Ion Channel Modulators

Abstract

To provide ion channel modulators.SOLUTION: The present invention is directed to, in part, fused heteroaryl compounds and compositions useful for preventing and / or treating a disease or condition relating to an aberrant function of a voltage-gated sodium ion channel, e.g., abnormal late / persistent sodium current. Methods of treating a disease or condition relating to an aberrant function of a sodium ion channel including neurological disorders (e.g., Dravet syndrome, epilepsy), pain, and neuromuscular disorders are also provided herein.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Patent Application No. 62 / 677,903, filed May 30, 2018, and U.S. Provisional Patent Application No. 62 / 738,508, filed September 28, 2018, each of which is incorporated by reference herein in its entirety. [Background technology]

[0002] Sodium ion (Na+) channels primarily open in a transient manner and are rapidly inactivated, thereby generating a fast Na+ current for initiating action potentials. Late or persistent sodium current (INaL) is a persistent component of the fast Na+ current in cardiomyocytes and neurons. Many common neurological and cardiac conditions are associated with abnormal INaL enhancement, contributing to the pathogenesis of both electrical and contractile dysfunction in mammals (see, e.g., Pharmacol Ther (2008) 119:326-339). Therefore, pharmaceutical compounds that selectively modulate sodium channel activity, such as abnormal INaL, are useful for treating such conditions. [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] Pharmacol Ther(2008)119:326-339 Summary of the Invention [Means for solving the problem]

[0004] Described herein are fused heteroaryl compounds and compositions useful for preventing and / or treating diseases, disorders, or conditions, e.g., diseases, disorders, or conditions associated with abnormal sodium ion channel function, e.g., abnormal late sodium current (INaL). In one aspect, the disclosure features a compound of Formula (I): In one aspect, the present invention provides a compound having formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein: X and Y each independently represent CR d or N, R 1 teeth, [ka] , monocyclic C cycloalkyl, or 4- to 7-membered monocyclic heterocyclyl, wherein the cycloalkyl and heterocyclyl are optionally selected from one or more R a is replaced by R 2 is C haloalkyl, phenyl, or optionally one or more R b is a monocyclic C3-6 cycloalkyl substituted with R 3 is hydrogen, C1-4 alkyl, or C1-4 haloalkyl; R 4 is hydrogen or C1-4 alkyl, R 5 is a halo, R 6 is C1-4 alkyl or C1-4 haloalkyl, and said C1-4 alkyl or C1-4 haloalkyl is each c is replaced by t is 0, 1, or 2; R a and R b are each independently selected from halo, C alkyl, C haloalkyl, C alkoxy, and C haloalkoxy; Rc is optionally C cycloalkyl or C 1-4 C1-4 alkyl or C3-6 cycloalkyl substituted with alkoxy; R d is hydrogen or C1-4 alkyl, provided that the compound has the formula: [ka] or a pharmaceutically acceptable salt thereof.

[0005] In some embodiments, the compound is of formula Ia: [ka] or a pharmaceutically acceptable salt thereof, in which the variables are as defined herein.

[0006] In some embodiments, the compound is of formula Ib: [ka] or a pharmaceutically acceptable salt thereof, in which the variables are as defined herein.

[0007] In some embodiments, the compound is of formula II: [ka] or a pharmaceutically acceptable salt thereof, in which the variables are as defined herein.

[0008] In some embodiments, the compound is of formula III: [ka] or a pharmaceutically acceptable salt thereof, in which the variables are as defined herein.

[0009] In some embodiments, the compound is of formula Ic: [ka] or a pharmaceutically acceptable salt thereof, in which the variables are as defined herein.

[0010] In another aspect, the present disclosure provides a compound having formula Id: [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 teeth, [ka] , monocyclic C cycloalkyl, or 4- to 7-membered monocyclic heterocyclyl, wherein the cycloalkyl and heterocyclyl are optionally selected from one or more R a is replaced by R 2 is C haloalkyl, phenyl, or optionally one or more R b is a monocyclic C3-6 cycloalkyl substituted with R 3 is hydrogen, C1-4 alkyl, or C1-4 haloalkyl; R 4 is hydrogen or C1-4 alkyl, R 5 is a halo, R 6 is C1-4 alkyl or C1-4 haloalkyl, and said C1-4 alkyl or C1-4 haloalkyl is each c is replaced by t is 0, 1, or 2; R a and R b are each independently selected from halo, C alkyl, C haloalkyl, C alkoxy, and C haloalkoxy; R c is optionally C cycloalkyl or C 1-4C1-4 alkyl or C3-6 cycloalkyl substituted with alkoxy; R d is hydrogen or C1-4 alkyl.

[0011] In some embodiments, the compound is of formula V: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0012] In some embodiments, the compound is of formula VII: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0013] In some embodiments, the compound is of formula VIII: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0014] In some embodiments, the compound is of formula VIII: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0015] In another aspect, provided herein is a crystalline compound of the formula: [ka] 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.

[0016] In another aspect, provided herein is a crystalline compound of the formula: [ka] 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.

[0017] In another aspect, the present invention provides a crystalline compound of the formula: [ka] 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.

[0018] In another aspect, the disclosure provides a crystalline compound of the formula: [ka] 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.

[0019] In another aspect, the present invention provides a crystalline compound of the formula: [ka] 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.

[0020] In another aspect, the present invention provides a crystalline compound of the formula: [ka] 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.

[0021] In another aspect, the present invention provides a crystalline compound of the formula: [ka] 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.

[0022] In another aspect, the present invention provides a crystalline compound of the formula: [ka] 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.

[0023] In another aspect, the disclosure provides a crystalline compound of the formula: [ka] 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.

[0024] In another aspect, provided herein is a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0025] In another aspect of the present disclosure, there is provided a composition comprising 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, and a pharmaceutically acceptable carrier.

[0026] Also provided herein is a pharmaceutical composition comprising 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, and a pharmaceutically acceptable carrier, for use in medicine.

[0027] In another aspect, provided herein is a method of treating a condition associated with abnormal function of a sodium ion channel in a subject, comprising administering to the subject 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.

[0028] In some embodiments, the condition is a neurological or psychiatric disorder. In some embodiments, the condition is epilepsy or an epilepsy syndrome. In some embodiments, the condition is genetic epilepsy or a genetic epilepsy syndrome. In some embodiments, the condition is childhood epilepsy or a childhood epilepsy syndrome. In some embodiments, the condition is epileptic encephalopathy. In some embodiments, the epileptic encephalopathy is selected from the group consisting of Dravet syndrome, infantile spasms, and Lennox-Gastaut syndrome.

[0029] 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, Dravet syndrome, Dravet syndrome with SCN1A mutations, generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile convulsions, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutations, childhood partial epilepsy of unknown cause with SCN3A mutations, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussen encephalitis, malignant migratory partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, sudden expected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy.

[0030] In another aspect, provided herein is a method for treating a neurological or psychiatric disorder, The method includes administering to a subject in need thereof 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] In another aspect, the present invention provides a method of treating pain, the method comprising administering to a subject in need thereof 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.

[0032] The present disclosure also provides 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 pharmaceutical composition disclosed herein, or a composition comprising a composition disclosed herein for treating a condition associated with abnormal function of a sodium ion channel in a subject.

[0033] In some embodiments, the condition is a neurological or psychiatric disorder. In some embodiments, the condition is pain. In some embodiments, the condition is epilepsy or an epilepsy syndrome. In some embodiments, the condition is genetic epilepsy or a genetic epilepsy syndrome. In some embodiments, the condition is childhood epilepsy or a childhood epilepsy syndrome. In some embodiments, the condition is epileptic encephalopathy. In some embodiments, the epileptic encephalopathy is selected from the group consisting of Dravet syndrome, infantile spasms, and Lennox-Gastaut syndrome.

[0034] 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, Dravet syndrome, Dravet syndrome with SCN1A mutations, generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile convulsions, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutations, childhood partial epilepsy of unknown cause with SCN3A mutations, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussen encephalitis, malignant migratory partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, sudden expected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy.

[0035] In another aspect, the present disclosure provides a composition comprising 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, a pharmaceutical composition disclosed herein, or a composition disclosed herein for treating a neurological or psychiatric disorder.

[0036] Other objects and advantages will become apparent to those skilled in the art from consideration of the subsequent detailed description, examples, and claims. [Brief explanation of the drawings]

[0037] [Figure 1] (Figure 1A) shows the XRPD pattern of raw compound 10. (Figure 1B) shows the DSC pattern of compound 10. [Figure 2] (Figure 2A) XRPD pattern of raw compound 62. (Figure 2B) DSC pattern of compound 62. [Figure 3] (Figure 3A) XRPD pattern of raw compound 6B. (Figure 3B) DSC pattern of compound 6B. [Figure 4] (Figure 4A) XRPD pattern of raw compound 56. (Figure 4B) DSC pattern of compound 56. [Figure 5] (Figure 5A) shows the XRPD pattern of raw compound 3. (Figure 5B) shows the DSC pattern of compound 3. [Figure 6] (Figure 6A) shows the XRPD pattern of raw compound 11. (Figure 6B) shows the DSC pattern of compound 11. [Figure 7] (Figure 7A) XRPD pattern of raw compound 53. (Figure 7B) DSC pattern of compound 53. [Figure 8] (Figure 8A) shows the XRPD pattern of raw compound 59. (Figure 8B) shows the DSC pattern of compound 59. [Figure 9] (Figure 9A) XRPD pattern of raw compound 48. (Figure 9B) DSC pattern of compound 48. DETAILED DESCRIPTION OF THE INVENTION

[0038] As described herein, the present invention provides compounds and compositions useful for preventing and / or treating a disease, disorder, or condition described herein, e.g., a disease, disorder, or condition associated with abnormal function of a sodium ion channel, such as abnormal late sodium current (INaL). Exemplary diseases, disorders, or conditions include neurological disorders (e.g., epilepsy or epilepsy syndromes, neurodevelopmental disorders, or neuromuscular disorders), psychiatric disorders, pain, or gastrointestinal disorders.

[0039] definition chemical definition Definitions of specific functional groups and chemical terms are detailed below. Chemical elements are listed in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Ed., and specific functional groups are generally defined as described herein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivities, are described in detail in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5 th 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, 3 rd Edition, Cambridge University Press, Cambridge, 1987.

[0040] The compounds described herein may contain one or more asymmetric centers and therefore can exist in various isomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts, or preferred isomers can be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, NY). ork, 1981), Wilen et al., Tetrahedron 33:2725(1977), Eliel, Stereochemistry of Carbon See, for example, "Compounds" (McGraw-Hill, NY, 1962), and "Wilen, Tables of Resolving Agents and Optical Resolutions" p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present invention additionally encompasses the compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0041] As used herein, a pure enantiomer compound is substantially free of other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, the "S" form of a compound is substantially free of the "R" form of the compound and is thus in enantiomeric excess of the "R" form. The terms "enantiomerically pure" or "pure enantiomer" mean that a compound contains more than 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 98.5%, 99%, 99.2%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% by weight of an enantiomer. In certain embodiments, the weight is based on the total weight of all enantiomers or stereoisomers of the compound.

[0042] In the compositions provided herein, the enantiomerically pure compound may be present together with other active or inactive ingredients. For example, a pharmaceutical composition containing an enantiomerically pure R compound may contain, for example, about 90% excipients and about 10% enantiomerically pure R compound. In certain embodiments, the enantiomerically pure R compound in such a composition may contain, for example, at least about 95% by weight of the R compound and at most about 5% by weight of the S compound, based on the total weight of the compound. For example, a pharmaceutical composition containing an enantiomerically pure S compound may contain, for example, about 90% excipients and about 10% of the enantiomerically pure S compound. In certain embodiments, the enantiomerically pure S compound in such a composition may contain, for example, at least about 95% by weight of the S compound and at most about 5% by weight of the R compound, based on the total weight of the compound. In certain embodiments, the active ingredient may be formulated with little or no excipients or carriers.

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

[0044] The following terms are intended to have the meanings presented below and are useful in understanding the description and intended scope of the present invention. In describing the present invention, which may include compounds and pharmaceutically acceptable salts thereof, pharmaceutical compositions containing such compounds, and methods of using such compounds and compositions, the following terms, when present, have the following meanings unless otherwise indicated. As described herein, it is also understood that any of the moieties defined below may be substituted with various substituents, and that each definition is intended to include such substituted moieties within their scope as set forth below. Unless otherwise indicated, the term "substituted" is defined as set forth below. It is further understood that the terms "group" and "radical" can be considered interchangeable as used herein. The articles "a" and "an" can be used to refer to one or to more than one (i.e., at least one) of the grammatical object of the article. By way of example, an "analog" is , means one analog or two or more analogs.

[0045] When a range of values ​​is listed, it is intended to encompass each value and subrange within the range. For example, "C 1-6 "Alkyl" refers to C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C3-4 , C 4-6 , C 4-5 , and C 5-6 It is intended to include alkyl.

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

[0047] As used herein, "alkenyl" refers to the radical of 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 optionally one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds) ("C2-20 In certain embodiments, the alkenyl does not contain any triple bonds. In some embodiments, the alkenyl group has 2 to 10 carbon atoms ("C 2-10 In some embodiments, an alkenyl group has 2 to 9 carbon atoms ("C 2-9 In some embodiments, an alkenyl group has 2 to 8 carbon atoms ("C 2-8 In some embodiments, an alkenyl group has 2 to 7 carbon atoms ("C 2-7 In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C 2-6 In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C 2-5 In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C 2-4 In some embodiments, the alkenyl group has 2 to 3 carbon atoms ("C 2-3 In some embodiments, the alkenyl group has two carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (such as 2-butenyl) or terminal (such as 1-butenyl). C 2-4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. 2-6 Examples of alkenyl groups include the aforementioned C 2-4 Alkenyl groups also include pentenyl (C5), pentadienyl (C5), hexenyl (C6), etc. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), etc.

[0048] As used herein, "alkynyl" refers to an alkyl 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 optionally one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds). refers to the radical of a linear or branched hydrocarbon group containing a double bond ("C 2-20 In certain embodiments, alkynyl does not contain any double bonds. In some embodiments, alkynyl groups have 2 to 10 carbon atoms ("C 2-10 In some embodiments, an alkynyl group has 2 to 9 carbon atoms ("C 2-9 In some embodiments, an alkynyl group has 2 to 8 carbon atoms ("C 2-8 In some embodiments, an alkynyl group has 2 to 7 carbon atoms ("C 2-7 In some embodiments, an alkynyl group has 2 to 6 carbon atoms ("C 2-6 In some embodiments, an alkynyl group has 2 to 5 carbon atoms ("C 2-5 In some embodiments, an alkynyl group has 2 to 4 carbon atoms ("C 2-4 In some embodiments, an alkynyl group has 2 to 3 carbon atoms ("C 2-3 In some embodiments, the alkynyl group has two carbon atoms ("C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). C 2-4 Examples of alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. 2-6 Examples of alkenyl groups include the aforementioned C 2-4 Alkynyl groups also include pentynyl (C5), hexynyl (C6), etc. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), etc.

[0049] As used herein, "alkylene," "alkenylene," and "alkynylene" refer to the divalent radical of an alkyl, alkenyl, and alkynyl group, respectively. When a range or number of carbons is provided for a particular "alkylene," "alkenylene," or "alkynylene" group, it is understood that the range or number refers to the range or number of carbons in a linear divalent chain of carbons. "Alkylene," "alkenylene," and "alkynylene" groups can be substituted or unsubstituted with one or more substituents as described herein.

[0050] As used herein, "aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic arrangement) having 6 to 14 ring carbon atoms and 0 heteroatoms provided in the aromatic ring system ("C 6-14 In some embodiments, an aryl group has 6 ring carbon atoms ("C aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 aryl"; e.g., naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms ("C 14"Aryl"; e.g., anthracyl). "Aryl" also includes ring systems in which the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups, and the radical or point of attachment is on the aryl ring; in such instances, the number of carbon atoms continues to designate the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Particular aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl.

[0051] As used herein, "heteroaryl" refers to the radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 electrons shared in a cyclic arrangement) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). "aryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be at a carbon or nitrogen atom, valence permitting. Heteroaryl bicyclic ring systems can contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups, and the point of attachment is on the heteroaryl ring; in such instances, the number of ring members continues to designate the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which the heteroaryl ring, as defined above, is fused with one or more aryl groups, and the point of attachment is on either the aryl or heteroaryl ring; in such instances, the number of ring members designates the number of ring members in the fused (aryl / heteroaryl) ring system. In bicyclic heteroaryl groups in which one ring does not contain heteroatoms (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be in either ring, i.e., either the ring with the heteroatom (e.g., 2-indolyl) or the ring without the heteroatom (e.g., 5-indolyl).

[0052] In some embodiments, a heteroaryl group is a 5- to 10-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In some embodiments, a heteroaryl group is a 5- to 8-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5- to 8-membered heteroaryl"). In some embodiments, a heteroaryl group is a 5- to 6-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5- to 6-membered heteroaryl"). In some embodiments, a 5- to 6-membered heteroaryl has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heteroaryl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0053] Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0054] Representative examples of heteroaryl include: [ka] where each Z is a carbonyl, N, NR 65 , O, and S; R 65 are independently hydrogen, C1-8 alkyl, C3- 10 Carbocyclyl, 4-10 membered heterocyclyl, C6-C 10aryl, and 5- to 10-membered heteroaryl.

[0055] As used herein, "carbocyclyl" or "carbocyclic" refers to a ring system having 3 to 10 ring carbon atoms ("C 3-10 "Carbocyclyl" refers to a radical of a non-aromatic cyclic hydrocarbon group having 3 to 8 ring carbon atoms ("C 3-8 In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms ("C 3-7 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3-6 In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5-10 carbocyclyl). Exemplary C 3-6 Carbocyclyl groups include, without limitation, cyclopropyl (C), cyclobutyl (C), cyclobutenyl (C), cyclopentyl (C), cyclopentenyl (C), cyclohexyl (C), cyclohexenyl (C), cyclohexadienyl (C), and the like. 3-8 The carbocyclyl group may be any of the above-mentioned C 3-6 Carbocyclyl groups, as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C 3-10 The carbocyclyl group may be any of the above-mentioned C 3-8 Carbocyclyl groups, as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10), and the like. As the foregoing examples illustrate, in certain embodiments, a carbocyclyl group is either monocyclic ("monocyclic carbocyclyl") or includes a fused, bridged, or spiro ring system, such as a bicyclic system ("bicyclic carbocyclyl"), and can be saturated or partially unsaturated. "Carbocyclyl" also includes ring systems in which the carbocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, and the point of attachment is on the carbocyclyl ring, and in such instances the number of carbons continues to designate 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 of 3 to 12, 3 to 8, 4 to 8, or 4 to 6 carbons, and is used herein to refer to, for example, "C" derived from a cycloalkane. 4-8 Exemplary cycloalkyl groups include, but are not limited to, cyclohexane, cyclopentane, cyclobutane, and cyclopropane.

[0057] As used herein, "C monocyclic cycloalkyl" or "monocyclic C cycloalkyl" refers to a saturated 3- to 7-membered monocyclic hydrocarbon ring system. 3- to 7-membered monocyclic cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. When specified as optionally substituted or substituted, the substituents on the cycloalkyl (e.g., in the case of an optionally substituted cycloalkyl) can be at any substitutable position, including, for example, the position to which the cycloalkyl group is attached.

[0058] As used herein, "heterocyclyl" or "heterocyclic" refers to the radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (a "3- to 10-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon or nitrogen atom, valence permitting. Heterocyclyl groups may be either monocyclic (a "monocyclic heterocyclyl") or fused, bridged, or spiro ring systems, such as bicyclic systems (a "bicyclic heterocyclyl"), and may be saturated or partially unsaturated. Heterocyclyl bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which the heterocyclyl ring defined above is fused to one or more carbocyclyl groups and the point of attachment is on either the carbocyclyl or heterocyclyl ring or ring system, or the heterocyclyl ring defined above is fused to one or more aryl or heteroaryl groups and the point of attachment is on the heterocyclyl ring, in such instances the number of ring members continues to designate the number of ring members in the heterocyclyl ring system. The terms "heterocycle," "heterocyclyl," "heterocyclyl ring," "heterocyclic group," "heterocyclic moiety," and "heterocyclic radical" may be used interchangeably.

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

[0060] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0061] Examples of saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, pyrrolidinyl, pyridinonyl, pyrrolidonyl, piperidinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, morpholinyl, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, oxetanyl, azetidinyl, and tetrahydropyrimidinyl. When specified as optionally substituted or substituted, substituents on the heterocyclyl (e.g., in the case of an optionally substituted heterocyclyl) can be located at any substitutable position, including, for example, the position at which the heterocyclyl group is attached.

[0062] "Hetero," when used to describe a compound or a group present in a compound, means that one or more carbon atoms in the compound or group have been replaced with a nitrogen, oxygen, or sulfur heteroatom. Hetero can apply to any of the above hydrocarbyl groups, such as alkyl, e.g., heteroalkyl; carbocyclyl, e.g., heterocyclyl; and aryl, e.g., heteroaryl, having 1 to 5, especially 1 to 3, heteroatoms.

[0063] As used herein, "cyano" refers to --CN.

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

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

[0066] A "haloalkoxy" is a haloalkyl group attached to another moiety through an oxygen atom, such as, for example, but not limited to, -OCHCF2 or -OCF3.

[0067] The term "haloalkyl" includes mono-, poly-, and perhaloalkyl groups substituted with one or more halogen atoms, where the halogens are independently selected from fluorine, chlorine, bromine, and iodine. For C1-4 haloalkyl-O-C1-4 alkyl, the point of attachment occurs on the halogenated alkyl portion.

[0068] As used herein, "nitro" refers to --NO.sub.2.

[0069] As used herein, "oxo" refers to -C=O.

[0070] In general, the term "substituted," whether preceded by the term "optionally," means that at least one hydrogen present on the group (e.g., a carbon or nitrogen atom) is replaced with an acceptable substituent, e.g., a substituent that, upon substitution, results in a stable compound, e.g., a compound that does not undergo spontaneous transformation by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position.

[0071] Nitrogen atoms can be substituted or unsubstituted where valence allows, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents are hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR bb )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(Rcc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5-14 membered heteroaryl, or two R cc The groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with R aa , R bb , R cc、 and R dd is as defined above.

[0072] These and other exemplary substituents are described in further detail in the detailed description, examples, and claims. The present invention is not intended to be limited in any way by the above exemplary list of substituents.

[0073] Other definitions As used herein, "pharmaceutically acceptable carrier" refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound in which it is formulated. Pharmaceutically acceptable carriers, adjuvants, or vehicles that can be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, saturated vegetable fatty acids such as glycine, sorbic acid, potassium sorbate, and protamine sulfate, water, partial glyceride mixtures of salts or electrolytes, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

[0074] As used herein, "pharmaceutically acceptable salts" refers to those salts which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts such as: and salts of amino groups formed with inorganic acids such as acetic acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate. , lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (C 1-4 Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates, where appropriate.

[0075] As used herein, a "subject" to which administration is contemplated includes, but is not limited to, humans (i.e., male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or an adult subject (e.g., young adult, middle-aged adult, or elderly adult)) and / or non-human animals, e.g., mammals such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0076] Disease, disorder, and condition are used interchangeably herein.

[0077] As used herein, unless otherwise specified, the terms "treat," "treating," and "treatment" contemplate actions that occur while a subject is afflicted with the specified disease, disorder, or condition and that reduce the severity of the disease, disorder, or condition or slow or delay the progression of the disease, disorder, or condition ("therapeutic treatment"), as well as actions that occur before a subject begins to suffer from the specified disease, disorder, or condition ("prophylactic treatment").

[0078] As used herein, the "effective amount" of a compound refers to an amount sufficient to induce a desired biological response.As will be understood by those skilled in the art, the effective amount of the compound of the present invention may 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 age, health, and condition of the subject.The effective amount encompasses both therapeutic and prophylactic treatment.

[0079] As used herein, and unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. A therapeutically effective amount of a compound means the amount of therapeutic agent alone, or in combination with other therapies, that provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" refers to the amount of therapeutic agent that provides an overall therapeutic benefit. It can encompass an amount that improves the therapeutic effect of another therapeutic agent, reduces or avoids the symptoms or etiology of a disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0080] compound In one aspect, the present invention provides a compound having formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein: X and Y each independently represent CR d or N, R 1 teeth, [ka] , monocyclic C cycloalkyl, or 4- to 7-membered monocyclic heterocyclyl, wherein the cycloalkyl and heterocyclyl are optionally selected from one or more R a is replaced by R 2 is C haloalkyl, phenyl, or optionally one or more R b is a monocyclic C3-6 cycloalkyl substituted with R 3 is hydrogen, C1-4 alkyl, or C1-4 haloalkyl; R 4 is hydrogen or C1-4 alkyl, R 5 is a halo, R 6 is C1-4 alkyl or C1-4 haloalkyl, and said C1-4 alkyl or C1-4 haloalkyl is eachc is replaced by t is 0, 1, or 2; R a and R b are each independently selected from halo, C alkyl, C haloalkyl, C alkoxy, and C haloalkoxy; R c is optionally C cycloalkyl or C 1-4 C1-4 alkyl or C3-6 cycloalkyl substituted with alkoxy; R d is hydrogen or C1-4 alkyl, provided that the compound has the formula: [ka] or a pharmaceutically acceptable salt thereof.

[0081] In one aspect, the present invention provides a compound having formula I': [ka] , or a pharmaceutically acceptable salt thereof, wherein: X and Y each independently represent CR d or N, R 1 teeth, [ka] monocyclic C cycloalkyl, or 4- to 7-membered monocyclic heterocyclyl, wherein the cycloalkyl and heterocyclyl are optionally each independently one or more R a is replaced by R 2 is C haloalkyl, phenyl, or optionally one or more R b is a monocyclic C3-6 cycloalkyl substituted with R 3 is hydrogen, C1-4 alkyl, or C1-4 haloalkyl; R 4is hydrogen or C1-4 alkyl, R 5 is a halo, R 6 is C1-4 alkyl or C1-4 haloalkyl, and said C1-4 alkyl or C1-4 haloalkyl is each c is replaced by t is 0, 1, or 2; R a and R b are each independently selected from halo, C alkyl, C haloalkyl, C alkoxy, and C haloalkoxy; R c is optionally C cycloalkyl or C 1-4 C1-4 alkyl or C3-6 cycloalkyl substituted with alkoxy; R d is hydrogen or C1-4 alkyl, or a pharmaceutically acceptable salt thereof.

[0082] In some embodiments, the compound has Formula Ia: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0083] In some embodiments, the compound has Formula Ib: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0084] In some embodiments, the compound has Formula II: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0085] In some embodiments, the compound has Formula III: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0086] In some embodiments, the compound has formula Ic: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0087] In another aspect, the present disclosure provides a compound having formula Id: [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 teeth, [ka] monocyclic C cycloalkyl, or 4- to 7-membered monocyclic heterocyclyl, wherein the cycloalkyl and heterocyclyl are optionally each independently one or more R a is replaced by R 2 is C haloalkyl, phenyl, or optionally one or more R b is a monocyclic C3-6 cycloalkyl substituted with R 3 is hydrogen, C1-4 alkyl, or C1-4 haloalkyl; R 4 is hydrogen or C1-4 alkyl, R 5 is a halo, R 6 is C1-4 alkyl or C1-4 haloalkyl, or C1-4 haloalkyl, each of which is OR c is replaced by t is 0, 1, or 2; R a and R b are each independently selected from halo, C alkyl, C haloalkyl, C alkoxy, and C haloalkoxy; R c is optionally C cycloalkyl or C 1-4 C1-4 alkyl or C3-6 cycloalkyl substituted with alkoxy; R d is hydrogen or C1-4 alkyl.

[0088] In some embodiments, the compound has Formula V: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0089] In some embodiments, the compound has Formula VII: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0090] In some embodiments, the compound has Formula VIII: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0091] In some embodiments, the compound has Formula VIII: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein. It is.

[0092] In some embodiments, R 1 teeth, [ka] is.

[0093] In some embodiments, R 1 optionally one or more R a and cyclobutyl substituted with .

[0094] In some embodiments, R 2 is C haloalkyl. In some embodiments, R 2 is CF. In some embodiments, R 2 is phenyl.

