Ion channel modulators

Abstract

The present invention relates, in part, to fused heteroaryl compounds and compositions useful in the prevention and / or treatment of diseases or conditions associated with abnormal function of voltage-gated sodium ion channels, such as abnormal late / persistent sodium current. Also provided herein are methods of treating diseases or conditions associated with abnormal function of sodium ion channels, including neurological conditions (e.g., Degravir Syndrome, Epilepsy), pain, and neuromuscular disorders.

Description

[0001] This application is a divisional application of the Chinese invention patent application (application date: May 30, 2019; application number: 201980047216.4 (International application number: PCT / US2019 / 034653); invention name: Ion channel regulator).

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to and the benefit of U.S. Provisional Patent Application No. 62 / 677,903, filed May 30, 2018, and No. 62 / 738,508, filed September 28, 2018, each of which is incorporated herein by reference in its entirety. Background Art

[0004] Sodium ion (Na+) channels open primarily in a transient manner and rapidly inactivate, thereby generating a fast Na+ current to initiate an action potential. Late or persistent sodium current (INaL) is a persistent component of the fast Na+ current in cardiac myocytes and neurons. Many common neurological and cardiac diseases are associated with abnormal INaL enhancement, which contributes to the pathogenicity of both electrical and contractile dysfunction in mammals (e.g., see Pharmacol Ther (2008) 119: 326-339). Therefore, pharmaceutical compounds that selectively modulate sodium channel activity (e.g., abnormal INaL) can be used to treat such disease states. Summary of the Invention

[0005] Described herein are fused heteroaryl compounds and compositions that are useful for preventing and / or treating diseases, disorders, or conditions, such as those associated with abnormal function of sodium ion channels, such as abnormal late sodium current (INaL).

[0006] In one aspect, the present invention provides compounds having Formula I:

[0007]

[0008] or a pharmaceutically acceptable salt thereof, wherein

[0009] X and Y are each independently CR d or N;

[0010] R 1 yes Monocyclic C 3-6 Cycloalkyl or 4 to 7 membered monocyclic heterocyclic group, wherein the cycloalkyl and heterocyclic group are optionally substituted by one or more R a replace;

[0011] R 2 It is C 1-4Halogenated alkyl, phenyl or monocyclic C 3-6 Cycloalkyl, which is optionally substituted by one or more R b replace;

[0012] R 3 It is hydrogen, C 1-4 Alkyl or C 1-4 alkyl halide;

[0013] R 4 is hydrogen or C 1-4 alkyl;

[0014] R 5 It is a halogen;

[0015] R 6 It is C 1-4 Alkyl or C 1-4 haloalkyl, wherein the C 1-4 Alkyl or C 1-4 Each of the haloalkyl groups is substituted by OR c replace;

[0016] t is 0, 1, or 2;

[0017] R a and R b are each independently selected from halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy and C 1-4 Haloalkoxy,

[0018] R c Is optional C 3-6 Cycloalkyl or C 1-4 Alkoxy-substituted C 1-4 Alkyl, or C 3-6 cycloalkyl; and

[0019] R d is hydrogen or C 1-4 alkyl;

[0020] Provided that the compound is not a compound having the formula:

[0021] or a pharmaceutically acceptable salt thereof.

[0022] In some embodiments, the compound has Formula Ia:

[0023]

[0024] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0025] In some embodiments, the compound has Formula Ib:

[0026]

[0027] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0028] In some embodiments, the compound has Formula II:

[0029]

[0030] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0031] In some embodiments, the compound has Formula III:

[0032]

[0033] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0034] In some embodiments, the compound has Formula Ic:

[0035]

[0036] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0037] In another aspect, the present invention provides compounds having Formula Id:

[0038]

[0039] or a pharmaceutically acceptable salt thereof, wherein

[0040] R 1 yes Monocyclic C 3-6 Cycloalkyl or 4 to 7 membered monocyclic heterocyclic group, wherein the cycloalkyl and heterocyclic group are optionally substituted by one or more R a replace;

[0041] R 2 It is C 1-4 Halogenated alkyl, phenyl or monocyclic C 3-6 Cycloalkyl, which is optionally substituted by one or more R b replace;

[0042] R 3 It is hydrogen, C 1-4 Alkyl or C 1-4 alkyl halide;

[0043] R 4 is hydrogen or C 1-4 alkyl;

[0044] R 5 It is a halogen;

[0045] R 6 It is C 1-4 Alkyl or C 1-4 haloalkyl, wherein the C 1-4 Alkyl or C 1-4 Each of the haloalkyl groups is substituted by OR c replace;

[0046] t is 0, 1, or 2;

[0047] R a and R b are each independently selected from halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy and C 1-4 Haloalkoxy;

[0048] R c Is optional C 3-6 Cycloalkyl or C 1-4 Alkoxy-substituted C 1-4 Alkyl, or C 3-6 cycloalkyl; and

[0049] R d is hydrogen or C 1-4 alkyl.

[0050] In some embodiments, the compound has Formula V:

[0051]

[0052] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0053] In some embodiments, the compound has Formula VII:

[0054]

[0055] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0056] In some embodiments, the compound has Formula VIII:

[0057]

[0058] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0059] In some embodiments, the compound has Formula VIII:

[0060]

[0061] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0062] In another aspect, provided herein is a crystalline compound of the formula:

[0063]

[0064] wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 6.9±0.2, 16.5±0.2, and 20.8±0.2.

[0065] In another aspect, provided herein is a crystalline compound of the formula:

[0066]

[0067] wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 16.7±0.2, 19.0±0.2, and 20.4±0.2.

[0068] In another aspect, the present invention provides a crystalline compound of the formula:

[0069]

[0070] wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 7.3±0.2, 14.5±0.2, and 21.9±0.2.

[0071] In another aspect, the present invention provides a crystalline compound of the formula:

[0072]

[0073] wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 12.6±0.2, 15.8±0.2, and 18.6±0.2.

[0074] In another aspect, the present invention provides a crystalline compound of the formula:

[0075]

[0076] wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 5.8±0.2, 19.7±0.2, and 21.0±0.2.

[0077] In another aspect, the present invention provides a crystalline compound of the formula:

[0078]

[0079] wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 7.3±0.2, 16.6±0.2, and 18.4±0.2.

[0080] In another aspect, the present invention provides a crystalline compound of the formula:

[0081]

[0082] wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 6.9±0.2, 16.4±0.2, and 19.5±0.2.

[0083] In another aspect, the present invention provides a crystalline compound of the formula:

[0084]

[0085] wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 9.9±0.2, 19.8±0.2, and 23.7±0.2.

[0086] In another aspect, the present invention provides a crystalline compound of the formula:

[0087]

[0088] wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 9.3±0.2, 18.8±0.2, and 21.4±0.2.

[0089] In another aspect, provided herein are pharmaceutical compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0090] In another aspect of the present invention, compositions comprising a compound disclosed herein (e.g., a compound of Formula I, I', Ia, Ib, Ic, Id, II, III, V, VII, VIII, or IX), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier are provided.

[0091] Also provided herein are pharmaceutical compositions comprising a compound disclosed herein (e.g., a compound of Formula I, I', Ia, Ib, Ic, Id, II, III, V, VII, VIII, or IX), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier for use in medicine.

[0092] In another aspect, provided herein are methods for treating a disorder associated with abnormal function of sodium ion channels in a subject, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I, I', Ia, Ib, Ic, Id, II, III, V, VII, VIII, or IX), or a pharmaceutically acceptable salt thereof, or a composition or pharmaceutical composition disclosed herein.

[0093] In some embodiments, the condition is a neurological disorder or a psychiatric disorder. In some embodiments, the condition is epilepsy or an epileptic syndrome. In some embodiments, the condition is hereditary epilepsy or a hereditary epileptic syndrome. In some embodiments, the condition is pediatric epilepsy or a pediatric epilepsy syndrome. In some embodiments, the condition is an epileptic encephalopathy. In some embodiments, the epileptic encephalopathy is selected from the group consisting of: Dravet syndrome, infantile spasms, and Lennox-Gastaut syndrome.

[0094] In some embodiments, the disorder is selected from the group consisting of epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutations, generalized epilepsy with febrile seizures, intractable childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutations, cryptogenic partial epilepsy of childhood with SCN3A mutations, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussen encephalitis, malignant migratory partial epilepsy of infancy, autosomal dominant nocturnal frontal lobe epilepsy, sudden unexpected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy.

[0095] In another aspect, provided herein are methods of treating a neurological or psychiatric disorder, wherein the method comprises administering to a subject in need thereof a compound disclosed herein (e.g., a compound of Formula I, I', Ia, Ib, Ic, Id, II, III, V, VII, VIII, or IX), or a pharmaceutically acceptable salt thereof, or a composition or pharmaceutical composition disclosed herein.

[0096] In another aspect, the present invention provides a method of treating pain, wherein the method comprises administering to a subject in need thereof a compound disclosed herein (e.g., a compound of Formula I, I', Ia, Ib, Ic, Id, II, III, V, VII, VIII, or IX), or a pharmaceutically acceptable salt thereof, or a composition or pharmaceutical composition disclosed herein.

[0097] The present invention also provides compositions comprising a compound disclosed herein (e.g., a compound of Formula I, I', Ia, Ib, Ic, Id, II, III, V, VII, VIII, or IX) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, or a composition disclosed herein for use in treating a disorder associated with abnormal function of a sodium ion channel in a subject.

[0098] In some embodiments, the condition is a neurological disorder or a psychiatric disorder. In some embodiments, the condition is pain. In some embodiments, the condition is epilepsy or an epilepsy syndrome. In some embodiments, the condition is hereditary epilepsy or a hereditary epilepsy syndrome. In some embodiments, the condition is pediatric epilepsy or a pediatric epilepsy syndrome. In some embodiments, the condition is an epileptic encephalopathy. In some embodiments, the epileptic encephalopathy is selected from the group consisting of Dravet syndrome, infantile spasms, and Regelian syndrome.

[0099] In some embodiments, the disorder is selected from: epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutations, generalized epilepsy with febrile seizures, intractable childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutations, cryptogenic partial epilepsy of childhood with SCN3A mutations, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussen encephalitis, malignant migratory partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, sudden unexpected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy.

[0100] In another aspect, the present invention provides a composition comprising a compound disclosed herein (e.g., a compound of Formula I, I', Ia, Ib, Ic, Id, II, III, V, VII, VIII, or IX), or a pharmaceutically acceptable salt thereof, a pharmaceutical composition disclosed herein, or a composition disclosed herein for use in treating a neurological disorder or a psychiatric disorder.

[0101] Other objects and advantages will become apparent to those skilled in the art from consideration of the following detailed description, examples, and claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0102] Figure 1A The XRPD pattern of Compound 10 starting material is shown.

[0103] Figure 1B DSC of compound 10 is shown.

[0104] Figure 2AThe XRPD pattern of Compound 62 starting material is shown.

[0105] Figure 2B DSC of compound 62 is shown.

[0106] Figure 3A The XRPD pattern of Compound 6B starting material is shown.

[0107] Figure 3B Shown is the DSC of compound 6B.

[0108] Figure 4A The XRPD pattern of Compound 56 starting material is shown.

[0109] Figure 4B DSC of compound 56 is shown.

[0110] Figure 5A The XRPD pattern of Compound 3 raw material is shown.

[0111] Figure 5B DSC of compound 3 is shown.

[0112] Figure 6A The XRPD pattern of Compound 11 raw material is shown.

[0113] Figure 6B DSC of compound 11 is shown.

[0114] Figure 7A The XRPD pattern of Compound 53 starting material is shown.

[0115] Figure 7B DSC of compound 53 is shown.

[0116] Figure 8A The XRPD pattern of Compound 59 starting material is shown.

[0117] Figure 8B DSC of compound 59 is shown.

[0118] Figure 9A The XRPD pattern of Compound 48 starting material is shown.

[0119] Figure 9B DSC of compound 48 is shown. DETAILED DESCRIPTION

[0120] As generally described herein, the present invention provides compounds and compositions that can be used to prevent and / or treat the diseases, disorders, or conditions described herein, for example, diseases, disorders, or conditions associated with abnormal function of sodium ion channels, such as abnormal late sodium current (INaL). Exemplary diseases, disorders, or conditions include neurological disorders (e.g., epilepsy or epilepsy syndromes, neurodevelopmental disorders, or neuromuscular disorders), psychiatric disorders, pain, or gastrointestinal disorders.

[0121] definition

[0122] Chemical definition

[0123] Definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the Periodic Table of the Elements, CAS edition, Handbook of Chemistry and Physics, Plate 75, inside cover, and specific functional groups are generally defined as described herein. In addition, general principles of organic chemistry as well as specific functional moieties and reactivities are described in: Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd edition, Cambridge University Press, Cambridge, 1987.

[0124] The compounds described herein may contain one or more asymmetric centers and, therefore, may exist in various isomeric forms (e.g., enantiomers and / or diastereomers). For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of mixtures of stereoisomers (including racemic mixtures) and mixtures enriched in one or more stereoisomers. Isomers can be separated from the mixture by methods known to those skilled in the art, including chiral high performance liquid chromatography (HPLC), and chiral salts can be formed and crystallized; or preferred isomers can be prepared by asymmetric synthesis. For example, see Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions, p. 268 (E.L. Eliel, ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present invention further encompasses the compounds described herein as individual isomers substantially free of other isomers and as mixtures of various isomers.

[0125] As used herein, pure enantiomer compounds are substantially free of other enantiomers or stereoisomers of the compound (i.e., enantiomer excess). In other words, the compound of the "S" form is substantially free of the compound of the "R" form, and therefore, the enantiomer excess in the "R" form. The term "enantiomerically pure" or "pure enantiomer" means 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 certain embodiments, weight is based on the total weight of all enantiomers or stereoisomers of the compound.

[0126] In the compositions provided herein, the enantiomerically pure compounds may be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising an enantiomerically pure R-compound may comprise, for example, about 90% excipient and about 10% enantiomerically pure R-compound. In certain embodiments, the enantiomerically pure R-compound in the composition may, for example, comprise at least about 95% by weight of the R-compound and up to about 5% by weight of the S-compound, based on the total weight of the compound. For example, a pharmaceutical composition comprising an enantiomerically pure S-compound may comprise, for example, about 90% excipient and about 10% enantiomerically pure S-compound. In certain embodiments, the enantiomerically pure S-compound in the composition may, for example, comprise at least about 95% by weight of the S-compound and up to about 5% by weight of the R-compound, based on the total weight of the compound. In certain embodiments, the active ingredient may be formulated with minimal or no excipients or carriers.

[0127] The compounds described herein may also contain one or more isotopic substitutions. For example, H may be in any isotopic form, including 1 H. 2 H (D or deuterium) and 3 H (T or tritium); C can be in any isotopic form, including 12 C. 13 C and 14 C; O can be in any isotopic form, including 16 O and 18 O; F can be in any isotopic form, including 18 F and 19 F; and so on.

[0128] The following terms are intended to have the meanings provided below regarding them and can be used to understand the description and established scope of the present invention. When describing the present invention (which may include compounds and pharmaceutically acceptable salts thereof, pharmaceutical compositions containing the compounds, and methods of using the compounds and compositions), unless otherwise indicated, the following terms (if present) have the following meanings. It should also be understood that when described herein, any of the moieties defined below may be substituted with multiple substituents, and the respective definitions are intended to include the substituted moieties within their scope below. Unless otherwise indicated, the term "substituted" should be defined as described below. It should be further understood that the terms "group" and "radical" are considered interchangeable when used herein. The articles "a" and "an" that can be used herein refer to one or more (i.e., at least one) of the grammatical objects of the article. For example, "analog" means one analog or more than one analog.

[0129] When a range of values ​​is listed, it is intended to include every value and sub-range within that range. For example, "C 1-6"Alkyl" is intended to encompass C1, C2, C3, C4, C5, C6, C 1-6 、C 1-5 、C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-5 、C 2-4 、C 2-3 、C 3-6 、C 3-5 、C 3-4 、C 4-6 、C 4-5 and C 5-6 alkyl.

[0130] As used herein, "alkyl" refers to a group such as a straight-chain or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C 1-20 In some embodiments, the alkyl group has 1 to 10 carbon atoms ("C 1-10 In some embodiments, an alkyl group has 1 to 9 carbon atoms ("C 1-9 In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C 1-8 In some embodiments, the alkyl group has 1 to 7 carbon atoms ("C 1-7 In some embodiments, the alkyl group has 1 to 6 carbon atoms ("C 1-6 In some embodiments, the alkyl group has 1 to 5 carbon atoms ("C 1-5 In some embodiments, the alkyl group has 1 to 4 carbon atoms ("C 1-4 In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C 1-3 In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C 1-2 In some embodiments, an alkyl group has 1 carbon atom ("C1 alkyl"). 1-6 Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, and the like.

[0131] As used herein, "alkenyl" refers to a straight or branched hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds), and optionally one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds). 2-20 In certain embodiments, an alkenyl group does not contain any triple bonds. In some embodiments, an alkenyl group has 2 to 10 carbon atoms ("C 2-10 In some embodiments, an alkenyl group has 2 to 9 carbon atoms ("C2-9 In some embodiments, an alkenyl group has 2 to 8 carbon atoms ("C 2-8 In some embodiments, an alkenyl group has 2 to 7 carbon atoms ("C 2-7 In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C 2-6 In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C 2-5 In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C 2-4 In some embodiments, an alkenyl group has 2 to 3 carbon atoms ("C 2-3 In some embodiments, an alkenyl group has 2 carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). C 2-4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. 2-6 Examples of alkenyl groups include the above-mentioned C 2-4 Alkenyl and pentenyl (C5), pentadienyl (C5), hexenyl (C6) and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8) and the like.

[0132] As used herein, "alkynyl" refers to a straight-chain or branched hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds), and optionally one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds). 2-20 In certain embodiments, an alkynyl group does not contain any double bonds. In certain embodiments, an alkynyl group has 2 to 10 carbon atoms ("C 2-10 In some embodiments, an alkynyl group has 2 to 9 carbon atoms ("C 2-9 In some embodiments, an alkynyl group has 2 to 8 carbon atoms ("C 2-8 In some embodiments, an alkynyl group has 2 to 7 carbon atoms ("C 2-7 In some embodiments, an alkynyl group has 2 to 6 carbon atoms ("C 2-6 In some embodiments, an alkynyl group has 2 to 5 carbon atoms ("C 2-5 In some embodiments, an alkynyl group has 2 to 4 carbon atoms ("C 2-4 In some embodiments, an alkynyl group has 2 to 3 carbon atoms ("C 2-3In some embodiments, an alkynyl group has 2 carbon atoms (a "C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). C 2-4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. 2-6 Examples of alkynyl groups include the above-mentioned C 2-4 Alkynyl and pentynyl (C5), hexynyl (C6) and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8) and the like.

[0133] As used herein, "alkylene," "alkenylene," and "alkynylene" refer to divalent radicals of alkyl, alkenyl, and alkynyl groups, respectively. When a range or number of carbon atoms is provided for a particular "alkylene," "alkenylene," or "alkynylene," it is understood that the range or number refers to the range or number of carbon atoms in a linear carbon divalent chain. "Alkylene," "alkenylene," and "alkynylene" groups may be substituted or unsubstituted with one or more substituents as described herein.

[0134] As used herein, "aryl" refers to a group that provides a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in the cyclic array) having 6-14 ring carbon atoms and 0 heteroatoms in the aromatic ring system ("C 6-14 In some embodiments, an aryl group has 6 ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 In some embodiments, an aryl group has 14 ring carbon atoms ("C 14 "Aryl" also includes ring systems in which an aryl ring as defined above is fused to one or more carbocyclic or heterocyclic groups, wherein the radical or point of attachment is on the aryl ring, and in such cases, the number of carbon atoms continues to specify the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, groups derived from aceanthrene, acenaphthylene, acephenanthren, anthracene, azulene, benzene, hexabenzone, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-dicyclopentadienacene, s-dicyclopentadienacene, dihydroindene, indene, naphthalene, octacene, octaphene, octalene, ovalene, pentadiene, pentacene, pentaacene, dibenzophenone, perylene, phenanthene, phenanthren, pyrenes, pyranthrene, rubicene, terphenyl, and ternaphthyl. Specific aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl.

[0135] As used herein, "heteroaryl" refers to a group that provides a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 electrons shared in the cyclic array) having ring carbon atoms and 1-4 ring heteroatoms in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valence permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl group as defined above is fused to one or more carbocyclyl or heterocyclyl groups, wherein the point of attachment is on the heteroaryl ring, and in such cases, the number of ring members continues to specify the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl group as defined above is fused to one or more aryl groups, wherein the point of attachment is on the aryl or heteroaryl ring, and in such cases, the number of ring members specifies the number of ring members in the fused (aryl / heteroaryl) ring system. For bicyclic heteroaryls, one of which contains no heteroatoms (e.g., indolyl, quinolinyl, carbazolyl, and the like), the point of attachment can be on either ring, i.e., the ring with the heteroatom (e.g., 2-indolyl) or the ring without the heteroatom (e.g., 5-indolyl).

[0136] In some embodiments, heteroaryl groups are 5-10 membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, heteroaryl groups are 5-8 membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, heteroaryl groups are 5-6 membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, 5-6 membered heteroaryl groups have 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, 5-6 membered heteroaryl groups have 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, 5-6 membered heteroaryl groups have 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0137] Example 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thienyl. Example 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Example 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Example 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Example 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Example 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Example 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azacycloheptatrienyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0138] Examples of representative heteroaryl groups include the following:

[0139]

[0140] wherein each Z is selected from carbonyl, N, NR 65 , O and S; and R65 are independently hydrogen, C 1-8 Alkyl, C 3-10 Carbocyclic group, 4-10 membered heterocyclic group, C6-C 10 Aryl and 5-10 membered heteroaryl.

[0141] As used herein, "carbocyclyl" or "carbocycle" refers to a non-aromatic ring system having 3 to 10 ring carbon atoms ("C 3-10 In some embodiments, the carbocyclyl group has 3 to 8 ring carbon atoms ("C 3-8 In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms ("C 3-7 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3-6 In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5-10 Carbocyclyl"). Example C 3-6 Carbocyclyl groups include, but are not limited to, cyclopropyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C 3-8 Carbocyclic groups include (but are not limited to) the C 3-6 Carbocyclyl and cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatraenyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo [2.2.1] heptyl (C7), bicyclo [2.2.2] octyl (C8) and the like. Exemplary C 3-10 Carbocyclic groups include (but are not limited to) the C 3-8 Carbocyclic groups and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C 10 ), spiro[4.5]decyl (C 10 ) and the like. As illustrated by the above examples, in certain embodiments, a carbocyclyl is a monocyclic ring ("monocyclic carbocyclyl") or contains a fused, bridged, or spiro ring system, such as a bicyclic ring system ("bicyclic carbocyclyl"), and may be saturated or partially unsaturated. "Carbocyclyl" also includes ring systems in which a carbocyclyl ring as defined above is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the carbocyclyl ring, and in such cases, the number of carbon atoms continues to designate the number of carbon atoms in the carbocyclyl ring system.

[0142] 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 carbon atoms, referred to herein as a "C" derived from a cycloalkane. 4-8 Exemplary cycloalkyl groups include, but are not limited to, cyclohexane, cyclopentane, cyclobutane, and cyclopropane.

[0143] As used herein, “C 3-6 Monocyclic cycloalkyl" or "monocyclic C 3-6 "Cycloalkyl" refers to a saturated 3- to 7-membered monocyclic hydrocarbon ring system. 3- to 7-membered monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. If indicated as optionally substituted or substituted, the substituents on the cycloalkyl group (such as in the case of optionally substituted cycloalkyl) may be present at any substitutable position, including, for example, the position at which the cycloalkyl group is attached.

[0144] As used herein, "heterocyclyl" or "heterocycle" refers to a radical of a 3- to 10-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 containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as valence permits. A heterocyclyl group may be a monocyclic ring ("monocyclic heterocyclyl") or a fused, bridged, or spiro ring system, such as a bicyclic ring system ("bicyclic heterocyclyl"), and may be saturated or partially unsaturated. Heterocyclyl bicyclic ring systems may include one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocyclyl ring as defined above is fused to one or more carbocyclyl groups, wherein the point of attachment is on the carbocyclyl or heterocyclyl ring; or ring systems in which a heterocyclyl ring as defined above is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such cases, the number of ring members continues to specify the number of ring members in the heterocyclyl ring system. The terms "heterocycle," "heterocyclyl," "heterocyclyl ring," "heterocyclyl," "heterocyclic moiety," and "heterocyclic group" are used interchangeably.

