mmol) and 2-(3,3-difluorocyclobutoxy)-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborpinecyclo-2-yl)pyridine (1.17 g, 3.55 mmol) in 1,4-dioxane (15.0 mL). Pd(dppf)Cl₂·DCM (0.29 g, 0.36 mmol) was added to the reaction mixture under a nitrogen atmosphere, and the mixture was heated at 80 °C for 8 hours. The reaction mixture was cooled to room temperature, filtered through diatomaceous earth, and concentrated under reduced pressure. The crude product was purified by column chromatography on silicone with 30% ethyl acetate / PE to obtain the product (1.11 g, 2.75 mmol, 77% yield). [LCMS]: 405.9 (M+H), Rt 2.30 min, column: ZORBAX XDB C-18 (50 X 4.6 mm), 3.5 µm, mobile phase: A: 0.1% HCOOH in water: ACN (95:5), B: ACN; flow rate: 1.5 mL / min. [ ] [Compound]

[76] [Synthesis:] Cs₂CO₃ (668 mg, 2.06 mmol) and methanol (0.14 mL, 3.4 mmol) were added to a stirred solution of 3-(chlorodifluoromethyl)-6-(6-(3,3-difluorocyclobutoxy)-5-fluoropyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine (140 mg, 0.34 mmol) in MeCN (7.5 mL). The reaction mixture was stirred for 1 h at room temperature. The reaction mixture was treated with water (20.0 mL) and extracted with ethyl acetate (2 × 20 mL). The organic layer was washed with brine (15 mL), dried over anhydrous Na₂SO₄, and concentrated. The crude compound was purified by preparative HPLC to give a solid (18 mg, 0.04 mmol, 13% yield). Prep. HPLC method: Rt 12.9; column: YMC Phenyl (150 X 19 mm), 5.0 µm; mobile phase: 0.1% TFA / acetonitrile in water; flow rate: 15.0 mL / min. [HPLC]: Rt 5.01 min, 97.3%, Column: XBridge C8 (50 X 4.6) mm, 3.5 µm, Mobile phase: A: 0.1% TFA in water, B: 0.1% TFA in ACN; Flow rate: 2.0 mL / min. [LCMS]: 402.0 (M+H), Rt 2.48 min, column: Atlantis dC18 (50 X 4.6 mm), 5.0 µm, mobile phase: A: 0.1% HCOOH in water: ACN (95:5), B: ACN; flow rate: 1.5 mL / min. [ 1 ] [H NMR] (400 MHz, DMSO-d6): δ 9.70 (d, 1H), 8.97 (s, 1H), 8.77 (d, 1H), 8.49 (dd, 1H), 5.30-5.26 (m, 1H), 3.92 (s, 3H), 3.26-3.19 (m, 2H), 2.89-2.84 (m, 2H).

[0280] [Example]

[75] [:] [6-(6-(3,3-] [Difluorocyclobutoxy] [)-5-] [Fluoropyridine] [-3-] [base] [)-3-(] [Ethoxydifluoromethyl] [)-[1,2,4]] [Triazo] [[4,3-, a , ]] [Pyrazine] Cs₂CO₃ (668 mg, 2.06 mmol) and ethanol (0.2 mL, 3.4 mmol) were added to a stirred solution of 3-(chlorodifluoromethyl)-6-(6-(3,3-difluorocyclobutoxy)-5-fluoropyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine (150 mg, 0.34 mmol) in MeCN (7.5 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was treated with water (20.0 mL) and extracted with ethyl acetate (2 × 25 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na₂SO₄, and concentrated. The crude compound was purified by preparative HPLC to give a solid (22 mg, 0.05 mmol, 15% yield). Prep. HPLC method: Rt 13.1; column: XBridge C-18 (150 X 19 mm), 5.0 µm; mobile phase: 0.1% TFA / acetonitrile in water; flow rate: 15.0 mL / min. [HPLC]: Rt 5.08 min, 94.8%, column: XBridge C8 (50 X 4.6) mm, 3.5 µm, mobile phase: A: 0.1% TFA in water, B: 0.1% TFA in ACN; flow rate: 2.0 mL / min. [LCMS]: 416.1 (M+H), Rt 2.44 min, column: ZORBAX XDB C-18 (50 X 4.6 mm), 3.5 µm, mobile phase: A: 0.1% HCOOH in water: ACN (95:5), B: ACN; flow rate: 1.5 mL / min. [ 1 ] [H NMR] (400 MHz, CD3OD): δ 9.54 (d, 1H), 8.83 (d, 1H), 8.67 (d, 1H), 8.26 (dd, 1H), 5.32-5.30 (m, 1H), 4.40 (q, 2H), 3.25-3.15 (m, 2H), 2.90-2.77 (m, 2H), 1.49 (t, 3H).