[0095] In some embodiments, R 3 is C1-4 alkyl, and R 4 is hydrogen or C alkyl. In some embodiments, R 3 and R 4 are each C alkyl. In some embodiments, R 3 and R 4 and each is methyl. In some embodiments, R 3 is methyl and R 4 is hydrogen. In some embodiments, R 3 and R 4 are each hydrogen.

[0096] In some embodiments, R 6 is -CF2-OR c is.

[0097] In some embodiments, R c is C alkyl optionally substituted with cyclopropyl. In some embodiments, R cis cyclopropyl.

[0098] In some embodiments, R 6 is -C(F2)OCH2CH(CH3)2, -C(F2)OCH3, -C(F2)OCH2CH3, -C(F2)OCH(CH3)2, or -C(F2)OCH2C3H5.

[0099] In some embodiments, R 6 is -CH2-OR c is.

[0100] In some embodiments, R c is C 1-4 It is alkyl.

[0101] In some embodiments, R 6 is -CH2OCH3, -CH2OCH2CH3, or -CH2OCH2CH(CH3)2.

[0102] In some embodiments, R a is C haloalkyl. In some embodiments, R a is CF. In some embodiments, R a is fluoro.

[0103] In some embodiments, t is 1. In some embodiments, t is 0.

[0104] In some embodiments, R d is methyl. In some embodiments, R d is hydrogen.

[0105] In some embodiments, the compound is [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0106] In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof.

[0107] In another aspect, the present invention provides a crystalline compound of the formula: [ka] 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.

[0108] 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, 13.9±0.2, 16.5±0.2, 19.5±0.2, and 20.8±0.2.

[0109] In some embodiments, the crystalline compound comprises 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. It exhibits an X-ray powder diffraction pattern.

[0110] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern substantially the same as that depicted in Figure 2A.

[0111] In some embodiments, the crystalline compound has a melting point onset as determined by differential scanning calorimetry at about 140°C.

[0112] In some embodiments, the crystalline compound has a differential scanning calorimetry curve substantially similar to that shown in Figure 2B.

[0113] In another aspect, provided herein is a crystalline compound of the formula: [ka] 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.

[0114] 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, 19.0±0.2, 20.4±0.2, and 25.7±0.2.

[0115] 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.

[0116] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern substantially similar to that depicted in Figure 3A.

[0117] In some embodiments, the crystalline compound has a melting point onset as determined by differential scanning calorimetry at about 68°C.

[0118] In some embodiments, the crystalline compound has a differential scanning calorimetry curve substantially similar to that shown in Figure 3B.

[0119] In another aspect, the present invention provides a crystalline compound of the formula: [ka] 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.

[0120] 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, 14.5±0.2, 17.9±0.2, 19.0±0.2, and 21.9±0.2.

[0121] 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.

[0122] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern substantially similar to that depicted in Figure 4A.

[0123] In some embodiments, the crystalline compound has a melting point onset as determined by differential scanning calorimetry at about 136°C.

[0124] In some embodiments, the crystalline compound has a differential scanning calorimetry curve substantially similar to that shown in Figure 4B.

[0125] In another aspect, provided herein is a crystalline compound of the formula: [ka] 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.

[0126] 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, 15.8±0.2, 18.6±0.2, and 22.6±0.2.

[0127] 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.

[0128] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern substantially similar to that depicted in Figure 5A.

[0129] In some embodiments, the crystalline compound has a melting point onset as determined by differential scanning calorimetry at about 107°C.

[0130] In some embodiments, the crystalline compound has a differential scanning calorimetry curve substantially similar to that shown in Figure 5B.

[0131] In another aspect, provided herein is a crystalline compound of the formula: [ka] 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.

[0132] 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, 14.5±0.2, 15.3±0.2, 19.7±0.2, 21.0±0.2, and 24.2±0.2.

[0133] 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.

[0134] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern substantially similar to that depicted in Figure 6A.

[0135] In some embodiments, the crystalline compound has a melting point onset as determined by differential scanning calorimetry at about 94°C.

[0136] In some embodiments, the crystalline compound has a differential scanning calorimetry curve substantially similar to that shown in Figure 6B.

[0137] In another aspect, the present invention provides a crystalline compound of the formula: [ka] 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.

[0138] 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, 13.8±0.2, 16.6±0.2, 18.4±0.2, 20.3±0.2, and 24.3±0.2.

[0139] 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.

[0140] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern substantially similar to that depicted in Figure 7A.

[0141] In some embodiments, the crystalline compound has a melting point onset as determined by differential scanning calorimetry at about 103°C.

[0142] In some embodiments, the crystalline compound has a differential scanning calorimetry curve substantially similar to that shown in Figure 7B.

[0143] In another aspect, the present invention provides a crystalline compound of the formula: [ka] 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.

[0144] 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, 16.4±0.2, 17.4±0.2, 18.0±0.2, 19.5±0.2, and 20.8±0.2.

[0145] 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, 13.6±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.

[0146] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern substantially the same as that depicted in Figure 8A.

[0147] In some embodiments, the crystalline compound has a melting point onset as determined by differential scanning calorimetry at about 133°C.

[0148] In some embodiments, the crystalline compound has a differential scanning calorimetry curve substantially similar to that shown in Figure 8B.

[0149] In another aspect, the disclosure provides a crystalline compound of the formula: [ka] 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.

[0150] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern comprising 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.

[0151] 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.

[0152] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern substantially similar to that depicted in Figure 9A.

[0153] In some embodiments, the crystalline compound has a melting point onset as determined by differential scanning calorimetry at about 111°C.

[0154] In some embodiments, the crystalline compound has a differential scanning calorimetry curve substantially similar to that shown in Figure 9B.

[0155] In another aspect, provided herein is a crystalline compound of the formula: [ka] 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.

[0156] 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, and 21.6±0.2.

[0157] 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.

[0158] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern substantially the same as that depicted in FIG. 1A.

[0159] In some embodiments, the crystalline compound has a melting point onset as determined by differential scanning calorimetry at about 122°C.

[0160] In some embodiments, the crystalline compound has a differential scanning calorimetry curve substantially similar to that shown in FIG. 1B.

[0161] In some embodiments, the X-ray powder diffraction pattern was obtained using Cu Kα radiation.

[0162] Pharmaceutical Compositions and Routes of Administration The compounds provided according to the present invention are usually administered in the form of a pharmaceutical composition. Accordingly, the present invention provides pharmaceutical compositions comprising, as an active ingredient, one or more of the described compounds, or pharmaceutically acceptable salts or esters thereof, and one or more pharmaceutically acceptable excipients, carriers, including sterile aqueous solutions and various organic solvents, inert solid diluents and fillers, including penetration enhancers, solubilizers, and adjuvants. Pharmaceutical compositions can be administered alone or in combination with other therapeutic agents. Such compositions are prepared in a manner well known in the pharmaceutical arts (see, e.g., Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985), and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G.S. Banker & Co.)). See CTRhodes, Eds.).

[0163] The pharmaceutical compositions may be administered in either single or multiple doses by any of the accepted mechanisms of administration for agents having similar utilities, for example, by rectal, buccal, intranasal and subcutaneous routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, as an inhalant, or via an impregnated or coated device such as, for example, a stent or an arterially inserted cylindrical polymer, as described in those patents and patent applications incorporated by reference.

[0164] One mode of administration is parenteral, particularly by injection. Forms in which the novel compositions of the present invention can be incorporated for administration by injection include aqueous or oily suspensions, or emulsions with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical vehicles. Aqueous solutions in saline can also be conventionally used for injection, but are less preferred in the context of the present invention. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils can also be used. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. Prevention of microbial action can be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

[0165] Sterile injectable solution can be prepared by incorporating the compound of the present invention in the required amount in a suitable solvent with various other components as mentioned above, and then optionally filter sterilization.Generally, dispersion is prepared by incorporating various sterilized active ingredients into a sterile vehicle that contains basic dispersion medium and other required components from the above.For the preparation of sterile powder for sterile injectable solution, the preferred method of preparation is vacuum drying and freeze-drying technique, which produces powder of active ingredient plus any additional desired component from its previously sterile-filtered solution.

[0166] Oral administration is another route for administering the compounds according to the present invention. Administration can be via capsules or enteric-coated tablets, etc. When preparing pharmaceutical compositions containing at least one compound described herein, the active ingredient is usually diluted with an excipient and / or enclosed in such a carrier, which can be in the form of a capsule, sachet, paper, or other container. When an excipient serves as a diluent, it can be a solid, semi-solid, or liquid material (as above) that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the composition can be in the form of a tablet, pill, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol (as a solid or in a liquid medium), for example, an ointment containing up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0167] Some examples of suitable excipients are lactose, dextrose, sucrose, sorbitol, The formulations include cellulose, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulations may additionally contain lubricants such as talc, magnesium stearate, and mineral oil, wetting agents, emulsifying and suspending agents, preservatives such as methyl and propylhydroxybenzoates, sweeteners, and flavoring agents.

[0168] The compositions of the present invention can be formulated to provide rapid, sustained, or delayed release of the active ingredient after administration to a patient by using procedures known in the art. Controlled-release drug delivery systems for oral administration include osmotic pump systems and dissolution systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled-release systems are described in U.S. Patent Nos. 3,845,770, 4,326,525, 4,902,514, and 5,616,345. Another formulation for use in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal 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 transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Patent Nos. 5,023,252, 4,992,445, and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

[0169] The compositions are preferably formulated in unit dosage form. The term "unit dosage form" refers to a physically discrete unit suitable as a unitary dosage for human subjects and other mammals, each unit containing a predetermined amount of active ingredient calculated to produce a desired therapeutic effect in association with a suitable pharmaceutical excipient (e.g., tablet, capsule, ampoule). The compounds are generally administered in a pharmaceutically effective amount. Preferably, for oral administration, each dosage unit contains 1 mg to 2 g of a compound described herein, and for parenteral administration, preferably 0.1 to 700 mg of a compound described herein. However, it will be understood that the amount of compound actually administered will typically be determined by a physician in light of relevant circumstances, including the condition being treated, the selected route of administration, the actual compound administered and its relative activity, the age, weight, and response of the individual patient, the severity of the patient's symptoms, etc.

[0170] To prepare solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention. When these preformulation compositions are referred to as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules.

[0171] The tablets or pills of the present invention can be coated or otherwise compounded to provide a dosage form offering the advantage of prolonged action or to protect against the acidic conditions of the stomach. For example, the tablets or pills can comprise an inner dosage component and an outer dosage component, the latter being in the form of a coating over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and allow the inner component to enter the duodenum intact or be released later. A variety of materials can be used for such enteric layers or coatings, including many polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0172] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. Preferably, compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions, preferably in pharmaceutically acceptable solvents, may be nebulized by use of inert gases. Nebulized solutions may be administered by the oral or nasal respiratory route. Liquids may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a face mask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.

[0173] In some embodiments, a pharmaceutical composition comprising a disclosed compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0174] How to use The compounds and compositions described herein are generally useful for modulating the activity of sodium channels and for treating conditions associated with abnormal function of sodium channel ion channels, e.g., abnormal late sodium (INaL) currents. In some embodiments, the compounds provided by the present invention are effective in treating epilepsy or epilepsy syndromes, neurodevelopmental disorders, pain, or neuromuscular disorders. The provided compounds, pharmaceutically acceptable salts thereof, or compositions may also be capable of modulating all sodium ion channels, or may modulate one or more sodium ion channels, e.g., Na V It may be specific for only 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, and / or 1.9.

[0175] In typical embodiments, the invention is intended to encompass the compounds disclosed herein, as well as pharmaceutically acceptable salts, pharmaceutically acceptable esters, tautomeric forms, polymorphs, and prodrugs of such compounds. In some embodiments, the invention includes pharmaceutically acceptable addition salts, pharmaceutically acceptable esters, solvates (e.g., hydrates) of addition salts, tautomers, polymorphs, enantiomers, mixtures of enantiomers, stereoisomers, or mixtures of stereoisomers (either pure or as racemic or non-racemic mixtures) of the compounds described herein, such as compounds of the formulae named herein, e.g., compounds of Formula I, I', Ia, Ib, Ic, Id, II, III, V, VII, VIII, or IX.

[0176] Epilepsy and epilepsy syndromes The compounds described herein are useful for treating epilepsy and epilepsy syndromes. Epilepsy is a CNS disorder in which neuronal activity in the brain is disrupted, causing periods of convulsions or abnormal behavior, sensation, and sometimes loss of consciousness. Convulsive symptoms may vary widely, from a simple blank stare for a few seconds to repeated twitching of the patient's arms or legs during a convulsion.

[0177] Epilepsy may involve generalized seizures or partial or focal seizures. All areas of the brain are involved in generalized seizures. A person experiencing a generalized seizure may scream or make noises, stiffen for a few seconds to a minute, and then have rhythmic movements of the arms and legs. The eyes are generally open, and the person may appear not to be breathing and may actually turn blue. Consciousness returns gradually, and the person may be confused for minutes to hours. There are six main types of generalized seizures: tonic-clonic, tonic-clonic, myoclonic, absence, and atonic. In partial or focal seizures, only part of the brain is involved, and therefore only part of the body is affected. Symptoms may vary depending on the part of the brain that has abnormal electrical activity.

[0178] Epilepsy as referred to herein includes generalized, partial, complex partial, tonic-clonic, clonic, tonic, refractory seizures, status epilepticus, absence seizures, febrile seizures, or temporal lobe epilepsy.

[0179] Compounds described herein (e.g., Formulas I, I', Ia, Ib, Ic, Id, I Compounds of formula I, III, V, VII, VIII, or IX may also be useful in treating epilepsy syndromes. Severe syndromes involving diffuse brain dysfunction, at least in part caused by some aspects of epilepsy, are also called epileptic encephalopathies. These are associated with frequent seizures that are resistant to treatment and severe cognitive impairment, such as West syndrome.

[0180] In some embodiments, the epilepsy syndrome comprises an epileptic encephalopathy such as Dravet syndrome, Angelman syndrome, CDKL5 disorder, frontal lobe epilepsy, infantile spasms, West syndrome, juvenile myoclonic epilepsy, Landau-Kleffner syndrome, Lennox-Gastaut syndrome, Ohtahara syndrome, PCDH19 epilepsy, or Glut1 deficiency.

[0181] In some embodiments, the epilepsy or epilepsy syndrome is a genetic epilepsy or genetic epilepsy syndrome. In some embodiments, the epilepsy or epilepsy syndrome is selected from the group consisting of epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutations, generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile spasms, SCN2A mutations, and SCN8A mutations. Includes epileptic encephalopathy, focal epilepsy with SCN3A mutations, childhood partial epilepsy of unknown cause with SCN3A mutations, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussen encephalitis, malignant migratory partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, sudden unexpected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, or KCNT1 epileptic encephalopathy.

[0182] In some embodiments, the methods described herein include administering a compound described herein (e.g., a compound of Formula I, I', Ia, Ib, Ic, Id, II, III, V, VII, VIII, or IX) to a patient with epilepsy or an epilepsy syndrome (e.g., epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutations, generalized epilepsy with febrile seizures, refractory childhood seizures with generalized tonic-clonic seizures, or the like). epilepsy, infantile spasms, benign familial neonatal-infantile spasms, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutations, childhood partial epilepsy of unknown cause with SCN3A mutations, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussen encephalitis, malignant migratory partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, sudden unexpected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, or KCNT1 epileptic encephalopathy).

[0183] In one aspect, the present invention provides a method for treating epilepsy or epilepsy syndromes (e.g., epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutations, generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile convulsions, SCN2A epileptic encephalopathy, SCN3A sudden onset epilepsy, and the like). and a method for treating a condition characterized by the following: focal epilepsy with an SCN3A mutation, childhood partial epilepsy of unknown etiology with an SCN3A mutation, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussen encephalitis, malignant migratory partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, sudden unexpected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, or KCNT1 epileptic encephalopathy, comprising administering to a subject in need thereof a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0184] The compounds of the 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 which a subject is taking any of the following drugs: 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, 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.

[0185] In some embodiments, the methods described herein include administering to a subject a compound described herein (e.g., a compound of Formula I, I', Ia, Ib, Ic, Id, II, III, V, VII, VIII, or IX) prior to administration of the compound described herein (e.g., a compound of Formula I, I', Ia, Ib, Ic, Id, II, III, V, VII, VIII, or IX), a therapeutically effective amount of 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, KCNB1, KCNC1, KCNM The method further includes identifying subjects with a mutation in one or more of: A1, 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.

[0186] Neurodevelopmental disorders The compounds described herein may be useful for treating neurodevelopmental disorders. In some embodiments, the neurodevelopmental disorder includes autism, autism with epilepsy, tuberous sclerosis, fragile X syndrome, Rett syndrome, Angelman syndrome, Dup15q syndrome, 22q13.3 deletion syndrome, Prader-Willi syndrome, palatocardiofacial syndrome, Smith-Lemli-Opitz syndrome, or neurodevelopmental disorders with epilepsy. In some embodiments, the methods described herein include the use of a compound described herein (e.g., a compound represented by Formula I, I', Ia , Ib, Ic, Id, II, III, V, VII, VIII, or IX), identifying the subject as having a neurodevelopmental disorder (e.g., autism, autism with epilepsy, tuberous sclerosis complex, Fragile X syndrome, Rett syndrome, Angelman syndrome, Dup15q syndrome, 22q13.3 deletion syndrome, Prader-Willi syndrome, velocardiofacial syndrome, Smith-Lemli-Opitz syndrome, or neurodevelopmental disorder with epilepsy).

[0187] In one aspect, the invention features a method of treating a neurodevelopmental disorder (e.g., autism, autism with epilepsy, tuberous sclerosis, Fragile X syndrome, Rett syndrome, Angelman syndrome, Dup15q syndrome, 22q13.3 deletion syndrome, Prader-Willi syndrome, velocardiofacial syndrome, Smith-Lemli-Opitz syndrome, or neurodevelopmental disorder with epilepsy), comprising administering to a subject in need thereof a compound of (I): [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0188] pain The compounds described herein can be useful for the treatment of pain. In some embodiments, the pain includes neuropathic pain, trigeminal neuralgia, migraine, hemiplegic migraine, familial hemiplegic migraine, familial hemiplegic migraine type 3, cluster headache, trigeminal neuralgia, cerebellar ataxia, or related headache disorders. In some embodiments, the methods described herein further include identifying a subject with pain (e.g., neuropathic pain, trigeminal neuralgia, migraine, hemiplegic migraine, familial hemiplegic migraine, familial hemiplegic migraine type 3, cluster headache, trigeminal neuralgia, cerebellar ataxia, or related headache disorders) before administering a compound described herein (e.g., a compound of Formula I, I', Ia, Ib, Ic, Id, II, III, V, VII, VIII, or IX).

[0189] In one aspect, the invention features a method of treating pain (e.g., neuropathic pain, trigeminal neuralgia, migraine, hemiplegic migraine, familial hemiplegic migraine, familial hemiplegic migraine type 3, cluster headache, trigeminal neuralgia, cerebellar ataxia, or a related headache disorder) by administering to a subject in need thereof a compound of (I): [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0190] Neuromuscular disorders The compounds described herein may be useful for treating neuromuscular disorders. In some embodiments, the neuromuscular disorders include amyotrophic lateral sclerosis, multiple sclerosis, myotonia, congenital paramyotonia, potassium-exacerbated myotonia, periodic paralysis, hyperkalemic periodic paralysis, hypokalemic periodic paralysis, or laryngospasm associated with SCN4A mutations. In some embodiments, the compounds described herein may be useful for treating neuromuscular disorders including amyotrophic lateral sclerosis, multiple sclerosis, myotonia, congenital paramyotonia, potassium-exacerbated myotonia, periodic paralysis, hyperkalemic periodic paralysis, hypokalemic periodic paralysis, or laryngospasm associated with SCN4A mutations. The methods described herein further include identifying a subject with a neuromuscular disorder (e.g., amyotrophic lateral sclerosis, multiple sclerosis, myotonia, paramyotonia congenita, potassium-aggravated myotonia, periodic paralysis, hyperkalemic periodic paralysis, hypokalemic periodic paralysis, or laryngospasm associated with an SCN4A mutation) prior to administration of a compound described herein (e.g., a compound of Formula I, I', Ia, Ib, Ic, Id, II, III, V, VII, VIII, or IX).

[0191] In one aspect, the invention features a method of treating a neuromuscular disorder (e.g., amyotrophic lateral sclerosis, multiple sclerosis, myotonia, paramyotonia congenita, potassium-aggravated myotonia, periodic paralysis, hyperkalemic periodic paralysis, hypokalemic periodic paralysis, or laryngospasm associated with an SCN4A mutation), comprising administering to a subject in need thereof a compound of (I): [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0192] Other disorders In some embodiments, compounds of the 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 may be active with respect to the central and / or peripheral nervous system. In some embodiments, compounds provided herein are used to treat cardiovascular diseases such as atrial and ventricular arrhythmias, including atrial fibrillation, Prinzmetal (variant) angina, stable angina, unstable angina, ischemia and reperfusion injury in the heart, kidney, liver, and brain, exercise-induced angina, pulmonary hypertension, congestive heart disease, including diastolic and systolic heart failure, recurrent ischemia, cerebral ischemia, stroke, renal ischemia, ischemia associated with organ transplantation, acute coronary syndrome, peripheral arterial disease, intermittent claudication, and myocardial infarction. In some embodiments, the compounds provided herein can be used in the treatment of diseases affecting the neuromuscular system that result in itching, cramps, or numbness, or in the treatment of disease states associated with diabetes, such as diabetes or reduced insulin sensitivity and diabetic peripheral neuropathy. In some embodiments, the disclosed methods comprise administering a pharmaceutical composition.

[0193] In some embodiments, provided herein is a method of treating a neurological or psychiatric disorder, the method comprising administering to a subject in need thereof a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0194] Combination therapy The compounds or compositions described herein (e.g., for use in modulating sodium ion channels, e.g., delayed sodium (INaL) current) can be administered in combination with another drug or therapy.The subject who receives the compounds disclosed herein can have a disease, disorder, or condition that will benefit from treatment with another drug or therapy, or its symptoms.These diseases or conditions can be related to epilepsy or epilepsy syndromes, neurodevelopmental disorders, pain, or neuromuscular disorders.

[0195] Antiepileptic drugs Antiepileptic drugs include brivaracetam, carbamazepine, clobazam, clonazepam, and diazepam. Includes azepam, divalproex, eslicarbazepine, ethosuximide, ezogabine, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, lorazepam, oxcarbazepine, permpanel, phenobarbital, phenytoin, pregabalin, primidone, rufinamide, tigabine, topiramate, valproic acid, vigabatrin, zonisamide, and cannabidiol.

[0196] Combination cardiovascular drug therapy Cardiovascular-related diseases or conditions that may benefit from combination treatment with the sodium channel blockers of the present invention with other therapeutic agents include, without limitation, angina pectoris, including stable angina, unstable angina (UA), exercise-induced angina, variant angina, arrhythmias, intermittent claudication, myocardial infarction, including non-STE myocardial infarction (NSTEMI), pulmonary hypertension, including pulmonary arterial hypertension, heart failure, such as congestive (or chronic) heart failure and diastolic heart failure and heart failure with preserved emptying fraction (diastolic dysfunction), acute heart failure, or recurrent ischemia.

[0197] Suitable therapeutic agents for treating cardiovascular-related diseases or conditions include antianginal agents, heart failure agents, antithrombotic agents, antiarrhythmic agents, antihypertensive agents, and lipid-lowering agents.

[0198] Co-administration of the sodium channel blockers of the present invention with therapeutic agents suitable for treating cardiovascular-related conditions allows for the augmentation of standard of care therapy currently being received by patients.

[0199] Antianginal drugs Antianginal drugs include beta-blockers, calcium channel blockers, and nitrates. Beta-blockers reduce the heart's need for oxygen by reducing its workload, resulting in a slower heart rate and less vigorous heart contractions. Examples of beta-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).

[0200] Nitrates dilate arteries and veins, thereby increasing coronary blood flow and decreasing blood pressure. Examples of nitrates include nitroglycerin, nitrate patches, isosorbide dinitrate, and 5-isosorbide mononitrate.

[0201] Calcium channel blockers prevent the normal flow of calcium into cells of the heart and blood vessels, relaxing the blood vessels and thereby 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.

[0202] Heart failure drugs Medications used to treat heart failure include diuretics, ACE inhibitors, vasodilators, and cardiac glycosides. Diuretics remove excess fluid from tissues and circulation, thereby alleviating many of the symptoms of heart failure. Examples of diuretics include hydrochlorothiazide, metolazone (Zaroxolyn), furosemide (Lasix), bumetanide (Bumex), spironolactone (Aldactone), and eplerenone (Inspra).

[0203] Angiotensin-converting enzyme (ACE) inhibitors reduce the workload on the heart by dilating blood vessels and decreasing 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).

[0204] 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 also act as vasodilators.

[0205] Cardiac glycosides are compounds that increase the force of cardiac contraction. These compounds enhance the heart's pumping ability and improve irregular heartbeat activity. Examples of cardiac glycosides include digitalis, digoxin, and digitoxin.

[0206] antithrombotic agents Antithrombotic agents inhibit the blood's ability to clot. There are three main types of antithrombotic agents: platelet inhibitors, anticoagulants, and thrombolytic agents.

[0207] Platelet inhibitors inhibit the coagulation activity of platelets, thereby reducing clotting in arteries. Examples of platelet inhibitors include acetylsalicylic acid (aspirin), ticlopidine, clopidogrel (Plavix®), dipyridamole, cilostazol, persantinsulfinpyrazone, dipyridamole, indomethacin, and glycoprotein IIb / IIIa inhibitors such as abciximab, tirofiban, and eptifibatide (Integrelin). Beta-blockers and calcium channel blockers also have platelet-inhibiting effects.

[0208] Anticoagulants prevent clots from growing larger and prevent the formation of new clots. Examples of anticoagulants include bivalirudin (Angiomax), warfarin (Coumadin), unfractionated heparin, low molecular weight heparin, danaparoid, lepirudin, and argatroban.

[0209] Thrombolytic agents act to break up existing blood clots. Examples of thrombolytic agents include streptokinase, urokinase, and tenecteplase (TNK), and tissue plasminogen activator (t-PA).

[0210] Antiarrhythmic drugs Antiarrhythmic drugs are used to treat heart rate and rhythm disorders. Examples of antiarrhythmic drugs include amiodarone, dronedarone, quinidine, procainamide, lidocaine, and propafenone. Cardiac glycosides and beta-blockers are also used as antiarrhythmic drugs.

[0211] The combination of amiodarone and dronedarone is of particular interest given the recently discovered synergistic effects of the sodium channel blocker ranolazine and amiodarone and dronedarone.

[0212] 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 aspects of cardiovascular disease, including congestive heart failure, atherosclerosis, and blood clot formation. Examples of antihypertensive drugs include alpha-1-adrenergic antagonists, such as prazosin (Minipress), doxazosin mesylate (Cardura), prazosin hydrochloride (Minipress), prazosin, polythiazide (Minizide), and terazosin hydrochloride (Hytrin), and beta-adrenergic antagonists, such as propranolol (Inderal), nadolol (Corgard), timolol (Blocadren), metoprolol (Lopressor), and pindolol (Visken). and central alpha adrenergic receptor agonists such as clonidine hydrochloride (Catapres), clonidine hydrochloride and chlorthalidone (Clorpres, Combipres), guanabenz acetate (Wytensin), guanfacine hydrochloride (Tenex), methyldopa (Aldomet), methyldopa and chlorothiazide (Aldoclor), methyldopa and hydrochlorothiazide (Aldoril), and labetalol (Normodyne, Trandate), carvedilol (Coreg), combined alpha / beta adrenergic antagonists such as guanethidine (Ismelin), reserpine (Serpasil), adrenergic neuron blockers such as clonidine (Catapres), methyldopa (Aldomet), guanabenz (Wytensin), centrally acting antihypertensives such as antiangiotensin II drugs, perindopril (Aceon), captopril (Capoten), enalapril (Vasotec), lisinopril (Prinivil, Zestri), ACE inhibitors such as candesartan (Atacand), eprosartan (Teveten), irbesartan (Avapro), losartan (Cozaar), telmisartan (Micardis), and valsartan (Diovan); calcium channel blockers such as verapamil (Calan, Isoptin), diltiazem (Cardizem), and nifedipine (Adalat, Procardia); diuretics; and nitroprusside (Nipride).These include direct vasodilators such as diazoxide (Hyperstat IV), hydralazine (Apresoline), minoxidil (Loniten), and verapamil, and potassium channel activators such as aprikalim, bimakalim, cromakalim, emakalim, nicorandil, and pinacidil.