[0145] 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 is independently 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, a 5-6 membered heterocyclyl group 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 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0146] Example three-membered heterocyclic groups containing one heteroatom include, but are not limited to, aziridine, oxirane, and thiirane. Example four-membered heterocyclic groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Example five-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Example five-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxapentafluorosulfanyl, dipentafluorosulfanyl, and oxazolidin-2-one. Example five-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, hexahydropyridinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, hexahydropyrazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocycles) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as 6,6-bicyclic heterocycles) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0147] Examples of saturated or partially unsaturated heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, pyrrolidinyl, pyridonyl, pyrrolidonyl, hexahydropyridinyl, oxazolidinyl, hexahydropyrazinyl, dioxanyl, dioxolanyl, morpholinyl, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, oxetanyl, azetidinyl, and tetrahydropyrimidinyl. If indicated as optionally substituted or substituted, the substituents on the heterocyclic group (for example, in the case of an optionally substituted heterocyclic group) may be present at any substitutable position, including, for example, the position at which the heterocyclic group is attached.

[0148] "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 are replaced by nitrogen, oxygen, or sulfur heteroatoms. Hetero can apply to any of the above-mentioned hydrocarbon groups, for example, alkyl, such as heteroalkyl; carbocyclyl, such as heterocyclyl; aryl, such as heteroaryl; and the like having 1 to 5, and particularly 1 to 3, heteroatoms.

[0149] As used herein, "cyano" refers to -CN.

[0150] As used herein, the term "halogen" refers to an atom selected from fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), and iodine (iodine, -I). In certain embodiments, the halogen is fluorine or chlorine.

[0151] As used herein, the term "alkoxy" refers to an alkyl group attached to another moiety through an oxygen atom (-O(alkyl)). Non-limiting examples include, for example, methoxy, ethoxy, propoxy, and butoxy.

[0152] A "haloalkoxy" group is a haloalkyl group attached to another moiety through an oxygen atom, such as, but not limited to, -OCHCF2 or -OCF3.

[0153] The term "haloalkyl" includes mono-, poly- and perhaloalkyl groups substituted with one or more halogen atoms, wherein the halogen is independently selected from fluorine, chlorine, bromine and iodine. 1-4 Halogenated alkyl-OC 1-4 For alkyl groups, the point of attachment occurs on the halogenated alkyl portion.

[0154] As used herein, "nitro" refers to -NO2.

[0155] As used herein, a "pendent oxy group" refers to a -C=O group.

[0156] 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 permitted substituent, e.g., a substituent that, upon substitution, results in a stable compound (e.g., a compound that does not spontaneously undergo transformation by, for example, 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 may be the same or different at each position.

[0157] The nitrogen atoms may be substituted or unsubstituted as valence permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, -OH, -OR aa 、-N(R cc )2, -CN, -C(=O)R aa 、-C(=O)N(R cc )2, -CO2R aa 、-SO2R aa 、-C(=NR bb )R aa 、-C(=NR cc )OR aa 、-C(=NR cc )N(R cc )2、-SO2N(R cc )2, -SO2R cc 、-SO2OR cc 、-SOR aa 、-C(=S)N(R cc )2, -C(=O)SR cc 、-C(=S)SR cc 、-P(=O)2R aa 、-P(=O)(R aa )2、-P(=O)2N(R cc )2、-P(=O)(NR cc )2、C 1-10 Alkyl, C 1-10 Perhalogenated alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic group, 3-14 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, or two R groups connected to the nitrogen atom cc The groups are combined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4, or 5 R dd Group substituted, and wherein R aa 、R bb 、R cc and R dd As defined above.

[0158] These and other exemplary substituents are described in more detail in the embodiments, examples, and claims. The present invention is not intended to be limited in any way by the above exemplary list of substituents.

[0159] Other definitions

[0160] 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 can be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based materials, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block copolymers, polyethylene glycol, and lanolin.

[0161] As used herein, "pharmaceutically acceptable salts" refer to salts that are suitable for use in contact with human and lower animal tissues without producing excessive toxicity, irritation, allergic reaction, and the like, within the scope of sound medical judgment and with a commensurate and reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66: 1-19. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or with organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid) or by using other methods used in the industry (e.g., ion exchange) and amine groups. 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, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N + (C 1-4Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations, formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates, as appropriate.

[0162] As used herein, a "subject" to whom administration is intended includes, but is not limited to, humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly)) and / or non-human animals (e.g., mammals, such as primates (e.g., cynomolgus monkeys, macaques), cows, pigs, horses, sheep, goats, rodents, cats, and / or dogs). In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0163] Disease, disorder and condition are used interchangeably herein.

[0164] As used herein, and unless otherwise indicated, the terms "treat," "treating," and "treatment" encompass actions that occur while a subject has a specified disease, disorder, or condition that reduces the severity of the disease, disorder, or condition, or delays or slows the progression of the disease, disorder, or condition ("therapeutic treatment"), and also encompass actions that occur before a subject becomes ill with a specified disease, disorder, or condition ("prophylactic treatment").

[0165] As used herein, an "effective amount" of a compound is an amount sufficient to elicit a desired biological response. As will be appreciated by those skilled in the art, an effective amount of a compound of the invention may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and condition of the individual. An effective amount encompasses both therapeutic and prophylactic treatments.

[0166] As used herein and unless otherwise indicated, 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 a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of a disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0167] Compound

[0168] In one aspect, the present invention provides compounds having Formula I:

[0169]

[0170] or a pharmaceutically acceptable salt thereof, wherein

[0171] X and Y are each independently CR d or N;

[0172] R 1 yes Monocyclic C 3-6 Cycloalkyl or 4 to 7 membered monocyclic heterocyclic group, wherein the cycloalkyl and heterocyclic group are optionally substituted by one or more R a replace;

[0173] R 2 It is C 1-4 Halogenated alkyl, phenyl or monocyclic C 3-6 Cycloalkyl, which is optionally substituted by one or more R b replace;

[0174] R 3 It is hydrogen, C 1-4 Alkyl or C 1-4 alkyl halide;

[0175] R 4 is hydrogen or C 1-4 alkyl;

[0176] R 5 It is a halogen;

[0177] R 6 It is C 1-4 Alkyl or C 1-4 haloalkyl, wherein the C 1-4 Alkyl or C 1-4 Each of the haloalkyl groups is substituted by OR c replace;

[0178] t is 0, 1, or 2;

[0179] R a and R b are each independently selected from halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy and C 1-4 Haloalkoxy,

[0180] R c Is optional C 3-6 Cycloalkyl or C 1-4 Alkoxy-substituted C 1-4 Alkyl, or C 3-6 cycloalkyl; and

[0181] R d is hydrogen or C 1-4 alkyl;

[0182] Provided that the compound is not a compound having the formula:

[0183] or a pharmaceutically acceptable salt thereof.

[0184] In one aspect, the present invention provides compounds having Formula I':

[0185]

[0186] or a pharmaceutically acceptable salt thereof, wherein

[0187] X and Y are each independently CR d or N;

[0188] R 1 yes Monocyclic C 3-6 Cycloalkyl or 4 to 7 membered monocyclic heterocyclic group, wherein the cycloalkyl and heterocyclic group are optionally substituted by one or more R a replace;

[0189] R 2 It is C 1-4 Halogenated alkyl, phenyl or monocyclic C 3-6 Cycloalkyl, which is optionally substituted by one or more R b replace;

[0190] R 3 It is hydrogen, C 1-4 Alkyl or C 1-4 alkyl halide;

[0191] R 4 is hydrogen or C 1-4 alkyl;

[0192] R 5 It is a halogen;

[0193] R 6 It is C 1-4 Alkyl or C 1-4 haloalkyl, wherein the C 1-4 Alkyl or C 1-4 Each of the haloalkyl groups is substituted by OR c replace;

[0194] t is 0, 1, or 2;

[0195] R a and R b are each independently selected from halogen, C 1-4 Alkyl, C 1-4Halogenated alkyl, C 1-4 Alkoxy and C 1-4 Haloalkoxy,

[0196] R c Is optional C 3-6 Cycloalkyl or C 1-4 Alkoxy-substituted C 1-4 Alkyl, or C 3-6 cycloalkyl; and

[0197] R d is hydrogen or C 1-4 alkyl;

[0198] or a pharmaceutically acceptable salt thereof.

[0199] In some embodiments, the compound has Formula Ia:

[0200]

[0201] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0202] In some embodiments, the compound has Formula Ib:

[0203]

[0204] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0205] In some embodiments, the compound has Formula II:

[0206]

[0207] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0208] In some embodiments, the compound has Formula III:

[0209]

[0210] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0211] In some embodiments, the compound has Formula Ic:

[0212]

[0213] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0214] In another aspect, the present invention provides compounds having Formula Id:

[0215]

[0216] or a pharmaceutically acceptable salt thereof, wherein

[0217] R 1 yes Monocyclic C 3-6 Cycloalkyl or 4 to 7 membered monocyclic heterocyclic group, wherein the cycloalkyl and heterocyclic group are optionally substituted by one or more R a replace;

[0218] R 2 It is C 1-4 Halogenated alkyl, phenyl or monocyclic C 3-6 Cycloalkyl, which is optionally substituted by one or more R b replace;

[0219] R 3 It is hydrogen, C 1-4 Alkyl or C 1-4 alkyl halide;

[0220] R 4 is hydrogen or C 1-4 alkyl;

[0221] R 5 It is a halogen;

[0222] R 6 It is C 1-4 Alkyl or C 1-4 haloalkyl, wherein the C 1-4 Alkyl or C 1-4 Each of the haloalkyl groups is substituted by OR c replace;

[0223] t is 0, 1, or 2;

[0224] R a and R b are each independently selected from halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy and C 1-4 Haloalkoxy;

[0225] R c Is optional C 3-6 Cycloalkyl or C 1-4 Alkoxy-substituted C 1-4 Alkyl, or C 3-6 cycloalkyl; and

[0226] R d is hydrogen or C 1-4 alkyl.

[0227] In some embodiments, the compound has Formula V:

[0228]

[0229] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0230] In some embodiments, the compound has Formula VII:

[0231]

[0232] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0233] In some embodiments, the compound has Formula VIII:

[0234]

[0235] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0236] In some embodiments, the compound has Formula VIII:

[0237]

[0238] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0239] In some embodiments, R 1 yes

[0240] In some embodiments, R 1 is optionally passed through one or more R a Substituted cyclobutyl.

[0241] In some embodiments, R 2 It is C 1-4 In some embodiments, R 2 is CF3. In some embodiments, R 2 It is phenyl.

[0242] In one embodiment, R 3 It is C 1-4 Alkyl and R 4 Is H or C 1-4 In some embodiments, R 3 and R 4 Each is C 1-4 In some embodiments, R 3 and R 4 In some embodiments, R 3 is methyl and R 4 is hydrogen. In some embodiments, R3 and R 4 Each is hydrogen.

[0243] In some embodiments, R 6 Yes-CF2-OR c .

[0244] In some embodiments, R c is C optionally substituted by cyclopropyl 1-4 In some embodiments, R c It is cyclopropyl.

[0245] In some embodiments, R 6 is -C(F2)OCH2CH(CH3)2, -C(F2)OCH3, -C(F2)OCH2CH3, -C(F2)OCH(CH3)2, or -C(F2)OCH2C3H5. In some embodiments, R 6 Yes -CH2-OR c .

[0246] In some embodiments, R c It is C 1-4 alkyl.

[0247] In some embodiments, R 6 It is -CH2OCH3, -CH2OCH2CH3 or -CH2OCH2CH(CH3)2.

[0248] In some embodiments, R a It is C 1-4 In some embodiments, R a is CF3. In some embodiments, R a It's fluorine.

[0249] In some embodiments, t is 1. In some embodiments, t is 0.

[0250] In some embodiments, R d In some embodiments, R d It's hydrogen.

[0251] In some embodiments, the compound is selected from:

[0252]

[0253]

[0254]

[0255]

[0256]

[0257]

[0258]

[0259] and or a pharmaceutically acceptable salt thereof.

[0260] In some embodiments, the compound is selected from:

[0261]

[0262] and or a pharmaceutically acceptable salt thereof, and

[0263] In another aspect, the present invention provides a crystalline compound of the formula:

[0264]

[0265] wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 6.9±0.2, 16.5±0.2, and 20.8±0.2.

[0266] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ): 6.9±0.2, 13.9±0.2, 16.5±0.2, 19.5±0.2, and 20.8±0.2.

[0267] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 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.

[0268] In some embodiments, the crystalline compound exhibits Figure 2A , which exhibits substantially the same X-ray powder diffraction pattern as shown in .

[0269] In some embodiments, the crystalline compound has a melting onset of about 140°C as determined by differential scanning calorimetry.

[0270] In some embodiments, the crystalline compound has Figure 2B Essentially the same differential scanning calorimetry curve as shown in .

[0271] In another aspect, provided herein is a crystalline compound of the formula:

[0272]

[0273] wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 16.7±0.2, 19.0±0.2, and 20.4±0.2.

[0274] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ): 7.2±0.2, 14.4±0.2, 16.7±0.2, 19.0±0.2, 20.4±0.2, and 25.7±0.2.

[0275] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 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.

[0276] In some embodiments, the crystalline compound exhibits Figure 3A , which exhibits substantially the same X-ray powder diffraction pattern as shown in .

[0277] In some embodiments, the crystalline compound has a melting onset of about 68°C as determined by differential scanning calorimetry.

[0278] In some embodiments, the crystalline compound has Figure 3B Essentially the same differential scanning calorimetry curve as shown in .

[0279] In another aspect, the present invention provides a crystalline compound of the formula:

[0280]

[0281] wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 7.3±0.2, 14.5±0.2, and 21.9±0.2.

[0282] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ): 7.3±0.2, 14.5±0.2, 17.9±0.2, 19.0±0.2, and 21.9±0.2.

[0283] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 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.

[0284] In some embodiments, the crystalline compound exhibits Figure 4A , which exhibits substantially the same X-ray powder diffraction pattern as shown in .

[0285] In some embodiments, the crystalline compound has a melting onset of about 136°C as determined by differential scanning calorimetry.

[0286] In some embodiments, the crystalline compound has Figure 4B Essentially the same differential scanning calorimetry curve as shown in .

[0287] In another aspect, provided herein is a crystalline compound of the formula:

[0288]

[0289] wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 12.6±0.2, 15.8±0.2, and 18.6±0.2.

[0290] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ): 10.7±0.2, 12.3±0.2, 12.6±0.2, 15.8±0.2, 18.6±0.2, and 22.6±0.2.

[0291] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ): 10.7±0.2, 12.3±0.2, 12.6±0.2, 14.9±0.2, 15.8±0.2, 16.6±0.2, 16.8±0.2, 18.6±0.2, 21.0±0.2, and 22.6±0.2.

[0292] In some embodiments, the crystalline compound exhibits Figure 5A , which exhibits substantially the same X-ray powder diffraction pattern as shown in .

[0293] In some embodiments, the crystalline compound has a melting onset of about 107°C as determined by differential scanning calorimetry.

[0294] In some embodiments, the crystalline compound has Figure 5BEssentially the same differential scanning calorimetry curve as shown in .

[0295] In another aspect, provided herein is a crystalline compound of the formula:

[0296]

[0297] wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 5.8±0.2, 19.7±0.2, and 21.0±0.2.

[0298] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ): 5.8±0.2, 14.5±0.2, 15.3±0.2, 19.7±0.2, 21.0±0.2, and 24.2±0.2.

[0299] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 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.

[0300] In some embodiments, the crystalline compound exhibits Figure 6A , which exhibits substantially the same X-ray powder diffraction pattern as shown in .

[0301] In some embodiments, the crystalline compound has a melting onset of about 94°C as determined by differential scanning calorimetry.

[0302] In some embodiments, the crystalline compound has Figure 6B Essentially the same differential scanning calorimetry curve as shown in .

[0303] In another aspect, the present invention provides a crystalline compound of the formula:

[0304]

[0305] wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 7.3±0.2, 16.6±0.2, and 18.4±0.2.

[0306] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ): 7.3±0.2, 13.8±0.2, 16.6±0.2, 18.4±0.2, 20.3±0.2, and 24.3±0.2.

[0307] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 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.

[0308] In some embodiments, the crystalline compound exhibits Figure 7A , which exhibits substantially the same X-ray powder diffraction pattern as shown in .

[0309] In some embodiments, the crystalline compound has a melting onset of about 103°C as determined by differential scanning calorimetry.

[0310] In some embodiments, the crystalline compound has Figure 7B Essentially the same differential scanning calorimetry curve as shown in .

[0311] In another aspect, the present invention provides a crystalline compound of the formula:

[0312]

[0313] wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 6.9±0.2, 16.4±0.2, and 19.5±0.2.

[0314] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ): 6.9±0.2, 16.4±0.2, 17.4±0.2, 18.0±0.2, 19.5±0.2, and 20.8±0.2.

[0315] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 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.

[0316] In some embodiments, the crystalline compound exhibits Figure 8A , which exhibits substantially the same X-ray powder diffraction pattern as shown in .

[0317] In some embodiments, the crystalline compound has a melting onset of about 133°C as determined by differential scanning calorimetry.

[0318] In some embodiments, the crystalline compound has Figure 8BEssentially the same differential scanning calorimetry curve as shown in .

[0319] In another aspect, the present invention provides a crystalline compound of the formula:

[0320]

[0321] wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 9.9±0.2, 19.8±0.2, and 23.7±0.2.

[0322] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ): 9.9±0.2, 12.3±0.2, 14.1±0.2, 19.8±0.2, 20.7±0.2, and 23.7±0.2.

[0323] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 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.

[0324] In some embodiments, the crystalline compound exhibits Figure 9A , which exhibits substantially the same X-ray powder diffraction pattern as shown in .

[0325] In some embodiments, the crystalline compound has a melting onset of about 111 °C as determined by differential scanning calorimetry.

[0326] In some embodiments, the crystalline compound has Figure 9B Essentially the same differential scanning calorimetry curve as shown in .

[0327] In another aspect, provided herein is a crystalline compound of the formula:

[0328]

[0329] wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 9.3±0.2, 18.8±0.2, and 21.4±0.2.

[0330] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ): 9.3±0.2, 16.1±0.2, 18.8±0.2, 21.1±0.2, 21.4±0.2, and 21.6±0.2.

[0331] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 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.

[0332] In some embodiments, the crystalline compound exhibits Figure 1A , which exhibits substantially the same X-ray powder diffraction pattern as shown in .

[0333] In some embodiments, the crystalline compound has a melting onset of about 122°C as determined by differential scanning calorimetry.

[0334] In some embodiments, the crystalline compound has Figure 1B Essentially the same differential scanning calorimetry curve as shown in .

[0335] In some embodiments, the X-ray powder diffraction pattern is obtained using Cu Ka radiation.

[0336] Pharmaceutical compositions and routes of administration

[0337] The compound provided according to the present invention is usually administered in the form of a pharmaceutical composition. Therefore, the present invention provides a pharmaceutical composition containing one or more of the compounds or their pharmaceutically acceptable salts or esters as active ingredients and one or more pharmaceutically acceptable excipients, carriers (including inert solid diluents and fillers), diluents (including sterile aqueous solutions and various organic solvents), penetration enhancers, solubilizers and adjuvants. The pharmaceutical composition can be administered alone or in combination with other therapeutic agents. The composition is prepared in a manner well known in pharmaceutical technology (e.g., see Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa, 17th edition (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd edition (GS Banker and CT Rhodes, ed.).

[0338] The pharmaceutical compositions can be administered in single or multiple doses by any of the accepted modes of administration for similarly efficacious pharmaceutical agents, including rectal, buccal, intranasal, and transdermal routes, by intraarterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, in the form of an inhalant, or via an impregnated or coated device (e.g., a stent) or a cylindrical polymer inserted, for example, into an artery, as described in those patents and patent applications incorporated by reference.

[0339] One mode of administration is parenteral, specifically by injection. Forms of the novel compositions of the present invention that can 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 sterile aqueous solutions and similar pharmaceutical vehicles. Aqueous solutions in saline are also commonly used for injection, but are less preferred in the context of the present invention. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils can also be used. Suitable fluidity can be maintained, for example, by using a coating (e.g., lecithin), by maintaining the desired particle size (in the case of a dispersion), and by using a surfactant. Microbial action can be prevented by various antibacterial and antifungal agents (e.g., parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like).

[0340] Sterile injectable solutions are prepared by incorporating the desired amount of a compound of the invention into an appropriate solvent with the various other ingredients listed above, followed by sterilization filtration as needed. Typically, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle containing a basic dispersion medium and the desired additional ingredients from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, preferred methods of preparation are vacuum drying and freeze-drying techniques, which can produce a powder of the active ingredient plus any desired additional ingredients from a previously sterile-filtered solution thereof.

[0341] Oral administration is another route of administering the compounds according to the present invention. Administration can be via capsules or enteric-coated tablets or the like. In preparing pharmaceutical compositions comprising at least one compound described herein, the active ingredient is typically diluted with an excipient and / or enclosed in a carrier that can be in the form of a capsule, sachet, paper, or other container. When an excipient serves as a diluent, it can be in the form of a solid, semisolid, or liquid material (as described above) that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the composition can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (in solid form or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0342] Some examples of suitable excipients include lactose, glucose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginates, tragacanth gum, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup and methylcellulose. The formulation may additionally include: lubricants such as talc, magnesium stearate and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl benzoate and propylhydroxybenzoate; sweeteners; and flavoring agents.

[0343] The compositions of the present invention can be formulated using procedures known in the industry to provide rapid, sustained or delayed release of the active ingredient after administration to the patient. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolution systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are provided in U.S. Patents 3,845,770, 4,326,525, 4,902,514 and 5,616,345. Another formulation used in the method of the present invention uses a transdermal delivery device ("patch"). The transdermal patch can be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for delivering medicaments are well known in the industry. See, for example, U.S. Patents 5,023,252, 4,992,445 and 5,001,139. ​​The patch can be constructed for continuous, pulsed or on-demand delivery of medicaments.

[0344] The composition is preferably formulated in a unit dosage form. The term "unit dosage form" refers to a physically discrete unit suitable for use as a unit dose for human subjects and other mammals, each unit containing a predetermined amount of active substance calculated to produce the desired therapeutic effect and a suitable pharmaceutical excipient (e.g., tablets, capsules, ampoules). The compound is usually administered in a pharmaceutically effective amount. Preferably, for oral administration, each dosage unit contains 1 mg to 2 g of the compound described herein, and for parenteral administration, preferably contains 0.1 to 700 mg of the compound described herein. However, it should be understood that the actual dosage of the compound will be determined by the physician in view of the following relevant circumstances: the condition to be treated, the selected route of administration, the compound actually administered and its relative activity, the age, weight and response of the individual patient, the severity of the patient's symptoms, and the like.

[0345] To prepare solid compositions (e.g., tablets), the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of the compound of the present invention. When referring to the preformulation composition as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules.

[0346] The tablets or pills of the present invention can be coated or otherwise compounded to provide a dosage form that provides an advantage of prolonged action, or to protect against the acid conditions of the stomach. For example, a tablet or pill can comprise an inner dosage component and an outer dosage component, the latter being a film-coated form of the former. The two components can be separated by an enteric layer that resists disintegration in the stomach and allows the inner component to pass intact into the duodenum or to delay release. The enteric layer or coating can use a variety of materials, including a large amount of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0347] 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 above. Preferably, the compositions are administered via the oral or nasal respiratory route for local or systemic effect. Compositions in pharmaceutically acceptable solvents are preferably nebulized using an inert gas. Nebulized solutions may be inhaled directly from the nebulizing device, or the nebulizing device may be attached to a mask curtain or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered preferably orally or nasally from a device that delivers the formulation in an appropriate manner.

