ION CHANNEL MODULATORS

Abstract

Fused heteroaryl compounds and compositions useful for preventing and / or treating a disease or condition related to aberrant function of voltage-gated sodium ion channels, e.g., an abnormal, delayed / persistent sodium current. Treatment methods for a disease or condition related to aberrant function of sodium ion channels are also provided herein, including neurological disorders (e.g., Dravet syndrome, epilepsy), pain, and neuromuscular disorders.

Description

ION CHANNEL MODULATORSCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and the benefit of U.S. Provisional PatentApplication Number 62 / 677,903, filed May 30, 2018, and 62 / 738,508, filed September 28, 2018, each of which is incorporated herein by reference in its entirety.BACKGROUND

[0002] Sodium ion (Na+) channels primarily open in a transient manner and are quickly inactivated, thereby generating a fast Na+ current to initiate the action potential. The late or persistent sodium current (INaL) is a sustained component of the fast Na+ current of cardiac myocytes and neurons. Many common neurological and cardiac conditions are associated with abnormal INaL enhancement, which contributes to the pathogenesis of both electrical and contractile dysfunction in mammals (see, e.g., Pharmacol Ther (2008) 119:326-339). Accordingly, pharmaceutical compounds that selectively modulate sodium channel activity, e.g., abnormal INaL, are useful in treating such disease states.SUMMARY

[0003] Described herein are fused heteroaryl compounds and compositions useful for preventing and / or treating a disease, disorder, or condition, e.g., a disease, disorder, or condition relating to aberrant function of a sodium ion channel, e.g., abnormal late sodium current (INaL). In one aspect, the present disclosure features compounds of Formula (I):In one aspect, the present invention provides a compound having the Formula I:or a pharmaceutically acceptable salt thereof, whereinX and Y are each independently CRdor N;"XR2R1is R3R , monocyclic C cycloalkyl, or 4- to 7-membered monocyclic heterocyclyl, wherein said cycloalkyl and heterocyclyl are optionally substituted with one or more Ra;R is Cthaloalkyl, phenyl, or monocyclic C3-6cycloalkyl optionally substituted with one or more r R>b ;R is hydrogen, Ci-4alkyl, or Cthaloalkyl;R4is hydrogen or Ci-4alkyl;R5is halo;R6is Ci-4alkyl or Ci-4haloalkyl, wherein said Ci-4alkyl or Ci-4haloalkyl are each substituted with ORc;t is 0, 1, or 2;a bR and R are each independently selected from is selected from halo, Ci-4alkyl, - 4haloalkyl, Ci-4alkoxy, and Ci-4haloalkoxy,Rcis Ci-4alkyl optionally substituted with C3-6 cycloalkyl or ^alkoxy, or C3-6 cycloalkyl; andRdis hydrogen or Ci-4alkyl;provided the compound is not a compound having the formula:pharmaceutically acceptable salt thereof.

[0004] In some embodiments, the compound is of the Formula I-a:or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0005] In some embodiments, the compound is of the Formula I-b:or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0006] In some embodiments, the compound is of the Formula II:or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0007] In some embodiments, the compound is of the Formula III:or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0008] In some embodiments, the compound is of the Formula I-c:or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0009] In another aspect, the present disclosure provides a ompound having theFormula I-d:or a pharmaceutically acceptable salt thereof, wherein^XR2R1is R3R , monocyclic C3-6cycloalkyl, or 4- to 7-membered monocyclic heterocyclyl, wherein said cycloalkyl and heterocyclyl are optionally substituted with one or more Ra;R is Ci-4haloalkyl, phenyl, or monocyclic C3-6cycloalkyl optionally substituted with one or more Rb;R is hydrogen, Ci-4alkyl, or Ci-4haloalkyl;R4is hydrogen or Ci-4alkyl;R5is halo;R6is Ci-4alkyl or Cthaloalkyl, wherein said Ci-4alkyl or Ci-4haloalkyl are each substituted with ORc;t is 0, 1, or 2;Raand Rbare each independently selected from is selected from halo, Ci-4alkyl, -4haloalkyl, Ci-4alkoxy, and Ci-4haloalkoxy;Rcis Ci-4alkyl optionally substituted with C3-6cycloalkyl or Ci^alkoxy, or C3-6cycloalkyl; andRdis hydrogen or Ci-4alkyl.

[0010] In some embodiments, the compound is of the Formula V:or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

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

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

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

[0014] In another aspect, provided herein is a crystalline compound of formula:wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 6.9+0.2, 16.5+0.2, and 20.8+0.2.

[0015] In another aspect, provided herein is a crystalline compound of formula:wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 16.7+0.2, 19.0+0.2, and 20.4+0.2.

[0016] In another aspect, the present invention provides a crystalline compound of formula:wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 7.3+0.2, 14.5+0.2, and 21.9+0.2.

[0017] In another aspect, the present disclosure provides a crystalline compound of formula:wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 12.6+0.2, 15.8+0.2, and 18.6+0.2.

[0018] In another aspect, the present invention provides a crystalline compound of formula:wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 5.8+0.2, 19.7+0.2, and 21.0+0.2.

[0019] In another aspect, the present invention provides a crystalline compound of formula:wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 7.3+0.2, 16.6+0.2, and 18.4+0.2.

[0020] In another aspect, the present invention provides a crystalline compound of formula:wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 6.9+0.2, 16.4+0.2, and 19.5+0.2.

[0021] In another aspect, the present invention provides a crystalline compound of formula:wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 9.9+0.2, 19.8+0.2, and 23.7+0.2.

[0022] In another aspect, the present disclosure provides a crystalline compound of formula:wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 9.3+0.2, 18.8+0.2, and 21.4+0.2.

[0023] 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.

[0024] In another aspect of the disclosure, a composition comprising a compound disclosed herein (e.g., a compound of Formula I, G, I-a, I-b, I-c, I-d, II, III, V, VII, VIII, or IX), or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier is provided.

[0025] Also provided herein is a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound of Formula I, G, I-a, I-b, I-c, I-d, II, III, V, VII, VIII, or IX), or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier, for use in medicine.

[0026] In another aspect, provided herein is a method of treating a condition relating to aberrant 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 compoundof Formula I, G, I-a, I-b, I-c, I-d, II, III, V, VII, VIII, or IX), or a pharmaceutically acceptable salt thereof, or a composition or a pharmaceutical composition disclosed herein.

[0027] 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 a genetic epilepsy or a genetic epilepsy syndrome. In some embodiments, the condition is a pediatric epilepsy or a pediatric 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.

[0028] 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 mutation, generalized epilepsy with febrile seizures, intractable childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutation, cryptogenic pediatric partial epilepsy with SCN3A mutation, SCN8A epilepticencephalopathy, sudden unexpected death in epilepsy, Rasmussen encephalitis, malignant migrating partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, sudden expected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy.

[0029] In another aspect, provided herein is a method of treating a neurological disorder or a psychiatric disorder, wherein the method comprises administering to a subject in need thereof a compound disclosed herein (e.g., a compound of Formula I, G, I-a, I-b, I-c, I-d, II, III, V, VII, VIII, or IX), or a pharmaceutically acceptable salt thereof or a composition or a pharmaceutical composition disclosed herein.

[0030] In another aspect, the present invention provides a method of treating a pain, wherein the method comprises administering to a subject in need thereof a compound disclosed herein (e.g., a compound of Formula I, G, I-a, I-b, I-c, I-d, II, III, V, VII, VIII, or IX), or a pharmaceutically acceptable salt thereof or a composition or a pharmaceutical composition disclosed herein.

[0031] The present disclosure also provides a composition comprising a compound disclosed herein (e.g., a compound of Formula I, G, I-a, I-b, I-c, I-d, II, III, V, VII, VIII, orIX), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, or a composition disclosed herein for treating a condition relating to aberrant function of a sodium ion channel in a subject.

[0032] In some embodiments, the condition is a neurological or psychiatric disorder.In some embodiments, the condition is a pain. In some embodiments, the condition is epilepsy or an epilepsy syndrome. In some embodiments, the condition is a genetic epilepsy or a genetic epilepsy syndrome. In some embodiments, the condition is a pediatric epilepsy or a pediatric 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.

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

[0034] In another aspect, the present disclosure provides a composition comprising a compound disclosed herein (e.g., a compound of Formula I, G, I-a, I-b, I-c, I-d, 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 disorder or a psychiatric disorder.

[0035] Other objects and advantages will become apparent to those skilled in the art from a consideration of the ensuing Detailed Description, Examples, and Claims.BRIEF DESCRIPTION OF THE DRAWINGS

[0036] FIG. 1A shows XRPD pattern of Compound 10 raw material.

[0037] FIG. IB shows DSC of Compound 10.

[0038] FIG. 2A shows XRPD pattern of Compound 62 raw material.

[0039] FIG. 2B shows DSC of Compound 62.

[0040] FIG. 3A shows XRPD pattern of Compound 6B raw material.

[0041] FIG. 3B shows DSC of Compound 6B.

[0042] FIG. 4A shows XRPD pattern of Compound 56 raw material.

[0043] FIG. 4B shows DSC of Compound 56.

[0044] FIG. 5A shows XRPD pattern of Compound 3 raw material.

[0045] FIG. 5B shows DSC of Compound 3.

[0046] FIG. 6A shows XRPD pattern of Compound 11 raw material.

[0047] FIG. 6B shows DSC of Compound 11.

[0048] FIG. 7A shows XRPD pattern of Compound 53 raw material.

[0049] FIG. 7B shows DSC of Compound 53.

[0050] FIG. 8A shows XRPD pattern of Compound 59 raw material.

[0051] FIG. 8B shows DSC of Compound 59.

[0052] FIG. 9A shows XRPD pattern of Compound 48 raw material.

[0053] FIG. 9B shows DSC of Compound 48.DETAILED DESCRIPTION

[0054] As generally 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 relating to aberrant function of a sodium ion channel, such as abnormal late sodium current (INaL). Exemplary diseases, disorders, or conditions include a neurological disorder (e.g., epilepsy or an epilepsy syndrome, a neurodevelopmental disorder or a neuromuscular disorder), a psychiatric disorder, pain, or a gastrointestinal disorder.DefinitionsChemical definitions

[0055] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the PeriodicTable of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein.Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March’s Advanced Organic Chemistry, 5thEdition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modem Methods of Organic Synthesis, 3 Edition, Cambridge University Press, Cambridge, 1987.

[0056] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. 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 syntheses. See, for example, Jacques et al, Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et ah , Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon 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 invention additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0057] As used herein a pure enantiomeric compound is substantially free from other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, an“S” form of the compound is substantially free from the“R” form of the compound and is, thus, in enantiomeric excess of the“R” form. The term“enantiomerically pure” or“pure enantiomer” denotes that the compound comprises more than 75 % by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight or more than 99.9% by weight, of the enantiomer. In certainembodiments, the weights are based upon total weight of all enantiomers or stereoisomers of the compound.

[0058] In the compositions provided herein, an enantiomerically pure compound can be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising enantiomerically pure R-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure R-compound. In certain embodiments, the enantiomerically pure R-compound in such compositions can, for example, comprise, at least about 95% by weight R-compound and at most about 5% by weight S-compound, by total weight of the compound. For example, a pharmaceutical composition comprising enantiomerically pure S-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure S-compound. In certain embodiments, the enantiomerically pure S-compound in such compositions can, for example, comprise, at least about 95% by weight S-compound and at most about 5% by weight R- compound, by total weight of the compound. In certain embodiments, the active ingredient can be formulated with little or no excipient or carrier.

[0059] Compound described herein may also comprise one or more isotopic substitutions. For example, Fl may be in any isotopic form, including H, H (D or deuterium), and H (T or tritium); C may be in any isotopic form, including C, C, and C; O may be in any isotopic form, including160 and180; F may be in any isotopic form, including18F and19F; and the like.

[0060] The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present invention. When describing the invention, which may include compounds andpharmaceutically acceptable salts thereof, pharmaceutical compositions containing such compounds and methods of using such compounds and compositions, the following terms, if present, have the following meanings unless otherwise indicated. It should also be understood that when described herein any of the moieties defined forth below may be substituted with a variety of substituents, and that the respective definitions are intended to include such substituted moieties within their scope as set out below. Unless otherwise stated, the term“substituted” is to be defined as set out below. It should be further understood that the terms“groups” and“radicals” can be considered interchangeable when used herein. The articles“a” and“an” may be used herein to refer to one or to more than one (i.e. at least one)of the grammatical objects of the article. By way of example“an analogue” means one analogue or more than one analogue.

[0061] When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example,“Ci_6alkyl” is intended to encompass, , C2,C¾,C4, C5, C6, Ci_6, Ci_5, Ci_4, C1-3, Ci_2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3^, C4-6, C4-5, and C5-6alkyl.

[0062] As used herein,“alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group, e.g., having 1 to 20 carbon atoms (“Ci_2o alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“Ci_io alkyl”). In someembodiments, an alkyl group has 1 to 9 carbon atoms (“Ci_9alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“Ci_8alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“Ci_7alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“Ci_6alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“Ci_5alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“Ci_ alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“Ci_3alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“ _2alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“Ci alkyl”). Examples of Ci_6alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, and the like.

[0063] As used herein,“alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 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) (“C2-2o alkenyl”). In certain embodiments, alkenyl does not contain any triple bonds. In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C2_io alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2-9alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2_s alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2-7alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-6alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-5alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2-4alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-3alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C2alkenyl”). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in l-butenyl). Examples of C2-4alkenyl groups include ethenyl (C2), l-propenyl (C3), 2-propenyl (C3), l-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2_6alkenyl groups include the aforementioned C2-4alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like.

[0064] As used herein,“alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 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) (“C2-2o alkynyl”). In certain embodiments, alkynyl does not contain any double bonds. In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C2_io alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2-9alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2-8alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2-7alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2-6alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2-5alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2-4alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2-3alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C2alkynyl”). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1- butynyl). Examples of C2-4alkynyl groups include, without limitation, ethynyl (C2), 1- propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C2-6alkenyl groups include the aforementioned C2-4alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like.

[0065] As used herein,“alkylene,”“alkenylene,” and“alkynylene,” refer to a 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 the linear carbon divalent chain. “Alkylene,”“alkenylene,” and“alkynylene,” groups may be substituted or unsubstituted with one or more substituents as described herein.

[0066] 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 p electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6-i4aryl”). In some embodiments, an aryl group has six ring carbonatoms (“C6aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“Cio aryl”; e.g., naphthyl such as l-naphthyl and 2-naphthyl). In someembodiments, an aryl group has fourteen ring carbon atoms (“CM aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue 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. Particularly aryl groups include phenyl, naphthyl, indenyl, andtetrahydronaphthyl.

[0067] As used herein,“heteroaryl” refers to a 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 array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5-10 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits.Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused(aryl / heteroaryl) ring system. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).

[0068] In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 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.

[0069] 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, benzoisofuranyl, 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.

[0070] Examples of representative heteroaryls include the following:wherein each Z is selected from carbonyl, N, NR65, O, and S; and R65is independently hydrogen, Ci-8alkyl, C3-10 carbocyclyl, 4-10 membered heterocyclyl, C6-C10 aryl, and 5-10 membered heteroaryl.

[0071] As used herein,“carbocyclyl” or“carbocyclic” refers to a radical of a non aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C3_io carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms C'CVx carbocyclyl”). In someembodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C3_7 carbocycyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3_6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10 carbocyclyl”). Exemplary C w, carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C x carbocyclyl groups include, without limitation, the aforementioned C3-6 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 C3_io carbocyclyl groups include, without limitation, the aforementioned C x carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1 / / -indcnyl (C9), decahydronaphthalenyl (C10),spiro[4.5]decanyl (C10), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged or spiro ring system such as a bicyclic system (“bicycliccarbocyclyl”) and can be saturated or can be partially unsaturated.“Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system.

[0072] The term“cycloalkyl” refers to a monovalent saturated cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) hydrocarbon group of 3-12, 3-8, 4-8, or 4-6 carbons, referred to herein, e.g., as "Ct-scycloalkyl," derived from a cycloalkane. Exemplary cycloalkyl groups include, but are not limited to, cyclohexanes, cyclopentanes, cyclobutanes and cyclopropanes.

[0073] As used herein,“C3-6 monocyclic cycloalkyl” or“monocyclic C3-6 cycloalkyl” refers to a 3- to 7-membered monocyclic hydrocarbon ring system that is saturated. 3- to 7- membered monocyclic cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Where specified as being optionally substituted or substituted, substituents on a cycloalkyl (e.g., in the case of an optionally substituted cycloalkyl) may be present on any substitutable position and, include, e.g., the position at which the cycloalkyl group is attached.

[0074] As used herein,“heterocyclyl” or“heterocyclic” refers to a radical of a 3- to10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3-10 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic(“monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated.Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue 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.

[0075] In some embodiments, a heterocyclyl group is a 4-7 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“4-7 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom isindependently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5-10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0076] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, 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, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, 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 C6aryl 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.

[0077] Examples of saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, terahydropyranyl, pyrrolidinyl, pyridinonyl, pyrrolidonyl, piperidinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, morpholinyl, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, oxetanyl, azetidinyl and tetrahydropyrimidinyl. Where specified as being optionally substituted or substituted, substituents on a heterocyclyl (e.g., in the case of an optionally substituted heterocyclyl) may be present on any substitutable position and, include, e.g., the position at which the heterocyclyl group is attached.

[0078] ‘Hetero” when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g., heteroalkyl; carbocyclyl, e.g., heterocyclyl; aryl, e.g,. heteroaryl; and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms.As used herein,“cyano” refers to -CN.

[0079] The terms“halo” and“halogen” as used herein refer to an atom selected from fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), and iodine (iodo, -I). In certain embodiments, the halo group is either fluoro or chloro.

[0080] The term“alkoxy,” as used herein, refers to an alkyl group which is attached to another moiety via an oxygen atom (-0( alkyl)). Non-limiting examples include e.g., methoxy, ethoxy, propoxy, and butoxy.

[0081] “Haloalkoxy” is a haloalkyl group which is attached to another moiety via an oxygen atom such as, e.g., but are not limited to -OCHCF2or -OCF3.

[0082] The term“haloalkyl” includes mono, poly, and perhaloalkyl groups substituted with one or more halogen atoms where the halogens are independently selectedfrom fluorine, chlorine, bromine, and iodine. For the group Ci-4haloalkyl-0-Ci-4alkyl, the point of attachment occurs on the alkyl moiety which is halogenated.As used herein,“nitro” refers to -N02.As used herein,“oxo” refers to -C=0.

[0083] In general, the term“substituted”, whether preceded by the term“optionally” or not, means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergotransformation such as 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.

[0084] Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quarternary nitrogen atoms. Exemplary nitrogen atom substitutents include, but are not limited to, hydrogen, -OH, -ORaa, -N(RCC)2, -CN, - C(=0)Raa, -C(=0)N(Rcc)2, -C02Raa, -S02Raa, -C(=NRbb)Raa, -C(=NRcc)ORaa, - C(=NRCC)N(Rcc)2, -S02N(Rcc)2, -S02Rcc, -S02ORcc, -SORaa, -C(=S)N(Rcc)2, -C(=0)SRcc, - C(=S)SRCC, -P(=0)2Raa, -P(=0)(Raa)2, -P(=0)2N(Rcc)2, -P(=0)(NRcc)2, C,_,„ alkyl, C,_,„ perhaloalkyl, C2_io alkenyl, C2_io alkynyl, C3_io carbocyclyl, 3-14 membered heterocyclyl, Ce-14 aryl, and 5-14 membered heteroaryl, or two Rccgroups attached to a nitrogen atom are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups, and wherein Raa, Rbb, Rccand Rddare as defined above.

[0085] These and other exemplary substituents are described in more detail in theDetailed Description, Examples, and Claims. The invention is not intended to be limited in any manner by the above exemplary listing of substituents.Other Definitions

[0086] 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 with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may 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, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose- based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0087] As used herein,“pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. , describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric 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-hydroxy- ethanesulfonate, 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 salts, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(Ci_4alkyl )4salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such ashalide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0088] As used herein, a“subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g, infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and / or a non-human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, 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.

[0089] Disease, disorder, and condition are used interchangeably herein.

[0090] As used herein, and unless otherwise specified, the terms“treat,”“treating” and“treatment” contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or retards or slows the progression of the disease, disorder or condition(“therapeutic treatment”), and also contemplates an action that occurs before a subject begins to suffer from the specified disease, disorder or condition (“prophylactic treatment”).

[0091] As used herein, the“effective amount” of a compound refers to an amount sufficient to elicit the desired biological response. As will be appreciated by those of ordinary skill in this art, the effective amount of a compound of the invention may vary depending on such factors 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. An effective amount encompasses therapeutic and prophylactic treatment.

[0092] 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 an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the disease, disorder or condition. The term“therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.Compounds

[0093] In one aspect, the present invention provides a compound having the FormulaI:or a pharmaceutically acceptable salt thereof, whereinX and Y are each independently CRdor N;^XR2R1is R3R , monocyclic C3-6 cycloalkyl, or 4- to 7-membered monocyclic heterocyclyl, wherein said cycloalkyl and heterocyclyl are optionally substituted with one or more Ra;R is Cthaloalkyl, phenyl, or monocyclic C3-6cycloalkyl optionally substituted with one or more Rb;R is hydrogen, Ci-4alkyl, or Ci-zthaloalkyl;R4is hydrogen or Ci-4alkyl;R5is halo;R6is Ci-4alkyl or Ci-4haloalkyl, wherein said Ci-4alkyl or Ci-4haloalkyl are each substituted with ORc;t is 0, 1, or 2;R a and R b are each independently selected from is selected from halo, Ci-4alkyl, Ci- 4haloalkyl, Ci-4alkoxy, and Ci-4haloalkoxy,Rcis Ci-4alkyl optionally substituted with C3-6cycloalkyl or ^alkoxy, or C3-6cycloalkyl; andRdis hydrogen or Ci-4alkyl;provided the compound is not a compound having the formula:pharmaceutically acceptable salt thereof.

[0094] In one aspect, the present invention provides a compound having the FormulaG:or a pharmaceutically acceptable salt thereof, whereinX and Y are each independently CRdor N;"ScR1is R R , monocyclic C3-6cycloalkyl, or 4- to 7-membered monocyclic heterocyclyl, wherein said cycloalkyl and heterocyclyl are optionally substituted with one or more Ra;R2is Ci-zthaloalkyl, phenyl, or monocyclic C3-6cycloalkyl optionally substituted with one or more Rb;R is hydrogen, Ci-4alkyl, or Cthaloalkyl;R4is hydrogen or Ci-4alkyl;R5is halo;R6is Ci-4alkyl or Ci-4haloalkyl, wherein said Ci-4alkyl or Ci-4haloalkyl are each substituted with ORc;t is 0, 1, or 2;Raand Rbare each independently selected from is selected from halo, Ci-4alkyl, -4haloalkyl, Ci-4alkoxy, and Ci-4haloalkoxy,Rcis Ci-4alkyl optionally substituted with C3-6cycloalkyl or ^alkoxy, or C3-6cycloalkyl; andRdis hydrogen or Ci-4alkyl;or a pharmaceutically acceptable salt thereof.

[0095] In some embodiments, the compound is of the Formula I-a:or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0096] In some embodiments, the compound is of the Formula I-b:or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0097] In some embodiments, the compound is of the Formula II:or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0098] In some embodiments, the compound is of the Formula III:or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0099] In some embodiments, the compound is of the Formula I-c:or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0100] In another aspect, the present disclosure provides a ompound having the Formula I-d:or a pharmaceutically acceptable salt thereof, whereins< ‘R1is R3R4, monocyclic C3-6cycloalkyl, or 4- to 7-membered monocyclic heterocyclyl, wherein said cycloalkyl and heterocyclyl are optionally substituted with one or more Ra;R is Ci-4haloalkyl, phenyl, or monocyclic C3-6cycloalkyl optionally substituted with one or more Rb;R is hydrogen, Ci-4alkyl, or Ci-4haloalkyl;R4is hydrogen or Ci-4alkyl;R5is halo;R6is Ci-4alkyl or Ci-4haloalkyl, wherein said Ci-4alkyl or Ci-4haloalkyl are each substituted with ORc;t is 0, 1, or 2;Raand Rbare each independently selected from is selected from halo, Ci-4alkyl, -4haloalkyl, Ci-4alkoxy, and Ci-4haloalkoxy;Rcis Ci-4alkyl optionally substituted with C3-6cycloalkyl or ^alkoxy, or C3-6cycloalkyl; andRdis hydrogen or Ci-4alkyl.

[0101] In some embodiments, the compound is of the Formula V:or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0102] In some embodiments, the compound is of the Formula VII:or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0103] In some embodiments, the compound is of the Formula VIII:or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0104] In some embodiments, the compound is of the Formula VIII:or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein."XR2

[0105] In some embodiments, R1is R3R4.

[0106] In some embodiments, R1is cyclobutyl optionally substituted with one or more Ra.

[0107] In some embodiments, R2is Ci-4haloalkyl. In some embodiments, R2is CF3. In some embodiments, R is phenyl.

[0108] In some embodiments, R3is Ci-4alkyl and R4is hydrogen or Ci-4alkyl. In some embodiments, R3and R4are each ^alkyl. In some embodiments, R3and R4are each methyl. In some embodiments, R 3 is methyl and R 4 is hydrogen. In some embodiments, R 3 and R4are each hydrogen.

[0109] In some embodiments, R6is -CF2-ORc.

[0110] In some embodiments, Rcis Ci-4alkyl optionally substituted with cyclopropyl.In some embodiments, Rcis cyclopropyl.

[0111] In some embodiments, R6is -C(F2)OCH2CH(CH3)2, -C(F2)OCH3, -C(F2)OCH2CH3, -C(F2)OCH(CH3)2,or -C(F2)OCH2C3H5.

[0112] In some embodiments, R6is -CH2-ORc.

[0113] In some embodiments, Rcis C3_4 alkyl.

[0114] In some embodiments, R6is -CH2OCH3, -CH2OCH2CH3, or - CH2OCH2CH(CH3)2.

[0115] In some embodiments, Rais Ci-dialoalkyl. In some embodiments, Rais CF3. In some embodiments, Rais fluoro.

[0116] In some embodiments, t is 1. In some embodiments, t is 0.

[0117] In some embodiments, Rdis methyl. In some embodiments, Rdis hydrogen.

[0118] In some embodiments, the compound is selected from the group consisting of:wo 2019 / 232209wo 2019 / 232209wo 2019 / 232209pharmaceutically acceptable salt thereof.

[0119] In some embodiments, the compound is selected from the group consisting of:pharmaceutically acceptable salt thereof.

[0120] In another aspect, the present invention provides a crystalline compound of formula:wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 6.9+0.2, 16.5+0.2, and 20.8+0.2.

[0121] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 6.9+0.2, 13.9+0.2, 16.5+0.2, 19.5+0.2, and 20.8+0.2.

[0122] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 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.

[0123] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern substantially the same as depicted in FIG. 2A.

[0124] In some embodiments, the crystalline compound has a melting point onset as determined by differential scanning calorimetry at about 140 °C.

[0125] In some embodiments, the crystalline compound has a differential scanning calorimetry curve substantially the same as shown in FIG. 2B.

[0126] In another aspect, provided herein is a crystalline compound of formula:wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 16.7+0.2, 19.0+0.2, and 20.4+0.2.

[0127] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 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.

[0128] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 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.

[0129] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern substantially the same as depicted in FIG. 3A.

[0130] In some embodiments, the crystalline compound has a melting point onset as determined by differential scanning calorimetry at about 68 °C.

[0131] In some embodiments, the crystalline compound has a differential scanning calorimetry curve substantially the same as shown in FIG. 3B.

[0132] In another aspect, the present invention provides a crystalline compound of formula:wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 7.3+0.2, 14.5+0.2, and 21.9+0.2.

[0133] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 7.3+0.2, 14.5+0.2, 17.9+0.2, 19.0+0.2, and 21.9+0.2.

[0134] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 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.

[0135] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern substantially the same as depicted in FIG. 4A.

[0136] In some embodiments, the crystalline compound has a melting point onset as determined by differential scanning calorimetry at about 136 °C.

[0137] In some embodiments, the crystalline compound has a differential scanning calorimetry curve substantially the same as shown in FIG. 4B.

[0138] In another aspect, provided herein is a crystalline compound of formula:wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 12.6+0.2, 15.8+0.2, and 18.6+0.2.

[0139] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 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.

[0140] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 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 and22.6+0.2.

[0141] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern substantially the same as depicted in FIG. 5A.

[0142] In some embodiments, the crystalline compound has a melting point onset as determined by differential scanning calorimetry at about 107 °C.

[0143] In some embodiments, the crystalline compound has a differential scanning calorimetry curve substantially the same as shown in FIG. 5B.

[0144] In another aspect, provided herein is a crystalline compound of formula:wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 5.8+0.2, 19.7+0.2, and 21.0+0.2.

[0145] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 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.

[0146] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 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.

[0147] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern substantially the same as depicted in FIG. 6A.

[0148] In some embodiments, the crystalline compound has a melting point onset as determined by differential scanning calorimetry at about 94 °C.

[0149] In some embodiments, the crystalline compound has a differential scanning calorimetry curve substantially the same as shown in FIG. 6B.

[0150] In another aspect, the present invention provides a crystalline compound of formula:wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 7.3+0.2, 16.6+0.2, and 18.4+0.2.

[0151] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 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.

[0152] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 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.

[0153] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern substantially the same as depicted in FIG. 7A.

[0154] In some embodiments, the crystalline compound has a melting point onset as determined by differential scanning calorimetry at about 103 °C.

[0155] In some embodiments, the crystalline compound has a differential scanning calorimetry curve substantially the same as shown in FIG. 7B.

[0156] In another aspect, the present invention provides a crystalline compound of formula:wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 6.9+0.2, 16.4+0.2, and 19.5+0.2.

[0157] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 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.

[0158] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 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.

[0159] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern substantially the same as depicted in FIG. 8A.

[0160] In some embodiments, the crystalline compound has a melting point onset as determined by differential scanning calorimetry at about 133 °C.

[0161] In some embodiments, the crystalline compound has a differential scanning calorimetry curve substantially the same as shown in FIG. 8B.

[0162] In another aspect, the present disclosure provides a crystalline compound of formula:wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 9.9+0.2, 19.8+0.2, and 23.7+0.2.

[0163] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 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.

[0164] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 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.

[0165] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern substantially the same as depicted in FIG. 9A.

[0166] In some embodiments, the crystalline compound has a melting point onset as determined by differential scanning calorimetry at about 111 °C.

[0167] In some embodiments, the crystalline compound has a differential scanning calorimetry curve substantially the same as shown in FIG. 9B.

[0168] In another aspect, provided herein is a crystalline compound of formula:wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 9.3+0.2, 18.8+0.2, and 21.4+0.2.

[0169] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 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.

[0170] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 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.

[0171] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern substantially the same as depicted in FIG. 1A.

[0172] In some embodiments, the crystalline compound has a melting point onset as determined by differential scanning calorimetry at about 122 °C.

[0173] In some embodiments, the crystalline compound has a differential scanning calorimetry curve substantially the same as shown in FIG. 1B.

[0174] In some embodiments, the X-ray powder diffraction pattern was obtained using Cu Ka radiation.Pharmaceutical Compositions and Routes of Administration

[0175] Compounds provided in accordance with the present invention are usually administered in the form of pharmaceutical compositions. This invention therefore providespharmaceutical compositions that contain, as the active ingredient, one or more of the compounds described, or a pharmaceutically acceptable salt or ester thereof, and one or more pharmaceutically acceptable excipients, carriers, including inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants. The pharmaceutical compositions may be administered alone or in combination with other therapeutic agents. Such compositions are prepared in a manner well known in the pharmaceutical art (see, e.g., Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. l7th Ed. (1985); and ModernPharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G. S. Banker & C. T. Rhodes, Eds.)

[0176] The pharmaceutical compositions may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, for example as described in those patents and patent applications incorporated by reference, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, as an inhalant, or via an impregnated or coated device such as a stent, for example, or an artery-inserted cylindrical polymer.

[0177] One mode for administration is parenteral, particularly by injection. The forms in which the novel compositions of the present invention may be incorporated for administration by injection include aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles. Aqueous solutions in saline are also conventionally used for injection, but 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 may also be employed. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

[0178] Sterile injectable solutions are prepared by incorporating a compound according to the present invention in the required amount in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredientsinto a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[0179] Oral administration is another route for administration of compounds in accordance with the invention. Administration may be via capsule or enteric coated tablets, or the like. In making the pharmaceutical compositions that include at least one compound described herein, the active ingredient is usually diluted by an excipient and / or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material (as above), which acts as a vehicle, carrier or medium for the active ingredient.Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0180] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and propylhydroxy-benzoates;sweetening agents; and flavoring agents.

[0181] The compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer- coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Pat. 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 may 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 wellknown in the art. See, e.g., U.S. Pat. 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.

[0182] The compositions are preferably formulated in a unit dosage form. The term "unit dosage forms" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitablepharmaceutical excipient (e.g., a tablet, capsule, ampoule). The compounds are generally administered in a pharmaceutically effective amount. Preferably, for oral administration, each dosage unit contains from 1 mg to 2 g of a compound described herein, and for parenteral administration, preferably from 0.1 to 700 mg of a compound a compound described herein.It will be understood, however, that the amount of the compound actually administered usually will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen 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, and the like.