[0213] Lipid-lowering drugs Lipid-lowering drugs are used to lower the amount of cholesterol or fatty sugars present in the blood. Examples of lipid-lowering drugs 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).

[0214] In the present invention, patients presenting with an acute coronary event often suffer from secondary medical conditions, such as one or more of a metabolic disorder, a pulmonary disorder, a peripheral vascular disorder, or a gastrointestinal disorder, and such patients may benefit from combination therapy treatment, which comprises administering ranolazine to the patient in combination with at least one therapeutic agent.

[0215] Combination therapy for lung disorders Pulmonary disorder refers to any disease or condition related to the lungs. Examples of pulmonary disorders include, but are not limited to, asthma, chronic obstructive pulmonary disease (COPD), bronchitis, and emphysema.

[0216] Examples of therapeutic agents used to treat pulmonary disorders include bronchodilators, including beta-2 agonists and anticholinergics, corticosteroids, and electrolyte supplements. Specific examples of therapeutic agents used to treat the disorder include epinephrine, terbutaline (Brethaire, Bricanyl), albuterol (Proventil), salmeterol (Serevent, Serevent Diskus), theophylline, ipratropium bromide (Atrovent), tiotropium (Spiriva), methylprednisolone (Solu-Medrol, Medrol), magnesium, and potassium.

[0217] Combination Therapy for Metabolic Disorders Examples of metabolic disorders include, but are not limited to, diabetes, including type I and type II diabetes, metabolic syndrome, dyslipidemia, obesity, impaired glucose tolerance, hypertension, elevated serum cholesterol, and elevated triglycerides.

[0218] Examples of therapeutic agents used to treat metabolic disorders include antihypertensive and lipid-lowering agents, as described above in the "Cardiovascular Combination Therapy" section. Additional therapeutic agents used to treat metabolic disorders include insulin, sulfonylureas, biguanides, alpha-glucosidase inhibitors, and incretin mimetics.

[0219] Combination therapy for peripheral vascular disease Peripheral vascular disorders are disorders involving blood vessels (arteries and veins) located outside the heart and brain, including, for example, peripheral arterial disease (PAD), a condition that occurs when the arteries supplying blood to the internal organs, arms, and legs become completely or partially blocked as a result of atherosclerosis.

[0220] Combination therapy for gastrointestinal disorders Gastrointestinal disorders refer to diseases and conditions associated with the gastrointestinal tract. Examples of gastrointestinal disorders include gastroesophageal reflux disease (GERD), inflammatory bowel disease (IBD), gastroenteritis, gastritis and peptic ulcer disease, and pancreatitis.

[0221] Examples of therapeutic agents used to treat gastrointestinal disorders include proton pump inhibitors such as pantoprazole (Protonix), lansoprazole (Prevacid), esomeprazole (Nexium), omeprazole (Prilosec), rabeprazole, H2 blockers such as cimetidine (Tagamet), ranitidine (Zantac), famotidine (Pepcid), nizatidine (Axid), prostaglandins such as misoprostol (Cytotec), sucralfate, and antacids.

[0222] Combination therapy with antibiotics, analgesics, antidepressants, and anti-anxiety medications Patients presenting with an acute coronary event may present a condition that would benefit from the administration of therapeutic agent(s) that are antibiotics, analgesics, antidepressants, and anxiolytics in combination with ranolazine.

[0223] antibiotics Antibiotics are therapeutic drugs that kill or stop the growth of microorganisms, including both bacteria and fungi. Examples of antibiotics include penicillin (amoxicillin), 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), ceftibuten (Cedax), ceftidinir (Omnicef), ceftriaxone (Rocephin), carbapenems, and monobactams, and tetracyclines such as tetracycline. and beta-lactam antibiotics, including macrolide antibiotics such as erythromycin, aminoglycosides such as gentamicin, tobramycin, amikacin, quinolones such as ciprofloxacin, cyclic peptides such as vancomycin, streptogramins, polymyxins, lincosamides such as clindamycin, oxazolidinos such as linezolid, and sulfa antibiotics such as sulfisoxazole.

[0224] painkillers Analgesics are therapeutic drugs used to relieve pain. Examples of analgesics include opiates and morphine mimetics, such as fentanyl and morphine, paracetamol, NSAIDs, and COX-2 inhibitors. V Given the ability of the sodium channel blockers of the present invention to treat neuropathic pain through inhibition of the 1.7 and 1.8 sodium channels, combination with analgesics is particularly contemplated. See U.S. Patent Application Publication No. 20090203707.

[0225] Antidepressants and anti-anxiety medications Antidepressants and anti-anxiety medications include those medications used to treat anxiety disorders, depression, and medications 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, Stimuloton), escitalopram (Lexapro, Cipralex), fluoxetine (Prozac, Sarafem, Fluctin, Fontex, Prodep, Fludep, Lovan), and venlafaxine (Effexor). XR, Efexor), citalopram (Celexa, Cipramil, Talohexane), paroxetine (Paxil, Seroxat, Aropax), trazodone (Desyrel), amitriptyline (Elavil), and bupropion (Wellbutrin, Zyban). Antidepressants and anti-anxiety medications may include neuroactive steroids and ketamine, and related NMDA receptor antagonists.

[0226] Thus, one aspect of the invention provides a composition comprising a sodium channel blocker of the invention and at least one therapeutic agent. In an alternative embodiment, the composition comprises a sodium channel blocker of the invention and at least two therapeutic agents. In further alternative embodiments, the composition comprises a sodium channel blocker of the invention and at least three therapeutic agents, a sodium channel blocker of the invention and at least four therapeutic agents, or a sodium channel blocker of the invention and at least five therapeutic agents.

[0227] Methods of combination therapy include the simultaneous administration of two or more formulations comprising a sodium channel blocker of the present invention and a therapeutic agent(s), as well as the simultaneous administration of a single formulation containing a sodium channel blocker of the present invention and a therapeutic agent(s), which is sequential administration of the sodium channel blocker of the present invention and a therapeutic agent(s) in any order, preferably during which there is a period of time during which the sodium channel blocker of the present invention and the therapeutic agent(s) simultaneously exert their therapeutic effects. [Example]

[0228] The representative examples that follow are intended to serve to illustrate the present invention and are not intended to, nor should they be construed to, limit the scope of the invention.

[0229] The compounds provided herein are readily available using the following general methods and procedures. The compounds can be prepared from suitable starting materials. Of course, where typical or suitable process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, it will be understood that other process conditions can also be used unless otherwise indicated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by one skilled in the art by routine optimization.

[0230] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to protect certain functional groups from undergoing undesired reactions. The selection of a suitable protecting group for a particular functional group, as well as suitable conditions for protection and deprotection, are well known in the art. For example, numerous protecting groups, and their introduction and removal, are described in detail in T.W. Greene and PGMWuts,Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein.

[0231] The compounds provided herein can be isolated and purified by known standard procedures. Such procedures include recrystallization, filtration, flash chromatography, trituration, high-pressure liquid chromatography (HPLC), or supercritical fluid chromatography (SFC). Note that flash chromatography can be performed either manually or via an automated system. The compounds provided herein can be characterized by known standard procedures, such as nuclear magnetic resonance spectroscopy (NMR) or liquid chromatography mass spectrometry (LCMS). NMR chemical shifts are reported in parts per million (ppm) and are generated using methods well known to those skilled in the art.

[0232] An exemplary general method for analytical LCMS is Method A (Xtimate C 18 (2.1 mm x 30 mm, 3 μm), A = H2O (0.04% TFA) and B = CH3CN (0.02% TFA), 50 °C, 1.2 mL / min, 10 to 80% B over 0.9 min, then 80% B in 0.6 min) and Method B (Chromolith Flash RP-18 endcapped C 18 (2 mm × 25 mm), A = H2O (0.04% TFA) and B = CH3CN (0.02% TFA), 50 °C, 1.5 mL / min, 5 to 95% B over 0.7 min, then 95% B in 0.4 min).

[0233] 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'-dimethoxybiphenylEt3N 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 Ethoxide TsOH p-toluenesulfonic acid DEA N,N-diethylaniline DIPEA N,N-diisopropylethylamine TFA trifluoroacetic acid KOAc Potassium Acetate T3P Propanephosphonic Anhydride

[0234] Example 1: 3-[cyclopropylmethoxy(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyridine [ka] Synthesis of B: To a suspension of NaH (2.94 g, 73.56 mmol) in THF (50 mL), 2,2,2-trifluoroethanol (7.36 g, 73.56 mmol) was slowly added at 20 °C, and the mixture was stirred for 1 h. Then, 5-chloro-2,3-difluoro-pyridine (10 g, 66.88 mmol) was added, and the mixture was stirred at 20 °C for another 4 h. The mixture was quenched with saturated NH Cl (50 mL) and extracted with EtOAc (100 mL × 2). The combined organic phases were washed with brine (50 mL), dried over Na SO , filtered, and concentrated to give B (15000 mg, 65.34 mmol) as an oil. 1 H NMR (400 MHz, CDCl) δ H=7.83(d, 1H), 7.38(dd, 1H), 4.73(q, 2H).

[0235] Synthesis of A3: A mixture of B (8 g, 34.85 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (26.55 g, 104.55 mmol), KPO (14.79 g, 69.7 mmol), SPhos (4.29 g, 10.45 mmol), and Pd(OAc) (782.4 mg, 3.48 mmol) in 1,4-dioxane (250 mL) was stirred at 85° C. for 16 h. After cooling to room temperature, the mixture was filtered through Celite and eluted with EtOAc (50 mL × 2). The filtrate was concentrated, diluted with EtOAc (200 mL), washed with water (100 mL × 2) and brine (100 mL), dried over Na2SO4, filtered, and concentrated to give the crude product, which was purified by flash chromatography on silica gel (EtOAc in PE = 0 to 10% to 40%) to give the product (3 g, 4.6021 mmol) as an oil. 1 H NMR (400 MHz, CDCl) δ H =8.26 (d, 1H), 7.72 (dd, 1H), 4.87 (q, 2H), 1.35 (s, 12H). Using Method B, LCMS R t =0.94 min, C 13 H 17 BF4NO3[M+H] + MS ES Calculated value: 322.1, measured value: 322.3. [ka]

[0236] Synthesis of A2: To a mixture of cyclopropylmethanol (382.93 mg, 5.31 mmol) in THF (10 mL), NaH (212.41 mg, 5.31 mmol) was added, 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, and the mixture was stirred at 20 °C for 2 h. The reaction was quenched with saturated NH Cl (10 mL), and the mixture was extracted with EtOAc (10 mL × 2). The combined organic phases were washed with brine (10 mL), dried over Na SO , filtered, and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (10% to 40% EtOAc in PE) to give the product (240 mg, 0.73 mmol) as a solid. LCMS Rt=2.29 min on chromatography at 4 min.

[0237] Synthesis of compound 1: A mixture of 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (111.02 mg, 0.35 mmol), Pd(dppf)Cl (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 KCO (86.89 mg, 0.63 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was added to 90 mL of 1,4-dioxane. ℃ The mixture was stirred at rt for 16 h under N. After cooling to room temperature, the mixture was filtered through Celite, eluting with EtOAc (10 mL × 2), and the filtrate was concentrated to give the crude product. The crude product was purified by preparative HPLC (Waters Xbridge 150 mm × 25 mm 5 μm) A = HO (10 mM NHHCO) and B = CHCN, 50-70% B over 7 min to give the product (100.49 mg, 0.23 mmol) as a solid. 1 H NMR (400MHz, DMSO-d6) δ H=8.75(s, 1H), 8.46(d, 1H), 8.34(dd, 11.2Hz, 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 R t = 1.31 min in 2.0 min chromatography, C 18 H 15 F6N4O2[M+H] + MS ESI calculated value for 433.1, found value 433.0.

[0238] Example 2: 3-[Difluoro(isobutoxy)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-[1,2,4]triazolo[4, 3-a]pyridine [ka] Synthesis of A4: To a mixture of 2-methylpropan-1-ol (393.6 mg, 5.31 mmol) in THF (10 mL), NaH (212.41 mg, 5.31 mmol) was added, 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, and the mixture was stirred at 20 °C for 2 h. The reaction was quenched with saturated NH Cl (10 mL), and the mixture was extracted with EtOAc (20 mL × 2). The combined organic phases were washed with brine (10 mL), dried over Na SO , filtered, and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (10% to 40% EtOAc in PE) to give the product (100 mg, 0.30 mmol) as a solid. LCMS Rt = 1.5 min chromatography 0.86 min, MS ESI calculated C 11 H 13 BrF2N3O[M+H+2] + 320.0, actual value 320.2.

[0239] Synthesis of compound 2: A mixture of 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (110.33 mg, 0.34 mmol), Pd(dppf)Cl (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 KCO (86.35 mg, 0.62 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was stirred at 90 °C for 16 h under N. After cooling to room temperature, the mixture was filtered through Celite, eluting with EtOAc (10 mL × 2), and the filtrate was concentrated to give the crude product. The crude product was purified by preparative HPLC (Waters Xbridge 150 mm × 25 mm 5 μm) A = H2O (10 mM NH4HCO3) and B = CH3CN, 50-70% B over 8 min) to give the product (53.41 mg, 0.12 mmol) as a solid. 1 H NMR (400MHz, DMSO-d6) δ H =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 R t = 1.34 min in 2.0 min chromatography, C 18 H 17 F6N4O2[M+H] + MS ESI calculated value for 435.1, found value 435.1.

[0240] Example 3: 3-[Ethoxy(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyridine [ka] Synthesis of A5: 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 h. After cooling to room temperature, the reaction was quenched with saturated NH Cl (10 mL), and the mixture was extracted with EtOAc (20 mL × 2). The combined organic phases were washed with brine (10 mL), dried over Na SO , filtered, and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (10% to 40% EtOAc in PE) to give the product (70 mg, 0.17 mmol) as a solid. LCMS R t = 1.97 min in 4 min chromatography, MS ESI calculated C9H9BrF2N3O [M+H+2] + 294.0, actual value 293.8.

[0241] Synthesis of compound 3: A mixture of 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (84.65 mg, 0.26 mmol), Pd(dppf)Cl (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 KCO (66.25 mg, 0.48 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was stirred at 90 °C for 16 h under N. After cooling to room temperature, the mixture was filtered through Celite, eluting with EtOAc (10 mL × 2), and the filtrate was concentrated to give the crude product. The crude product was purified by preparative HPLC (Waters Xbridge 150 mm x 25 mm 5 μm) A = H2O (10 mM NH4HCO3) and B = CH3CN, 42-62% B over 8 min) to give the product (44.33 mg, 0.11 mmol) as a solid. 1 H NMR (400MHz, DMSO-d6) δ H=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) t = 1.25 min with 2.0 min of chromatography, C 16 H 13 F6N4O2[M+H] + MS ESI calculated value for 407.1, found value 407.0.

[0242] Example 4: 3-[Difluoro(isopropoxy)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyridine [ka] Synthesis of A6: To a mixture of propan-2-ol (319.15 mg, 5.31 mmol) in THF (10 mL), NaH (127.45 mg, 3.19 mmol) was added, 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, and the mixture was stirred at 20 °C for 2 h. The reaction was quenched with saturated NH Cl (10 mL), and the mixture was extracted with EtOAc (10 mL × 2). The combined organic phases were washed with brine (10 mL), dried over Na SO , filtered, and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (10% to 40% EtOAc in PE) to give the product (240 mg, 0.72 mmol) as a solid. LCMS Rt = 4 min chromatography 2.18 min, MS ESI calculated C 10 H 11 BrF2N3O[M+H+2] + 306.0, actual value 305.9.

[0243] Synthesis of compound 4: A mixture of 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (115.38 mg, 0.36 mmol), Pd(dppf)Cl (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 KCO (90.3 mg, 0.65 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was stirred at 90 °C for 16 h under N. After cooling to room temperature, the mixture was filtered through Celite, eluting with EtOAc (10 mL × 2), and the filtrate was concentrated to give the crude product. The crude product was purified by preparative HPLC (Waters Xbridge 150 mm × 25 mm 5 μm) A = H2O (10 mM NH4HCO3) and B = CH3CN, 45-65% B over 8 min) to give the product (80.25 mg, 0.19 mmol) as a solid. 1 H NMR (400MHz, DMSO-d6) δ H =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 R t = 1.29 min in 2.0 min chromatography, C 17 H 15 F6N4O2[M+H] + MS ESI calculated value for 421.1, found value 421.0.

[0244] Example 5: 3-[Difluoro(methoxy)methyl]-6-[5-fluoro-6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyridazine [ka] Synthesis of A7: To a mixture of (6-chloropyridazin-3-yl)hydrazine (3 g, 20.75 mmol) in toluene (40 mL), (2-chloro-2,2-difluoro-acetyl) 2-chloro-2,2-difluoro-acetate (5.55 g, 22.83 mmol) was added. 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 NaHCO (50 mL), and the mixture was extracted with EtOAc (50 mL × 2). The combined organic phases were washed with brine (20 mL), dried over NaSO, filtered, and concentrated to give the crude product as a solid. 1 H NMR (400MHz, DMSO-d6) δ H =8.67(d, 1H), 7.78(d, 1H).

[0245] Synthesis of A9: A mixture of 6-chloro-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-b]pyridazine (200 mg, 0.84 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)pyridine (350.58 mg, 1 mmol), Pd(t-BuP) (64.15 mg, 0.13 mmol), and KPO (532.95 mg, 2.51 mmol) in 1,4-dioxane (2 mL) and water (0.20 mL) was stirred at 80° C. for 16 h. After cooling to room temperature, the suspension was diluted with EtOAc (10 mL) and filtered through silica gel, eluting with EtOAc (20 mL). The combined filtrate was concentrated to give the crude product, which was purified by flash chromatography on silica gel (20% to 50% to 80% EtOAc in PE) to give the product (260 mg, 0.50 mmol) as a solid. LCMS R t = 0.96 min in 1.5 min of chromatography, C 15 H 11 ClF6N5O[M+H] + MS ESI calculated value for 426.1, found value 425.9.

[0246] Synthesis of Compound 5: 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]pyridazine (150 mg, 0.35 mmol) in MeCN (1 mL), AgOTf (905.31 mg, 3.52 mmol) and MeOH (8 mL, 0.35 mmol) were added. The mixture was stirred at 90 °C for 10 days. After cooling to room temperature, the mixture was concentrated to give a residue. The residue was diluted with water (30 mL) and extracted with EtOAc (30 mL × 2). The combined organic phase was washed with water (20 mL × 2), brine (30 mL × 2), dried over anhydrous Na SO , filtered, and concentrated to give the crude product. The crude product was purified by preparative HPLC (Waters Xbridge 150 mm x 25 mm, 5 μm), A = H2O (0.05% NH4OH) and B = CH3CN, 57-87% B over 9 min to give the product as a solid. 1 H NMR (CDCl3, 400MHz) δ H =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 R t = 1.32 min in 2.0 min chromatography, C 16 H 14 F6N5O2[M+H] + MS ESI calculated value for 422.1, found value 422.0.

[0247] Example 6: 3-[Difluoro(methoxy)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyridine [ka] 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-dioxaborolan-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (144.62 mg, 430 μmol), KCO (99.41 mg, 720 μmol), and Pd(dppf)Cl (39.47 mg, 50 μmol) in 1,4-dioxane (5 mL) and water (500 μL) was stirred at 80 °C for 12 h under N. After cooling to room temperature, the mixture was diluted with HO (10 mL), and the mixture was 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 give the crude product. The crude product was purified by preparative HPLC (Boston Purification by Prime C18 (150 x 30 mm, 5 μm), A = H2O (0.05% NH4OH) and B = CH3CN, 53-83% B over 8 min gave the product as a solid. 1 H NMR (400MHz, DMSO-d6) δ H =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 R t = 1.27 min in 2.0 min chromatography, MS ESI calculated C 18 H 13 F6N4O2[M+H] + 407.09, actual value 406.9.

[0248] Example 7: 3-[Difluoro(methoxy)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyridine [ka] 6-Bromo-3-[difluoromethyl]propanol in 1,4-dioxane (5 mL) and water (500 μL) A mixture of [(1R)-2,2,2-trifluoro-1-methylethoxy]pyridine (100 mg, 360 μmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methylethoxy]pyridine (144.62 mg, 430 μmol), KCO (99.41 mg, 720 μmol), and Pd(dppf)Cl (39.47 mg, 50 μmol) was stirred at 80 °C for 12 h under N. After cooling to room temperature, the mixture was diluted with HO (10 mL), and the mixture was extracted with EtOAc (20 mL × 2). The combined organic phases were washed with water (10 mL) and brine (10 mL), dried over NaSO, filtered, and concentrated to give the crude product. The crude product was purified by preparative HPLC (Boston Prime C18 (150 mm × 30 mm, 5 μm), A = H2O (0.05% NH4OH) and B = CH3CN, 53-83% B over 8 min) to give the product as a solid. 1 H-NMR (400MHz, DMSO-d6) δ H =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 R t = 1.27 min in 2.0 min chromatography, MS ESI calculated C 18 H 13 F6N4O2[M+H] + 407.1, actual value 406.9.

[0249] Example 8: 3-[cyclopropylmethoxy(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine [ka] 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 CHCN (15 mL) was stirred at 90 °C for 14 days. After cooling to room temperature, the reaction was diluted with EtOAc (40 mL), saturated NaCl (40 mL) was added to the mixture, and the mixture was filtered through Celite, eluting with EtOAc (20 mL × 2). The filtrate was concentrated to give the crude product. The crude product was purified by preparative TLC (EtOAc:PE = 1:1) to give an impure product. The impure product was purified by preparative HPLC (Waters Xbridge 150 mm x 25 mm 5 μm) A = H2O (10 mM NH4HCO3) and B = CH3CN, 48-68% B over 8 min to give the product as a solid. 1 H-NMR (CDCl3, 400MHz) δ H =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 R t = 1.33 min in 2.0 min chromatography, C 17 H 14 F6N5O2[M+H] + MS ESI calculated value for 434.1, found value 434.0.

[0250] Example 9: 3-[cyclopropylmethoxy(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine [ka] Synthesis of A19: A mixture of Pd(dppf)Cl (15.13 g, 20.68 mmol), CsCO (269.49 g, 827.17 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (141.18 g, 439.69 mmol), and 2-bromo-5-chloro-pyrazine (80 g, 413.59 mmol) in 1,4-dioxane (1 L) and water (150 mL) under N was stirred at 35° C. for 2 h. After cooling to room temperature, water (300 mL) was added to the mixture, and the mixture was filtered through Celite. After separation, the organic phase was washed with brine (300 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product. The crude product was redissolved in EA / PE = 1 / 3 (500 mL) and then filtered through a silica gel mat. The cake was washed with EA / PE = 1 / 3 (500 mL). The combined organic phase was concentrated to give the residue as an oil. PE (500 mL) was slowly added to the oil to give some solid. The solid was collected and dried in an oven to give the product (100 g, 242.4 mmol, 58% yield) as a solid. LCMS R t = 1.28 min in 2.0 min chromatography, 10-80AB, C 11 H7ClF4N3O[M+H] + MS ESI calculated value for 308.0, found value 307.9.

[0251] Synthesis of A20: 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 poured into water (4.5 L). Some solid was observed, and the solid was collected by filtration. The cake was washed with water (500 mL×2). The solid was redissolved in EtOAc (3 L), washed with brine (500 mL×2), dried over anhydrous NaSO, filtered, and concentrated to give the crude product (100 g, 329.8 mmol, 97% yield) as a solid. LCMS Rt = 0.74 min in 1.5 min chromatography, 5-95AB, C 11 H 10 F4N5O[M+H] + MS ESI calculated value for 304.1, found value 303.9.

[0252] Synthesis of A13: To a solution of 2-bromo-2,2-difluoroacetic acid (87 g, 497.34 mmol) in THF (1 L) was added 1 drop of DMF and (COCl) (50.5 mL, 596.81 mmol). The resulting mixture was stirred at 20 °C for 1 h. The resulting solution was used directly in the next step. To a solution of 2-bromo-2,2-difluoro-acetyl chloride (95.66 g, 494.69 mmol) in THF (1 L) was added [5-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-2-methylpropional]. To the resulting mixture was added [diethyl]pyrazin-2-yl]hydrazine (100 g, 329.79 mmol). The resulting mixture was stirred at 20° C. for 2 hours. To the solution was added water (1 L) and extracted with EtOAc (1 L×2). The combined organic phases were washed with brine (500 mL×2), dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product (150 g, 326.0 mmol, 98% yield, mixture of mono- and bis-alkylated products) as a solid. LCMS R t = 0.92 min in 1.5 min chromatography, 5-95AB, C 13 H9BrF6N5O2[M+H] + MS ESI calculated value for 460.1, found value 459.8.

[0253] Synthesis of A14: A solution of 2-bromo-2,2-difluoro-N'-[5-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]pyrazin-2-yl]acetohydrazide (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 h. 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 give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 15% to 30%) to give the product (80 g, 181.0 mmol, 55% yield) as an oil. 1 H NMR (CDCl, 400MHz)δ H =9.60(d, 1H), 8.55(d, 1H), 8.45(s, 1H), 8.09(dd, 1H), 4.93(q, 2H).

[0254] Synthesis of Compound 10: 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 AgBF (66.93 g, 343.81 mmol) in ethanol (760 mL) was stirred at 60 °C for 1 h. After cooling to room temperature, the mixture was poured into saturated aqueous NaCl (1 L) and EtOAc (2 L). The mixture was filtered through Celite. After separation, the aqueous layer was extracted with EtOAc (500 mL × 2). The combined organic phases were washed with brine (500 mL × 2), dried over anhydrous NaSO, filtered, and concentrated to give the crude product. The crude product was purified by flash column chromatography on silica gel (EtOAc in PE = 0% to 30% to 50%) and then triturated from EtOH (50 mL) to give the product (44.45 g, 109.01 mmol, 63% yield) as a solid. 1 H NMR (CDCl3 400 MHz) δ H=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 R t = 2.0 min chromatography, 1.25 min, 10-80AB, C 15 H 12 F6N5O2[M+H] + MS ESI calculated value for 408.1, found value 408.0.

[0255] Example 10: 3-[Difluoro(methoxy)methyl]-6-[5-fluoro-6-[1-(trifluoromethyl)cyclobutoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine [ka] 3-[chloro(difluoromethyl)methyl]-2-(2-chloro-2-methyl-1-propanol) in a mixed solvent of methanol (14 mL) and DMF (14 mL) A mixture of [(2,3-dimethyl-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) was stirred at 90 °C for 24 h. After cooling to room temperature, the reaction mixture was treated with brine (40 mL), and the precipitate was filtered. The filtrate was extracted with EtOAc (40 mL × 2). The combined organic phases were washed with brine (20 mL), dried over NaSO, and concentrated to give the crude product. The crude product was purified by preparative HPLC (Waters Xbridge (150 mm × 25 mm 5 μm) A = HO (10 mM NHHCO) and B = CHCN, 57–67% B over 8 min) to give the product (240 mg). Another batch was started with 1.2 g of A24 and approximately 110 mg of product was obtained by preparative HPLC (Boston Prime C18 (150 mm × 30 mm, 5 μm) A = HO (0.05% NH4OH) and B = CH3CN, 50-80% B over 9 min). The two batches of product were combined and lyophilized to give the product as a solid.1 H NMR (CDCl3, 400MHz) δ H =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 R t = 2 min chromatography, 1.30 min, 10-80AB, C 17 H 14 F6N5O2[M+H] + MS ESI calculated value for 434.1, found value 433.9.