[0348] In some embodiments, a pharmaceutical composition comprises a disclosed compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0349] How to use

[0350] The compounds and compositions described herein are generally useful for modulating the activity of sodium channels and for treating disorders associated with abnormal function of sodium channel ion channels, such as abnormal late sodium (INaL) currents. In some embodiments, the compounds provided herein are effective for treating epilepsy or epilepsy syndromes, neurodevelopmental disorders, pain, or neuromuscular disorders. The compounds, pharmaceutically acceptable salts, or compositions provided herein may also modulate all sodium channels, or may be specifically directed against only one or more sodium channels, such as Na V 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8 and / or 1.9.

[0351] In typical embodiments, the present invention is intended to encompass the compounds disclosed herein, and pharmaceutically acceptable salts, pharmaceutically acceptable esters, tautomeric forms, polymorphs, and prodrugs of the compounds. In some embodiments, the present invention includes pharmaceutically acceptable addition salts, pharmaceutically acceptable esters, solvates (e.g., hydrates) of the compounds described herein (e.g., compounds of Formula I, I', Ia, Ib, Ic, Id, II, III, V, VII, VIII, or IX) (e.g., compounds of the formulas named herein), tautomeric forms, polymorphs, enantiomers, mixtures of enantiomers, stereoisomers, or mixtures of stereoisomers (pure or in the form of racemic or non-racemic mixtures).

[0352] Epilepsy and epileptic syndromes

[0353] The compounds described herein can be used to treat epilepsy and epileptic syndromes. Epilepsy is a CNS disorder in which nerve cell activity in the brain is disrupted, causing seizures or periods of unusual behavior, sensations, and sometimes loss of consciousness. Seizure symptoms can vary widely from a simple blank stare for a few seconds to repetitive twitching of an arm or leg during an epileptic seizure.

[0354] Epilepsy can involve generalized seizures or localized or focal seizures. All areas of the brain are involved in generalized seizures. A person experiencing a generalized seizure may cry out or make some noises, become stiff for several seconds to a minute, and then have rhythmic movements of the arms and legs. The eyes are usually open, and the person may not seem to be breathing and may actually turn blue. Recovery of consciousness is gradual and the person may be confused for several minutes to several hours. There are six main types of generalized seizures: tonic-clonic, tonic, clonic, myoclonic, absence, and atonic seizures. In localized or focal seizures, only part of the brain is involved, so only part of the body is affected. Depending on the part of the brain with abnormal activity, symptoms can be variable.

[0355] Epilepsy as described herein includes generalized, focal, complex focal, tonic-clonic, clonic, tonic, refractory seizures, status epilepticus, absence seizures, febrile seizures, or temporal lobe epilepsy.

[0356] The compounds described herein (e.g., compounds of Formula I, I', Ia, Ib, Ic, Id, II, III, V, VII, VIII, or IX) can be used to treat epileptic syndromes. Severe syndromes characterized by diffuse brain dysfunction caused at least in part by an aspect of epilepsy are also known as epileptic encephalopathy. Such epileptic encephalopathy is associated with frequent, treatment-resistant seizures and severe cognitive impairment, such as West syndrome.

[0357] In some embodiments, the epilepsy syndrome comprises an epileptic encephalopathy, e.g., Dravet syndrome, Angelman syndrome, a CDKL5 disorder, frontal lobe epilepsy, infantile spasms, West syndrome, juvenile myoclonic epilepsy, Landau-Kleffner syndrome, Regelian syndrome, Ohtahara syndrome, PCDH19 epilepsy, or Glut1 deficiency.

[0358] In some embodiments, the epilepsy or epilepsy syndrome is a hereditary epilepsy or hereditary epilepsy syndrome. In some embodiments, the epilepsy or epilepsy syndrome comprises epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutations, generalized epilepsy with febrile seizures, intractable childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile epilepsy, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutations, cryptogenic partial epilepsy in children with SCN3A mutations, SCN8A epileptic encephalopathy, Rasmussen's encephalitis, malignant migratory partial epilepsy in infancy, autosomal dominant nocturnal frontal lobe epilepsy, sudden unexpected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, or KCNT1 epileptic encephalopathy.

[0359] In some embodiments, the methods described herein further comprise methods of identifying an individual 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 mutations, generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutations, cryptogenic partial epilepsy of childhood with SCN3A mutations, SCN8A epileptic encephalopathy, Rasmussen's encephalitis, malignant migratory partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, sudden unexpected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, or KCNT1 epileptic encephalopathy) prior to administering a compound described herein (e.g., a compound of Formula I, I', Ia, Ib, Ic, Id, II, III, V, VII, VIII, or IX).

[0360] In one aspect, the 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 mutations, 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 mutations, cryptogenic partial epilepsy of childhood with SCN3A mutations, SCN8A epileptic encephalopathy, Rasmussen's encephalitis, malignant migratory partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, sudden unexpected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, or KCNT1 epileptic encephalopathy) comprising administering to a subject in need thereof a compound of formula (I):

[0361]

[0362] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0363] Compounds of the invention (e.g., compounds of Formula I, I', Ia, Ib, Ic, Id, II, III, V, VII, VIII, or IX) may also be used to treat epileptic encephalopathy in subjects with a mutation in one or more of the following: ALDH7A1, ALG13, ARHGEF9, ARX, ASAH1, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLN8, CNTNAP2, CPA6, CSTB, DEPDC5, DNM1, EEF1A2, EPM2A, EPM2B, GABRA1, GABRB3, GABRG2, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, HCN1, IER3IP1, KCNA2, KCN B1, KCNC1, KCNMA1, KCNQ2, KCNQ3, KCNT1, KCTD7, LGI1, MEF2C, NHLRC1, PCDH19, PLCB1, PNKP, PNPO, PRICKLE1, PRICKLE2, PRRT2, RELN, SCARB2, SCN1A, SCN1B, SCN2A, SC N8A, SCN9A, SIAT9, SIK1, SLC13A5, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SNIP1, SPTAN1, SRPX2, ST3GAL3, STRADA, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, and WWOX.

[0364] In some embodiments, the methods described herein further comprise identifying, prior to administering a compound described herein (e.g., a compound of Formula I, I', Ia, Ib, Ic, Id, II, III, V, VII, VIII, or IX), a subject having a mutation in one or more of the following: ALDH7A1, ALG13, ARHGEF9, ARX, ASAH1, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLN8, CNTNAP2, CPA6, CSTB, DEPDC5, DNM1, EEF1A2, EPM2A, EPM2B, GABRA1, GABRB3, GABRG2, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, HCN1, IER3IP1, KC NA2, KCNB1, KCNC1, KCNMA1, KCNQ2, KCNQ3, KCNT1, KCTD7, LGI1, MEF2C, NHLRC1, PCDH19, PLCB1, PNKP, PNPO, PRICKLE1, PRICKLE2, PRRT2, RELN, SCARB2, SCN1A, SCN1B, SCN2A , SCN8A, SCN9A, SIAT9, SIK1, SLC13A5, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SNIP1, SPTAN1, SRPX2, ST3GAL3, STRADA, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24 and WWOX.

[0365] neurodevelopmental disorders

[0366] The compounds described herein can be used to treat neurodevelopmental disorders. In some embodiments, the neurodevelopmental disorder comprises autism, autism with epilepsy, tuberous sclerosis, fragile X syndrome, Rett syndrome, Angelman syndrome, Dup15q syndrome, 22q13.3 deletion syndrome, Prader-Willi syndrome, soft palate-cardio-facial syndrome, Smith-Lemli-Opitz syndrome, or a neurodevelopmental disorder with epilepsy. In some embodiments, the methods described herein further comprise identifying an individual with a neurodevelopmental disorder (e.g., autism, autism with epilepsy, tuberous sclerosis, Fragile X syndrome, Rett syndrome, Angelman syndrome, Dup15q syndrome, 22q13.3 deletion syndrome, Prader-Willi syndrome, velar-cardio-facial syndrome, Smith-Lanley-Orbis syndrome, or a neurodevelopmental disorder with epilepsy) prior to administering a compound described herein (e.g., a compound of Formula I, I', Ia, Ib, Ic, Id, II, III, V, VII, VIII, or IX).

[0367] In one aspect, the invention features a method of treating a neurodevelopmental disorder (e.g., autism, autism with epilepsy, tuberous sclerosis, Fragile X syndrome, Rett syndrome, Angelman syndrome, Dup15q syndrome, 22q13.3 deletion syndrome, Prader-Willi syndrome, velalocardiofacial syndrome, Smith-Lanley-Orbis syndrome, or a neurodevelopmental disorder with epilepsy) comprising administering to a subject in need thereof a compound of formula (I):

[0368]

[0369] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0370] pain

[0371] The compounds described herein can be used to treat pain. In some embodiments, the pain comprises neuropathic pain, trigeminal neuralgia, migraine, hemiplegic migraine, familial hemiplegic migraine, familial hemiplegic migraine type 3, cluster headache, cerebellar ataxia, or a related headache disorder. In some embodiments, the methods described herein further comprise identifying a subject suffering from pain (e.g., neuropathic pain, trigeminal neuralgia, migraine, hemiplegic migraine, familial hemiplegic migraine, familial hemiplegic migraine type 3, cluster headache, cerebellar ataxia, or a related headache disorder) prior to administering a compound described herein (e.g., a compound of Formula I, I', Ia, Ib, Ic, Id, II, III, V, VII, VIII, or IX).

[0372] In one aspect, the invention features a method of treating pain (e.g., neuropathic pain, trigeminal neuralgia, migraine, hemiplegic migraine, familial hemiplegic migraine, familial hemiplegic migraine type 3, cluster headache, cerebellar ataxia, or a related headache disorder) comprising administering to a subject in need thereof a compound of formula (I):

[0373]

[0374] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0375] Neuromuscular disorders

[0376] The compounds described herein can be used to treat neuromuscular disorders. In some embodiments, the neuromuscular disorder comprises amyotrophic lateral sclerosis, multiple sclerosis, myotonia, congenital paramyotonia, potassium-aggravated myotonia, periodic paralysis, periodic hyperkalemic paralysis, periodic hypokalemic paralysis, or laryngospasm with an SCN4A mutation. In some embodiments, the methods described herein further comprise identifying an individual with a neuromuscular disorder (e.g., amyotrophic lateral sclerosis, multiple sclerosis, myotonia, congenital paramyotonia, potassium-aggravated myotonia, periodic paralysis, periodic hyperkalemic paralysis, periodic hypokalemic paralysis, or laryngospasm with an SCN4A mutation) prior to administering a compound described herein (e.g., a compound of Formula I, I', Ia, Ib, Ic, Id, II, III, V, VII, VIII, or IX).

[0377] In one aspect, the invention features a method of treating a neuromuscular disorder (e.g., amyotrophic lateral sclerosis, multiple sclerosis, myotonia, paramyotonia congenita, potassium-aggravated myotonia, periodic paralysis, periodic hyperkalemic paralysis, periodic hypokalemic paralysis, or laryngospasm with an SCN4A mutation) comprising administering to a subject in need thereof a compound of formula (I):

[0378]

[0379] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0380] Other conditions

[0381] In some embodiments, the compounds of the present invention (e.g., compounds of Formula I, I', Ia, Ib, Ic, Id, II, III, V, VII, VIII, or IX) may have suitable pharmacokinetic properties such that they may be active in the central and / or peripheral nervous systems. In some embodiments, the compounds provided herein are useful for treating cardiovascular diseases, such as atrial and ventricular arrhythmias, including atrial fibrillation, Prinzmetal's (variant) angina, stable angina, unstable angina, ischemia and reperfusion injury in the heart, kidney, liver, and brain, exercise-induced angina, pulmonary hypertension, congestive heart disease (including diastolic and systolic heart failure), recurrent ischemia, cerebral ischemia, stroke, renal ischemia, ischemia associated with organ transplantation, acute coronary syndrome, peripheral arterial disease, intermittent claudication, and myocardial infarction. In some embodiments, the compounds provided herein are useful for treating diseases that affect the neuromuscular system, leading to pruritus, seizures, or paralysis, or for treating diabetes or decreased insulin sensitivity and disease states associated with diabetes (e.g., diabetic peripheral neuropathy). In some embodiments, the disclosed methods comprise administering a pharmaceutical composition.

[0382] In some embodiments, provided herein are methods 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.

[0383] Combination therapy

[0384] The compounds or compositions described herein (e.g., for modulating sodium ion channels, such as late sodium (INaL) current) can be administered in combination with another agent or therapy. The individual to whom the compounds disclosed herein are administered may have a disease, disorder, or condition, or symptoms thereof, that would benefit from treatment with another agent or therapy. The disease or condition may be associated with epilepsy or an epileptic syndrome, a neurodevelopmental disorder, pain, or a neuromuscular disorder.

[0385] Antiepileptic drugs

[0386] Antiepileptic drugs include brivaracetam, carbamazepine, clobazam, clonazepam, diazepam, divalproex, eslicarbazepine, ethosuximide, ezogabine, felbamate, gabapentin, lacosamide, lamotrigine, and levetiracetam levetiracetam, lorazepam, oxcarbezepine, permpanel, phenobarbital, phenytoin, pregabalin, primidone, rufinamide, tigabine, topiramate, valproic acid, vigabatrin, zonisamide, and cannabidiol.

[0387] Cardiovascular agent combination therapy

[0388] Cardiovascular-related diseases or conditions that may benefit from treatment with a sodium channel blocker of the present invention in combination with other therapeutic agents include, but are not limited to, angina (including stable angina, unstable angina (UA), exercise-induced angina, variant angina), arrhythmia, intermittent claudication, myocardial infarction (including non-STE myocardial infarction (NSTEMI)), pulmonary hypertension (including pulmonary 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.

[0389] Therapeutic agents suitable for treating cardiovascular-related diseases or conditions include antianginal agents, heart failure agents, antithrombotic agents, antiarrhythmic agents, antihypertensive agents, and lipid-lowering agents.

[0390] Co-administration of the sodium channel blockers of the present invention with therapeutic agents suitable for treating cardiovascular-related disorders allows for enhancement of the standard of care therapy currently received by patients.

[0391] Antianginal drugs

[0392] Antianginal drugs include beta-blockers, calcium channel blockers, and nitrates. Beta-blockers reduce the heart's need for oxygen by lowering its workload, causing a lower heart rate and fewer intense heart contractions. Examples of beta-blockers include acebutolol (Sectral), atenolol (Tenormin), betaxolol (Kerlone), bisoprolol / hydrochlorothiazide (Ziac), bisoprolol (Zebeta), carteolol (Cartrol), esmolol (Brevibloc), labetalol (Normodyne, Trandate), metoprolol (Lopressor, Toprol XL), nadolol (Corgard), propranolol (Inderal), sotalol (Betapace), and timolol (Blocadren).

[0393] Nitrates dilate arteries and veins by increasing coronary blood flow and lowering blood pressure. Examples of nitrates include nitroglycerin, nitrate patches, isosorbide dinitrate, and isosorbide 5-mononitrate.

[0394] Calcium channel blockers prevent the normal flow of calcium into 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.

[0395] Heart failure medications

[0396] Medications used to treat heart failure include diuretics, ACE inhibitors, vasodilators, and cardiac glycosides. Diuretics eliminate excess fluid from tissues and circulation, thereby alleviating many of the symptoms of heart failure. Examples of diuretics include hydrochlorothiazide, metolazone (Zaroxolyn), furosemide (Lasix), bumetanide (Bumex), spironolactone (Aldactone), and eplerenone (Inspra).

[0397] Angiotensin converting enzyme (ACE) inhibitors reduce the workload on the heart by dilating blood vessels and reducing resistance to blood flow. Examples of ACE inhibitors include benazepril (Lotensin), captopril (Capoten), enalapril (Vasotec), fosinopril (Monopril), lisinopril (Prinivil, Zestril), moexipril (Univasc), perindopril (Aceon), quinapril (Accupril), ramipril (Altace), and trandolapril (Mavik).

[0398] Vasodilators reduce pressure on blood vessels by causing them to relax and dilate. Examples of vasodilators include hydralazine, diazoxide, prazosin, clonidine, and methyldopa. ACE inhibitors, nitrates, potassium channel activators, and calcium channel blockers are also used as vasodilators.

[0399] Cardiac glycosides are compounds that increase the force of heart contraction. They strengthen the heart's pumping ability and improve irregular heartbeats. Examples of cardiac glycosides include digitalis, digoxin, and digitoxin.

[0400] Antithrombotic agents

[0401] Antithrombotic drugs inhibit the blood's ability to clot. There are three main types of antithrombotic drugs—platelet inhibitors, anticoagulants, and thrombolytics.

[0402] Platelet inhibitors inhibit the clotting activity of platelets, thereby reducing clots in arteries. Examples of platelet inhibitors include acetylsalicylic acid (aspirin), ticlopidine, clopidogrel (plavix), dipyridamole, cilostazol, persantine, sulfinpyrazone, indomethacin, and glycoprotein IIb / IIIa inhibitors such as abciximab, tirofiban, and eptifibatide (integrelin). Beta-blockers and calcium channel blockers also have platelet-inhibiting effects.

[0403] Anticoagulants prevent blood clots from growing larger and prevent new clots from forming. Examples of anticoagulants include bivalirudin (Angiomax), warfarin (Coumadin), unfractionated heparin, low molecular weight heparin, danaparoid, lepirudin, and argatroban.

[0404] Thrombolytics are used to break down existing blood clots. Examples of thrombolytics include streptokinase, urokinase, and tenecteplase (TNK) and tissue plasminogen activator (t-PA).

[0405] Antiarrhythmic drugs

[0406] Antiarrhythmics are used to treat disorders of heart rate and rhythm. Examples of antiarrhythmics include amiodarone, dronedarone, quinidine, procainamide, lidocaine, and propafenone. Cardiac glycosides and beta-blockers are also used as antiarrhythmics.

[0407] The combination of amiodarone and dronedarone is of particular interest given the recently discovered synergistic effects of the sodium channel blocker ranolazine and amiodarone and dronedarone.

[0408] Antihypertensive agents

[0409] Antihypertensive drugs are used to treat hypertension, a condition in which blood pressure is consistently higher than normal. High blood pressure is associated with many aspects of cardiovascular disease, including congestive heart failure, atherosclerosis, and blood clot formation. Examples of antihypertensive agents include alpha-1-adrenergic antagonists such as prazosin (Minipress), doxazosin mesylate (Cardura), prazosin hydrochloride (Minipress), prazosin, polythiazide (Minizide), and terazosin hydrochloride (Hytrin); beta-adrenergic antagonists such as propranolol (Inderal), nadolol (Corgard), timolol (Blocadren), metoprolol (Lopressor), and pindolol (Visken); central alpha-adrenergic receptor agonists such as clothianidin hydrochloride (Catapres), clothianidin hydrochloride and chlorthalidone (Clorpres, Combipres), guanabenzacetate (Wytensin), guanfacine hydrochloride (Guanfacine hydrochloride), and chlorthalidone (Corapres). hydrochloride) (Tenex), methyldopa (Aldomet), methyldopa and chlorothiazide (Aldoclor), methyldopa and hydrochlorothiazide (Aldoril); combined α / β-adrenergic antagonists, such as labetalol (Normodyne, Trandate), carvedilol (Coreg); adrenergic neuron blockers, such as guanethidine (ismelin), serpentine (Serpasil); central nervous system-acting antihypertensives, such as clothianidin (Catapres), methyldopa (Aldomet), guanabenz (Wyten sin); anti-vasoconstrictor peptide II agents; ACE inhibitors, such as perindopril (Aceon), captopril (Capoten), enalapril (Vasotec), lisinopril (Prinivil, Zestril); vasoconstrictor peptide-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 as nitroprusside (Nipride), diazoxide (Hyperstat IV), hydralazine (Apresoline), minoxidil (Loniten), verapamil; and potassium channel activators, such as aprikalim, bimakalim, cromakalim, emakalim, nicorandil, and pinacidil.

[0410] lipid-lowering agents

[0411] Lipid-lowering agents are used to reduce the amount of cholesterol or fat sugar 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 (mevastatin), pitavastatin (Livalo, Pitava), pravastatin (pravastatin) (Lipostat), rosuvastatin (rosuvastatin) (Crestor) and simvastatin (Zocor).

[0412] In the present invention, patients presenting with an acute coronary artery disease event often suffer from secondary medical conditions, such as one or more of a metabolic disorder, a pulmonary disorder, a peripheral vascular disorder, or a gastrointestinal disorder. Such patients may benefit from treatment with a combination therapy comprising administering to the patient a combination of ranolazine and at least one therapeutic agent.

[0413] Combination therapy for lung diseases

[0414] A pulmonary disorder refers to any disease or disorder related to the lungs. Examples of pulmonary disorders include, but are not limited to, asthma, chronic obstructive pulmonary disease (COPD), bronchitis, and emphysema.

[0415] Examples of therapeutic agents for treating pulmonary disorders include bronchodilators, including beta2 agonists and anti-parasympathetic drugs, corticosteroids, and electrolyte supplements. Specific examples of therapeutic agents for treating pulmonary disorders include epinephrine, terbutaline (Brethaire, Bricanyl), albuterol (Proventil), salmeterol (Serevent, Serevent Diskus), theophylline, ipratropium bromide (Atrovent), tiotropium bromide (Spiriva), methylprednisolone (Solu-Medrol, Medrol), magnesium, and potassium.

[0416] Combination therapy for metabolic disorders

[0417] Examples of metabolic disorders include, but are not limited to, diabetes (including type I and type II diabetes), metabolic syndrome, dyslipidemia, obesity, glucose intolerance, hypertension, elevated serum cholesterol, and elevated triglycerides.

[0418] Examples of therapeutic agents for treating metabolic disorders include antihypertensive agents and lipid-lowering agents, as described above in the section "Cardiovascular Combination Therapy." Additional therapeutic agents for treating metabolic disorders include insulin, sulfonylureas, biguanides, α-glucosidase inhibitors, and incretin mimetics.

[0419] Combination therapy for peripheral vascular diseases

[0420] Peripheral vascular disorders are conditions involving the blood vessels (arteries and veins) outside the heart and brain and include, for example, peripheral arterial disease (PAD), a condition that occurs when arteries supplying blood to internal organs, arms, and legs become completely or partially blocked due to atherosclerosis.

[0421] Combination therapy for gastrointestinal disorders

[0422] Gastrointestinal disorders refer to diseases and disorders related to the gastrointestinal tract. Examples of gastrointestinal disorders include gastroesophageal reflux disease (GERD), inflammatory bowel disease (IBD), gastroenteritis, gastritis and peptic ulcer disease, and pancreatitis.

[0423] Examples of therapeutic agents used to treat gastrointestinal disorders include proton pump inhibitors, e.g., pantoprazole (Protonix), lansoprazole (Prevacid), esomeprazole (Nexium), omeprazole (Prilosec), rabeprazole; H2 blockers, e.g., cimetidine (Tagamet), ranitidine (Zantac), famotidine (Pepcid), nizatidine (Axid); prostaglandins, e.g., misoprostol (Cytotec); sucralfate; and antacids.

[0424] Combination therapy with antibiotics, painkillers, antidepressants, and antianxiety drugs

[0425] Patients presenting with an acute coronary artery disease event may exhibit conditions that would benefit from the administration of therapeutic agents or agents such as antibiotics, analgesics, antidepressants, and anxiolytics in combination with ranolazine.

[0426] antibiotic

[0427] Antibiotics are therapeutic agents that kill or stop the growth of microorganisms, including bacteria and fungi. Examples of antibiotic agents include β-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,

[0428] (Omnicef), ceftriaxone (Rocephin), carbapenems, and monobactams; tetracyclines, such as tetracycline; macrolide antibiotics, such as erythromycin; aminoglycosides, such as gentamicin, tobramycin, and amikacin; quinolinones, such as ciprofloxacin; cyclic peptides, such as vancomycin, streptogramin, and polymyxin; lincosamides, such as clindamycin; oxazolidinones, such as linezolid; and sulfonamide antibiotics, such as sulfisoxazole.

[0429] painkillers

[0430] Analgesics are therapeutic agents used to relieve pain. Examples of analgesics include, for example, fentanyl; acetaminophen; NSAIDs and COX-2 inhibitors. V The ability of 1.7 and 1.8 sodium channels to treat neuropathic pain is particularly contemplated in combination with analgesics. See U.S. Patent Application Publication No. 20090203707.