[0183] For preparing 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 referring to these preformulation compositions 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.

[0184] The tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.

[0185] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. Preferably, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferablypharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.

[0186] In some embodiments, a pharmaceutical composition comprising a disclosed compound, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.Methods of Use

[0187] Compounds and compositions described herein are generally useful for the modulating the activity of sodium channels and are useful in treating conditions relating to aberrant function of a sodium channel ion channel, e.g., abnormal late sodium (INaL) current. In some embodiments, a compound provided by the present invention is effective in the treatment of epilepsy or an epilepsy syndrome, a neurodevelopmental disorder, pain, or a neuromuscular disorder. A provided compound, pharmaceutically acceptable salt thereof, or composition may also modulate all sodium ion channels, or may be specific to only one or a plurality of sodium ion channels, e.g., Nav1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, and / or 1.9.

[0188] In typical embodiments, the present invention is intended to encompass the compounds disclosed herein, and the pharmaceutically acceptable salts, pharmaceutically acceptable esters, tautomeric forms, polymorphs, and prodrugs of such compounds. In some embodiments, the present invention includes a pharmaceutically acceptable addition salt, a pharmaceutically acceptable ester, a solvate (e.g., hydrate) of an addition salt, a tautomeric form, a polymorph, an enantiomer, a mixture of enantiomers, a stereoisomer or mixture of stereoisomers (pure or as a racemic or non-racemic mixture) of a compound described herein, e.g. a compound of Formula I, G, I-a, I-b, I-c, I-d, II, III, V, VII, VIII, or IX); such as a compound of Formula named herein.Epilepsy and Epilepsy Syndromes

[0189] The compounds described herein are useful in the treatment of epilepsy and epilepsy syndromes. Epilepsy is a CNS disorder in which nerve cell activity in the brain becomes disrupted, causing seizures or periods of unusual behavior, sensations and sometimes loss of consciousness. Seizure symptoms will vary widely, from a simple blank stare for a few seconds to repeated twitching of their arms or legs during a seizure.

[0190] Epilepsy may involve a generalized seizure or a partial or focal seizure. All areas of the brain are involved in a generalized seizure. A person experiencing a generalized seizure may cry out or make some sound, stiffen for several seconds to a minute a then have rhythmic movements of the arms and legs. The eyes are generally open, the person may appear not to be breathing and may actually turn blue. The return to consciousness is gradual and the person maybe confused from minutes to hours. There are six main types of generalized seizures: tonic-clonic, tonic, clonic, myoclonic, absence, and atonic seizures. In a partial or focal seizure, only part of the brain is involved, so only part of the body is affected. Depending on the part of the brain having abnormal electrical activity, symptoms may vary.

[0191] Epilepsy, as described herein, includes a generalized, partial, complex partial, tonic clonic, clonic, tonic, refractory seizures, status epilepticus, absence seizures, febrile seizures, or temporal lobe epilepsy.

[0192] The compounds described herein (e.g., a compound of Formula I, G, I-a, I-b, I- c, I-d, II, III, V, VII, VIII, or IX) may also be useful in the treatment of epilepsy syndromes. Severe syndromes with diffuse brain dysfunction caused, at least partly, by some aspect of epilepsy, are also referred to as epileptic encephalopathies. These are associated with frequent seizures that are resistant to treatment and severe cognitive dysfunction, for instance West syndrome.

[0193] In some embodiments, the epilepsy syndrome comprises an epileptic encephalopathy, such as Dravet syndrome, Angelman syndrome, CDKL5 disorder, frontal lobe epilepsy, infantile spasms, West’s syndrome, Juvenile Myoclonic Epilepsy, Landau- Kleffner syndrome, Lennox-Gastaut syndrome, Ohtahara syndrome, PCDH19 epilepsy, or Glutl deficiency.

[0194] In some embodiments, the epilepsy or epilepsy syndrome is a genetic epilepsy or a genetic epilepsy syndrome. In some embodiments, epilepsy or an epilepsy syndrome comprises epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8Amutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutation, generalized epilepsy with febrile seizures, intractable childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutation, cryptogenic pediatric partial epilepsy with SCN3A mutation, SCN8A epilepticencephalopathy, sudden unexpected death in epilepsy, Rasmussen encephalitis, malignant migrating partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, sudden expected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, or KCNT1 epileptic encephalopathy.

[0195] In some embodiments, the methods described herein further comprise identifying a subject having 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 mutation, generalized Epilepsy with febrile seizures, intractable childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutation, cryptogenic pediatric partial epilepsy with SCN3A mutation, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussen encephalitis, malignant migrating partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, sudden unexpected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, or KCNT1 epileptic encephalopathy) prior toadministration of a compound described herein (e.g., a compound of Formula I, G, I-a, I-b, I- c, I-d, II, III, V, VII, VIII, or IX).

[0196] In one aspect, the present invention features a method of treating 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 mutation, generalized Epilepsy with febrile seizures, intractable childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutation, cryptogenic pediatric partial epilepsy with SCN3A mutation, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussen encephalitis, malignant migrating partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, sudden expected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, orKCNT1 epileptic encephalopathy) comprising administering to a subject in need thereof a compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0197] A compound of the present invention (e.g., a compound of Formula I, G, I-a, I- b, I-c, I-d, II, III, V, VII, VIII, or IX) may also be used to treat an epileptic encephalopathy, wherein the subject has a mutation in one or more of ALDH7A1, ALG13, ARHGEF9, ARX, ASAH1, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLN8, CNTNAP2, CPA6,CSTB, DEPDC5, DNM1, EEF1A2, EPM2A, EPM2B, GABRA1, GABRB3, GABRG2, GNAOl, GOSR2, GRIN1, GRIN2A, GRIN2B, HCN1, IER3IP1, KCNA2, KCNB 1, KCNC1, KCNMA1, KCNQ2, KCNQ3, KCNT1, KCTD7, LGI1, MEF2C, NHLRC1, PCDH19, PLCB1, PNKP, PNPO, PRICKLE 1, 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.

[0198] In some embodiments, the methods described herein further comprise identifying a subject having a mutation in one or more of ALDH7A1, ALG13, ARHGEF9, ARX, ASAH1, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLN8, CNTNAP2, CPA6, CSTB, DEPDC5, DNM1, EEF1A2, EPM2A, EPM2B, GABRA1, GABRB3, GABRG2, GNAOl, GOSR2, GRIN1, GRIN2A, GRIN2B, HCN1, IER3IP1, KCNA2, KCNB 1, KCNC1, KCNMA1, KCNQ2, KCNQ3, KCNT1, KCTD7, LGI1, MEF2C, NHLRC1, PCDH19, PLCB1, PNKP, PNPO, PRICKLE 1, 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 prior to administration of a compound described herein (e.g., a compound of Formula I, G, I-a, I-b, I-c, I-d, II, III, V, VII, VIII, or IX).Neurodevelopmental Disorders

[0199] The compounds described herein may be useful in the treatment of a neurodevelopmental disorder. In some embodiments, the neurodevelopmental disorder comprises autism, autism with epilepsy, tuberous sclerosis, Fragile X syndrome, Rett syndrome, Angelman syndrome, Dupl5q syndrome, 22ql3.3 Deletion syndrome, Prader- Willi syndrome, velocardiofacial syndrome, Smith-Lemli-Opitz syndrome, or aneurodevelopmental disorder with epilepsy. In some embodiments, the methods described herein further comprise identifying a subject having a neurodevelopmental disorder (e.g., autism, autism with epilepsy, tuberous sclerosis, Fragile X syndrome, Rett syndrome, Angelman syndrome, Dupl5q syndrome, 22ql3.3 Deletion syndrome, Prader-Willi syndrome, velocardiofacial syndrome, Smith-Lemli-Opitz syndrome, or aneurodevelopmental disorder with epilepsy) prior to administration of a compound described herein (e.g., a compound of Formula I, G, I-a, I-b, I-c, I-d, II, III, V, VII, VIII, or IX).

[0200] In one aspect, the present invention features a method of treating a neurodevelopmental disorder (e.g., autism, autism with epilepsy, tuberous sclerosis, Fragile X syndrome, Rett syndrome, Angelman syndrome, Dupl5q syndrome, 22ql3.3 Deletion syndrome, Prader-Willi syndrome, velocardiofacial syndrome, Smith-Lemli-Opitz syndrome, or a neurodevelopmental disorder with epilepsy) comprising administering to a subject in need thereof a compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein. Pain

[0201] The compounds described herein may be useful in the treatment of pain. In some embodiments, the pain comprises 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. In some embodiments, the methods described herein further comprise identifying a subject having 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) prior to administration of a compound described herein (e.g., a compound of Formula I, G, I-a, I-b, I-c, I-d, II, III, V, VII, VIII, or IX).

[0202] In one aspect, the present 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) comprising administering to a subject in need thereof a compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein. Neuromuscular Disorders

[0203] The compounds described herein may be useful in the treatment of a neuromuscular disorder. In some embodiments, the neuromuscular disorder comprises amyotrophic lateral sclerosis, multiple sclerosism, myotonia, paramyotonia congenita, potassium-aggravated myotonia, periodic paralysis, hyperkalemic periodic paralysis, hypokalemic periodic paralysis, or laryngospasm with SCN4A mutation. In some embodiments, the methods described herein further comprise identifying a subject having a neuromuscular disorder (e.g., amyotrophic lateral sclerosis, multiple sclerosism, myotonia, paramyotonia congenita, potassium-aggravated myotonia, periodic paralysis, hyperkalemic periodic paralysis, hypokalemic periodic paralysis, or laryngospasm with SCN4A mutation) prior to administration of a compound described herein (e.g., a compound of Formula I, G, I- a, I-b, I-c, I-d, II, III, V, VII, VIII, or IX).

[0204] In one aspect, the present invention features a method of treating a neuromuscular disorder (e.g., amyotrophic lateral sclerosis, multiple sclerosism, myotonia, paramyotonia congenita, potassium-aggravated myotonia, periodic paralysis, hyperkalemic periodic paralysis, hypokalemic periodic paralysis, or laryngospasm with SCN4A mutation) comprising administering to a subject in need thereof a compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein. Other Disorders

[0205] In some embodiments, a compound of the present invention (e.g., a compound of Formula I, G, I-a, I-b, I-c, I-d, II, III, V, VII, VIII, or IX) may have appropriate pharmacokinetic properties such that they may be active with regard to the central and / or peripheral nervous system. In some embodiments, the compounds provided herein are used to treat a cardiovascular disease such as atrial and ventricular arrhythmias, including atrial fibrillation, Prinzmetal's (variant) angina, stable angina, unstable angina, ischemia and reperfusion injury in cardiac, kidney, liver and the 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 transplant, acute coronary syndrome, peripheral arterial disease, intermittent claudication, and myocardial infarction. In some embodiments, the compounds provided herein may be used in the treatment of diseases affecting the neuromuscular system resulting in itching, seizures, or paralysis, or in the treatment of diabetes or reduced insulin sensitivity, and disease states related to diabetes, such as diabetic peripheral neuropathy. In some embodiments, a disclosed method comprises administering the pharmaceutical composition.

[0206] In some embodiments, provided herein is a method of treating a neurological disorder or a psychiatric disorder, wherein the method comprises administering to a subject in need thereof a compound disclosed herein, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition disclosed herein.Combination Therapy

[0207] A compound or composition described herein (e.g., for use in modulating a sodium ion channel, e.g., the late sodium (INaL) current) may be administered in combination with another agent or therapy. A subject to be administered a compound disclosed herein may have a disease, disorder, or condition, or a symptom thereof, that would benefit from treatment with another agent or therapy. These diseases or conditions can relateto epilepsy or an epilepsy syndrome, a neurodevelopmental disorder, pain, or aneuromuscular disorder.Antiepilepsy Agents

[0208] Anti-epilepsy agents include brivaracetam, carbamazepine, clobazam, clonazepam, diazepam, divalproex, eslicarbazepine, ethosuximide, ezogabine, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, lorazepam, oxcarbezepine, permpanel, phenobarbital, phenytoin, pregabalin, primidone, rufinamide, tigabine, topiramate, valproic acid, vigabatrin, zonisamide, and cannabidiol.Cardiovascular Agent Combination Therapy

[0209] Cardiovascular related diseases or conditions that can benefit from a combination treatment of the sodium channel blockers of the invention with other therapeutic agents include, without limitation, angina including stable angina, unstable angina (UA), exercised-induced angina, variant angina, arrhythmias, intermittent claudication, myocardial infarction including non-STE myocardial infarction (NSTEMI), pulmonary hypertension including pulmonary arterial hypertension, heart failure including congestive (or chronic) heart failure and diastolic heart failure and heart failure with preserved ejection fraction (diastolic dysfunction), acute heart failure, or recurrent ischemia.

[0210] Therapeutic agents suitable for treating cardiovascular related diseases or conditions include anti-anginals, heart failure agents, antithrombotic agents, antiarrhythmic agents, antihypertensive agents, and lipid lowering agents.

[0211] The co-administration of the sodium channel blockers of the invention with therapeutic agents suitable for treating cardiovascular related conditions allows enhancement in the standard of care therapy the patient is currently receiving.Anti-Anginals

[0212] Anti-anginals include beta-blockers, calcium channel blockers, and nitrates. Beta blockers reduce the heart's need for oxygen by reducing its workload resulting in a decreased heart rate and less vigorous heart contraction. 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).

[0213] Nitrates dilate the arteries and veins thereby increasing coronary blood flow and decreasing blood pressure. Examples of nitrates include nitroglycerin, nitrate patches, isosorbide dinitrate, and isosorbide-5-mononitrate.

[0214] Calcium channel blockers prevent the normal flow of calcium into the cells of the heart and blood vessels causing the blood vessels to relax 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.Heart Failure Agents

[0215] Agents used to treat heart failure include diuretics, ACE inhibitors, vasodilators, and cardiac glycosides. Diuretics eliminate excess fluids in the tissues and circulation thereby relieving many of the symptoms of heart failure. Examples of diuretics include hydrochlorothiazide, metolazone (Zaroxolyn), furosemide (Lasix), bumetanide (Bumex), spironolactone (Aldactone), and eplerenone (lnspra).

[0216] Angiotensin converting enzyme (ACE) inhibitors reduce the workload on the heart by expanding the 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).

[0217] Vasodilators reduce pressure on the blood vessels by making them relax and expand. Examples of vasodilators include hydralazine, diazoxide, prazosin, clonidine, and methyldopa. ACE inhibitors, nitrates, potassium channel activators, and calcium channel blockers also act as vasodilators.

[0218] Cardiac glycosides are compounds that increase the force of the heart's contractions. These compounds strengthen the pumping capacity of the heart and improve irregular heartbeat activity. Examples of cardiac glycosides include digitalis, digoxin, and digitoxin.Antithrombotic Agents

[0219] Antithrombotics inhibit the clotting ability of the blood. There are three main types of antithrombotics— platelet inhibitors, anticoagulants, and thrombolytic agents.

[0220] Platelet inhibitors inhibit the clotting activity of platelets, thereby reducing clotting in the arteries. Examples of platelet inhibitors include acetylsalicylic acid (aspirin), ticlopidine, clopidogrel (plavix), dipyridamole, cilostazol, persantine sulfinpyrazone, dipyridamole, indomethacin, and glycoprotein Ilb / IIIa inhibitors, such as abciximab, tirofiban, and eptifibatide (Integrelin). Beta blockers and calcium channel blockers also have a platelet-inhibiting effect.

[0221] Anticoagulants prevent blood 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.

[0222] Thrombolytic agents act to break down an existing blood clot. Examples of thrombolytic agents include streptokinase, urokinase, and tenecteplase (TNK), and tissue plasminogen activator (t-PA).Antiar rhythmic Agents

[0223] Antiarrhythmic agents are used to treat disorders of the heart rate and rhythm. Examples of antiarrhythmic agents include amiodarone, dronedarone, quinidine,procainamide, lidocaine, and propafenone. Cardiac glycosides and beta blockers are also used as antiarrhythmic agents.

[0224] Combinations with amiodarone and dronedarone are of particular interest given the recently discovered synergistic effects of the sodium channel blocker ranolazine and amioarone and dronedarone.Antihypertensive Agents

[0225] Antihypertensive agents are used to treat hypertension, a condition in which the blood pressure is consistently higher than normal. Hypertension is associated with many aspects of cardiovascular disease, including congestive heart failure, atherosclerosis, and clot for illation. Examples of antihypertensive agents include alpha- 1 -adrenergic antagonists, such as prazosin (Minipress), doxazosin mesylate (Cardura), prazosin hydrochloride (Minipress), prazosin, polythiazide (Minizide), and terazosin hydrochloride (Hytrin); beta-adrenergic antagonists, such as propranolol (Inderal), nadolol (Corgard), timolol (Blocadren), metoprolol (Lopressor), and pindolol (Visken); central alpha-adrenoceptor 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); combined alpha / beta-adrenergic antagonists, such as labetalol (Normodyne, Trandate), Carvedilol (Coreg); adrenergic neuron blocking agents, such as guanethidine (ismelin), reserpine (Serpasil); central nervous system-acting antihypertensives, such as clonidine (Catapres), methyldopa (Aldomet), guanabenz (Wytensin); anti-angiotensin II agents; ACE inhibitors, such as perindopril (Aceon) captopril (Capoten), enalapril (Vasotec), lisinopril (Prinivil, Zestril); angiotensin-II receptor antagonists, such as Candesartan (Atacand), Eprosartan (Teveten), Irbesartan (Avapro), Losartan (Cozaar), Telmisartan (Micardis), Valsartan (Diovan); calcium channel blockers, such as verapamil (Calan, Isoptin), diltiazem (Cardizem), nifedipine (Adalat, Procardia); diuretics; direct vasodilators, such asnitroprusside (Nipride), diazoxide (Hyperstat IV), hydralazine (Apresoline), minoxidil (Loniten), verapamil; and potassium channel activators, such as aprikalim, bimakalim, cromakalim, emakalim, nicorandil, and pinacidil.Lipid Lowering Agents

[0226] Lipid lowering agents are used to lower the amounts of cholesterol or fatty sugars present in the blood. Examples of lipid lowering agents include bezafibrate (Bezalip), ciprofibrate (Modalim), and statins, such as atorvastatin (Lipitor), fluvastatin (Lescol), lovastatin (Mevacor, Altocor), mevastatin, pitavastatin (Livalo, Pitava) pravastatin (Lipostat), rosuvastatin (Crestor), and simvastatin (Zocor).

[0227] In this invention, the patient presenting with an acute coronary disease event often suffers from secondary medical conditions such as one or more of a metabolic disorder, a pulmonary disorder, a peripheral vascular disorder, or a gastrointestinal disorder. Such patients can benefit from treatment of a combination therapy comprising administering to the patient ranolazine in combination with at least one therapeutic agent.Pulmonary Disorders Combination Therapy

[0228] Pulmonary disorder refers to any disease or condition related to the lungs. Examples of pulmonary disorders include, without limitation, asthma, chronic obstructive pulmonary disease (COPD), bronchitis, and emphysema.

[0229] Examples of therapeutics agents used to treat pulmonary disorders include bronchodilators including beta2 agonists and anticholinergics, corticosteroids, and electrolyte supplements. Specific examples of therapeutic agents used to treat pulmonary disorders include epinephrine, terbutaline (Brethaire, Bricanyl), albuterol (Proventil), salmeterol(Serevent, Serevent Diskus), theophylline, ipratropium bromide (Atrovent), tiotropium (Spiriva), methylprednisolone (Solu-Medrol, Medrol), magnesium, and potassium.Metabolic Disorders Combination Therapy

[0230] Examples of metabolic disorders include, without limitation, diabetes, including type I and type II diabetes, metabolic syndrome, dyslipidemia, obesity, glucose intolerance, hypertension, elevated serum cholesterol, and elevated triglycerides.

[0231] Examples of therapeutic agents used to beat metabolic disorders include antihypertensive agents and lipid lowering agents, as described in the section "Cardiovascular Agent Combination Therapy" above. Additional therapeutic agents used to heat metabolic disorders include insulin, sulfonylureas, biguanides, alpha-glucosidase inhibitors, and incretin mime tics.Peripheral Vascular Disorders Combination Therapy

[0232] Peripheral vascular disorders are disorders related to the blood vessels (arteries and veins) located outside the heart and brain, including, for example peripheral arterial disease (PAD), a condition that develops when the arteries that supply blood to the internal organs, arms, and legs become completely or partially blocked as a result of atherosclerosis. Gastrointestinal Disorders Combination Therapy

[0233] 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.

[0234] 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.Antibiotics, Analgesics, Antidepressants and Anti-anxiety Agents Combination Therapy

[0235] Patients presenting with an acute coronary disease event may exhibit conditions that benefit from administration of therapeutic agent or agents that are antibiotics, analgesics, antidepressant and anti-anxiety agents in combination with ranolazine.Antibiotics

[0236] Antibiotics are therapeutic agents that kill, or stop the growth of,microorganisms, including both bacteria and fungi. Example of antibiotic agents include .beta. -Lactam antibiotics, including penicillins (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), cefdinir (Omnicef), ceftriaxone (Rocephin), carbapenems, and monobactams; tetracyclines, such as tetracycline; 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; oxazolidinoes, such as linezolid; and sulfa antibiotics, such as sulfisoxazole.Analgesics

[0237] Analgesics are therapeutic agents that are used to relieve pain. Examples of analgesics include opiates and morphinomimetics, such as fentanyl and morphine;paracetamol; NSAIDs, and COX-2 inhibitors. Given the ability of the sodium channel blockers of the invention to treat neuropathic pain via inhibition of the Nay 1.7 and 1.8 sodium channels, combination with analgesics are particularly envisioned. See U.S. Patent Application Publication 20090203707.Antidepressant and Anti-anxiety Agents

[0238] Antidepressant and anti-anxiety agents include those agents used to treat anxiety disorders, depression, and those used as sedatives and tranquillizers. Examples of antidepressant and anti-anxiety agents 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); venlafaxine (Effexor XR, Efexor); citalopram (Celexa, Cipramil,Talohexane); paroxetine (Paxil, Seroxat, Aropax); trazodone (Desyrel); amitriptyline (Elavil); and bupropion (Wellbutrin, Zyban). Antidepressant and anti-anxiety agents may include neuroactive steroid and ketamine and related NMD A receptor antagonists.

[0239] Accordingly, one aspect of the invention provides for a composition comprising the sodium channel blockers of the invention and at least one therapeutic agent.In an alternative embodiment, the composition comprises the sodium channel blockers of the invention and at least two therapeutic agents. In further alternative embodiments, the composition comprises the sodium channel blockers of the invention and at least three therapeutic agents, the sodium channel blockers of the invention and at least four therapeutic agents, or the sodium channel blockers of the invention and at least five therapeutic agents.

[0240] The methods of combination therapy include co-administration of a single formulation containing the sodium channel blockers of the invention and therapeutic agent or agents, essentially contemporaneous administration of more than one formulation comprising the sodium channel blocker of the invention and therapeutic agent or agents, and consecutive administration of a sodium channel blocker of the invention and therapeutic agent or agents, in any order, wherein preferably there is a time period where the sodium channel blocker of the invention and therapeutic agent or agents simultaneously exert their therapeutic effect.EXEMPLIFICATION

[0241] The representative examples that follow are intended to help illustrate the invention, and are not intended to, nor should they be construed to, limit the scope of the invention.

[0242] The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimal reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization.

[0243] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The choice 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 T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein.

[0244] The compounds provided herein may be isolated and purified by known standard procedures. Such procedures include recrystallization, filtration, flashchromatography, trituration, high pressure liquid chromatography (HPLC), or supercritical fluid chromatography (SFC). Note that flash chromatography may either be performed manually or via an automated system. The compounds provided herein may 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 part per million (ppm) and are generated using methods well known to those of skill in the art.

[0245] Exemplary general methods for analytical LCMS include Method A (Xtimate Ci8(2. lmm x 30mm, 3 pm); A = H20 (0.04% TFA) and B = CH3CN (0.02% TFA); 50 °C; 1.2 mL / min; 10-80% B over 0.9 minutes, then 80% B for 0.6 minutes) and Method B (Chromolith Flash RP-18 endcapped C ix (2mm x 25mm); A = H20 (0.04% TFA) and B = CH3CN (0.02% TFA); 50 °C; 1.5 mL / min; 5-95% B over 0.7 minutes, then 95% B for 0.4 minutes).List of abbreviationsPd(dppf)Cl2[1,1’-bis(diphenylphosphino)ferrocene]palladium(II) dichloridePd( / -Bu3P)2bis(tri-teri-butylphosphine)palladium(0)Pd(OAc)2palladium(II) acetateSPhos 2-dicyclohexylphosphino-2',6'-dimethoxybiphenylEt3N triethylamineAgOTf silver trifluoromethanesulfonateDMF N, / V- d i m c th y I f r m a m i dcMeOH methanolEtOH ethanoli-Pr20 diisopropyl etherTHF tetrahydrofuranDCM dichloromethaneAcN or MeCN acetonitrileEA or EtOAc ethyl acetatePE petroleum etherDMSO dimethyl sulfoxideAcOH acetic acidNBS / V-hmmosuccinimidcNaOMe sodium methoxideEtONa sodium ethoxideTsOH p-toluenesulfonic acidDEA N, / V-diethylanilineDIPEA N, / V-di isopropyl ethyl amineTFA trifluoroacetic acidKOAc potassium acetateT3P propanephosphonic acid anhydrideExample 1 : 3-[cyclopropylmethoxy(difluoro)methyl]-6-[5-fluoro-6-(2,2,2- trifluoroethoxy)-3-pyridyl]-[l,2,4]triazolo[4,3-a]pyridineSynthesis of B: To a suspension of NaH (2.94 g, 73.56 mmol) in THF (50 mL) was added 2,2,2-trifluoroethanol (7.36 g, 73.56 mmol) slowly at 20 °C, and the mixture was stirred for 1 hour. 5-chloro-2,3-difluoro-pyridine (10 g, 66.88 mmol) was then added, and the mixture was stirred at 20 °C for another 4 hours. The mixture was quenched with sat.NH4CI (50 mL) and extracted with EtOAc (100 mL x 2). The combined organic phase was washed with brine (50 mL), dried over Na2S04,filtered and concentrated to afford B (15000 mg, 65.34 mmol) as an oil.lH NMR (400MHz, CDCl3) SH= 7.83 (d, 1H), 7.38 (dd, 1H), 4.73 (q, 2H).

[0246] Synthesis of A3: A mixture of B (8 g, 34.85 mmol), 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (26.55 g, 104.55 mmol), K3PO4 (14.79 g, 69.7 mmol), SPhos (4.29 g, 10.45 mmol) and Pd(OAc)2(782.4 mg, 3.48 mmol) in l,4-dioxane (250 mL) was stirred at 85 °C for 16 hours. After cooling to room temperature, the mixture was filtered through Celite and eluted with EtOAc (50 mL x 2). Thefiltrate was concentrated and diluted with EtOAc (200 mL), washed with water (100 mL x 2) and brine (100 mL), dried over Na2S04, 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 afford the product (3 g, 4.6021 mmol) as an oil. 'H NMR (400MHZ, CDCI3) <¾ = 8.26 (d, 1H), 7.72 (dd, 1H), 4.87 (q, 2H), 1.35 (s, 12H). LCMS Rt= 0.94 min using Method B, MS ESI calcd. for Ci3Hi7BF4N03[M+H]+322.1, found 322.3.

[0247] Synthesis of A2: To a mixture of cyclopropylmethanol (382.93 mg, 5.31 mmol) in THF (10 mL) was added NaH (212.41 mg, 5.31 mmol), and the mixture was stirred at 20 °C for 0.5 hour. Then to the mixture was added 6-bromo-3-[chloro(difluoro)methyl]- [l,2,4]triazolo[4,3-a]pyridine (300 mg, 1.06 mmol), and the mixture was stirred at 20 °C for 2 hours. The reaction was quenched with sat.NH4Cl (10 mL), and the mixture was extracted with EtOAc (10 mL x 2). The combined organic phase was washed with brine (10 mL), dried over Na2S04, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 10% to 40%) to give the product (240 mg, 0.73 mmol) as a solid. LCMS Rt = 2.29 min in 4 min chromatography.

[0248] 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-trifluorocthoxy) pyridine (111.02 mg, 0.35 mmol), Pd(dppf)Cl2 (34.5 mg, 0.05 mmol), 6-bromo-3-[cyclopropylmethoxy(difluoro)methyl]- [l,2,4]triazolo[4,3-a]pyridine (100 mg, 0.31 mmol) and K2CO3 (86.89 mg, 0.63 mmol) in l,4-Dioxane (5 mL) and Water (1 mL) was stirred at 90 °C for 16 hours under N2. After cooling to room temperature, the mixture was filtered through Celite, and eluted with EtOAc (10 mL x 2), and the filtrate was concentrated to give the crude product. The crude product was purified by Prep-HPLC (Waters Xbridge 150 mm x 25 mm 5 pm) A = l¾0 (10 mM NH4HCO3) and B = CH3CN; 50 - 70% B over 7 minutes) to give the product (100.49 mg,0.23 mmol) as a solid. H NMR (400MHz, DMSO-de) dp = 8.75 (s, 1H), 8.46 (d, 1H), 8.34 (dd, 11.2 Hz, 1H), 8.14 - 8.09 (m, 1H), 7.97 (dd, 1H), 5.18 (q, 2H), 4.09 (d, 2H), 1.31 - 1.21 (m, 1H), 0.61 - 0.55 (m, 2H), 0.43 - 0.37 (m, 2H). LCMS Rt= 1.31 min in 2.0 min chromatography, MS ESI calcd. for CixH i ilA^Cb [M+H]+433.1, found 433.0.Example 2: 3-[difluoro(isobutoxy)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3- pyridyl]-[l,2,4]triazolo[4,3-a]pyridine

[0249] Synthesis of A4: To a mixture of 2-methylpropan-l-ol (393.6 mg, 5.31 mmol) in THF (10 mL) was added NaH (212.41 mg, 5.31 mmol), and the mixture was stirred at 20 °C for 0.5 hour. Then to the mixture was added 6-bromo-3-[chloro(difluoro)methyl]- [l,2,4]triazolo[4,3-a]pyridine (300 mg, 1.06 mmol), and the mixture was stirred at 20 °C for 2 hours. The reaction was quenched with sat.NH^Cl (10 mL), and the mixture was extracted with EtOAc (20 mL x 2). The combined organic phase was washed with brine (10 mL), dried over Na2S04, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 10% to 40%) to give the product (100 mg, 0.30 mmol) as a solid. LCMS Rt = 0.86 min in 1.5 min chromatography, MS ESI calcd. CiiH13BrF2N30 [M+H+2]+320.0, found 320.2.

[0250] Synthesis of Compound 2: A mixture of 3-fluoro-5-(4,4,5,5-tetramethyl- l ,3, 2-dioxaborolan-2-yl)-2-(2,2,2-trifluorocthoxy) pyridine (110.33 mg, 0.34 mmol), Pd(dppf)Cl2 (34.28 mg, 0.05 mmol), 6-bromo-3-[difluoro(isobutoxy)methyl]- [l,2,4]triazolo[4,3-a]pyridine (100 mg, 0.31 mmol) and K2CO3 (86.35 mg, 0.62 mmol) in l,4-Dioxane (5 mL) and Water (1 mL) was stirred at 90 °C for 16 hours under N2. After cooling to room temperamre, the mixture was filtered through Celite, and eluted with EtOAc (10 mL x 2), and the filtrate was concentrated to give the crude product. The crude productwas purified by Prep-HPLC (Waters Xbridge 150 mm x 25 mm 5 pm) A = H2O (10 mM NH4HCO3) and B = CH3CN; 50 - 70% B over 8 minutes) to give the product (53.41 mg, 0.12 mmol) as a solid. 'H NMR (400MHZ, D SO-r / f,) 5H= 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 Rt= 1.34 min in 2.0 min chromatography, MS ESI calcd. for C18H17F6N4O2 [M+H]+435.1, found 435.1.Example 3: 3-[ethoxy(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]- [l,2,4]triazolo[4,3-a]pyridine

[0251] Synthesis of A5: A mixture of 6-bromo-3-[chloro(difluoro)methyl]- [l,2,4]triazolo[4,3-a]pyridine (300 mg, 1.06 mmol) and EtONa (361.37 mg, 5.31 mmol) in Ethanol (10 mL) was stirred at 80 °C for 24 hours. After cooling to room temperature, the reaction was quenched with sat.NfLtCl (10 mL), and the mixture was extracted with EtOAc (20 mL x 2). The combined organic phase was washed with brine (10 mL), dried over Na2S04, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE= 10% to 40%) to give the product (70 mg, 0.17 mmol) as a solid. LCMS Rt= 1.97 min in 4 min chromatography, MS ESI calcd. C9H9BrF2N30 [M+H+2]+294.0, found 293.8.