[0256] Example 11: 3-[Difluoro(methoxy)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyridazine [ka] Synthesis of A25: A mixture of 6-chloro-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-b]pyridazine (120 mg, 0.50 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (201.9 mg, 0.60 mmol), KPO (319.74 mg, 1.51 mmol), and Pd(t-BuP) (25.66 mg, 0.05 mmol) in 1,4-dioxane (12 mL) and HO (4 mL) was stirred at 90 °C for 16 h. After cooling to room temperature, the reaction mixture was concentrated, diluted with water (20 mL), and extracted with ethyl acetate (20 mL × 2). The combined organic phase was washed with brine (40 mL) and concentrated over Na2SO4 Drying and concentration gave a residue, which was purified by flash chromatography on silica gel (0% to 60% EtOAc in PE) to give the product (120 mg, 0.29 mmol) as a solid. 1 H-NMR (CDCl3, 400MHz) δH =8.57(d, 1H), 8.35(d, 1H), 8.15(dd, 1H), 7.74(d, 1H), 5.93(m, 1H)1.61(d, 3H).

[0257] Synthesis of Compound 12: A mixture of AgOTf (599.15 mg, 2.33 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-b]pyridazine (120 mg, 0.29 mmol) in methanol (6 mL) was stirred at 90 °C for 120 h. After cooling to room temperature, the reaction mixture was treated with brine (20 mL), and the precipitate was filtered. 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 NaSO, and concentrated to give a residue. The residue was purified by preparative HPLC (Boston Purification by Prime C18 150 x 30 mm 5 μm) A = H2O (0.05% NH4OH) and B = CH3CN, 52-82% B over 8 min gave the product (5.12 mg, 13 μmol). 1 H-NMR (CDCl3, 400MHz) δ H =8.55(d, 1H), 8.30(d, 1H), 8.14(dd, 1H), 7.66(d, 1H), 5.92(m, 1H), 3.94(s, 3H), 1.61(d, 3H). LCMS R t = 1.28 min in 2.0 min chromatography, C 15 H 12 F6N5O2[M+H] + MS ESI calculated value for 408.1, found value 408.0.

[0258] Example 12: 3-[Difluoro(methoxy)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyridazine [ka] Synthesis of A26: A mixture of 6-chloro-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-b]pyridazine (120 mg, 0.50 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (201.9 mg, 0.60 mmol), KPO (319.74 mg, 1.51 mmol), and Pd(t-BuP) (25.66 mg, 0.05 mmol) in 1,4-dioxane (12 mL) and HO (4 mL) was heated at 90 °C for 16 h. 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 give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 60%) to give the product (140 mg, 0.34 mmol) as a solid. 1 H-NMR (CDCl3, 400MHz) δ H =8.57(d, 1H), 8.35(d, 1H), 8.14(dd, 1H), 7.74(d, 1H), 5.93(m, 1H), 1.61(d, 3H).

[0259] Synthesis of Compound 13: 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]pyridazine (140 mg, 0.34 mmol), AgOTf (699 mg, 2.72 mmol) in methanol (8 mL) was stirred at 90 °C for 120 h. After cooling to room temperature, the reaction mixture was treated with brine (20 mL), and the precipitate was filtered. The filtrate was concentrated, 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 Na SO , and concentrated to give a residue. The residue was purified by preparative HPLC (Boston Prime C18 150 x 30 mm 5 μM) A = H2O (0.05% NH4OH) and B = CH3CN, 52-82% B over 8 min) to give the product (5 mg, 12.2 μmol). 1 H-NMR (CDCl3, 400MHz) δ H =8.55(d, 1H), 8.30(d, 1H), 8.14(dd, 1H), 7.66(d, 1H), 5.92(m, 1H), 3.94(s, 3H), 1.61(d, 3H). LCMS R t = 1.26 min in 2.0 min chromatography C 15 H 12 F6N5O2[M+H] + MS ESI calculated value for 408.1, found value 408.0.

[0260] Example 13: 3-[cyclopropylmethoxy(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyridazine [ka] Synthesis of A27: 6-chloro-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-b]pyridazine (500 mg, 2.09 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (2015.06 mg, 6.28 mmol), Pd(t-BuP) (160.37 mg, 0.31 mmol), and KPO (888.25 mg, 4 mmol) in 1,4-dioxane (15 mL) and water (1.5 mL). A mixture of 1.000 mg (0.18 mmol) of 1,000 sachets ... 13 H7ClF6N5O[M+H] + 398.0, actual value 398.0.

[0261] Synthesis of Compound 14: A mixture of 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyridazine (200 mg, 0.50 mmol) and AgOTf (1292.26 mg, 5.03 mmol) in cyclopropylmethanol (10 mL, 0.50 mmol) and CHCN (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 Celite, eluting with EtOAc (20 mL × 2), and the filtrate was concentrated to give the crude product. The crude product was purified by preparative HPLC (Boston Prime C18 150 mm × 30 mm 5 μm) using A = HO (0.05% NH4OH v / v) and B = CH3CN (58–88% B over 8 min) to give impure product. The impure product was triturated from n-hexane / i-Pr2O3 (v / v = 1:1, 2 mL) to give the product (9.82 mg, 22.2 μmol) as a solid. 1 H NMR (DMSO-d6, 400MHz) δ H =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 R t = 2.87 min in 4.0 min chromatography, C 17 H 14 F6N5O2[M+H] + MS ESI calculated value for 434.1, found value 434.0.

[0262] Example 14: 3-[Difluoro(methoxy)methyl]-6-[5-fluoro-6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine [ka] Synthesis of A29: 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-difluoro-acetyl) 2-chloro-2,2-difluoro-acetate (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 give a residue. To the residue was added water (50 mL), and the mixture was diluted with EtOAc (50 mL×2). The combined organic phase was washed with water (50 mL), brine (50 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 10% to 20%) to give the product (150 mg, 346.3 μmol) as a solid. LCMS R t = 3.06 min in 4.0 min chromatography, C 15 H 11 ClF6N5O[M+H] + MS ESI calculated value for 426.0, found value 426.0.

[0263] Synthesis of Compound 15: 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) was added AgOTf (1.81 g, 7.05 mmol). The resulting mixture was stirred at 90 °C in a sealed tube under N 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), brine (20 mL × 2), dried over anhydrous NaSO, filtered, and concentrated to give the crude product. The crude product was purified by preparative TLC (PE: EtOAc = 4:1) to give the product (14.23 mg, 33.2 mmol) as a solid. 1H NMR (CDCl3, 400MHz) δ H= 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 R t = 1.33 min in 2.0 min chromatography, C 16 H 14 F6N5O2[M+H] + MS ESI calculated value for 422.1, found value 422.0.

[0264] Example 15: 3-[ethoxy(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyridazine [ka] A mixture of 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyridazine (200 mg, 0.50 mmol) and AgOTf (1292.26 mg, 5.03 mmol) in ethanol (10 mL, 0.50 mmol) and CHCN (10 mL) was stirred at 90 °C for 13 days. After cooling to room temperature, the reaction was diluted with EtOAc (40 mL) and brine (40 mL). The mixture was filtered through Celite, eluting with EtOAc (20 mL × 2), and the filtrate was concentrated to give the crude product. The crude product was purified by preparative TLC (EtOAc:DCM:PE = 1:1:1) to give an impure product. The impure product was triturated from n-hexane / CH2Cl2 (v / v = 1:2, 6 mL) to give the product (15.95 mg, 39.2 mmol) as a solid. 1 H NMR (DMSO-d6, 400MHz) δ H =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 R t= 1.26 min in 2.0 min chromatography, C 15 H 12 F6N5O2[M+H] + MS ESI calculated value for 408.1, found value 408.0.

[0265] Example 16: 3-[difluoro(methoxy)methyl]-6-[5-fluoro-6-[1- (Trifluoromethyl)cyclobutoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyridazine [ka] Synthesis of A7-a: To a mixture of (6-chloropyridazin-3-yl)hydrazine (3.0 g, 20.75 mmol) in toluene (40 mL), (2-chloro-2,2-difluoro-acetyl)-2-chloro-2,2-difluoro-acetate (7.56 g, 31.13 mmol) was added. 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 NaHCO (50 mL), and the mixture was extracted with EtOAc (50 mL × 2). The combined organic phases were washed with brine (20 mL), dried over NaSO, filtered, and concentrated to give the crude product (4700 mg, 19.66 mmol) as a solid. 1 H NMR (400 MHz, CDCl) δ H =7.35(d, 1H), 8.23(d, 1H).

[0266] Synthesis of A30: A mixture of 6-chloro-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-b]pyridazine (150 mg, 0.63 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[1-(trifluoromethyl)cyclobutoxy]pyridine (362.64 mg, 1 mmol), KPO (399.65 mg, 1.88 mmol), and 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 h. TLC showed a new spot (Rf = 0.45, UV) and no starting material (Rf = 0.8, UV) remained. 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 give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 60%) to give the product (120 mg, 0.27 mmol) as a solid. 1 H NMR (CDCl3, 400MHz) δ H =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).

[0267] Synthesis of Compound 17: A mixture of 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[1-(trifluoromethyl)cyclobutoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyridazine (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 h. After cooling to room temperature, the reaction mixture was The reaction mixture was treated with brine (20 mL), and the precipitate was filtered. 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 NaSO, and concentrated to give a residue. The crude product was purified by preparative HPLC (Boston Prime C18 150 mm × 30 mm 5 μm) A = HO (0.05% NHOH) and B = ACN, 52–82% B over 8 min) to give the product (27.93 mg, 64.5 μmol) as a solid. 1 H NMR (CDCl3, 400MHz) δ H =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 R t = 1.32 min in 2.0 min chromatography, C 17 H 14 F6N5O2[M+H] + MS ESI calculated value for 434.1, found value 434.0.

[0268] Example 17: 3-[Difluoro(methoxy)methyl]-6-[5-fluoro-6-[1-(trifluoromethyl)cyclobutoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyridine [ka] Synthesis of A1: A mixture of (5-bromo-2-pyridyl)hydrazine (2.6 g, 13.83 mmol) and (2-chloro-2,2-difluoro-acetyl)2-chloro-2,2-difluoro-acetate (5.04 g, 20.74 mmol) in toluene (100 mL) was stirred at 10 °C for 1 hour, and then the mixture was warmed to 120 °C and stirred for 36 hours. After cooling to room temperature, the reaction was quenched with saturated NaHCO (50 mL), and the mixture was extracted with EtOAc (50 mL × 2). The organic layer was washed with brine (50 mL), dried over NaSO, filtered, and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 20% to 30%) to give the product (3900 mg, 13.81 mmol) as a solid. 1 H NMR (400 MHz, CDCl) δ H =8.42(s, 1H), 7.84(d, 1H), 7.53(dd, 1H). LCMS R t = 3.19 min in 7.0 min chromatography, C7H4BrClF2N3[M+H+2] + MS ESI calculated value for 283.9, found value 283.6.

[0269] Synthesis of A15: 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 h. After cooling to room temperature, the reaction 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 (5 mL). The mixture was washed with 100 mL of HCl, dried over NaSO, filtered, and concentrated to give the crude product, which was purified by flash chromatography on silica gel (0% to 30% to 40% EtOAc in PE) to give the product (380 mg, 127.56 μmol) as a solid. 1 H-NMR (CDCl3, 400MHz) δ H =8.43(s, 1H), 7.77(d, 1H), 7.47-7.41(m, 1H), 3.92(s, 3H). LCMS R t = 2.95 min in 7.0 min chromatography, C8H7BrF2N3O[M+H+2] + MS ESI calculated value for 280.0, found value 279.7.

[0270] Synthesis of compound 18: 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-dioxaborolan-2-yl)-2-[1-(trifluoromethyl)cyclobutoxy]pyridine (155.86 mg, 0.43 mmol), KCO (99.41 mg, 0.72 mmol), and Pd(dppf)Cl (39.47 mg, 0.05 mmol) in 1,4-dioxane (5 mL) and water (0.50 mL) was stirred at 80 °C for 12 h. After cooling to room temperature, the mixture was diluted with HO (10 mL), and the mixture was extracted with EtOAc (20 mL × 2). The combined organic phases were washed with water (30 mL) and brine (10 mL), dried over NaSO, filtered, and concentrated to give the crude product, which was purified by preparative HPLC (Boston Prime C18 (150 mm × 30 mm, 5 μm), A = HO (0.05% NHOH) and B = CHCN, 58–88% B over 8 min) to give the product (66.89 mg, 15.47 μmol) as a solid. 1 H NMR (DMSO-d6, 400MHz) δ H =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 R t = 1.32 min in 2.0 min chromatography, MS ESI calculated C 18 H 15 F6N4O2[M+H]+ 433.1, actual value 432.9.

[0271] Example 18: Synthesis of 3-[cyclopropylmethoxy(difluoro)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyridine [ka] 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-dioxaborolan-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (82.16 mg, 250 μmol), KCO (56.48 mg, 410 μmol), and Pd(dppf)Cl (22.43 mg, 30 μmol) in 1,4-dioxane (5 mL) and water (0.50 mL) was stirred at 80 °C for 12 h under N. After cooling to room temperature, the mixture was diluted with HO (10 mL), and the mixture was extracted with EtOAc (20 mL × 2). The combined organic phase was washed with water (20 mL) and brine (30 mL) and Drying over aSO, filtration, and concentration gave the crude product, which was purified by preparative HPLC (Boston Prime C18 (150 × 30 mm, 5 μm) A = HO (0.05% NHOH) and B = CHCN, 62–92% B over 8 min) to give the product (43.42 mg, 97.3 μmol, 48% yield) as a solid. 1 H NMR (DMSO-d6, 400MHz) δ H =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 R t = 1.37 min in 2.0 min chromatography, 10-80AB, MS ESI calculated C 19 H 17 F6N4O2[M+H] + 447.1, actual value 447.0.

[0272] Example 19: 3-[Difluoro(isopropoxy)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyridine [ka] 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-dioxaborolan-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (91.96 mg, 270 μmol), KCO (63.21 mg, 460 μmol), and Pd(dppf)Cl (25.1 mg, 30 μmol) in 1,4-dioxane (5 mL) and water (0.50 mL) was stirred at 80 °C for 12 h under N. After cooling to room temperature, the mixture was diluted with HO (10 mL), and the mixture was extracted with EtOAc (20 mL × 2). The combined organic phases were washed with water (20 mL) and brine (30 mL), dried over NaSO, filtered, and concentrated to give the crude product, which was purified by preparative HPLC (Boston Prime C18 (150 × 30 mm, 5 μm), A = HO (0.05% NHOH) and B = CHCN, 60–90% B over 8 min) to give the product (33.94 mg, 78.1 μmol, 34% yield) as a solid. 1 H NMR (DMSO-d6, 400MHz) δ H=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 R t = 1.35 min with 2.0 min chromatography, 10-80AB, MS ESI calculated C 18 H 17 F6N4O2[M+H] + 435.1, actual value 435.0.

[0273] Example 20: 3-[Difluoro(isopropoxy)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyridine [ka] A mixture of 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methylethoxy]pyridine (84.29 mg, 0.25 mmol), Pd(dppf)Cl (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 KCO (63.21 mg, 0.46 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was stirred at 90 °C for 16 h under N. After cooling to room temperature, the mixture was filtered through Celite, eluting with EtOAc (10 mL × 2), and the filtrate was concentrated to give the crude product. The crude product was purified by preparative HPLC (Boston Prime C18 (150 mm × 30 mm 5 μm) A = HO (0.05% ammonia hydroxide vol / vol) and B = CH3CN, 60–90% B over 8 min) to give the product (24.78 mg, 57.1 μmol, 25% yield) as a solid. 1 H NMR (DMSO-d6, 400MHz) δ H=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 R t = 1.37 min in 2.0 min chromatography, 10-80AB, C 18 H 17 F6N4O2[M+H] + MS ESI calculated value for 435.1, found value 435.1.

[0274] Example 21: 3-[Difluoro(isobutoxy)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyridine [ka] Synthesis of A1-a: A mixture of (5-bromo-2-pyridyl)hydrazine (5 g, 26.59 mmol) and (2-chloro-2,2-difluoro-acetyl) 2-chloro-2,2-difluoro-acetate (9690.21 mg, 39.89 mmol) in toluene (200 mL) was stirred for 1 h at 10 °C, and then the mixture was heated to 120 °C for 36 h. After cooling to room temperature, the reaction was quenched with saturated NaHCO (200 mL), and then the mixture was The product was extracted with EtOAc (80 mL × 2). The organic layer was washed with brine (200 mL), dried over NaSO, filtered, and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 5% to 20%) to give the product (5700 mg, 20.18 mmol, 76% yield) as a solid. 1 H NMR (CDCl3, 400MHz) δ H =8.43(s, 1H), 7.84(dd, 1H), 7.54(dd, 1H).

[0275] Synthesis of A4-a: To a mixture of 2-methylpropan-1-ol (1312 mg, 17.7 mmol) in THF (40 mL) was added NaH (708.04 mg, 17.7 mmol), 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 was quenched with saturated NH Cl (40 mL), and the mixture was extracted with EtOAc (30 mL × 2). The combined organic phase was washed with brine (70 mL), dried over Na SO , filtered, and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (10% to 40% EtOAc in PE) to give the product (750 mg, 2.34 mmol, 66% yield) as an oil. 1 H NMR (CDCl3, 400MHz) δ H =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).

[0276] Synthesis of Compound 22: 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-dioxaborolan-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (125.61 mg, 370 μmol), KCO (86.35 mg, 620 μmol), and Pd(dppf)Cl (34.28 mg, 50 μmol) in 1,4-dioxane (5 mL) and water (0.50 mL) was stirred at 80 °C for 12 h under N. After cooling to room temperature, the mixture was diluted with HO (10 mL) and then extracted with EtOAc (20 mL × 2). The combined organic phases were washed with water (20 mL) and brine (30 mL), dried over NaSO, filtered, and concentrated to give the crude product, which was purified by preparative HPLC (Boston Prime C18 (150 × 30 mm, 5 μm), A = HO (0.05% NHOH) and B = CHCN, 65–95% B over 8 min) to give the product (47.11 mg, 105.1 μmol, 34% yield) as a solid. 1 H NMR (DMSO-d6, 400MHz) δ H= 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 R t = 1.41 min in 2.0 min chromatography, 10-80AB, MS ESI calculated C 19 H 19 F6N4O2[M+H] + 449.1, actual value 449.1.

[0277] Example 22: 3-[Difluoro(isobutoxy)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyridine [ka] A mixture of 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (115.14 mg, 0.34 mmol), Pd(dppf)Cl (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 KCO (86.35 mg, 0.62 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was stirred at 90 °C for 16 h under N. After cooling to room temperature, the mixture was filtered through Celite, eluting with EtOAc (10 mL × 2), and the filtrate was concentrated to give the crude product. The crude product was purified by preparative HPLC (Boston Prime Purification by HPLC with C18 (150 mm x 30 mm, 5 μm) A = HO (0.05% ammonia hydroxide vol / vol) and B = CHCN, 61-91% B over 8 min, gave the product (68.11 mg, 0.15 mmol, 48% yield) as a solid. 1 H NMR (DMSO-d6, 400MHz) δ H =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 R t = 1.42 min in 2.0 min chromatography, 10-80AB C 19 H 19 F6N4O2[M+H] + MS ESI calculated value for 449.1, found value 449.1.

[0278] Example 23: 3-[Difluoro(methoxy)methyl]-6-[5-fluoro-6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyridine [ka] Synthesis of A15-a: 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 was quenched with saturated NH4Cl (50 mL), and the mixture was then extracted with EtOAc (50 mL x 2). The organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 30% to 40%) to give the product (230 mg, 754.3 μmol, 21% yield) as an oil. LCMS R t = 1.41 min in 1.5 min chromatography, 5-95AB, MS ESI calculated C8H8BrF2N3O [M+H+2] + 280.0, actual value 279.9.

[0279] Synthesis of compound 24: 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-dioxaborolan-2-yl)-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)pyridine (105.47 mg, 300 μmol), KCO (69.59 mg, 500 μmol), and Pd(dppf)Cl (27.63 mg, 40 μmol) in 1,4-dioxane (5 mL) and water (0.50 mL) was stirred at 80 °C for 12 h under N. After cooling to room temperature, the mixture was diluted with HO (20 mL), and the mixture was extracted with EtOAc (20 mL × 2). The combined organic phases were washed with water (30 mL) and brine (30 mL), dried over NaSO, filtered, and concentrated to give the crude product, which was purified by preparative HPLC (Boston Prime C18 (150 × 30 mm, 5 μm), A = HO (0.05% NHOH) and B = CHCN; 56–86% B over 8 min) to give the product (22.72 mg, 54.1 μmol, 21% yield) as a solid. 1 H NMR (DMSO-d6, 400MHz) δ H =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 R t = 1.31 min in 2.0 min chromatography, 10-80AB, MS ESI calculated C 17 H 15 F6N4O2[M+H] + 421.1, actual value 421.1.

[0280] Example 24: 3-[Cyclopropylmethoxy(difluoro)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyridine [ka] A mixture of 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (69.52 mg, 0.21 mmol), Pd(dppf)Cl (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 KCO (52.14 mg, 0.38 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was stirred at 90 °C for 16 h under N. After cooling to room temperature, the mixture was filtered through Celite, eluting with EtOAc (10 mL × 2), and the filtrate was concentrated to give the crude product. The crude product was purified by preparative HPLC (Boston Prime C18 150 mm × 30 mm 5 μm) A = HO (0.05% ammonia hydroxide vol / vol) and B = CH3CN, 60–90% B over 8 min, to give the product (51.82 mg, 0.12 mmol, 62% yield) as a solid. 1 H NMR (DMSO-d6, 400MHz) δ H =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 R t = 1.39 min in 2.0 min chromatography, 10-80AB C 19 H 17 F6N4O2[M+H] + MS ESI calculated value for 447.1, found value 447.1.

[0281] Example 25: 3-[ethoxy(difluoro)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine [ka] 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, and the resulting suspension was filtered through Celite. The filtrate was separated, and the aqueous phase was extracted with EtOAc (50 mL). The combined organic phase was dried over anhydrous NaSO, filtered, and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (10% to 30% to 50% EtOAc in PE) and then triturated from DCM (3 mL) and n-hexane (4 mL) to give the product (31.35 mg, 74 μmol, 6% yield) as a solid. 1 H NMR (CDCl3, 400MHz) δ H =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 R t = 1.35 min with 2 min chromatography, 10-80AB, C 16 H 14 F6N5O2[M+H] + MS ESI calculated value for 422.1, found value 422.1.

[0282] Example 26: 6-[5-fluoro-6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridyl]-3-(methoxymethyl)-[1,2,4]triazolo[4,3-b]pyridazine [ka] A mixture of 6-chloro-3-(methoxymethyl)-[1,2,4]triazolo[4,3-b]pyridazine (100 mg, 0.5 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)pyridine (210.94 mg, 0.6 mmol), KPO (213.79 mg, 1.01 mmol), and Pd(t-BuP) (38.6 mg, 0.08 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was stirred at 80 °C for 16 h under N. After cooling to room temperature, the mixture was diluted with HO (10 mL), and the mixture was extracted with EtOAc (20 mL × 2). The combined organic phase was The mixture was washed with water (10 mL) and brine (10 mL), dried over NaSO, filtered, and concentrated to give the crude product, which was purified by preparative HPLC (Boston Prime C18 (150 mm × 30 mm, 5 μm; mobile phase: [water (0.05% NHOH)-ACN]; B%: 40-70%, 9 min) to give the product (47.66 mg, 0.12 mmol, 25% yield) as a solid. 1 H NMR (CDCl3, 400MHz) δ H =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 R t = 2.0 min chromatography at 1.21 min, 10-80AB, C 16 H 16 F4N5O2[M+H] + MS ESI calculated value for 386.1, found value 386.0.

[0283] Example 27: 6-[5-fluoro-6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridyl]-3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyridine [ka] Synthesis of A33: To a solution of (5-bromo-2-pyridyl)hydrazine (8.5 g, 45.21 mmol) in toluene (80 mL) was added 2-methoxyacetyl chloride (5.4 g, 49.73 mmol) dropwise at 25° C. The solution was stirred at 25° C. for 30 minutes and then refluxed at 120° C. for 48 hours. After cooling to room temperature, the reaction mixture was concentrated to give a residue. The residue was triturated from DCM (100 mL) to give the product (3.0 g, 10.01 mmol, 22% yield) as a solid. 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).

[0284] Synthesis of compound 28: 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-dioxaborolan-2-yl)-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)pyridine (259.61 mg, 0.74 mmol), KCO (171.29 mg, 1.24 mmol), and Pd(dppf)Cl (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 h. After cooling to room temperature, the reaction mixture was concentrated, diluted with HO (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 give the crude product. The crude product was purified by preparative HPLC (YMC-Actus Purification on Triart C18 (100 mm × 30 mm, 5 μm) with A = HO (0.05% HCl) and B = CH3CN (50–75% B over 8 min) gave the product in CH3CN / HO (approximately 150 mL). The solution was concentrated to remove most of the CH3CN, basified with NaHCO3 (solid) to pH ∼9, and then extracted with DCM (50 mL × 3). The combined organic phases were concentrated to give the product (121.16 mg, 0.32 mmol, 51% yield) as a solid. 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 R t = 2.0 min chromatography, 1.25 min, 10-80AB, C 17 H 17 F4N4O2[M+ H] + MS ESI calculated value for 385.1, found value 384.9.

[0285] Example 28: 6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyridine [ka] 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-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (238.75 mg, 0.74 mmol), KCO (171.29 mg, 1.24 mmol), and Pd(dppf)Cl (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 h. After cooling to room temperature, the reaction was concentrated, diluted with HO (20 mL), and then extracted with DCM (20 mL × 2). The combined organic phases were washed with brine (30 mL), dried over NaSO, filtered, and concentrated to give the crude product, which was purified by preparative HPLC (Boston Prime C18 (150 mm × 30 mm, 5 μm) A = HO (0.05% NHOH) and B = CHCN, 40–70% B in 8 min) to give the product (141.29 mg, 0.39 mmol, 64% yield) as a solid. 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 R t = 1.17 min in 2.0 min chromatography, 10-80AB, C 15 H 13 F4N4O2[M+H] + MS Calculated ESI value: 357.1, measured value: 356.9.

[0286] Example 29: 3-[Difluoro(methoxy)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyridine [ka] 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-dioxaborolan-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 heated at 80°C. The mixture was stirred at rt for 12 h under N2. After cooling to room temperature, the mixture was diluted with HO (10 mL), and the mixture was 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 give the crude product. The crude product was first purified by preparative HPLC (Boston Prime C18 (150 mm × 30 mm, 5 μm), A = HO (0.05% NH4OH) and B = CH3CN, 43–73% B over 8 min), and then by preparative HPLC (Boston Green ODS (150 mm × 30 mm, 5 μm), A = HO (0.075% TFA) and B = CH3CN, 49–63% B over 10 min). The combined fractions were concentrated to remove ACN, basified with saturated NaHCO to pH 8, and the mixture was extracted with EtOAc (30 mL × 2). The combined organic phases were washed with brine (40 mL), dried over NaSO, filtered, and concentrated to give the product (41.36 mg, 105.4 μmol, 42% yield) as a solid. 1 H NMR (DMSO-d6, 400MHz) δ H= 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 R t = 1.19 min in 2.0 min chromatography, 10-80AB, MS ESI calculated C 15 H 11 F6N4O2[M+H] +393.1, actual value 393.0.

[0287] Example 30: 6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyrazine [ka] 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-dioxaborolan-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (141.73 mg, 0.42 mmol), CsCO (229.66 mg, 0.70 mmol), and Pd(dppf)Cl (38.68 mg, 0.05 mmol) in 1,4-dioxane (5 mL) and water (0.50 mL) was stirred at 70 °C for 5 h under N. After cooling to room temperature, the mixture was diluted with HO (20 mL) and extracted with EtOAc (30 mL × 2). The combined organic phases were washed with water (30 mL) and brine (30 mL), dried over Na2SO4, filtered, and concentrated to give the crude product. The crude product was first purified by preparative TLC (silica gel, PE:EtOAc = 1:1). The resulting product was purified by preparative HPLC (Boston Prime C18 (150 mm × 30 mm, 5 μm), A = HO (0.05% NH4OH) and B = CH3CN, 38–68% B over 9 min) to give the product (4.43 mg, 11.9 μmol, 3% yield) as a solid. 1 H NMR (CDCl3, 400MHz) δ H =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 R t = 1.18 min in 2.0 min chromatography, 10-80AB, MS ESI calculated C15 H 14 F4N5O2[M+H] + 372.1, actual value 371.9.