[0281] [Example]

[76] [:] [3-(] [Cyclopropoxydifluoromethyl] [)-6-(6-(3,3-] [Difluorocyclobutoxy] [)] [Pyridine] [-3-] [base] [)-[1,2,4]] [Triazo] [[4,3-, a , ]] [Pyrazine] [ ] Cs₂CO₃ (504 mg, 1.55 mmol) and cyclopropanol (0.33 mL, 5.16 mmol) were added to a stirred solution of 3-(chlorodifluoromethyl)-6-(6-(3,3-difluorocyclobutoxy)-5-fluoropyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine (100 mg, 0.26 mmol) in MeCN (9.0 mL). The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was treated with water (20.0 mL) and extracted with ethyl acetate (2 × 20 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na₂SO₄, and concentrated. The crude compound was purified by preparative HPLC to give a solid (14 mg, 0.034 mmol, 13% yield). Prep. HPLC method: Rt 10.67; column: Sunfire C-18 (150 X 19 mm), 5.0 µm; mobile phase: 0.1% TFA / acetonitrile in water; flow rate: 15.0 mL / min. [HPLC]: Rt 5.19 min, column: XBridge C8 (50 X 4.6) mm, 3.5 µm, mobile phase: A: 0.1% TFA in water, B: 0.1% TFA in ACN; flow rate: 2.0 mL / min. [LCMS]: 410.1 (M+H), Rt 2.36 min, column: XBridge C8 (50 X 4.6 mm), 3.5 µm, mobile phase: A: 0.1% TFA in water : ACN (95:5), B: 0.1% TFA in ACN; flow rate: 1.5 mL / min. [ 1 ] [H NMR] (400 MHz, CD3OD): δ 9.54 (d, 1H), 8.84 (d, 1H), 8.71 (s, 1H), 8.37 (dd, 1H), 7.00 (d, 1H), 5.25 (m, 1H), 4.26-4.23 (m, 1H), 3.23-3.13 (m, 2H), 2.82-2.70 (m, 2H), 0.99 (m, 2H), 0.84-0.79 (m, 2H).

[0282] [Example]