[0252] Synthesis of Compound 3: A mixture of 3-fluoro-5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (84.65 mg, 0.26 mmol), Pd(dppf)Cl2 (26.3 mg, 0.04 mmol), 6-bromo-3-[ethoxy(difluoro)methyl]-[l,2,4]triazolo[4,3- a] pyridine (70 mg, 0.24 mmol) and K2CO3 (66.25 mg, 0.48 mmol) in l,4-Dioxane (5 mL) and Water (lmL) was stirred at 90 °C for 16 hours under N2. After cooling to roomtemperature, the mixture was filtered through Celite, and eluted with EtOAc (10 mL x 2), and the filtrate was concentrated to give the crude product. The crude product was purified by Prep-HPLC (Waters Xbridge 150 mm x 25 mm 5 pm) A = ¾0 (10 mM NH4HCO3) and B = CH3CN; 42 - 62% B over 8 minutes) to give the product (44.33 mg, 0.11 mmol) as a solid.1H NMR (400MHz, DMSO-<¾) dH= 8.73 (s, 1H), 8.46 (d, 1H), 8.35 (br d, 1H), 8.11 (d, 1H), 7.96 (d, 1H), 5.18 (q, 2H), 4.29 (q, 2H), 1.36 (t, 3H) LCMS Rt= 1.25 min in 2.0 min chromatography, MS ESI calcd. for C14H 13F4N4O2 [M+H]+407.1, found 407.0.Example 4: 3-[difluoro(isopropoxy)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3- pyridyl]-[l,2,4]triazolo[4,3-a]pyridine

[0253] Synthesis of A6: To a mixture of propan-2-ol (319.15 mg, 5.31 mmol) in THF (10 mL) was added NaH (127.45 mg, 3.19 mmol), and the mixture was stirred at 20 °C for 0.5 hour. Then to the mixture was added 6-bromo-3-[chloro(difluoro)methyl]- [l,2,4]triazolo[4,3-a]pyridine (300 mg, 1.06 mmol), and the mixture was stirred at 20 °C for 2 hours. The reaction was quenched with sat.NFLtCl (10 mL), and the mixture was extracted with EtOAc (10 mL x 2). The combined organic phase was washed with brine (10 mL), dried over Na2S04, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 10% to 40%) to give the product (240 mg, 0.72 mmol) as a solid. LCMS Rt = 2.18 min in 4 min chromatography, MS ESI calcd. CioHnBrFjNsO [M+H+2]+306.0, found 305.9.

[0254] Synthesis of Compound 4: A mixture of 3-fluoro-5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (115.38 mg, 0.36 mmol), Pd(dppf)Cl2 (35.85 mg, 0.05 mmol), 6-bromo-3-[difluoro(isopropoxy)methyl]- [l,2,4]triazolo[4,3-a]pyridine (100 mg, 0.33 mmol) and K2CO3 (90.3 mg, 0.65 mmol) in 1,4-Dioxane (5 mL) and Water (1 mL) was stirred at 90 °C for 16 hours under N2. After cooling to room temperature, the mixture was filtered through Celite, and eluted with EtOAc (10 mL x 2), and the filtrate was concentrated to give the crude product. The crude product was purified by Prep-HPLC (Waters Xbridge 150 mm x 25 mm 5 pm) A = fEO (10 mMNH4HCO3) and B = CH3CN; 45 - 65% B over 8 minutes) to give the product (80.25 mg, 0.19 mmol) as a solid. H NMR (400MHz, DMSO-de) 5H= 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 Rt= 1.29 min in 2.0 min chromatography, MS ESI calcd. for C17H 13F4N4O2 [M+H]+421.1, found 421.0.Example 5 : 3- [difluoro(methoxy) methyl] -6- [5-fluoro-6-(2,2,2- trifluoro- 1 , 1 -dimethyl- ethoxy)-3-pyridyl]-[l,2,4]triazolo[4,3-b]pyridazine

[0255] Synthesis of A7: To a mixture of (6-chloropyridazin-3-yl)hydrazine (3 g,20.75 mmol) in Toluene (40 mL) was added (2-chloro-2,2-difluoro-acetyl) 2-chloro-2,2- difluoro-acetate (5.55 g, 22.83 mmol). 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 NaHC(¾ (50 mL), and the mixture was extracted with EtOAc (50 mL x 2). The combined organic phase was washed with brine (20 mL), dried over Na SCh, filtered and concentrated to give the crude product as a solid. 'H NMR (400MHz, DMSO-de) dH= 8.67 (d, 1H), 7.78 (d, 1H).

[0256] Synthesis of A9: A mixture of 6-chloro-3-[chloro(difluoro)methyl]- [l,2,4]triazolo[4,3-b]pyridazine (200 mg, 0.84 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-2-(2,2,2-trifluoro-l,l-dimethyl-ethoxy)pyridine (350.58 mg, 1 mmol), Pd(?-Bu iP) (64.15 mg, 0.13 mmol), and K3PO4 (532.95 mg, 2.51 mmol) in l,4-Dioxane (2 mL) and Water (0.20 mL) was stirred at 80 °C for 16 hours. After cooling to room temperature, the suspension was diluted with EtOAc (10 mL), filtered through silica gel, eluted with EtOAc (20 mL). The combined filtrates were concentrated to afford crude product. The crude product was purified by flash chromatograph on silica gel (EtOAc in PE = 20% to 50% to 80%) to give the product (260 mg, 0.50 mmol) as a solid. LCMS Rt= 0.96 min in 1.5 min chromatography, MS ESI calcd. for C13H 1 1CIF4N3O [M+H]+426.1, found 425.9.

[0257] Synthesis of Compound 5: To a mixture of 3-[chloro(difluoro)methyl]-6-[5- fluoro-6-(2,2,2-trifluoro-l,l-dimethyl-ethoxy)-3-pyridyl]-[l,2,4]triazolo[4,3-b]pyridazine (150 mg, 0.35 mmol) in MeCN (lmL) was added AgOTf (905.31 mg, 3.52 mmol) and MeOH (8 mL, 0.35 mmol). 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), extracted with EtOAc (30 mL x 2). The combined organic phase was washed with water (20 mL x 2), brine (30 mL x 2), dried over anhydrous Na2SO / t, filtered and concentrated to give the crude product. The crude product was purified by Prep-HPLC (Waters Xbridge 150mm x 25mm, 5 pm), A = FLO (0.05% NH4OH) and B = CH3CN; 57- 87% B over 9 minutes) to give the product as a solid. 'H NMR (CDCI3, 400MHz) 5H= 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, = 1.32 min in 2.0 min chromatography, MS ESI calcd. for C16H14L6N5O2 [M+H]+422. l, found 422.0.Example 6: 3- [difluoro(methoxy)methyl] -6- [5-fluoro-6- [(1 S)-2,2,2-trifluoro- 1 -methyl- ethoxy]-3-pyridyl]-[l,2,4]triazolo[4,3-a]pyridine

[0258] A mixture of 6-bromo-3-[difluoro(methoxy)methyl]-[l,2,4]triazolo[4,3-a]pyridine (100 mg, 360 p mol ), 3-fluoro-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-2-[(lS)-2,2,2-trifluoro-l-methyl-ethoxy]pyridine (144.62 mg, 430 pmol), K2CC>3(99.4l mg, 720 pmol) and Pd(dppf)Cl2 (39.47 mg, 50 pmol) in 1 ,4-Dioxane(5mL) andWater (500 pL) was stirred at 80 °C for 12 hours under N2. After cooling to room temperature, the mixture was diluted with H2O (10 mL), and the mixture was extracted with EtOAc (20 mL x 2). The combined organic phase was washed with water(l0 mL) and brine(l0 mL), dried over Na2S04, filtered and concentrated to give the crude product. The crude product was purified by Prep-HPLC (Boston Prime C18 (150 x 30 mm, 5 pm), A =H2O (0.05% NH4OH) and B = CH3CN; 53-83% B over 8 minutes) to give the product as a solid. 1H NMR (400MHz, DMSO-d6) dH= 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 Rt= 1.27 min in 2.0 min chromatography, MS ESI calcd. CixHi iL^O [M+H]+407.09, found 406.9.Example 7: 3-[difluoro(methoxy)methyl]-6-[5-fluoro-6-[(lR)-2,2,2-trifluoro-l-methyl- ethoxy]-3-pyridyl]-[l,2,4]triazolo[4,3-a]pyridine

[0259] A mixture of 6-bromo-3-[difluoro(methoxy)methyl]-[l,2,4]triazolo[4,3- a]pyridine(l00 mg, 360 pmol), 3-fluoro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2- [(lR)-2,2,2-trifluoro-l-methyl-ethoxy]pyridine(l44.62 mg, 430 pmol), K2C03(99.4lmg, 720 pmol) and Pd(dppf)Cl2 (39.47 mg, 50 pmol) in l,4-Dioxane (5 mL) and Water (500 pL) was stirred at 80 °C for 12 hours under N2. After cooling to room temperature, the mixture wasdiluted with ¾0 (10 mL), and the mixture was extracted with EtOAc (20 mL x 2). The combined organic phase was washed with water (10 mL) and brine (10 mL), dried over Na S04,filtered and concentrated to give the crude product. The crude product was purified by Prep-HPLC (Boston Prime C18 (150 mm x 30 mm, 5 pm), A = ¾0 (0.05% NH4OH) and B = CH3CN; 53-83% B over 8 minutes) to give the product as a solid. 'H-NMR (400MHZ, DMSO-de) dH= 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 Rt= 1.27 min in 2.0 minchromatography, MS ESI calcd. C1XH1 3F4N4O2 [M+H]+407.1, found 406.9.Example 8: 3-[cyclopropylmethoxy(difluoro)methyl]-6-[5-fluoro-6-(2,2,2- trifluoroethoxy)-3-pyridyl]-[l,2,4]triazolo[4,3-a]pyrazine

[0260] A mixture of 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)- 3-pyridyl]-[l,2,4]triazolo[4,3-a]pyrazine (300 mg, 0.75 mmol) and AgOTf (1938.39 mg, 7.54 mmol) in cyclopropylmethanol (15 mL, 0.75 mmol) and CH3CN (15 mL) was stirred at 90 °C for 14 days. After cooling to room temperature, the reaction was diluted with EtOAc (40 mL), and to the mixture was added saturated NaCl (40 mL), the mixture was filtered through Celite and eluted with EtOAc (20 mL x 2), and the filtrate was concentrated to give the crude product. The crude product was purified by Prep-TLC (EtOAc : PE = 1 : 1) to give the impure product. The impure product was purified by Prep-HPLC (Waters Xbridge 150 mm x 25 mm 5 pm) A = ¾0 (10 mM NH4HCO3) and B = CH3CN; 48 - 68% B over 8 minutes) to give the product as a solid.1H-NMR (CDCI3, 400MHz) 5H= 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 Rt= 1.33 min in 2.0 min chromatography, MS ESI calcd. for Ci7H14F6N502 [M+H]+434.1, found 434.0.Example 9: 3-[cyclopropylmethoxy(difluoro)methyl]-6-[5-fluoro-6-(2,2,2- trifluoroethoxy)-3-pyridyl]-[l,2,4]triazolo[4,3-a]pyrazine

[0261] Synthesis of A19: A mixture of Pd(dppf)Cl2 (15.13 g, 20.68 mmol), CS2CO3 (269.49 g, 827.17 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-l,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 l,4-Dioxane (1 L) and Water (150 mL) under N2 was stirred at 35 °C for 2 hours. After cooling to room temperature, to the mixture was added water (300 mL) and the mixture was filtered through Celite. After separating, the organic phase was washed with brine (300 mL), dried over anhydrous Na2S04, filtered and concentrated to give the crude product. The crude product was re-dissolved in EA / PE = 1 / 3 (500 mL) and then filtered through silica gel mat. The cake was washed with EA / PE = 1 / 3 (500 mL). The combined organic phase was concentrated to give a residue as oil. To the oil was added PE (500 mL) slowly and some solid was obtained. The solid was collected and dried in oven to give the product (100 g, 242.4 mmol, 58% yield) as a solid. LCMS Rt= 1.28 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. for C11H7CIF4N3O [M+H]+308.0, found 307.9.

[0262] 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 filtered. The cake was washed with water (500 mL x 2). The solid was re-dissolved in EtOAc (3 L), washed with brine (500 mL x 2), dried over anhydrous Na2S04, 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, MS ESI calcd. for C11H10F4N5O [M+H]+304.1, found 303.9.

[0263] Synthesis of A13: To a solution of 2-bromo-2,2-difluoro-acetic acid (87 g, 497.34 mmol) in THF (1 L) was added one drop of DMF and (COCl)2 (50.5 mL, 596.81 mmol). The resulting mixture was stirred at 20 °C for 1 hour. The resulting solution was used into next step directly. To the solution of 2-bromo-2,2-difluoro-acetyl chloride (95.66 g, 494.69 mmol) in THF (1 F) was added [5-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3- pyridyl]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 F), extracted with EtOAc (1F x 2).The combined organic phase was washed with brine (500 mL x 2), dried over anhydrous Na SCF, 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 Rt= 0.92 min in 1.5 min chromatography, 5-95AB, MS ESI calcd. for C nHyBi FyNyO [M+H]+460.1, found 459.8.

[0264] 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 hours. After cooling to room temperature, the mixture was poured into water (2 L), extracted with EtOAc (2L x 2). The combined organic phase was washed with brine (1 L x 2), dried over anhydrous Na SOy, filtered and concentrated to give the crude product. The crude product was purified by chromatography flash on siliga gel (EtOAc in PE = 0% to 15% to 30%) to give the product (80 g, 181.0 mmol, 55% yield) as oil. 'H NMR (CDCI3, 400MHz) 5H = 9.60 (d, 1H), 8.55 (d, 1H), 8.45 (s, 1H), 8.09 (dd, 1H), 4.93 (q, 2H).

[0265] Synthesis of Compound 10: A mixture of 3-[bromo(difluoro)methyl]-6-[5- fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-[l,2,4]triazolo[4,3-a]pyrazine (76 g, 171.9 mmol) and AgBF4(66.93 g, 343.81 mmol) in Ethanol (760 mL) was stirred at 60 °C for 1 hour.After cooling to room temperature, the mixture was poured into saturated aqueous NaCl (1 L) and EtOAc (2 L). The mixture was filtered through Celite. After separating, the aqueous layer was extracted with EtOAc (500 mL x 2). The combined organic phase was washed with brine (500 mL x 2), dried over anhydrous Na SO^ filtered and concentrated to give the crude product. The crude product was purified by chromatography flash column 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. 'H NMR (CDCI3 400MHz) 5H = 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, =1.25 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. for C13H12F4N3CF [M+H]+408.1, found 408.0.Example 10: 3-[difluoro(methoxy)methyl]-6-[5-fluoro-6-[l- (trifluoromethyl)cyclobutoxy]-3-pyridyl]-[l,2,4]triazolo[4,3-a]pyrazine

[0266] A mixture of 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[l-(trifluoromethyl)cyclobutoxy]-3-pyridyl]-[l,2,4]triazolo[4,3-a]pyrazine (1.4 g, 3.2 mmol) and AgOTf (8.22 g, 31.98 mmol), in mixed solvent Methanol (14 mL) and DMF (14 mL) was stirred at 90 °C for 24 hours. After cooling to room temperature, the reaction mixture was treated with brine (40 mL), and the precipitate was filtered. The filtrate was extracted with EtOAc (40 mL x 2). The combined organic phase was washed with brine (20 mL), dried over Na S04and concentrated to give a crude product. The crude product was purified by Prep- HPLC (Waters Xbridge (150 mm x 25 mm 5 pm) A = ¾0 (10 mM NH4HCO3) and B = CH3CN; 57-67 % B over 8 minutes) to give the product (240 mg). Another batch was started with 1.2 g of A24, and about 110 mg of the product was obtained by Prep-HPLC (BostonPrime C18 (150 mm x 30 mm, 5 pm) A = H2O (0.05% NH4OH) and B = CH3CN; 50-80 % B over 9 minutes). Two batches of the product were combined and lyophilized to give the product as a solid.lH NMR (CDCl3, 400 MHz) dH= 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 Rt= 1.30 min in 2 min chromatography, 10-80AB, MS ESI calcd. for C17H 14F4N3O2 [M+H]+434.1, found 433.9.Example 11 : 3- [difluoro(methoxy)methyl] -6- [5-fluoro-6- [(IS) -2,2,2-trifluoro- 1 -methyl- ethoxy]-3-pyridyl]-[l,2,4]triazolo[4,3-b]pyridazine

[0267] Synthesis of A25: A mixture of 6-chloro-3-[chloro(difluoro)methyl]-[l,2,4]triazolo[4,3-b]pyridazine (120 mg, 0.50 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-2-[(lS)-2,2,2-trifluoro-l-methyl-ethoxy]pyridine (201.9 mg, 0.60 mmol), K3PO4 (319.74 mg, 1.51 mmol), Pd(?-Bu iP) (25.66 mg, 0.05 mmol) in l,4-dioxane (12 mL) and H2O (4 mL) was stirred at 90 °C for 16 hours. After cooling to room temperature, the reaction mixture was concentrated, diluted with water (20 mL), and extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with brine (40 mL), dried over Na SCp and concentrated to give a residue. The residue was purified by flashchromatography on silica gel (EtOAc in PE = 0 % to 60 %) to give the product (120 mg, 0.29 mmol) as a solid. 1H-NMR (CDCI3, 400MHz) dH= 8.57 (d, 1 H), 8.35 (d, 1 H), 8.15 (dd, 1 H), 7.74 (d, 1 H), 5.93 (m, 1 H) 1.61 (d, 3 H).

[0268] Synthesis of Compound 12: A mixture of AgOTf (599.15 mg, 2.33 mmol), 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[(lS)-2,2,2-trifluoro-l-methyl-ethoxy]-3-pyridyl]- [l,2,4]triazolo[4,3-b]pyridazine (120 mg, 0.29 mmol) in methanol (6 mL) was stirred at 90 °C for 120 hours. After cooling to room temperature, the reaction mixture was treated with brine (20 mL), and the precipitate was filtrated. The filtrate was concentrated, diluted with water (20 mL), and extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with brine (40 mL), dried over Na SCp and concentrated to give a residue. The residue was purified by prep-HPLC (Boston Prime C18 150 x 30 mm 5 pm) A = 1¾0 (0.05 % NH4OH) and B = CH3CN; 52-82 % B over 8 minutes) to give the product (5.12 mg, 13 pmol). 'H-NMR (CDCI3, 400MHz) dH= 8.55 (d, 1 H), 8.30 (d, 1 H), 8.14 (dd, 1 H), 7.66 (d,1 H), 5.92 (m, 1 H), 3.94 (s, 3 H), 1.61 (d, 3 H). LCMS R, = 1.28 min in 2.0 minchromatography, MS ESI calcd. for CY H i F^N O [M+H]+408.1, found 408.0.Example 12: 3-[difluoro(methoxy)methyl]-6-[5-fluoro-6-[(lR)-2,2,2-trifluoro-l-methyl- ethoxy]-3-pyridyl]-[l,2,4]triazolo[4,3-b]pyridazine

[0269] Synthesis of A26: A mixture of 6-chloro-3-[chloro(difluoro)methyl]- [l,2,4]triazolo[4,3-b]pyridazine (120 mg, 0.50 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-2- [(lR)-2,2,2-trifluoro-l-methyl-ethoxy]pyridine (201.9 mg, 0.60 mmol), K3PO4 (319.74 mg, 1.51 mmol), Pd(7-Bu iP) (25.66 mg, 0.05 mmol) in l,4-dioxane (12 mL) and H2O (4 mL) at 90 °C for 16 hours. After cooling to room temperature, the reaction mixture was concentrated to remove solvent, diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with brine (40 mL), dried over Na SCp 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. 'H-NMR (CDCI3, 400MHz) 5H= 8.57 (d, 1 H), 8.35 (d, 1 H), 8.14 (dd, 1 H), 7.74 (d, 1 H), 5.93 (m, 1 H), 1.61 (d, 3 H).

[0270] Synthesis of Compound 13: A mixture of 3-[chloro(difluoro)methyl]-6-[5- fluoro-6-[(lR)-2,2,2-trifluoro-l-methyl-ethoxy]-3-pyridyl]-[l,2,4]triazolo[4,3-b]pyridazine (140 mg, 0.34 mmol), AgOTf (699 mg, 2.72 mmol) in methanol (8 mL) and was stirred at 90 °C for 120 hours. After cooling to room temperature, the reaction mixture was treated withbrine (20 mL), and the precipitate was filtrated. The filtrate was concentrated and diluted with water (20 mL), then extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with brine (40 mL), dried over Na SCL and concentrated to give a residue. The residue was purified by Prep-HPLC (Boston Prime C18 150 x 30 mm 5pm) A = ]¾0 (0.05 % NH4OH) and B = CH3CN; 52-82 % B over 8 minutes) to give the product (5 mg,12.2 pmol). 'H-NIVIR (CDCL, 400MHz) dH= 8.55 (d, 1 H), 8.30 (d, 1 H), 8.14 (dd, 1 H), 7.66 (d, 1 H), 5.92 (m, 1 H), 3.94 (s, 3 H), 1.61 (d, 3 H). LCMS Rt= 1.26 min in 2.0 min chromatography MS ESI calcd. for CisH^FeNsCL [M+H]+408.1, found 408.0.Example 13: 3-[cyclopropylmethoxy(difluoro)methyl]-6-[5-fluoro-6-(2,2,2- trifluoroethoxy)-3-pyridyl]-[l,2,4]triazolo[4,3-b]pyridazine

[0271] Synthesis of A27: A mixture of 6-chloro-3-[chloro(difluoro)methyl]- [l,2,4]triazolo[4,3-b]pyridazine (500 mg, 2.09 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (2015.06 mg, 6.28 mmol), Pd(7-Bu iPL (160.37 mg, 0.31 mmol) and K3PO4 (888.25 mg, 4.18 mmol) in l,4-Dioxane (15 mL) andWater (1.5 mL) was stirred at 90 °C for 16 hours under N2. The mixture was filtered through Celite, and eluted with EtOAc (10 mL x 2), and the filtrate was concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 20% to 60% ) to give the product (900 mg, 1.90 mmol) as a solid. LCMS Rt = 0.85 min in 1.5 min chromatography, MS ESI calcd. C13H7CIF6N5O [M+H]+398.0, found 398.0.

[0272] Synthesis of Compound 14: A mixture of 3-[chloro(difluoro)methyl]-6-[5- fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-[l,2,4]triazolo[4,3-b]pyridazine (200 mg, 0.50mmol) and AgOTf (1292.26 mg, 5.03 mmol) in cyclopropylmethanol (10 mL, 0.50 mmol) and CH3CN (10 mL) was stirred at 90 °C for 13 days. After cooling to room temperature, the reaction was diluted with EtOAc (40 mL) and brine (40 mL). The mixture was filtered through Celite, eluted with EtOAc (20 mL x 2), and the filtrate was concentrated to give the crude product. The crude product was purified by Prep-HPLC (Boston Prime Cl 8 150 mm x 30 mm 5 pm) A = H2O (0.05% NH4OH v / v) and B = CH3CN; 58 - 88% B over 8 minutes) to give the impure product. The impure product was triturated from / i-hcxane / / -Pr20(v / v = 1 : 1, 2 mL) to give the product (9.82 mg, 22.2 pmol) as a solid. 'H NMR (DMSO-CL, 400MHZ) 5H= 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 Rt= 2.87 min in 4.0 min chromatography, MS ESI calcd. for C17H14F4N3O2[M+H]+434.1, found 434.0.Example 14: 3-[difluoro(methoxy)methyl]-6-[5-fluoro-6-(2, 2, 2-trifluoro-l, 1-dimethyl- ethoxy)-3-pyridyl]-[l,2,4]triazolo[4,3-a]pyrazine

[0273] Synthesis of A29: A solution of [5- [5-fluoro-6-(2, 2, 2-trifluoro-l, l-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 extracted with EtOAc (50 mL x 2). The combined organic phase was washed with water (50 mL), brine (50 mL x 2), dried over anhydrous Na2S04, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography column on silica gel (EtOAc in PE = 0% to 10% to 20%) to give the product (150 mg, 346.3 pmol) as a solid. LCMS Rt= 3.06min in 4.0 min chromatography, MS ESI calcd. for C13H1 1CIIAN3O [M+H]+426.0, found 426.0.

[0274] Synthesis of Compound 15: To a solution of 3-[chloro(difluoro)methyl]-6-[5- fluoro-6-(2,2,2-trifluoro-l,l-dimethyl-ethoxy)-3-pyridyl]-[l,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 the filtrate was separated, the organic phase was washed with water (20 mL x 2), brine (20 mL x 2), dried over anhydrous Na SO^ filtered and concentrated to give the crude product. The crude product was purified by Prep-TLC (PE: EtOAc = 4: 1) to give the product (14.23 mg, 33.2 mmol) as a solid. 'H NMR (CDCI3,400MHz) dH= 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 Rt= 1.33 min in 2.0 min chromatography, MS ESI calcd. for C^H^L^N^O[M+H]+422. l, found 422.0.Example 15: 3-[ethoxy(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]- [l,2,4]triazolo[4,3-b]pyridazine

[0275] A mixture of 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)- 3-pyridyl]-[l,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 CH3CN (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, eluted with EtOAc (20 mL x 2), and the filtrate was concentrated to give the crude product. The crude product was purified by Prep-TLC (EtOAc : DCM : PE = 1 : 1 : 1) to give the impure product. The impure product was triturated from «-hcxanc / CH CL (v / v = 1 : 2, 6 mL) to give the product (15.95 mg, 39.2 mmol) as a solid.1H NMR (DMSO-cT, 400MHz) 5H= 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 Rt= 1.26 min in 2.0 min chromatography, MS ESI calcd. for CYiH i F^NiO [M+H]+408.1, found 408.0.Example 16: 3-[difluoro(methoxy)methyl]-6-[5-fluoro-6-[l- (trifluoromethyl)cyclobutoxy]-3-pyridyl]-[l,2,4]triazolo[4,3-b]pyridazine

[0276] Synthesis of A7-a : To a mixture of (6-chloropyridazin-3-yl)hydrazine (3.0 g, 20.75 mmol) in toluene (40 mL) was added (2-chloro-2,2-difluoro-acetyl)-2-chloro-2,2- difluoro- acetate (7.56 g, 31.13 mmol). 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 sat. NaHCCL (50 mL), and the mixture was extracted with EtOAc (50 mL x 2). The combined organic phase was washed with brine (20 mL), dried over Na2S04, filtered and concentrated to give the crude product (4700 mg, 19.66 mmol) as a solid. 1H NMR (400MHZ, CDCI3) dH= 7.35 (d, 1H), 8.23 (d, 1H).

[0277] Synthesis of A30: A mixture of 6-chloro-3-[chloro(difluoro)methyl]- [l,2,4]triazolo[4,3-b]pyridazine (150 mg, 0.63 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-2- [l-(trifluoromethyl)cyclobutoxy]pyridine (362.64 mg, 1 mmol), K3PO4 (399.65 mg, 1.88 mmol), Bis(tri-tert-butylphosphine) palladium(O) (64.15 mg, 0.1300 mmol) in l,4-Dioxane (12 mL) and Water (4 mL) was stirred at 80 °C for 16 hours. From TLC, newspot (Rf = 0.45, UV) was observed, and no starting material (Rf = 0.8, UV) remained. After cooling to room temperature, the reaction mixture was concentrated to remove solvent, diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with brine (40 mL), dried over NibSCL 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. 'H NMR (CDCI3, 400MHz) dH= 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).

[0278] Synthesis of Compound 17: A mixture of 3-[chloro(difluoro)methyl]-6- [5- fluoro-6- [l-(trifluoromethyl)cyclobutoxy]-3-pyridyl]-[l,2,4]triazolo[4,3-b]pyridazine (120 mg, 0.27 mmol), silver trifluoromethanesulfonate (0.7 g, 2.74 mmol), in mixed solvent methanol (12 mL) and MeCN (4 mL) was stirred at 80 °C for 72 hours. After cooling to room temperature, the reaction mixture was treated with brine (20 mL) and the precipitate was filtrated. The filtrate was concentrated to remove solvent, and diluted with water (20 mL), and extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with brine (40 mL), dried over Na SCL and concentrated to give a residue. The crude product was purified by prep-HPLC (Boston Prime Cl 8 150 x 30 mm 5 pm) A = ¾0 (0.05% NH4OH) and B = ACN; 52-82 % B over 8 minutes) to give the product (27.93 mg, 64.5 pmol) as a solid.lH NMR (CDCI3, 400 MHz) dH= 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 Rt= 1.32 min in 2.0 min chromatography, MS ESI calcd. for C17H14F6N502 [M+H]+434.1, found 434.0.Example 17: 3-[difluoro(methoxy)methyl]-6-[5-fluoro-6-[l- (trifluoromethyl)cyclobutoxy]-3-pyridyl]-[l,2,4]triazolo[4,3-a]pyridine

[0279] 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 NaHCCL (50 mL), and the mixture was extracted with EtOAc (50 mL x 2).The organic layer was washed with brine (50 mL), drived over Na SO^ filtered and concentrated to give the crude product. The crude product was purified by flashchromatography on silica gel (EtOAc in PE= 0% to 20% to 30%) to give the product (3900 mg, 13.81 mmol) as a solid. 1H NMR (400MHz, CDCI3) dH= 8.42 (s, 1H), 7.84 (d, 1H), 7.53 (dd, 1H). LCMS Rt= 3.19 min in 7.0 min chromatography, MS ESI calcd. forC7H4BrClF2N3 [M+H+2]+283.9, found 283.6.

[0280] Synthesis of A15: A mixture of 6-bromo-3-[chloro(difluoro)methyl]- [l,2,4]triazolo[4,3-a]pyridine (1 g, 3.54 mmol) and NaOMe (956.21 mg, 17.7 mmol) inMethanol (20 mL) was stirred at 80□ for 24 hours. After cooling to room temperature, the reaction was quenched with sat.NPLCl (50 mL), and the mixture was extracted with EtOAc (50 mL x 2). The combine organic layer was washed with brine (50 mL), dried over Na SCL, 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 (380 mg, 127.56 pmol) as a solid. 'H-NMR (CDCI3, 400MHz) 5H= 8.43 (s, 1H), 7.77 (d, 1H), 7.47 - 7.41 (m, 1H), 3.92 (s, 3H). LCMS Rt= 2.95 min in 7.0 min chromatography, MS ESI calcd. for CglLBrF NsO [M+H+2]+280.0, found 279.7.

[0281] Synthesis of Compound 18: A mixture of 6-bromo-3- [difluoro(methoxy)methyl]-[l,2,4]triazolo[4,3-a]pyridine (100 mg, 0.36 mmol), 3-fluoro-5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2-[l-(trifluoromethyl)cyclobutoxy]pyridine (155.86 mg, 0.43 mmol), K2CO3 (99.41 mg, 0.72 mmol) and Pd(dppf)Cl2 (39.47 mg, 0.05 mmol) in l,4-Dioxane (5 mL) and Water (0.50 mL) was stirred at 80 °C for 12 hours. After cooling to room temperature, the mixture was diluted with H2O (10 mL), and the mixture was extracted with EtOAc (20 mL x 2). The combined organic phase was washed with water (30 mL) and brine (10 mL), dried over Na2S04, filtered and concentrated to give the crude product. The crude product was purified by Prep-HPLC (Boston Prime C18 (150 x 30 mm, 5 pm), A = H2O (0.05% NH4OH) and B = CH3CN; 58-88% B over 8 minutes) to give the product (66.89 mg, 15.47 pmol) as a solid. 'H NMR (DMSO-CL, 400MHZ) 5H= 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 Rt= 1.32 min in 2.0 min chromatography, MS ESI calcd. CisH ^'r^CL [M+H]+433.1, found 432.9.Example 18: Synthesis of 3-[cyclopropylmethoxy(difluoro)methyl]-6-[5-fluoro-6-[(lS)- 2,2,2-trifluoro-l-methyl-ethoxy]-3-pyridyl]-[l,2,4]triazolo[4,3-a]pyridine

[0282] A mixture of 6-bromo-3-[cyclopropylmethoxy(difluoro)methyl]- [l,2,4]triazolo[4,3-a]pyridine(65 mg, 200 pmol), 3-fluoro-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-2-[(lS)-2,2,2-trifluoro-l-methyl-ethoxy]pyridine(82. l6 mg, 250 pmol), K^(¾(56.48 mg, 410 pmol) and Pd(dppf)Cl2 (22.43 mg, 30 pmol) in l,4-Dioxane (5 mL) and Water (0.50 mL) was stirred at 80 °C for 12 hours under N2. After cooling to room temperature, the mixture was diluted with H2O (10 mL), and the mixture was extracted with EtOAc (20 mL x 2). The combined organic phase was washed with water (20 mL) and brine (30 mL), dried over Na2S04, filtered and concentrated to give the crude product. The crude product was purified by Prep-HPLC (Boston Prime Cl 8 (150 x 30 mm, 5 pm) A = H2O(0.05% NH4OH) and B = CH3CN; 62 - 92% B over 8 minutes) yielding the product (43.42 mg, 97.3 pmol, 48% yield) as a solid. 'H NMR (D SO-cL, 400MHz) dp = 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 Rt= 1.37 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. CigHnFeNtCL [M+H]+447.1, found 447.0.Example 19: 3-[difluoro(isopropoxy)methyl]-6-[5-fluoro-6-[(lS)-2,2,2-trifluoro-l- methyl-ethoxy]-3-pyridyl]-[l,2,4]triazolo[4,3-a]pyridine

[0283] A mixture of 6-bromo-3-[difluoro(isopropoxy)methyl]-[l,2,4]triazolo[4,3- a]pyridine(70 mg, 230 pmol), 3-fluoro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2- [(lS)-2,2,2-trifluoro-l-methyl-ethoxy]pyridine (91.96 mg, 270 pmol), K2CC>3(63.2l mg, 460 pmol) and Pd(dppf)Cl2 (25.1 mg, 30 pmol) in l,4-Dioxane (5 mL) and Water (0.50 mL) was stirred at 80 °C for 12 hours under N2. After cooling to room temperature, the mixture was diluted with H2O (10 mL), and the mixture was extracted with EtOAc (20 mL x 2). The combined organic phase was washed with water (20 mL) and brine (30 mL), dried over Na2S04, filtered and concentrated to give the crude product. The crude product was purified by Prep-HPLC (Boston Prime C18 (150 x 30 mm, 5 pm), A = H2O (0.05% NH4OH) and B = CH3CN; 60-90% B over 8 minutes) to give the product (33.94 mg, 78.1 pmol, 34% yield) as a solid.JH NMR (DMSO-d6, 400MHz) dH= 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, = 1.35 min in 2.0 min chromatography, 10-80AB, MS ESI calcd.€icHi7HήN402 [M+H]+435.1, found 435.0.Example 20 : 3- [difluoro(isopropoxy)methyl] -6- [5-fluoro-6- [(lR)-2,2,2-trifluoro- 1 - methyl-ethoxy]-3-pyridyl]-[l,2,4]triazolo[4,3-a]pyridine

[0284] A mixture of 3-fluoro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2- [(lR)-2,2,2-trifluoro-l-methyl-ethoxy]pyridine (84.29 mg, 0.25 mmol), Pd(dppf)Cl2 (25.1 mg, 0.03 mmol), 6-bromo-3-[difluoro(isopropoxy)methyl]-[l,2,4]triazolo[4,3-a]pyridine (70 mg, 0.23 mmol) and K2CO3 (63.21 mg, 0.46 mmol) in l,4-Dioxane (5 mL) and Water (1 mL) was stirred at 90 °C for 16 hours under N2. After cooling to room temperature, the mixture was filtered through Celite, and eluted with EtOAc (10 mL x 2), and the filtrate was concentrated to give the crude product. The crude product was purified by Prep-HPLC (Boston Prime C18 (150 mm x 30 mm 5 pm) A = H2O (0.05% ammonia hydroxide v / v) and B = CH3CN; 60 - 90% B over 8 minutes) to give the product (24.78 mg, 57.1 pmol, 25% yield) as a solid.lH NMR (DMSO-d6, 400MHz) dH= 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 Rt= 1.37 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. for CI8H17F6N402 [M+H]+435.1, found 435.1.