[0288] Example 31: 3-[ethoxy(difluoro)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyridine [ka] 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-dioxaborolan-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (137.67 mg, 0.41 mmol), KCO (94.64 mg, 0.68 mmol), and Pd(dppf)Cl (37.58 mg, 0.05 mmol) in 1,4-dioxane (5 mL) and water (0.50 mL) was stirred at 80 °C for 12 h under N. After cooling to room temperature, the mixture was diluted with HO (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 NaSO, filtered, and concentrated to give the crude product, which was purified by preparative HPLC (Boston Prime C18 (150 mm × 30 mm, 5 μm), A = HO (0.05% NHOH) and B = CHCN, 60–90% B over 9 min) to give the product (39.75 mg, 93.5 μmol, 27% yield) as a solid. 1 H NMR (DMSO-d6, 400MHz) δ H =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 R t= 1.28 min in 2.0 min chromatography, 10-80AB MS ESI calculated C 17 H 15 F6N4O2[M+H] + 421.1, actual value 421.0.

[0289] Example 32: 3-[ethoxy(difluoro)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine [ka] 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 cooled to room temperature. EtOAc (50 mL) and brine (50 mL) were added to the mixture, and the mixture was filtered through Celite. The liquids were separated, and the aqueous layer was extracted with EtOAc (50 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (10% to 30% to 50% EtOAc in PE) and then triturated with n-hexane (5 mL) to give the product (41.27 mg, 98.0 μmol, 20% yield) as a solid. 1 H NMR (CDCl, 400MHz)δ H =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 R t = 1.29 min in 2.0 min chromatography, 10-80AB, C 16 H 14 F6N5O2[M+H]+ MS ESI calculated value for 422.1, found value 422.0.

[0290] Example 33: 3-[ethoxy(difluoro)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyridine [ka] A mixture of 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (126.2 mg, 0.38 mmol), Pd(dppf)Cl (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 KCO (94.64 mg, 0.68 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was stirred at 90 °C for 16 h under N. After cooling to room temperature, the mixture was filtered through Celite, eluting with EtOAc (10 mL × 2), and the filtrate was concentrated to give the crude product. The crude product was purified by preparative HPLC (Boston Prime C18 (150 mm × 30 mm, 5 μm) A = HO (0.05% NH4OH) and B = CH3CN, 45–75% B over 9 min) to give the product (62.87 mg, 0.15 mmol, 43% yield) as a solid. 1 H NMR (DMSO-d6, 400MHz) δ H =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 R t = 1.26 min in 2.0 min chromatography, 10-80AB, C 17 H 15 F6N4O2[M+H] +MS ESI calculated value for 421.1, found value 421.0.

[0291] Example 34: 6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-3-(methoxymethyl)-[1,2,4]triazolo[4,3-b]pyridazine [ka] A mixture of 6-chloro-3-(methoxymethyl)-[1,2,4]triazolo[4,3-b]pyridazine (100 mg, 0.50 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (194 mg, 0.60 mmol), KPO (213.79 mg, 1.01 mmol), and Pd(t-BuP) (38.6 mg, 0.08 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was stirred at 80 °C under N for 3 h. After cooling to room temperature, water (20 mL) and EtOAc (20 mL) were added to the mixture, and the mixture was filtered through Celite. After separation, the organic phase was washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated to give the crude product, which was purified by preparative HPLC (Boston Prime C18 (150 mm × 30 mm, 5 μm) A = HO (0.05% NHOH) and B = CHCN, 33–63% B over 8 min) to give the product (49 mg, 137.2 μmol, 27% yield) as a solid. 1 H NMR (CDCl3, 400MHz) δ H =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 R t = 1.08 min in 2.0 min chromatography, 10-80AB, C 14 H 12 F4N5O2[M+H] + MS ESI calculated value for 358.1, found value 357.9.

[0292] Example 35: 3-[Cyclopropoxy(difluoro)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyridine [ka] A mixture of 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (121.22 mg, 0.36 mmol), Pd(dppf)Cl (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 KCO (90.9 mg, 0.66 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was stirred at 90 °C for 16 h under N. After cooling to room temperature, the mixture was filtered through Celite, eluting with EtOAc (10 mL × 2), and the filtrate was concentrated to give the crude product. The crude product was analyzed by preparative HPLC (Boston Prime C18 (150 mm x 30 mm, 5 μm) A=H2O (0.05% NH4OH) and Purification by elution with B = CH3CN (47-77% B over 9 min) gave the product (54.98 mg, 0.13 mmol, 39% yield) as a solid. 1 H NMR (DMSO-d6, 400MHz) δ H =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 R t = 1.33 min in 2.0 min chromatography, 10-80AB C 18 H 15 F6N4O2[M+H] +MS ESI calculated value for 433.1, found value 433.1.

[0293] Example 36: 3-[Cyclopropoxy(difluoro)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyridine [ka] Synthesis of A36: To a mixture of cyclopropanol (246.74 mg, 4.25 mmol), 6-bromo-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyridine (600 mg, 2.12 mmol) in DMF (10 mL) was added potassium tert-butoxide (476.69 mg, 4.25 mmol). The reaction mixture was stirred at 20 °C for 2 h. The reaction was quenched with saturated NH Cl (40 mL), and then the mixture was extracted with EtOAc (50 mL × 2). The combined organic phases were washed with water (80 mL) and brine (80 mL), dried over Na SO , filtered, and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 20% to 40%) to give the product (270 mg, 0.89 mmol, 42% yield) as a solid. LCMS R t = 3.74 min in 7.0 min chromatography, 0-60AB MS ESI calculated C 10 H9BrF2N3O[M+H+2] + 306.0, actual value 305.8.

[0294] Synthesis of compound 37: 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-dioxaborolan-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (132.24 mg, 0.39 mmol), KCO (90.9 mg, 0.66 mmol), and Pd(dppf)Cl (36.09 mg, 0.05 mmol) in 1,4-dioxane (5 mL) and water (0.50 mL) was stirred at 80 °C for 12 h under N. After cooling to room temperature, the mixture was diluted with HO (10 mL), and the mixture was extracted with EtOAc (20 mL × 2). The combined organic phases were washed with water (10 mL) and brine (10 mL), dried over NaSO, filtered, and concentrated to give the crude product. The crude product was purified by preparative HPLC (Boston Prime C18 (150 mm × 30 mm, 5 μm), A = HO (0.05% NHOH) and B = CHCN; 50–70% B over 9 min) to give the product (35.99 mg, 83.2 μmol, 25% yield) as a solid. 1 H NMR (DMSO-d6, 400MHz) δ H =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 R t = 1.29 min in 2.0 min chromatography, 10-80AB, MS ESI calculated C 18 H 15 F6N4O2[M+H] + 433.1, actual value 433.0.

[0295] Example 37: 6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyrazine [ka] Synthesis of A37: To a mixture of 1,1,2-trimethoxyethane (1.25 g, 10.38 mmol) and (5-chloropyrazin-2-yl)hydrazine (1 g, 6.92 mmol) in ethanol (20 mL), 12 N HCl (1.73 mL, 20.75 mmol) was added, and the mixture was stirred at 20 °C for 20 h. Water (20 mL) was added to the mixture, which was then basified with NaCO (solid) to pH 9 and extracted with EtOAc (50 mL × 4). The combined organic phases were washed with brine (30 mL), dried over NaSO, filtered, and concentrated to give the crude product. The crude product was triturated from EtOAc / PE (2 / 10 mL) and dried in an oven to give 5-chloro-N-(2-methoxyethylideneamino)pyrazin-2-amine (1050 mg, 3.73 mmol, 54% yield) as a solid. LCMS R t = 0.70 min in 1.5 min chromatography, 5-95AB, C7H 10 ClNO[M+H] + MS ESI calculated value for 201.0, found value 201.0.

[0296] Synthesis of A38: To a mixture of 5-chloro-N-(2-methoxyethylideneamino)pyrazin-2-amine (1 g, 4.98 mmol) in DMF (10 mL) was added a solution of NBS (1.24 g, 6.98 mmol) in DMF (7 mL) dropwise over 0.5 h, and the mixture was then stirred at 20° C. for 1 h. The mixture was diluted with HO (50 mL) and extracted with EtOAc (50 mL×4). The combined organic phases were washed with brine (50 mL), dried over NaSO, filtered, and concentrated to give the crude product (1000 mg, 3.58 mmol, 72% yield) as a solid, which was used directly without any further purification. LCMS R t= 0.80 min in 1.5 min chromatography, 5-95AB, C7H9BrClN4O [M+H+2] + MS ESI calculated value for 281.0, found value 280.9.

[0297] Synthesis of A34: To a mixture of N-(5-chloropyrazin-2-yl)-2-methoxy-ethanehydrazonoyl bromide (1 g, 3.58 mmol) in toluene (15 mL), EtN (0.99 mL, 7.16 mmol) was added, and the mixture was stirred at 20 °C for 1 h. The mixture was diluted with HO (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 NaSO, filtered, and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 40% to 80%) to give the product (380 mg, 1.87 mmol, 52% yield) as a solid. 1 H NMR (CDCl3, 400MHz) δ H= 9.21(d, 1H), 8.28(d, 1H), 5.07(s, 2H), 3.45(s, 3H). LCMS R t = 0.30 min in 1.5 min chromatography, 5-95AB, C7H8ClNO4[M+H] + MS ESI calculated value for 199.0, found value 199.0.

[0298] Synthesis of compound 38: 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-dioxaborolan-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methylethoxy]pyridine (177.16 mg, 0.53 mmol), Pd(dppf)Cl (64.47 mg, 88.1 μmol), and CsCO (229.66 mg, 0.70 mmol) in 1,4-dioxane (8 mL) and water (0.80 mL) was stirred at 75 °C for 12 h under N. After cooling to room temperature, the mixture was diluted with HO (30 mL), and the mixture was 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 give the crude product. The crude product was first purified by preparative TLC (silica gel, PE:EtOAc = 1:1) and then by preparative HPLC [Boston Prime C18 (150 mm × 30 mm, 5 μm) A = HO (0.05% NH4OH) and B = CH3CN, 38–68% B over 9 min] to give the product (12.63 mg, 34.0 μmol, 10% yield) as a solid. 1 H NMR (CDCl3, 400MHz) δ H= 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 R t = 1.17 min in 2.0 min chromatography, 10-80AB C 15 H 14 F4N5O2[M+H] + MS ESI calculated value for 372.1, found value 371.9.

[0299] Example 38: 6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyrazine [ka] 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-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (169.75 mg, 0.53 mmol), Pd(dppf)Cl (64.47 mg, 88.1 μmol), and CsCO (229.66 mg, 0.70 mmol) in 1,4-dioxane (8 mL) and water (0.80 mL) was stirred at 75 °C for 12 h under N. After cooling to room temperature, the mixture was diluted with HO (20 mL), and the mixture was extracted with EtOAc (30 mL × 2). The combined organic phase was washed with water (20 mL) and brine (20 mL), dried over NaSO, filtered, and concentrated to give the crude product, which was purified by preparative TLC (silica gel, PE: EtOAc = 1:1) to give the product (14.65 mg, 40.7 μmol, 12% yield) as a solid. 1 H NMR (CDCl3, 400MHz) δ H= 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 R t = 1.19 min in 2.0 min chromatography, 10-80AB C 14 H 12 F4N5O2[M+H] + MS ESI calculated value for 358.1, found value 357.9.

[0300] Example 39: 6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyridine [ka] 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-dioxaborolan-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (332.23 mg, 0.99 mmol), KCO (228.38 mg, 1.65 mmol), and Pd(dppf)Cl (90.68 mg, 0.12 mmol) in 1,4-dioxane (15 mL) and water (5 mL) was heated at 85 °C for 16 h. After cooling to room temperature, the reaction was concentrated, diluted with HO (20 mL), and then extracted with DCM (20 mL × 2). The combined organic phases were washed with brine (30 mL), dried over NaSO, filtered, and concentrated to give the crude product, which was purified using preparative HPLC (Boston Prime C18 (150 mm × 30 mm 5 μm) A = HO (0.05% NHOH) and B = CHCN, 35–65% B over 9 min) to give the product (104.44 mg, 0.28 mmol, 34% yield) as a solid. 1 H NMR (DMSO-d6, 400MHz) δ H =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 R t = 2.0 min of chromatography at 1.150 min, 10-80AB, C 16 H 15 F4N4O2[M+H] + MS ESI calculated value for 371.1, found value 371.1.

[0301] Example 40: 3-[ethoxy(difluoro)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyridazine [ka] A solution 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]pyridazine (300 mg, 0.73 mmol) and AgOTf (1872.33 mg, 7.29 mmol) in ethanol (10 mL) and MeCN (10 mL) was added. The mixture of (i) was stirred at 90°C for 9 days. After cooling to room temperature, the reaction was diluted with EtOAc (60 mL), and brine (20 mL) was added to the mixture. The mixture was filtered through Celite and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (0% to 70% EtOAc in PE). The (i) product was then triturated from n-hexane (1 mL) and i-Pr2O (1 mL) to give the product (28.86 mg, 67.3 μmol, 9% yield) as a solid. 1 H NMR (CDCl3, 400MHz) δ H =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 R t = 1.27 min in 2.0 min chromatography, 10-80AB, MS ESI calculated C 16 H 14 F6N5O2[M+H] + 422.1, actual value 422.0.

[0302] Example 41: 3-[ethoxy(difluoro)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyridazine [ka] Synthesis of A26-a: A mixture of 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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]pyridazine (1 g, 4.18 mmol), Pd(t-BuP) (320.73 mg, 0.63 mmol), and KPO (1.78 g, 8.37 mmol) in 1,4-dioxane (20 mL) and water (4 mL) was stirred at 80 °C for 16 h under N. After cooling to room temperature, the mixture was filtered through Celite, eluting with EtOAc (20 mL × 2), and the filtrate was concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (30% to 60% EtOAc in PE) to give the product (1000 mg, 2.12 mmol, 51% yield) as a solid. LCMS R t = 0.93 min in 1.5 min chromatography, 5-95AB, C 14 H9ClF6N5O[M+H] + MS ESI calculated value for 412.0, found value 412.1.

[0303] Synthesis of Compound 42: 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]pyridazine (300 mg, 0.73 mmol) and AgOTf (1872.33 mg, 7.29 mmol) in ethanol (10 mL, 0.73 mmol) and CHCN (10 mL) was stirred at 90 °C for 8 days. After cooling to room temperature, the reaction was diluted with EtOAc (40 mL) and the mixture was washed with saturated NaCl ( The mixture was added to a 40 mL column, and the mixture was filtered through Celite, eluting with EtOAc (20 mL × 2). The filtrate was concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (0% to 50% to 100% EtOAc in PE). The product was further purified by preparative HPLC (Boston Prime C18 (150 mm × 30 mm 5 μm) A = HO (0.05% NH4OH v / v) and B = CH3CN, 51–81% B over 9 min) to give the product (8.12 mg, 19.3 μmol, 3% yield) as a solid. 1 H NMR (CDCl3, 400MHz) δ H =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 R t = 1.29 min in 2.0 min chromatography, 10-80AB, C 16 H 14 F6N5O2[M+H] + MS ESI calculated value for 422.1, found value 422.0.

[0304] Example 42: 6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyridine [ka] A mixture of 6-bromo-3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyridine (100 mg, 0.41 mmol), Pd(dppf)Cl (45.34 mg, 0.06 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (166.12 mg, 0.50 mmol), and KCO (114.19 mg, 0.83 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was stirred at 80 °C for 16 h under N. After cooling to room temperature, the mixture was filtered through Celite, eluting with EtOAc (10 mL × 2), and the filtrate was concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (50% to 100% EtOAc in PE). The product was then triturated from n-hexane / DCM (5:1, 10 mL) to give the product (46.5 mg, 0.13 mmol, 30% yield) as a solid. 1 H NMR (DMSO-d6, 400MHz) δ H =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 R t = 1.13 min in 2.0 min chromatography, 10-80AB, C 16 H 15 F4N4O2[M+H] + MS ESI calculated value for 371.1, found value 370.9.

[0305] Example 43: 6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-3-(methoxymethyl)-[1,2,4]triazolo[4,3-b]pyridazine [ka] A mixture of 6-chloro-3-(methoxymethyl)-[1,2,4]triazolo[4,3-b]pyridazine (100 mg, 0.50 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (202.47 mg, 0.60 mmol), KPO (213.79 mg, 1.01 mmol), and Pd(t-BuP) (38.6 mg, 0.08 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was stirred at 80 °C under N for 3 h. After cooling to room temperature, water (20 mL) and EtOAc (20 mL) were added to the mixture and filtered through Celite. After separation, the organic phase was washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated to give the crude product, which was purified by preparative HPLC (Boston Prime C18 (150 mm × 30 mm, 5 μm) A = HO (0.05% NHOH) and B = CHCN, 33–63% B over 8 min) to give the product (38 mg, 102.3 μmol, 20% yield) as a solid. 1 H NMR (CDCl3, 400MHz) δ H =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 R t = 1.13 min in 2.0 min chromatography, 10-80AB, C 15 H 14 F4N5O2[M+H] + MS ESI calculated value for 372.1, found value 371.9.

[0306] Example 44: 3-[Difluoro(isobutoxy)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine [ka] 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 solid was observed. The mixture was filtered through Celite. 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 give the crude product. The crude product was purified by flash chromatography on silica gel (10% to 30% to 50% EtOAc in PE) to give the product (80 mg) as an oil.

[0307] The impure product (80 mg, 0.18 mmol) was purified by preparative HPLC (Boston Gr The residue was purified by chloroform (150 mm × 30 mm, 5 μm) with A = HO (0.075% TFA) and B = CHCN (66–96% B over 8 min) and concentrated to give a residue. Saturated aqueous NaHCO (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 NaSO, filtered, and concentrated to give the product (55.97 mg, 124.6 μmol, 70% yield) as a solid. 1 H NMR (CDCl3 + D2O, 400MHz) δ H =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 R t = 1.37 min in 2.0 min chromatography, 10-80AB, C 18 H 18 F6N5O2[M+H] +MS ESI calculated value for 450.1, found value 450.0.

[0308] Example 45: 6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-3-(methoxymethyl)-[1,2,4]triazolo[4,3-b]pyridazine [ka] Synthesis of A32: To a solution of (6-chloropyridazin-3-yl)hydrazine (3 g, 20.75 mmol) in toluene (80 mL) was added 2-methoxyacetyl chloride (2.48 g, 22.83 mmol) dropwise at 25° C. The solution was stirred at 25° C. for 30 minutes and refluxed at 120° C. for 24 hours. After cooling to room temperature, the mixture was diluted with HO (40 mL) and extracted with EtOAc (40 mL×2). The combined organic phases were washed with brine (40 mL), dried over NaSO, filtered, and concentrated to give the crude product. The crude product was triturated from i-PrO (10 mL) to give the product (1500 mg, 7.31 mmol, 35% yield) as a solid. LCMS R t = 0.43 min in 1.5 min chromatography, 5-95AB, C7H8ClNO4[M+H] + MS ESI calculated value for 198.0, found value 199.0.

[0309] Synthesis of compound 46: A mixture of 6-chloro-3-(methoxymethyl)-[1,2,4]triazolo[4,3-b]pyridazine (100 mg, 0.5 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methylethoxy]pyridine (202.47 mg, 0.6 mmol), KPO (213.79 mg, 1.01 mmol), and Pd(t-BuP) (38.6 mg, 0.08 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was stirred at 80 °C for 12 h under N. After cooling to room temperature, the mixture was diluted with HO (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 NaSO, filtered, and concentrated to give the crude product, which was purified by preparative HPLC (column: Boston Prime (150 mm × 30 mm, 5 μm; mobile phase: A = HO (0.05% NHOH); B = CHCN, 35–65% B over 9 min) to give the product (43.29 mg, 0.12 mmol, 23% yield) as a solid. 1 H NMR (CDCl3, 400MHz) δ H =8.53(d, 1H), 8.25(d, 1H), 8.14(dd, 1H), 7.57(d, 1H), 5.98-5.5.85(m, 1H), 5.11(s, 2H), 3.54(s, 3 H), 1.61(d, 3H). LCMS R t = 1.17 min in 2.0 min chromatography, 10-80AB, C 15 H 14 F4N5O2[M+H] + MS ESI calculated value for 372.1, found value 372.1.

[0310] Example 46: 3-[Difluoro(isobutoxy)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyridazine [ka] 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]pyridazine (300 mg, 0.73 mmol) and AgOTf (1872.33 mg, 7.29 mmol) in 2-methylpropan-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 was diluted with EtOAc (60 mL) and brine (20 mL), filtered through Celite, and extracted with EtOAc (50 mL × 2). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over NaSO, filtered, and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (0% to 70% EtOAc in PE). The isolated product was further purified by preparative HPLC (Boston Prime C18 (150 mm × 30 mm, 5 μm), A = HO (0.05% NH4OH) and B = CH3CN, 60 to 90% B in 9 min) to give the product (7.42 mg, 16.5 μmol, 2% yield) as a solid. 1 H NMR (CDCl3, 400MHz) δ H= 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 R t = 1.39 min in 2.0 min chromatography, 10-80AB, MS ESI calculated C 18 H 18 F6N5O2[M+H] + 450.1, actual value 450.1.

[0311] Example 47: 3-[ethoxy(difluoro)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyridazine [ka] 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-dioxane) in 1,4-dioxane (8 mL) and water (0.80 mL). A mixture of (saborolan-2-yl)-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)pyridine (527.36 mg, 1.51 mmol), CsCO (738.18 mg, 2.27 mmol), and Pd(dppf)Cl (110.52 mg, 0.15 mmol) was stirred at 75 °C for 9 h under N. After cooling to room temperature, the mixture was diluted with HO (20 mL), and the mixture was extracted with EtOAc (30 mL × 2). The combined organic phases were washed with water (30 mL × 1) and brine (30 mL), dried over NaSO, filtered, and concentrated to give the crude product. The crude product was purified by preparative HPLC (Boston Prime C18 (150 mm × 30 mm, 5 μm), A = HO (0.05% NH4OH) and B = CH3CN, 49–59% B over 9 min) to give the product (90.56 mg, 235 μmol, 31% yield) as a solid. 1 H NMR (CDCl3, 400MHz) δ H= 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 R t = 1.24 min in 2.0 min chromatography, 10-80AB, MS ESI calculated C 16 H 16 F4N5O2[M+H] + 386.1 Actual value 386.1

[0312] Example 48: 3-[Difluoro(isobutoxy)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyridazine [ka] 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]pyridazine (500 mg, 1.21 mmol) and AgOTf (3120.6 mg, 12.15 mmol) in 2-methylpropan-1-ol (10 mL, 1.21 mmol) and CHCN (10 mL) was stirred at 90 °C for 8 days. After cooling to room temperature, the reaction mixture was diluted with EtOAc (40 mL), brine (40 mL) was added to the mixture, and the mixture was filtered through Celite, eluting with EtOAc (20 mL × 2). The filtrate was concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (0% to 50% to 100% EtOAc in PE) to give the impure product. The impure product was purified by preparative HPLC (Waters Xbridge 150 mm × 25 mm, 5 μm) with A = HO (10 mM NH4HCO3) and B = CH3CN (54–84% B over 8 min) to give the product (53.85 mg, 0.12 mmol, 10% yield) as a solid. 1 H NMR (CDCl3, 400MHz) δ H =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 R t = 1.42 min in 2.0 min chromatography, 10-80AB, C 18 H 18 F6N5O2[M+H] + MS ESI calculated value for 450.1, found value 450.1.

[0313] Example 49: 3-(ethoxymethyl)-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine [ka] Synthesis of A40: 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 CHCl (10 mL) was stirred at 25° C. for 16 hours. The mixture was concentrated to a residue, which was redissolved in EtOAc (20 mL), washed with water (10 mL×2), brine (10 mL×2), dried over anhydrous NaSO, filtered, and concentrated to give the product (150 mg, 0.13 mmol, 20% yield) as a solid. LCMS R t = 0.84 min in 1.5 min chromatography, 5-95AB, C 16 H 18 F4N5O3[M+H] + MS ESI calculated value 404.1, actual value 404.2.

[0314] Synthesis of Compound 50: A mixture of 2-ethoxy-N'-[5-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]pyrazin-2-yl]acetohydrazide (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 give a solid. The solid was redissolved in EtOAc (20 mL), basified with saturated Na2CO3 to pH 9, washed with water (10 mL × 2), brine (10 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product. The crude product was purified by preparative HPLC (Boston Prime C18 150 mm x 30 mm 5 μM) A = HO (0.05% ammonia hydroxide) and B = CH3CN, 45-75% B over 9 min. Purification gave the product (48.08 mg, 0.12 mmol, 34% yield) as a solid. 1 H NMR (DMSO-d6, 400MHz) δ H =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 R t = 1.23 min in 2.0 min chromatography, 10-80AB, C 16 H 16 F4N5O2[M+H] + MS ESI calculated value for 386.1, found value 386.0.

[0315] Example 50: 3-[Cyclopropoxy(difluoro)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine [ka] 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) was added potassium tert-butoxide (54.51 mg, 0.49 mmol). The reaction mixture was stirred at 20 °C for 2 h. The reaction was quenched with saturated NH Cl (10 mL), and the mixture was extracted with EtOAc (10 mL × 2). The combined organic phases were washed with brine (10 mL), dried over Na SO , filtered, and concentrated to give the crude product. The crude product was purified by preparative HPLC (Waters Xbridge (150 mm × 25 mm, 5 μm) A = HO (10 mM NHHCO) and B = CHCN, 57–67% B over 8 min) to give the product (3.98 mg, 0.01 mmol, 4% yield) as an oil. 1 H NMR (CD3CN, 400MHz) δ H =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 R t = 1.31 min in 2 min chromatography, 10-80AB, C 17 H 14 F6N5O2[M+H] + MS ESI calculated value for 434.1, found value 433.9.

[0316] Example 51: 3-(ethoxymethyl)-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine [ka] Synthesis of A41: A mixture of (5-chloropyrazin-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 and then heated to 130 °C for 3 days. Most of the toluene was then removed, and acetic acid (40 mL) was added and stirred at 120 °C for 16 hours. After cooling to room temperature, the mixture was concentrated to give a residue. The residue was redissolved in EtOAc (40 mL), basified with saturated NaCO to pH 9, washed with water (20 mL × 2), brine (20 mL × 2), dried over anhydrous NaSO, filtered, and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (40% to 70% EtOAc in PE) to give the product (240 mg, 1.11 mmol, 32% yield) as a solid. LCMS R t = 0.60 min in 1.5 min chromatography, 5-95AB, C8H 10 ClNO[M+H] + MS ESI calculated value for 213.0, found value 213.0.

[0317] Synthesis of compound 52: 3-Fluorocarbonyl 52 in 1,4-dioxane (10 mL) and water (2 mL) A mixture of 1H-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methylethoxy]pyridine (453.86 mg, 1.35 mmol), CsCO (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)Cl (123.88 mg, 0.17 mmol) was stirred at 75 °C for 16 h under N. After cooling to room temperature, the mixture was filtered through Celite, eluting with EtOAc (10 mL × 2), and the filtrate was concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (30% to 60% to 100% EtOAc in PE) to give an impure product. The impure product was purified by preparative HPLC (Waters Xbridge 150 mm × 25 mm, 5 μm) A = HO (10 mM NHHCO) and B = CHCN, 40–70% B over 8 min) to give the product (37.8 mg, 98.1 μmol, 9% yield) as a solid. 1 H NMR (DMSO-d6, 400MHz) δ H =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 R t = 1.24 min in 2.0 min chromatography, 10-80AB, C 16 H 16 F4N5O2[M+H] + MS ESI calculated value for 386.1, found value 386.1.

[0318] Example 52: 3-[Difluoro(methoxy)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine [ka] Synthesis of A19-a: A mixture of 2-bromo-5-chloro-pyrazine (3 g, 15.51 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (4.98 g, 15.51 mmol), CsCO (10.11 g, 31.02 mmol), and Pd(dppf)Cl (1.7 g, 2.33 mmol) in 1,4-dioxane (50 mL) and water (5 mL) was stirred at 55 °C under N for 5 hours. The reaction was cooled to room temperature and concentrated to give a residue. To the residue was added water (50 mL) and EtOAc (50 mL), and the mixture was then filtered. After separation, the organic phase was washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated to give the crude product, which was purified by flash chromatography on silica gel (0% to 5% to 10% EtOAc in PE) to give the product (3700 mg, 10.69 mmol, 69% yield) as a solid. 1 H NMR (DMSO-d6, 400MHz) δ H =9.19(d, 1H), 8.88(d, 1H), 8.80(d, 1H), 8.49(dd, 1H ), 5.18(q, 2H). LCMS R t = 0.93 min in 1.5 min chromatography, 5-95AB, C 11 H7ClF4N3O[M+H] + MS ESI calculated value for 308.0, found value 308.0.