[77] [:] [3-(] [Ethoxymethyl] [)-6-(5-] [fluorine] [-6-((1,1,1-] [Trifluoride] [-2-] [Methylpropionyl] [-2-] [base] [)] [Oxygen group] [)] [Pyridine] [-3-] [base] [)-[1,2,4]] [Triazo] [[4,3-, a , ]] [Pyrazine] [ ] [A119] [Synthesis:] NaH (60%, in mineral oil, 0.23 g, 5.67 mmol) was added aliquots to a stirred solution of 1,1,1-trifluoro-2-methylprop-2-ol (0.57 g, 4.43 mmol) in THF (20 mL) at 0 °C. The reaction mixture was slowly heated to room temperature and stirred for 15 min. 5-Bromo-2,3-difluoropyridine (1.0 g, 5.16 mmol) was added dropwise to the reaction mixture and stirred for 16 h. The reaction mixture was cooled to 10 °C and treated with ice water (30 mL). The reaction mixture was extracted with ethyl acetate (2 × 50 mL). The organic layer was washed with brine (30 mL), dried over anhydrous Na₂SO₄, and concentrated. The crude compound was purified by column chromatography on silicone with 2% ethyl acetate / PE to give the product (765 mg, 2.54 mmol, 49% yield). [ 1 ] [H NMR] (400 MHz, CDCl3): δ 7.99 (d, 1H), 7.54 (dd, 1H), 1.80 (s, 6H). [A8] [Synthesis:] Potassium acetate (497 mg, 5.07 mmol) was added to a stirred solution of 5-bromo-3-fluoro-2-((1,1,1-trifluoro-2-methylprop-2-yl)oxy)pyridine (765 mg, 2.54 mmol) and bis(pinacol)diboron (0.71 g, 2.79 mmol) in 1,4-dioxane (20.0 mL). Pd(dppf)Cl2·DCM (0.21 g, 0.25 mmol) was added to the reaction mixture under a nitrogen atmosphere, and the mixture was heated at 80 °C for 16 hours. The reaction mixture was cooled to room temperature, filtered through diatomaceous earth, and concentrated under reduced pressure. The crude compound was purified by column chromatography on silica gel containing 30% ethyl acetate / PE to give the product (300 mg, 0.86 mmol, 33% yield). [LCMS]: 350.1 (M+H), Rt 3.31 min, Column: Atlantis dC18 (50 X 4.6 mm), 3.5 µm, Mobile phase: A: 0.1% HCOOH in water: ACN (95:5), B: ACN; Flow rate: 1.5 mL / min. [ ] [A120] [Synthesis:] Et3N (3.78 mL, 27.07 mmol) was added to a stirred solution of (5-chloropyrazine-2-yl)hydrazine (2.0 g, 13.53 mmol) in DCM (15 mL) at 0 °C, followed by the addition of 2-ethoxyacetyl chloride (2.36 mL, 13.53 mmol). The reaction mixture was slowly heated to room temperature and stirred for 16 hours. The reaction mixture was treated with a saturated ammonium chloride solution (25 mL) and extracted with ethyl acetate (2 × 25 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4, and concentrated. The crude product was purified by column chromatography on silicone with 22% EtOAc / PE to give the product (0.8 g, 3.47 mmol, 25% yield). [LCMS]: 231.1 (M+H), Rt 1.07 min, column: ZORBAX XDB C-18 (50 X 4.6 mm), 3.5 µm, mobile phase: A: 0.1% HCOOH in water: ACN (95:5), B: ACN; flow rate: 1.5 mL / min. [ ] [A41-a] [Synthesis:] Trifluoromethanesulfonic anhydride (0.38 mL, 2.25 mmol) and 2-methoxypyridine (377 mg, 3.46 mmol) were added to a stirred solution of N'-(5-chloropyrazin-2-yl)-2-ethoxyacetylhydrazine (400 mg, 1.73 mmol) in DCM (15.0 mL) at 0 °C. The reaction mixture was slowly heated to room temperature and stirred for 16 hours. The reaction mixture was treated with 10% sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (2 × 25 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4, and concentrated. The crude product was purified by column chromatography on silicone with 35% EtOAc / PE to give the product (100 mg, 0.47 mmol, 27% yield). [LCMS]: 213.1 (M+H), Rt 1.46 min; Column: Atlantis dC18 (50 X 4.6 mm), 5.0 µm; Mobile phase: A: 0.1% HCOOH in water: ACN (95:5), B: ACN; Flow rate: 1.5 mL / min. [ ] [Compound]

[79] [Synthesis:] Water (1.0 mL) and Cs₂CO₃ (460 mg, 1.41 mmol) were added to a stirred solution of 6-chloro-3-(ethoxymethyl)-[1,2,4]triazolo[4,3-a]pyrazine (150 mg, 0.71 mmol) and 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborpinecyclo-2-yl)-2-((1,1,1-trifluoro-2-methylprop-2-yl)oxy)pyridine (271 mg, 0.78 mmol) in 1,4-dioxane (10.0 mL). Pd(dppf)Cl₂·DCM (57 mg, 0.07 mmol) was added to the reaction mixture under a nitrogen atmosphere, and the mixture was heated at 80 °C for 16 hours. The reaction mixture was cooled to room temperature, filtered through diatomaceous earth, and concentrated under reduced pressure. The crude compound was purified by preparative HPLC to obtain a solid (105 mg, 0.26 mmol, 36% yield). Prep. HPLC method: Rt 12.75; column: X-Select (150 x 19 mm), 5.0 µm; mobile phase: 0.1% TFA / acetonitrile in water; flow rate: 15.0 mL / min. [HPLC]: Rt 4.95 min, column: XBridge C8 (50 X 4.6) mm, 3.5 µm, mobile phase: A: 0.1% TFA in water, B: 0.1% TFA in ACN; flow rate: 2.0 mL / min. [LCMS]: 400.3 (M+H), Rt 2.41 min, column: ZORBAX XDB C-18 (50 X 4.6 mm), 3.5 µm, mobile phase: A: 0.1% HCOOH in water: ACN (95:5), B: ACN; flow rate: 1.5 mL / min. [ 1 ] [H NMR] (400 MHz, DMSO-d6): δ 9.56 (d, 1H), 9.17 (d, 1H), 8.78 (d, 1H), 8.45 (dd, 1H), 5.09 (s, 2H), 3.61 (q, 2H), 1.83 (s, 6H), 1.15 (t, 3H).