[0285] Example 21: 3-[difluoro(isobutoxy)methyl]-6-[5-fluoro-6-[(lS)-2,2,2- trifluoro-l-methyl-ethoxy]-3-pyridyl]-[l,2,4]triazolo[4,3-a]pyridine

[0286] Synthesis of Al-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(9690.2l mg, 39.89 mmol) in Toluene (200 mL) was stirred at 10 °C for 1 hour, and then the mixture was heated at 120 °C for 36 hours. After cooling to room temperature, the reaction was quenched with sat. NaHCCL (200 mL), then the mixture was extracted with EtOAc (80 mL x 2). The organic layer was washed with brine (200 mL), dried over Na2S04, 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.lH NMR (CDCl3, 400MHz) dH= 8.43 (s, 1H), 7.84 (dd, 1H), 7.54 (dd, 1H).

[0287] Synthesis of A4-a : To a mixture of 2-methylpropan-l-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 hour. Then to the mixture was added 6-bromo-3-[chloro(difluoro)methyl]- [l,2,4]triazolo[4,3-a]pyridine(l000 mg, 3.54 mmol), and the mixture was stirred at 20 °C for 2 hours. The reaction was quenched with sat. NH4CI (40 mL), and the mixture was extracted with EtOAc(30 mL x 2). The combined organic phase was washed with brine (70 mL), dried over Na SCb, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE= 10% to 40%) to give the product (750 mg, 2.34 mmol, 66% yield) as an oil. 'H NMR (CDCI3, 400MHz) 5H= 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).

[0288] Synthesis of Compound 22: A mixture of 6-bromo-3- [difluoro(isobutoxy)methyl]-[l,2,4]triazolo[4,3-a]pyridine(l00 mg, 310 pmol), 3-fluoro-5- (4,4,5 ,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)-2- [( 1 S)-2,2,2-trifluoro- 1 -methyl- ethoxy]pyridine(l25.6l mg, 370 pmol), K2CO3 (86.35 mg, 620 pmol) and Pd(dppf)Cl2 (34.28 mg, 50 pmol) in l,4-Dioxane (5 mL) and Water (0.50 mL) was stirred at 80 °C for 12 hours under N2. After cooling to room temperature, the mixture was diluted with l¾0 (10 mL), and then extracted with EtOAc (20 mL x 2). The combined organic phase was washed with water (20 mL) and brine (30 mL), dried over Na2S04, filtered and concentrated to give the crude product. The crude product was purified by Prep-HPLC (Boston Prime Cl 8 (150 x 30 mm, 5 pm), A = ]¾0 (0.05% NH4OH) and B = CH3CN; 65-95% B over 8 minutes) to give the product (47.11 mg, 105.1 pmol, 34% yield) as a solid. 'H NMR (DMSO-cL, 400MHz) 5H= 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 Rt= 1.41 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. CiyHiyFyNyO [M+H]+449.1, found 449.1.Example 22: 3-[difluoro(isobutoxy)methyl]-6-[5-fluoro-6-[(lR)-2,2,2-trifluoro-l-methyl- ethoxy]-3-pyridyl]-[l,2,4]triazolo[4,3-a]pyridine

[0289] A mixture of 3-fluoro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2- [(lR)-2,2,2-trifluoro-l-methyl-ethoxy]pyridine (115.14 mg, 0.34 mmol), Pd(dppf)Cl2 (34.28 mg, 0.05 mmol), 6-bromo-3-[difluoro(isobutoxy)methyl]-[l,2,4]triazolo[4,3-a]pyridine (100 mg, 0.31 mmol) and K2CO3 (86.35 mg, 0.62 mmol) in l,4-Dioxane (5 mL) and Water (1 mL) was stirred at 90 °C for 16 hours under N2. After cooling to room temperature, the mixture was filtered through Celite, and eluted with EtOAc (10 mL x 2), and the filtrate was concentrated to give the crude product. The crude product was purified by Prep-HPLC (Boston Prime Cl 8 150 mm x 30 mm 5 pm) A = H2O (0.05% ammonia hydroxide v / v) and B = CH3CN; 61 - 91% B over 8 minutes) to give the product (68.11 mg, 0.15 mmol, 48% yield) as a solid. (DMSO-<¾, 400MHz) dH= 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 Rt= 1.42 min in 2.0 min chromatography, 10-80ABMS ESI calcd. for CI9H19F6N402 [M+H]+449.1, found 449.1.Example 23 : 3- [difluoro(methoxy)methyl] -6- [5-fluoro-6-(2,2,2-trifluoro- 1 , 1 -dimethyl- ethoxy)-3-pyridyl]-[l,2,4]triazolo[4,3-a]pyridine

[0290] Synthesis of A15-a : A mixture of 6-bromo-3-[chloro(difluoro)methyl]-[l,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 sat. NH4CI (50 mL), then the mixture was extracted with EtOAc (50 mL x 2). The organic layer was washed with brine (50 mL), dried over Na2S04, 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 pmol, 21% yield) as an oil. LCMS Rt= 1.41 min in 1.5 min chromatography, 5- 95 AB, MS ESI calcd. CgHgBrF NgO [M+H+2]+280.0, found 279.9.

[0291] Synthesis of Compound 24: A mixture of 6-bromo-3- [difluoro(methoxy)methyl]-[l,2,4]triazolo[4,3-a]pyridine (70 mg, 250 m mol ), 3-fluoro-5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoro-l,l-dimethyl- ethoxy)pyridine(l05.47 mg, 300 pmol), K2CO3(69.59 mg, 500 pmol) and Pd(dppf)Cl2(27.63 mg, 40 pmol) in l,4-Dioxane (5 mL) and Water (0.50 mL) was stirred at 80 °C for 12 hours under N2. After cooling to room temperature, the mixture was diluted with H20 (20 mL), and the mixture was extracted with EtOAc (20 mL x 2). The combined organic phase was washed with water (30 mL) and brine (30 mL), dried over Na2S04, filtered and concentrated to give the crude product. The crude product was purified by Prep-HPLC (Boston Prime C18 (150 x 30 mm, 5 pm), A = 1¾0 (0.05% NH4OH) and B = CH3CN; 56- 86% B over 8 minutes) to give the product (22.72 mg, 54.1 pmol, 21% yield) as a solid. 'H NMR (DMSO-d6, 400MHz) dH= 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 Rt= 1.31 min in 2.0 minchromatography, 10-80AB, MS ESI calcd.€ΐ 7Hi4H4N402[M+H]+421.1, found 421.1.Example 24: 3-[cyclopropylmethoxy(difluoro)methyl]-6-[5-fluoro-6-[(lR)-2,2,2- trifluoro-l-methyl-ethoxy]-3-pyridyl]-[l,2,4]triazolo[4,3-a]pyridine

[0292] A mixture of 3-fluoro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2- [(lR)-2,2,2-trifluoro-l-methyl-ethoxy]pyridine (69.52 mg, 0.21 mmol), Pd(dppf)Cl2 (20.7 mg, 0.03 mmol), 6-bromo-3-[cyclopropylmethoxy(difluoro)methyl]-[l,2,4]triazolo[4,3- a] pyridine (60 mg, 0.19 mmol) and K2CO3 (52.14 mg, 0.38 mmol) in l,4-Dioxane (5 mL) and Water (1 mL) was stirred at 90 °C for 16 hours under N2. After cooling to room temperature, the mixture was filtered through Celite, and eluted with EtOAc (10 mL x 2), and the filtrate was concentrated to give the crude product. The crude product was purified by Prep-HPLC (Boston Prime C18 150 mm x 30 mm 5 pm) A = H2O (0.05% ammonia hydroxide v / v) and B = CH3CN; 60 - 90% B over 8 minutes) to give the product (51.82 mg, O. l2mmol, 62% yield) as a solid. 'H NMR (DMSO-CL, 400MHZ) dH= 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 Rt= 1.39 min in 2.0 min chromatography, 10-80ABMS ESI calcd. for C19H17F6N4O2 [M+H]+447.1, found 447.1.Example 25: 3-[ethoxy(difluoro)methyl]-6-[5-fluoro-6-[(lR)-2,2,2-trifluoro-l-methyl- ethoxy]-3-pyridyl]-[l,2,4]triazolo[4,3-a]pyrazine

[0293] A mixture of 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[(lR)-2,2,2-trifluoro-l- methyl-ethoxy]-3-pyridyl]-[l,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 then EtOAc (20 mL) and brine (50 mL) were added to the mixture, the resulting suspension was filtered through Celite. The filtrate was separated and the aqueous phase was extracted with EtOAc (50 mL). The combinedorganic phase was dried over anhydrous Na SCp, filtered and concentrated to give the crude product. The crude product was purified by chromatography flash on silica gel (EtOAc in PE = 10% to 30 % to 50%) and then triturated from DCM (3 mL) and n-hexane (4 mL) to give the product (31.35 mg, 74 pmol, 6% yield) as a solid. 'H NMR (CDCI3, 400MHz) dp = 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 Rt= 1.35 min in 2 min chromatography, 10-80AB, MS ESI calcd. forCi6H14F6N502 [M+H]+422.1, found 422.1.Example 26: 6-[5-fluoro-6-(2,2,2-trifluoro-l,l-dimethyl-ethoxy)-3-pyridyl]-3- (methoxymethyl)-[l,2,4]triazolo[4,3-b]pyridazine

[0294] A mixture of 6-chloro-3-(methoxymethyl)-[l,2,4]triazolo[4,3-b]pyridazine (100 mg, 0.5 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2-(2,2,2- trifluoro- 1,1 -dimethyl-ethoxy )pyridine (210.94 mg, 0.6 mmol), K3PO4 (213.79 mg, 1.01 mmol), Pd(7-Bu iP) (38.6 mg, 0.08 mmol) in l,4-Dioxane (5 mL) and Water (0.5 mL) was stirred at 80 °C for 16 hours under N2. After cooling to room temperature, the mixmre was diluted with 1¾0 (10 mL), and the mixture was extracted with EtOAc (20 mL x 2). The combined organic phase was washed with water (10 mL) and brine (10 mL), dried over Na SCb, filtered and concentrated to give the crude product. The crude product was purified by Prep-HPLC (Boston Prime C18 (150 mm x 30 mm, 5 pm; mobile phase: [water (0.05% NHtOPQ-ACN]; B%: 40-70%, 9 min) to give the product (47.66 mg, 0.12 mmol, 25% yield) as a solid. 'H NMR (CDCI3, 400MHz) dH= 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 Rt= 1.21 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. for C i^H ifTdNiO [M +H]+386.1, found 386.0.Example 27: 6-[5-fluoro-6-(2,2,2-trifluoro-l,l-dimethyl-ethoxy)-3-pyridyl]-3- (methoxymethyl)-[l,2,4]triazolo[4,3-a]pyridine

[0295] 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 min, 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) the yield the product (3.0 g, 10.01 mmol, 22 % yield) as a solid. 'H NMR (MCOD-C / 4,400MHz) d = 9.15 (s, 1H), 8.19 - 8.32 (m, 1H), 8.11 - 7.96 (m, 1H), 5.09 (s, 2H), 3.49 (s, 3H).

[0296] Synthesis of Compound 28: A mixture of 6-bromo-3-(methoxymethyl)- [l,2,4]triazolo[4,3-a]pyridine (150 mg, 0.62 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-2-(2,2,2-trifluoro-l,l-dimethyl-ethoxy)pyridine (259.61 mg, 0.74 mmol), K2CO3 (171.29 mg, 1.24 mmol), Pd(dppf)Cl2 (68.01 mg, 0.09 mmol) in mixed solvents 1,4- Dioxane (15 mL) and Water (3 mL) was heated at 85°C for 16 hours. After cooling to room temperature, the reaction was concentrated and diluted with H2O (20 mL), then extracted with DCM (20 mL x 2). The combined organic phase was washed with brine (30 mL), dried over Na2S04, filtered and concentrated to give the crude product. The crude product was purified using Prep-HPLC (YMC- Actus Triart C18 (100 mm x 30 mm, 5 pm) A = H2O (0.05% HC1) and B = CH3CN; 50-75 % B over 8 minutes) yielding the product inCH3CN / H2O (~ 150 mL). The solution was concentrated to remove most of the CH3CN, basified with NaHCCL (solid) to pH~9, then extracted with DCM (50 mL x 3). The combined organic phase was concentrated yielding the product (121.16 mg, 0.32 mmol, 51% yield) as a solid. ' H NMR (CDCl3, 400MHz) d = 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 Rt= 1.25 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. for C17H17F4N4O2 [M+H]+385.1, found 384.9.Example 28: 6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-3-(methoxymethyl)- [l,2,4]triazolo[4,3-a]pyridine

[0297] A mixture of 6-bromo-3-(methoxymethyl)-[l,2,4]triazolo[4,3-a]pyridine (150 mg, 0.62 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2-(2,2,2- trifluoroethoxy)pyridine (238.75 mg, 0.74 mmol), K2CO3 (171.29 mg, 1.24 mmol),Pd(dppf)Cl2 (68.01 mg, 0.09 mmol) in mixed solvents l,4-Dioxane (15 mL) and Water (3 mL) was stirred at 85 °C for 16 hours. After cooling to room temperature, the reaction was concentrated and diluted with H2O (20 mL), then extracted with DCM (20 mL x 2). The combined organic phase was washed with brine (30 mL), dried over Na2S04, filtered and concentrated to give the crude product. The crude product was purified by Prep-HPLC ((Boston Prime C18 (l50mm x 30 mm, 5pm) A = H2O (0.05% NH4OH) and B = CH3CN; 40-70 % B over 8 minutes) to give the product (141.29 mg, 0.39 mmol, 64% yield) as a solid. 1H NMR (CDCI3, 400MHz) d = 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 Rt= 1.17 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. for C 13H 13F4N4O2 [M+H]+357.1, found 356.9.Example 29: 3-[difluoro(methoxy)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3- pyridyl]-[l,2,4]triazolo[4,3-a]pyridine

[0298] A mixture of 6-bromo-3-[difluoro(methoxy)methyl]-[l,2,4]triazolo[4,3- a] pyridine (70 mg, 250 m mol ), 3-fluoro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2- (2,2,2-trifluoroethoxy)pyridine (97 mg, 300 p mol), K2CO3 (69.59 mg, 0.50 mmol) and Pd(dppf)Cl2 (27.63mg, 0.04 mmol) in l,4-Dioxane (5mL) and Water (0.50 mL) was stirred at 80 °C for 12 hours under N2. After cooling to room temperature, the mixture was dilutedwith H2O (10 mL), and the mixture was extracted with EtOAc (20 mL x 2). The combined organic phase was washed with water (10 mL) and brine (10 mL), dried over Na2S04, filtered and concentrated to give the crude product. The crude product was first purified by Prep- HPLC (Boston Prime C18 (150 mm x 30 mm, 5 pm), A = ¾0 (0.05% NPLOH) and B = CH3CN; 43-73% B over 8 minutes), then followed by Prep-HPLC (Boston Green ODS (150 mm x 30 mm, 5 pm), A = ¾0 (0.075% TFA) and B = CH3CN; 49-63% B over 10 minutes). The combined fractions were concentrated to remove ACN, and basified with sat. NaHCCL to pH~8, and the mixture was extracted with EtOAc (30 mL x 2). The combined organic phase was washed with brine (40 mL), dried over Na2S04, filtered and concentrated to give the product (41.36 mg, 105.4 pmol, 42% yield) as a solid. 'H NMR (DMSO-CL, 400MHZ) 5H= 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 Rt= 1.19 min in 2.0 min chromatography, 10-80AB, MS ESI calcd.C15H„F6N402 [M+H]+393.1, found 393.0.Example 30: 6-[5-fluoro-6-[(lR)-2,2,2-trifluoro-l-methyl-ethoxy]-3-pyridyl]-3- (methoxymethyl)-[l,2,4]triazolo[4,3-a]pyrazine

[0299] A mixture of 6-chloro-3-(methoxymethyl)-[l,2,4]triazolo[4,3-a]pyrazine (70 mg, 0.35 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2-[(lR)-2,2,2- trifluoro-l-methyl-ethoxy]pyridine (141.73 mg, 0.42 mmol), CS2CO3 (229.66 mg, 0.70 mmol), Pd(dppf)Cl2 (38.68 mg, 0.05 mmol) in l,4-Dioxane (5 mL) and Water (0.50 mL) was stirred at 70 °C for 5 hours under N2. After cooling to room temperature, the mixmre was diluted with H2O (20 mL) and extracted with EtOAc(30 mL x 2). The combined organic phase was washed with water (30 mL) and brine (30 mL), dried over Na2S04, filtered and concentrated to give the crude product. The crude product was first purified by Prep-TLC (silica gel, PE : EtOAc = 1 : 1). The resulting product was further purified by Prep-HPLC (Boston Prime C18 (150 mm x 30 mm, 5 pm), A = H2O (0.05% NH4OH) and B = CH3CN; 38-68% B over 9 minutes), to give the product (4.43 mg, 11.9 pmol, 3% yield) as a solid. 'HNMR (CDCI3, 400MHz) dH= 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 Rt= 1.18 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. C13H14F4N3O2 [M+H]+372.1, found 371.9.Example 31: 3-[ethoxy(difluoro)methyl]-6-[5-fluoro-6-[(lS)-2,2,2-trifluoro-l-methyl- ethoxy]-3-pyridyl]-[l,2,4]triazolo[4,3-a]pyridine

[0300] A mixture of 6-bromo-3-[ethoxy(difluoro)methyl]-[l,2,4]triazolo[4,3- a] pyridine (100 mg, 0.34 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2- [(lS)-2,2,2-trifluoro-l-methyl-ethoxy]pyridine (137.67 mg, 0.41 mmol), K2CO3 (94.64 mg, 0.68 mmol) and Pd(dppf)Cl2 (37.58 mg, 0.05 mmol) in l,4-Dioxane (5 mL) and Water (0.50 mL) was stirred at 80 °C for 12 hours under N2. After cooling to room temperature, the mixture was diluted with H20 (10 mL), and extracted with EtOAc (20 mL x 2). The combined organic phase was washed with water (10 mL) and brine (10 mL), dried over Na2S04, filtered and concentrated to give the crude product. The crude product was purified by Prep-HPLC (Boston Prime C18 (150 mm x 30 mm, 5um), A = ¾0 (0.05% NH4OH) and B = CH3CN; 60-90% B over 9 minutes) to give the product (39.75 mg, 93.5 pmol, 27% yield) as a solid.lH NMR (DMSO-<¾, 400MHz) dH= 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 Rt= 1.28 min in 2.0 min chromatography, 10-80ABMS ESI calcd. C17H15L6N4O2 [M+H]+421.1, found 421.0.Example 32: 3-[ethoxy(difluoro)methyl]-6-[5-fluoro-6-[(lS)-2,2,2-trifluoro-l-methyl- ethoxy]-3-pyridyl]-[l,2,4]triazolo[4,3-a]pyrazine

[0301] A mixture of 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[(lS)-2,2,2-trifluoro-l- methyl-ethoxy]-3-pyridyl]-[l,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 filtrate was separated and the aqueous layer was extracted with EtOAc (50 mL). The combined organic phase was 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 = 10% to 30 % to 50%) and then triturated from n-hexane (5 mL) to give the product (41.27 mg, 98.0 pmol,20% yield) as a solid. 'H NMR (CDCl3, 400MHz) dH= 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, = 1.29 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. for C16H14F6N5O2 [M+H]+422.1, found 422.0.Example 33: 3-[ethoxy(difluoro)methyl]-6-[5-fluoro-6-[(lR)-2,2,2-trifluoro-l-methyl- ethoxy]-3-pyridyl]-[l,2,4]triazolo[4,3-a]pyridine

[0302] A mixture of 3-fluoro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2- [(lR)-2,2,2-trifluoro-l-methyl-ethoxy]pyridine (126.2 mg, 0.38 mmol), Pd(dppf)Cl2 (37.58 mg, 0.05 mmol), 6-bromo-3-[ethoxy(difluoro)methyl]-[l,2,4]triazolo[4,3-a]pyridine (100 mg, 0.34 mmol) and K2CO3 (94.64 mg, 0.68 mmol) in l,4-Dioxane (5 mL) and Water (1 mL) was stirred at 90 °C for 16 hours under N2. After cooling to room temperature, the mixture was filtered through Celite, and eluted with EtOAc (10 mL x 2), and the filtrate was concentratedto give the crude product. The crude product was purified by Prep-HPLC (Boston Prime C18 (150 mm x 30 mm, 5 pm) A = H20 (0.05%NH40H) and B = CH3CN; 45 - 75% B over 9 minutes) to give the product (62.87 mg, 0.15 mmol, 43% yield) as a solid. 'H NMR(DMSO-de, 400MHz) dH= 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 Rt= 1.26 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. for CnHisFeNtCh [M+H]+421.1, found 421.0.Example 34: 6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-3-(methoxymethyl)- [l,2,4]triazolo[4,3-b]pyridazine

[0303] A mixture of 6-chloro-3-(methoxymethyl)-[l,2,4]triazolo[4,3-b]pyridazine (100 mg, 0.50 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2-(2,2,2- trifluoroethoxy)pyridine (194 mg, 0.60 mmol), K3PO4(213.79 mg, 1.01 mmol) and Pd( t- BU3P)2(38.6 mg, 0.08 mmol) in l,4-Dioxane (10 mL) and Water (1 mL) was stirred at 80 °C under N2for 3 hours. After cooling to room temperature, water (20 mL) and EtOAc (20 mL) were added to the mixture and the mixture was filtered through Celite. After separating, the organic phase was washed with brine (20 mL), dried over anhydrous Na2S04,filtered and concentrated to give the crude product. The crude product was purified by Prep-HPLC (Boston Prime C18 (150 mm x 30 mm, 5 pm) A = H20 (0.05% NH4OH) and B = CH3CN; 33-63% B over 8 minutes) to give the product (49 mg, 137.2 pmol, 27% yield) as a solid. 'H NMR (CDCl3, 400MHz) dH= 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 Rt= 1.08 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. for CI4H12F4N502[M+H]+358.1, found 357.9.Example 35: 3-[cyclopropoxy(difluoro)methyl]-6-[5-fluoro-6-[(lR)-2,2,2-trifluoro-l- methyl-ethoxy]-3-pyridyl]-[l,2,4]triazolo[4,3-a]pyridine

[0304] A mixture of 3-fluoro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2- [(lR)-2,2,2-trifluoro-l-methyl-ethoxy]pyridine (121.22 mg, 0.36 mmol), Pd(dppf)Cl2 (36.09 mg, 0.05 mmol), 6-bromo-3-[cyclopropoxy(difluoro)methyl]-[l,2,4]triazolo[4,3-a]pyridine (100 mg, 0.33 mmol) and K2CO3 (90.9 mg, 0.66 mmol) in l,4-Dioxane (5 mL) and water (1 mL) was stirred at 90 °C for 16 hours under N2. After cooling to room temperature, the mixture was filtered through Celite, and eluted with EtOAc (10 mL x 2), and the filtrate was concentrated to give the crude product. The crude product was purified by Prep-HPLC (Boston Prime C18 (150 mm x 30 mm, 5 pm) A = 1¾0 (0.05%N¾OH) and B = CH3CN; 47 - 77% B over 9 minutes) to give the product (54.98 mg, 0.13 mmol, 39% yield) as a solid. 'H NMR (DMSO-de, 400MHz) dH= 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 Rt= 1.33 min in 2.0 min chromatography, 10-80ABMS ESI calcd. for Ci8H15F6N402 [M+H]+433.1, found 433.1.Example 36: 3-[cyclopropoxy(difluoro)methyl]-6-[5-fluoro-6-[(lS)-2,2,2-trifluoro-l- methyl-ethoxy]-3-pyridyl]-[l,2,4]triazolo[4,3-a]pyridine

[0305] Synthesis of A36: To a mixture of cyclopropanol (246.74 mg, 4.25 mmol), 6- bromo-3-[chloro(difluoro)methyl]-[l,2,4]triazolo[4,3-a]pyridine(600 mg, 2.12 mmol) in DMF (lOmL) was added potassium tert-butoxide (476.69 mg, 4.25 mmol). The reaction mixture was stirred at 20 °C for 2 hours. The reaction was quenched with sat. NH4CI (40 mL), then the mixture was extracted with EtOAc (50 mL x 2). The combined organic phase was washed with water (80 mL) and brine (80 mL), dried over Na SCL, filtered andconcentrated to give the crude product. The crude product was purified by flashchromatography 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 Rt= 3.74 min in 7.0 min chromatography, 0- 60ABMS ESI calcd. oIEBrF NsO [M+H+2]+306.0, found 305.8.

[0306] Synthesis of Compound 37: A mixture of 6-bromo-3- [cyclopropoxy(difluoro)methyl]-[l,2,4]triazolo[4,3-a]pyridine (100 mg, 0.33 mmol), 3- fluoro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2-[(lS)-2,2,2-trifluoro-l-methyl- cthoxy Ipyndinc (132.24 mg, 0.39 mmol), K2CO3 (90.9 mg, 0.66 mmol) and Pd(dppf)Cl2 (36.09 mg, 0.05 mmol) in l,4-Dioxane (5 mL) and water (0.50 mL) was stirred at 80 °C for12 hours under N2. After cooling to room temperature, the mixture was diluted with H2O (10 mL), and the mixture was extracted with EtOAc (20 mL x 2). The combined organic phase was washed with water (10 mL) and brine (10 mL), dried over Na2S04, filtered and concentrated to give the crude product. The crude product was purified by Prep-HPLC (Boston Prime C18 (150 mm x 30 mm, 5 pm), A = ]¾0 (0.05% NH4OH) and B = CH3CN; 50-70% B over 9 minutes) to give the product (35.99 mg, 83.2 pmol, 25% yield) as a solid. 1H NMR (DMSO-de, 400MHz) dH= 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 Rt= 1.29 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. Ci8H15F6N402 [M+H]+433.1, found 433.0.Example 37: 6-[5-fluoro-6-[(lS)-2,2,2-trifluoro-l-methyl-ethoxy]-3-pyridyl]-3- (methoxymethyl)-[l,2,4]triazolo[4,3-a]pyrazine

[0307] Synthesis of A37: To a mixture of l,l,2-trimethoxyethane (1.25 g, 10.38 mmol) and (5-chloropyrazin-2-yl)hydrazine (1 g, 6.92 mmol) in Ethanol (20 mL) was added 12N F1C1 (1.73 mL, 20.75 mmol), then the mixture was stirred at 20 °C for 20 hours. To the mixture was added water (20 mL), then basified with Na CCP (solid) to pFl~ 9 and extracted wtih EtOAc (50 mL x 4). The combined organic phase was washed with brine (30 mL), dried over Na2S04, filtered and concentrated to give the crude product. The crude product was triturated from EtOAc / PE (2 / 10 mL) and dried in oven, yielding 5-chloro- / V-(2- methoxyethylideneamino)pyrazin-2-amine (1050 mg, 3.73 mmol, 54% yield) as a solid. LCMS Rt= 0.70 min in 1.5 min chromatography, 5-95 AB, MS ESI calcd. for C7FL0CIN4O [M+H]+201.0, found 201.0.

[0308] Synthesis of A38: To a mixture of 5-chloro- / V-(2- methoxyethylideneamino)pyrazin-2-amine (1 g, 4.98 mmol) in DMF (10 mL) was added a soution of NBS (1.24 g, 6.98 mmol) in DMF (7 mL) dropwise over 0.5 hour, then the mixture was stirred at 20 °C for 1 hour. The mixture was diluted with fLO (50 mL) and extracted with EtOAc (50 mL x 4). The combined organic phase was washed with brine (50 mL), dried over Na2S04,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 Rt= 0.80 min in 1.5 min chromatography, 5-95AB, MS ESI calcd. for C FlgBrClNtC) [M+Fl+2]+281.0, found 280.9.

[0309] Synthesis of A34: To a mixture of / V-(5-chloropyrazin-2-yl)-2-methoxy- ethanehydrazonoyl bromide (1 g, 3.58 mmol) in Toluene (15 mL) was added Lt¾N (0.99 mL, 7.16 mmol), then the mixture was stirred at 20 °C for 1 hour. The mixture was diluted with H20 (30 mL), and extracted with EtOAc (50 mL x 2). The combined organic phase was washed with water (20 mL x 2) and brine (20 mL), dried over Na2S04,filtered and concentrated to give the crude product. The crude product was purified by flashchromatography 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. 'H NMR (CDCI3, 400MFlz) 5H= 9.21 (d, 1H), 8.28 (d, 1H), 5.07 (s, 2F1), 3.45 (s, 3H). LCMS Rt= 0.30 min in 1.5 min chromatography, 5- 95 AB, MS ESI calcd. for C7H8ClN40 [M+H]+199.0, found 199.0.