[0431] Antidepressants and antianxiety medications

[0432] Antidepressants and antianxiety drugs include those used to treat anxiety disorders, depression, and those used as sedatives and tranquilizers. Examples of antidepressants and antianxiety drugs 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). Antidepressants and antianxiety drugs may include neuroactive steroids and ketamine and related NMDA receptor antagonists.

[0433] Thus, one aspect of the present invention provides a composition comprising a sodium channel blocker of the present invention and at least one therapeutic agent. In alternative embodiments, the composition comprises a sodium channel blocker of the present invention and at least two therapeutic agents. In other alternative embodiments, the composition comprises a sodium channel blocker of the present invention and at least three therapeutic agents, a sodium channel blocker of the present invention and at least four therapeutic agents, or a sodium channel blocker of the present invention and at least five therapeutic agents.

[0434] Methods of combination therapy include co-administration of a single formulation containing a sodium channel blocker of the invention and a therapeutic or pharmaceutical agent, substantially simultaneous administration of more than one formulation containing a sodium channel blocker of the invention and a therapeutic or pharmaceutical agent, and sequential administration of a sodium channel blocker of the invention and a therapeutic or pharmaceutical agent in any order, wherein preferably there is a time period while the sodium channel blocker of the invention and the therapeutic or pharmaceutical agent simultaneously exert their therapeutic effects.

[0435] Example

[0436] The following representative examples are intended to help illustrate the present invention and are not intended to, and should not be construed to, limit the scope of the invention.

[0437] The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. It should be understood that although typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, other process conditions may also be used unless otherwise stated. Optimal reaction conditions may vary depending on the specific reactants or solvents used, but such conditions can be determined by those skilled in the art through routine optimization.

[0438] In addition, as will be appreciated by those skilled in the art, conventional protecting groups may be required to prevent certain functional groups from undergoing undesirable reactions. The selection of suitable protecting groups for particular functional groups and suitable conditions for protection and deprotection is well known in the art. For example, TW Greene and PGM Wuts, Protecting Groups in Organic Synthesis (Second Edition, Wiley, New York, 1991), and the references cited therein, describe numerous protecting groups and their introduction and removal.

[0439] The compounds provided herein can be separated and purified by known standard procedures. Such procedures include recrystallization, filtration, flash chromatography, grinding, high pressure liquid chromatography (HPLC) or supercritical fluid chromatography (SFC). Note that flash chromatography can be performed manually or via an automated system. The compounds provided herein can be characterized by known standard procedures such as nuclear magnetic resonance spectroscopy (NMR) or liquid chromatography mass spectrometry (LCMS). NMR chemical shifts are reported in parts per million (ppm) and are generated using methods well known to those skilled in the art.

[0440] Exemplary general methods for analytical LCMS include Method A (Xtimate C 18 (2.1mm×30mm, 3μm); A=H2O (0.04% TFA) and B=CH3CN (0.02% TFA); 50℃; 1.2

[0441] mL / min; 10-80% B in 0.9 min, then 80% B for 0.6 min) and Method B (ChromolithFlash RP-18 capped C 18 (2 mm x 25 mm); A = H2O (0.04% TFA) and B = CH3CN (0.02% TFA); 50°C; 1.5 mL / min; 5-95% B in 0.7 min, then 95% B for 0.4 min).

[0442] List of abbreviations

[0443] Pd(dppf)Cl2 [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride

[0444] Pd(t-Bu3P)2 Bis(tri-tert-butylphosphine)palladium(0)

[0445] Pd(OAc)2 Palladium(II) acetate

[0446] SPhos 2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl

[0447] Et3N triethylamine

[0448] AgOTf silver trifluoromethanesulfonate

[0449] DMF N,N-dimethylformamide

[0450] MeOH methanol

[0451] EtOH

[0452] i-Pr2O diisopropyl ether

[0453] THF Tetrahydrofuran

[0454] DCM dichloromethane

[0455] AcN or MeCN acetonitrile

[0456] EA or EtOAc Ethyl acetate

[0457] PE petroleum ether

[0458] DMSO dimethyl sulfoxide

[0459] AcOH acetic acid

[0460] NBS N-bromosuccinimide

[0461] NaOMe sodium methoxide

[0462] EtONa sodium ethoxide

[0463] TsOH p-Toluenesulfonic acid

[0464] DEA N,N-Diethylaniline

[0465] DIPEA N,N-Diisopropylethylamine

[0466] TFA trifluoroacetic acid

[0467] KOAc potassium acetate

[0468] T3P Propanephosphonic Anhydride

[0469] Example 1: 3-[cyclopropylmethoxy(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyridine

[0470]

[0471] Synthesis of B: To a suspension of NaH (2.94 g, 73.56 mmol) in THF (50 mL) was slowly added 2,2,2-trifluoroethanol (7.36 g, 73.56 mmol) 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 saturated NH4Cl (50 mL) and extracted with EtOAc (100 mL x 2). The combined organic phases were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to give B (15000 mg, 65.34 mmol) as an oil. 1 H NMR (400 MHz, CDCl3) δ H =7.83(d,1H),7.38(dd,1H),4.73(q,2H).

[0472] Synthesis of A3: A mixture of B (8 g, 34.85 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (26.55 g, 104.55 mmol), K 3 PO 4 (14.79 g, 69.7 mmol), SPhos (4.29 g, 10.45 mmol) and Pd(OAc) 2 (782.4 mg, 3.48 mmol) in 1,4-dioxane (250 mL) was stirred at 85° C. for 16 h. After cooling to room temperature, the mixture was filtered through celite and eluted with EtOAc (50 mL×2). The filtrate was concentrated and diluted with EtOAc (200 mL), washed with water (100 mL×2) and brine (100 mL), dried over Na 2 SO 4 , filtered and concentrated to give the crude product, which was purified by flash chromatography on silica gel (EtOAc in PE=0 to 10% to 40%) to give the product as an oil (3 g, 4.6021 mmol). 1 HNMR (400MHz, CDCl3)δ H =8.26(d,1H),7.72(dd,1H),4.87(q,2H),1.35(s,12H). LCMS R t= 0.94 min using method B, MSESI calculated value C 13 H 17 BF4NO3[M+H] + 322.1, experimental value 322.3.

[0473]

[0474] 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 hours. Then, 6-bromo-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyridine (300 mg, 1.06 mmol) was added to the mixture, and the mixture was stirred at 20 ° C for 2 hours. The reactants were quenched with saturated NH4Cl (10 mL), and the mixture was extracted with EtOAc (10 mL × 2). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to 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 as a solid (240 mg, 0.73 mmol). LCMS Rt = 2.29 min in 4 min chromatography.

[0475] Synthesis of Compound 1: A mixture of 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (111.02 mg, 0.35 mmol), Pd(dppf)Cl2 (34.5 mg, 0.05 mmol), 6-bromo-3-[cyclopropylmethoxy(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyridine (100 mg, 0.31 mmol) and K2CO3 (86.89 mg, 0.63 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was stirred at 90° C. under N2 for 16 hours. After cooling to room temperature, the mixture was filtered through celite and eluted with EtOAc (10 mL×2), and the filtrate was concentrated to give the crude product. The crude product was purified by Prep-HPLC (Waters Xbridge 150 mm×25 mm 5 μm) A═H 2 O (10 mM NH 4 HCO 3 ) and B═CH 3 CN; 50-70% B in 7 min) to give the product as a solid (100.49 mg, 0.23 mmol). 1 HNMR (400 MHz, DMSO-d6) δ H=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 chromatogram in 2.0 min R t = 1.31 min, MS ESI calculated value C 18 H 15 F6N4O2[M+H] + 433.1, experimental value 433.0.

[0476] Example 2: 3-[Difluoro(isobutyloxy)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyridine

[0477]

[0478] Synthesis of A4: To a mixture of 2-methylpropan-1-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 hours. 6-Bromo-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyridine (300 mg, 1.06 mmol) was then added to the mixture, and the mixture was stirred at 20 ° C for 2 hours. The reaction was quenched with saturated NH4Cl (10 mL), and the mixture was extracted with EtOAc (20 mL×2). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to produce the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 10% to 40%) to produce the product as a solid (100 mg, 0.30 mmol). LCMS Rt = 0.86 min in 1.5 min chromatography, MS ESI calculated value C 11 H 13 BrF2N3O[M+H+2] + 320.0, experimental value 320.2.

[0479] Synthesis of Compound 2: A mixture of 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (110.33 mg, 0.34 mmol), Pd(dppf)Cl2 (34.28 mg, 0.05 mmol), 6-bromo-3-[difluoro(isobutyloxy)methyl]-[1,2,4]triazolo[4,3-a]pyridine (100 mg, 0.31 mmol) and K2CO3 (86.35 mg, 0.62 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was stirred at 90° C. under N2 for 16 hours. After cooling to room temperature, the mixture was filtered through celite and eluted with EtOAc (10 mL×2), and the filtrate was concentrated to give the crude product. The crude product was purified by Prep-HPLC (Waters Xbridge 150 mm×25 mm 5 μm) A═H 2 O (10 mM NH 4 HCO 3 ) and B═CH 3 CN; 50-70% B in 8 min) to give the product as a solid (53.41 mg, 0.12 mmol). 1 HNMR (400 MHz, DMSO-d6) δ H =8.70 (s, 1H), 8.44 (d, 1H), 8.33 (dd, 1H), 8.12 (dd, 1H), 7.96 (dd, 1H), 5.18 (q, 2H), 4.02 (d, 2H), 2.09-1.98 (m, 1H), 0.96 (d, 6H). LCMS chromatogram in 2.0 min R t = 1.34 min, MS ESI calculated value C 18 H 17 F6N4O2[M+H] + 435.1, experimental value 435.1.

[0480] Example 3: 3-[Ethoxy(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyridine

[0481]

[0482] Synthesis of A5: A mixture of 6-bromo-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyridine (300 mg, 1.06 mmol) and EtONa (361.37 mg, 5.31 mmol) in ethanol (10 mL) was stirred at 80 ° C for 24 hours. After cooling to room temperature, the reactant was quenched with saturated NH4Cl (10 mL), and the mixture was extracted with EtOAc (20 mL×2). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to produce a crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 10% to 40%) to produce a solid product (70 mg, 0.17 mmol). LCMS R in 4 min chromatography t =1.97 min, MS ESI calculated value C9H9BrF2N3O[M+H+2] + 294.0, experimental value 293.8.

[0483] Synthesis of Compound 3: A mixture of 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (84.65 mg, 0.26 mmol), Pd(dppf)Cl2 (26.3 mg, 0.04 mmol), 6-bromo-3-[ethoxy(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyridine (70 mg, 0.24 mmol) and K2CO3 (66.25 mg, 0.48 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was stirred at 90° C. under N2 for 16 hours. After cooling to room temperature, the mixture was filtered through celite and eluted with EtOAc (10 mL×2), and the filtrate was concentrated to give the crude product. The crude product was purified by Prep-HPLC (Waters Xbridge 150 mm×25 mm 5 μm) A═H 2 O (10 mM NH 4 HCO 3 ) and B═CH 3 CN; 42-62% B in 8 min) to give the product as a solid (44.33 mg, 0.11 mmol). 1 H NMR (400 MHz, DMSO-d6) δ H =8.73(s,1H),8.46(d,1H),8.35(br d,1H),8.11(d,1H),7.96(d,1H),5.18(q,2H),4.29(q,2H),1.36(t,3H)LCMS in 2.0min chromatogram R t = 1.25 min, MS ESI calculated value C 16 H 13 F6N4O2[M+H]+ 407.1, experimental value 407.0.

[0484] Example 4: 3-[Difluoro(isopropoxy)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyridine

[0485]

[0486] 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 hours. 6-Bromo-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyridine (300 mg, 1.06 mmol) was then added to the mixture, and the mixture was stirred at 20 ° C for 2 hours. The reactants were quenched with saturated NH4Cl (10 mL), and the mixture was extracted with EtOAc (10 mL × 2). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to produce the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 10% to 40%) to produce the product as a solid (240 mg, 0.72 mmol). LCMS Rt = 2.18 min in 4 min chromatography, MS ESI calculated value C 10 H 11 BrF2N3O[M+H+2] + 306.0, experimental value 305.9.

[0487] Synthesis of compound 4: A mixture of 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (115.38 mg, 0.36 mmol), Pd(dppf)Cl2 (35.85 mg, 0.05 mmol), 6-bromo-3-[difluoro(isopropoxy)methyl]-[1,2,4]triazolo[4,3-a]pyridine (100 mg, 0.33 mmol) and K2CO3 (90.3 mg, 0.65 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was stirred at 90° C. under N2 for 16 hours. After cooling to room temperature, the mixture was filtered through celite and eluted with EtOAc (10 mL×2), and the filtrate was concentrated to give the crude product. The crude product was purified by Prep-HPLC (Waters Xbridge 150 mm×25 mm 5 μm) A═H 2 O (10 mM NH 4 HCO 3 ) and B═CH 3 CN; 45-65% B in 8 min) to give the product as a solid (80.25 mg, 0.19 mmol). 1 H NMR (400 MHz, DMSO-d6) δ H =8.60 (s, 1H), 8.43 (d, 1H), 8.32 (dd, 1H), 8.11 (d, 1H), 7.95 (dd, 1H), 5.17 (q, 2H), 4.90 (spt, 1H), 1.41 (d, 6H). LCMS R in 2.0 min chromatogram t = 1.29 min, MS ESI calculated value C 17 H 15 F6N4O2[M+H] + 421.1, experimental value 421.0.

[0488] Example 5: 3-[Difluoro(methoxy)methyl]-6-[5-fluoro-6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyridazine

[0489]

[0490] 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-acetic acid (2-chloro-2,2-difluoro-acetyl) ester (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 NaHCO 3 (50 mL), and the mixture was extracted with EtOAc (50 mL × 2). The combined organic phases were washed with brine (20 mL), dried over Na 2 SO 4, filtered and concentrated to produce a solid crude product. 1 H NMR (400 MHz, DMSO-d6) δ H =8.67(d,1H),7.78(d,1H).

[0491] Synthesis of A9: A mixture of 6-chloro-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-b]pyridazine (200 mg, 0.84 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)pyridine (350.58 mg, 1 mmol), Pd(t-Bu3P)2 (64.15 mg, 0.13 mmol), and K3PO4 (532.95 mg, 2.51 mmol) in 1,4-dioxane (2 mL) and water (0.20 mL) was stirred at 80°C for 16 hours. After cooling to room temperature, the suspension was diluted with EtOAc (10 mL), filtered through silica gel, and eluted with EtOAc (20 mL). The combined filtrates were concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 20% to 50% to 80%) to give the product as a solid (260 mg, 0.50 mmol). LCMS R in 1.5 min chromatogram t =0.96min, MSESI calculated value C 15 H 11 ClF6N5O[M+H] + 426.1, experimental value 425.9.

[0492] Synthesis of Compound 5: To a mixture of 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyridazine (150 mg, 0.35 mmol) in MeCN (1 mL) 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) and extracted with EtOAc (30 mL×2). The combined organic phases were washed with water (20 mL×2), brine (30 mL×2), dried over anhydrous Na 2 SO 4 , filtered, and concentrated to give the crude product. The crude product was purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm), A=H 2 O (0.05% NH 4 OH) and B=CH 3 CN; 57-87% B in 9 minutes) to give the product as a solid. 1 H NMR (CDCl3, 400MHz)δ H =8.55 (d, 1H), 8.29 (d, 1H), 8.09 (dd, 1H), 7.65 (d, 1H), 3.94 (s, 3H), 1.90 (s, 6H). LCMS in 2.0min chromatogram R t = 1.32 min, MS ESI calculated value C 16 H 14 F6N5O2[M+H] + 422.1, experimental value 422.0.

[0493] Example 6: 3-[Difluoro(methoxy)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyridine

[0494]

[0495] A mixture of 6-bromo-3-[difluoro(methoxy)methyl]-[1,2,4]triazolo[4,3-a]pyridine (100 mg, 360 μmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (144.62 mg, 430 μmol), K2CO3 (99.41 mg, 720 μmol) and Pd(dppf)Cl2 (39.47 mg, 50 μmol) in 1,4-dioxane (5 mL) and water (500 μL) was stirred at 80°C under N2 for 12 hours. After cooling to room temperature, the mixture was diluted with H2O (10 mL) and extracted with EtOAc (20 mL×2). The combined organic phases were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated to give the crude product. The crude product was purified by Prep-HPLC (Boston Prime C18 (150 x 30 mm, 5 μm), A = H2O (0.05% NH4OH) and B = CH3CN; 53-83% B in 8 minutes) to give the product as a solid. 1 H NMR (400 MHz, DMSO-d6) δ H =8.73(s,1H),8.45(d,1H),8.33(dd,1H),8.10(d,1H),7.94(d,1H),6.01(spt,1H),3.89(s,3H),1.54(d,3H). LCMS R in 2.0min chromatogram t = 1.27 min, MS ESI calculated value C 18 H 13 F6N4O2[M+H] + 407.09, experimental value 406.9.

[0496] Example 7: 3-[Difluoro(methoxy)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyridine

[0497]

[0498] A mixture of 6-bromo-3-[difluoro(methoxy)methyl]-[1,2,4]triazolo[4,3-a]pyridine (100 mg, 360 μmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (144.62 mg, 430 μmol), K2CO3 (99.41 mg, 720 μmol) and Pd(dppf)Cl2 (39.47 mg, 50 μmol) in 1,4-dioxane (5 mL) and water (500 μL) was stirred at 80°C under N2 for 12 hours. After cooling to room temperature, the mixture was diluted with H2O (10 mL) and extracted with EtOAc (20 mL×2). The combined organic phases were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated to give the crude product. The crude product was purified by Prep-HPLC (Boston Prime C18 (150 mm x 30 mm, 5 μm), A = H2O (0.05% NH4OH) and B = CH3CN; 53-83% B in 8 minutes) to give the product as a solid. 1 H-NMR (400 MHz, DMSO-d6) δ H =8.74 (s, 1H), 8.46 (d, 1H), 8.35 (dd, 1H), 8.11 (d, 1H), 7.95 (dd, 1H), 6.02 (spt, 1H), 3.95-3.82 (m, 3H), 1.55 (d, 3H). LCMS R in 2.0 min chromatogram t = 1.27 min, MS ESI calculated value C 18 H 13 F6N4O2[M+H] + 407.1, experimental value 406.9.

[0499] Example 8: 3-[Cyclopropylmethoxy(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyrazine

[0500]

[0501] A mixture of 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyrazine (300 mg, 0.75 mmol) and AgOTf (1938.39 mg, 7.54 mmol) in cyclopropylmethanol (15 mL, 0.75 mmol) and CH 3 CN (15 mL) was stirred at 90° C. for 14 days. After cooling to room temperature, the reaction was diluted with EtOAc (40 mL) and saturated NaCl (40 mL) was added to the mixture, the mixture was filtered through celite and eluted with EtOAc (20 mL×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 an impure product. The impure product was purified by Prep-HPLC (Waters Xbridge 150 mm x 25 mm 5 μm) A = H2O (10 mM NH4HCO3) and B = CH3CN; 48-68% B in 8 min) to give the product as a solid. 1 H-NMR (CDCl3, 400MHz)δ H =9.52 (d, 1H), 8.57 (d, 1H), 8.50 (d, 1H), 8.07 (dd, 1H), 4.93 (q, 2H), 4.13 (d, 2H), 1.40-1.30 (m, 1H), 0.79-0.73 (m, 2H), 0.49-0.42 (m, 2H). LCMS chromatogram in 2.0 min R t = 1.33 min, MS ESI calculated value C 17 H 14 F6N5O2[M+H] + 434.1, experimental value 434.0.

[0502] Example 9: 3-[Cyclopropylmethoxy(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyrazine

[0503]

[0504] 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-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (141.18 g, 439.69 mmol) and 2-bromo-5-chloro-pyrazine (80 g, 413.59 mmol) in 1,4-dioxane (1 L) and water (150 mL) was stirred at 35°C for 2 hours under N2. After cooling to room temperature, water (300 mL) was added to the mixture and the mixture was filtered through celite. After separation, the organic phase was washed with brine (300 mL), dried over anhydrous Na2SO4, filtered and concentrated to give the crude product. The crude product was redissolved in EA / PE=1 / 3 (500 mL) and then filtered through a silica gel pad. The cake was washed with EA / PE=1 / 3 (500 mL). The combined organic phases were concentrated to produce an oily residue. PE (500 mL) was slowly added to the oil and some solids were obtained. The solids were collected and dried in an oven to produce a solid product (100 g, 242.4 mmol, 58% yield). LCMS R in 2.0 min chromatogram t =1.28 min, 10-80 AB, MS ESI calculated value C 11 H7ClF4N3O[M+H] + 308.0, experimental value 307.9.

[0505] 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 slowly poured into water (4.5 L). Some solids were observed and the solids were collected by filtration. The cake was washed with water (500 mL×2). The solid was redissolved in EtOAc (3 L), washed with brine (500 mL×2), dried over anhydrous Na2SO4, filtered and concentrated to give a solid crude product (100 g, 329.8 mmol, 97% yield). LCMS R in 1.5 min chromatogram t = 0.74 min, 5-95 AB, MS ESI calculated value C 11 H 10 F4N5O[M+H] + 304.1, experimental value 303.9.

[0506] 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 directly in the next step. To a solution of 2-bromo-2,2-difluoro-acetyl chloride (95.66 g, 494.69 mmol) in THF (1 L) was added [5-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]pyrazin-2-yl]hydrazine (100 g, 329.79 mmol). The resulting mixture was stirred at 20°C for 2 hours. Water (1 L) was added to the solution, and the mixture was extracted with EtOAc (1 L x 2). The combined organic phases were washed with brine (500 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated to give a crude solid product (150 g, 326.0 mmol, 98% yield, a mixture of mono- and bis-alkylated products). LCMS chromatogram at 5-95AB in 1.5 min, R t =0.92min, MS ESI C 13 H9BrF6N5O2[M+H] + Calculated value 460.1, experimental value 459.8.

[0507] Synthesis of A14: A solution of 2-bromo-2,2-difluoro-N'-[5-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridinyl]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) and extracted with EtOAc (2 L x 2). The combined organic phases were washed with brine (1 L x 2), dried over anhydrous Na2SO4, filtered, and concentrated to yield the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 15% to 30%) to yield the product as an oil (80 g, 181.0 mmol, 55% yield). 1 H NMR (CDCl3, 400MHz)δ H =9.60(d,1H),8.55(d,1H),8.45(s,1H),8.09(dd,1H),4.93(q,2H).

[0508] Synthesis of Compound 10: A mixture of 3-[bromo(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyrazine (76 g, 171.9 mmol) and AgBF4 (66.93 g, 343.81 mmol) in ethanol (760 mL) was stirred at 60°C for 1 hour. After cooling to room temperature, the mixture was poured into saturated aqueous NaCl solution (1 L) and EtOAc (2 L). The mixture was filtered through Celite. After separation, the aqueous layer was extracted with 500 mL x 2. The combined organic phases were washed with brine (500 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated to yield the crude product. The crude product was purified by flash column chromatography on silica gel (EtOAc in PE = 0% to 30% to 50%) and then triturated with EtOH (50 mL) to give the product as a solid (44.45 g, 109.01 mmol, 63% yield). 1 H NMR (CDCl3400MHz)δ H =9.52 (d, 1H), 8.49 (dd, 2H), 8.07 (dd, 1H), 4.93 (q, 2H), 4.37 (q, 2H), 1.51 (t, 3H). LCMS in 10-80AB 2.0min chromatogram, R t =1.25min, MS ESI C 15 H 12 F6N5O2[M+H] + Calculated value 408.1, experimental value 408.0.