[0283] [Example]

[79] [:] [3-(] [Ethoxydifluoromethyl] [)-6-(6-(2,2,2-] [Trifluoroethoxy] [)] [Pyridine] [-3-] [base] [)-[1,2,4]] [Triazo] [[4,3-, a , ]] [Pyrazine] [ ] Cs₂CO₃ (978 mg, 3.0 mmol) and ethanol (0.58 mL, 10 mmol) were added to a stirred solution of 3-(chlorodifluoromethyl)-6-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine (190 mg, 0.50 mmol) in MeCN (10.0 mL) and stirred for 3 hours. The reaction mixture was treated with water (15 mL) and extracted with ethyl acetate (2 × 20 mL). The organic layer was washed with brine (15 mL), dried over anhydrous Na₂SO₄, and concentrated. The crude compound was purified by preparative HPLC to give a solid (10 mg, 0.025 mmol, 5.1% yield). Prep-HPLC method: Rt 9.35; column: XBridge (150 X 19 mm), 5.0 µm; 0.1% TFA / acetonitrile in water; flow rate: 15.0 mL / min. [HPLC]: Rt 4.89 min, column: XBridge C8 (50 X 4.6) mm, 3.5 µm, mobile phase: A: 0.1% TFA in water, B: 0.1% TFA in ACN; flow rate: 2.0 mL / min. [LCMS]: 390.0 (M+H), Rt 2.70 min, Column: Atlantis dC-18 (50 X 4.6 mm), 5 µm, Mobile phase: A: 0.1% HCOOH in water: ACN (95:5), B: ACN; Flow rate: 1.5 mL / min. [ 1 ] [H NMR] (400 MHz, CDCl3): δ 9.54 (d, 1H), 8.74 (d, 1H), 8.48 (d, 1H), 8.26 (dd, 1H), 7.06 (d, 1H), 4.87 (q, 2H), 4.38 (q, 2H), 1.52 (t, 3H).

[0284] [Example]

[80] [:] [3-(] [Difluoride] [(] [Isobutyroxy] [)] [methyl] [)-6-(5-] [fluorine] [-6-(2,2,2-] [Trifluoroethoxy] [)] [Pyridine] [-3-] [base] [)-[1,2,4]] [Triazo] [[4,3-, a , ]] [Pyrazine] [ ] Cs₂CO₃ (4.92 g, 15.09 mmol) was added to a stirred solution of 2-methylprop-1-ol (4.65 mL, 50.29 mmol) in MeCN (20 mL), and the reaction mixture was heated at 70 °C for 20 min. The reaction mixture was cooled to room temperature, and 3-(chlorodifluoromethyl)-6-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine (1.0 g, 2.51 mmol) was added. The reaction mixture was stirred at room temperature for 4 h and treated with water (30 mL). The reaction mixture was extracted with ethyl acetate (2 × 30 mL), washed with brine (20 mL), dried over Na₂SO₄, and concentrated. The crude compound was purified by preparative HPLC to give a solid (35 mg, 0.08 mmol, 3% yield). Prep-HPLC method: Rt 9.37; column: XBridge C8 (150 X 19 mm), 5.0 µm; 0.1% TFA / acetonitrile in water; flow rate: 15.0 mL / min. [HPLC]: Rt 5.60 min, column: XBridge C8 (50 X 4.6) mm, 3.5 µm, mobile phase: A: 0.1% TFA in water, B: 0.1% TFA in ACN; flow rate: 2.0 mL / min. [LCMS]: 436.1 (M+H), Rt 2.63 min, column: XBridge C8 (50 X 4.6 mm), 3.5 µm, mobile phase: A: 0.1% TFA in water : ACN (95:5), B: 0.1% TFA in ACN; flow rate: 1.5 mL / min. [ 1 ] [H NMR] (400 MHz, DMSO-d6): δ 9.72 (d, 1H), 8.97 (d, 1H), 8.77 (d, 1H), 8.54 (dd, 1H), 5.19 (q, 2H), 4.04 (d, 2H), 2.10-2.02 (m, 1H), 0.98 (d, 6H). [ ]