[0310] Synthesis of Compound 38: A mixture of 6-chloro-3-(methoxymethyl)- [l,2,4]triazolo[4,3-a]pyrazine (70 mg, 0.35 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-2-[(lS)-2,2,2-trifluoro-l-methyl-ethoxy]pyridine (177.16 mg, 0.53 mmol), Pd(dppf)Cl2 (64.47 mg, 88.1 pmol) and CS2CO3 (229.66 mg, 0.70 mmol) in 1,4- Dioxane (8 mL) and Water (0.80 mL) was stirred at 75 °C for 12 hours under N2. After cooling to room temperature, the mixture was diluted with H2O (30 mL), and the mixture was extracted with EtOAc (50 mL x 2). The combined organic phase was washed with water (20 mL x 2) and brine (20 mL), dried over Na2S04, filtered and concentrated to give the crude product. The crude product was first purified by Prep-TLC (silica gel, PE : EtOAc = 1: 1), followed by prep-HPLC [Boston Prime C18 (150 mm x 30 mm, 5 pm) A = H20 (0.05% NH4OH) and B = CH3CN; 38-68 % B over 9 minutes], to give the product (12.63 mg, 34.0 pmol, 10% yield) as a solid. 'H NMR (CDCL, 400MHz) dH= 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 Rt= 1.17 min in 2.0 min chromatography, 10-80ABMS ESI calcd. for Ci5H14F4Ns02 [M+H]+372.1, found 371.9.Example 38: 6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-3-(methoxymethyl)- [l,2,4]triazolo[4,3-a]pyrazine

[0311] A mixture of 6-chloro-3-(methoxymethyl)-[l,2,4]triazolo[4,3-a]pyrazine (70 mg, 0.35 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2-(2,2,2- trifluoroethoxy)pyridine (169.75 mg, 0.53 mmol), Pd(dppf)Cl2 (64.47mg, 88.1 pmol) and CS2CO3 (229.66 mg, 0.70 mmol) in l,4-Dioxane (8 mL) and water (0.80 mL) was stirred at 75 °C for 12 hours under N2. After cooling to room temperature, the mixture was diluted with H2O (20 mL), and the mixture was extracted with EtOAc (30 mL x 2). The combined organic phase was washed with water (20 mL) and brine (20 mL), dried over Na2S04, filtered and concentrated to give the crude product. The crude product was purified by Prep-TLC (silica gel, PE:EtOAc = 1: 1) to give the product (14.65 mg, 40.7 pmol, 12% yield) as a solid.1H NMR (CDCI3, 400MHz) dH= 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 Rt= 1.19 min in 2.0 min chromatography, 10- 80ABMS ESI calcd. for C14H12F4N5Q2 [M+H]+358. l, found 357.9.Example 39: 6-[5-fluoro-6-[(lR)-2,2,2-trifluoro-l-methyl-ethoxy]-3-pyridyl]-3- (methoxymethyl)-[l,2,4]triazolo[4,3-a]pyridine

[0312] A mixture of 6-bromo-3-(methoxymethyl)-[l,2,4]triazolo[4,3-a]pyridine (200 mg, 0.83 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2-[(lR)-2,2,2- trifluoro-l-methyl-ethoxy]pyridine (332.23 mg, 0.99 mmol), K2CO3 (228.38 mg, 1.65 mmol), Pd(dppf)Cl2 (90.68 mg, 0.12 mmol) in l,4-dioxane (15 mL) and Water (5 mL) 85 °C for 16 hours. After cooling to room temperature, the reaction was concentrated and diluted with H2O (20 mL), then extracted with DCM (20 mL x 2). The combined organic phase was washed with brine (30 mL), dried over Na2S04, filtered and concentrated to give the crude product. The crude product was purified using Prep-HPLC (Boston Prime C18 (150 mm x 30 mm 5pm) A = H2O (0.05% NH4OH) and B = CH3CN; 35-65 % B over 9 minutes) to give the product (104.44 mg, 0.28 mmol, 34% yield) as a solid. 'H NMR (DMSO-CL, 400 MHz) 5H= 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 Rt= 1.150 min in 2.0 min chromatography, 10-80AB, MS ESI calcd.[M+H]+371.1, found 371.1.Example 40: 3-[ethoxy(difluoro)methyl]-6-[5-fluoro-6-[(lS)-2,2,2-trifluoro-l-methyl- ethoxy]-3-pyridyl]-[l,2,4]triazolo[4,3-b]pyridazine

[0313] A mixture of 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[(lS)-2,2,2-trifluoro-l- methyl-ethoxy]-3-pyridyl]-[l,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 stirred at 90 °C for 9 days. After cooling to room temperature, the reaction was diluted with EtOAc (60 mL), and the mixture was added with brine (20 mL). The mixture was filtered through Celite and extracted with EtOAc (50 mL x 2). The combined organic layer was washed with water (50 mL) and brine (50 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 70. The iproduct was then triturated from n-Hexane (1 mL) and i- Pr20 (1 mL), to give the product (28.86 mg, 67.3 pmol, 9% yield) as a solid. 'H NMR (CDCI3, 400MHz) 5H= 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 Rt= 1.27 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. Oi6H14E6N5q2 [M+H]+422.1, found 422.0.Example 41: 3-[ethoxy(difluoro)methyl]-6-[5-fluoro-6-[(lR)-2,2,2-trifluoro-l-methyl- ethoxy]-3-pyridyl]-[l,2,4]triazolo[4,3-b]pyridazine

[0314] Synthesis of A26-a : A mixture of 3-fluoro-5-(4, 4,5, 5-tetramethyl- 1,3,2- dioxaborolan-2-yl)-2-[(lR)-2,2,2-trifluoro-l-methyl-ethoxy]pyridine (1.54 g, 4.6 mmol), 6- chloro-3-[chloro(difluoro)methyl]-[l,2,4]triazolo[4,3-b]pyridazine (1 g, 4.18 mmol), Pd (7-B¾R)2 (320.73 mg, 0.63 mmol) and K3PO4 (1.78 g, 8.37 mmol) in l,4-Dioxane (20 mL) and water (4 mL) was stirred at 80 °C for 16 hours under N2. After cooling to room temperature, the mixture was filtered through Celite, and eluted with EtOAc (20 mL x 2), and the filtrate was concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 30% to 60%) to give the product (1000 mg, 2.12 mmol, 51% yield) as a solid. LCMS Rt= 0.93 min in 1.5 min chromatography, 5- 95 AB, MS ESI calcd. for Ci4H9ClF6N50 [M+H]+412.0, found 412.1.

[0315] Synthesis of Compound 42: A mixture of 3-[chloro(difluoro)methyl]-6-[5- fluoro-6-[(lR)-2,2,2-trifluoro-l-methyl-ethoxy]-3-pyridyl]-[l,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 CH3CN (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 added to saturated NaCl (40 mL), the mixture was filtered through Celite, and eluted with EtOAc (20 mL x 2), and the filtrate was concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 50% to 100%). The product was further purified by Prep-HPLC (Boston Prime C18 (150 mm x 30 mm 5 pm) A = H2O (0.05% NH4OH v / v) and B = CH3CN; 51 - 81% B over 9 minutes), to give the product (8.12 mg,19.3 pmol, 3% yield) as a solid.lH NMR (CDCl3, 400MHz) dH= 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 Rt= 1.29 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. forC16H14F6N502 [M+H]+422.1, found 422.0.Example 42: 6-[5-fluoro-6-[(lS)-2,2,2-trifluoro-l-methyl-ethoxy]-3-pyridyl]-3- (methoxymethyl)-[l,2,4]triazolo[4,3-a]pyridine

[0316] A mixture of 6-bromo-3-(methoxymethyl)-[l,2,4]triazolo[4,3-a]pyridine (100 mg, 0.41 mmol), Pd(dppf)Cl2 (45.34 mg, 0.06 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-2-[(lS)-2,2,2-trifluoro-l-methyl-ethoxy]pyridine (166.12 mg, 0.50 mmol) and K2CO3 (114.19 mg, 0.83 mmol) in l,4-Dioxane (5 mL) and water (1 mL) was stirred at 80 °C for 16 hours under N2. After cooling to room temperature, the mixture was filtered through Celite, and eluted with EtOAc (10 mL x 2), and the filtrate was concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 50% to 100%). The product was then triturated from u-hexane / DCM (5: 1,10 mL) to give the product (46.5 mg, 0.13 mmol, 30% yield) as a solid. 'H NMR (DMSO- <k, 400MHz) dH= 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 Rt= 1.13 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. for C16H15F4N4O2 [M+H]+371.1, found 370.9.Example 43: 6-[5-fluoro-6-[(lS)-2,2,2-trifluoro-l-methyl-ethoxy]-3-pyridyl]-3- (methoxymethyl)-[l,2,4]triazolo[4,3-b]pyridazine

[0317] A mixture of 6-chloro-3-(methoxymethyl)-[l,2,4]triazolo[4,3-b]pyridazine (100 mg, 0.50 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2-[(lS)-2,2,2- trifluoro-l-methyl-ethoxy]pyridine (202.47 mg, 0.60 mmol), K3PO4 (213.79 mg, 1.01 mmol) and Pd(t-Bu iP) (38.6 mg, 0.08 mmol) in l,4-Dioxane (10 mL) and water (1 mL) was stirred at 80 °C under N for 3 hours. After cooling to room temperature, water (20 mL) and EtOAc (20 mL) was added to the mixture and filtered through Celite. After separating, the organic phase was washed with brine (20 mL), dried over anhydrous Na SCL, filtered and concentrated to give the crude product. The crude product was purified by Prep-HPLC (Boston Prime C18 (150 mm x 30 mm, 5 pm) A = H2O (0.05% NH4OH) and B = CH3CN; 33-63 % B over 8 minutes) to give the product (38 mg, 102.3 pmol, 20% yield) as a solid. 'H NMR (CDCI3, 400MHz) dH= 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 Rt= 1.13 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. for C 13H 14F4N3CF [M+H]+372.1, found 371.9.Example 44: 3-[difluoro(isobutoxy)methyl]-6-[5-fluoro-6-[(lS)-2,2,2-trifluoro-l-methyl- ethoxy]-3-pyridyl]-[l,2,4]triazolo[4,3-a]pyrazine

[0318] A mixture of 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[(lS)-2,2,2-trifluoro-l- methyl-ethoxy]-3-pyridyl]-[l,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. The 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 phase was dried over anhydrous Na SCF, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 10% to 30 % to 50%) to give the product (80 mg) as an oil.

[0319] The impure product (80 mg, 0.18 mmol) was purified by Prep-HPLC (Boston Green ODS (150 mm x 30 mm, 5 pm) A = ]¾0 (0.075% TFA) and B = CH3CN; 66-96 % B over 8 minutes) and concentrated to give a residue. To the residue was added saturated aqueous NaHCC>3 (10 mL), and the mixture was extracted with EtOAc (15 mL x 2). The combined organic phase was washed with brine (20 mL), dried over anhydrous NibSCF, filtered and concentrated to give the product (55.97 mg, 124.6 pmol, 70% yield) as a solid. 1H NMR (CDCI3 + D20, 400MHz) dH= 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, = 1.37 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. for CisHixF^NiO [M+H]+450.1, found 450.0.Example 45: 6-[5-fluoro-6-[(lR)-2,2,2-trifluoro-l-methyl-ethoxy]-3-pyridyl]-3- (methoxymethyl)-[l,2,4]triazolo[4,3-b]pyridazine

[0320] 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 min, and refluxed at 120 °C for 24 hours. After cooling to room temperature, the mixture was diluted with fEO (40 mL) and extracted with EtOAc (40 mL x 2). The combined organic phase was washed with brine (40 mL), dried over Na2S04, filtered and concentrated to give the crude product. The crude product was triturated from / -Pr20 (10 mL), to give the product (1500 mg, 7.31 mmol, 35% yield) as a solid. LCMS Rt= 0.43 min in 1.5 min chromatography, 5-95AB, MS ESI calcd. for C7H8ClN40 [M+H]+198.0, found 199.0.

[0321] Synthesis of Compound 46: A mixture of 6-chloro-3-(methoxymethyl)- [l,2,4]triazolo[4,3-b]pyridazine (100 mg, 0.5 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-2-[(lR)-2,2,2-trifluoro-l-methyl-ethoxy]pyridine (202.47 mg, 0.6 mmol), K3PO4 (213.79 mg, 1.01 mmol), Pd(t-Bu3P)2(38.6 mg, 0.08 mmol) in l,4-Dioxane (5 mL) and water (0.5 mL) was stirred at 80 °C for 12 hours under N2. After cooling to room temperature, the mixture was diluted with fBO (10 mL) and extracted with EtOAc (20 mL x 2). The combined organic phase was washed with water (10 mL) and brine (10 mL), dried over Na SCp, filtered and concentrated to give the crude product. The crude product was purified by Prep-HPLC (column: Boston Prime (150 mm x 30 mm, 5 pm; mobile phase: A = H O (0.05% NH4OH); B = CH3CN, 35-65% B over 9 min) to give the product (43.29 mg, 0.12 mmol, 23% yield) as a solid.lH NMR (CDCl3, 400MHz) dH= 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, 3H), 1.61 (d, 3H). LCMS Rt= 1.17 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. for C15H34F4N5O2 [M +H]+372.1, found 372.1.Example 46: 3-[difluoro(isobutoxy)methyl]-6-[5-fluoro-6-[(lS)-2,2,2-trifluoro-l-methyl- ethoxy]-3-pyridyl]-[l,2,4]triazolo[4,3-b]pyridazine

[0322] A mixture of 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[(lS)-2,2,2-trifluoro-l- methyl-ethoxy]-3-pyridyl]-[l,2,4]triazolo[4,3-b]pyridazine (300 mg, 0.73 mmol) and AgOTf (1872.33 mg, 7.29 mmol) in 2-methylpropan-l-ol (10 mL, 0.73 mmol) and MeCN (lOmL) 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 x 2). The combined organic layer was washed with water (50 mL) and brine (50 mL), dried over Na2S04, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 70%) The isolated product was further purified by Prep-HPLC (Boston Prime Cl 8 (150 mm x 30 mm, 5 pm), A = H2O (0.05% NH4OH) and B = CH3CN; 60-90% B over 9 minutes) to give the product (7.42 mg, 16.5 pmol, 2% yield) as a solid. 'H NMR (CDCI3, 400MHz) 5H= 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 Rt= 1.39 min in 2.0 min chromatography, 10- 80AB, MS ESI calcd. gH gFeNsCL [M+H]+450.1, found 450.1.Example 47: 3-[ethoxy(difluoro)methyl]-6-[5-fluoro-6-[(lS)-2,2,2-trifluoro-l-methyl- ethoxy]-3-pyridyl]-[l,2,4]triazolo[4,3-b]pyridazine

[0323] A mixture of 6-chloro-3-(methoxymethyl)-[l,2,4]triazolo[4,3-a]pyrazine (150 mg, 0.76 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoro- l,l-dimethyl-ethoxy)pyridine (527.36 mg, 1.51 mmol), CS2CO3 (738.18 mg, 2.27 mmol), Pd(dppf)Cl2 (110.52 mg, 0.15 mmol) in l,4-Dioxane (8 mL) and water (0.80 mL) was stirred at 75 °C for 9 hours under N2. After cooling to room temperature, the mixture was dilutedwith H2O (20 mL), and the mixture was extracted with EtOAc (30 mL x 2). The combined organic phase was washed with water (30 mL x 1) and brine (30 mL), dried over Na2S04, filtered and concentrated to give the crude product. The crude product was purified by Prep- HPLC (Boston Prime C18 (150 mm x 30 mm, 5 pm), A = ¾0 (0.05% NH4OH) and B = CH3CN; 49-59% B over 9 minutes) to give the product (90.56 mg, 235 pmol, 31% yield) as a solid. NMR (CDCI3, 400MHz) dH= 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 Rt= 1.24 min in 2.0 min chromatography, 10- 80AB, MS ESI calcd. CI6H16F4N502 [M+H]+386.1 found 386.1Example 48: 3-[difluoro(isobutoxy)methyl]-6-[5-fluoro-6-[(lR)-2,2,2-trifluoro-l-methyl- ethoxy]-3-pyridyl]-[l,2,4]triazolo[4,3-b]pyridazine

[0324] A mixture of 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[(lR)-2,2,2-trifluoro-l- methyl-ethoxy]-3-pyridyl]-[l,2,4]triazolo[4,3-b]pyridazine (500 mg, 1.21 mmol) and AgOTf (3120.6 mg, 12.15 mmol) in 2-methylpropan-l-ol (10 mL, 1.21 mmol) and CH3CN (10 mL) was stirred at 90 °C for 8 days. After cooling to room temperature, the reaction was diluted with EtOAc (40 mL), and the mixture was added with brine (40 mL), the mixture was filtered through Celite, and eluted with EtOAc (20 mL x 2), and the filtrate was concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 50% to 100%) to give the impure product. The impure product was purified by Prep-HPLC (Waters Xbridge 150 mm x 25 mm, 5 pm) A = ¾0 (10 mMNH4HCO3) and B = CH3CN; 54 - 84% B over 8 minutes) to give the product (53.85 mg, 0.12 mmol, 10% yield) as a solid. 'H NMR (CDC13, 400MHz) dH= 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 Rt= 1.42 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. for C18H18F6N5O2 [M+H]+450.1, found 450.1.Example 49: 3-(ethoxymethyl)-6-[5-fluoro-6-[(lS)-2,2,2-trifluoro-l-methyl-ethoxy]-3- pyridyl]-[l,2,4]triazolo[4,3-a]pyrazine

[0325] Synthesis of A40: A mixture of [5-[5-fluoro-6-[(lS)-2,2,2-trifluoro-l-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 CH2CI2 (10 mL) was stirred at 25 °C for 16 hours. The mixture was concentrated to the residue, and the residue was re dissolved in EtOAc (20 mL), washed with water (10 mL x 2), brine (10 mL x 2), dried over anhydrous Na2S04, filtered and concentrated to give the product (150 mg, 0.13 mmol, 20% yield) as a solid. LCMS Rt= 0.84 min in 1.5 min chromatography, 5-95AB, MS ESI calcd. for CieH gLiNsOs [M+H]+404.1, found 404.2.

[0326] Synthesis of Compound 50: To a mixture of 2-ethoxy-N'-[5-[5-fluoro-6- [(lS)-2,2,2-trifluoro-l-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 yielding a solid. The solid was re-dissolved in EtOAc (20 mL), basified with sat. Na2C03 to pH ~ 9, washed with water (10 mL x 2), brine (10 mL x 2), dried over anhydrous Na2S04, filtered and concentrated to give the crude product. The crude product was purified by Prep-HPLC (Boston Prime C18 150 mm x 30 mm 5 pm) A = ¾0 (0.05% ammonia hydroxide) and B = CH3CN; 45 - 75% B over 9 minutes) to give the product (48.08 mg, 0.12 mmol, 34% yield) as a solid. 'H NMR(DMSO-de, 400MHz) dH= 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, = 1.23 min in 2.0min chromatography, 10-80AB, MS ESI calcd. for C14H14F4N3O2 [M+H]+386.1, found 386.0.Example 50: 3-[cyclopropoxy(difluoro)methyl]-6-[5-fluoro-6-[(lR)-2,2,2-trifluoro-l- methyl-ethoxy]-3-pyridyl]-[l,2,4]triazolo[4,3-a]pyrazine51A31

[0327] To a mixture of cyclopropanol (28.22 mg, 0.49 mmol), 3-[chloro(difluoro)methyl] -6- [5-fluoro-6- [( 1 R)-2, 2, 2-trifluoro- 1 -methyl-ethoxy] -3-pyridyl] - [l,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) dropwise. The reaction mixture was stirred at 20 °C for 2 hours. The reaction was quenched with saturated NH4CI (10 mL), and the mixture was extracted with EtOAc (10 mL x 2). The combined organic phase was washed with brine (10 mL), dried over Na SCL, filtered and concentrated to give the crude product. The crude product was purified by Prep-HPLC (Waters Xbridge (150 mm x 25 mm, 5 pm) A = H2O (10 mM NH4HCO3) and B = CH3CN; 57-67 % B over 8 minutes) to give the product (3.98 mg, 0.01 mmol, 4% yield) as an oil. H NMR (CD3CN, 400 MHz) 5H= 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 Rt= 1.31 min in 2 min chromatography, 10-80AB, MS ESI calcd. for CnH^FeNsCL [M+H]+434.1, found 433.9.Example 51: 3-(ethoxymethyl)-6-[5-fluoro-6-[(lR)-2,2,2-trifluoro-l-methyl-ethoxy]-3- pyridyl]-[l,2,4]triazolo[4,3-a]pyrazine

[0328] Synthesis of A41: To 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 then heated to 130 °C for 3 days. Then most of the toluene was removed, and Acetic acid (40 mL) was added and and stirred at 120 °C for 16 hours. After cooling to room temperature, the mixture was concentrated to give a residue. The residue was re-dissolved in EtOAc (40 mL), basified with saturated Na2C03 to pH ~ 9, washed with water (20 mL x 2), brine (20 mL x 2), dried over anhydrous Na2S04, filtered andconcentrated to give the crude product. The crude product was purified by flashchromatography on silica gel (EtOAc in PE = 40% to 70%), to give the product (240 mg, l. l lmmol, 32% yield) as a solid. LCMS Rt= 0.60 min in 1.5 min chromatography, 5-95AB, MS ESI calcd. for C8H10ClN4O [M+H]+213.0, found 213.0.

[0329] Synthesis of Compound 52: A mixture of 3-fluoro-5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-2-| ( 1 R)-2,2,2-tnfluoro- 1 -mcthyl-cthoxy Ipyriclinc (453.86 mg, 1.35 mmol), CS2CO3 (1103.16 mg, 3.39 mmol), 6-chloro-3-(ethoxymethyl)-[l,2,4]triazolo[4,3- a]pyrazine (240 mg, 1.13 mmol) and Pd(dppf)Cl2 (123.88 mg, 0.17 mmol) in l,4-Dioxane (10 mL) and water (2 mL) was stirred at 75 °C for 16 hours under N2. After cooling to room temperature, the mixture was filtered through Celite, and eluted with EtOAc (10 mL x 2), and the filtrate was concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 30% to 60% to 100%) to give the impure product. The impure product was purified by Prep-HPLC (Waters Xbridge 150 mm x 25 mm, 5 pm) A = H20 (10 mM NH4HCO3) and B = CH3CN; 40 - 70% B over 8 minutes) to give the product (37.8 mg, 98.1 pmol, 9% yield) as a solid. 'H NMR (DMSO-C / L,400MHz) dH= 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 Rt= 1.24 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. for CI6H16F4N502 [M+H]+386.1, found 386.1.Example 52: 3-[difluoro(methoxy)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3- pyridyl]-[l,2,4]triazolo[4,3-a]pyrazine

[0330] 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-l,3,2-dioxaborolan-2-yl)-2-(2,2,2- trifluoroethoxy)pyridine (4.98 g, 15.51 mmol), CS2CO3(10.11 g, 31.02 mmol) andPd(dppf)Cl2(1.7 g, 2.33 mmol) in l,4-Dioxane (50 mL) and water (5 mL) was stirred at 55 °C under N2for 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 then the mixture was filtered. After separatation, the organic phase was washed with brine (50 mL), dried over anhydrous Na2S04, filtered and concentrated to give the crude product. The crude product was purified by chromatography flash on silica gel (EtOAc in PE = 0% to 5% to10%) to give the product (3700 mg, 10.69 mmol, 69% yield) as a solid. 'H NMR (DMSO-CL, 400MHz) dH= 9.19 (d, 1H), 8.88 (d, 1H), 8.80 (d, 1H), 8.49 (dd, 1H), 5.18 (q, 2H). LCMS R, = 0.93 min in 1.5 min chromatography, 5-95AB, MS ESI calcd. for C11H7CIF4N3O [M+H]+308.0, found 308.0.

[0331] 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 x 2). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na2S04, filtered and concentrated to give the crude product (3500 mg, 9.60 mmol, 80% yield) as a solid. 'HNMR (DMSO-de, 400MHz) dH= 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 Rt= 0.73 min in 1.5 min chromatography, 5-95 AB, MS ESI calcd. for C11H10F4N5O [M+lH]+304.1, found 304.0.

[0332] 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-difluoro-acetate (7.21 g, 29.68 mmol) in Toluene (60 mL) was stirred at 110 °C for 96 hours, Then to the mixture was added molecular sieves (3 g), and the mixture was stirred at 130 °C for another 16 hours. After cooling to room temperature, the mixture was concentrated to give a residue. To the residue was added water (20 mL), extracted with EtOAc (30 mL x 2). The combined organic phase was washed with water (20 mL), brine (20 mL x 2), dried over anhydrous Na SCL, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography column 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 Rt= 2.63 min in 4 min chromatography, 10-80AB, MS ESI calcd. for C13H7CIF6N5O [M+H]+398.0, found 397.9.

[0333] Synthesis of Compound 53: A mixture of 3-[chloro(difluoro)methyl]-6-[5- fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-[l,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 filtrated. The filtrate was concentrated and diluted with water (20 mL), then extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (20 mL), dried over Na SCp and concentrated to give a 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. 'H NMR (CDCI3, 400MHz) dH= 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 Rt= 1.23 min in 1.5 min chromatography, 5-95AB, MS ESI calcd. for Ci4H10F6N5O2 [M+H]+394.1, found 394.0.Example 53: 3-[difluoro(methoxy)methyl]-6-[6-(2,2,2-trifluoro-l,l-dimethyl-ethoxy)-3- pyridyl]-[l,2,4]triazolo[4,3-a]pyrazine

[0334] A mixture of 3-[chloro(difluoro)methyl]-6-[6-(2,2,2-trifluoro-l,l-dimethyl- ethoxy)-3-pyridyl]-[l,2,4]triazolo[4,3-a]pyrazine (1.9 g, 4.66 mmol) and AgOTf (11.97 g, 46.59 mmol) in solvents DMF (15 mL) and methanol (15 mL) was stirred at 90 °C for 96 hours. After cooling to room temperature, the reaction mixture was treated with brine (50 mL), and the precipitate was filtrated. The filtrate was concentrated and diluted with water (40 mL), then extracted with EtOAc (50 mL x 2). The combined organic phase was washed with brine (50 mL), dried over Na2S04 and concentrated to give a crude product. The crude product was purified with flash chromatography on silica gel (EtOAc in PE = 0% to 40%) to give the product (170 mg). Another 88 mg of the product was obtained from other batch. Three batches of the product were combined and lyophilized to give the product (193.0 mg, 0.48 mmol) as a solid. 1H NMR (400MHz, CDCl3) d = 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, = 1.235 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. for C16H15F5N5O2 [M+F1]+404.1, found 403.9.Example 54 : 3- [chloro(difluoro)methyl] -6- [6- [1 - (trifluoromethyl)cyclobutoxy] -3- pyridyl]-[l,2,4]triazolo[4,3-a]pyrazine

[0335] Synthesis of A54: To a solution of l-(trifluoromethyl)cyclobutanol (5 g, 35.69 mmol) in THF (300 mL) was added NaH (1.86 g, 46.4 mmol) at 0 °C over 20 minutes, and the mixture was stirred at 0 °C for 30 mins. Then to the mixture was added 5-bromo-2- fluoro-pyridine (8.48 g, 48.18 mmol), and the mixture was stirred at 30 °C for 3 hours. The mixture was quenched with sat. NH4CI (50 mL), then the mixture was extracted with EtOAc (50 mL). The combined organic phase was washed with brine (50 mLx3), dried over Na SO^ filtered and concentrated to give the crude product (4.8 g, 15.49 mmol, 43% yield, ) as an oil. LCMS Rt= 0.99 min in 1.5 min chromatography, 5-95 AB, MS ESI calcd. for C 10H ioBi F¾NO [M+H]+295.9, found 296.0.

[0336] Synthesis of A55: A mixture of 5-bromo-2-[l-(trifluoromethyl)cyclobutoxy]pyridine (2.5 g, 8.44 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (3.22 g, 12.67 mmol), KOAc (1.66 g, 16.89 mmol) and Pd(dppf)Cl2 (432.48 mg, 0.59 mmol) in l,4-Dioxane (50 mL) was stirred at 90 °C for 12 hours under N2. After cooling to room temperature, the mixture was concentrated to give the residue. The residue was diluted with fLO (40 mL), and the mixture was extracted with EtOAc (40 mL x 2). The combined organic phase was washed with water (40 mL) and brine (40 mL), dried over Na SO^ filtered and concentrated to give the crudeproduct. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 1%) to give the crude product (2.65 g, 3.92 mmol, 46% yield) as an oil. 'H NMR (CDCI3, 400MHz) dH= 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).

[0337] Synthesis of A56: A mixture of 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-2-[l-(trifluoromethyl)cyclobutoxy]pyridine (2.1 g, 6.12 mmol), 2-bromo-5-chloro- pyrazine (1.18 g, 6.12 mmol), Pd(dppf)Cl2(671.68 mg, 0.92 mmol) and CS2CO3(3.99 g, 12.24 mmol) in l,4-Dioxane (20 mL) and Water (2 mL)was stirred at 60 °C for 6 hours under N2. After cooling to room temperature, the mixture was concentrated to give the residue. The residue was diluted with H2O (20 mL), and the mixture was extracted with EtOAc (20 mL x 2). The combined organic phase was washed with water (20 mL) and brine (40 mL), dried over Na2S04, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 1% to 10%) to give the product (1.5 g, 4.263mmol, 70% yield) as an oil. 'H NMR (CDCI3, 400MHz) 5H = 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).

[0338] Synthesis of A57: A mixture of 2-chloro-5-[6-[l-(trifluoromethyl)cyclobutoxy]-3-pyridyl]pyrazine (1.2 g, 3.64 mmol) and hydrazine (1.17 g, 36.4 mmol) in MeCN (20 mL) was heated to 90 °C and stirred for 16 hours. After cooling to room temperature, the reaction mixture was concentrated and diluted with ¾0 (30 mL) and extracted with EtOAc (30 mL x 2). The combined organic phase was washed with brine (30 mL), dried over Na2S04, filtered and concentrated to give crude product (950 mg, 2.48 mmol, 68% yield) as a solid. LCMS Rt= 0.99 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. for 0i4H15E3N50 [M +H]+326.1, found 326.0.

[0339] Synthesis of A58: A mixture of [5-[6-[l-(trifluoromethyl)cyclobutoxy]-3- pyridyl]pyrazin-2-yl]hydrazine (1.13 g, 3.47 mmol), 4A Molecular sieve (1 g, 3.47 mmol) and (2-chloro-2,2-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 hours. After cooling to room temperature, the reaction mixture was filtered and diluted with ¾0 (50 mL) and extractedwith EtOAc (50 mL x 2). The combined organic phase was washed with brine (50 mL), dried over Na S04,filtered and concentrated to give the crude product (820 mg, 1.13 mmol, 33% yield) as a solid.LCMS Rt= 1.38 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. forCieH ClFsNsO [M +H]+420.1, found 420.0.

[0340] Synthesis of Compound 57: A mixture of 3-[chloro(difluoro)methyl]-6-[6-[l- (trifluoromethyl)cyclobutoxy]-3-pyridyl]-[l,2,4]triazolo[4,3-a]pyrazine (600 mg, 1.43 mmol), AgOTf (4.4 g, 17. l5mmol) in DMF (6 mL) and methanol (6 mL, 1.43 mmol) was stirred at 90 °C forl6 hours. After cooling to room temperature , the reaction was quenched with sat. NaCl (30 mL) and extracted with EtOAc (30 mL x 2). The organic layer was washed with brine (30 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 40% to 70%) to give the product (194.76 mg, 0.47mmol, 33% yield) as a solid. 'H NMR (CDCI3, 400MHz) dH= 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 Rt= 1.33 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. forC17H15F5N5O2[M +H]+416.1, found 416.1.Example 56: 3-[difluoro(methoxy)methyl]-6-[5-fluoro-6-[(lS)-2,2,2-trifluoro-l-methyl- ethoxy]-3-pyridyl]-5-methyl-[l,2,4]triazolo[4,3-a]pyrazine

[0341] Synthesis of A59: A mixture of 2-bromo-5-chloro-3-methyl-pyrazine (900 mg, 4.34 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2-[(lS)-2,2,2- trifluoro-l-methyl-ethoxy]pyridine (1.31 g, 3.9 mmol), Pd(dppf)Cl2 (0.48 g, 0.65 mmol) and CS2CO3 (2.83 g, 8.68 mmol) in l,4-Dioxane (40 mL) and Water (8 mL) was stirred under N2at 50 °C for 5 hours. The mixture was cooled to room temperature, diluted with EtOAc (30 mL), filtered through silica gel and eluted with EtOAc (20 mL), and the filtrate was concentrated to give the crude product. The product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 3%) to give the product (1100 mg, 2.83 mmol, 65% yield) as a solid. LCMS Rt= 1.41 min in 1.5 min chromatography, 10-80AB, MS ESI calcd. for Ci3H„ClF4N30 [M+H]+336.0, found 336.0.

[0342] Synthesis of A60: A mixture of 5-chloro-2-[5-fluoro-6-[(lS)-2,2,2-trifluoro-l- methyl-ethoxy]-3-pyridyl]-3-methyl-pyrazine (1.1 g, 3.28 mmol) and hydrazine (1.05 g,32.83 mmol) in MeCN (20 mL) was heated to 90 °C and stirred for 16 hours. After cooling to room temperature, the reaction mixture was concentrated. The mixture was diluted with H20 (20 mL), extracted with EtOAc (20 mL x 2). The combined organic phase was washed with brine (20 mL), dried over Na SCL, filtered and concentrated to give the crude product. The crude product was triturated from PE (5 mL) to give the product (800 mg, 2.41 mmol, 68% yield) as a solid. The crude product was used into the next step without further purification. LCMS Rt= 0.75 min in 1.5 min chromatography, 5-95 AB, MS ESI calcd. for C13H14F4N5O [M+H]+332.1, found 332.1.

[0343] Synthesis of A61: To a mixture of [5-[5-fluoro-6-[(lS)-2,2,2-trifluoro-l- methyl-ethoxy]-3-pyridyl]-6-methyl-pyrazin-2-yl]hydrazine (500 mg, 1.51 mmol) in Toluene (10 mL) was added (2-chloro-2,2-difluoro-acetyl) 2-chloro-2,2-difluoro-acetate (366.68 mg, 1.51 mmol) and 4A Molecular Sieves (1 g). The reaction mixture was stirred at 110 °C for 5 days. After cooling to room temperature, the reaction mixture was concentrated. The residue was diluted with sat. NaHCCL (30 mL), and the mixture was extracted with EtOAc (30 mL x 2). The combined organic phase was washed with brine (20 mL), dried over Na SO^ filtered and concentrated to give a residue. The residue was purification 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 Rt= 0.92 min in 1.5 min chromatography, 5-95 AB, MS ESI calcd. forCi5H„ClF6N50 [M+H]+426.0, found 426.2.