[0509] Example 10: 3-[Difluoro(methoxy)methyl]-6-[5-fluoro-6-[1-(trifluoromethyl)cyclobutyloxy]-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyrazine

[0510]

[0511] A mixture of 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[1-(trifluoromethyl)cyclobutyloxy]-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyrazine (1.4 g, 3.2 mmol) and AgOTf (8.22 g, 31.98 mmol) in a mixed solvent of methanol (14 mL) and DMF (14 mL) was stirred at 90° C. for 24 hours. After cooling to room temperature, the reaction mixture was treated with brine (40 mL) and the precipitate was filtered. The filtrate was extracted with EtOAc (40 mL×2). The combined organic phases were washed with brine (20 mL), dried over Na 2 SO 4 , and concentrated to give the crude product. The crude product was purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm 5 μm) A=H 2 O (10 mM NH 4 HCO 3 ) and B=CH 3 CN; 57-67% B in 8 minutes) to give the product (240 mg). Another batch started with 1.2 g of A24 and was purified by Prep-HPLC (Boston Prime C18 (150 mm×30 mm, 5 μm) A=H 2 O (0.05% NH 4 OH) and B=

[0512] CH3CN; 50-80% in 9 minutes B) Approximately 110 mg of product was obtained. The two crops were combined and lyophilized to give the product as a solid. 1 H NMR (CDCl3, 400MHz)δ H =9.51 (d, 1H), 8.49 (d, 1H), 8.47 (d, 1H), 8.05 (dd, 1H), 3.98 (s, 3H), 2.98-2.86 (m, 2H), 2.81-2.72 (m, 2H), 2.11-1.93 (m, 2H). LCMS chromatogram in 2min R t =1.30 min, 10-80 AB, MS ESI calculated value C 17 H 14 F6N5O2[M+H] + 434.1, experimental value 433.9.

[0513] Example 11: 3-[Difluoro(methoxy)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridinyl]-[1,2,4]triazolo[4,3-b]pyridazine

[0514]

[0515] Synthesis of A25: 6-chloro-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-b]pyridazine (120 mg, 0.50 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-

[0516] A mixture of (1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (201.9 mg, 0.60 mmol), K 3 PO 4 (319.74 mg, 1.51 mmol), Pd(t-Bu 3 P) 2 (25.66 mg, 0.05 mmol) in 1,4-dioxane (12 mL) and H 2 O (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×2). The combined organic phases were washed with brine (40 mL), dried over Na 2 SO 4 , and concentrated to give a residue. The residue was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 60%) to give the product as a solid (120 mg, 0.29 mmol). 1 H-NMR (CDCl3, 400MHz)δ H =8.57(d,1H),8.35(d,1H),8.15(dd,1H),7.74(d,1H),5.93(m,1H)1.61(d,3H).

[0517] Synthesis of compound 12: A mixture of AgOTf (599.15 mg, 2.33 mmol), 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyridazine (120 mg, 0.29 mmol) in methanol (6 mL) was stirred at 90 ° C for 120 hours. After cooling to room temperature, the reaction mixture was treated with brine (20 mL) and the precipitate was filtered. The filtrate was concentrated, diluted with water (20 mL) and extracted with ethyl acetate (20 mL×2). The combined organic phases were washed with brine (40 mL), dried over Na 2 SO 4 and concentrated to produce a residue. The residue was purified by prep-HPLC (Boston Prime C18 150 x 30 mm 5 μm) A = H2O (0.05% NH4OH) and B = CH3CN; 52-82% B in 8 min) to give the product (5.12 mg, 13 μmol). 1 H-NMR (CDCl3, 400MHz)δ H=8.55 (d, 1H), 8.30 (d, 1H), 8.14 (dd, 1H), 7.66 (d, 1H), 5.92 (m, 1H), 3.94 (s, 3H), 1.61 (d, 3H). LCMS R in 2.0 min chromatogram t = 1.28 min, MS ESI calculated value C 15 H 12 F6N5O2[M+H] + 408.1, experimental value 408.0.

[0518] Example 12: 3-[Difluoro(methoxy)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridinyl]-[1,2,4]triazolo[4,3-b]pyridazine

[0519]

[0520] Synthesis of A26: 6-chloro-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-b]pyridazine (120 mg, 0.50 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-

[0521] A mixture of (1R)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (201.9 mg, 0.60 mmol), K 3 PO 4 (319.74 mg, 1.51 mmol), Pd(t-Bu 3 P) 2 (25.66 mg, 0.05 mmol) in 1,4-dioxane (12 mL) and H 2 O (4 mL) was stirred at 90° C. for 16 hours. After cooling to room temperature, the reaction mixture was concentrated to remove the solvent, diluted with water (20 mL), and extracted with ethyl acetate (20 mL×2). The combined organic phases were washed with brine (40 mL), dried over Na 2 SO 4, 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 as a solid (140 mg, 0.34 mmol). 1 H-NMR (CDCl3, 400MHz)δ H =8.57(d,1H),8.35(d,1H),8.14(dd,1H),7.74(d,1H),5.93(m,1H),1.61(d,3H).

[0522] Synthesis of compound 13: A mixture of 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyridazine (140 mg, 0.34 mmol) and AgOTf (699 mg, 2.72 mmol) in methanol (8 mL) was stirred at 90 ° C for 120 hours. After cooling to room temperature, the reaction mixture was treated with brine (20 mL) and the precipitate was filtered. The filtrate was concentrated and diluted with water (20 mL), then extracted with ethyl acetate (20 mL×2). The combined organic phases were washed with brine (40 mL), dried over Na 2 SO 4 and concentrated to produce a residue. The residue was purified by Prep-HPLC (Boston Prime C18 150 x 30 mm 5 μm) A = H2O (0.05% NH4OH) and B = CH3CN; 52-82% B in 8 min) to give the product (5 mg, 12.2 μmol). 1 H-NMR (CDCl3, 400MHz)δ H =8.55 (d, 1H), 8.30 (d, 1H), 8.14 (dd, 1H), 7.66 (d, 1H), 5.92 (m, 1H), 3.94 (s, 3H), 1.61 (d, 3H). LCMS R in 2.0 min chromatogram t = 1.26 min, MS ESI calculated value C 15 H 12 F6N5O2[M+H] + 408.1, experimental value 408.0.

[0523] Example 13: 3-[Cyclopropylmethoxy(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyridazine

[0524]

[0525] Synthesis of A27: A mixture of 6-chloro-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-b]pyridazine (500 mg, 2.09 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (2015.06 mg, 6.28 mmol), Pd(t-Bu3P)2 (160.37 mg, 0.31 mmol) and K3PO4 (888.25 mg, 4.18 mmol) in 1,4-dioxane (15 mL) and water (1.5 mL) was stirred at 90° C. under N2 for 16 hours. The mixture was filtered through celite and eluted with EtOAc (10 mL×2), and the filtrate was concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 20% to 60%) to give the product as a solid (900 mg, 1.90 mmol). LCMS Rt = 0.85 min in 1.5 min chromatography, MS ESI calculated value C 13 H7ClF6N5O[M+H] + 398.0, experimental value 398.0.

[0526] Synthesis of Compound 14: A mixture of 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyridazine (200 mg, 0.50 mmol) and AgOTf (1292.26 mg, 5.03 mmol) in cyclopropylmethanol (10 mL, 0.50 mmol) and 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 C18 150 mm×30 mm 5 μm) (A=H 2 O (0.05% NH 4 OH v / v) and B=CH 3 CN; 58-88% B in 8 minutes) to give an impure product. The impure product was triturated from n-hexane / i-Pr 2 O (v / v=1:1, 2 mL) to give the product as a solid (9.82 mg, 22.2 μmol). 1 H NMR (DMSO-d6, 400 MHz) δ H=8.83 (d, 1H), 8.67 (d, 1H), 8.45 (dd, 1H), 8.21 (d, 1H), 5.22 (q, 2H), 4.03 (d, 2H), 1.26-1.18 (m, 1H), 0.62-0.54 (m, 2H), 0.43-0.33 (m, 2H). LCMS chromatogram in 4.0min R t = 2.87 min, MS ESI calculated value C 17 H 14 F6N5O2[M+H] + 434.1, experimental value 434.0.

[0527] Example 14: 3-[Difluoro(methoxy)methyl]-6-[5-fluoro-6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine

[0528]

[0529] Synthesis of A29: A solution of [5-[5-fluoro-6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridyl]pyrazin-2-yl]hydrazine (300 mg, 0.91 mmol) and 2-chloro-2,2-difluoro-acetic acid (2-chloro-2,2-difluoro-acetyl) ester (660.02 mg, 2.72 mmol) in toluene (30 mL) was stirred at 110 ° C. for 72 hours. After cooling to room temperature, the mixture was concentrated to give a residue. Water (50 mL) was added to the residue, and the mixture was extracted with EtOAc (50 mL×2). The combined organic phases were washed with water (50 mL), brine (50 mL×2), dried over anhydrous Na2SO4, 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 10% to 20%) to give the product as a solid (150 mg, 346.3 μmol). LCMS R in 4.0 min chromatogram t = 3.06 min, MS ESI calculated value C 15 H 11 ClF6N5O[M+H] + 426.0, experimental value 426.0.

[0530] Synthesis of compound 15: To a solution of 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine (150 mg, 0.35 mmol) in methanol (5 mL) and MeCN (5 mL) was added AgOTf (1.81 g, 7.05 mmol). The resulting mixture was stirred at 90 ° C. in a sealed tube under N 2 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 separation of the filtrate, the organic phase was washed with water (20 mL×2), brine (20 mL×2), dried over anhydrous Na 2 SO 4, filtered and concentrated to give the crude product. The crude product was purified by Prep-TLC (PE:EtOAc=4:1) to give the product as a solid (14.23 mg, 33.2 mmol). 1 H NMR (CDCl3, 400MHz)δ H =9.52 (d, 1H), 8.51 (d, 1H), 8.45 (d, 1H), 8.02 (dd, 1H), 3.98 (s, 3H), 1.89 (s, 6H). LCMS chromatogram in 2.0min R t = 1.33 min, MS ESI calculated value C 16 H 14 F6N5O2[M+H] + 422.1, experimental value 422.0.

[0531] Example 15: 3-[Ethoxy(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridinyl]-[1,2,4]triazolo[4,3-b]pyridazine

[0532]

[0533] A mixture of 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyridazine (200 mg, 0.50 mmol) and AgOTf (1292.26 mg, 5.03 mmol) in ethanol (10 mL, 0.50 mmol) and 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×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 an impure product. The impure product was triturated from n-hexane / CH 2 Cl 2 (v / v=1:2, 6 mL) to give the product as a solid (15.95 mg, 39.2 mmol). 1 HNMR (DMSO-d6, 400MHz)δ H =8.81(d,1H),8.68(d,1H),8.43(dd,1H),8.21(d,1H),5.22(q,2H),4.24(q,2H),1.36(t,3H). LCMS in 2.0min chromatogram R t = 1.26 min, MS ESI calculated value C 15 H 12 F6N5O2[M+H] + 408.1, experimental value 408.0.

[0534] Example 16: 3-[Difluoro(methoxy)methyl]-6-[5-fluoro-6-[1-(trifluoromethyl)cyclobutyloxy]-3-pyridinyl]-[1,2,4]triazolo[4,3-b]pyridazine

[0535]

[0536] 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-acetic acid (2-chloro-2,2-difluoro-acetyl) ester (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 saturated NaHCO 3 (50 mL), and the mixture was extracted with EtOAc (50 mL × 2). The combined organic phases were washed with brine (20 mL), dried over Na 2 SO 4, filtered and concentrated to produce a crude solid product (4700 mg, 19.66 mmol). 1H NMR (400 MHZ, CDCl3) δ H =7.35(d,1H),8.23(d,1H).

[0537] Synthesis of A30: A mixture of 6-chloro-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-b]pyridazine (150 mg, 0.63 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[1-(trifluoromethyl)cyclobutyloxy]pyridine (362.64 mg, 1 mmol), K 3 PO 4 (399.65 mg, 1.88 mmol), and bis(tri-tert-butylphosphine)palladium(0) (64.15 mg, 0.1300 mmol) in 1,4-dioxane (12 mL) and water (4 mL) was stirred at 80° C. for 16 hours. From TLC, a new spot was observed (Rf=0.45, UV), and no starting material remained (Rf=0.8, UV). After cooling to room temperature, the reaction mixture was concentrated to remove the solvent, diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with brine (40 mL), dried over Na SO and concentrated to produce a crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 60%) to produce a solid product (120 mg, 0.27 mmol). 1 H NMR (CDCl3, 400MHz)δ H =8.57(d,1H),8.33(d,1H),8.15-8.06(m,1H),7.73(d,1H),2.82-2.96(m,2H),2.78-2.81(m,2H),2.00-2.08(m,2H).

[0538] Synthesis of Compound 17: A mixture of 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[1-(trifluoromethyl)cyclobutyloxy]-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyridazine (120 mg, 0.27 mmol) and silver trifluoromethanesulfonate (0.7 g, 2.74 mmol) in a mixed solvent of methanol (12 mL) and MeCN (4 mL) was stirred at 80° C. for 72 hours. After cooling to room temperature, the reaction mixture was treated with brine (20 mL) and the precipitate was filtered. The filtrate was concentrated to remove the solvent, diluted with water (20 mL) and extracted with ethyl acetate (20 mL×2). The combined organic phases were washed with brine (40 mL), dried over Na 2 SO 4 and concentrated to yield a residue. The crude product was purified by prep-HPLC (Boston Prime C18 150 x 30 mm 5 μm) A = H2O (0.05% NH4OH) and B = ACN; 52-82% B in 8 min) to give the product as a solid (27.93 mg, 64.5 μmol). 1 H NMR (CDCl3, 400MHz)δ H =8.54 (d, 1H), 8.28 (d, 1H), 8.11 (dd, 1H), 7.64 (d, 1H), 3.93 (s, 3H), 2.82-2.96 (m, 2H), 2.76-2.81 (m, 2H), 1.57-2.07 (m, 2H). LCMS chromatogram in 2.0min R t = 1.32 min, MS ESI calculated value C 17 H 14 F6N5O2[M+H] + 434.1, experimental value 434.0.

[0539] Example 17: 3-[Difluoro(methoxy)methyl]-6-[5-fluoro-6-[1-(trifluoromethyl)cyclobutyloxy]-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyridine

[0540]

[0541] Synthesis of A1: A mixture of (5-bromo-2-pyridyl)hydrazine (2.6 g, 13.83 mmol) and 2-chloro-2,2-difluoro-acetic acid (2-chloro-2,2-difluoro-acetyl) ester (5.04 g, 20.74 mmol) in toluene (100 mL) was stirred at 10 ° C for 1 hour, and then the mixture was warmed to 120 ° C and stirred for 36 hours. After cooling to room temperature, the reaction was quenched with saturated NaHCO 3 (50 mL), and the mixture was extracted with EtOAc (50 mL × 2). The organic layer was washed with brine (50 mL), dried over Na 2 SO 4, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 20% to 30%) to give the product as a solid (3900 mg, 13.81 mmol). 1 H NMR (400 MHz, CDCl3) δ H =8.42 (s, 1H), 7.84 (d, 1H), 7.53 (dd, 1H). LCMS in 7.0min chromatogram R t =3.19 min, MS ESI calculated value C7H4BrClF2N3[M+H+2] + 283.9, experimental value 283.6.

[0542] Synthesis of A15: A mixture of 6-bromo-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyridine (1 g, 3.54 mmol) and NaOMe (956.21 mg, 17.7 mmol) in methanol (20 mL) was stirred at 80°C for 24 hours. After cooling to room temperature, the reaction was quenched with saturated NH4Cl (50 mL) and the mixture was extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (50 ml), dried over Na2SO4, filtered, and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 30% to 40%) to give the product as a solid (380 mg, 127.56 μmol). 1 H-NMR (CDCl3, 400MHz)δ H =8.43 (s, 1H), 7.77 (d, 1H), 7.47-7.41 (m, 1H), 3.92 (s, 3H). LCMS chromatogram in 7.0min R t = 2.95 min, MS ESI calculated value C8H7BrF2N3O [M+H+2] + 280.0, experimental value 279.7.

[0543] Synthesis of Compound 18: A mixture of 6-bromo-3-[difluoro(methyloxy)methyl]-[1,2,4]triazolo[4,3-a]pyridine (100 mg, 0.36 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[1-(trifluoromethyl)cyclobutyloxy]pyridine (155.86 mg, 0.43 mmol), KCO (99.41 mg, 0.72 mmol), and Pd(dppf)Cl (39.47 mg, 0.05 mmol) in 1,4-dioxane (5 mL) and water (0.50 mL) was stirred at 80° C. for 12 hours. After cooling to room temperature, the mixture was diluted with H O (10 mL) and extracted with EtOAc (20 mL×2). The combined organic phases were washed with water (30 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated to give the crude product. The crude product was purified by Prep-HPLC (Boston Prime C18 (150 x 30 mm, 5 μm), A = H2O (0.05% NH4OH) and B = CH3CN; 58-88% B in 8 minutes) to give the product as a solid (66.89 mg, 15.47 μmol). 1 H NMR (DMSO-d6, 400 MHz) δ H =8.75 (s, 1H), 8.46 (d, 1H), 8.33 (dd, 1H), 8.10 (d, 1H), 7.96 (dd, 1H), 3.89 (s, 3H), 2.97-2.85 (m, 2H), 2.72-2.62 (m, 2H), 2.07-1.95 (m, 1H), 1.93-1.81 (m, 1H). LCMS chromatogram in 2.0 min R t = 1.32 min, MS ESI calculated value C 18 H 15 F6N4O2[M+H] + 433.1, experimental value 432.9.

[0544] Example 18: Synthesis of 3-[cyclopropylmethoxy(difluoro)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyridine

[0545]

[0546] A mixture of 6-bromo-3-[cyclopropylmethoxy(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyridine (65 mg, 200 μmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (82.16 mg, 250 μmol), K2CO3 (56.48 mg, 410 μmol) and Pd(dppf)Cl2 (22.43 mg, 30 μmol) in 1,4-dioxane (5 mL) and water (0.50 mL) was stirred at 80°C under N2 for 12 hours. After cooling to room temperature, the mixture was diluted with H2O (10 mL) and extracted with EtOAc (20 mL×2). The combined organic phases were washed with water (20 mL) and brine (30 mL), dried over Na2SO4, filtered, and concentrated to give the crude product. The crude product was purified by Prep-HPLC (Boston Prime C18 (150 x 30 mm, 5 μm) A = H2O (0.05% NH4OH) and B = CH3CN; 62-92% B in 8 minutes) to give the product as a solid (43.42 mg, 97.3 μmol, 48% yield). 1 H NMR (DMSO-d6, 400 MHz) δ H =8.74 (s, 1H), 8.44 (d, 1H), 8.32 (dd, 1H), 8.11 (dd, 1H), 7.95 (dd, 1H), 6.02 (spt, 1H), 4.09 (d, 2H), 1.54 (d, 3H), 1.32-1.21 (m, 1H), 0.62-0.52 (m, 2H), 0.44-0.33 (m, 2H). LCMS chromatogram in 2.0 min R t = 1.37 min, 10-80 AB, MS ESI calculated value C 19 H 17 F6N4O2[M+H] + 447.1, experimental value 447.0.

[0547] Example 19: 3-[Difluoro(isopropoxy)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyridine

[0548]

[0549] A mixture of 6-bromo-3-[difluoro(isopropoxy)methyl]-[1,2,4]triazolo[4,3-a]pyridine (70 mg, 230 μmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (91.96 mg, 270 μmol), K2CO3 (63.21 mg, 460 μmol) and Pd(dppf)Cl2 (25.1 mg, 30 μmol) in 1,4-dioxane (5 mL) and water (0.50 mL) was stirred at 80°C under N2 for 12 hours. After cooling to room temperature, the mixture was diluted with H2O (10 mL) and extracted with EtOAc (20 mL×2). The combined organic phases were washed with water (20 mL) and brine (30 mL), dried over Na2SO4, filtered, and concentrated to give the crude product. The crude product was purified by Prep-HPLC (Boston Prime C18 (150 x 30 mm, 5 μm), A = H2O (0.05% NH4OH) and B = CH3CN; 60-90% B in 8 minutes) to give the product as a solid (33.94 mg, 78.1 μmol, 34% yield). 1 H NMR (DMSO-d6, 400 MHz) δ H =8.61(s,1H),8.43(d,1H),8.31(dd,1H),8.11(dd,1H),7.95(dd,1H),6.02(spt,1H),4.90(spt,1H),1.54(d,3H),1.41(d,6H). LCMS R in 2.0min chromatogram t =1.35 min, 10-80 AB, MS ESI calculated value C 18 H 17 F6N4O2[M+H] + 435.1, experimental value 435.0.

[0550] Example 20: 3-[Difluoro(isopropoxy)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyridine

[0551]

[0552] A mixture of 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (84.29 mg, 0.25 mmol), Pd(dppf)Cl2 (25.1 mg, 0.03 mmol), 6-bromo-3-[difluoro(isopropoxy)methyl]-[1,2,4]triazolo[4,3-a]pyridine (70 mg, 0.23 mmol) and K2CO3 (63.21 mg, 0.46 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was stirred at 90° C. under N2 for 16 hours. After cooling to room temperature, the mixture was filtered through celite and eluted with EtOAc (10 mL×2), and the filtrate was concentrated to give the crude product. The crude product was purified by Prep-HPLC (Boston Prime C18 (150 mm×30 mm 5 μm) A═H 2 O (0.05% ammonia hydroxide v / v) and B═CH 3 CN; 60-90% B in 8 min) to give the product as a solid (24.78 mg, 57.1 μmol, 25% yield). 1 H NMR (DMSO-d6, 400 MHz) δ H =8.61(s,1H),8.43(d,1H),8.32(dd,1H),8.12(d,1H),7.95(dd,1H),6.03(spt,1H),4.95-4.85(m,1H),1.54(d,3H),1.41(d,6H). LCMS R in 2.0min chromatogram t = 1.37 min, 10-80 AB, MS ESI calculated value C 18 H 17 F6N4O2[M+H] + 435.1, experimental value 435.1.

[0553] Example 21: 3-[Difluoro(isobutyloxy)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyridine

[0554]

[0555] Synthesis of A1-a: A mixture of (5-bromo-2-pyridyl)hydrazine (5 g, 26.59 mmol) and 2-chloro-2,2-difluoro-acetic acid (2-chloro-2,2-difluoro-acetyl) ester (9690.21 mg, 39.89 mmol) in toluene (200 mL) was stirred at 10°C for 1 hour, and the mixture was then heated at 120°C for 36 hours. After cooling to room temperature, the reaction was quenched with saturated NaHCO (200 mL), and the mixture was extracted with EtOAc (80 mL x 2). The organic layer was washed with brine (200 mL), dried over NaSO, filtered, and concentrated to yield the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 5% to 20%) to yield the product as a solid (5700 mg, 20.18 mmol, 76% yield). 1 HNMR (CDCl3, 400MHz)δ H =8.43(s,1H),7.84(dd,1H),7.54(dd,1H).

[0556] Synthesis of A4-a: To a mixture of 2-methylpropan-1-ol (1312 mg, 17.7 mmol) in THF (40 mL) was added NaH (708.04 mg, 17.7 mmol), and the mixture was stirred at 20° C. for 0.5 hours. 6-Bromo-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyridine (1000 mg, 3.54 mmol) was then added to the mixture, and the mixture was stirred at 20° C. for 2 hours. The reaction was quenched with saturated NH4Cl (40 mL), and the mixture was extracted with EtOAc (30 mL×2). The combined organic phases were washed with brine (70 mL), dried over Na2SO4, filtered, and concentrated to yield the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 10% to 40%) to give the product as an oil (750 mg, 2.34 mmol, 66% yield). 1 H NMR (CDCl3, 400MHz)δ H =8.44(s,1H),7.77(d,1H),7.44(dd,1H),4.00(d,2H),2.16-2.06(m,1H),1.04(d,6H).

[0557] Synthesis of Compound 22: A mixture of 6-bromo-3-[difluoro(isobutyloxy)methyl]-[1,2,4]triazolo[4,3-a]pyridine (100 mg, 310 μmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (125.61 mg, 370 μmol), K2CO3 (86.35 mg, 620 μmol) and Pd(dppf)Cl2 (34.28 mg, 50 μmol) in 1,4-dioxane (5 mL) and water (0.50 mL) was stirred at 80°C under N2 for 12 hours. After cooling to room temperature, the mixture was diluted with H2O (10 mL) and then extracted with EtOAc (20 mL x 2). The combined organic phases were washed with water (20 mL) and brine (30 mL), dried over Na2SO4, filtered, and concentrated to give the crude product. The crude product was purified by Prep-HPLC (Boston Prime C18 (150 x 30 mm, 5 μm), A = H2O (0.05% NH4OH) and B = CH3CN; 65-95% B in 8 minutes) to give the product as a solid (47.11 mg, 105.1 μmol, 34% yield). 1 HNMR (DMSO-d6, 400MHz)δ H =8.70 (s, 1H), 8.43 (d, 1H), 8.31 (dd, 1H), 8.11 (dd, 1H), 7.95 (dd, 1H), 6.02 (spt, 1H), 4.01 (d, 2H), 2.10-1.95 (m, 1H), 1.54 (d, 3H), 0.96 (d, 6H). LCMS chromatogram in 2.0 min R t =1.41 min, 10-80 AB, MS ESI calculated value C 19 H 19 F6N4O2[M+H] + 449.1, experimental value 449.1.