[0285] [Example]

[81] [:] [5-[3-[] [Difluoride] [(] [Methoxy] [)] [methyl] []-[1,2,4]] [Triazo] [[4,3-, a , ]] [Pyrazine] [-6-] [base] []] [Pyridine] [-2-] [alcohol] [and] [6-(6-)] [Benzyloxy] [-5-] [fluorine] [-3-] [Pyridyl] [)-3-[] [Ethoxy] [(] [Difluoride] [)] [methyl] []-[1,2,4]] [Triazo] [[4,3-, a , ]] [Pyrazine] [ ] [A92] [Synthesis:] NaH (4.88 g, 122.06 mmol) was added fractionally to a solution of phenylmethanol (12 g, 110.97 mmol) in THF (100 mL) at 0 °C for 0.5 h. After addition, the mixture was stirred at 20 °C for 1 h. Then, 5-bromo-2-fluoropyridine (18.55 g, 105.42 mmol) was added to the mixture. The resulting mixture was stirred at 20 °C for 3 h. The mixture was poured into a saturated aqueous NH4 solution (150 mL) and extracted with EtOAc (200 mL × 2). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated to produce an oily crude product (27 g, 95.62 mmol, 86% yield). [LCMS] In 1.5 min chromatography, Rt = 0.96 min, 5-95 AB, MS ESI calculated value C12H11BrNO[M+H+2]+ 266.0, experimental value 265.8. [A93] [Synthesis:] A mixture of 2-benzyloxy-5-bromopyridine (27 g, 102.23 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborpine-2-yl)-1,3,2-dioxaborpine (31.15 g, 122.67 mmol), KOAc (20.06 g, 204.45 mmol), and Pd(dppf)Cl2 (7.48 g, 10.22 mmol) in 300 mL of 1,4-dioxane was stirred at 90 °C under N2 for 16 hours. After cooling to room temperature, the mixture was filtered through diatomaceous earth and concentrated to produce a crude product. The crude product was filtered through silicone (approximately 50 g) and dissolved in PE / EtOAc (5:1, 150 mL × 5), and the filtrate was concentrated to produce an impure product. The impure product was then ground with i-Pr₂O (100 mL) to produce a solid product (20 g, 64.27 mmol, 63% yield). [LCMS] In 1.5 min chromatography, Rt = 0.74 min, 5-95 AB, MS ESI calculated value C12H13BNO3[M-C6H10+H]+ 230.1, experimental value 230.0. [A94] [Synthesis:] A mixture of 2-bromo-5-chloropyrazine (4 g, 20.68 mmol), 2-benzyloxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborpine-2-yl)pyridine (7.08 g, 22.75 mmol), Cs₂CO₃ (13.47 g, 41.36 mmol), and Pd(dppf)Cl₂ (1.51 g, 2.07 mmol) in 1,4-dioxane (50 mL) and water (10 mL) was stirred at 50 °C under N₂ for 3 hours. After cooling to room temperature, the mixture was filtered and concentrated to obtain a residue. Water (100 mL) was added to the residue, and the mixture was extracted with EtOAc (150 mL × 2). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain a crude product. The crude product was filtered through silica gel (approximately 50 g) and dissolved using DCM (150 mL × 3). The filtrate was concentrated, resulting in an impure product. The impure product was ground with i-Pr₂O (15 mL) to produce a solid product (4 g, 13.44 mmol, 65% yield). [LCMS] In 1.5 min chromatography, Rt = 1.03 min, 5-95 AB, MS ESI calculated value C16H13ClN3O [M+H]+ 298.1, experimental value 297.9. [A95] [Synthesis:] A mixture of 2-(6-benzyloxy-3-pyridyl)-5-chloropyrazine (4 g, 13.43 mmol) and N2H4·H2O (8.61 g) in MeCN (20 mL) was stirred at 90 °C for 16 hours. After cooling to room temperature, the solution was concentrated to produce a residue. Water (30 mL) was added to the residue, and the mixture was extracted with EtOAc (50 mL × 3). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated to produce a solid product (4 g, 7.84 mmol, 58% yield). [LCMS] In 1.5 min chromatography, Rt = 0.74 min, 5-95 AB, MS ESI calculated value C16H16N5O [M+H]+ 294.1, experimental value 293.9. [A96] [Synthesis:] To a solution of 2-bromo-2,2-difluoroacetyl chloride (1.78 g, 9.2 mmol) in DCM (20 mL), [5-(6-benzyloxy-3-pyridinyl)pyrazin-2-yl]hydrazine (1.8 g, 6.14 mmol) was added, and the suspension was stirred at 20 °C for 2 hours. The mixture was diluted with H₂O (20 mL) and extracted with EtOAc (100 mL × 2). The combined organic phases were washed with brine (30 mL), dried over Na₂SO₄, filtered, and concentrated to yield the product. The crude product was purified by rapid chromatography on silica gel (EtOAc in PE = 20% to 40% to 60% to 80%) to yield a solid product (1.5 g, 3.33 mmol, 54% yield). [LCMS] In 1.5 min chromatography, Rt = 0.88 min, 10-80 AB, MS ESI calculated value C18H15F2N5O2 [M+H]+ 450.0, experimental value 449.9. [A97] [Synthesis] [:] A mixture of N'-[5-(6-benzyloxy-3-pyridinyl)pyrazin-2-yl]-2-bromo-2,2-difluoro-acetylhydrazine (1.3 g, 2.89 mmol) in DCM (10 mL) was mixed with 2-methoxypyridine (0.67 mL, 6.35 mmol) and Tf₂O (0.59 mL, 3.46 mmol), and the mixture was stirred at 20 °C for 2 hours. Water (20 mL) was added to the mixture, and it was extracted with DCM (50 mL...