[0344] Synthesis of Compound 58: A mixture of 3-[chloro(difluoro)methyl]-6-[5- fluoro-6-[(lS)-2,2,2-trifluoro-l-methyl-ethoxy]-3-pyridyl]-5-methyl-[l,2,4]triazolo[4,3- a]pyrazine (105 mg, 0.25 mmol) and AgOTf (633.7 mg, 2.47 mmol) in mixed solvent Methanol (1 mL) and DMF (1 mL) was stirred at 90 °C for 48 hours. After cooling to room temperature, the reaction mixture was treated with brine (15 mL), and the precipitate was filtered off. The filtrate was extracted with EtOAc (15 mL x 2). The combined organic phase was dried over Na SCL and concentrated to give a crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 30% to 50%).. The e product was then triturated from DCM (0.5 mL) and n-hexane (0.5 mL) to give the product (2.05 mg, 4.90 pmol, 2% yield). 1H NMR (CDCl3, 400MHz) dH= 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, = 1.24 min in 2 min chromatography, 10-80AB, MS ESI calcd. for C ^H[M+H]+422.1, found 422.0.Example 57: 3-[difluoro(methoxy)methyl]-6-[6-[(lS)-2,2,2-trifluoro-l-methyl-ethoxy]-3- pyridyl]-[l,2,4]triazolo[4,3-a]pyrazine

[0345] Synthesis of A62: To a mixture of (2S)-2-(trifluoromethyl)oxirane (3 g, 26.77 mmol) in THF (25 mL) was added LiAlH4 (0.5 g, 13.2 mmol) at 0 °C under N over 30 minutes, then the mixture was stirred at 20 °C for 2 hours. After cooling to 0 °C, the mixturewas quenched with water (0.9 g), the mixture was stirred at 35 °C for 30 minutes. The mixture was filtered through Celite, eluted with THF (20 mL x 2), the organic phase was washed with brine (20 mL x 2) and dried over Na2S04,filtered to give the crude product of (2S)-l,l, l-trifluoropropan-2-ol (3 g, 26.3 mmol, 98% yield) as a solution in THF, which was used directly without any further purification.

[0346] Synthesis of A63: To a solution of (2S)-l,l,l-trifluoropropan-2-ol in THF (50 mL) was added NaH (0.8 g, 19.94 mmol) at 0 °C over 20 minutes, and the mixture was stirred at 0 °C for 40 minutes. Then to the mixture was added 5-bromo-2-fluoro-pyridine (2.7 g, 15.34 mmol), and the mixture was stirred at 50 °C for 2 hours. The mixture was quenched with sat. NH4CI (40 mL), extracted with EtOAc (60 mL), the combined organic phase was washed with brine (40 mL x 2), dried over Na SCp, filtered and concentrated to give the crude product (3.48 g, 9.29 mmol, 61% yield) as an oil. LCMS Rt= 0.95 min in 1.5 min chromatography, 5-95 AB, MS ESI calcd. for CsHsBrFiNO [M+Fl]+270.0, found 269.9.

[0347] Synthesis of A64: A mixture of 5-bromo-2-[(lS)-2,2,2-trifluoro-l-methyl- cthoxy Ipyridinc (3.48 g, 12.89 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-l,3,2-dioxaborolane (4.91 g, 19.33 mmol), KOAc (2.53 g, 25.77 mmol) and Pd(dppf)Cl2 (1.13 g, 1.55 mmol) in l,4-Dioxane (35 mL) was stirred at 85 °C for 12 hours under N2. After cooling to room temperature, the mixture was concentrated to give a residue. The residue was diluted with fFO (30 mL), and the mixture was extracted with EtOAc (40 mL x 2). The combined organic phase was washed with water (40 mL) and brine (40 mL), dried over Na2S04, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 1 %) to give the product (3 g, 5.72mmol, 44% yield) as an oil. 'H NMR (DMSO-cL, 400MHZ) 5H= 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 Rt= 1.02 min in 1.5 min chromatography, 5-95 AB, MS ESI calcd. for C14H20BF3NO3 [M+H]+318.1, found 318.1.

[0348] Synthesis of A65: A mixture of 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-2-[(lS)-2,2,2-trifluoro-l-methyl-ethoxy]pyridine (600 mg, 1.89 mmol), 2-bromo-5- chloro-pyrazine (329.39 mg, 1.7 mmol), Pd(dppf)Cl2 (207.67 mg, 0.28 mmol) and CS2CO3(1232.88 mg, 3.78 mmol) in l,4-Dioxane (15 mL) and Water (1.5 mL) was stirred at 60 °C for 5 hours under N2. After cooling to room temperature, the mixture was concentrated to give the residue. The residue was diluted with FLO (20 mL), and the mixture was extracted with EtOAc (30 mL x 2). The combined organic phase was washed with water (20 mL) and brine (20 mL), dried over Na2S04,filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 3%) to give the product (350 mg, 1.15 mmol, 61% yield) as an oil. LCMS Rt= 0.95 min in 1.5 min chromatography, 5-95 AB, MS ESI calcd. for C i HioCIFiN iO [M+H]+304.0, found 304.1.

[0349] Synthesis of A66: A mixture of 2-chloro-5-[6-[(lS)-2,2,2-trifluoro-l-methyl- ethoxy]-3-pyridyl]pyrazine (351.14 mg, 1.16 mmol) and hydrazine (741.21 mg, 23.13 mmol) in CH3CN (5 mL) was stirred at 90 °C for 16 hours. After cooling to room temperature, the reaction was quenched with sat.NFLCl (30 mL), and the mixture was extracted with EtOAc (20 mL x 2). The combined organic phase was washed with brine (30 mL), dried over Na2SOt, filtered and concentrated to give the crude product (350 mg, 1.05 mmol, 91% yield) as a solid. LCMS Rt= 0.74 min in 1.5 min chromatography, 5-95AB, MS ESI calcd. for C^HJSFSNSO [M+H]+300.1, found 300.1.

[0350] Synthesis of A67: A mixture of [5-[6-[(lS)-2,2,2-trifluoro-l-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 NaHC(¾ (20 mL), and the mixture was extracted with EtOAc (20 mL x 2). The combined organic phase was washed with water (20 mL) and brine (20 mL), dried over Na SCh, filtered and concentrated to give the product (420 mg, 1.01 mmol, 86% yield) as a solid. LCMS Rt= 0.92 min in 1.5 minchromatography, 5-95ABMS ESI calcd. for CMHJOQFSNSO [M+H]+394.0, found 394.1.

[0351] Synthesis of Compound 59: A mixture of 3-[chloro(difluoro)methyl]-6-[6- [(lS)-2,2,2-trifluoro-l-methyl-ethoxy]-3-pyridyl]-[l,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, 1.07mmol) was stirred at 90 °C for 24 hours. After cooling to room temperature, the reaction was diluted with EtOAc (30 mL) and quenched with saturated NaCl (30 mL), and the mixture was filtered through Celite and eluted with EtOAc (10 mL). The filtrate was washed with water (30 mL) and brine (30 mL), dried over Na2S04, 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. 1H NMR (CD3CN, 400MHz) dH= 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 Rt= 1.28 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. for C13H13F3N3O2[M+H]+390.1, found 390.0.Example 58: 3-[difluoro(methoxy)methyl]-6-[5-fluoro-6-[(lR)-2,2,2-trifluoro-l-methyl- ethoxy]-3-pyridyl]-5-methyl-[l,2,4]triazolo[4,3-a]pyrazine

[0352] 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-l,3,2-dioxaborolan-2-yl)-2-[(lR)-2,2,2- trifluoro-l-methyl-ethoxy]pyridine (1.31 g, 3.9 mmol), Pd(dppf)Cl2(0.48 g, 0.65 mmol) and CS2CO3(2.83 g, 8.68 mmol) in l,4-Dioxane (40 mL) and water (8 mL) was stirred under N2at 55 °C for 16 hours. The mixture was cooling to room temperature, diluted with EtOAc (50 mL), filtered with 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%) yielding the product (930 mg, 2.62 mmol, 60% yield) as a colorless oil. LCMS Rt= 0.95 min in 1.5 min chromatography, 5-95AB, MS ESI calcd. for C13H11CIF4N3O [M+H]+336.0, found 336.1.

[0353] Synthesis of A69: A mixture of hydrazine (1775.89 mg, 55.41 mmol) and 5- chloro-2-[5-fluoro-6-[(lR)-2,2,2-trifluoro-l-methyl-ethoxy]-3-pyridyl]-3-methyl-pyrazine (930 mg, 2.77 mmol) in CH3CN (10 mL) was stirred at 90 °C for 16 hours. After cooling to room temperature, the reaction was quenched with sat.NH4CI (30 mL), and the mixture was extracted with EtOAc (40 mL x 2). The combined organic phase was 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 mmol, 89% yield) as a solid. LCMS Rt= 0.75 min in 1.5 min chromatography, 5-95 AB, MS ESI calcd. for C 13H 14F4N3O [M+H]+332.1, found 332.2.

[0354] Synthesis of A70: A mixture of [5-[5-fluoro-6-[(lR)-2,2,2-trifluoro-l-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, l.8lmmol) in Toluene (10 mL) was stirred at 120 °C for 5 days. After cooling to room temperature, the reaction was quenched with saturated NaHCC>3 (20 mL), and the mixture was extracted with EtOAc (20 mL x 2). The combined organic phase was washed with water (20 mL) and brine (20 mL), dried over Na SCL, 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 Rt= 0.92 min in 1.5 min chromatography, 5-95AB, MS ESI calcd. for CisHuClFeNsO [M+H]+426.0, found 426.1.

[0355] Synthesis of Compound 60: A mixture of 3-[chloro(difluoro)methyl]-6-[5- fluoro-6-[(lR)-2,2,2-trifluoro-l-methyl-ethoxy]-3-pyridyl]-5-methyl-[l,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 Na SO^ filtered and concentrated to give the crude product. The crude product was purified by Prep-TLC (silica gel, PE : EtOAc = 2 : 1) to give the impure product. The impure product was triturated from n-hexane / DCM(2 : 1, 3 mL) to give the product (11.92 mg, 28.3 pmol, 9% yield) as asolid. 1H NMR (CDCI3, 400MHz) dH= 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 Rt= 1.28 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. for C iftH ^FftNiO [M+H]+422.1, found 422.2.Example 59: 3-[difluoro(methoxy)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3- pyridyl]-5-methyl-[l,2,4]triazolo[4,3-a]pyrazine

[0356] Synthesis of A71: To a solution of 5-chloropyrazin-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 hour. After cooling to room temperature and concentrated, water (200 mL) was added to give residue, extracted with EtOAc (150 mL x 2). The combined organic phase was washed with brine (150 mL), dried over Na2S04, filtered and concentrated to give the crude product. The crude product was purified by chromatography column 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. 'H NMR (DMSO-cL, 400MHz) 5H = 8.09 (s, 1H), 6.96 (s, 2H).

[0357] Synthesis of A72: A mixture of 3-bromo-5-chloro-pyrazin-2-amine (31 g, 148.72 mmol), Pd(dppf)Cl2 (16.32 g, 22.31 mmol), methylboronic acid (13.35 g, 223.09 mmol) and CS2CO3 (96.91 g, 297.45 mmol) in Water (30 mL) and l,4-Dioxane (300 mL) was stirred at 90 °C for 16 hours. After cooling to room temperature, the mixture wasconcentrated to give a residue. To the residue was added water (100 mL), extracted with EtOAc (100 mL x 2). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2S04, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 20% to 40% to 60% to 80%) to give the product (13 g, 90.548 mmol, 61% yield) as a solid. 'H NMR(DMSO -ck, 400MHz) dH= 7.83 (s, 1H), 6.40 (s, 2H), 2.26 (s, 3H).

[0358] 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 hours. The mixture was diluted with ]¾0 (30 mL), and the mixture was extracted with EtOAc (70 mL x 2). The combined organic phase was washed with water (30 mL x 2) and brine (30 mL), dried over Na SCL 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.8.22 (s, 1H), 2.68 (s, 3H). LCMS Rt= 1.10 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. for C5H5BrClN2[M+H]+208.9, found 208.7.

[0359] 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-l,3,2-dioxaborolan-2-yl)-2-(2,2,2- trifluoroethoxy)pyridine (1.3 g, 4.05 mmol), CS2CO3 (3.77 g, 11.57 mmol) and Pd(dppf)Cl2 (634.85 mg, 0.87 mmol) in l,4-Dioxane (30 mL) and water (3 mL) was stirred at 60 °C under N2for 16 hours. After cooling to room temperature, water (30 mL) and EtOAc (50 mL) were added to the mixture and the mixture was filtered through Celite. After the filtrate was separated, the organic phase was washed with brine (30 mL), dried over anhydrous Na2S04, 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 1 % to 2%) to give the product (580 mg, 1.71 mmol, 30% yield) as a solid.1H NMR (CDCI3, 400MHz) dp = 8.52 (s, 1H), 8.19 (d, 1H), 7.73 (dd, 1H), 4.91 (q, 2H), 2.69 (s, 3H). LCMS Rt= 0.93 min in 1.5 min chromatography, 5-95AB, MS ESI calcd. for C12H9CIF4N3O [M+H]+322.0, found 322.0.

[0360] 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 (605.42mg, 18.89 mmol) in MeCN (20 mL) was stirred at 90 °C for 16 hours. After cooling to room temperature, the mixture was concentrated, water (20 mL) was added, and the mixture was extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (20 mL x 2), dried over anhydrous Na2S04, filtered and concentrated to give the crude product (530 mg, 1.30 mmol, 69% yield) as a solid. 'H NMR (DMSO-cL, 400MHz) 5H= 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 Rt= 0.72 min in 1.5 min chromatography, 5-95 AB, MS ESI calcd. for CI2H12F4NSO [M+H]+318.1, found 318.1.

[0361] 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. To the residue was added water (50 mL) then extracted with EtOAc (50 mL x 2). The combined organic phase was washed with water (50 mL) and brine (50 mL x 2), dried over anhydrous Na2S04, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography column on silica gel (EtOAc in PE = 0% to 15% to 30%) to give the product (180 mg, 426.2 pmol, 26% yield) as an oil. LCMS Rt= 3.64 min in 7.0 min chromatography, 10-80AB, MS ESI calcd. for C14H9CIF6N5O [M+H]+412.0, found 412.1.

[0362] Synthesis of Compound 61: A solution of 3-[chloro(difluoro)methyl]-6-[5- fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-5-methyl-[l,2,4]triazolo[4,3-a]pyrazine (180 mg, 0.44 mmol) and AgOTf (1.69 g, 6.56 mmol) in Methanol (5 mL) and DMF (5 mL) was stirred at 90 °C under N2for 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 Na2S04, 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 pmol, 22% yield) as a solid. 'H NMR (CDCI3, 400MHz) dH= 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 Rt= 1.20 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. for CI5H12F6N502[M+H]+408.1, found 407.9.Example 60: 3-[difluoro(methoxy)methyl]-6-[6-[(lR)-2,2,2-trifluoro-l-methyl-ethoxy]-3- pyridyl]-[l,2,4]triazolo[4,3-a]pyrazine

[0363] To a suspension of 3-[bromo(difluoro)methyl]-6-[6-[rac-(lR)-2,2,2-trifluoro- l-methyl- ethoxy]-3-pyridyl]-[l,2,4]triazolo[4,3-a]pyrazine (2.9 g, 6.62 mmol) in methanol (30 mL) was added AgBF4(2.58 g, 13.24 mmol) at 25°C under N2. The mixture was protected from light and stirred at 60°C for 1 hour. The solution was added to saturated NaCl (30 mL) and filtered. The filter was extracted with EtOAc (20 mL x 2). The combined organic phase was washed with brine (50 mL), dried over Na2S04,filtered and concentrated. The crude product was purified by chromatography flash column on silica gel (EtOAc in PE = 0% to 10% to 20%) to give the product (1.96 g, ee = 92.28%) as a solid. Analytical SFC: Analysis by SFC (Chiralpak OJ-3 150 X 4.6 mm I.D., 3 um Mobile phase: A: C02, B: ethanol (0.05% DEA); Gradient: from 5% to 40% of B in 5 min and from 40% to 5% of B in 0.5 min, hold 5% of B for 1.5 min; Flow rate: 2.5 mL / min Column temp: 35°C) showed two peaks at = 2.71 min and 2.96 min. The product was separated by SFC (DAICEL CHIRALCEL OJ (250 mm x 50 mm, 10 °<m); A = C02and B = 0.1%N1¾H20 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. 'H NMR (400MHZ, CD3CN) dH = 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 Rt= 1.27 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. for CisHnFsNsCh [M+H]+389.1, found 390.0.Example 61: 3-[cyclopropoxy(difluoro)methyl]-6-[5-fluoro-6-[(lS)-2,2,2-trifluoro-l- methyl-ethoxy]-3-pyridyl]-[l,2,4]triazolo[4,3-a]pyrazine

[0364] To a mixture of cyclopropanol (84.65 mg, 1.46 mmol), 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[(lS)-2,2,2-trifluoro-l-methyl-ethoxy]-3-pyridyl]- [l,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 hour. The mixture was diluted with FLO (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic phase was washed with brine (20 mL), dried over Na2S04,filtered and concentrated to give the crude product. The crude product was purified by flashchromatography on silica gel (EtOAc in PE = 0% to 30%) to give the impure product. The impure product was triturated from u-hexane / DCM (2 : 1, 3 mL) to give the product (33.18 mg, 76.6 pmol, 11% yield). 'H NMR (CDCl3, 400MHz) dH= 9.52 (d, 1H), 8.49 (d, 1H),8.43 (d, 1H), 8.05 (dd, 1H), 5.96 - 5.86 (m, 1H), 4.21 - 4.16 (m, 1H), 1.61 (d, 3H), 1.04 - 0.99 (m, 2H), 0.87 - 0.81 (m, 2H). LCMS Rt= 1.34 min in 2.0 min chromatography, 10-80AB. MS ESI calcd. for CI7H14F6N502 [M+H]+434.1, found 434.1.Example 62: 6-(6-benzyloxy-5-fluoro-3-pyridyl)-3-[ethoxy(difluoro)methyl]- [l,2,4]triazolo[4,3-a]pyrazine

[0365] Synthesis of A84: To a solution of phenylmethanol (10.5 g, 97.1 mmol) in TF1F (100 mL) was added NaFl (7 g, 175 mmol) in portions at 0 °C over 0.5 hour. After theaddition, the mixture was stirred at 20 °C for another 1 hour. 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 hours. The mixture was poured into saturated NH4CI solution (100 mL) and the mixture was extracted with EtOAc (100 mL x 2). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2S04, filtered and concentrated to give the crude product (27 g, 89.52 mmol) as an oil.

[0366] 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-l,3,2-dioxaborolan-2-yl)-l,3,2- dioxaborolane (29.16 g, 114.85 mmol), KOAc (18.79 g, 191.41 mmol) and Pd(dppf)Cl2 (10.5 g, 14.36 mmol) in l,4-dioxane (300 mL) was stirred at 90 °C under N for 16 hours. 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. 'H NMR (400MHZ, CDCI3) 5H = 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).

[0367] 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-l,3,2-dioxaborolan-2-yl)pyridine (6.81 g, 20.68 mmol), CS2CO3 (13.47 g, 41.36 mmol) and Pd(dppf)Cl2 (2.27 g, 3.1 mmol) in 1,4- dioxane (30 mL) and water (3 mL) was stirred at 50 °C under N2 for 16 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated. Water (50 mL) was added and the aqueous layer was extracted with EtOAc (50 mL x 2). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2S04, 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. 'H NMR (400MHz, DMSO-r¾) dH= 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).

[0368] 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 wasextracted with EtOAc (30 mL x 2). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na3S04,filtered and concentrated to give the crude product (4 g, 7.38 mmol) as a solid. LCMS Rt= 0.76 min in 1.5 min chromatography, 5-95AB, MS ESI calcd. for Ci6H15FN50 [M+H]+312.1, found 311.9.

[0369] Synthesis of A88: To the solution of 2-bromo-2,2-difluoro-acetyl 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 x 2). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na3S04,filtered and concentrated to give the crude product (900 mg, 1.92 mmol) as a solid. 'H NMR (400MHZ, DMSO-dfs) dH= 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).

[0370] 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 TLO (0.19 mL, 1.15 mmol). The mixture was stirred at 20 °C for 16 hours. Water (50 mL) was added and the aqueous layer was extracted with EtOAc (50 mL x 2). The combined organic phase was washed with saturated NaHC03solution (30 mL) and brine (30 mL), dried over anhydrous Na3S04,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 pmol, 55% yield) as a solid. NMR (400MHz, CDC13) dH= 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).

[0371] Synthesis of Compound 64: A mixture of 6-(6-benzyloxy-5-fluoro-3- pyridyl)-3-[bromo(difluoro)methyl]-[l,2,4]triazolo[4,3-fl]pyrazine (240 mg, 0.53 mmol) and AgBF4(207.55 mg, 1.07 mmol) in ethanol (5 mL) was stirred at 60 °C in the dark for 1 hour. 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 pmol, 14% yield) as a solid. NMR (400MHz, CDC13) dH= 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 Rt= 1.38 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. for C2oH17F3Ns02[M+H]+416.1, found 416.0.Example 63: 3-[difluoro(methoxy)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3- pyridyl]-7-methyl-[l,2,4]triazolo[4,3-Z»]pyridazine

[0372] Synthesis of A100: A mixture of 3-[bromo(difluoro)methyl]-6-chloro-7- methyl-[l,2,4]triazolo[4,3-Zdpyridazine (900 mg, 3.03 mmol) and AgBF4(1.17 g, 6.05 mmol) in methanol (10 mL) was stirred at 60 °C under dark for 1 hour. After cooling to room temperature, brine (50 mL) and EtOAc (50 mL) were added to the mixture and the mixture was filtered through Celite. The organic phase was separated and washed with brine (30 mL), dried over anhydrous Na2S04, 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 (180 mg, 724.0 pmol, 23% yield) as a solid. 'H NMR (400MHz, CDCI3) 5H = 7.99 (s, 1H), 3.90 (s, 3H), 2.53 (s, 3H). LCMS Rt= 0.78 min in 1.5 min chromatography, 5- 95 AB, MS ESI calcd. for C8H8ClF2N40 [M+H]+249.0, found 248.9.

[0373] Synthesis of Compound 65: A mixture of 6-chloro-3-[difluoro(methoxy)methyl]-7-methyl-[l,2,4]triazolo[4,3-^]pyridazine (100 mg, 0.40 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (193.72 mg, 0.60 mmol), K3PO4 (170.78 mg, 0.80 mmol) and Pd(t-Bu3P)2(30.83 mg, 0.06 mmol) in 1,4-dioxane (5 mL) and water (0.50 mL) was stirred at 80 °C under N2for 3 hours. After cooling to room temperature, water (20 mL) was added to the mixture and the aqueous layer was extracted with EtOAc (20 mL x 2). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na2S04, 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 (64.84 mg, 158.9 pmol, 39% yield) as a solid. 'H NMR (400MHZ, CDCI3)dH= 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 Rt= 1.18 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. forC15IL2F6N5O2 [M+H]+408.1, found 408.0.Example 64: 3-[difluoro(methoxy)methyl]-6-[5-fluoro-6-[(lR)-2,2,2-trifluoro-l-methyl- ethoxy]-3-pyridyl]-7-methyl-[l,2,4]triazolo[4,3-Z»]pyridazine

[0374] A mixture of 3-fluoro-2-[(lR)-2,2,2-trifluoro-l-methyl-ethoxy]-5-(4,4,5,5- tctramcthyl- 1 ,3,2-dioxaborolan-2-yl)pyridinc (121.31 mg, 0.36 mmol), 6-chloro-3- [difluoro(methoxy)methyl]-7-methyl-[l,2,4]triazolo[4,3- / ?]pyridazine (75 mg, 0.3 mmol), Pd(t-Bu iP) (23.13 mg, 0.05 mmol), K3PO4 (128.09 mg, 0.6 mmol) in l,4-dioxane (5 mL) and water (0.5 mL) was stirred at 80 °C for 3 hours. After cooling to room temperature, the mixture was concentrated and diluted with H2O (20 mL). The aqueous layer was extracted with EtOAc (20 mL x 2). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na SCp, filtered and concentrated. The crude product was purified with flash chromatography on silica gel (EtOAc 100%) to give the product (70.46 mg, 0.17 mmol, 55% yield) as a solid.lH NMR (400MHZ, CDCL) dH= 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 = 1.24 min in 2 min chromatography, 10-80AB, MS ESI calcd. C16IL4F6N5O2 [M+H]+422.1, found 422.0.Example 65: 3-[ethoxy(difluoro)methyl]-6-[5-fluoro-6-[(lS)-2,2,2-trifluoro-l-methyl- ethoxy]-3-pyridyl]-5-methyl-[l,2,4]triazolo[4,3-a]pyrazine

[0375] A mixture of 3-[bromo(difluoro)methyl]-6-[5-fluoro-6-[(lS)-2,2,2-trifluoro-l- methyl-ethoxy]-3-pyridyl]-5-methyl-[l,2,4]triazolo[4,3-fl]pyrazine (100 mg, 0.21 mmol) and AgBF4(82.81 mg, 0.43 mmol) in ethanol (1 mL) was stirred at 60 °C in the dark for 1 hour. 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 Na SO^ filtered and concentrated. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 30% to 50%) to give 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. 1H NMR (400MHz, CDCI3) dH= 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 Rt= 1.34 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. for Oΐ7HiήHήN4O [M+H]+436.1, found436.0.Example 66: 3-[difluoro(methoxy)methyl]-6-[5-fluoro-6-[(lS)-2,2,2-trifluoro-l-methyl- ethoxy]-3-pyridyl]-7-methyl-[l,2,4]triazolo[4,3-6]pyridazine

[0376] Synthesis of A103: A mixture of 3,6-dichloro-4-methyl-pyridazine (14 g, 85.89 mmol) and N2H4Ή2O (4.29 g, 85.89 mmol) in ethanol (200 mL) was stirred at 70 °C for 30 hours. After cooling to room temperature, the suspension was filtered. The filter cake was washed with EtOH (50 mL x 3) and dried in oven to give the product as a mixture of two regioisomers (A103, A103-2) and in a ratio of approximately 1 :1 (determined byNMR) (8 g, 50.45 mmol, 58% yield) as a solid.

[0377] 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 H2O (50 mL). The mixture was extracted with EtOAc (100 mL x 2). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na SCL, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 20% to 40% to 60%) to give A99 (400 mg, 1.34 mmol, 10% yield) and A99-2 (600 mg, 2.01 mmol, 14% yield) both as solids. A99 'H NMR (400MHZ, CDCI3) dH= 8.08 (s, 1H), 2.58 (s, 3H). A99-2 1H NMR (400MHz, CDCL) dH= 7.14 (s, 1H), 2.81 (s, 3H).

[0378] Synthesis of AlOO-a : A mixture of 3-[bromo(difluoro)methyl]-6-chloro-7- methyl-[l,2,4]triazolo[4,3-Zdpyridazine (400 mg, 1.34 mmol) and AgBF4(523.5 mg, 2.69 mmol) in methanol (5 mL) was stirred at 55 °C in the dark for 12 hours. After cooling to room temperature, aqueous saturated NaCl solution (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 phase was washed with brine (20 mL), dried over anhydrous Na SCL, 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 (230 mg, 0.93 mmol, 68% yield) as a solid. 1H NMR (400MHz, CDCl3)dH= 7.98 (d, 1H), 3.89 (s, 3H), 2.53 (s, 3H). LCMS Rt = 0.73 min in 1.5 min chromatography, 10-80AB, MS ESI calcd. CsHgC^NtO [M+H]+249.0, found 248.8.

[0379] Synthesis of Compound 68: A mixture of 6-chloro-3- [difluoro(methoxy)methyl]-7-methyl-[l,2,4]triazolo[4,3-Zdpyridazine (70 mg, 0.28 mmol), 3-fluoro-2-(lS)-2,2,2-trifluoro-l-methyl-ethoxy]-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridine (113.22 mg, 0.34 mmol), K3PO4 (119.55 mg, 0.56 mmol) and Pd(t-Bu iP)2(21.58 mg, 0.04 mmol) in l,4-dioxane (5 mL) and water (0.5 mL) was stirred at 80 °C under N2for 3 hours. 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 x 2). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na2S04, filtered and concentrated. The crude product was purified by prep- TLC (silica gel, EtOAc) to give the product (65 mg, 154.3 pmol, 54% yield) as a solid. 'H NMR (400MHz, CDCl3) dH= 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 Rt= 1.31 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. for CI6H14F6N502[M+H]+422.1, found 422.2.Example 67: 6-[5-fluoro-6-(2,2,2-trifluoro-l,l-dimethyl-ethoxy)-3-pyridyl]-3- (methoxymethyl)-7-methyl-[l,2,4]triazolo[4,3-6]pyridazine

[0380] A mixture of 6-chloro-3-(methoxymethyl)-7-methyl-[l,2,4]triazolo[4,3- Z?]pyridazine (80 mg, 0.38 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 2-(2,2,2-trifluoro-l,l-dimethyl-ethoxy)pyridine (197.03 mg, 0.56 mmol), K3PO4 (159.74 mg, 0.75 mmol) and Pd(t-Bu iP)2(28.84 mg, 0.06 mmol) in l,4-dioxane (5 mL) and H2O (0.5 mL) was stirred at 80 °C under N2for 3 hours. 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 x 2). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na SCL, filtered and concentrated. The crude product was purified by prep-HPLC (Waters XBridge BEH C18 (150 mm x 25 mm, 5 pm) A = H20 (0.075% NH4HCO3) and B = CH3CN; 50-60% B over 9.5 min) to give the product (21.64 mg, 0.05 mmol, 14% yield) as a solid. 'H NMR (400 MHz, CDCI3) 5H= 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, = 1.28min in 2.0 min chromatography, 10-80AB, MS ESI calcd. for C17IL8F4N5O2 [M+H]+400.1, found 400.1.Example 68: 6-[5-fluoro-6-[(lS)-2,2,2-trifluoro-l-methyl-ethoxy]-3-pyridyl]-3- (methoxymethyl)-7-methyl-[l,2,4]triazolo[4,3-6]pyridazine

[0381] A mixture of 6-chloro-3-(methoxymethyl)-7-methyl-[l,2,4]triazolo[4,3- Z?]pyridazine (70 mg, 0.33 mmol), 3-fluoro-2-[(lS)-2,2,2-trifluoro-l-methyl-ethoxy]-5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (132.38 mg, 0.40 mmol), K3PO4 (139.78 mg, 0.66 mmol) and PdO-Bu iPp (25.24 mg, 0.05 mmol) in l,4-dioxane (5 mL) and water (0.5 mL) was stirred at 80 °C under N2for 3 hours. 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 x 2). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na SCL, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 10% to 20%) to give the product (33.02 mg, 0.09 mmol, 26% yield) as a solid.1H NMR (400MHz, CDCI3) dH= 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 Rt= 1.24 min in 2.0 min chromatography, 10- 80AB, MS ESI calcd. for CI6H16F4N502 [M+H]+386.1, found 385.9.Example 69: 6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-3-(methoxymethyl)-7- methyl-[l,2,4]triazolo[4,3-6]pyridazineA104

[0382] Synthesis of A105: The corresponding pinacol ester was dissolved in MeCN and aqueous HC1 was added. The mixture was stirred for 2 hours at room temperature and then concentrated to give A 105, which was used crude.

[0383] Synthesis of Compound 71: A mixture of 6-chloro-3-(methoxymethyl)-7- methyl-[l,2,4]triazolo[4,3-Zdpyridazine (70 mg, 0.33 mmol), [5-fluoro-6-(2,2,2- trifluoroethoxy)-3-pyridyl]boronic acid (94.39 mg, 0.40 mmol), K3PO4 (139.78 mg, 0.66 mmol) and Pd(t-Bu iP) (25.24 mg, 0.05 mmol) in l,4-dioxane (5 mL) and water (0.5 mL) was stirred at 80 °C under N for 3 hours. 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 x 2). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na SCL, filtered and concentrated. The crude product was purified by prep-TLC (silica gel, EtOAc) to give the product (9.8 mg, 0.03 mmol, 8 % yield) as a solid. 'H NMR (400MHZ, CDCI3) 5H= 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 Rt= 1.19 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. for C15H14F4N5O2 [M+H]+372.1, found 372.0.Example 70: 6-[5-fluoro-6-[(lR)-2,2,2-trifluoro-l-methyl-ethoxy]-3-pyridyl]-3- (methoxymethyl)-7-methyl-[l,2,4]triazolo[4,3-¾]pyridazine

[0384] 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) was added 2-methoxyacetyl chloride (2737.12 mg, 25.22 mmol) at 25 °C. The mixture was heated to 120 °C and stirred for 16 hours. After cooling to roomtemperature, the mixture was concentrated, and the residue was diluted with l¾0 (30 mL). The mixture was extracted with EtOAc (50 mL x 2). The combined organic phase was washed with brine (10 mL), dried over anhydrous Na SO^ filtered and concentrated. The crude product was purified by flash chromatography on silica gel (EtOAc) for 3 times to give the A104 (250 mg, 1.17 mmol, 9% yield) and A104-2 (500 mg, 2.35 mmol, 19% yield) both as solids. NMR (400MHz, CDCl3) dH= 7.94 (d, 1H), 5.02 (s, 2H), 3.50 (s, 3H), 2.51 (s, 3H).