[0319] Synthesis of A20-a: 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) was added hydrazine (3.85 g, 120.27 mmol), and the mixture was stirred at 90 °C for 16 hours. The reaction was cooled to room temperature and concentrated to give a residue. Water (30 mL) was added to the residue, and extracted with EtOAc (30 mL × 2). The combined organic phases were washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated to give the crude product (3500 mg, 9.60 mmol, 80% yield) as a solid. 1 H NMR (DMSO-d6, 400MHz) δ H =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 R t = 0.73 min in 1.5 min chromatography, 5-95AB, C 11 H 10 F4N5O[M+1H] + MS ESI calculated value for 304.1, found value 304.0.

[0320] Synthesis of A18: 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-difluoro-acetyl)2-chloro-2,2-difluoroacetate (7.21 g, 29.68 mmol) in toluene (60 mL) was stirred at 110 °C for 96 hours. Then, molecular sieves (3 g) were added to the mixture, and the mixture was stirred at 130 °C for an additional 16 hours. After cooling to room temperature, the mixture was concentrated to give a residue. Water (20 mL) was added to the residue, and it was extracted with EtOAc (30 mL × 2). The combined organic phase was washed with water (20 mL), brine (20 mL × 2), dried over anhydrous Na SO , filtered, and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 10% to 20%) to give the product (1300 mg, 3.24 mmol, 33% yield) as an oil. LCMS R t = 2.63 min in 4 min chromatography, 10-80AB, C 13 H7ClF6N5O[M+H] + MS ESI calculated value for 398.0, found value 397.9.

[0321] Synthesis of Compound 53: 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. The filtrate was concentrated, diluted with water (20 mL), and then extracted with EtOAc (20 mL × 3). The combined organic phase was washed with brine (20 mL), dried over Na SO , and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 10% to 30%) to give the product (247.53 mg, 0.63 mmol, 42% yield) as a solid.1 H NMR (CDCl3, 400MHz) δ H =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 R t = 1.23 min in 1.5 min chromatography, 5-95AB, C 14 H 10 F6N5O2[M+H] + MS ESI calculated value for 394.1, found value 394.0.

[0322] Example 53: 3-[Difluoro(methoxy)methyl]-6-[6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine [ka] 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 the solvents DMF (15 mL) and methanol (15 mL) was stirred at 90 °C for 96 h. After cooling to room temperature, the reaction mixture was treated with brine (50 mL), and the precipitate was filtered. The filtrate was concentrated, 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 Na SO , and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (0% to 40% EtOAc in PE) to give the product (170 mg). Another 88 mg of product was obtained from the other batches. The three batches of product were combined and lyophilized to give the product (193.0 mg, 0.48 mmol) as a solid. 1H 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 R t = 2.0 min chromatography at 1.235 min, 10-80AB, C 16 H 15 F5N5O2[M+H] + MS ESI calculated value for 404.1, found value 403.9.

[0323] Example 54: 3-[chloro(difluoro)methyl]-6-[6-[1-(trifluoromethyl)cyclobutoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine [ka] Synthesis of A54: To a solution of 1-(trifluoromethyl)cyclobutanol (5 g, 35.69 mmol) in THF (300 mL) was added NaH (1.86 g, 46.4 mmol) over 20 min at 0 °C, and the mixture was stirred at 0 °C for 30 min. Then, the mixture was added with 5- Bromo-2-fluoro-pyridine (8.48 g, 48.18 mmol) was added and the mixture was stirred at 30° C. for 3 hours. The mixture was quenched with saturated NH4Cl (50 mL), and then the mixture was extracted with EtOAc (50 mL). The combined organic phases were washed with brine (50 mL×3), dried over Na2SO4, filtered, and concentrated to give the crude product (4.8 g, 15.49 mmol, 43% yield) as an oil. LCMS R t = 0.99 min in 1.5 min chromatography, 5-95AB, C 10 H 10 BrF3NO[M+H] + MS ESI calculated value for 295.9, found value 296.0.

[0324] Synthesis of A55: 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-dioxaborolan-2-yl)-1,3,2-dioxaborolane (3.22 g, 12.67 mmol), KOAc (1.66 g, 16.89 mmol), and Pd(dppf)Cl (432.48 mg, 0.59 mmol) in 1,4-dioxane (50 mL) was stirred at 90 °C for 12 h under N. After cooling to room temperature, the mixture was concentrated to give a residue. The residue was diluted with HO (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 NaSO, filtered, and concentrated to give the crude product, which was purified by flash chromatography on silica gel (0% to 1% EtOAc in PE) to give the crude product (2.65 g, 3.92 mmol, 46% yield) as an oil. 1 H NMR (CDCl3, 400MHz) δ H =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).

[0325] Synthesis of A56: A mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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)Cl (671.68 mg, 0.92 mmol), and CsCO (3.99 g, 12.24 mmol) in 1,4-dioxane (20 mL) and water (2 mL) was stirred at 60 °C for 6 h under N. After cooling to room temperature, the mixture was concentrated to give a residue. The residue was diluted with HO (20 mL), and the mixture was extracted with EtOAc (20 mL × 2). The combined organic phase was washed with water (20 mL) and brine (40 mL), dried over Na2SO4, filtered, and concentrated to give the crude product, which was purified by flash chromatography on silica gel (0% to 1% to 10% EtOAc in PE) to give the product (1.5 g, 4.263 mmol, 70% yield) as an oil. 1 H NMR (CDCl3, 400MHz) δ H =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).

[0326] Synthesis of A57: 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 h. After cooling to room temperature, the reaction mixture was concentrated, diluted with HO (30 mL), and extracted with EtOAc (30 mL × 2). The combined organic phases were washed with brine (30 mL), dried over NaSO, filtered, and concentrated to give the crude product (950 mg, 2.48 mmol, 68% yield) as a solid. LCMS R t = 0.99 min in 2.0 min chromatography, 10-80AB, C 14 H 15 F3N5O[M+H]+ MS ESI calculated value for 326.1, found value 326.0.

[0327] Synthesis of A58: A mixture of [5-[6-[1-(trifluoromethyl)cyclobutoxy]-3-pyridyl]pyrazin-2-yl]hydrazine (1.13 g, 3.47 mmol), 4A molecular sieves (1 g, 3.47 mmol), and (2-chloro-2,2-difluoro-acetyl) 2-chloro-2,2-difluoro-acetate (1.69 g, 6.95 mmol) in toluene (15 mL) was heated to 130 °C and stirred for 16 h. After cooling to room temperature, the reaction mixture was filtered, diluted with HO (50 mL), and extracted with EtOAc (50 mL × 2). The combined organic phases were washed with brine (50 mL), dried over NaSO, filtered, and concentrated to give the crude product (820 mg, 1.13 mmol, 33% yield) as a solid. LCMS R t = 1.38 min in 2.0 min chromatography, 10-80AB, C 16 H 12 ClF5N5O[M+H] + MS ESI calculated value for 420.1, found value 420.0.

[0328] Synthesis of compound 57: 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), 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 h. After cooling to room temperature, the reaction 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 NaSO, filtered, and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (PE=0% to 40% to 70% EtOAc) to give the product (194.76 mg, 0.47 mmol, 33% yield) as a solid. 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 R t = 1.33 min in 2.0 min chromatography, 10-80AB, C 17 H 15 F5N5O2[M+H] + MS ESI calculated value for 416.1, found value 416.1.

[0329] Example 56: 3-[Difluoro(methoxy)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 [ka] Synthesis of A59: 2-bromo-5-chloro-3-methyl-pyrazine (900 mg, 4.34 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (1.31 g) in 1,4-dioxane (40 mL) and water (8 mL). A mixture of Pd(dppf)Cl (0.48 g, 0.65 mmol), Pd(dppf)Cl (0.48 g, 0.65 mmol), and CsCO (2.83 g, 8.68 mmol) was stirred at 50 °C under N for 5 h. The mixture was cooled to room temperature, diluted with EtOAc (30 mL), and filtered through silica gel, eluting with EtOAc (20 mL). The filtrate was concentrated to give the crude product. The product was purified by flash chromatography on silica gel (0% to 3% EtOAc in PE) to give the product (1100 mg, 2.83 mmol, 65% yield) as a solid. LCMS R t = 1.41 min in 1.5 min chromatography, 10-80AB, C 13 H 11ClF4N3O[M+H] + MS ESI calculated value for 336.0, found value 336.0.

[0330] Synthesis of A60: 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 h. After cooling to room temperature, the reaction mixture was concentrated. The mixture was diluted with HO (20 mL) and extracted with EtOAc (20 mL × 2). The combined organic phases were washed with brine (20 mL), dried over NaSO, filtered, and concentrated to give the crude product. The crude product was triturated with PE (5 mL) to give the product (800 mg, 2.41 mmol, 68% yield) as a solid. The crude product was used in the next step without further purification. LCMS R t = 0.75 min with 1.5 min chromatography, 5-95AB, C 13 H 14 F4N5O[M+H] + MS ESI calculated value for 332.1, found value 332.1.

[0331] Synthesis of A61: To 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), (2-chloro-2,2-difluoro-acetyl) 2-chloro-2,2-difluoro-acetate (366.68 mg, 1.51 mmol) and 4A molecular sieves (1 g) were added. 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 saturated NaHCO (30 mL), and the mixture was extracted with EtOAc (30 mL × 2). The combined organic phase was washed with brine (20 mL), dried over NaSO, filtered, and concentrated to give a residue. The residue was purified by flash column on silica gel (EtOAc in PE = 0% to 20%) to give the product (105 mg, 0.16 mmol, 11% yield) as a solid. LCMS R t = 0.92 min in 1.5 min chromatography, 5-95AB, C 15 H 11 ClF6N5O[M+H] + MS ESI calculated value for 426.0, found value 426.2.

[0332] Synthesis of Compound 58: 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 h. After cooling to room temperature, the reaction mixture was treated with brine (15 mL), and the precipitate was filtered. The filtrate was extracted with EtOAc (15 mL × 2). The combined organic phases were dried over NaSO and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 30% to 50%). The product was then triturated from DCM (0.5 mL) and n-hexane (0.5 mL) to give the product (2.05 mg, 4.90 μmol, 2% yield). 1 H NMR (CDCl3, 400MHz) δ H =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 R t = 2 minutes of chroma 1.24 min in toography, 10-80AB, C 16 H 14 F6N5O2[M+H] + MS ESI calculated value for 422.1, found value 422.0.

[0333] Example 57: 3-[Difluoro(methoxy)methyl]-6-[6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine [ka] Synthesis of A62: To a mixture of (2S)-2-(trifluoromethyl)oxirane (3 g, 26.77 mmol) in THF (25 mL) was added LiAlH (0.5 g, 13.2 mmol) at 0 °C under N for 30 min, and then the mixture was stirred at 20 °C for 2 h. After cooling to 0 °C, the mixture was quenched with water (0.9 g), and the mixture was stirred at 35 °C for 30 min. The mixture was filtered through Celite and eluted with THF (20 mL × 2). The organic phase was washed with brine (20 mL × 2), dried over Na SO , and filtered to give the crude product of (2S)-1,1,1-trifluoropropan-2-ol (3 g, 26.3 mmol, 98% yield) as a solution in THF, which was used directly without further purification.

[0334] Synthesis of A63: To a solution of (2S)-1,1,1-trifluoropropan-2-ol in THF (50 mL) was added NaH (0.8 g, 19.94 mmol) over 20 minutes at 0° C., and the mixture was stirred at 0° C. for 40 minutes. 5-Bromo-2-fluoro-pyridine (2.7 g, 15.34 mmol) was then 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 phase was washed with brine (40 mL×2), dried over Na2SO4, filtered, and concentrated to give the crude product (3.48 g, 9.29 mmol, 61% yield) as an oil. LCMS R t = 0.95 min in 1.5 min chromatography, 5-95AB, C8H8BrF3NO[M+H] + MS ESI calculated value for 270.0, found value 269.9.

[0335] Synthesis of A64: 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-dioxaborolan-2-yl)-1,3,2-dioxaborolane (4.91 g, 19.33 mmol), KOAc (2.53 g, 25.77 mmol), and Pd(dppf)Cl (1.13 g, 1.55 mmol) in 1,4-dioxane (35 mL) was stirred at 85 °C for 12 hours under N. After cooling to room temperature, the mixture was concentrated to give a residue. The residue was diluted with HO (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 NaSO, filtered, and concentrated to give the crude product, which was purified by flash chromatography on silica gel (0% to 1% EtOAc in PE) to give the product (3 g, 5.72%). 44% yield) as an oil. 1 H NMR (DMSO-d6, 400MHz) δ H =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 R t = 1.02 min in 1.5 min chromatography, 5-95AB, C 14 H 20 BF3NO3[M+H] + MS ESI calculated value for 318.1, found value 318.1.

[0336] Synthesis of A65: A mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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)Cl (207.67 mg, 0.28 mmol), and CsCO (1232.88 mg, 3.78 mmol) in 1,4-dioxane (15 mL) and water (1.5 mL) was stirred at 60 °C for 5 h under N. After cooling to room temperature, the mixture was concentrated to give a residue. The residue was diluted with HO (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 give the crude product, which was purified by flash chromatography on silica gel (0% to 3% EtOAc in PE) to give the product (350 mg, 1.15 mmol, 61% yield) as an oil. LCMS R t = 0.95 min with 1.5 min chromatography, 5-95AB, C 12 H 10 ClF3N3O[M+H] + MS ESI calculated value for 304.0, found value 304.1.

[0337] Synthesis of A66: 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 CHCN (5 mL) was stirred at 90 °C for 16 h. After cooling to room temperature, the reaction was quenched with saturated NHCl (30 mL) and the mixture was extracted with EtOAc (20 mL × 2). The combined organic phases were washed with brine (30 mL), dried over NaSO, filtered, and concentrated to give the crude product (350 mg, 1.05 mmol, 91% yield) as a solid. LCMS R t = 0.74 min in 1.5 min chromatography, 5-95AB, C 12 H 13 F3N5O[M+H] +MS ESI calculated value for 300.1, found value 300.1.

[0338] Synthesis of A67: 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-difluoro-acetyl) 2-chloro-2,2-difluoro-acetate (852.42 mg, 3.51 mmol), and 4A molecular sieves (500 mg, 1.17 mmol) in toluene (8 mL) was stirred at 120 °C for 2 days. After cooling to room temperature, the reaction was quenched with saturated NaHCO (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 NaSO, filtered, and concentrated to give the product (420 mg, 1.01 mmol, 86% yield) as a solid. LCMS R t = 0.92 min in 1.5 min chromatography, 5-95AB C 14 H 10 ClF5N5O[M+H] + MS ESI calculated value for 394.0, found value 394.1.

[0339] Synthesis of compound 59: 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), 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 h. After cooling to room temperature, the reaction was diluted with EtOAc (30 mL) and quenched with saturated NaCl (30 mL), and the mixture was eluted. The residue was filtered through Celite and eluted with EtOAc (10 mL). The filtrate was washed with water (30 mL) and brine (30 mL), dried over Na2SO4, filtered, and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 15% to 30%) to give the impure product. The impure product was triturated from n-hexane / DCM (2:1, 6 mL) to give the product (118.39 mg, 0.30 mmol, 29% yield) as a solid. 1 H NMR (CD3CN, 400MHz) δ H =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 R t = 1.28 min in 2.0 min chromatography, 10-80AB, C 15 H 13 F5N5O2[M+H] + MS ESI calculated value for 390.1, found value 390.0.

[0340] Example 58: 3-[Difluoro(methoxy)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 [ka] Synthesis of A68: A mixture of 2-bromo-5-chloro-3-methyl-pyrazine (900 mg, 4.34 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (1.31 g, 3.9 mmol), Pd(dppf)Cl (0.48 g, 0.65 mmol), and CsCO (2.83 g, 8.68 mmol) in 1,4-dioxane (40 mL) and water (8 mL) was stirred at 55 °C under N for 16 h. The mixture was cooled to room temperature, diluted with EtOAc (50 mL), filtered through silica gel, eluted with EtOAc (20 mL), and concentrated to give the crude product. The product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 20%) to give the product (930 mg, 2.62 mmol, 60% yield) as a colorless oil. LCMS R t = 0.95 min with 1.5 min chromatography, 5-95AB, C 13 H 11 ClF4N3O[M+H] + MS ESI calculated value for 336.0, found value 336.1.

[0341] Synthesis of A69: 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 CHCN (10 mL) was stirred at 90 °C for 16 h. After cooling to room temperature, the reaction was quenched with saturated NH Cl (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 Na SO , filtered, and concentrated to give the crude product (980 mg, 2.45 mcg). mol, 89% yield) as a solid. t = 0.75 min with 1.5 min chromatography, 5-95AB, C 13 H 14 F4N5O[M+H] +MS ESI calculated value for 332.1, found value 332.2.

[0342] Synthesis of A70: 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-difluoro-acetyl) 2-chloro-2,2-difluoro-acetate (1320.05 mg, 5.43 mmol), and 4A molecular sieves (600 mg, 1.81 mmol) in toluene (10 mL) was stirred at 120 °C for 5 days. After cooling to room temperature, the reaction was quenched with saturated NaHCO (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 NaSO, filtered, and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 40%) to give the product (140 mg, 0.22 mmol, 12% yield) as a solid. LCMS R t = 0.92 min in 1.5 min chromatography, 5-95AB, C 15 H 11 ClF6N5O[M+H] + MS ESI calculated value for 426.0, found value 426.1.

[0343] Synthesis of Compound 60: 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), 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 reaction was diluted with EtOAc (10 mL) and saturated NaCl (10 mL), and the mixture was filtered through Celite and eluted with EtOAc (10 mL). The combined organic phase was washed with water (10 mL) and brine (10 mL), dried over NaSO, filtered, and concentrated to give the crude product. The crude product was purified by preparative TLC (silica gel, PE: EtOAc = 2:1) to give an impure product, which was triturated from n-hexane / DCM (2:1, 3 mL) to give the product (11.92 mg, 28.3 μmol, 9% yield) as a solid. 1 H NMR (CDCl3, 400MHz) δ H =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 R t = 1.28 min in 2.0 min chromatography, 10-80AB, C 16 H 14 F6N5O2[M+H] + MS ESI calculated value for 422.1, found value 422.2.

[0344] Example 59: 3-[Difluoro(methoxy)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-5-methyl-[1,2,4]triazolo[4,3-a]pyrazine [ka] Synthesis of A71: To a solution of 5-chloropyrazine-2-amine (25 g, 192.98 mmol) in DCM (250 mL) was added NBS (34.35 g, 192.98 mmol). The resulting mixture was stirred at 40 °C for 1 h. After cooling to room temperature and concentration, water (200 mL) was added to give a residue, which was extracted with EtOAc (150 mL × 2). The combined organic phases were washed with brine (150 mL), dried over Na SO , filtered, and concentrated to give the crude product. The crude product was purified by chromatography on silica gel (EtOAc in PE = 0% to 15% to 30%) to give the product (31 g, 148.72 mmol, 77% yield) as a solid. 1 H NMR (DMSO-d6, 400MHz) δ H =8.09(s, 1H), 6.96(s, 2H).

[0345] Synthesis of A72: A mixture of 3-bromo-5-chloro-pyrazin-2-amine (31 g, 148.72 mmol), Pd(dppf)Cl (16.32 g, 22.31 mmol), methylboronic acid (13.35 g, 223.09 mmol), and CsCO (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 give a residue. Water (100 mL) was added to the residue and extracted with EtOAc (100 mL × 2). The combined organic phase was washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (20% to 40% to 60% to 80% EtOAc in PE) to give the product (13 g, 90.548 mmol, 61% yield) as a solid. 1 H NMR (DMSO-d6, 400MHz) δ H =7.83(s, 1H), 6.40(s, 2H), 2.26(s, 3H).

[0346] Synthesis of A73: A mixture of 5-chloro-3-methyl-pyrazin-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 h. The mixture was diluted with HO (30 mL), and the mixture was extracted with EtOAc (70 mL × 2). The combined organic phases were washed with water (30 mL × 2) and brine (30 mL), dried over NaSO, filtered, and concentrated to give the crude product. The crude product was purified by flash column chromatography on silica gel (DCM in PE = 0% to 2%) to give the product (1.2 g, 5.78 mmol, 28% yield) as an oil. 1 H NMR (CDCl3, 400MHz) δ H =8.22(s, 1H), 2.68(s, 3H). LCMS R t -2.0 min chromatography at 1.10 min, 10-80AB, C5H5BrClN2 [M+H] + MS ESI calculated value 208.9, experimental value Value 208.7.

[0347] Synthesis of A74: A mixture of 2-bromo-5-chloro-3-methyl-pyrazine (1.2 g, 5.78 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (1.3 g, 4.05 mmol), CsCO (3.77 g, 11.57 mmol), and Pd(dppf)Cl (634.85 mg, 0.87 mmol) in 1,4-dioxane (30 mL) and water (3 mL) was stirred at 60 °C under N for 16 h. After cooling to room temperature, water (30 mL) and EtOAc (50 mL) were added to the mixture, and the mixture was filtered through Celite. After separating the filtrate, the organic phase was washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated to give the crude product, which was purified by flash column chromatography on silica gel (0% to 1% to 2% EtOAc in PE) to give the product (580 mg, 1.71 mmol, 30% yield) as a solid.1 H NMR (CDCl3, 400MHz) δ H =8.52(s, 1H), 8.19(d, 1H), 7.73(dd, 1H), 4.91(q, 2H), 2.69(s, 3H). LCMS R t = 0.93 min in 1.5 min chromatography, 5-95AB, C 12 H9ClF4N3O[M+H] + MS ESI calculated value 322.0, actual value 322.0.

[0348] Synthesis of A75: 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 h. 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 NaSO, filtered, and concentrated to give the crude product (530 mg, 1.30 mmol, 69% yield) as a solid. 1 H NMR (DMSO-d6, 400MHz) δ H =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 R t = 0.72 min in 1.5 min chromatography, 5-95AB, C 12 H 12 F4N5O[M+H] + MS ESI calculated value for 318.1, found value 318.1.

[0349] Synthesis of A76: 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-difluoro-acetyl) 2-chloro-2,2-difluoro-acetate (1.22 g, 5.01 mmol), and 4A molecular sieves (3 g) in toluene (30 mL) was stirred at 120 °C for 6 days. After cooling to room temperature, the mixture was concentrated to give a residue. Water (50 mL) was added to the residue, which was then extracted with EtOAc (50 mL × 2). The combined organic phase was washed with water (50 mL) and brine (50 mL × 2), dried over anhydrous Na SO , filtered, and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 15% to 30%) to give the product (180 mg, 426.2 μmol, 26% yield) as an oil. LCMS R t = 3.64 min in 7.0 min chromatography, 10-80AB, C 14 H9ClF6N5O[M+H] + MS Calculated ESI value: 412.0, measured value: 412.1.

[0350] Synthesis of compound 61: 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). The mixture was stirred at 90° C. under N 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 Celite. After separation, the organic phase was washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated to give the crude product. The crude product was purified by flash column chromatography on silica gel (EtOAc in PE = 0% to 15% to 30%) to give the product (38.62 mg, 94.1 μmol, 22% yield) as a solid.1 H NMR (CDCl3, 400MHz) δ H =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 R t = 2.0 min chromatography, 1.20 min, 10-80AB, C 15 H 12 F6N5O2[M+H] + MS ESI calculated value for 408.1, found value 407.9.

[0351] Example 60: 3-[Difluoro(methoxy)methyl]-6-[6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine [ka] To a suspension of 3-[bromo(difluoro)methyl]-6-[6-[rac-(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) was added AgBF (2.58 g, 13.24 mmol) at 25 °C under N. The mixture was protected from light and stirred at 60 °C for 1 h. The solution was added to saturated NaCl (30 mL) and filtered. The filtrate was extracted with EtOAc (20 mL × 2). The combined organic phase was washed with brine (50 mL), dried over NaSO, filtered, and concentrated. The crude product was purified by flash column chromatography on silica gel (0% to 10% to 20% EtOAc in PE) to give the product (1.96 g, ee = 92.28%) as a solid. 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: 5% to 40% B in 5 min and 40% to 5% B in 0.5 min, hold 5% B for 1.5 min; flow rate: 2.5 mL / min, column temperature: 35 °C) showed two peaks at 2.71 and 2.96 min. The product was separated by SFC (DAICEL CHIRALCEL OJ (250 mm × 50 mm, 10∝m); A = CO and B = 0.1% NH₃H₂O EtOH; 35 °C; 200 mL / min; 25% B; 8 min run; 100 injections, Rt of peak 1 = 4.2 min and peak 2 = 4.7 min) to give the product (1415.6 mg, 3.64 mmol, 55% yield) as a solid. 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 R t = 1.27 min in 2.0 min chromatography, 10-80AB, C 15 H 13 F5N5O2[M+H] + MS Calculated ESI value: 389.1, measured value: 390.0.

[0352] Example 61: 3-[cyclopropoxy(difluoro)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]- [1,2,4]Triazolo[4,3-a]pyrazine [ka] 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) was added potassium tert-butoxide (163.54 mg, 1.46 mmol). The reaction mixture was stirred at 20 °C for 1 h. The mixture was diluted with HO (10 mL) and extracted with EtOAc (10 mL × 2). The combined organic phases were washed with brine (20 mL), dried over NaSO, filtered, and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (0% to 30% EtOAc in PE) to give an impure product. The impure product was triturated from n-hexane / DCM (2:1, 3 mL) to give the product (33.18 mg, 76.6 μmol, 11% yield). 1 H NMR (CDCl3, 400MHz) δ H =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 R t = 1.34 min in 2.0 min chromatography, 10-80AB. C 17 H 14 F6N5O2[M+H] +MS ESI calculated value for 434.1, found value 434.1.

[0353] Example 62: 6-(6-benzyloxy-5-fluoro-3-pyridyl)-3-[ethoxy(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyrazine [ka] Synthesis of A84: To a solution of phenylmethanol (10.5 g, 97.1 mmol) in THF (100 mL) was added NaH (7 g, 175 mmol) portionwise over 0.5 h at 0 °C. After the addition, the mixture was stirred at 20 °C for an additional 1 h. Then, 5-bromo-2,3-difluoro-pyridine (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 saturated NH Cl solution (100 mL), and the mixture was extracted with EtOAc (100 mL × 2). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na SO , filtered, and concentrated to give the crude product (27 g, 89.52 mmol) as an oil.

[0354] Synthesis of A85: A mixture of 2-benzyloxy-5-bromo-3-fluoro-pyridine (27 g, 95.71 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (29.16 g, 114.85 mmol), KOAc (18.79 g, 191.41 mmol), and Pd(dppf)Cl (10.5 g, 14.36 mmol) in 1,4-dioxane (300 mL) was stirred at 90 °C under N for 16 h. After cooling to room temperature, the mixture was filtered through Celite, and the filtrate was concentrated. The crude product was purified by flash chromatography on silica gel (PE) to give the product (20 g, 60.75 mmol, 63% yield) as a solid. 1 H NMR (400 MHz, CDCl) δ H=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).

[0355] Synthesis of A86: A mixture of 2-bromo-5-chloro-pyrazine (4 g, 20.68 mmol), 2-benzyloxy-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (6.81 g, 20.68 mmol), CsCO (13.47 g, 41.36 mmol), and Pd(dppf)Cl (2.27 g, 3.1 mmol) in 1,4-dioxane (30 mL) and water (3 mL) was stirred at 50 °C under N for 16 h. 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 anhydrous NaSO, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 15% to 30%) to give the product (5.5 g, 17.42 mmol, 84% yield) as a solid. 1 H NMR (400MHz, DMSO-d6) δ H =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).