[0558] Example 22: 3-[Difluoro(isobutyloxy)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyridine

[0559]

[0560] A mixture of 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (115.14 mg, 0.34 mmol), Pd(dppf)Cl2 (34.28 mg, 0.05 mmol), 6-bromo-3-[difluoro(isobutyloxy)methyl]-[1,2,4]triazolo[4,3-a]pyridine (100 mg, 0.31 mmol) and K2CO3 (86.35 mg, 0.62 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was stirred at 90° C. under N2 for 16 hours. After cooling to room temperature, the mixture was filtered through celite and eluted with EtOAc (10 mL×2), and the filtrate was concentrated to give the crude product. The crude product was purified by Prep-HPLC (Boston Prime C18 150 mm×30 mm 5 μm) A=H 2 O (0.05% ammonia hydroxide v / v) and B=CH 3 CN; 61-91% B in 8 minutes) to give the product as a solid (68.11 mg, 0.15 mmol, 48% yield). 1 H NMR (DMSO-d6, 400 MHz) δ H =8.70 (s, 1H), 8.43 (d, 1H), 8.31 (dd, 1H), 8.15-8.09 (m, 1H), 7.95 (dd, 1H), 6.08-5.96 (m, 1H), 4.02 (d, 2H), 2.09-1.96 (m, 1H), 1.54 (d, 3H), 0.96 (d, 6H). LCMS R in 2.0 min chromatogram t =1.42 min, 10-80A BMS ESI calculated value C 19 H 19 F6N4O2[M+H] + 449.1, experimental value 449.1.

[0561] Example 23: 3-[Difluoro(methoxy)methyl]-6-[5-fluoro-6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyridine

[0562]

[0563] Synthesis of A15-a: A mixture of 6-bromo-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyridine (1000 mg, 3.54 mmol) and NaOMe (956.21 mg, 17.7 mmol) in methanol (20 mL) was stirred at 80 ° C for 24 hours. After cooling to room temperature, the reactant was quenched with saturated NH4Cl (50 mL), and the mixture was extracted with EtOAc (50 mL×2). The organic layer was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated to produce a crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 30% to 40%) to produce an oily product (230 mg, 754.3 μmol, 21% yield). LCMS R in 1.5 min chromatogram t =1.41 min, 5-95 AB, MS ESI calcd. C8H8BrF2N3O[M+H+2] + 280.0, experimental value 279.9.

[0564] Synthesis of compound 24: A mixture of 6-bromo-3-[difluoro(methoxy)methyl]-[1,2,4]triazolo[4,3-a]pyridine (70 mg, 250 μmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)pyridine (105.47 mg, 300 μmol), K2CO3 (69.59 mg, 500 μmol) and Pd(dppf)Cl2 (27.63 mg, 40 μmol) in 1,4-dioxane (5 mL) and water (0.50 mL) was stirred at 80°C under N2 for 12 hours. After cooling to room temperature, the mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic phases were washed with water (30 mL) and brine (30 mL), dried over Na2SO4, filtered, and concentrated to give the crude product. The crude product was purified by Prep-HPLC (Boston Prime C18 (150 x 30 mm, 5 μm), A = H2O (0.05% NH4OH) and B = CH3CN; 56-86% B in 8 minutes) to give the product as a solid (22.72 mg, 54.1 μmol, 21% yield). 1 HNMR (DMSO-d6, 400MHz)δ H=8.75 (s, 1H), 8.47 (d, 1H), 8.31 (dd, 1H), 8.14-8.05 (m, 1H), 7.95 (dd, 1H), 3.89 (s, 3H), 1.82 (s, 6H). LCMS chromatogram in 2.0min R t = 1.31 min, 10-80 AB, MS ESI calculated value C 17 H 15 F6N4O2[M+H] + 421.1, experimental value 421.1.

[0565] Example 24: 3-[Cyclopropylmethoxy(difluoro)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyridine

[0566]

[0567] A mixture of 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (69.52 mg, 0.21 mmol), Pd(dppf)Cl2 (20.7 mg, 0.03 mmol), 6-bromo-3-[cyclopropylmethoxy(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyridine (60 mg, 0.19 mmol) and K2CO3 (52.14 mg, 0.38 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was stirred at 90° C. under N2 for 16 hours. After cooling to room temperature, the mixture was filtered through celite and eluted with EtOAc (10 mL×2), and the filtrate was concentrated to give the crude product. The crude product was purified by Prep-HPLC (Boston Prime C18 150 mm×30 mm 5 μm) A=H 2 O (0.05% ammonia hydroxide v / v) and B=CH 3 CN; 60-90% B in 8 minutes) to give the product as a solid (51.82 mg, 0.12 mmol, 62% yield). 1 H NMR (DMSO-d6, 400 MHz) δ H =8.74 (s, 1H), 8.45 (d, 1H), 8.32 (dd, 1H), 8.11 (dd, 1H), 7.96 (dd, 1H), 6.02 (spt, 1H), 4.09 (d, 2H), 1.54 (d, 3H), 1.32-1.21 (m, 1H), 0.62-0.54 (m, 2H), 0.43-0.36 (m, 2H). LCMS chromatogram in 2.0 min Rt =1.39 min, 10-80A BMSESI calculated value C 19 H 17 F6N4O2[M+H] + 447.1, experimental value 447.1.

[0568] Example 25: 3-[Ethoxy(difluoro)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyrazine

[0569]

[0570] A mixture of 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyrazine (500 mg, 1.21 mmol) and AgOTf (3120.55 mg, 12.15 mmol) in ethanol (7 mL) and MeCN (7 mL) was stirred at 90 ° C for 5 days. The mixture was cooled to room temperature, and then EtOAc (20 mL) and brine (50 mL) were added to the mixture, and the resulting suspension was filtered through celite. The layers were separated and the aqueous phase was extracted with EtOAc (50 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 10% to 30% to 50%) and then triturated from DCM (3 mL) and n-hexane (4 mL) to give the product as a solid (31.35 mg, 74 μιηοΐ, 6% yield). 1 H NMR (CDCl3, 400MHz)δ H =9.52 (d, 1H), 8.48 (dd, 2H), 8.04 (dd, 1H), 5.95-5.87 (m, 1H), 4.37 (q, 2H), 1.60 (d, 3H), 1.51 (t, 3H). LCMS R in 2min chromatogram t =1.35 min, 10-80 AB, MS ESI calculated value C 16 H 14 F6N5O2[M+H] + 422.1, experimental value 422.1.

[0571] Example 26: 6-[5-Fluoro-6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridinyl]-3-(methoxymethyl)-[1,2,4]triazolo[4,3-b]pyridazine

[0572]

[0573] A mixture of 6-chloro-3-(methoxymethyl)-[1,2,4]triazolo[4,3-b]pyridazine (100 mg, 0.5 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)pyridine (210.94 mg, 0.6 mmol), K 3 PO 4 (213.79 mg, 1.01 mmol), Pd(t-Bu 3 P) 2 (38.6 mg, 0.08 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was stirred at 80° C. under N 2 for 16 hours. After cooling to room temperature, the mixture was diluted with H 2 O (10 mL) and extracted with EtOAc (20 mL×2). The combined organic phases were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated to yield the crude product. The crude product was purified by Prep-HPLC (Boston Prime C18 (150 mm × 30 mm, 5 μm; mobile phase: [water (0.05% NH4OH)-ACN]; B%: 40-70%, 9 min) to yield the product as a solid (47.66 mg, 0.12 mmol, 25% yield). 1 H NMR (CDCl3, 400MHz)δ H =8.54 (d, 1H), 8.24 (d, 1H), 8.09 (dd, 1H), 7.57 (d, 1H), 5.11 (s, 2H), 3.53 (s, 3H), 1.90 (s, 6H). LCMS chromatogram in 2.0min R t = 1.21 min, 10-80 AB, MS ESI calculated value C 16 H 16 F4N5O2[M+H] + 386.1, experimental value 386.0.

[0574] Example 27: 6-[5-Fluoro-6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridinyl]-3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyridine

[0575]

[0576] 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 and then refluxed at 120°C for 48 hours. After cooling to room temperature, the reaction mixture was concentrated to yield a residue. The residue was triturated from DCM (100 mL) to yield the product as a solid (3.0 g, 10.01 mmol, 22% yield). 1 H NMR (MeOD-d4, 400MHz) δ = 9.15 (s, 1H), 8.19-8.32 (m, 1H), 8.11-7.96 (m, 1H), 5.09 (s, 2H), 3.49 (s, 3H).

[0577] Synthesis of Compound 28: A mixture of 6-bromo-3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyridine (150 mg, 0.62 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)pyridine (259.61 mg, 0.74 mmol), KCO (171.29 mg, 1.24 mmol), and Pd(dppf)Cl (68.01 mg, 0.09 mmol) in a mixed solvent of 1,4-dioxane (15 mL) and water (3 mL) was heated at 85° C. for 16 hours. After cooling to room temperature, the reaction was concentrated and diluted with H O (20 mL), then extracted with DCM (20 mL×2). The combined organic phases were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to yield the crude product. The crude product was purified using Prep-HPLC (YMC-Actus Triart C18 (100 mm × 30 mm, 5 μm) A = H2O (0.05% HCl) and B = CH3CN; 50-75% B over 8 minutes) to yield the product in CH3CN / H2O (approximately 150 mL). The solution was concentrated to remove most of the CH3CN, basified with NaHCO3 (solid) to pH approximately 9, and then extracted with DCM (50 mL × 3). The combined organic phases were concentrated to yield the product as a solid (121.16 mg, 0.32 mmol, 51% yield). 1 H NMR (CDCl3, 400MHz) δ=8.34(s,1H),8.16(d,1H),7.89(d,1H),7.60(dd,1H),7.47(dd,1H),5.08(s,2H),3.42(s,3H),1.87(s,6H). LCMS chromatogram in 2.0min Rt =1.25 min, 10-80 AB, MS ESI calculated value C 17 H 17 F4N4O2[M+H] + 385.1, experimental value 384.9.

[0578] Example 28: 6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridinyl]-3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyridine

[0579]

[0580] A mixture of 6-bromo-3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyridine (150 mg, 0.62 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (238.75 mg, 0.74 mmol), KCO (171.29 mg, 1.24 mmol), and Pd(dppf)Cl (68.01 mg, 0.09 mmol) in a mixed solvent of 1,4-dioxane (15 mL) and water (3 mL) was stirred at 85° C. for 16 hours. After cooling to room temperature, the reaction was concentrated and diluted with H O (20 mL), then extracted with DCM (20 mL×2). The combined organic phases were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to give the crude product. The crude product was purified by Prep-HPLC ((Boston Prime C18 (150 mm×30 mm, 5 μm) A=H2O (0.05% NH4OH) and B=CH3CN; 40-70% B in 8 minutes) to give the product as a solid (141.29 mg, 0.39 mmol, 64% yield). 1 H NMR (CDCl3, 400MHz) δ=8.35(s,1H),8.17(d,1H),7.90(d,1H),7.65(dd,1H),7.47(dd,1H),5.09(s,2H),4.91(q,2H),3.43(s,3H). LCMS chromatogram in 2.0min R t = 1.17 min, 10-80 AB, MS ESI calculated value C 15 H 13 F4N4O2[M+H] + 357.1, experimental value 356.9.

[0581] Example 29: 3-[Difluoro(methoxy)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyridine

[0582]

[0583] A mixture of 6-bromo-3-[difluoro(methoxy)methyl]-[1,2,4]triazolo[4,3-a]pyridine (70 mg, 250 μmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (97 mg, 300 μmol), KCO (69.59 mg, 0.50 mmol) and Pd(dppf)Cl (27.63 mg, 0.04 mmol) in 1,4-dioxane (5 mL) and water (0.50 mL) was stirred at 80° C. under N for 12 hours. After cooling to room temperature, the mixture was diluted with H0 (10 mL) and extracted with EtOAc (20 mL×2). The combined organic phases were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated to yield the crude product. The crude product was purified first by Prep-HPLC (Boston Prime C18 (150 mm x 30 mm, 5 μm), A = H2O (0.05% NH4OH) and B = CH3CN; 43-73% B in 8 minutes) and then by Prep-HPLC (Boston Green ODS (150 mm x 30 mm, 5 μm), A = H2O (0.075% TFA) and B = CH3CN; 49-63% B in 10 minutes). The combined fractions were concentrated to remove ACN and basified with saturated NaHCO3 to pH approximately 8. The mixture was extracted with EtOAc (30 mL x 2). The combined organic phases were washed with brine (40 mL), dried over Na 2 SO 4 , filtered and concentrated to give the product as a solid (41.36 mg, 105.4 μmol, 42% yield). 1 H NMR (DMSO-d6, 400 MHz) δ H =8.74 (s, 1H), 8.47 (d, 1H), 8.36 (dd, 1H), 8.11 (dd, 1H), 7.96 (dd, 1H), 5.18 (q, 2H), 3.89 (s, 3H). LCMS in 2.0min chromatogram R t = 1.19 min, 10-80 AB, MS ESI calculated value C 15 H 11 F6N4O2[M+H] +393.1, experimental value 393.0.

[0584] Example 30: 6-[5-Fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridinyl]-3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyrazine

[0585]

[0586] A mixture of 6-chloro-3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyrazine (70 mg, 0.35 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (141.73 mg, 0.42 mmol), Cs2CO3 (229.66 mg, 0.70 mmol), Pd(dppf)Cl2 (38.68 mg, 0.05 mmol) in 1,4-dioxane (5 mL) and water (0.50 mL) was stirred at 70° C. under N2 for 5 hours. After cooling to room temperature, the mixture was diluted with H2O (20 mL) and extracted with EtOAc (30 mL×2). The combined organic phases were washed with water (30 mL) and brine (30 mL), dried over NaSO, filtered, and concentrated to yield 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 × 30 mm, 5 μm), A = H2O (0.05% NH4OH) and B = CH3CN; 38-68% B in 9 minutes) to yield the product as a solid (4.43 mg, 11.9 μmol, 3% yield). 1 H NMR (CDCl3, 400MHz)δ H =9.44 (d, 1H), 8.49 (dd, 1H), 8.47 (s, 1H), 8.05 (dd, 1H), 5.95-5.83 (m, 1H), 5.14 (s, 2H), 3.47 (s, 3H), 1.60 (d, 3H). LCMS chromatogram in 2.0 min R t = 1.18 min, 10-80 AB, MS ESI calculated value C 15 H 14 F4N5O2[M+H] + 372.1, experimental value 371.9.

[0587] Example 31: 3-[Ethoxy(difluoro)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyridine

[0588]

[0589] A mixture of 6-bromo-3-[ethoxy(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyridine (100 mg, 0.34 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (137.67 mg, 0.41 mmol), K2CO3 (94.64 mg, 0.68 mmol) and Pd(dppf)Cl2 (37.58 mg, 0.05 mmol) in 1,4-dioxane (5 mL) and water (0.50 mL) was stirred at 80° C. under N2 for 12 hours. After cooling to room temperature, the mixture was diluted with H2O (10 mL) and extracted with EtOAc (20 mL×2). The combined organic phases were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated to give the crude product. The crude product was purified by Prep-HPLC (Boston Prime C18 (150 mm x 30 mm, 5 um), A = H2O (0.05% NH4OH) and B = CH3CN; 60-90% B in 9 minutes) to give the product as a solid (39.75 mg, 93.5 μmol, 27% yield). 1 H NMR (DMSO-d6, 400 MHz) δ H =8.72(s,1H),8.44(d,1H),8.33(dd,1H),8.10(d,1H),7.94(dd,1H),6.02(spt,1H),4.29(q,2H),1.54(d,3H),1.36(t,3H). LCMS R in 2.0min chromatogram t =1.28 min, 10-80A BMS ESI calculated value C 17 H 15 F6N4O2[M+H] + 421.1, experimental value 421.0.

[0590] Example 32: 3-[Ethoxy(difluoro)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyrazine

[0591]

[0592] A mixture of 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyrazine (200 mg, 0.49 mmol) and AgOTf (1.25 g, 4.86 mmol) in ethanol (10 mL) and MeCN (10 mL) was stirred at 90° C. for 5 days. The mixture was cooled to room temperature. EtOAc (50 mL) and brine (50 mL) were added to the mixture, and the mixture was filtered through celite. The filtrate was separated and the aqueous layer was extracted with EtOAc (50 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 10% to 30% to 50%) and then triturated from n-hexane (5 mL) to give the product as a solid (41.27 mg, 98.0 μιηοΐ, 20% yield). 1 H NMR (CDCl3, 400MHz)δ H =9.52 (d, 1H), 8.50-8.45 (m, 2H), 8.04 (dd, 1H), 6.00-5.82 (m, 1H), 4.37 (q, 2H), 1.60 (d, 3H), 1.51 (t, 3H). LCMS R in 2.0 min chromatogram t =1.29 min, 10-80 AB, MS ESI calculated value C 16 H 14 F6N5O2[M+H] + 422.1, experimental value 422.0.

[0593] Example 33: 3-[Ethoxy(difluoro)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyridine

[0594]

[0595] A mixture of 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (126.2 mg, 0.38 mmol), Pd(dppf)Cl2 (37.58 mg, 0.05 mmol), 6-bromo-3-[ethoxy(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyridine (100 mg, 0.34 mmol) and K2CO3 (94.64 mg, 0.68 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was stirred at 90° C. under N2 for 16 hours. After cooling to room temperature, the mixture was filtered through celite and eluted with EtOAc (10 mL×2), and the filtrate was concentrated to give the crude product. The results were analyzed by Prep-HPLC (Boston Prime C18 (150 mm × 30 mm, 5 μm) with A = H 2 O

[0596] The crude product was purified by elution with 4% HCl (0.05% NH4OH) and B = CH3CN; 45-75% B in 9 min) to give the product as a solid (62.87 mg, 0.15 mmol, 43% yield). 1 H NMR (DMSO-d6, 400 MHz) δ H =8.72 (s, 1H), 8.44 (d, 1H), 8.33 (dd, 1H), 8.14-8.06 (m, 1H), 7.94 (dd, 1H), 6.01 (spt, 1H), 4.28 (q, 2H), 1.54 (d, 3H), 1.36 (t, 3H). LCMS chromatogram in 2.0 min R t =1.26 min, 10-80 AB, MS ESI calculated value C 17 H 15 F6N4O2[M+H] + 421.1, experimental value 421.0.

[0597] Example 34: 6-[5-Fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridinyl]-3-(methoxymethyl)-[1,2,4]triazolo[4,3-b]pyridazine

[0598]

[0599] A mixture of 6-chloro-3-(methoxymethyl)-[1,2,4]triazolo[4,3-b]pyridazine (100 mg, 0.50 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (194 mg, 0.60 mmol), K 3 PO 4 (213.79 mg, 1.01 mmol) and Pd(t-Bu 3 P) 2 (38.6 mg, 0.08 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was stirred at 80° C. under N 2 for 3 h. After cooling to room temperature, water (20 mL) and EtOAc (20 mL) were added to the mixture and the mixture was filtered through celite. After separation, the organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, 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 μm) A = H2O (0.05% NH4OH) and B = CH3CN; 33-63% B in 8 minutes) to give the product as a solid (49 mg, 137.2 μmol, 27% yield). 1 H NMR (CDCl3, 400MHz)δ H =8.54 (d, 1H), 8.25 (d, 1H), 8.17 (dd, 1H), 7.58 (d, 1H), 5.11 (s, 2H), 4.94 (q, 2H), 3.54 (s, 3H). LCMS in 2.0min chromatogram R t =1.08 min, 10-80 AB, MS ESI calculated value C 14 H 12 F4N5O2[M+H] + 358.1, experimental value 357.9.

[0600] Example 35: 3-[Cyclopropyloxy(difluoro)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyridine

[0601]

[0602] A mixture of 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (121.22 mg, 0.36 mmol), Pd(dppf)Cl2 (36.09 mg, 0.05 mmol), 6-bromo-3-[cyclopropyloxy(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyridine (100 mg, 0.33 mmol) and K2CO3 (90.9 mg, 0.66 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was stirred at 90° C. under N2 for 16 hours. After cooling to room temperature, the mixture was filtered through celite and eluted with EtOAc (10 mL×2), and the filtrate was concentrated to give the crude product. The results were analyzed by Prep-HPLC (Boston Prime C18 (150 mm × 30 mm, 5 μm) with A = H 2 O

[0603] The crude product was purified by elution with 4% HCl (0.05% NH4OH) and B = CH3CN; 47-77% B in 9 min) to give the product as a solid (54.98 mg, 0.13 mmol, 39% yield). 1 H NMR (DMSO-d6, 400 MHz) δ H =8.65 (s, 1H), 8.44 (d, 1H), 8.33 (dd, 1H), 8.11 (d, 1H), 7.94 (dd, 1H), 6.07-5.97 (m, 1H), 4.25-4.15 (m, 1H), 1.54 (d, 3H), 0.95-0.86 (m, 2H), 0.77-0.69 (m, 2H). LCMS chromatogram in 2.0 min R t =1.33 min, 10-80A BMSESI calculated value C 18 H 15 F6N4O2[M+H] + 433.1, experimental value 433.1.

[0604] Example 36: 3-[Cyclopropyloxy(difluoro)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyridine

[0605]

[0606] Synthesis of A36: To a mixture of cyclopropanol (246.74 mg, 4.25 mmol), 6-bromo-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyridine (600 mg, 2.12 mmol) in DMF (10 mL) was added potassium tert-butoxide (476.69 mg, 4.25 mmol). The reaction mixture was stirred at 20 ° C for 2 hours. The reactants were quenched with saturated NH4Cl (40 mL), and the mixture was extracted with EtOAc (50 mL×2). The combined organic phases were washed with water (80 mL) and brine (80 mL), dried over Na2SO4, filtered and concentrated to produce a crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 20% to 40%) to produce a solid product (270 mg, 0.89 mmol, 42% yield). LCMS R in 7.0 min chromatogram t = 3.74 min, 0-60A BMS ESI calculated value C 10 H9BrF2N3O[M+H+2] + 306.0, experimental value 305.8.

[0607] Synthesis of compound 37: A mixture of 6-bromo-3-[cyclopropyloxy(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyridine (100 mg, 0.33 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (132.24 mg, 0.39 mmol), K2CO3 (90.9 mg, 0.66 mmol) and Pd(dppf)Cl2 (36.09 mg, 0.05 mmol) in 1,4-dioxane (5 mL) and water (0.50 mL) was stirred at 80 ° C under N2 for 12 hours. After cooling to room temperature, the mixture was diluted with H2O (10 mL) and extracted with EtOAc (20 mL x 2). The combined organic phases were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated to yield the crude product. The crude product was purified by Prep-HPLC (Boston Prime C18 (150 mm x 30 mm, 5 μm), A = H2O (0.05% NH4OH) and B = CH3CN; 50-70% B in 9 minutes) to yield the product as a solid (35.99 mg, 83.2 μmol, 25% yield). 1 H NMR (DMSO-d6, 400 MHz) δ H=8.65 (s, 1H), 8.44 (d, 1H), 8.33 (dd, 1H), 8.11 (dd, 1H), 7.94 (dd, 1H), 6.09-5.95 (m, 1H), 4.25-4.14 (m, 1H), 1.54 (d, 3H), 0.95-0.86 (m, 2H), 0.79-0.67 (m, 2H). LCMS R in 2.0 min chromatogram t =1.29 min, 10-80 AB, MS ESI calculated value C 18 H 15 F6N4O2[M+H] + 433.1, experimental value 433.0.