[0385] Synthesis of Compound 72: A mixture of 6-chloro-3-(methoxymethyl)-7- methyl-[l,2,4]triazolo[4,3- / >]pyridazine (60 mg, 0.28 mmol), 3-fluoro-2-[(lR)-2,2,2-trifluoro- l-methyl-ethoxy]-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (113.47 mg, 0.34 mmol), K3PO4 (119.81 mg, 0.56 mmol) and Pd(t-Bu iP) (21.63 mg, 0.04 mmol) in 1,4- dioxane (5 mL) and l¾0 (0.5 mL) was stirred at 80 °C under N for 1 hours. 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 x 2). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na SCL, filtered and concentrated. The crude product was purified by prep-TLC (silica gel, EtOAc) to give the product (23.22 mg, 59.2 pmol, 21% yield) as a solid. 'H NMR (400MHZ, CDCI3)dH= 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 Rt= 1.24 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. for CI6H16F4N502[M+H]+386.1, found 386.1.Example 71 : 3-(difluoro(methoxy)methyl)-6-(6-(3,3-difluorocyclobutoxy)pyridin-3-yl)- [l,2,4]triazolo[4,3-a]pyrazine

[0386] Synthesis of A107: To a stirred solution of 6-chloro-3- [chloro(difluoro)methyl]-[l,2,4]triazolo[4,3-fl]pyrazine (1.0 g, 4.18 mmol) and 2-(3,3- difluorocyclobutoxy)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (1.43 g, 4.6 mmol) in l,4-dioxane (27.0 mL) was added water (3.0 mL) and CS2CO3(2.73 g, 8.37 mmol). Pd(dppf)Cl2DCM (0.34 g, 0.42 mmol) was added to the reaction mixture under 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 product was purified by column chromatography on silica gel with 25% ethyl acetate / PE to afford the product (430 mg, 1.11 mmol, 26% yield). LCMS: 388.1 (M+H), Rt 2.4 minColumn: ZORBAX XDB C-18 (50 X 4.6 mm), 3.5 pm Mobile Phase: A: 0.1% HCOOH in water : ACN (95:5), B: ACN; Flow Rate: 1.5 mL / min.

[0387] Synthesis of Compound 73: To a stirred solution of 3- (chlorodifluoromethyl)-6-(6-(3,3-difluorocyclobutoxy)pyridin-3-yl)-[l,2,4] triazolo[4,3- ajpyrazine (100 mg, 0.26 mmol) in MeCN (4.5 mL) was added CS2CO3(515 mg, 1.58 mmol) and methanol (0.21 mL, 5.2 mmol). The reaction was stirred for 1 h at room temperature. The reaction mixture was treated with water (20.0 mL) and extracted with ethyl acetate (2 x 20 mL). The organic layer was washed with brine (15 mL), dried over anhydrous Na SCL and concentrated. The crude compound was purified by preparative HPLC to afford a solid (32 mg, 0.08 mmol, 32% yield). Prep-HPLC method: Rt = 16.1 ; Column: XBridge C8 (150 X 19mm), 5.0 pm; 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 pm Mobile phase: A: 0.1% TFA in water, B: 0.1% TFA in ACN; Flow Rate: 2.0 mL / min. LCMS: 384.1 (M+Fl), Rt 2.22 min, Column: ZORBAX XDB C-18 (50 X 4.6 mm), 3.5 pm Mobile Phase: A: 0.1% F1COOF1 in water : ACN (95:5), B: ACN; Flow Rate: 1.5 mL / min. 'H NMR (400 MFlz, CD3OD): d 9.54 (d, 1H), 8.86 (d, 1H), 8.78 (s, 1H), 8.39 (dd, 1H), 6.99 (d, 1H), 5.25-5.22 (m, 1H), 3.99 (s, 3H), 3.23-3.13 (m, 2H), 2.82-2.70 (m, 2H).Example 72: 3-(cyclopropoxydifluoromethyl)-6-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)- [l,2,4]triazolo[4,3-a]pyrazine

[0388] 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 was added NaH (60% in mineral oil, 1.25 g, 31.25 mmol) in small portions. The reaction mixture was slowly warmed to room temperature and stirred for 15 min. 5-bromo-2-fluoro-pyridine (5.0 g, 28.41 mmol) was added drop-wise 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 x 60 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na SCL and concentrated. The crude compound was purified by column chromatography on silica gel with 5% ethyl acetate / PE to afford 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), 3.5pm Mobile Phase: A: 0.1% HCOOH in water : ACN (95:5), B: ACN; Flow Rate: 1.5 mL / min.

[0389] 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 l,4-dioxane (50.0 mL) was added potassium acetate (3.83 g, 39.0 mmol).Pd(dppf)Cl2 DCM (1.59 g, 1.95 mmol) was added to the reaction mixture under 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 with 5% ethyl acetate / PE to afford the product_(4.32 g, 14.3 mmol, 73% yield). LCMS: 304.1 (M+H), Rt 2.85 min Column: ZORBAX XDB C-18 (50 X 4.6 mm), 3.5 pm Mobile Phase: A: 0.1% HCOOH in water : ACN (95:5), B: ACN; Flow Rate: 1.5 mL / min.

[0390] Synthesis of A112: To a stirred solution of 6-chloro-3- [chloro(difluoro)methyl]-[l,2,4]triazolo[4,3-fl]pyrazine (1.3 g, 5.44 mmol) and 5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy) pyridine (1.5 g, 4.95 mmol) in l,4-dioxane (25.0 mL) was added water (2.5 mL) and CS2CO3 (3.22 g, 9.9 mmol).Pd(dppf)Cl2 DCM (0.4 g, 0.49 mmol) was added to the reaction mixture under 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 product was purified by column chromatography on silica gel with 30% ethyl acetate / PE to afford the product (500 mg, 1.3 mmol, 26% yield). LCMS: 380.0 (M+H), Rt 2.45 minColumn: ZORBAX XDB C-18 (50 X 4.6 mm), 3.5 pm Mobile Phase: A: 0.1% HCOOH in water : ACN (95:5), B: ACN; Flow Rate: 1.5 mL / min.

[0391] Synthesis of Compound 74: To a stirred solution of 3- (chlorodifluoromethyl)-6-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)-[l,2,4]triazolo[4,3- ajpyrazine (100 mg, 0.26 mmol) in MeCN (10 mL) was added CS2CO3 (514 mg, 1.58 mmol) and cyclopropanol (0.21 mL, 3.29 mmol). The reaction was stirred for 1 hour at room temperature. The reaction mixture was treated with water (15.0 mL) and extracted with ethyl acetate (2 x 20 mL). The organic layer was washed with brine (15 mL), dried over anhydrousNa SCh and concentrated. The crude compound was purified by preparative HPLC to afford a solid (10 mg, 0.024 mmol, 9% yield). Prep-HPLC method: Rt = 14.2; Column: XBridge C8 (150 X 19 mm), 5.0 pm; 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 pm 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 pm Mobile Phase: A: 0.1% TFA in water : ACN (95:5), B: 0.1% TFA in ACN; Flow Rate: 1.5 mL / min. 'B NMR (400 MHz, CD3OD): d 9.55 (d, 1H), 8.89 (d, 1H), 8.75 (s, 1H), 8.43 (dd, 1H), 7.09 (d, 1H), 4.98 (q, 2H), 4.26-4.23 (m, 1H), 0.99 (m, 2H), 0.85-0.81 (m, 2H).Example 73: 3-(cyclopropoxydifluoromethyl)-6-(5-fluoro-6-(2,2,2- trifluoroethoxy)pyridin-3-yl)-[l,2,4]triazolo[4,3-a]pyrazine

[0392] 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 was added NaH (60% in mineral oil, 2.26 g, 56.71 mmol) in small portions. The reaction mixture was stirred for 15 min and 5-bromo-2,3- difluoro-pyridine (10.0 g, 51.55 mmol) was added drop-wise. The reaction mixture was slowly warmed to room temperature and stirred for 2 hours. The reaction mixture was cooled to 10 °C and treated with ice water (100 mL). The reaction mixture was extracted with ethyl acetate (2 x 100 mL). The organic layer was washed with brine (80 mL), dried over anhydrous Na SCp and concentrated. The crude compound was purified by columnchromatography on silica gel with 2% ethyl acetate / PE to afford the product (10.5 g, 38.1 mmol, 73% yield). LCMS: 273.9 (M+H) and 276.0 (M+2+H), Rt 2.53 min Column:ZORBAX XDB C-18 (50 X 4.6 mm), 3.5 pm Mobile Phase: A: 0.1% HCOOH in water : ACN (95:5), B: ACN; Flow Rate: 1.5 mL / min.

[0393] 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 l,4-dioxane (30.0 mL) was added potassium acetate (2.15 g, 21.9 mmol).Pd(dppf)Cl2DCM (0.89 g, 1.09 mmol) was added to the reaction mixture under 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 with 15% ethyl acetate / PE to afford the product_(2.0 g, 6.2 mmol, 56% yield). LCMS: 322.1 (M+H), Rt 2.97 min Column: Atlantis dCl8(50 X 4.6 mm), 5 pm Mobile Phase: A: 0.1% HCOOH in water : ACN (95:5), B: ACN; Flow Rate: 1.5 mL / min.

[0394] Synthesis of A18-a : To a stirred solution of 6-chloro-3- [chloro(difluoro)methyl]-[l,2,4]triazolo[4,3-fl]pyrazine (2.0 g, 8.37 mmol) and 3-fluoro-5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (2.96 g, 9.2 mmol) in l,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 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 product was purified by column chromatography on silica gel with 30% ethyl acetate / PE to afford the product (1.35 g, 3.4 mmol, 40% yield). LCMS: 398.0 (M+H), Rt 2.51 minColumn: Atlantis dC-l8 (50 X 4.6 mm), 3.5 pm Mobile Phase: A: 0.1% HCOOH in water : ACN (95:5), B: ACN; Flow Rate: 1.5 mL / min. 'H NMR (400 MHz, DMSO-dg): d 9.77 (d, 1H), 9.14 (s, 1H), 8.84 (d, 1H), 8.66 (dd, 1H), 5.20 (q, 2H).

[0395] Synthesis of Compound 75: To a stirred solution of 3- (chlorodifluoromethyl)-6-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)-[l,2,4]triazolo[4,3- ajpyrazine (150.0 mg, 0.38 mmol) in MeCN (8.0 mL) was added CS2CO3(737 mg, 2.26mmol) and cyclopropanol (0.48 mL, 7.54 mmol). 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 x 20 mL). The organic layer was washed with brine (15 mL), dried over anhydrous Na SCL and concentrated. The crude compound was purified by preparative HPLC to afford a solid (15 mg, 0.035 mmol, 9% yield). Prep. HPLC method: Rt 14.8; Column: XBridge C-18 (150 X 19 mm), 5.0 pm; 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 pm 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 dCl8(50 X 4.6 mm), 3.5 pm Mobile Phase: A: 0.1% HCOOH in water, B: ACN; Flow Rate: 1.5 mL / min. 'H NMR (400 MHz, DMSO-d6): d 9.71 (d, 1H), 8.93 (d, 1H), 8.78 (d, 1H), 8.56 (dd, 1H), 5.19 (q, 2H), 4.24-4.20 (m, 1H), 0.96-0.92 (m, 2H), 0.77-0.72 (m, 2H).Example 74: 3-(difluoro(methoxy)methyl)-6-(6-(3,3-difluorocyclobutoxy)-5- fluoropyridin-3-yl)-[l,2,4]triazolo[4,3-a]pyrazine

[0396] Synthesis of A115: To stirred solution of 2-chloro-5-hydrazineylpyrazine (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 hour. The reaction mixture was cooled to room temperature and concentrated. The crude reaction mixture was treated with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The organic layer was washed with brine (30 mL), dried over Na S04and concentrated to a solid (6 g). It was used for the next step without further purification.

[0397] 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) wasadded trifluoromethanesulfonic anhydride (4.73 mL, 28.01 mmol) and 2-methoxypridine (4.91 mL, 46.69 mmol) at 0 °C. The reaction mixture was slowly warmed to room temperature and stirred for 2 hours. The reaction mixture was treated with 10%sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (2 x 50 mL). The organic layer was washed with brine (50 mL), dried over Na SCL and concentrated. The crude product was purified by column chromatography on silica gel with 15% EtOAc / PE to afford 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 X 4.6 mm), 3.5 pm Mobile Phase: A: 0.1% HCOOH in water : ACN (95:5), B: ACN; Flow Rate: 1.5 mL / min.

[0398] Synthesis of A116: To a stirred solution of 3,3-difluorocyclobutanol (500 mg, 4.63 mmol) in THF (10 mL) at 0 °C was added NaH (60% in mineral oil, 204 mg, 5.09 mmol) in small portions. The reaction mixture was slowly warmed to room temperature and stirred for 15 min. 5-Bromo-2,3-difluoro-pyridine (0.9 g, 4.63 mmol) was then added drop- wise 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 x 30 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na SCp and concentrated. The crude compound was purified by column chromatography on silica gel with 10% ethyl acetate / PE to afford 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 pm Mobile Phase: A: 0.1% HCOOH in water : ACN (95:5), B: ACN; Flow Rate: 1.5 ml, / min.

[0399] 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 l,4-dioxane (20.0 mL) was added potassium acetate (0.77 g, 7.83 mmol). Pd(dppf)Cl2DCM (0.32 g, 0.39 mmol)was added to the reaction mixture under 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 with 5% ethyl acetate / PE to afford the product_(l.2 g, 3.6 mmol, 93% yield). LCMS: 330.1 (M+H), Rt 2.97 min Column: ZORBAX XDB C-18 (50 X 4.6 mm), 3.5 pm Mobile Phase: A: 0.1% HCOOH in water : ACN (95:5), B: ACN; Flow Rate: 1.5 mL / min.

[0400] Synthesis of A118: To a stirred solution of 6-chloro-3- (chlorodifluoromethyl)-[l,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-l,3,2-dioxaborolan-2-yl)pyridine (1.17 g, 3.55 mmol) in l,4-dioxane (15.0 mL) was added water (3.0 mL) and CS2CO3(2.31 g, 7.13 mmol). Pd(dppf)Cl2DCM (0.29 g, 0.36 mmol) was added to the reaction mixture under nitrogen atmosphere and heated at 80 °C for 8 hours. 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 with 30% ethyl acetate / PE to afford the product (1.11 g, 2.75 mmol, 77% yield). LCMS: 405.9 (M+H), Rt 2.30 min Column: ZORBAX XDB C-18 (50 X 4.6 mm), 3.5 pm Mobile Phase: A: 0.1% HCOOH in water : ACN (95:5), B: ACN; Flow Rate: 1.5 mL / min.

[0401] Synthesis of Compound 76: To a stirred solution of 3- (chlorodifluoromethyl)-6-(6-(3,3-difluorocyclobutoxy)-5-fluoropyridin-3-yl)- [l,2,4]triazolo[4,3-fl]pyrazine (140 mg, 0.34 mmol) in MeCN (7.5 mL) was added CS2CO3(668 mg, 2.06 mmol) and methanol (0.14 mL, 3.4 mmol). The reaction was stirred for 1 h at room temperature. The reaction mixture was treated with water (20.0 mL) and extracted with ethyl acetate (2 x 20 mL). The organic layer was washed with brine (15 mL), dried over anhydrous Na2S04and concentrated. The crude compound was purified by preparative HPLC to afford a solid (18 mg, 0.04 mmol, 13% yield). Prep. HPLC method: Rt 12.9; Column:YMC Phenyl (150 X 19 mm), 5.0 pm; Mobile phase: 0.1% TFA in water / acetonitrile; FlowRate: 15.0 mL / min. HPLC: Rt 5.01 min, 97.3% Column: XBridge C8 (50 X 4.6) mm, 3.5 pm Mobile phase: A: 0.1% TFA in water, B: 0.1% TFA in ACN; Flow Rate: 2.0 mL / min. LCMS: 402.0 (M+H), Rt 2.48 min, Column: Atlantis dCl8 (50 X 4.6 mm), 5.0 pm Mobile Phase: A: 0.1% HCOOH in water : ACN (95:5), B: ACN; Flow Rate: 1.5 mL / min. 'H NMR (400 MHz, DMSO-d6): d 9.70 (d, 1H), 8.97 (s, 1H), 8.77 (d, 1H), 8.49 (dd, 1H), 5.30-5.26 (m, 1H), 3.92 (s, 3H), 3.26-3.19 (m, 2H), 2.89-2.84 (m, 2H).Example 75: 6-(6-(3,3-difluorocyclobutoxy)-5-fluoropyridin-3-yl)-3- (ethoxydifluoromethyl)-[l,2,4]triazolo[4,3-a]pyrazine

[0402] To a stirred solution of 3-(chlorodifluoromethyl)-6-(6-(3,3- difluorocyclobutoxy)-5-fluoropyridin-3-yl)-[l,2,4]triazolo[4,3-a]pyrazine (150 mg, 0.34 mmol)) in MeCN (7.5 mL) was added CS2CO3(668 mg, 2.06 mmol) and ethanol (0.2 mL, 3.4 mmol). The reaction mixture was stirred for 1 h at room temperature. The reaction mixture was treated with water (20.0 mL) and extracted with ethyl acetate (2 x 25 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na SCL and concentrated. The crude compound was purified by preparative HPLC to afford a solid (22 mg, 0.05 mmol, 15% yield). Prep. HPLC method: Rt 13.1 ; Column: XBridge C-18 (150 X 19 mm), 5.0 pm;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 pm 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 pm Mobile Phase: A: 0.1% HCOOH in water : ACN (95:5), B: ACN; Flow Rate: 1.5 mL / min. 'H NMR (400 MHz, CD3OD): d 9.54 (d, 1H), 8.83 (d, 1H), 8.67 (d, 1H), 8.26 (dd, 1H), 5.32-5.30 (m, 1H), 4.40 (q, 2H), 3.25-3.15 (m, 2H), 2.90-2.77 (m, 2H), 1.49 (t, 3H).Example 76: 3-(cyclopropoxydifluoromethyl)-6-(6-(3,3-difluorocyclobutoxy)pyridin-3- yl)-[l,2,4Jtriazolo[4,3-aJpyrazine

[0403] To a stirred solution of 3-(chlorodifluoromethyl)-6-(6-(3,3- difluorocyclobutoxy)-5-fluoropyridin-3-yl)-[l,2,4]triazolo[4,3-a]pyrazine (100 mg, 0.26 mmol) in MeCN (9.0 mL) was added CS2CO3(504 mg, 1.55 mmol) and cyclopropanol (0.33 mL, 5.16 mmol). The reaction mixture was stirred for 4 h at room temperature. The reaction mixture was treated with water (20.0 mL) and extracted with ethyl acetate (2 x 20 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na SCL andconcentrated. The crude compound was purified by preparative HPLC to afford a solid (14 mg, 0.034 mmol, 13% yield). Prep. HPLC method: Rt 10.67; Column: Sunfire C-18 (150 X 19 mm), 5.0 pm; 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 pm 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 pm Mobile Phase: A: 0.1% TFA in water : ACN (95:5), B: 0.1% TFA in ACN; Flow Rate: 1.5 mL / min. 'H NMR (400 MHz, CD3OD): d 9.54 (d, 1H), 8.84 (d, 1H), 8.71 (s, 1H), 8.37 (dd, 1H), 7.00 (d, 1H), 5.25 (m, 1H), 4.26-4.23 (m, 1H), 3.23-3.13 (m, 2H), 2.82-2.70 (m, 2H), 0.99 (m, 2H), 0.84-0.79 (m, 2H).Example 77: 3-(ethoxymethyl)-6-(5-fluoro-6-((l,l,l-trifluoro-2-methylpropan-2- yl)oxy)pyridin-3-yl)-[l,2,4]triazolo[4,3-a]pyrazine

[0404] Synthesis of A119: To a stirred solution of l,l,l-trifluoro-2-methylpropan-2- ol (0.57 g, 4.43 mmol) in THF (20 mL) at 0 °C was added NaH (60% in mineral oil, 0.23 g,5.67 mmol) in small portions. The reaction mixture was slowly warmed to room temperature and stirred for 15 min. 5-bromo-2,3-difluoro-pyridine (1.0 g, 5.16 mmol) was added drop- wise 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 x 50 mL). The organic layer was washed with brine (30 mL), dried over anhydrous Na SCh and concentrated. The crude compound was purified by column chromatography on silica gel with 2% ethyl acetate / PE to afford the product (765 mg, 2.54 mmol, 49% yield) 'll NMR (400 MHz, CDCl3): d 7.99 (d, 1H), 7.54 (dd, 1H), 1.80 (s, 6H).

[0405] Synthesis of A8: To a stirred solution of 5-bromo-3-fluoro-2-((l,l,l-trifluoro- 2-methylpropan-2-yl)oxy)pyridine (765 mg, 2.54 mmol) and bis(pinacolato)diboron (0.71 g, 2.79 mmol) in l,4-dioxane (20.0 mL) was added potassium acetate (497 mg, 5.07 mmol). Pd(dppf)Cl2-DCM (0.21 g, 0.25 mmol) was added to the reaction mixture under 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 column chromatography on silica gel with 30% ethyl acetate / PE to afford the product_(300 mg, 0.86 mmol, 33% yield). LCMS: 350.1 (M+H), Rt 3.31 min Column: Atlantis dCl8(50 X 4.6 mm), 3.5 pm Mobile Phase: A: 0.1% HCOOH in water : ACN (95:5), B: ACN; Plow Rate: 1.5 mL / min.

[0406] 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 Et3N (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 hours. 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 Na SCLand concentrated. The crude product was purified by column chromatography on silica gel with 22% EtO Ac / PE to afford the product (0.8 g, 3.47 mmol, 25% yield). LCMS: 231.1 (M+H), Rt 1.07 min Column: ZORBAX XDB C-18 (50 X 4.6 mm), 3.5 pm Mobile Phase: A: 0.1% HCOOH in water : ACN (95:5), B: ACN; Plow Rate: 1.5 mL / min.

[0407] 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) wasadded trifluoromethanesulfonic anhydride (0.38 mL, 2.25 mmol) and 2-methoxypridine (377 mg, 3.46 mmol) at 0 °C. The reaction mixture was slowly warmed to room temperature and stirred for 16 hours. The reaction mixture was treated with 10% sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (2 x 25 mL). The organic layer was washed with brine (20 mL), dried over Na SCL and concentrated. The crude product was purified by column chromatography on silica gel with 35% EtOAc / PE to afford the product (100 mg, 0.47 mmol, 27% yield). LCMS: 213.1 (M+H), Rt 1.46 minColumn: Atlantis dCl8(50 X 4.6 mm), 5.0 pm Mobile Phase: A: 0.1% HCOOH in water : ACN (95:5), B: ACN; Flow Rate: 1.5 mL / min.

[0408] Synthesis of Compound 79: To a stirred solution of 6-chloro-3- (ethoxymethyl)-[l,2,4]triazolo[4,3-fl]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 l,4-dioxane (10.0 mL) was added water (1.0 mL) and CS2CO3(460 mg, 1.41 mmol). Pd(dppf)Cl2DCM (57 mg, 0.07 mmol) was added to the reaction mixture under 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 afford a solid (105 mg, 0.26 mmol, 36% yield). Prep. HPLC method: Rt 12.75; Column: X-Select (150 X 19 mm), 5.0 pm;Mobile phase: 0.1% TFA in water / acetonitrile; Flow Rate: 15.0 mL / min. HPLC: Rt 4.95 min, Column: XBridge C8 (50 X 4.6) mm, 3.5 pm Mobile phase: A: 0.1% TFA in water, B: 0.1% TFA in ACN; Flow Rate: 2.0 ml, / min. LCMS: 400.3 (M+H), Rt 2.41 min, Column: ZORBAX XDB C-18 (50 X 4.6 mm), 3.5 pm Mobile Phase: A: 0.1% HCOOH in water : ACN (95:5), B: ACN; Flow Rate: 1.5 mL / min. 'H NMR (400 MHz, DMSO-dg): d 9.56 (d, 1H), 9.17 (d, 1H), 8.78 (d, 1H), 8.45 (dd, 1H), 5.09 (s, 2H), 3.61 (q, 2H), 1.83 (s, 6H), 1.15 (t, 3H).Example 79: 3-(ethoxydifluoromethyl)-6-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)- [l,2,4]triazolo[4,3-a]pyrazine

[0409] To a stirred solution of 3-(chlorodifluoromethyl)-6-(6-(2,2,2- trifluoroethoxy)pyridin-3-yl)-[l,2,4]triazolo[4,3-a]pyrazine (190 mg, 0.50 mmol)) in MeCN (10.0 mL) was added CS2CO3(978 mg, 3.0 mmol) and ethanol (0.58 mL, 10 mmol) at room temperature and stirred for 3 hours. The reaction mixture was treated with water (15 mL) and extracted with ethyl acetate (2 x 20 mL). The organic layer was washed with brine (15 mL), dried over anhydrous Na2S04and concentrated. The crude compound was purified by preparative HPLC to afford a solid (10 mg, 0.025 mmol, 5.1% yield). Prep-HPLC method: Rt 9.35; Column: XBridge (150 X 19 mm), 5.0 pm; 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 pm 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-l8 (50 X 4.6 mm), 5 pm Mobile Phase: A: 0.1% HCOOH in water : ACN (95:5), B: ACN; Flow Rate: 1.5 mL / min. 'H NMR (400 MHz, CDCL): d 9.54 (d, 1H), 8.74 (d, 1H), 8.48 (d, 1H), 8.26 (dd, 1H), 7.06 (d, 1H), 4.87 (q, 2H), 4.38 (q, 2H), 1.52 (t, 3H).Example 80: 3-(difluoro(isobutoxy)methyl)-6-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin- 3-yl)-[l,2,4Jtriazolo[4,3-aJpyrazine

[0410] To a stirred solution of 2-methylpropan-l-ol (4.65 mL, 50.29 mmol) in MeCN(20 mL) was added CS2CO3(4.92 g, 15.09 mmol) and reaction mixture heated at 70 °C for 20 min. The reaction mixture was cooled to room temperature and 3-(chlorodifluoromethyl)-6- (5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)-[l,2,4]triazolo[4,3-a]pyrazine (1.0 g, 2.51mmol) was added. The reaction mixture was stirred for 4 h at room temperature and treated with water (30 mL). The reaction mixture was extracted with ethyl acetate (2 x 30 mL), washed with brine (20 mL), dried over Na SCp and concentrated. The crude compound was purified by preparative HPLC to afford a solid (35 mg, 0.08 mmol, 3% yield). Prep-HPLC method: Rt 9.37; Column: XBridge C8 (150 X 19 mm), 5.0 pm; 0.1% TFA inwater / acetonitrile; Flow Rate: 15.0 mL / min. HPLC: Rt 5.60 min, Column: XBridge C8 (50 X 4.6) mm, 3.5 pm Mobile phase: A: 0.1% TFA in water, B: 0.1% TFA in ACN; Flow Rate: 2.0 mL / min. LCMS: 436.1 (M+H), Rt 2.63 min, Column: XBridge C8 (50 X 4.6 mm), 3.5 pm Mobile Phase: A: 0.1% TFA in water : ACN (95:5), B: 0.1% TFA in ACN; Flow Rate: 1.5 mL / min. 'H NMR (400 MHz, DMSO-d6): d 9.72 (d, 1H), 8.97 (d, 1H), 8.77 (d, 1H), 8.54 (dd, 1H), 5.19 (q, 2H), 4.04 (d, 2H), 2.10-2.02 (m, 1H), 0.98 (d, 6H).Example 81: 5-[3-[difluoro(methoxy)methylJ-[l,2,4Jtriazolo[4,3-aJpyrazin-6-ylJpyridin- 2-oland 6-(6-benzyloxy-5-fluoro-3-pyridyl)-3-[ethoxy(difluoro)methyl]-[l,2,4]triazolo[4,3- ajpyrazine

[0411] 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) in portions at 0 °C over 0.5 hour.After the addition, the mixture was stirred at 20 °C for another 1 hour. Then 5-bromo-2- fluoro-pyridine (18.55 g, 105.4 2mmol) was added to the mixture. The resulting mixture was stirred at 20 °C for 3 hours. The mixture was poured into saturated aqueous NfL (150 mL)and extracted with EtOAc (200 mL x 2). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na3S04,filtered and concentrated to give the crude product (27 g, 95.62 mmol, 86% yield) as an oil. LCMS Rt= 0.96 min in 1.5 minchromatography, 5-95AB, MS ESI calcd. for Ci2HnBrNO[M+H+2]+266.0, found 265.8.

[0412] Synthesis of A93: A mixture of 2-benzyloxy-5-bromo-pyridine (27 g, 102.23 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2- dioxaborolane (31.15 g, 122.67 mmol), KOAc (20.06 g, 204.45 mmol) and Pd(dppf)Cl2 (7.48 g, l0.22mmol) in l,4-dioxane (300 mL) was stirred at 90 °C under N for 16 hours. 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 (~ 50 g) and eluted with PE / EtOAc (5:1, 150 mL x 5), and the filtrate was concentrated to give the impure product. The impure product was triturated from i-P^O (100 mL) to give the product (20 g, 64.27 mmol, 63% yield) as a solid.LCMS Rt= 0.74 min in 1.5 min chromatography, 5-95 AB, MS ESI calcd. forC^H sBNOslM-CeH o+Hf 230.1, found 230.0.

[0413] Synthesis of A94: A mixture of 2-bromo-5-chloro-pyrazine (4 g, 20.68 mmol), 2-benzyloxy-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (7.08 g, 22.75 mmol), CS2CO3 (l3.47g, 4l.36mmol) and Pd(dppf)Cl2 (1.51 g, 2.07 mmol) in l,4-dioxane (50mL) and water (lOmL) was stirred at 50 °C under N2 for 3 hours. After cooling to room temperature, the mixture was filtered and concentrated to give a residue. To the residue was added water (100 mL), extracted with EtOAc (150 mL x 2). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2S04, filtered and concentrated to give the crude product. The crude product was filtered through silica gel (~ 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 / -Pi O (15 mL) to give the product of (4 g, 13.44 mmol, 65% yield) as a solid. LCMS Rt= 1.03 min in 1.5 min chromatography, 5-95AB, MS ESI calcd. for Ci6H13ClN30 [M+H]+298.1, found 297.9.

[0414] Synthesis of A95: A mixture of 2-(6-benzyloxy-3-pyridyl)-5-chloro-pyrazine (4 g, 13.43 mmol) and N2H4Ή2O (8.61 g) in MeCN (20 mL) was stirred at 90 °C for 16hours. After cooling to room temperature, the solution was concentrated to give a residue. To the residue was added water (30 mL), extracted with EtOAc (50 mL x 3). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na SO^ filtered and concentrated to give the product (4g, 7.84 mmol, 58 % yield) as a solid. LCMS Rt= 0.74 min in 1.5 min chromatography, 5-95AB, MS ESI calcd. for E i4HiήN40 [M+H]+294.1, found 293.9.

[0415] Synthesis of A96: To a solution of 2-bromo-2,2-difluoro-acetyl chloride (1.78 g, 9.2 mmol) in DCM (20mL) 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 hours. The mixture was diluted with l¾0 (20 mL) and extracted with EtOAc (100 mL x 2). The combined organic phase was washed with brine (30 mL), dried over Na SCL, filtered and concentrated to give the product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 20% to 40% to 60% to 80%) to give the product of (1.5 g, 3.33 mmol, 54 % yield) as a solid. LCMS Rt= 0.88 min in 1.5 min chromatography, 10-80AB, MS ESI calcd. for C gH sF NsO [M+H]+450.0, found 449.9.

[0416] Synthesis of A97: To a mixture of N'-[5-(6-benzyloxy-3-pyridyl)pyrazin-2- yl]-2-bromo-2,2-difluoro-acetohydrazide (1.3 g, 2.89 mmol) in DCM (lOmL) was added 2- methoxypyridine (0.67mL, 6.35mmol) and TLO (0.59 mL, 3.46 mmol), and the mixture was stirred at 20 °C for 2 hours. To the mixture was added water (20 mL), extracted with DCM (50 mL x 2). The combined organic phase was washed with saturated aqueous NaHC(¾ (30 mL) and brine (30 mL), dried over Na SCp, filtered and concentrated to give the crude product. The crude product was purified by chromatography flash column 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 Rt= 0.93 min in 1.5 min chromatography, 10-80AB, MS ESI calcd. for CigH sBrF NsO [M+H+2]+434.0, found 434.0.

[0417] Synthesis of 83: A mixture of 6-(6-benzyloxy-3-pyridyl)-3- [bromo(difluoro)methyl]-[l,2,4]triazolo[4,3-fl]pyrazine (400 mg, 0.93 mmol) and AgBF4(900.79 mg, 4.63 mmol) in methanol (4 mL) was stirred at 60 °C under dark for 2 hours. After cooling to room temperature, saturated aqueous NaCl (10 mL) was added to themixture followed by EtOAc (30 mL), and the mixture was filtered through Celite. After the phases of the filtrate were separated, the organic phase was washed with brine (30 mL), dried over Na SCp, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 20% to 40%) to give the impure product (150 mg), which was triturated from / -P^O (2 mL) to give the pure product (130 mg). The product (39.76 mg, 0.10 mmol, 11% yield) was obtained as a solid. 'H NMR (400MHz, CDCI3) dH= 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 Rt= 1.26 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. for C iyH irTSN^O [M+H]+384.1, found 384.1.Example 82: 3-(difluoro(methoxy)methyl)-6-(6-(3,3-difluorocyclobutoxy)-5- fluoropyridin-3-yl)-[l,2,4]triazolo[4,3-a]pyridine

[0418] To a suspension of CS2CO3(928 mg, 2.85 mmol) in CH3CN (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 min. and a solution of 3-(chlorodifluoromethyl)-6-(6-(3,3- difluorocyclobutoxy)-5-fluoropyridin-3-yl)-[l,2,4]triazolo[4,3-a]pyridine (190 mg, 0.47 mmol) in CH3CN (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 x 25 mL). The organic layer was washed with brine (20 mL), dried over Na SCL and concentrated. The crude product was purified by preparative HPLC to afford 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 pm; 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 pm 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 pm Mobile Phase: A: 0.1% HCOOH in water : ACN (95:5), B: ACN; Flow Rate: 1.5mb / min. 'H NMR (400 MHz, CD3OD): d 8.65 (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).Example 83: 6-(6-(3,3-difluorocyclobutoxy)-5-fluoropyridin-3-yl)-3- (ethoxydifluoromethyl)-[l,2,4]triazolo[4,3-a]pyridine

[0419] Synthesis All: To a stirred solution of 5-bromo-2-fluoro-pyridine (10.0 g, 56.82 mmol) in ethanol (120 mL) was added hydrazine hydrate (11.38 g, 227 mmol) and heated to 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 get the product (10.7 g) as a solid. It was used for the next step without further purification.