[0356] Synthesis of A87: 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 NaSO, filtered, and concentrated to give the crude product (4 g, 7.38 mmol) as a solid. LCMS R t= 0.76 min in 1.5 min chromatography, 5-95AB, C 16 H 15 FN5O[M+H] + MS ESI calculated value for 312.1, found value 311.9.

[0357] Synthesis of A88: To a solution of 2-bromo-2,2-difluoroacetyl chloride (1.65 g, 8.53 mmol) in THF (30 mL) was added [5-(6-benzyloxy-5-fluoro-3-pyridyl)pyrazin-2-yl]hydrazine (2 g, 6.42 mmol). 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 Na SO , filtered, and concentrated to give the crude product (900 mg, 1.92 mmol) as a solid. 1 H NMR (400MHz, DMSO-d6) δ H =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).

[0358] Synthesis of A89: To a mixture of N'-[5-(6-benzyloxy-5-fluoro-3-pyridyl)pyrazin-2-yl]-2-bromo-2,2-difluoro-acetohydrazide (450 mg, 0.96 mmol) in DCM (9 mL) was added 2-methoxypyridine (230.74 mg, 2.11 mmol) and TfO (0.19 mL, 1.15 mmol). The mixture was stirred at 20 °C for 16 h. Water (50 mL) was added, and the aqueous layer was extracted with EtOAc (50 mL × 2). The combined organic phases were washed with saturated NaHCO solution (30 mL) and brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 30% to 50%) to give the product (240 mg, 533.1 μmol, 55% yield) as a solid. 1 H NMR (400 MHz, CDCl) δ H =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).

[0359] Synthesis of compound 64: 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 AgBF (207.55 mg, 1.07 mmol) in ethanol (5 mL) was stirred at 60 °C in the dark for 1 h. After cooling to room temperature, the mixture was filtered through Celite, and the filtrate was concentrated. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 30% to 50%) to give the product (31.09 mg, 74.8 μmol, 14% yield) as a solid. 1 H NMR (400 MHz, CDCl) δ H=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 R t = 1.38 min in 2.0 min chromatography, 10-80AB, C 20 H 17 F3N5O2[M+H] + MS ESI calculated value for 416.1, found value 416.0.

[0360] Example 63: 3-[Difluoro(methoxy)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine [ka] Synthesis of A100: A mixture of 3-[bromo(difluoro)methyl]-6-chloro-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine (900 mg, 3.03 mmol) and AgBF (1.17 g, 6.05 mmol) in methanol (10 mL) was stirred at 60 °C in the dark for 1 h. After cooling to room temperature, brine (50 mL) and EtOAc (50 mL) were added to the mixture, and the mixture was filtered through Celite. The organic phase was separated and washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (0% to 30% to 50% EtOAc in PE) to give the product (180 mg, 724.0 μmol, 23% yield) as a solid. 1 H NMR (400 MHz, CDCl) δ H =7.99(s, 1H), 3.90(s, 3H), 2.53(s, 3H) ) LCMS R t = 0.78 min in 1.5 min chromatography, 5-95AB, C8H8ClF2N4O [M+H] + MS ESI calculated value for 249.0, found value 248.9.

[0361] Synthesis of Compound 65: A mixture of 6-chloro-3-[difluoro(methoxy)methyl]-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine (100 mg, 0.40 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (193.72 mg, 0.60 mmol), KPO (170.78 mg, 0.80 mmol), and Pd(t-BuP) (30.83 mg, 0.06 mmol) in 1,4-dioxane (5 mL) and water (0.50 mL) was stirred at 80 °C under N for 3 h. 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 phase was washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (0% to 30% to 50% EtOAc in PE) to give the product (64.84 mg, 158.9 μmol, 39% yield) as a solid. 1 H NMR (400 MHz, CDCl) δ H =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 R t = 1.18 min in 2.0 min chromatography, 10-80AB, C 15 H 12 F6N5O2[M+H] + MS ESI calculated value for 408.1, found value 408.0.

[0362] Example 64: 3-[Difluoro(methoxy)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine [ka] A mixture of 3-fluoro-2-[(1R)-2,2,2-trifluoro-1-methylethoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (121.31 mg, 0.36 mmol), 6-chloro-3-[difluoro(methoxy)methyl]-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine (75 mg, 0.3 mmol), Pd(t-BuP) (23.13 mg, 0.05 mmol), and KPO (128.09 mg, 0.6 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was stirred at 80 °C for 3 h. After cooling to room temperature, the mixture was concentrated and diluted with HO (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 NaSO, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (100% EtOAc) to give the product (70.46 mg, 0.17 mmol, 55% yield) as a solid. 1 H NMR (400 MHz, CDCl) δ H =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 Rt = 2 min chromatographically. 24 minutes, 10-80AB, MS ESI calculation C 16 H 14 F6N5O2[M+H] + 422.1, actual value 422.0.

[0363] Example 65: 3-[ethoxy(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 [ka] 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 AgBF (82.81 mg, 0.43 mmol) in ethanol (1 mL) was stirred at 60 °C in the dark for 1 h. After cooling to room temperature, EtOAc (30 mL) and saturated aqueous NaCl (30 mL) were added to the mixture. The mixture was filtered through Celite, and the phases of the filtrate were separated. The aqueous phase was extracted with EtOAc (20 mL). The combined organic phase was washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (0% to 30% to 50% EtOAc in PE) to give the impure product (55 mg) as a solid. The impure product was triturated from EtOH (1 mL) to give the product (19.57 mg, 21% yield) as a solid. 1 H NMR (400 MHz, CDCl) δ H =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 R t = 1.34 min in 2.0 min chromatography, 10-80AB, C 17 H 16 F6N5O2[M+H] + MS ESI calculated value for 436.1, found value 436.0.

[0364] Example 66: 3-[Difluoro(methoxy)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine [ka] Synthesis of A103: 3,6-dichloro-4-methyl-pyridazine (14 g, 85.89 mmol) and N2H4 in ethanol (200 mL) . A mixture of HCl (4.29 g, 85.89 mmol) and HCl (4.29 g, 85.89 mmol) was stirred at 70 °C for 30 h. 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 give a crude product. The product was prepared as a mixture of two positional isomers (A103, A103-2) in a ratio of approximately 1:1 ( 1 H The compound was obtained as a solid (determined by NMR) (8 g, 50.45 mmol, 58% yield).

[0365] Synthesis of A99: A mixture of 6-chloro-5-methyl-pyridazin-3-amine (2.0 g, 13.93 mmol), (6-chloro-4-methyl-pyridazin-3-yl)hydrazine and 2-bromo-2,2-difluoro-acetyl 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 HO (50 mL). The mixture was extracted with EtOAc (100 mL × 2). The combined organic phase was washed with brine (30 mL), dried over anhydrous NaSO, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (20% to 40% to 60% EtOAc in PE) to give both A99 (400 mg, 1.34 mmol, 10% yield) and A99-2 (600 mg, 2.01 mmol, 14% yield) as solids. 1 H NMR (400 MHz, CDCl) δ H =8.08(s, 1H), 2.58(s, 3H). A99-2 1 H NMR (400 MHz, CDCl) δ H =7.14(s, 1H), 2.81(s, 3H).

[0366] Synthesis of A100-a: A mixture of 3-[bromo(difluoro)methyl]-6-chloro-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine (400 mg, 1.34 mmol) and AgBF (523.5 mg, 2.69 mmol) in methanol (5 mL) was stirred at 55 °C in the dark for 12 h. After cooling to room temperature, saturated aqueous NaCl (30 mL) and EtOAc (30 mL) were added. The mixture was filtered through Celite, and the filtrate was extracted with EtOAc (30 mL). The combined organic phases were washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (0% to 30% to 50% EtOAc in PE) to give the product (230 mg, 0.93 mmol, 68% yield) as a solid. 1 H NMR (400 MHz, CDCl 3) δ H = 7.98 (d, 1H), 3.89 (s, 3H), 2.53 (s, 3H). LCMS Rt = 0.73 min on chromatography at 1.5 min, 10-80AB, MS ESI calculated for C8H8ClF2N4O [M+H] + 249.0, actual value 248.8.

[0367] Synthesis of compound 68: A mixture of 6-chloro-3-[difluoro(methoxy)methyl]-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine (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-dioxaborolan-2-yl)pyridine (113.22 mg, 0.34 mmol), KPO (119.55 mg, 0.56 mmol), and Pd(t-BuP) (21.58 mg, 0.04 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was stirred at 80 °C under N for 3 h. After cooling to room temperature, the mixture was filtered through Celite, 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 NaSO, filtered, and concentrated. The crude product was purified by preparative TLC (silica gel, EtOAc) to give the product (65 mg, 154.3 μmol, 54% yield) as a solid. 1 H NMR (400 MHz, CDCl) δ H =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 R t = 1.31 min in 2.0 min chromatography, 10-80AB, C 16 H 14 F6N5O2[M+H] + MS ESI calculated value for 422.1, found value 422.2.

[0368] Example 67: 6-[5-fluoro-6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridyl]-3-(methoxymethyl)-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine [ka] A mixture of 6-chloro-3-(methoxymethyl)-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine (80 mg, 0.38 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)pyridine (197.03 mg, 0.56 mmol), KPO (159.74 mg, 0.75 mmol), and Pd(t-BuP) (28.84 mg, 0.06 mmol) in 1,4-dioxane (5 mL) and HO (0.5 mL) was stirred at 80 °C under N for 3 h. After cooling to 25 °C, the mixture was filtered through Celite, 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 NaSO, filtered, and concentrated. The crude product was purified by preparative HPLC (Waters XBridge BEH C18 (150 mm × 25 mm, 5 μm) A = HO (0.075% NHHCO) and B = CHCN, 50–60% B over 9.5 min) to give the product (21.64 mg, 0.05 mmol, 14% yield) as a solid. 1 H NMR (400 MHz, CDCl) δ H =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). LCMS R t = 1.28 min in 2.0 min chromatography, 10-80AB, C 17 H 18 F4N5O2[M+H] + MS ESI calculated value for 400.1, found value 400.1.

[0369] Example 68: 6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-3-(methoxymethyl)-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine [ka] 6-chloro-3-(methoxymethyl)-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine (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-dioxabo) in 1,4-dioxane (5 mL) and water (0.5 mL). A mixture of (loran-2-yl)pyridine (132.38 mg, 0.40 mmol), KPO (139.78 mg, 0.66 mmol), and Pd(t-BuP) (25.24 mg, 0.05 mmol) was stirred at 80 °C under N for 3 h. After cooling to 25 °C, the mixture was filtered through Celite, 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 NaSO, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (10% to 20% EtOAc in PE) to give the product (33.02 mg, 0.09 mmol, 26% yield) as a solid. 1 H NMR (400 MHz, CDCl) δ H =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 R t = 1.24 min in 2.0 min chromatography, 10-80AB, C 16 H 16 F4N5O2[M+H] + MS ESI calculated value for 386.1, found value 385.9.

[0370] Example 69: 6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-3-(methoxymethyl)-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine [ka] Synthesis of A105: The corresponding pinacol ester was dissolved in MeCN and aqueous HCl was added. The mixture was stirred at room temperature for 2 hours and then concentrated to give A105, which was used crude.

[0371] Synthesis of Compound 71: A mixture of 6-chloro-3-(methoxymethyl)-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine (70 mg, 0.33 mmol), [5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]boronic acid (94.39 mg, 0.40 mmol), KPO (139.78 mg, 0.66 mmol), and Pd(t-BuP) (25.24 mg, 0.05 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was stirred at 80 °C under N for 3 h. After cooling to room temperature, the mixture was filtered through Celite, 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 NaSO, filtered, and concentrated. The crude product was purified by preparative TLC (silica gel, EtOAc) to give the product (9.8 mg, 0.03 mmol, 8% yield) as a solid. 1 H NMR (400 MHz, CDCl) δ H =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 R t = 1.19 min in 2.0 min chromatography, 10-80AB, C 15 H 14 F4N5O2[M+H] + MS ESI calculated value for 372.1, found value 372.0.

[0372] Example 70: 6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-3-(methoxymethyl)-7-methyl-[1,2, 4]Triazolo[4,3-b]pyridazine [ka] Synthesis of A104: To a solution of a mixture of (6-chloro-5-methyl-pyridazin-3-yl)hydrazine and (6-chloro-4-methyl-pyridazin-3-yl)hydrazine (2 g, 12.61 mol) in toluene (30 mL), 2-methoxyacetyl chloride (2737.12 mg, 25.22 mmol) was added at 25 °C. The mixture was heated to 120 °C and stirred for 16 h. After cooling to room temperature, the mixture was concentrated and the residue was diluted with HO (30 mL). The mixture was extracted with EtOAc (50 mL × 2). The combined organic phase was washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified three times by flash chromatography on silica gel (EtOAc) to give both A104 (250 mg, 1.17 mmol, 9% yield) and A104-2 (500 mg, 2.35 mmol, 19% yield) as solids. 1 H NMR (400 MHz, CDCl) δ H =7.94(d, 1H), 5.02(s, 2H), 3.50(s, 3H), 2.51(s, 3H).

[0373] Synthesis of compound 72: A mixture of 6-chloro-3-(methoxymethyl)-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine (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-dioxaborolan-2-yl)pyridine (113.47 mg, 0.34 mmol), KPO (119.81 mg, 0.56 mmol), and Pd(t-BuP) (21.63 mg, 0.04 mmol) in 1,4-dioxane (5 mL) and HO (0.5 mL) was stirred at 80 °C under N for 1 h. After cooling to room temperature, the mixture was filtered through Celite, 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 NaSO, filtered, and concentrated. The crude product was purified by preparative TLC (silica gel, EtOAc) to give the product (23.22 mg, 59.2 μmol, 21% yield) as a solid. 1 H NMR (400 MHz, CDCl) δ H =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 R t = 1.24 min in 2.0 min chromatography, 10-80AB, C 16 H 16 F4N5O2[M+H] + MS ESI calculated value for 386.1, found value 386.1.

[0374] Example 71: 3-(Difluoro(methoxy)methyl)-6-(6-(3,3-difluorocyclobutoxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine [ka] Synthesis of A107: 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-dioxaborolan-2-yl)pyridine (1.43 g, 4.6 mmol) in 1,4-dioxane (27.0 mL) was added water (3.0 mL) and CsCO (2.73 g, 8.37 mmol). Pd(dppf)Cl . DCM (0.34 g, 0.42 mmol) was added to the reaction mixture under a nitrogen atmosphere and heated at 80° C. for 16 h. The reaction mixture was cooled to room temperature, filtered through Celite, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using 25% ethyl acetate / PE to give the product (430 mg, 1.11 mmol, 26% yield). LCMS: 388.1 (M+H), Rt 2.4 min. Column: ZORBAX XDB C-18 (50×4.6 mm), 3.5 μm. Mobile phase: A: 0.1% HCOOH:ACN in water (95:5), B: ACN; Flow rate: 1.5 mL / min.

[0375] Synthesis of compound 73: 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) was added CsCO (515 mg, 1.58 mmol) and methanol (0.21 mL, 5.2 mmol). The reaction was stirred at room temperature for 1 hour. 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 NaSO, and concentrated. The crude compound was purified by preparative HPLC to give a solid (32 mg, 0.08 mmol, 32% yield). Preparative HPLC method: Rt = 16.1; Column: XBridge C8 (150 x 19 mm), 5.0 μm; Mobile phase: 0.1% TFA in water / acetonitrile; 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:ACN (95:5) in water, B: ACN; Flow rate: 1.5 mL / min. 1 H NMR(400MHz, CD3OD): δ9.54(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).

[0376] Example 72: 3-(cyclopropoxydifluoromethyl)-6-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine [ka] Synthesis of A109: To a stirred solution of 2,2,2-trifluoroethanol (3.12 g, 31.25 mmol) in THF (25 mL) at 0 °C, NaH (60% in mineral oil, 1.25 g, 31.25 mmol) was added portionwise. The reaction mixture was slowly warmed to room temperature and stirred for 15 minutes. 5-Bromo-2-fluoro-pyridine (5.0 g, 28.41 mmol) was added dropwise to the reaction mixture and stirred for 2 hours. 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 NaSO, and concentrated. The crude compound was purified by column chromatography on silica gel using 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:ACN in water (95:5), B: ACN; Flow rate: 1.5 mL / min.

[0377] Synthesis of A110: To a stirred solution of 5-bromo-2-(2,2,2-trifluoroethoxy)pyridine (5.0 g, 19.53 mmol) and bis(pinacolato)diboron (6.45 g, 25.39 mmol) in 1,4-dioxane (50.0 mL) was added potassium acetate (3.83 g, 39.0 mmol). Pd(dppf)Cl . DCM (1.59 g, 1.95 mmol) was added to the reaction mixture under a nitrogen atmosphere and heated at 80° C. for 12 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and concentrated under reduced pressure. The crude compound was purified by column chromatography on silica gel using 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 (50×4.6 mm), 3.5 μm. Mobile phase: A: 0.1% HCOOH:ACN in water (95:5), B: ACN; Flow rate: 1.5 mL / min.

[0378] Synthesis of A112: 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-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (1.5 g, 4.95 mmol) in 1,4-dioxane (25.0 mL), water (2.5 mL) and CsCO (3.22 g, 9.9 mmol) were added. . DCM (0.4 g, 0.49 mmol) was added to the reaction mixture under a nitrogen atmosphere and heated at 80° C. for 12 h. The reaction mixture was cooled to room temperature, filtered through Celite, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using 30% ethyl acetate / PE. Purification gave the product (500 mg, 1.3 mmol, 26% yield). LCMS: 380.0 (M+H), Rt 2.45 min. Column: ZORBAX XDB C-18 (50 × 4.6 mm), 3.5 μm. Mobile phase: A: 0.1% HCOOH:ACN in water (95:5), B: ACN; Flow rate: 1.5 mL / min.

[0379] Synthesis of compound 74: 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) was added CsCO (514 mg, 1.58 mmol) and cyclopropanol (0.21 mL, 3.29 mmol). The reaction 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 NaSO, and concentrated. The crude compound was purified by preparative HPLC to give a solid (10 mg, 0.024 mmol, 9% yield). Preparative HPLC method: Rt = 14.2; Column: XBridge C8 (150 x 19 mm), 5.0 μm; Mobile phase: 0.1% TFA in water / acetonitrile; 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(400MHz, CD3OD): δ9.55(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).

[0380] Example 73: 3-(cyclopropoxydifluoromethyl)-6-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine [ka] Synthesis of A113: To a stirred solution of 2,2,2-trifluoroethanol (5.67 g, 56.71 mmol) in THF (200 mL) at 0 °C, NaH (60% in mineral oil, 2.26 g, 56.71 mmol) was added portionwise. The reaction mixture was stirred for 15 min, and 5-bromo-2,3-difluoro-pyridine (10.0 g, 51.55 mmol) was added dropwise. The reaction mixture was slowly warmed 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 silica gel using 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 × 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.

[0381] Synthesis of A3-a: To a stirred solution of 5-bromo-3-fluoro-2-(2,2,2-trifluoroethoxy)pyridine (3.0 g, 10.95 mmol) and bis(pinacolato)diboron (3.61 g, 14.23 mmol) in 1,4-dioxane (30.0 mL) was added potassium acetate (2.15 g, 21.9 mmol). Pd(dppf)Cl . DCM (0.89 g, 1.09 mmol) was added to the reaction mixture under a nitrogen atmosphere and heated at 80° C. for 12 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and concentrated under reduced pressure. The crude compound was purified by column chromatography on silica gel using 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 (50×4.6 mm), 5 μm. Mobile phase: A: 0.1% HCOOH:ACN in water (95:5), B: ACN; Flow rate: 1.5 mL / min.

[0382] Synthesis of A18-a: 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-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (2.96 g, 9.2 mmol) in 1,4-dioxane (26.0 mL) was added water (4.0 mL) and K2CO3 (2.31 g, 16.74 mmol). PdCl2(PPh3)2 (0.59 g, 0.84 mmol) was added to the reaction mixture under a nitrogen atmosphere and heated at 90 °C for 12 h. The reaction mixture was cooled to room temperature, filtered through Celite, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using 30% ethyl acetate / PE to give the product (1.35 g, 3.4 mmol, 40% yield). LCMS: 398.0 (M+H), Rt 2.51 min. Column: Atlantis dC-18 (50 × 4.6 mm), 3.5 μm. Mobile phase: A: 0.1% HCOOH:ACN in water (95:5), B: ACN; Flow rate: 1.5 mL / min. 1 H NMR (400 MHz, DMSO-d6): δ9.77(d, 1H), 9.14(s, 1H), 8.84(d, 1H), 8.66(dd, 1H), 5.20(q, 2H).

[0383] Synthesis of Compound 75: 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), CsCO (737 mg, 2.26 mmol) and cyclopropanol (0.48 mL, 7.54 mmol) were added. The reaction mixture was stirred for 6 hours at room temperature. 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 NaSO, 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 HNM R(400MHz, DMSO-d6):δ9.71(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).

[0384] Example 74: 3-(Difluoro(methoxy)methyl)-6-(6-(3,3-difluorocyclobutoxy)-5-fluoropyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine [ka] Synthesis of A115: To a stirred solution of 2-chloro-5-hydrazinylpyrazine (5.0 g, 33.99 mmol) in toluene (50 mL) was added chlorodifluoroacetic anhydride (6.54 mL, 37.39 mmol) at 0° C. The reaction mixture was heated at 110° C. for 1 h. 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 NaSO, and concentrated to a solid (6 g), which was used in the next step without further purification.

[0385] Synthesis of A111: To a stirred solution of 2-chloro-N'-(5-chloropyrazin-2-yl)-2,2-difluoroacetohydrazide (6.0 mg, 23.34 mmol) in DCM (120 mL) was added trifluoromethanesulfonic anhydride (4.73 mL, 28.01 mmol) and 2-methoxypyridine (4.91 mL, 46.69 mmol) at 0 °C. The reaction mixture was slowly warmed to room temperature and stirred for 2 h. 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 NaSO, and concentrated. The crude product was purified by column chromatography on silica gel using 15% EtOAc / PE to give the product (4.0 g, 16.5 mmol, 71% yield) as a solid. LCMS: 239.0 (M+H), Rt 1.66 min Column: ZORBAX XDB C-18 (50 × 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.

[0386] Synthesis of A116: 3,3-difluorocyclobutanol in THF (10 mL) at 0 °C To a stirred solution of (500 mg, 4.63 mmol), NaH (60% in mineral oil, 204 mg, 5.09 mmol) was added portionwise. The reaction mixture was slowly warmed to room temperature and stirred for 15 minutes. Then, 5-bromo-2,3-difluoro-pyridine (0.9 g, 4.63 mmol) was added dropwise to the reaction mixture and stirred for 4 hours. 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 silica gel using 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:ACN in water (95:5), B: ACN; Flow rate: 1.5 mL / min.

[0387] Synthesis of A117: To a stirred solution of 5-bromo-2-(3,3-difluorocyclobutoxy)-3-fluoropyridine (1.1 g, 3.91 mmol) and bis(pinacolato)diboron (1.29 g, 5.09 mmol) in 1,4-dioxane (20.0 mL) was added potassium acetate (0.77 g, 7.83 mmol). Pd(dppf)Cl . DCM (0.32 g, 0.39 mmol) was added to the reaction mixture under a nitrogen atmosphere and heated at 90° C. for 16 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and concentrated under reduced pressure. The crude compound was purified by column chromatography on silica gel using 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 × 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.

[0388] Synthesis of A118: 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-dioxaborolan-2-yl)pyridine (1.17 g, 3.55 mmol) in 1,4-dioxane (15.0 mL), water (3.0 mL) and CsCO (2.31 g, 7.13 mmol) were added. . DCM (0.29 g, 0.36 mmol) was added to the reaction mixture under a nitrogen atmosphere and heated at 80° C. for 8 h. The reaction mixture was cooled to room temperature, filtered through Celite, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using 30% ethyl acetate / PE to give the product (1.11 g, 2.75 mmol, 77% yield). LCMS: 405.9 (M+H), Rt 2.30 min. Column: ZORBAX XDB C-18 (50×4.6 mm), 3.5 μm. Mobile phase: A: 0.1% HCOOH:ACN in water (95:5), B: ACN; Flow rate: 1.5 mL / min.

[0389] Synthesis of compound 76: 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) was added CsCO (668 mg, 2.06 mmol) and methanol (0.14 mL, 3.4 mmol). The reaction was stirred at room temperature for 1 hour. 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 NaSO, and concentrated. The crude compound was purified by preparative HPLC to give a solid (18 mg, 0.04 mmol, 13% yield). Preparative HPLC method: Rt 12.9; Column: YMC Phenyl (150 x 19 mm), 5.0 μm; Mobile phase: 0.1% TFA in water / acetonitrile; 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. FA;Flow rate: 2.0mL / 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 (400MHz, DMSO-d6): δ9.70(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).

[0390] Example 75: 6-(6-(3,3-difluorocyclobutoxy)-5-fluoropyridin-3-yl)-3-(ethoxydifluoromethyl)-[1,2,4]triazolo[4,3-a]pyrazine [ka] 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) was added CsCO (668 mg, 2.06 mmol) and ethanol (0.2 mL, 3.4 mmol). 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 NaSO, and concentrated. The crude compound was purified by preparative HPLC to give a solid (22 mg, 0.05 mmol, 15% yield). Preparative HPLC method: Rt 13.1; 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 5.08 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 (400MHz, CD3OD): δ9.54(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).

[0391] Example 76: 3-(cyclopropoxydifluoromethyl)-6-(6-(3,3-difluorocyclobutoxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine [ka] 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) was added CsCO (504 mg, 1.55 mmol) and cyclopropanol (0.33 mL, 5.16 mmol). The reaction mixture was stirred at room temperature for 4 hours. 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 NaSO, and concentrated. The crude compound was purified by preparative HPLC to give a solid (14 mg, 0.034 mmol, 13% yield). Preparative HPLC method: Rt 10.67; Column: Sunfire 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 5.19 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(400MHz, CD3OD):δ9.54(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).

[0392] Example 77: 3-(ethoxymethyl)-6-(5-fluoro-6-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine [ka] Synthesis of A119: To a stirred solution of 1,1,1-trifluoro-2-methylpropan-2-ol (0.57 g, 4.43 mmol) in THF (20 mL) at 0 °C, NaH (60% in mineral oil, 0.23 g, 5.67 mmol) was added portionwise. The reaction mixture was slowly warmed to room temperature and stirred for 15 minutes. 5-Bromo-2,3-difluoro-pyridine (1.0 g, 5.16 mmol) was added dropwise to the reaction mixture and stirred for 16 hours. 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 NaSO, and concentrated. The crude compound was purified by column chromatography on silica gel using 2% ethyl acetate / PE to give the product (765 mg, 2.54 mmol, 49% yield). 1 H NMR (400MHz, CDCl3): δ7.99(d, 1H), 7.54(dd, 1H), 1.80(s, 6H).

[0393] Synthesis of A8: 5-bromo-3-fluoro-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)pyridine (765 mg, 2.54 mmol) and bis(pinacolato)diboron (0.71 g, 2. To a stirred solution of Pd(dppf)Cl.DCM (0.21 g, 0.25 mmol) was added potassium acetate (497 mg, 5.07 mmol). Pd(dppf)Cl.DCM (0.21 g, 0.25 mmol) was added to the reaction mixture under a nitrogen atmosphere and heated at 80 °C for 16 h. The reaction mixture was cooled to room temperature, filtered through Celite, and concentrated under reduced pressure. The crude compound was purified by column chromatography on silica gel using 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 × 4.6 mm), 3.5 μm. Mobile phase: A: 0.1% HCOOH:ACN in water (95:5), B: ACN. Flow rate: 1.5 mL / min.

[0394] Synthesis of A120: To a stirred solution of (5-chloropyrazin-2-yl)hydrazine (2.0 g, 13.53 mmol) in DCM (15 mL) was added EtN (3.78 mL, 27.07 mmol) followed by 2-ethoxyacetyl chloride (2.36 mL, 13.53 mmol) at 0 °C. The reaction mixture was slowly warmed to room temperature and stirred for 16 h. The reaction mixture was treated with saturated ammonium chloride solution (25 mL) and extracted with ethyl acetate (2 x 25 mL). The organic layer was washed with brine (20 mL), dried over NaSO, and concentrated. The crude product was purified by column chromatography on silica gel using 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 × 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.