[0608] Example 37: 6-[5-Fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridinyl]-3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyrazine

[0609]

[0610] Synthesis of A37: To a mixture of 1,1,2-trimethoxyethane (1.25 g, 10.38 mmol) and (5-chloropyrazin-2-yl)hydrazine (1 g, 6.92 mmol) in ethanol (20 mL) was added 12N HCl (1.73 mL, 20.75 mmol), and the mixture was stirred at 20° C. for 20 hours. Water (20 mL) was added to the mixture, which was then basified with NaCO (solid) to a pH of approximately 9 and extracted with EtOAc (50 mL×4). The combined organic phases were washed with brine (30 mL), dried over NaSO, filtered, and concentrated to yield the crude product. The crude product was triturated from EtOAc / PE (2 / 10 mL) and dried in an oven to yield 5-chloro-N-(2-methoxyethylideneamino)pyrazin-2-amine (1050 mg, 3.73 mmol, 54% yield) as a solid. LCMS in 1.5min chromatogram R t = 0.70 min, 5-95 AB, MS ESI calculated value C7H 10 ClN4O[M+H] + 201.0, experimental value 201.0.

[0611] Synthesis of A38: To a mixture of 5-chloro-N-(2-methoxyethylideneamino)pyrazin-2-amine (1 g, 4.98 mmol) in DMF (10 mL) was added dropwise a solution of NBS (1.24 g, 6.98 mmol) in DMF (7 mL) over 0.5 h, and the mixture was stirred at 20 ° C for 1 h. The mixture was diluted with water H2O (50 mL) and extracted with EtOAc (50 mL×4). The combined organic phases were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated to give a solid crude product (1000 mg, 3.58 mmol, 72% yield), which was used directly without any further purification. LCMS R in 1.5 min chromatogram t =0.80 min, 5-95 AB, MS ESI calculated value C7H9BrClN4O [M+H+2] + 281.0, experimental value 280.9.

[0612] Synthesis of A34: To a mixture of N-(5-chloropyrazin-2-yl)-2-methoxy-ethanehydrazonoyl bromide (1 g, 3.58 mmol) in toluene (15 mL) was added EtN (0.99 mL, 7.16 mmol), and the mixture was stirred at 20°C for 1 hour. The mixture was diluted with H2O (30 mL) and extracted with EtOAc (50 mL x 2). The combined organic phases were washed with water (20 mL x 2) and brine (20 mL), dried over Na2SO4, filtered, and concentrated to yield the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 40% to 80%) to yield the product as a solid (380 mg, 1.87 mmol, 52% yield). 1 H NMR (CDCl3, 400MHz)δ H =9.21 (d, 1H), 8.28 (d, 1H), 5.07 (s, 2H), 3.45 (s, 3H). LCMS in 1.5min chromatogram R t =0.30 min, 5-95 AB, MS ESI calculated value C7H8ClN4O [M+H] + 199.0, experimental value 199.0.

[0613] Synthesis of compound 38: 6-chloro-3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyrazine (70 mg, 0.35 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-

[0614] A mixture of (1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (177.16 mg, 0.53 mmol), Pd(dppf)Cl2 (64.47 mg, 88.1 μmol) and Cs2CO3 (229.66 mg, 0.70 mmol) in 1,4-dioxane (8 mL) and water (0.80 mL) was stirred at 75°C under N2 for 12 hours. After cooling to room temperature, the mixture was diluted with H2O (30 mL) and extracted with EtOAc (50 mL×2). The combined organic phases were washed with water (20 mL×2) and brine (20 mL), dried over Na2SO4, filtered and concentrated to give the crude product. The crude product was first purified by Prep-TLC (silica gel, PE:EtOAc=1:1) and then by prep-HPLC [Boston Prime C18 (150 mm×30 mm, 5 μm) A=H2O (0.05% NH4OH) and B=CH3CN; 38-68% B in 9 minutes] to give the product as a solid (12.63 mg, 34.0 μmol, 10% yield). 1 HNMR (CDCl3, 400MHz)δ H =9.44 (d, 1H), 8.50 (d, 1H), 8.47 (d, 1H), 8.05 (dd, 1H), 5.97-5.84 (m, 1H), 5.14 (s, 2H), 3.47 (s, 3H), 1.60 (d, 3H). LCMS chromatogram in 2.0min R t =1.17 min, 10-80A BMSESI calculated value C 15 H 14 F4N5O2[M+H] + 372.1, experimental value 371.9.

[0615] Example 38: 6-[5-Fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridinyl]-3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyrazine

[0616]

[0617] A mixture of 6-chloro-3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyrazine (70 mg, 0.35 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (169.75 mg, 0.53 mmol), Pd(dppf)Cl2 (64.47 mg, 88.1 μmol) and Cs2CO3 (229.66 mg, 0.70 mmol) in 1,4-dioxane (8 mL) and water (0.80 mL) was stirred at 75° C. under N2 for 12 hours. After cooling to room temperature, the mixture was diluted with H2O (20 mL) and extracted with EtOAc (30 mL×2). The combined organic phases were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, 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 as a solid (14.65 mg, 40.7 μmol, 12% yield). 1 H NMR (CDCl3, 400MHz)δ H =9.44 (d, H), 8.52 (d, 1H), 8.48 (d, 1H), 8.07 (dd, 1H), 5.14 (s, 2H), 4.92 (q, 2H), 3.47 (s, 3H). LCMS chromatogram in 2.0 min R t = 1.19 min, 10-80A BMS ESI calculated value C 14 H 12 F4N5O2[M+H] + 358.1, experimental value 357.9.

[0618] Example 39: 6-[5-Fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridinyl]-3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyridine

[0619]

[0620] A mixture of 6-bromo-3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyridine (200 mg, 0.83 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (332.23 mg, 0.99 mmol), KCO (228.38 mg, 1.65 mmol), Pd(dppf)Cl (90.68 mg, 0.12 mmol) in 1,4-dioxane (15 mL) and water (5 mL) was stirred at 85° C. for 16 hours. After cooling to room temperature, the reaction was concentrated and diluted with H O (20 mL), then extracted with DCM (20 mL×2). The combined organic phases were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to give the crude product. The crude product was purified using Prep-HPLC (Boston Prime C18 (150 mm x 30 mm 5 μm) A = H2O (0.05% NH4OH) and B = CH3CN; 35-65% B in 9 minutes) to give the product as a solid (104.44 mg, 0.28 mmol, 34% yield). 1 H NMR (DMSO-d6, 400 MHz) δ H =8.85 (s, 1H), 8.49 (d, 1H), 8.35 (dd, 1H), 7.89-8.05 (m, 1H), 7.77-7.88 (m, 1H), 6.05-5.87 (m, 1H), 5.02 (s, 2H), 3.35 (s, 3H), 1.55 (d, 3H). LCMS R in 2.0 min chromatogram t = 1.150 min, 10-80 AB, MS ESI calculated value C 16 H 15 F4N4O2[M+H] + 371.1, experimental value 371.1.

[0621] Example 40: 3-[Ethoxy(difluoro)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridinyl]-[1,2,4]triazolo[4,3-b]pyridazine

[0622]

[0623] A mixture of 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridinyl]-[1,2,4]triazolo[4,3-b]pyridazine (300 mg, 0.73 mmol) and AgOTf (1872.33 mg, 7.29 mmol) in ethanol (10 mL) and MeCN (10 mL) was 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×2). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over Na 2 SO 4, 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 product was then triturated from n-hexane (1 mL) and i-Pr2O (1 mL) to afford the product as a solid (28.86 mg, 67.3 μmol, 9% yield). 1 H NMR (CDCl3, 400MHz)δ H =8.54 (d, 1H), 8.29 (d, 1H), 8.13 (dd, 1H), 7.65 (d, 1H), 5.92 (spt, 1H), 4.33 (q, 2H), 1.61 (d, 3H), 1.48 (t, 3H). LCMS chromatogram in 2.0 min R t = 1.27 min, 10-80 AB, MS ESI calculated value C 16 H 14 F6N5O2[M+H] + 422.1, experimental value 422.0.

[0624] Example 41: 3-[Ethoxy(difluoro)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridinyl]-[1,2,4]triazolo[4,3-b]pyridazine

[0625]

[0626] Synthesis of A26-a: A mixture of 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (1.54 g, 4.6 mmol), 6-chloro-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-b]pyridazine (1 g, 4.18 mmol), Pd(t-Bu3P)2 (320.73 mg, 0.63 mmol) and K3PO4 (1.78 g, 8.37 mmol) in 1,4-dioxane (20 mL) and water (4 mL) was stirred at 80° C. under N2 for 16 hours. After cooling to room temperature, the mixture was filtered through celite and eluted with EtOAc (20 mL×2), and the filtrate was concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 30% to 60%) to give the product as a solid (1000 mg, 2.12 mmol, 51% yield). LCMS R t = 0.93 min, 5-95 AB, MS ESI calculated value C 14 H9ClF6N5O[M+H] + 412.0, experimental value 412.1.

[0627] Synthesis of compound 42: A mixture of 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyridazine (300 mg, 0.73 mmol) and AgOTf (1872.33 mg, 7.29 mmol) in ethanol (10 mL, 0.73 mmol) and 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 results were analyzed by Prep-HPLC (Boston Prime C18 (150 mm×30 mm 5 μm) with A=H2O (0.05% NH4OH v / v) and B=

[0628] CH3CN; 51-81% in 9 min. B) The product was further purified to give the product as a solid (8.12 mg, 19.3 μmol, 3% yield). 1 H NMR (CDCl3, 400MHz)δ H=8.54 (d, 1H), 8.30 (d, 1H), 8.13 (dd, 1H), 7.66 (d, 1H), 5.96-5.88 (m, 1H), 4.33 (q, 2H), 1.62 (s, 3H), 1.48 (t, 3H). LCMS chromatogram in 2.0 min R t =1.29 min, 10-80 AB, MS ESI calculated value C 16 H 14 F6N5O2[M+H] + 422.1, experimental value 422.0.

[0629] Example 42: 6-[5-Fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridinyl]-3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyridine

[0630]

[0631] A mixture of 6-bromo-3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyridine (100 mg, 0.41 mmol), Pd(dppf)Cl2 (45.34 mg, 0.06 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (166.12 mg, 0.50 mmol) and K2CO3 (114.19 mg, 0.83 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was stirred at 80° C. under N2 for 16 hours. After cooling to room temperature, the mixture was filtered through celite and eluted with EtOAc (10 mL×2), and the filtrate was concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 50% to 100%). The product was then triturated from n-hexane / DCM (5:1, 10 mL) to give the product as a solid (46.5 mg, 0.13 mmol, 30% yield). 1 H NMR (DMSO-d6, 400 MHz) δ H =8.84 (s, 1H), 8.49 (d, 1H), 8.35 (dd, 1H), 7.97-7.90 (m, 1H), 7.87-7.80 (m, 1H), 6.01 (spt, 1H), 5.01 (s, 2H), 3.34 (s, 3H), 1.54 (d, 3H). LCMS chromatogram in 2.0 min R t = 1.13 min, 10-80 AB, MS ESI calculated value C 16 H 15F4N4O2[M+H] + 371.1, experimental value 370.9.

[0632] Example 43: 6-[5-Fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridinyl]-3-(methoxymethyl)-[1,2,4]triazolo[4,3-b]pyridazine

[0633]

[0634] A mixture of 6-chloro-3-(methoxymethyl)-[1,2,4]triazolo[4,3-b]pyridazine (100 mg, 0.50 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (202.47 mg, 0.60 mmol), K 3 PO 4 (213.79 mg, 1.01 mmol) and Pd(t-Bu 3 P) 2 (38.6 mg, 0.08 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was stirred at 80° C. under N 2 for 3 h. After cooling to room temperature, water (20 mL) and EtOAc (20 mL) were added to the mixture and filtered through celite. After separation, the organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, 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 μm) A = H2O (0.05% NH4OH) and B = CH3CN; 33-63% B in 8 minutes) to give the product as a solid (38 mg, 102.3 μmol, 20% yield). 1 H NMR (CDCl3, 400MHz)δ H =8.53 (d, 1H), 8.25 (d, 1H), 8.14 (dd, 1H), 7.57 (d, 1H), 5.98-5.85 (m, 1H), 5.11 (s, 2H), 3.54 (s, 3H), 1.61 (d, 3H). LCMS chromatogram in 2.0min R t = 1.13 min, 10-80 AB, MS ESI calculated value C 15 H 14 F4N5O2[M+H] + 372.1, experimental value 371.9.

[0635] Example 44: 3-[Difluoro(isobutyloxy)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyrazine

[0636]

[0637] A mixture of 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyrazine (200 mg, 0.49 mmol) and AgOTf (1.25 g, 4.86 mmol) in isobutyl alcohol (10 mL) and MeCN (10 mL) was stirred at 90 ° C for 7 days. EtOAc (50 mL) and brine (50 mL) were added to the mixture and some solids were observed. The mixture was filtered through celite. The filtrate was separated and the aqueous layer was extracted with EtOAc (50 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 10% to 30% to 50%) to give an oily product (80 mg).

[0638] The impure product (80 mg, 0.18 mmol) was purified by Prep-HPLC (Boston Green ODS (150 mm × 30 mm, 5 μm) A = H 2 O (0.075% TFA) and B = CH 3 CN; 66-96% B in 8 minutes) and concentrated to give a residue. Saturated aqueous NaHCO 3 solution (10 mL) was added to the residue, and the mixture was extracted with EtOAc (15 mL × 2). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na 2 SO 4, filtered, and concentrated to give the product as a solid (55.97 mg, 124.6 μmol, 70% yield). 1 H NMR (CDCl3+D2O, 400MHz)δ H =9.52 (d, 1H), 8.53-8.43 (m, 2H), 8.04 (dd, 1H), 5.98-5.84 (m, 1H), 4.06 (d, 2H), 2.21-2.06 (m, 1H), 1.60 (d, 3H), 1.08 (d, 6H). LCMS chromatogram in 2.0min R t = 1.37 min, 10-80 AB, MS ESI calculated value C 18 H 18 F6N5O2[M+H] + 450.1, experimental value 450.0.

[0639] Example 45: 6-[5-Fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridinyl]-3-(methoxymethyl)-[1,2,4]triazolo[4,3-b]pyridazine

[0640]

[0641] Synthesis of A32: To a solution of (6-chloropyridazine-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 H2O (40 mL) and extracted with EtOAc (40 mL×2). The combined organic phases were washed with brine (40 mL), dried over Na2SO4, filtered and concentrated to give a crude product. The crude product was triturated from i-Pr2O (10 mL) to give a solid product (1500 mg, 7.31 mmol, 35% yield). LCMS chromatogram in 1.5 min R t =0.43 min, 5-95 AB, MS ESI calculated value C7H8ClN4O [M+H] + 198.0, experimental value 199.0.

[0642] Synthesis of compound 46: 6-chloro-3-(methoxymethyl)-[1,2,4]triazolo[4,3-b]pyridazine (100 mg, 0.5 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-

[0643] A mixture of (1R)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (202.47 mg, 0.6 mmol), K 3 PO 4 (213.79 mg, 1.01 mmol), Pd(t-Bu 3 P) 2 (38.6 mg, 0.08 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was stirred at 80° C. under N 2 for 12 hours. After cooling to room temperature, the mixture was diluted with H 2 O (10 mL) and extracted with EtOAc (20 mL×2). The combined organic phases were washed with water (10 mL) and brine (10 mL), dried over Na 2 SO 4, filtered, and concentrated to give the crude product. The crude product was purified by Prep-HPLC (column: Boston Prime (150 mm×30 mm, 5 μm; mobile phase: A=H 2 O (0.05% NH 4 OH); B=CH 3 CN, 35-65% B in 9 min) to give the product as a solid (43.29 mg, 0.12 mmol, 23% yield). 1 H NMR (CDCl3, 400MHz)δ H =8.53 (d, 1H), 8.25 (d, 1H), 8.14 (dd, 1H), 7.57 (d, 1H), 5.98-5.85 (m, 1H), 5.11 (s, 2H), 3.54 (s, 3H), 1.61 (d, 3H). LCMS chromatogram in 2.0min R t = 1.17 min, 10-80 AB, MS ESI calculated value C 15 H 14 F4N5O2[M+H] + 372.1, experimental value 372.1.

[0644] Example 46: 3-[Difluoro(isobutyloxy)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridinyl]-[1,2,4]triazolo[4,3-b]pyridazine

[0645]

[0646] A mixture of 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridinyl]-[1,2,4]triazolo[4,3-b]pyridazine (300 mg, 0.73 mmol) and AgOTf (1872.33 mg, 7.29 mmol) in 2-methylpropan-1-ol (10 mL, 0.73 mmol) and MeCN (10 mL) was stirred at 90° C. for 9 days. After cooling to room temperature, the reaction was diluted with EtOAc (60 mL) and brine (20 mL), filtered through celite, and extracted with EtOAc (50 mL×2). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over Na 2 SO 4 , 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 C18 (150 mm × 30 mm, 5 μm), A = H2O (0.05% NH4OH) and B = CH3CN; 60-90% B in 9 minutes) to give the product as a solid (7.42 mg, 16.5 μmol, 2% yield). 1 H NMR (CDCl3, 400MHz)δ H =8.54 (d, 1H), 8.30 (d, 1H), 8.14 (dd, 1H), 7.66 (d, 1H), 5.98-5.85 (m, 1H), 4.01 (d, 2H), 2.15-2.01 (m, 1H), 1.61 (d, 3H), 1.05 (d, 6H). LCMS chromatogram in 2.0min R t =1.39 min, 10-80 AB, MS ESI calculated value C 18 H 18 F6N5O2[M+H] + 450.1, experimental value 450.1.

[0647] Example 47: 3-[Ethoxy(difluoro)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridinyl]-[1,2,4]triazolo[4,3-b]pyridazine

[0648]

[0649] A mixture of 6-chloro-3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyrazine (150 mg, 0.76 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)pyridine (527.36 mg, 1.51 mmol), Cs2CO3 (738.18 mg, 2.27 mmol), Pd(dppf)Cl2 (110.52 mg, 0.15 mmol) in 1,4-dioxane (8 mL) and water (0.80 mL) was stirred at 75° C. under N2 for 9 hours. After cooling to room temperature, the mixture was diluted with H2O (20 mL) and extracted with EtOAc (30 mL×2). The combined organic phases were washed with water (30 mL x 1) and brine (30 mL), dried over Na2SO4, filtered, and concentrated to yield the crude product. The crude product was purified by Prep-HPLC (Boston Prime C18 (150 mm x 30 mm, 5 μm), A = H2O (0.05% NH4OH) and B = CH3CN; 49-59% B in 9 minutes) to yield the product as a solid (90.56 mg, 235 μmol, 31% yield). 1 HNMR (CDCl3, 400MHz)δ H =9.43 (s, 1H), 8.57-8.40 (m, 2H), 8.01 (d, 1H), 5.13 (s, 2H), 3.46 (s, 3H), 1.88 (s, 6H). LCMS in 2.0min chromatogram R t =1.24 min, 10-80 AB, MS ESI calculated value C 16 H 16 F4N5O2[M+H] + 386.1, experimental value 386.1

[0650] Example 48: 3-[Difluoro(isobutyloxy)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridinyl]-[1,2,4]triazolo[4,3-b]pyridazine

[0651]

[0652] A mixture of 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyridazine (500 mg, 1.21 mmol) and AgOTf (3120.6 mg, 12.15 mmol) in 2-methylpropan-1-ol (10 mL, 1.21 mmol) and 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 an impure product. The impure product was purified by Prep-HPLC (Waters Xbridge 150 mm×25 mm, 5 μm) A═H 2 O (10 mM NH 4 HCO 3 ) and B═CH 3 CN; 54-84% B in 8 minutes) to give the product as a solid (53.85 mg, 0.12 mmol, 10% yield). 1 H NMR (CDCl3, 400MHz)δ H =8.54 (d, 1H), 8.30 (d, 1H), 8.13 (dd, 1H), 7.66 (d, 1H), 5.92 (spt, 1H), 4.01 (d, 2H), 2.16-2.04 (m, 1H), 1.61 (d, 3H), 1.05 (d, 6H). LCMS chromatogram in 2.0min R t =1.42 min, 10-80 AB, MS ESI calculated value C 18 H 18 F6N5O2[M+H] + 450.1, experimental value 450.1.

[0653] Example 49: 3-(Ethoxymethyl)-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyrazine

[0654]

[0655] Synthesis of A40: A mixture of [5-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]pyrazin-2-yl]hydrazine (200 mg, 0.63 mmol), DIPEA (0.33 mL, 1.89 mmol) and 2-ethoxyacetyl chloride (92.71 mg, 0.76 mmol) in CH2Cl2 (10 mL) was stirred at 25°C for 16 hours. The mixture was concentrated to a residue, and the residue was redissolved in EtOAc (20 mL), washed with water (10 mL x 2), brine (10 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated to give the product as a solid (150 mg, 0.13 mmol, 20% yield). LCMS chromatogram in 1.5 min R t = 0.84 min, 5-95 AB, MS ESI calculated value C 16 H 18 F4N5O3[M+H] + 404.1, experimental value 404.2.

[0656] Synthesis of compound 50: A mixture of 2-ethoxy-N'-[5-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]pyrazin-2-yl]acetohydrazide (150 mg, 0.37 mmol) in acetic acid (15 mL) was stirred at 120 ° C for 4 days. After cooling to room temperature, the mixture was concentrated to give a solid. The solid was redissolved in EtOAc (20 mL), basified with saturated Na2CO3 to pH about 9, washed with water (10 mL×2), brine (10 mL×2), dried over anhydrous Na2SO4, filtered and concentrated to give a crude product. The crude product was purified by Prep-HPLC (Boston Prime C18 150 mm×30 mm 5 μm) A=H 2 O (0.05% ammonia hydroxide) and B=CH 3 CN; 45-75% B in 9 minutes) to give the product as a solid (48.08 mg, 0.12 mmol, 34% yield). 1 H NMR (DMSO-d6, 400 MHz) δ H =9.55 (d, 1H), 9.15 (d, 1H), 8.77 (d, 1H), 8.49 (dd, 1H), 6.08-5.98 (m, 1H), 5.08 (s, 2H), 3.61 (q, 2H), 1.55 (d, 3H), 1.15 (t, 3H). LCMS chromatogram in 2.0 min R t =1.23 min, 10-80 AB, MS ESI calculated value C 16 H 16 F4N5O2

[0657] [M+H] + 386.1, experimental value 386.0.

[0658] Example 50: 3-[Cyclopropyloxy(difluoro)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyrazine

[0659]

[0660] To a mixture of cyclopropanol (28.22 mg, 0.49 mmol), 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyrazine (100 mg, 0.24 mmol) in DMF (2 mL) was added potassium tert-butoxide (54.51 mg, 0.49 mmol) dropwise. The reaction mixture was stirred at 20 ° C for 2 hours. The reaction was quenched with saturated NH4Cl (10 mL) and the mixture was extracted with (10 mL×2). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm) A═H 2 O (10 mM NH 4 HCO 3 ) and B═CH 3 CN; 57-67% B in 8 min) to give the product as an oil (3.98 mg, 0.01 mmol, 4% yield). 1 H NMR (CD3CN, 400MHz)δ H =9.46 (s, 1H), 8.67-8.56 (m, 2H), 8.20 (dd, 1H), 6.01-5.92 (m, 1H), 4.21-4.14 (m, 1H), 1.58 (d, 3H), 1.00-0.91 (m, 2H), 0.81-0.73 (m, 2H). LCMS R in 2min chromatogram t =1.31 min, 10-80 AB, MSESI calculated value C 17 H 14 F6N5O2[M+H] + 434.1, experimental value 433.9.