Claims

1. A compound of formula (Ib) or a pharmaceutically acceptable salt thereof; wherein X and Y are each CRd; R1 is a monocyclic C3-6 cycloalkyl group, or a 4- to 7-membered monocyclic heterocyclic group, wherein such cycloalkyl and heterocyclic groups are unsubstituted or substituted by one or more Ra; R2 is a C1-4 haloalkyl group, phenyl group, or a monocyclic C3-6 cycloalkyl group, which are unsubstituted or substituted by one or more Rb; R3 is hydrogen, C1-4 alkyl, or C1-4 haloalkyl; R4 is hydrogen or C1-4 alkyl; R5 is a halogroup; R6 is a C1-4 alkyl or C1-4 haloalkyl group, wherein such C1-4 alkyl or C1-4 haloalkyl groups are each substituted by ORc; Ra and Rb are each independently selected from halogroup, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy. Rc refers to unsubstituted or C1-4 alkyl or C3-6 cycloalkyl or C1-4 alkoxy-substituted C1-4 alkyl; and Rd refers to hydrogen or C1-4 alkyl.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula III: ; wherein such variables are as defined in claim 1.

3. A compound or a pharmaceutically acceptable salt thereof, as claimed in claim 1 or 2, wherein the compound has the formula IX: ; wherein such variables are as defined in claim 1.

4. The compound of claim 1 or 2 or its pharmaceutically acceptable salt, wherein R1 is a series.

5. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R1 is a cyclobutyl group, wherein the cyclobutyl group is unsubstituted or substituted by one or more Ra groups.

6. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R2 is a C1-4 haloalkyl group.

7. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R2 is CF3.

8. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R2 is phenyl.

9. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R3 is a C1-4 alkyl group and R4 is hydrogen or a C1-4 alkyl group.

10. The compound of claim 1 or 2 or its pharmaceutically acceptable salt, wherein R3 and R4 are each C1-4 alkyl.

11. The compound of claim 1 or 2 or its pharmaceutically acceptable salt, wherein R3 and R4 are each methyl.

12. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R3 is methyl and R4 is hydrogen.

13. The compound of claim 1 or 2 or its pharmaceutically acceptable salt, wherein R3 and R4 are each hydrogen atoms.

14. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R6 is -CF2-ORc.

15. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein Rc is a C1-4 alkyl group, wherein the C1-4 alkyl group is unsubstituted or cyclopropyl substituted.

16. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein Rc is cyclopropyl.

17. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R6 is -C(F2)OCH2CH(CH3)2, -C(F2)OCH3, -C(F2)OCH2CH3, -C(F2)OCH(CH3)2 or -C(F2)OCH2C3H5.

18. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R6 is -CH2-ORc.

19. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein Rc is a C1-4 alkyl group.

20. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R6 is -CH2OCH3, -CH2OCH2CH3 or -CH2OCH2CH(CH3)2.

21. The compound of claim 1 or 2 or its pharmaceutically acceptable salt, wherein Ra is a C1-4 haloalkyl group.

22. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein Ra is CF3.

23. The compound of claim 1 or 2 or its pharmaceutically acceptable salt, wherein Ra is a fluorine compound.

24. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein Rd is a methyl group.

25. The compound of claim 1 or 2 or its pharmaceutically acceptable salt, wherein Rd is hydrogen.

26. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , and.

27. The compound of claim 26 or a pharmaceutically acceptable salt thereof, wherein the compound is: .

28. The compound of claim 27 or a pharmaceutically acceptable salt thereof, wherein the compound is a crystalline compound, wherein the crystalline compound is characterized by an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 12.6±0.2, 15.8±0.2 and 18.6±0.

2.

29. The compound of claim 28 or a pharmaceutically acceptable salt thereof, wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 10.7±0.2, 12.3±0.2, 12.6±0.2, 15.8±0.2, 18.6±0.2 and 22.6±0.

2.

30. The compound of claim 28 or 29 or a pharmaceutically acceptable salt thereof, wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 10.7±0.2, 12.3±0.2, 12.6±0.2, 14.9±0.2, 15.8±0.2, 16.6±0.2, 16.8±0.2, 18.6±0.2, 21.0±0.2 and 22.6±0.

2.

31. The compound of claim 28 or 29 or a pharmaceutically acceptable salt thereof, wherein the crystalline compound exhibits an X-ray powder diffraction pattern substantially the same as that shown in FIG5A.

32. The compound of claim 28 or 29 or a pharmaceutically acceptable salt thereof, wherein the crystalline compound has a melting initiation point of about 107°C, as determined by differential scanning calorimetry.

33. The compound of claim 28 or 29 or a pharmaceutically acceptable salt thereof, wherein the crystalline compound has a differential scanning calorimetry curve substantially the same as that shown in Figure 5B.

34. The compound of claim 28 or 29 or its pharmaceutically acceptable salt, wherein the X-ray powder diffraction pattern is obtained using Cu Kα radiation.

35. A pharmaceutical composition comprising a compound of any one of claims 1 to 34 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

36. A composition comprising a compound of any one of claims 1 to 34 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 35, for treating a condition in an individual related to abnormal function of sodium ion channels.

37. The composition or pharmaceutical composition of claim 36, wherein the condition is a neurological or psychiatric disorder.

38. The composition or pharmaceutical composition of claim 36, wherein the condition is epilepsy or epileptic syndrome.

39. The composition or pharmaceutical composition of claim 38, wherein the condition is hereditary epilepsy or hereditary epilepsy syndrome.

40. The composition or pharmaceutical composition of claim 38, wherein the condition is childhood epilepsy or childhood epilepsy syndrome.

41. The composition or pharmaceutical composition of claim 38, wherein the condition is epileptic encephalopathy.

42. The composition or pharmaceutical composition of claim 41, wherein the epileptic encephalopathy is selected from the group consisting of: Dravet syndrome, infantile spasms, or Lennox-Gastaut syndrome.

43. The composition or pharmaceutical composition of claim 38, wherein the epilepsy involves generalized epileptic seizures.

44. The composition or pharmaceutical composition of claim 38, wherein the epilepsy involves focal or localized seizures.

45. The composition or pharmaceutical composition of claim 44, wherein the epilepsy involves focal epileptic seizures.

46. ​​The composition or pharmaceutical composition of claim 38, wherein the epilepsy is a focal epilepsy with an SCN3A mutation.

47. The composition or pharmaceutical composition of claim 36, wherein the condition is pain.

48. The composition or pharmaceutical composition of claim 47, wherein the pain is neuropathic pain.

49. The composition or pharmaceutical composition of claim 36, wherein the condition is headache.

50. The composition or pharmaceutical composition of claim 36, wherein the condition is migraine.

51. The composition or pharmaceutical composition of claim 36, wherein the condition is trigeminal neuralgia.

52. The composition or pharmaceutical composition of claim 36, wherein the system is human.

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