[0395] Synthesis of A41-a: To a stirred solution of N'-(5-chloropyrazin-2-yl)-2-ethoxyacetohydrazide (400 mg, 1.73 mmol) in DCM (15.0 mL) was added trifluoromethanesulfonic anhydride (0.38 mL, 2.25 mmol) and 2-methoxypyridine (377 mg, 3.46 mmol) at 0 °C. The reaction mixture was slowly warmed to room temperature and stirred for 16 h. The reaction mixture was treated with 10% sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (2 x 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 silica gel using 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 × 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.

[0396] Synthesis of Compound 79: 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-dioxaborolan-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)pyridine (271 mg, 0.78 mmol) in 1,4-dioxane (10.0 mL), water (1.0 mL) and CsCO (460 mg, 1.41 mmol) were added. . DCM (57 mg, 0.07 mmol) was added to the reaction mixture under a nitrogen atmosphere and heated at 80° C. for 16 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and concentrated under reduced pressure. The crude compound was purified by preparative HPLC to give a solid (105 mg, 0.26 mmol, 36% yield). Preparative HPLC method: Rt 12.75; Column: X-Select (150×19 mm), 5.0 μm; Mobile phase: 0.1% TFA in water / acetonitrile; Flow rate: 15.0 mL / min. HPLC: Rt 4.95 min, Column: XBridge C8 (50×4.6) 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 × 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 (400MHz, DMSO-d6): δ9.56(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).

[0397] Example 79: 3-(ethoxydifluoromethyl)-6-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine [ka] 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) was added CsCO (978 mg, 3.0 mmol) and ethanol (0.58 mL, 10 mmol) at room temperature and stirred for 3 h. 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 NaSO, and concentrated. The crude compound was purified by preparative HPLC to give a solid (10 mg, 0.025 mmol, 5.1% yield). Preparative HPLC method: Rt 9.35; Column: XBridge (150 x 19 mm), 5.0 μm; 0.1% TFA in water / acetonitrile; 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:ACN (95:5) in water, B: ACN; Flow rate: 1.5 mL / min. 1 H NMR(400MHz, CDCl3):δ9.54(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).

[0398] Example 80: 3-(Difluoro(isobutoxy)methyl)-6-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine [ka] To a stirred solution of 2-methylpropan-1-ol (4.65 mL, 50.29 mmol) in MeCN (20 mL) was added CsCO (4.92 g, 15.09 mmol) and the reaction mixture was heated at 70 °C for 20 min. The reaction mixture was cooled to room temperature and 3-(chloro)- Difluoromethyl)-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 hours and then treated with water (30 mL). The reaction mixture was extracted with ethyl acetate (2 × 30 mL), washed with brine (20 mL), dried over NaSO, and concentrated. The crude compound was purified by preparative HPLC to give a solid (35 mg, 0.08 mmol, 3% yield). Preparative HPLC method: Rt 9.37; Column: XBridge C (150 × 19 mm), 5.0 μm; 0.1% TFA in water / acetonitrile; Flow rate: 15.0 mL / min. HPLC: Rt 5.60 min, Column: XBridge C8 (50 × 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 × 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 (400MHz, DMSO-d6): δ9.72(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).

[0399] Example 81: 5-[3-[difluoro(methoxy)methyl]-[1,2,4]triazolo[4,3-a]pyrazin-6-yl]pyridin-2-ol and 6-(6-benzyloxy-5-fluoro-3-pyridyl)-3-[ethoxy(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyrazine [ka] Synthesis of A92: To a solution of phenylmethanol (12 g, 110.97 mmol) in THF (100 mL) was added NaH (4.88 g, 122.06 mmol) portionwise over 0.5 h at 0 °C. After the addition, the mixture was stirred at 20 °C for an additional 1 h. Then, 5-bromo-2-fluoro-pyridine (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 saturated aqueous NH (150 mL) and extracted with EtOAc (200 mL × 2). The combined organic phases were washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated to give the crude product (27 g, 95.62 mmol, 86% yield) as an oil. LCMS R t = 0.96 min in 1.5 min chromatography, 5-95AB, C 12 H 11 BrNO[M+H+2] + MS ESI calculated value for 266.0, found value 265.8.

[0400] Synthesis of A93: 2-benzyloxy-5-bromo- A mixture of 2,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (31.15 g, 122.67 mmol), KOAc (20.06 g, 204.45 mmol), and Pd(dppf)Cl (7.48 g, 10.22 mmol) was stirred at 90 °C under N for 16 h. After cooling to room temperature, the mixture was filtered through Celite and concentrated to give the crude product. The crude product was filtered through silica gel (approximately 50 g) and eluted with PE / EtOAc (5:1, 150 mL × 5), and the filtrate was concentrated to give the impure product. The impure product was triturated from i-PrO (100 mL) to give the product (20 g, 64.27 mmol, 63% yield) as a solid. LCMS R t = 0.74 min in 1.5 min chromatography, 5-95AB, C12 H 13 BNO3[M-C6H 10 +H] + MS ESI calculated value for 230.1, found value 230.0.

[0401] Synthesis of A94: A mixture of 2-bromo-5-chloro-pyrazine (4 g, 20.68 mmol), 2-benzyloxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (7.08 g, 22.75 mmol), CsCO (13.47 g, 41.36 mmol), and Pd(dppf)Cl (1.51 g, 2.07 mmol) in 1,4-dioxane (50 mL) and water (10 mL) was stirred at 50 °C under N for 3 h. After cooling to room temperature, the mixture was filtered and concentrated to give a residue. Water (100 mL) was added to the residue and extracted with EtOAc (150 mL × 2). The combined organic phase was washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated to give the crude product. The crude product was filtered through silica gel (approximately 50 g) and eluted with DCM (150 mL x 3). The filtrate was concentrated to give the impure product. The impure product was triturated from i-PrO (15 mL) to give (4 g, 13.44 mmol, 65% yield) of the product as a solid. LCMS R t = 1.03 min in 1.5 min chromatography, 5-95AB, C 16 H 13 ClNO[M+H] + MS ESI calculated value for 298.1, found value 297.9.

[0402] Synthesis of A95: 2-(6-benzyloxy-3-pyridyl)-5-chloro-pyrazine (4 g, 13.43 mmol) and N2H4 in MeCN (20 mL) .A mixture of HCl (8.61 g) and HCl (8.61 g) was stirred at 90° C. for 16 hours. After cooling to room temperature, the solution was concentrated to give a residue. Water (30 mL) was added to the residue and extracted with EtOAc (50 mL×3). The combined organic phases were washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated to give the product (4 g, 7.84 mmol, 58% yield) as a solid. LCMS R t = 0.74 min in 1.5 min chromatography, 5-95AB, C 16 H 16 NO[M+H] + MS ESI calculated value for 294.1, found value 293.9.

[0403] Synthesis of A96: To a solution of 2-bromo-2,2-difluoroacetyl chloride (1.78 g, 9.2 mmol) in DCM (20 mL) was added [5-(6-benzyloxy-3-pyridyl)pyrazin-2-yl]hydrazine (1.8 g, 6.14 mmol), and the suspension was stirred at 20 °C for 2 h. The mixture was diluted with HO (20 mL) and extracted with EtOAc (100 mL × 2). The combined organic phases were washed with brine (30 mL), dried over NaSO, filtered, and concentrated to give the product. The crude product was purified by flash chromatography on silica gel (20% to 40% to 60% to 80% EtOAc in PE) to give the product (1.5 g, 3.33 mmol, 54% yield) as a solid. LCMS R t = 0.88 min in 1.5 min chromatography, 10-80AB, C 18 H 15 F2N5O2[M+H] + MS ESI calculated value for 450.0, found value 449.9.

[0404] Synthesis of A97: N'-[5-(6-benzyloxy-3-pyridyl)methyl]-3-(4-methyl-2-pyridyl)methyl] in DCM (10 mL) To a mixture of [(2-bromo-2,2-difluoro-2,2-difluoro-2,2-pyridyl)pyrazin-2-yl]-2-bromo-2,2-difluoro-acetohydrazide (1.3 g, 2.89 mmol), 2-methoxypyridine (0.67 mL, 6.35 mmol) and TfO (0.59 mL, 3.46 mmol) were added, 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 × 2). The combined organic phase was washed with saturated aqueous NaHCO (30 mL) and brine (30 mL), dried over NaSO, filtered, and concentrated to give the crude product. The crude product was purified by flash column chromatography on silica gel (EtOAc in PE = 0% to 30% to 50%) to give the product (400 mg, 0.93 mmol, 32% yield) as a solid. LCMS R t = 0.93 min in 1.5 min chromatography, 10-80AB, C 18 H 13 BrF2N5O[M+H+2] + MS ESI calculated value 434.0, actual value 434.0.

[0405] Synthesis of 83: A mixture of 6-(6-benzyloxy-3-pyridyl)-3-[bromo(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyrazine (400 mg, 0.93 mmol) and AgBF (900.79 mg, 4.63 mmol) in methanol (4 mL) was stirred at 60 °C for 2 h in the dark. After cooling to room temperature, saturated aqueous NaCl (10 mL) followed by EtOAc (30 mL) was added to the mixture, and the mixture was filtered through Celite. After phase separation of the filtrate, the organic phase was washed with brine (30 mL), dried over NaSO, filtered, and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (20% to 40% EtOAc in PE) to give the impure product (150 mg), which was triturated from i-PrO (2 mL) to give the pure product (130 mg). The product (39.76 mg, 0.10 mmol, 11% yield) was obtained as a solid. 1 H NMR (400 MHz, CDCl) δ H=9.52(d, 1H), 8.76(d, 1H), 8.42(d, 1H), 8.19(dd, 1H), 7.53-7.47(m, 2H), 7.45-7.32(m, 3H), 6.98(d, 1H), 5.48(s, 2H), 3.97(s, 3H). LCMS R t = 1.26 min in 2.0 min chromatography, 10-80AB, C 19 H 16 F2N5O2[M+H] + MS ESI calculated value for 384.1, found value 384.1.

[0406] Example 82: 3-(Difluoro(methoxy)methyl)-6-(6-(3,3-difluorocyclobutoxy)-5-fluoropyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyridine [ka] To a suspension of CsCO (928 mg, 2.85 mmol) in CHCN (2.0 mL) was added methanol (0.23 mL, 5.7 mmol) at room temperature. The reaction mixture was stirred at room temperature for 10 minutes, and a solution of 3-(chlorodifluoromethyl)-6-(6-(3,3-difluorocyclobutoxy)-5-fluoropyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyridine (190 mg, 0.47 mmol) in CHCN (10.0 mL) was added dropwise. The reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 × 25 mL). The organic layer was washed with brine (20 mL), dried over NaSO, and concentrated. The crude product was purified by preparative HPLC to give the product (50 mg, 0.12 mmol, 26% yield) as a solid. Prep HPLC method: Rt 11.75, Column: X-Bridge (150 x 19 mm), 5.0 μm; Mobile phase: 0.1% TFA in water / acetonitrile; Flow rate: 15.0 mL / min. HPLC: Rt 4.64 min, 99.8%. Column: X-Bridge 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: 401.1 (M+H), Rt 2.22 min, 99.6%. Column: ZORBAX XDB C-18 (50 x 4.6 mm), 3.5 μm. Mobile phase: A: 0.1% HCOOH:ACN (95:5) in water, B: ACN; Flow rate: 1.5 mL / min. 1 H NMR(400MHz, CD3OD):δ8.65(s, 1H), 8.31(d, 1H), 8.00-7.97(m, 2H), 7.90(dd, 1H), 5.32-5.28(m, 1H), 3.96(s, 3H), 3.26-3.15(m, 2H), 2.89-2.77(m, 2H).

[0407] Example 83: 6-(6-(3,3-difluorocyclobutoxy)-5-fluoropyridin-3-yl)-3-(ethoxydifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine [ka] Synthesis A11: To a stirred solution of 5-bromo-2-fluoro-pyridine (10.0 g, 56.82 mmol) in ethanol (120 mL), hydrazine hydrate (11.38 g, 227 mmol) was added and heated at 80° C. for 12 hours. The reaction mixture was cooled to room temperature and treated with ice water (200 mL). The precipitated solid was filtered, washed with water, and dried to give the product (10.7 g) as a solid, which was used in the next step without further purification.

[0408] Synthesis of A127: To a stirred solution of A11 (2.0 g, 10.6 mmol) in toluene (25 mL) was added 2-chloro-2,2-difluoroacetic anhydride (2.84 g, 11.7 mmol) at 0 °C. The reaction mixture was heated at 100 °C for 1 h. 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 saturated NaHCO solution (20 mL), followed by brine (30 mL), dried over NaSO, and concentrated to give the product (2.7 g) as a solid, which was used in the next step without further purification.

[0409] Synthesis of A128: To a stirred solution of A127 (2.7 g, 8.99 mmol) in DCM (30 mL) was added trifluoromethanesulfonic anhydride (1.66 mL, 9.88 mmol) and 2-methoxypyridine (1.96 g, 17.97 mmol) at 0 °C. The reaction mixture was slowly warmed to room temperature and stirred for 1 h. The reaction mixture was treated with 10% sodium bicarbonate solution (50 mL) and extracted with DCM (2 × 50 mL). The organic layer was washed with brine (50 mL), dried over NaSO, and concentrated. The crude product was purified by column chromatography on silica gel using 20% ​​EtOAc / PE. The product (1.1 g, 3.9 mmol, 43% yield) was obtained. LCMS: 282.0 (M+H) and 284.0 (M+2+H), Rt 1.72 min. Column: ZORBAX XDB C-18 (50 x 4.6 mm), 3.5 μm Mobile phase: A: 0.1% HCOOH:ACN (95:5) in water, B: ACN; flow rate: 1.5 mL / min.

[0410] Synthesis of A125: To a stirred solution of A128 (1.0 g, 3.54 mmol) and 2-(3,3-difluorocyclobutoxy)-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.28 g, 3.89 mmol) in 1,4-dioxane (20.0 mL), water (4.0 mL) and K2CO3 (0.98 g, 7.08 mmol) were added. Pd(PPh3)2Cl2 (0.25 g, 0.35 mmol) was added to the reaction mixture under a nitrogen atmosphere and heated at 80 °C for 16 h. The reaction mixture was cooled to room temperature and filtered through Celite. The crude reaction mixture was treated with water (30 mL) and extracted with ethyl acetate (2 × 30 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 silica gel using 40% ethyl acetate / PE to give the compound (1.1 g, 2.7 mmol, 76% yield) as a solid. LCMS: 405.0 (M+H), Rt 2.68 min. Column: Atlantis dC-18 (50 × 4.6 mm), 5.0 μm. Mobile phase: A: 0.1% HCOOH:ACN in water (95:5), B:ACN; Flow rate: 1.5 mL / min.

[0411] Synthesis of Compound 85: To a suspension of CsCO (966 mg, 2.97 mmol) in CHCN (2.0 mL) was added ethanol (0.35 mL, 5.93 mmol) at room temperature. The reaction mixture was stirred at room temperature for 10 minutes, and a solution of A125 (200 mg, 0.49 mmol) in CHCN (10.0 mL) was added dropwise. The reaction mixture was stirred for 1 hour, and ethanol (0.35 mL, 5.93 mmol) was added at room temperature. The reaction mixture was stirred for another hour at room temperature. The reaction mixture was treated with water (20 mL) and extracted with ethyl acetate (2 × 25 mL). The organic layer was washed with brine (20 mL), dried over NaSO, and concentrated. The crude product was purified by column chromatography on silica gel using 22% EtOAc / PE to give the product (30 mg, 0.07 mmol, 14% yield) as a solid. HPLC: Rt 4.92 min, 99.9%. Column: X-Bridge C8 (50 × 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: 415.1 (M+H), Rt 2.53 min, 99.8%. Column: Atlantis dC-18 (50 × 4.6 mm), 5.0 μm. Mobile phase: A: 0.1% HCOOH:ACN (95:5) in water, B: ACN; Flow rate: 1.5 mL / min. 1 H NMR(400MHz, CD3OD):δ8.65(s, 1H), 8.30(d, 1H), 8.00-7.96(m, 2H), 7.89(dd, 1H), 5.32-5.29(m, 1H), 4.36(q, 2H), 3.26-3, 16(m, 2H), 2.89-2.78(m, 2H), 1.47(t, 3H).

[0412] Example 84: (R)-3-(ethoxydifluoromethyl)-6-(6-((1,1,1-trifluoropropan-2-yl)oxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine [ka] Synthesis of A77: To a solution of A132 (2.2 g, 19.63 mmol) in THF (20.0 mL) was added LiAlH (2.0 M in THF, 4.91 mL, 9.82 mmol) dropwise at 0 °C. The reaction mixture was slowly warmed to room temperature and stirred for 3 h. The reaction mixture was cooled to 0 °C and treated with saturated Na SO solution (2.0 mL). The reaction mixture was filtered through Celite, and the filtrate was dried over Na SO and used in the next step as a solution in THF.

[0413] Synthesis of A78: To a solution of A77 (30.68 mmol) in THF, NaH (1.84 g, 46 mmol) was added portionwise at 0° C. and stirred for 30 minutes. 5-Bromo-2-fluoro-pyridine (4.32 g, 24.55 mmol) was slowly added to the reaction mixture at 0° C. The reaction mixture was slowly warmed to room temperature and stirred for 3 hours. The reaction mixture was cooled to 10° C., treated with ice water (10 mL), and extracted with ethyl acetate (2×50 mL). The organic layer was washed with brine (40 mL), dried over Na2SO4, and concentrated. The crude product was purified by column chromatography on silica gel using 20% ​​EtOAc / PE to give the product (3.1 g, 11.5 mmol, 37% yield) as a colorless liquid. LCMS: 270.0 (M+H) and 272.0 (M+2+H), Rt 2.78 min. Column: ZORBAX XDB C-18 (50 x 4.6 mm), 3.5 μm. Mobile phase: A: 0.1% HCOOH:ACN in water (95:5), B: ACN; Flow rate: 1.5 mL / min.

[0414] Synthesis of A79: To a stirred solution of A78 (3.1 g, 11.5 mmol) and bis(pinacolato)diboron (3.79 g, 14.92 mmol) in 1,4-dioxane (35.0 mL) was added potassium acetate (2.25 g, 22.96 mmol). Pd(dppf)Cl .DCM (1.41 g, 1.72 mmol) was added to the reaction mixture under a nitrogen atmosphere and heated at 90° C. for 12 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and concentrated under reduced pressure. The crude compound was purified by column chromatography on silica gel using 6% ethyl acetate / PE to give the product (2.8 g, 8.83 mmol, 76% yield) as a solid. LCMS: 318.0 (M+H), Rt 4.04 min. Column: ZORBAX Extend (50×4.6 mm), 5 μm. Mobile phase: A: 10 mM ammonium acetate in water, B: ACN; Flow rate: 1.2 mL / min.

[0415] Synthesis of A82: To a stirred solution of A79 (0.5 g, 1.58 mmol) and 6-chloro-3-(chlorodifluoromethyl)-[1,2,4]triazolo[4,3-a]pyrazine (0.45 g, 1.89 mmol) in 1,4-dioxane (12.0 mL), water (2.0 mL) and CsCO (1.03 g, 3.15 mmol) were added. . DCM (0.11 g, 0.16 mmol) was added to the reaction mixture under a nitrogen atmosphere. The mixture was added and heated at 90° C. for 16 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and concentrated under reduced pressure. The crude compound was purified by column chromatography on silica gel using 15% ethyl acetate / PE to give the product (350 mg, 0.89 mmol, 56% yield) as a solid. LCMS: 394.1 (M+H), Rt 2.54 min. Column: ZORBAX XDB C-18 (50×4.6 mm), 3.5 μm. Mobile phase: A: 0.1% HCOOH:ACN in water (95:5), B:ACN; Flow rate: 1.5 mL / min.

[0416] Synthesis of compound 86: To a stirred suspension of Cs2CO3 (993 mg, 3.05 mmol) in MeCN (5.0 mL), ethanol (0.36 mL, 6.1 mmol) was added at room temperature and stirred for 30 minutes. To the reaction mixture, A82 (200 mg, 0.51 mmol) in MeCN (5.0 mL) was added dropwise and stirred for 2 hours. The reaction mixture was treated with water (30 mL) and extracted with ethyl acetate (2 x 30 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4, and concentrated. The crude compound was purified by column chromatography on silica gel using 18% ethyl acetate / PE to give the product (35 mg, 0.08 mmol, 17% yield) as a solid. HPLC: Rt 5.22 min, 97.6%. Column: X-Bridge 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: 404.1 (M+H), Rt 2.53 min, 96.7%. Column: ZORBAX Extend C-18 (50 x 4.6 mm), 5.0 μm. Mobile phase: A: 10 mM ammonium acetate in water, B: ACN; Fl...

Claims

1. Formula (III): 【Chemistry 201】 or a pharmaceutically acceptable salt thereof, wherein X and Y are each CR ｄ and R １ teeth, 【Chemistry 192】 , monocyclic C ３ - ６ cycloalkyl, or 4- to 7-membered monocyclic heterocyclyl, wherein the cycloalkyl and heterocyclyl are optionally one or more R ａ is replaced by R ２ is C １ - ４ haloalkyl, phenyl, or optionally one or more R ｂ Monocyclic C substituted with ３ - ６ is cycloalkyl, R ３ is hydrogen, C １ - ４ Alkyl, or C １ - ４ is haloalkyl, R ４ is hydrogen or C １ - ４ is alkyl, R ６ is C １ - ４ Alkyl or C １ - ４ haloalkyl, １ - ４ Alkyl or C １ - ４ Haloalkyl is each OR ｃ is replaced by R ａ and R ｂ are each independently halo, C １ - ４ Alkyl, C １ - ４ Haloalkyl, C １ - ４ Alkoxy, and C １ - ４ haloalkoxy; R ｃ is optionally C ３ - ６ Cycloalkyl or C １－４ Alkoxy-substituted C １ - ４ Alkyl, or C ３ - ６ is cycloalkyl, and R ｄ is hydrogen or C １ - ４ or a pharmaceutically acceptable salt thereof, wherein:

2. The compound has the formula IX: 【Chemistry 194】 or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 1.

3. R １ but, 【Chemistry 195】 3. The compound of claim 1 or claim 2, wherein:

4. R １ optionally one or more R ａ 3. The compound of claim 1 or claim 2, wherein R is cyclobutyl substituted with R, or a pharmaceutically acceptable salt thereof.

5. R ２ But C １ - ４ The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, which is haloalkyl.

6. R ２ But CF ３ 6. The compound according to any one of claims 1 to 3 and 5, wherein:

7. R ２ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein is phenyl.

8. R ３ is C １ - ４ alkyl, and R ４ is hydrogen or C １ - ４ The compound according to any one of claims 1 to 3 and 5 to 7, or a pharmaceutically acceptable salt thereof, wherein R is alkyl.

9. R ３ and R ４ However, each １ - ４ The compound according to any one of claims 1 to 3 and 5 to 8, or a pharmaceutically acceptable salt thereof, wherein R is alkyl.

10. R ３ and R ４ The compound according to any one of claims 1 to 3 and 5 to 9, or a pharmaceutically acceptable salt thereof, wherein each of

11. R ３ is methyl, and R ４ The compound according to any one of claims 1 to 3 and 5 to 8, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

12. R ３ and R ４ The compound according to any one of claims 1 to 3 and 5 to 7, or a pharmaceutically acceptable salt thereof, wherein each of is hydrogen.

13. R ６ But, -CF ２ -OR ｃ 13. The compound according to any one of claims 1 to 12, wherein:

14. R ｃ optionally cyclopropyl-substituted C １ - ４ The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, which is alkyl.

15. R ｃ The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein is cyclopropyl.

16. R ６ But -C(F ２ ) OCH ２ CH (CH ３ ) ２ , -C(F ２ ) OCH ３ , -C(F ２ ) OCH ２ CH ３ , -C(F ２ ) OCH(CH ３ ) ２ , or -C(F ２ ) OCH ２ C ３ H ５ 15. The compound according to any one of claims 1 to 14, wherein:

17. R ６ But -CH ２ -OR ｃ 13. The compound according to any one of claims 1 to 12, wherein:

18. R ｃ But C １－４ 18. The compound of any one of claims 1 to 12 and 17, or a pharmaceutically acceptable salt thereof, wherein:

19. R ６ But -CH ２ OCH ３ , -CH ２ OCH ２ CH ３ , or -CH ２ OCH ２ CH (CH ３ ) ２ 19. The compound according to any one of claims 1 to 12 and 17 to 18, or a pharmaceutically acceptable salt thereof, wherein:

20. R ａ But C １ - ４ 20. The compound of any one of claims 1 to 2, 4, and 13 to 19, or a pharmaceutically acceptable salt thereof, which is haloalkyl.

21. R ａ But CF ３ 21. The compound according to any one of claims 1 to 2, 4 and 13 to 20, or a pharmaceutically acceptable salt thereof, wherein:

22. R ａ The compound according to any one of claims 1 to 2, 4 and 13 to 19, or a pharmaceutically acceptable salt thereof, wherein is fluoro.

23. R ｄ 23. The compound according to any one of claims 1 and 3 to 22, or a pharmaceutically acceptable salt thereof, wherein is methyl.

24. R ｄ 23. The compound according to any one of claims 1 and 3 to 22, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

25. The compound is 【Chemistry 196】 【Chemistry 197】 10. The compound of claim 1, selected from the group consisting of:

26. The compound is 【Chemistry 198】 26. The compound of claim 25, which is:

27. 27. The compound of claim 26, wherein the compound is a crystalline compound, and the crystalline compound has a diffraction angle (2θ) of: a) 12.6±0.2, 15.8±0.2, and 18.6±0.2; or b) 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; or c) 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 The compound is characterized by an X-ray powder diffraction pattern including a peak at

28. The crystalline compound is shown in FIG. 【Chemistry 199】 28. The compound of claim 27, which exhibits an X-ray powder diffraction pattern represented by:

29. 29. The compound of claim 27 or 28, wherein the crystalline compound has a melting point onset as determined by differential scanning calorimetry at 107°C.

30. The crystalline compound is shown in FIG. 【Chemistry 200】 30. The compound according to any one of claims 27 to 29, having a differential scanning calorimetry curve shown in

31. 29. The compound of claim 27 or 28, wherein the X-ray powder diffraction pattern is obtained using Cu Kα radiation.

32. A pharmaceutical composition comprising the compound of any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

33. A composition comprising a compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 32, for treating a condition associated with abnormal function of a sodium ion channel in a subject.

34. 34. The composition or pharmaceutical composition of claim 33, wherein the condition is a neurological or psychiatric disorder.

35. 35. The composition or pharmaceutical composition of claim 33 or 34, wherein the condition is epilepsy or an epilepsy syndrome.

36. 36. The composition or pharmaceutical composition of claim 35, wherein the condition is a genetic epilepsy or a genetic epilepsy syndrome.

37. 36. The composition or pharmaceutical composition of claim 35, wherein the condition is childhood epilepsy or a childhood epilepsy syndrome.

38. 36. The composition or pharmaceutical composition of claim 35, wherein the condition is epileptic encephalopathy.

39. 39. The composition or pharmaceutical composition of claim 38, wherein the epileptic encephalopathy is selected from the group consisting of Dravet syndrome, infantile spasms, or Lennox-Gastaut syndrome.

40. 36. The composition or pharmaceutical composition of claim 35, wherein the epilepsy is accompanied by generalized convulsions.

41. 36. The composition or pharmaceutical composition of claim 35, wherein the epilepsy involves partial or focal seizures.

42. 42. The composition or pharmaceutical composition of claim 41, wherein the epilepsy is accompanied by focal seizures.

43. 36. The composition or pharmaceutical composition of claim 35, wherein the epilepsy is focal epilepsy associated with an SCN3A mutation.

44. 34. The composition or pharmaceutical composition of claim 33, wherein the condition is pain.

45. 45. The composition or pharmaceutical composition of claim 44, wherein the pain is neuropathic pain.

46. 34. The composition or pharmaceutical composition of claim 33, wherein the condition is a headache.

47. 34. The composition or pharmaceutical composition of claim 33, wherein the condition is migraine or trigeminal neuralgia.

48. 48. The composition or pharmaceutical composition of any one of claims 33 to 47, wherein the subject is a human.

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