[0420] Synthesis of A127: To a stirred solution of All (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 hour. The reaction mixture was cooled to room temperature and concentrated. The crude reaction mixture was treated with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The organic layer was washed with sat NaHCCL solution (20 mL) followed by brine (30 mL), dried over Na S04and concentrated to afford the product (2.7 g) as a solid. It was used for the next step without further purification.

[0421] 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- methoxypridine (1.96 g, 17.97 mmol) at 0 °C. The reaction mixture was slowly warmed to room temperature and stirred for 1 hour The reaction mixture was treated with 10% sodium bicarbonate solution (50 mL) and extracted with DCM (2 x 50 mL). The organic layer was washed with brine (50 mL), dried over Na SCL and concentrated. The crude product was purified by column chromatography on silica gel with 20% EtOAc / PE to afford the product (1.1 g, 3.9 mmol, 43% yield). 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 pmMobile Phase: A: 0.1% HCOOH in water : ACN (95:5), B: ACN; Flow Rate: 1.5 mL / min.

[0422] 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-l,3,2-dioxaborolan-2-yl)pyridine (1.28 g, 3.89 mmol) in l,4-dioxane (20.0 mL) was added water (4.0 mL)and K2CO3 (0.98 g, 7.08 mmol). Pd(PPh3)2Cl2 (0.25 g, 0.35 mmol) was added to the reaction mixture under nitrogen atmosphere and heated at 80 °C for 16 hours 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 x 30 mL). The organic layer was washed with brine (30 mL), dried over anhydrous Na2S04and concentrated. The crude compound was purified by column chromatography on silica gel with 40% ethyl acetate / PE to afford 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-l8 (50 X 4.6 mm), 5.0 pm Mobile Phase: A: 0.1% HCOOH in water : ACN (95:5), B: ACN; Flow Rate: 1.5 mL / min.

[0423] Synthesis of Compound 85: To a suspension of CS2CO3 (966 mg, 2.97 mmol) in CH3CN (2.0 mL) was added ethanol (0.35 mL, 5.93 mmol) at roomtemperature. The reaction mixture was stirred at room temperature for 10 min. and a solution of A125 (200 mg, 0.49 mmol) in CH3CN (10.0 mL) was added dropwise. The reaction mixture was stirred for 1 h and ethanol (0.35 mL, 5.93 mmol) was added at roomtemperature. The reaction mixture was stirred for another 1 h at room temperature. The reaction mixture was treated with water (20 mL) and extracted with ethyl acetate (2 x 25 mL). The organic layer was washed with brine (20 mL), dried over Na SCLand concentrated. The crude product was purified by column chromatography on silica gel with 22% EtOAc / PE to afford the product (30 mg, 0.07 mmol, 14% yield) as a solid. HPLC: Rt 4.92 min, 99.9% Column: X-Bridge C8 (50 X 4.6) mm, 3.5 pm Mobile phase: A: 0.1% TFA in water, B: 0.1% TFA in ACN; Flow Rate: 2.0 mF / min. LCMS: 415.1 (M+H), Rt 2.53 min, 99.8% Column: Atlantis dC-l8 (50 X 4.6 mm), 5.0 pm. Mobile Phase: A: 0.1% HCOOH in water : ACN (95:5), B: ACN; Flow Rate: 1.5 mF / min. 'H NMR (400 MHz, CD3OD): d 8.65 (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).Example 84: (R)-3-(ethoxydifluoromethyl)-6-(6-((l,l,l-trifluoropropan-2- yl)oxy)pyridin-3-yl)-[l,2,4]triazolo[4,3-a]pyrazine

[0424] Synthesis of A77: To a solution of A132 (2.2 g, 19.63 mmol) in THF (20.0 mL) was added F1AIH4(2.0 M in THF, 4.91 mF, 9.82 mmol) dropwise at 0 °C. The reaction mixture was slowly warmed to room temperature and stirred for 3 hours. The reaction mixture was cooled to 0 °C and treated with sat Na SCF solution (2.0 mF). The reaction mixture was filtered through Celite, the filtrate was dried over Na SCF and used for the next step as a solution in THF.

[0425] Synthesis of A78: To a solution ofAll (30.68 mmol) in THF was added NaH (1.84 g, 46 mmol) portion wise at 0 °C and stirred for 30 min. 5-bromo-2-fluoro-pyridine (4.32 g, 24.55 mmol) was added to the reaction mixture slowly at 0 °C. The reaction mixture was slowly warmed to room temperature and stirred for 3 hours. The reaction mixture wascooled to 10 °C, treated with ice water (10 mL) and extracted with ethyl acetate (2 x 50 mL). The organic layer was washed with brine (40 mL), dried over Na2S04and concentrated. The crude product was purified by column chromatography on silica gel with 20% EtOAc / PE to afford the product (3.1 g, 11.5 mmol, 37% yield) as a colourless 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 pm Mobile Phase: A: 0.1% HCOOH in water : ACN (95:5), B: ACN; Flow Rate: 1.5 mL / min.

[0426] 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 l,4-dioxane (35.0 mL) was added potassium acetate (2.25 g, 22.96 mmol). Pd(dppf)Cl2DCM (1.41 g, 1.72 mmol) was added to the reaction mixture under 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 with 6% ethyl acetate / PE to afford 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 X 4.6 mm), 5 pm Mobile Phase: A: 10 mM Ammonium acetate in water, B: ACN; Flow Rate: 1.2 mL / min.

[0427] Synthesis of A82: To a stirred solution of A79 (0.5 g, 1.58 mmol) and 6- chloro-3-(chlorodifluoromethyl)-[l,2,4]triazolo[4,3-a]pyrazine (0.45 g, 1.89 mmol) in 1,4- dioxane (12.0 mL)was added water (2.0 mL)and CS2CO3(1.03 g, 3.15 mmol).Pd(dppf)Cl2DCM (0.11 g, 0.16 mmol) was added to the reaction mixture under 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 with 15% ethyl acetate / PE to afford 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 X 4.6 mm), 3.5 pm Mobile Phase: A: 0.1% HCOOH in water : ACN (95:5), B: ACN; Flow Rate: 1.5 mL / min.

[0428] Synthesis of Compound 86: To a stirred suspension of CS2CO3(993 mg, 3.05 mmol) in MeCN (5.0 mL) was added ethanol (0.36 mL, 6.1 mmol) at room temperature and stirred for 30 min. To the reaction mixture A82 (200 mg, 0.51 mmol)in MeCN (5.0 mL) wasadded 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 Na SCL and concentrated The crude compound was purified by column chromatography on silica gel with 18% ethyl acetate / PE to afford 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 pm 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 pm Mobile Phase: A: 10 mM Ammonium acetate in water, B: ACN; Flow Rate: 1.2 mL / min. Chiral method: Rt 1.54 min, SFC column: Chiralcel OJ-H; mobile phase: 60:40 (A: B), A = liquid C(¾, B = 0.5% isopropyl amine in methanol; flow rate: 3.0 mL / min; wave length: 254 nm. H NMR (400 MHz, CD3OD): d 9.55 (d, 1H), 8.88-8.87 (m, 1H), 8.80 (d, 1H), 8.42 (dd, 1H), 7.03 (dd, 1H), 6.00-5.93 (m, 1H), 4.39 (q, 2H), 1.55-1.48 (m, 6H).Example 84: 3-(methoxymethyl)-6-(6-((l,l,l-trifluoro-2-methylpropan-2-yl)oxy)pyridin- 3-yl)-[l,2,4]triazolo[4,3-a]pyridine

[0429] Synthesis of A130: To a stirred solution of methoxyacetic acid (958 mg, 10.64 mmol) in DMF (30.0 mL) was added Et3N (2.97 mL, 21.27 mmol) followed by T3P (50% in ethyl acetate, 0.43 mL, 21.27 mmol) and 5-bromo-2-hydrazineylpyridine (2.0 g, 10.64 mmol). The reaction mixture was stirred at room temperature for 4 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 (40 mL), dried over anhydrous NibSCp andconcentrated. The crude compound was purified by column chromatography on silica gel with 20% ethyl acetate / PE to afford the product (900 mg, 3.47 mmol, 32% yield). LCMS: 260.1 (M+H) and 262.1 (M+2+H), Rt 1.10 min Column: ZORBAX XDB C-18 (50 X 4.6 mm), 3.5 pm Mobile Phase: A: 0.1% HCOOH in water: ACN (95:5), B: ACN; Flow Rate: 1.5 mL / min.

[0430] Synthesis of A131: To a stirred solution of A130 (250 mg, 0.96 mmol) in acetic acid (4.0 mL) was irradiated in microwave at 160 °C for 1 hour The reaction mixture was cooled to room temperature and treated with 10% sodium bicarbonate solution (20 mL). The reaction mixture was extracted with ethyl acetate (2 x 25 mL). The organic layer was washed with brine (2 x 20 mL), dried over Na2S04and concentrated. The crude product was purified by column chromatography on silica gel with 35% EtO Ac / PE to afford the product (110 mg, 0.45 mmol, 47% yield). LCMS: 242.1 (M+H) and 244.1 (M+2+H), Rt 1.18 min Column: ZORBAX XDB C-18 (50 X 4.6 mm), 3.5 pm Mobile Phase: A: 0.1% HCOOH in water : ACN (95:5), B: ACN; Flow Rate: 1.5 mL / min.

[0431] Synthesis of Compound 87: To a stirred solution of 5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-2-((l,l,l-trifluoro-2-methylpropan-2-yl)oxy)pyridine (250 mg, 0.75 mmol) and A131 (200 mg, 0.83 mmol) in l,4-dioxane (5.0 mL) was added water (1.0 mL) and CS2CO3(491 mg, 1.51 mmol). Pd(dppf)Cl2DCM (65 mg, 0.08 mmol) was added to the reaction mixture under 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 afford the product (90 mg, 0.24 mmol, 32% yield) as a solid. Prep-HPLC method: Rt 8.37; Column: X- Bridge C-18 (150 X 19 mm), 5.0 pm; 0.1% TFA in water / acetonitrile; Flow Rate: 15.0 mL / min. HPLC: Rt 4.18 min, Column: X-Bridge C8 (50 X 4.6) mm, 3.5 pm Mobile phase: A: 0.1% TFA in water, B: 0.1% TFA in ACN; Flow Rate: 2.0 mL / min. LCMS: 367.1 (M+H), Rt 2.12 min, Column: ZORBAX XDB C-18 (50 X 4.6 mm), 3.5 pm Mobile Phase: A: 0.1% HCOOH in water: ACN (95:5), B: ACN; Flow Rate: 1.5 mL / min. 'H NMR (400 MHz, DMSO-d6): d 8.79-8.78 (m, 1H), 8.63 (d, 1H), 8.20 (dd, 1H), 7.92 (dd, 1H), 7.81 (dd, 1H), 7.04 (d, 1H), 5.02 (s, 2H), 3.34 (s, 3H), 1.82 (s, 6H).Example 86: 3-(ethoxydifluoromethyl)-6-(6-((l,l,l-trifluoro-2-methylpropan-2- yl)oxy)pyridin-3-yl)-[l,2,4]triazolo[4,3-a]pyrazine

[0432] Synthesis of A134: To a stirred solution of l,l,l-trifluoro-2-methyl-propan-2- ol (5.0 g, 39.04 mmol) in THF (60.0 mL) at 0 °C was added potassium tert-butoxide (6.57 g, 58.55 mmol) in small portions. The reaction mixture was slowly warmed to roomtemperature and stirred for 15 min. 5-bromo-2-fluoro-pyridine (6.87 g, 39.04 mmol) was added drop-wise 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 x 60 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na SCL and concentrated. The crude compound was purified by columnchromatography on silica gel with 5% ethyl acetate / PE to afford the product (2.3 g, 8.1 mmol, 20% yield). LCMS: 284.0 (M+H) and 286.0 (M+2+H), Rt 2.96 min Column:ZORBAX XDB C-18 (50 X 4.6 mm), 3.5 pm Mobile Phase: A: 0.1% HCOOH in water: ACN (95:5), B: ACN; Flow Rate: 1.5 mL / min.

[0433] Synthesis A50: To a stirred solution of A134 (2.3 g, 8.1mmol) and bis(pinacolato)diboron (2.26 g, 8.91 mmol) in l,4-dioxane (40.0 mL) was added potassium acetate (1.59 g, 16.19 mmol). Pd(dppf)Cl2 DCM (0.66 g, 0.81 mmol) was added to the reaction mixture under nitrogen atmosphere and heated at 80 °C for 12 hours. The reaction mixture was cooled to room temperature, filtered through Celite andconcentrated under reduced pressure. The crude compound was purified by column chromatography on silica gel with 5% ethyl acetate / PE to afford the product (1.8 g, 5.4 mmol, 66% yield). LCMS: 332.1 (M+H), Rt 3.21 min Column: ATLANTIS dC-18 (50 X 4.6 mm), 3.5 pm Mobile Phase: A: 0.1% HCOOH in water: ACN (95:5), B: ACN; Flow Rate: 1.5 mL / min.

[0434] Synthesis of A53: To a stirred solution of A50 (1.2 g, 3.62 mmol) and 6- chloro-3-(chlorodifluoromethyl)-[l,2,4]triazolo[4,3-a]pyrazine (0.95 g, 3.99 mmol) in 1,4- dioxane (20.0 mL) was added water (2.0 mL) and CS2CO3(2.36 g, 7.25 mmol).Pd(dppf)Cl2DCM (0.3 g, 0.36 mmol) was added to the reaction mixture under 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 product was purified by column chromatography on silica gel with 30% ethyl acetate / PE to afford the product (0.75 g, 1.84 mmol, 50% yield). LCMS: 408.0 (M+H), Rt 2.68 min Column: ZORBAX XDB C-18 (50 X 4.6 mm), 3.5 pm Mobile Phase: A: 0.1% HCOOH in water: ACN (95:5), B: ACN; Flow Rate: 1.5 mL / min.

[0435] Synthesis of Compound 88: To a stirred suspension of CS2CO3(1.43 g, 4.41 mmol) in MeCN (3.0 mL) was added ethanol (0.52 mL, 8.83 mmol) at room temperature and stirred for 15 min. To the reaction mixture A53 (300 mg, 0.74 mmol) in MeCN (3.0 mL) was added dropwise and stirred for 6 hours. The reaction mixture was treated with water (50 mL) and extracted with ethyl acetate (2 x 25 mL). The organic layer was washed with brine (2 x 20 mL), dried over Na2S04and concentrated. The crude product was purified by column chromatography on silica gel with 15% EtO Ac / PE to afford the product (20 mg, 0.047 mmol, 6% yield) as a solid. HPLC: Rt 5.50 min, 98.5% Column: X-Bridge C8 (50 X 4.6) mm, 3.5 pm Mobile phase: A: 0.1% TFA in water, B: 0.1% TFA in ACN; Flow Rate: 2.0 mL / min. LCMS: 418.1 (M+H), Rt 2.68 min, 97.8% Column: ZORBAX XDB C-18 (50 X 4.6 mm),3.5 pm Mobile Phase: A: 0.1% HCOOH in water : ACN (95:5), B: ACN; Flow Rate: 1.5 mL / min. 'H NMR (400 MHz, DMSO-d6): d 9.70 (d, 1H), 8.91 (d, 2H), 8.46 (dd, 1H), 7.04 (d, 1H), 4.32 (q, 2H), 1.83 (s, 6H), 1.39 (t, 3H).Example 87: Synthesis of Compound 89

[0436] To a stirred solution of 3-(chlorodifluoromethyl)-6-(6-(2,2,2- trifluoroethoxy)pyridin-3-yl)-[l,2,4]triazolo[4,3-a]pyrazine (146 mg, 0.38 mmol) in MeCN (5.0 mL) was added CS2CO3(751 mg, 2.3 mmol) and 2-methoxyethanol (0.38 mL, 4.8 mmol) at room temperature. The reaction mixture was stirred for 3 h. The reaction mixture was treated water (15 mL) and extracted with ethyl acetate (2 x 15 mL). The organic layer was washed with brine (20 mL), dried over Na SCL and concentrated. The crude compound was purified by preparative HPLC to afford the product (15 mg, 0.03 mmol, 9% yield) as a solid. Prep-HPLC method: Rt 11.3...

Claims

Listing of Claims:

1. A compound having the Formula I:or a pharmaceutically acceptable salt thereof, whereinX and Y are each independently CRdor N;"XR2R1is R3R4, monocyclic C3-6cycloalkyl, or 4- to 7-membered monocyclic heterocyclyl, wherein said cycloalkyl and heterocyclyl are optionally substituted with one or more Ra;R is Cthaloalkyl, phenyl, or monocyclic C3-6cycloalkyl optionally substituted with one or more Rb;R is hydrogen, Ci-4alkyl, or Cthaloalkyl;R4is hydrogen or Ci-4alkyl;R5is halo;R6is Ci-4alkyl or Ci-4haloalkyl, wherein said Ci-4alkyl or Ci-4haloalkyl are each substituted with ORc;t is 0, 1, or 2;R a and R b are each independently selected from is selected from halo, Ci-4alkyl, -4haloalkyl, Ci-4alkoxy, and Ci-4haloalkoxy,Rcis Ci-4alkyl optionally substituted with C3-6cycloalkyl or ^alkoxy, or C3-6cycloalkyl; andRdis hydrogen or Ci-4alkyl;provided the compound is not a compound having the formula:pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein the compound is of the Formula I-a:or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 1.

3. The compound of claim 1 or 2, wherein the compound is of the Formula I-b:or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 1.The compound of claim 1 or 2, wherein the compound is of the Formula II:or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 1.

5. The compound of claim 1, 2 or 4, wherein the compound is of the Formula III:or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 1.

6. The compound of claim 1, wherein the compound is of the Formula I-c:or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 1.

7. A compound having the Formula I-d:or a pharmaceutically acceptable salt thereof, wherein"XR2R1is R3R4, monocyclic C3-6 cycloalkyl, or 4- to 7-membered monocyclic heterocyclyl, wherein said cycloalkyl and heterocyclyl are optionally substituted with one or more Ra;R is Ci-4haloalkyl, phenyl, or monocyclic C3-6cycloalkyl optionally substituted with one or more Rb;R is hydrogen, Ci-4alkyl, or Ci-4haloalkyl;R4is hydrogen or Ci-4alkyl;R5is halo;R6is Ci-4alkyl or Ci-4haloalkyl, wherein said Ci-4alkyl or Ci-4haloalkyl are each substituted with ORc;t is 0, 1, or 2;Raand Rbare each independently selected from is selected from halo, Ci-4alkyl, - 4haloalkyl, Ci-4alkoxy, and Ci-4haloalkoxy;Rcis Ci-4alkyl optionally substituted with C3-6cycloalkyl or ^alkoxy, or C3-6cycloalkyl; andRdis hydrogen or Ci-4alkyl.The compound of any one of claims 1-5 and 7, wherein the compound is of theFormula V :or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 1.

9. The compound of any one of claims 1, 6, and 7, wherein the compound is of the Formula VII:or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 1.

10. The compound of any one of claims 1-5, wherein the compound is of the Formula VIII:or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 1.

11. The compound of any one of claims 1-5, wherein the compound is of the Formulaor a pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 1.

12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein13. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein R1is cyclobutyl optionally substituted with one or more Ra.

14. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt2thereof, wherein R is Cj^haloalkyl.

15. The compound of any one of claims 1-12 and 14, or a pharmaceutically acceptable2salt thereof, wherein R is CF3.

16. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt2thereof, wherein R is phenyl.

17. The compound of any one of claims 1-12 and 14-16, or a pharmaceutically acceptable salt thereof, wherein R3is Ci-4alkyl and R4is hydrogen or Ci-4alkyl.

18. The compound of any one of claims 1-12 and 14-17, or a pharmaceutically acceptable salt thereof, wherein R3and R4are each Ci-4alkyl.

19. The compound of any one of claims 1-12 and 14-18, or a pharmaceutically acceptable salt thereof, wherein R3and R4are each methyl.

20. The compound of any one of claims 1-12 and 14-17, or a pharmaceutically acceptable salt thereof, wherein R3is methyl and R4is hydrogen.

21. The compound of any one of claims 1-12 and 14-16, or a pharmaceutically acceptable salt thereof, wherein R3and R4are each hydrogen.

22. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, wherein R6is -CF2-ORc.

23. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein Rcis Ci-4alkyl optionally substituted with cyclopropyl.

24. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein Rcis cyclopropyl.

25. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt thereof, wherein R6is -C(F2)OCH2CH(CH3)2, -C(F2)OCH3, -C(F2)OCH2CH3, - C(F2)OCH(CH3)2,or -C(F2)OCH2C3H5.

26. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, wherein R6is -Cl¾-C)Rc.

27. The compound of any one of claims 1-21 and 26, or a pharmaceutically acceptable salt thereof, wherein Rcis C1 alkyl.

28. The compound of any one of claims 1-21, 26, and 27, or a pharmaceutically acceptable salt thereof, wherein R6is -CH2OCH3, -CH2OCH2CH3, or -CH20CH2CH(CH3)2.

29. The compound of any one of claims 1-11, 13, and 22-28, or a pharmaceutically acceptable salt thereof, wherein Rais Ci-4haloalkyl.

30. The compound of any one of claims 1-11, 13, and 22-29, or a pharmaceutically acceptable salt thereof, wherein Rais CF3.

31. The compound of any one of claims 1-11, 13, and 22-28, or a pharmaceutically acceptable salt thereof, wherein Rais fluoro.

32. The compound of any one of claims 1, 7, and 12-31, or a pharmaceutically acceptable salt thereof, wherein t is 1.

33. The compound of any one of claims 1, 7 and 12-31, or a pharmaceutically acceptable salt thereof, wherein t is 0.

34. The compound of any one of claims 1-7 and 12-33, or a pharmaceutically acceptable salt thereof, wherein Rdis methyl.

35. The compound of any one of claims 1-7 and 12-33, or a pharmaceutically acceptable salt thereof, wherein Rdis hydrogen.

36. The compound of claim 1, wherein the compound is selected from the group consisting of:wo 2019 / 232209wo 2019 / 232209wo 2019 / 232209pharmaceutically acceptable salt thereof.

37. The compound of claim 36, wherein the compound is selected from the group consisting of:pharmaceutically acceptable salt thereof.

38. A crystalline compound of formula:wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 6.9+0.2, 16.5+0.2, and 20.8+0.2.

39. The crystalline compound of claim 38, wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q):6.9+0.2, 13.9+0.2, 16.5+0.2, 19.5+0.2, and 20.8+0.2.

40. The crystalline compound of claim 38 or 39, wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 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.

41. The crystalline compound of any one of claims 38-40, wherein the crystalline compound exhibits an X-ray powder diffraction pattern substantially the same as depicted in FIG. 2A.

42. The crystalline compound of any one of claims 38-41, wherein the crystalline compound has a melting point onset as determined by differential scanning calorimetry at about 140 °C.

43. The crystalline compound of any one of claims 38-42, wherein the crystalline compound has a differential scanning calorimetry curve substantially the same as shown in FIG. 2B.

44. A crystalline compound of formula:wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 16.7+0.2, 19.0+0.2, and 20.4+0.2.

45. The crystalline compound of claim 43, wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q):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.

46. The crystalline compound of claim 44 or 45, wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 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.

47. The crystalline compound of any one of claims 44-46, wherein the crystalline compound exhibits an X-ray powder diffraction pattern substantially the same as depicted in FIG. 3 A.

48. The crystalline compound of any one of claims 44-47, wherein the crystalline compound has a melting point onset as determined by differential scanning calorimetry at about 68 °C.

49. The crystalline compound of any one of claims 44-48, wherein the crystalline compound has a differential scanning calorimetry curve substantially the same as shown in FIG. 3B.

50. A crystalline compound of formula:wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 7.3+0.2, 14.5+0.2, and 21.9+0.2.

51. The crystalline compound of claim 50, wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q):7.3+0.2, 14.5+0.2, 17.9+0.2, 19.0+0.2, and 21.9+0.2.

52. The crystalline compound of claim 50 or 51 , wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 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.

53. The crystalline compound of any one of claims 50-52, wherein the crystalline compound exhibits an X-ray powder diffraction pattern substantially the same as depicted in FIG. 4A.

54. The crystalline compound of any one of claims 50-53, wherein the crystalline compound has a melting point onset as determined by differential scanning calorimetry at about 136 °C.

55. The crystalline compound of any one of claims 50-54, wherein the crystalline compound has a differential scanning calorimetry curve substantially the same as shown in FIG. 4B.

56. A crystalline compound of formula:wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 12.6+0.2, 15.8+0.2, and 18.6+0.2.

57. The crystalline compound of claim 56, wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 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.

58. The crystalline compound of claim 56 or 57, wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 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.

59. The crystalline compound of any one of claims 56-58, wherein the crystalline compound exhibits an X-ray powder diffraction pattern substantially the same as depicted inFIG. 5 A.

60. The crystalline compound of any one of claims 56-59, wherein the crystalline compound has a melting point onset as determined by differential scanning calorimetry at about 107 °C.

61. The crystalline compound of any one of claims 56-60, wherein the crystalline compound has a differential scanning calorimetry curve substantially the same as shown in FIG. 5B.

62. A crystalline compound of formula:wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 5.8+0.2, 19.7+0.2, and 21.0+0.2.

63. The crystalline compound of claim 62, wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q):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.

64. The crystalline compound of claim 62 or 63, wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 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.

65. The crystalline compound of any one of claims 62-64, wherein the crystalline compound exhibits an X-ray powder diffraction pattern substantially the same as depicted in FIG. 6 A.

66. The crystalline compound of any one of claims 62-65, wherein the crystalline compound has a melting point onset as determined by differential scanning calorimetry at about 94 °C.

67. The crystalline compound of any one of claims 62-66, wherein the crystalline compound has a differential scanning calorimetry curve substantially the same as shown in FIG. 6B.

68. A crystalline compound of formula:wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 7.3+0.2, 16.6+0.2, and 18.4+0.2.

69. The crystalline compound of claim 68, wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q):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.

70. The crystalline compound of claim 68 or 69, wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 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.

71. The crystalline compound of any one of claims 68-70, wherein the crystalline compound exhibits an X-ray powder diffraction pattern substantially the same as depicted in FIG. 7 A.

72. The crystalline compound of any one of claims 68-71, wherein the crystalline compound has a melting point onset as determined by differential scanning calorimetry at about 103 °C.

73. The crystalline compound of any one of claims 68-72, wherein the crystalline compound has a differential scanning calorimetry curve substantially the same as shown in FIG. 7B.

74. A crystalline compound of formula:wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 6.9+0.2, 16.4+0.2, and 19.5+0.2.

75. The crystalline compound of claim 74, wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 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.

76. The crystalline compound of claim 74 or 75, wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 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.

77. The crystalline compound of any one of claims 74-76, wherein the crystalline compound exhibits an X-ray powder diffraction pattern substantially the same as depicted in FIG. 8 A.

78. The crystalline compound of any one of claims 74-77, wherein the crystalline compound has a melting point onset as determined by differential scanning calorimetry at about 133 °C.

79. The crystalline compound of any one of claims 74-78, wherein the crystalline compound has a differential scanning calorimetry curve substantially the same as shown in FIG. 8B.

80. A crystalline compound of formula:wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 9.9+0.2, 19.8+0.2, and 23.7+0.2.

81. The crystalline compound of claim 80, wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 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.

82. The crystalline compound of claim 80 or 81 , wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 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.

83. The crystalline compound of any one of claims 80-82, wherein the crystalline compound exhibits an X-ray powder diffraction pattern substantially the same as depicted in FIG. 9 A.

84. The crystalline compound of any one of claims 80-83, wherein the crystalline compound has a melting point onset as determined by differential scanning calorimetry at about 111 °C.

85. The crystalline compound of any one of claims 80-84, wherein the crystalline compound has a differential scanning calorimetry curve substantially the same as shown in FIG. 9B.

86. A crystalline compound of formula:wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 9.3+0.2, 18.8+0.2, and 21.4+0.2.

87. The crystalline compound of claim 86, wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q):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.

88. The crystalline compound of claim 86 or 87, wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2Q): 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.

89. The crystalline compound of any one of claims 86-88, wherein the crystalline compound exhibits an X-ray powder diffraction pattern substantially the same as depicted in FIG. 1A.

90. The crystalline compound of any one of claims 86-89, wherein the crystalline compound has a melting point onset as determined by differential scanning calorimetry at about 122 °C.

91. The crystalline compound of any one of claims 86-90, wherein the crystalline compound has a differential scanning calorimetry curve substantially the same as shown in FIG. 1B.

92. The crystalline compound of any one of claims 38-91, wherein the X-ray powder diffraction pattern was obtained using Cu Ka radiation.

93. A pharmaceutical composition comprising a compound of any one of claims 1-92, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

94. A composition comprising a compound of any one of cl aims 1-92, or apharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

95. A pharmaceutical composition comprising a compound of any one of claims 1-92, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier as claimed in claim 93, for use in medicine.

96. A method of treating a condition relating to aberrant function of a sodium ion channel in a subject, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-92, or a pharmaceutically acceptable salt thereof, a composition of claim 94, or a pharmaceutical composition of claim 93 or 95.

97. The method of claim 96, wherein the condition is a neurological or psychiatric disorder.

98. The method of claim 96 or 97, wherein the condition is epilepsy or an epilepsy syndrome.

99. The method of any one of claims 96-98, wherein the condition is a genetic epilepsy or a genetic epilepsy syndrome.

100. The method of any one of claims 96-99, wherein the condition is a pediatric epilepsy or a pediatric epilepsy syndrome.

101. The method of any one of claims 96-100, wherein the condition is epileptic encephalopathy.

102. The method of claim 101, wherein the epileptic encephalopathy is selected from the group consisting of Dravet syndrome, infantile spasms, or Lennox-Gastaut syndrome.

103. The method of claim 101 or 102, wherein 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 mutation, generalized epilepsy with febrile seizures, intractable childhood epilepsy with generalized tonic -clonic seizures, infantile spasms, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutation, cryptogenic pediatric partial epilepsy with SCN3A mutation, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussen encephalitis, malignant migrating partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, sudden expected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy.

104. A method of treating a neurological disorder or a psychiatric disorder, wherein the method comprises administering to a subject in need thereof the compound of any one of claims 1-92, or a pharmaceutically acceptable salt thereof, a composition of claim 94, or a pharmaceutical composition of claim 93 or 95.

105. A method of treating a pain, wherein the method comprises administering to a subject in need thereof a compound of any one of claims 1-92, or a pharmaceutically acceptable salt thereof, a composition of claim 94, or a pharmaceutical composition of claim 93 or 95.

106. A composition comprising a compound of any one of cl aims 1-92, or apharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 93 or 95, or the composition of claim 94 for treating a condition relating to aberrant function of a sodium ion channel in a subject.

107. The composition or the pharmaceutical composition of claim 106, wherein the condition is a neurological or psychiatric disorder.

108. The composition or the pharmaceutical composition of claim 106, wherein the condition is a pain.

109. The composition or the pharmaceutical composition of claim 106 or 107, wherein the condition is epilepsy or an epilepsy syndrome.

110. The composition or the pharmaceutical composition of any one of claims 106, 107, or 109, wherein the condition is a genetic epilepsy or a genetic epilepsy syndrome.

111. The composition or the pharmaceutical composition of any one of claims 106, 107, 109, or 110, wherein the condition is a pediatric epilepsy or a pediatric epilepsy syndrome.

112. The composition or the pharmaceutical composition of any one of claims 106, 107, and 109-111, wherein the condition is epileptic encephalopathy.

113. The composition or the pharmaceutical composition of claim 112, wherein the epileptic encephalopathy is selected from the group consisting of Dravet syndrome, infantile spasms, and Lennox-Gastaut syndrome.

114. The composition or the pharmaceutical composition of claim 112 or 113, wherein 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 mutation, generalized epilepsy with febrile seizures, intractable childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutation, cryptogenic pediatric partial epilepsy with SCN3A mutation, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussen encephalitis, malignant migrating partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, sudden expected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy.

115. A composition comprising a compound of any one of cl aims 1-92 or apharmaceutically acceptable salt thereof, the pharmaceutical composition of claim 93 or 95, or the composition of claim 94 for treating a neurological disorder or a psychiatric disorder.