[0661] Example 51: 3-(Ethoxymethyl)-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyrazine

[0662]

[0663] Synthesis of A41: A mixture of (5-chloropyrazin-2-yl)hydrazine (500 mg, 3.46 mmol) and 2-ethoxyacetyl chloride (551.03 mg, 4.5 mmol) in toluene (7 mL) was stirred at 20 ° C for 2 hours, then heated to 130 ° C and maintained for 3 days. Most of the toluene was then removed, and acetic acid (40 mL) was added and stirred at 120 ° C for 16 hours. After cooling to room temperature, the mixture was concentrated to produce a residue. The residue was redissolved in EtOAc (40 mL), basified with saturated Na2CO3 to pH about 9, washed with water (20 mL×2), brine (20 mL×2), dried over anhydrous Na2SO4, filtered and concentrated to produce a crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 40% to 70%) to produce a solid product (240 mg, 1.11 mmol, 32% yield). LCMS R in 1.5 min chromatogram t = 0.60 min, 5-95 AB, MS ESI calculated value C8H 10 ClN4O[M+H] + 213.0, experimental value 213.0.

[0664] Synthesis of compound 52: A mixture of 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (453.86 mg, 1.35 mmol), Cs2CO3 (1103.16 mg, 3.39 mmol), 6-chloro-3-(ethoxymethyl)-[1,2,4]triazolo[4,3-a]pyrazine (240 mg, 1.13 mmol) and Pd(dppf)Cl2 (123.88 mg, 0.17 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was stirred at 75 ° C. under N2 for 16 hours. After cooling to room temperature, the mixture was filtered through 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 an impure product. The impure product was purified by Prep-HPLC (Waters Xbridge 150 mm x 25 mm, 5 μm) (A = H2O (10 mM NH4HCO3) and B = CH3CN; 40-70% B in 8 minutes) to give the product as a solid (37.8 mg, 98.1 μmol, 9% yield). 1 H NMR (DMSO-d6, 400 MHz) δ H=9.56 (d, 1H), 9.15 (d, 1H), 8.77 (d, H), 8.49 (dd, 1H), 6.09-5.97 (m, 1H), 5.08 (s, 2H), 3.61 (q, 2H), 1.55 (d, 3H), 1.14 (t, 3H). LCMS chromatogram in 2.0 min R t =1.24 min, 10-80 AB, MS ESI calculated value C 16 H 16 F4N5O2

[0665] [M+H] + 386.1, experimental value 386.1.

[0666] Example 52: 3-[Difluoro(methoxy)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyrazine

[0667]

[0668] Synthesis of A19-a: A mixture of 2-bromo-5-chloro-pyrazine (3 g, 15.51 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (4.98 g, 15.51 mmol), CsCO (10.11 g, 31.02 mmol) and Pd(dppf)Cl (1.7 g, 2.33 mmol) in 1,4-dioxane (50 mL) and water (5 mL) was stirred at 55° C. under N for 5 hours. The reaction was cooled to room temperature and concentrated to give a residue. Water (50 mL) and EtOAc (50 mL) were added to the residue, and the mixture was then filtered. After separation, the organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 5% to 10%) to give the product as a solid (3700 mg, 10.69 mmol, 69% yield). 1 HNMR (DMSO-d6, 400MHz)δ H =9.19 (d, 1H), 8.88 (d, 1H), 8.80 (d, 1H), 8.49 (dd, 1H), 5.18 (q, 2H). LCMS in 1.5min chromatogram R t = 0.93 min, 5-95 AB, MS ESI calculated value C 11 H7ClF4N3O[M+H] + 308.0, experimental value 308.0.

[0669] 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 produce a residue. Water (30 mL) was added to the residue and the residue was extracted with EtOAc (30 mL×2). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated to produce the crude product as a solid (3500 mg, 9.60 mmol, 80% yield). 1 H NMR (DMSO-d6, 400 MHz) δ H =8.62 (d, 1H), 8.58 (d, 1H), 8.30-8.24 (m, 2H), 8.19 (d, 1H), 5.12 (q, 2H), 4.36 (s, 2H). LCMS in 1.5min chromatogram R t = 0.73 min, 5-95 AB, MS ESI calculated value C 11 H 10 F4N5O[M+1H] + 304.1, experimental value 304.0.

[0670] 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-acetic acid (2-chloro-2,2-difluoro-acetyl) ester (7.21 g, 29.68 mmol) in toluene (60 mL) was stirred at 110° C. for 96 hours, then molecular sieves (3 g) were added to the mixture, and the mixture was stirred at 130° C. for another 16 hours. After cooling to room temperature, the mixture was concentrated to give a residue. Water (20 mL) was added to the residue and extracted with EtOAc (30 mL×2). The combined organic phases were washed with water (20 mL), brine (20 mL×2), dried over anhydrous Na 2 SO 4 , 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 10% to 20%) to give the product as an oil (1300 mg, 3.24 mmol, 33% yield). LCMS R t = 2.63 min, 10-80 AB, MS ESI calculated value C 13 H7ClF6N5O[M+H] + 398.0, experimental value 397.9.

[0671] Synthesis of compound 53: A mixture of 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyrazine (600 mg, 1.51 mmol) and AgOTf (3.88 g, 15.09 mmol) in methanol (12 mL) and DMF (4 mL) was stirred at 90 ° C for 48 hours. After cooling to room temperature, the reaction mixture was treated with brine (20 mL) and the precipitate was filtered. The filtrate was concentrated and diluted with water (20 mL), then extracted with EtOAc (20 mL×3). The combined organic phases were washed with brine (20 mL), dried over Na 2 SO 4 and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 10% to 30%) to give the product as a solid (247.53 mg, 0.63 mmol, 42% yield). 1 H NMR (CDCl3, 400MHz)δ H =9.52(d,1H),8.52(d,1H),8.46(d,1H),8.07(dd,1H),4.93(q,2H),3.98(s,3H). LCMS in 1.5min chromatogram R t =1.23 min, 5-95 AB, MS ESI calculated value C 14 H 10 F6N5O2[M+H] + 394.1, experimental value 394.0.

[0672] Example 53: 3-[Difluoro(methoxy)methyl]-6-[6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyrazine

[0673]

[0674] A mixture of 3-[chloro(difluoro)methyl]-6-[6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyrazine (1.9 g, 4.66 mmol) and AgOTf (11.97 g, 46.59 mmol) in a solvent of DMF (15 mL) and methanol (15 mL) was stirred at 90 ° C for 96 hours. After cooling to room temperature, the reaction mixture was treated with brine (50 mL) and the precipitate was filtered. The filtrate was concentrated and diluted with water (40 mL), then extracted with EtOAc (50 mL×2). The combined organic phases were washed with brine (50 mL), dried over Na 2 SO 4 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 (170 mg). Another 88 mg of product was obtained from another batch. The three crops were combined and lyophilized to give the product as a solid (193.0 mg, 0.48 mmol). 1 H NMR (400 MHz, CDCl3) δ = 9.52 (d, 1H), 8.72 (d, 1H), 8.43 (s, 1H), 8.19 (dd, 1H), 6.94 (d, 1H), 3.98 (s, 3H), 1.87 ppm (s, 6H). LCMS chromatogram in 2.0 min R t = 1.235 min, 10-80 AB, MS ESI calculated value C 16 H 15 F5N5O2[M+H] + 404.1, experimental value 403.9.

[0675] Example 54: 3-[Chloro(difluoro)methyl]-6-[6-[1-(trifluoromethyl)cyclobutyloxy]-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyrazine

[0676]

[0677] Synthesis of A54: To a solution of 1-(trifluoromethyl)cyclobutanol (5 g, 35.69 mmol) in THF (300 mL) was added NaH (1.86 g, 46.4 mmol) at 0°C over 20 minutes, and the mixture was stirred at 0°C for 30 minutes. 5-Bromo-2-fluoro-pyridine (8.48 g, 48.18 mmol) was then added to the mixture, and the mixture was stirred at 30°C for 3 hours. The mixture was quenched with saturated NH4Cl (50 mL), and the mixture was extracted with EtOAc (50 mL). The combined organic phases were washed with brine (50 mL×3), dried over Na2SO4, filtered and concentrated to give an oily crude product (4.8 g, 15.49 mmol, 43% yield). LCMS chromatogram at 1.5 min: R t = 0.99 min, 5-95 AB, MS ESI calculated value C 10 H 10 BrF3NO[M+H] + 295.9, experimental value 296.0.

[0678] Synthesis of A55: A mixture of 5-bromo-2-[1-(trifluoromethyl)cyclobutyloxy]pyridine (2.5 g, 8.44 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (3.22 g, 12.67 mmol), KOAc (1.66 g, 16.89 mmol) and Pd(dppf)Cl2 (432.48 mg, 0.59 mmol) in 1,4-dioxane (50 mL) was stirred at 90° C. under N2 for 12 hours. After cooling to room temperature, the mixture was concentrated to give a residue. The residue was diluted with H2O (40 mL) and the mixture was extracted with EtOAc (40 mL×2). The combined organic phases were washed with water (40 mL) and brine (40 mL), dried over Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 1%) to give an oily crude product (2.65 g, 3.92 mmol, 46% yield). 1 H NMR (CDCl3, 400MHz)δ H =8.54(d,1H),7.95(dd,1H),6.74(d,1H),2.99-2.81(m,2H),2.75-2.53(m,2H),2.13-1.78(m,2H),1.34(s,12H).

[0679] Synthesis of A56: A mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[1-(trifluoromethyl)cyclobutyloxy]pyridine (2.1 g, 6.12 mmol), 2-bromo-5-chloro-pyrazine (1.18 g, 6.12 mmol), Pd(dppf)Cl2 (671.68 mg, 0.92 mmol) and Cs2CO3 (3.99 g, 12.24 mmol) in 1,4-dioxane (20 mL) and water (2 mL) was stirred at 60°C under N2 for 6 hours. After cooling to room temperature, the mixture was concentrated to give a residue. The residue was diluted with H2O (20 mL) and the mixture was extracted with EtOAc (20 mL x 2). The combined organic phases were washed with water (20 mL) and brine (40 mL), dried over Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 1% to 10%) to give the product as an oil (1.5 g, 4.263 mmol, 70% yield). 1 HNMR (CDCl3, 400MHz)δ H =8.80-8.72(m,2H),8.63(d,1H),8.25(dd,1H),6.91(d,1H),3.01-2.83(m,2H),2.78-2.62(m,2H),2.18-1.84(m,2H).

[0680] Synthesis of A57: A mixture of 2-chloro-5-[6-[1-(trifluoromethyl)cyclobutyloxy]-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 H2O (30 mL) and extracted with EtOAc (30 mL×2). The combined organic phases were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated to give the crude product as a solid (950 mg, 2.48 mmol, 68% yield). LCMS chromatogram R in 2.0 min t = 0.99 min, 10-80 AB, MS ESI calculated value C 14 H 15 F3N5O[M+H] + 326.1, experimental value 326.0.

[0681] Synthesis of A58: A mixture of [5-[6-[1-(trifluoromethyl)cyclobutyloxy]-3-pyridyl]pyrazin-2-yl]hydrazine (1.13 g, 3.47 mmol), 4A molecular sieves (1 g, 3.47 mmol), and 2-chloro-2,2-difluoro-acetic acid (2-chloro-2,2-difluoro-acetyl) ester (1.69 g, 6.95 mmol) in toluene (15 mL) was heated to 130° C. and stirred for 16 hours. After cooling to room temperature, the reaction mixture was filtered and diluted with H O (50 mL) and extracted with EtOAc (50 mL×2). The combined organic phases were washed with brine (50 mL), dried over Na SO , filtered, and concentrated to give the crude product as a solid (820 mg, 1.13 mmol, 33% yield).

[0682] LCMS in 2.0min chromatogram R t =1.38 min, 10-80 AB, MS ESI calculated value C 16 H 12 ClF5N5O[M+H] + 420.1, experimental value 420.0.

[0683] Synthesis of Compound 57: A mixture of 3-[chloro(difluoro)methyl]-6-[6-[1-(trifluoromethyl)cyclobutyloxy]-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyrazine (600 mg, 1.43 mmol) and AgOTf (4.4 g, 17.15 mmol) in DMF (6 mL) and methanol (6 mL, 1.43 mmol) was stirred at 90°C for 16 hours. After cooling to room temperature, the reaction was quenched with saturated NaCl (30 mL) and extracted with EtOAc (30 mL x 2). The organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 40% to 70%) to give the product as a solid (194.76 mg, 0.47 mmol, 33% yield). 1 HNMR (CDCl3, 400MHz)δ H =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 chromatogram in 2.0 min R t =1.33 min, 10-80 AB, MS ESI calculated value C 17 H 15F5N5O2[M+H] + 416.1, experimental value 416.1.

[0684] Example 56: 3-[Difluoro(methoxy)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridinyl]-5-methyl-[1,2,4]triazolo[4,3-a]pyrazine

[0685]

[0686]

[0146] 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-1,3,2-dioxaborolan-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (1.31 g, 3.9 mmol), Pd(dppf)Cl2 (0.48 g, 0.65 mmol) and Cs2CO3 (2.83 g, 8.68 mmol) in 1,4-dioxane (40 mL) and water (8 mL) was stirred at 50°C under N2 for 5 hours. The mixture was cooled to room temperature, diluted with EtOAc (30 mL), filtered through silica gel 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 as a solid (1100 mg, 2.83 mmol, 65% yield). LCMS R t =1.41 min, 10-80 AB, MS ESI calculated value C 13 H 11 ClF4N3O[M+H] + 336.0, experimental value 336.0.

[0687] Synthesis of A60: A mixture of 5-chloro-2-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridinyl]-3-methyl-pyrazine (1.1 g, 3.28 mmol) and hydrazine (1.05 g, 32.83 mmol) in MeCN (20 mL) was heated to 90 ° C and stirred for 16 hours. After cooling to room temperature, the reaction mixture was concentrated. The mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL×2). The combined organic phases were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated to give a crude product. The crude product was triturated from PE (5 mL) to give a solid product (800 mg, 2.41 mmol, 68% yield). The crude product was used in the next step without further purification. LCMS R in 1.5 min chromatogramt = 0.75 min, 5-95 AB, MS ESI calculated value C 13 H 14 F4N5O[M+H] + 332.1, experimental value 332.1.

[0688] Synthesis of A61: To a mixture of [5-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridinyl]-6-methyl-pyrazin-2-yl]hydrazine (500 mg, 1.51 mmol) in toluene (10 mL) was added 2-chloro-2,2-difluoro-acetic acid (2-chloro-2,2-difluoro-acetyl) ester (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 NaHCO 3 (30 mL), and the mixture was extracted with EtOAc (30 mL×2). The combined organic phases were washed with brine (20 mL), dried over Na 2 SO 4 , filtered, and concentrated to give a residue. The residue was purified by flash column on silica gel (EtOAc in PE = 0% to 20%) to give the product as a solid (105 mg, 0.16 mmol, 11% yield). LCMS R t = 0.92 min, 5-95 AB, MS ESI calculated value C 15 H 11 ClF6N5O[M+H] + 426.0, experimental value 426.2.

[0689] Synthesis of Compound 58: A mixture of 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridinyl]-5-methyl-[1,2,4]triazolo[4,3-a]pyrazine (105 mg, 0.25 mmol) and AgOTf (633.7 mg, 2.47 mmol) in a mixed solvent of methanol (1 mL) and DMF (1 mL) was stirred at 90° C. for 48 hours. After cooling to room temperature, the reaction mixture was treated with brine (15 mL) and the precipitate was filtered off. The filtrate was extracted with EtOAc (15 mL×2). The combined organic phases were dried over Na 2 SO 4 and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 30% to 50%). The crude product was then triturated with DCM (0.5 mL) and n-hexane (0.5 mL) to give the product (2.05 mg, 4.90 μmol, 2% yield). 1 H NMR (CDCl3, 400MHz)δ H=9.39 (s, 1H), 8.11 (d, 1H), 7.69 (dd, 1H), 5.94-5.86 (m, 1H), 3.92 (s, 3H), 2.88 (s, 3H), 1.60 (d, 3H). LCMS R in 2min chromatogram t =1.24 min, 10-80 AB, MS ESI calculated value C 16 H 14 F6N5O2[M+H] + 422.1, experimental value 422.0.

[0690] Example 57: 3-[Difluoro(methoxy)methyl]-6-[6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyrazine

[0691]

[0692] 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 N2 over 30 minutes, and the mixture was then stirred at 20°C for 2 hours. After cooling to 0°C, the mixture was quenched with water (0.9 g) and stirred at 35°C for 30 minutes. The mixture was filtered through celite and eluted with THF (20 mL x 2). The organic phase was washed with brine (20 mL x 2) and dried over Na2SO4, filtered, yielding the crude product (2S)-1,1,1-trifluoropropan-2-ol (3 g, 26.3 mmol, 98% yield) as a solution in THF, which was used directly without further purification.

[0693] Synthesis of A63: To a solution of (2S)-1,1,1-trifluoropropan-2-ol in THF (50 mL) was added NaH (0.8 g, 19.94 mmol) at 0°C over 20 minutes, and the mixture was stirred at 0°C for 40 minutes. 5-Bromo-2-fluoro-pyridine (2.7 g, 15.34 mmol) was then added to the mixture, and the mixture was stirred at 50°C for 2 hours. The mixture was quenched with saturated NH4Cl (40 mL), extracted with EtOAc (60 mL), and the combined organic phases were washed with brine (40 mL×2), dried over Na2SO4, filtered and concentrated to give an oily crude product (3.48 g, 9.29 mmol, 61% yield). LCMS chromatogram at 1.5 min R t =0.95 min, 5-95 AB, MS ESI calculated value C8H8BrF3NO[M+H] +270.0, experimental value 269.9.

[0694] Synthesis of A64: A mixture of 5-bromo-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (3.48 g, 12.89 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (4.91 g, 19.33 mmol), KOAc (2.53 g, 25.77 mmol) and Pd(dppf)Cl2 (1.13 g, 1.55 mmol) in 1,4-dioxane (35 mL) was stirred at 85° C. under N2 for 12 hours. After cooling to room temperature, the mixture was concentrated to give a residue. The residue was diluted with H2O (30 mL) and the mixture was extracted with EtOAc (40 mL×2). The combined organic phases were washed with water (40 mL) and brine (40 mL), dried over Na2SO4, filtered and concentrated to 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 as an oil (3 g, 5.72 mmol, 44% yield). 1 H NMR (DMSO-d6, 400 MHz) δ H =8.42 (d, 1H), 7.96 (dd, 1H), 6.93 (d, 1H), 6.00-5.93 (m, 1H), 1.45 (d, 3H), 1.30 (s, 12H). LCMS in 1.5min chromatogram R t =1.02 min, 5-95 AB, MS ESI calculated value C 14 H 20 BF3NO3[M+H] + 318.1, experimental value 318.1.

[0695] Synthesis of A65: 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-

[0696] A mixture of (1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (600 mg, 1.89 mmol), 2-bromo-5-chloro-pyrazine (329.39 mg, 1.7 mmol), Pd(dppf)Cl2 (207.67 mg, 0.28 mmol) and Cs2CO3 (1232.88 mg, 3.78 mmol) in 1,4-dioxane (15 mL) and water (1.5 mL) was stirred at 60°C under N2 for 5 hours. After cooling to room temperature, the mixture was concentrated to give a residue. The residue was diluted with H2O (20 mL) and the mixture was extracted with EtOAc (30 mL x 2). The combined organic phases were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 3%) to give the product as an oil (350 mg, 1.15 mmol, 61% yield). LCMS R t = 0.95 min, 5-95 AB, MS ESI calculated value C 12 H 10 ClF3N3O[M+H] + 304.0, experimental value 304.1.

[0697] Synthesis of A66: A mixture of 2-chloro-5-[6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]pyrazine (351.14 mg, 1.16 mmol) and hydrazine (741.21 mg, 23.13 mmol) in CH3CN (5 mL) was stirred at 90 ° C for 16 hours. After cooling to room temperature, the reactant was quenched with saturated NH4Cl (30 mL), and the mixture was extracted with EtOAc (20 mL×2). The combined organic phases were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated to give the crude solid product (350 mg, 1.05 mmol, 91% yield). LCMS chromatogram in 1.5 min R t = 0.74 min, 5-95 AB, MS ESI calculated value C 12 H 13 F3N5O[M+H] + 300.1, experimental value 300.1.

[0698] Synthesis of A67: A mixture of [5-[6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridinyl]pyrazin-2-yl]hydrazine (350 mg, 1.17 mmol), 2-chloro-2,2-difluoro-acetic acid (2-chloro-2,2-difluoro-acetyl) ester (852.42 mg, 3.51 mmol), and 4A molecular sieves (500 mg, 1.17 mmol) in toluene (8 mL) was stirred at 120° C. for 2 days. After cooling to room temperature, the reaction was quenched with saturated NaHCO (20 mL), and the mixture was extracted with EtOAc (20 mL×2). The combined organic phases were washed with water (20 mL) and brine (20 mL), dried over NaSO, filtered, and concentrated to yield the product as a solid (420 mg, 1.01 mmol, 86% yield). LCMS in 1.5min chromatogram R t = 0.92 min, 5-95A BMS ESI calculated value C 14 H 10 ClF5N5O[M+H] + 394.0, experimental value 394.1.

[0699] Synthesis of Compound 59: A mixture of 3-[chloro(difluoro)methyl]-6-[6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyrazine (420 mg, 1.07 mmol), AgOTf (3289.25 mg, 12.8 mmol) in DMF (6 mL) and methanol (6 mL, 1.07 mmol) was stirred at 90 ° C for 24 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 Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 15% to 30%) to give an impure product which was triturated from n-hexane / DCM (2:1, 6 mL) to give the product as a solid (118.39 mg, 0.30 mmol, 29% yield). 1 H NMR (CD3CN, 400MHz)δ H =9.46 (d, 1H), 8.81 (d, 1H), 8.66 (d, 1H), 8.35 (dd, 1H), 6.99 (d, 1H), 5.99-5.88 (m, 1H), 3.94 (s, 3H), 1.53 (d, 3H). LCMS R in 2.0 min chromatogram t=1.28 min, 10-80 AB, MS ESI calculated value C 15 H 13 F5N5O2[M+H] + 390.1, experimental value 390.0.

[0700] Example 58: 3-[Difluoro(methoxy)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridinyl]-5-methyl-[1,2,4]triazolo[4,3-a]pyrazine

[0701]

[0702] Synthesis of A68: A mixture of 2-bromo-5-chloro-3-methyl-pyrazine (900 mg, 4.34 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (1.31 g, 3.9 mmol), Pd(dppf)Cl2 (0.48 g, 0.65 mmol) and Cs2CO3 (2.83 g, 8.68 mmol) in 1,4-dioxane (40 mL) and water (8 mL) was stirred at 55° C. under N2 for 16 hours. The mixture was cooled to room temperature, diluted with EtOAc (50 mL), filtered through silica gel, eluted with EtOAc (20 mL) and concentrated to give the crude product. The product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 20%) to give the product as a colorless oil (930 mg, 2.62 mmol, 60% yield). LCMS R t = 0.95 min, 5-95 AB, MS ESI calculated value C 13 H 11 ClF4N3O[M+H] + 336.0, experimental value 336.1.

[0703] Synthesis of A69: A mixture of hydrazine (1775.89 mg, 55.41 mmol) and 5-chloro-2-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridinyl]-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 saturated NH4Cl (30 mL), and the mixture was extracted with EtOAc (40 mL×2). The combined organic phases were washed with water (30 mL) and brine (30 mL), dried over Na2SO4, filtered and concentrated to give the crude product as a solid (980 mg, 2.45 mmol, 89% yield). LCMS chromatogram in 1.5 min R t = 0.75 min, 5-95 AB, MS ESI calculated value C 13 H 14 F4N5O[M+H] + 332.1, experimental value 332.2.

[0704] Synthesis of A70: A mixture of [5-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridinyl]-6-methyl-pyrazin-2-yl]hydrazine (600 mg, 1.81 mmol), 2-chloro-2,2-difluoro-acetic acid (2-chloro-2,2-difluoro-acetyl) ester (1320.05 mg, 5.43 mmol) and 4A molecular sieves (600 mg, 1.81 mmol) in toluene (10 mL) was stirred at 120 ° C. for 5 days. After cooling to room temperature, the reaction was quenched with saturated NaHCO 3 (20 mL) and the mixture was extracted with EtOAc (20 mL×2). The combined organic phases were washed with water (20 mL) and brine (20 mL), dried over Na 2 SO 4, 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 as a solid (140 mg, 0.22 mmol, 12% yield). LCMS R in 1.5 min chromatogram t = 0.92 min, 5-95 AB, MS ESI calculated value C 15 H 11 ClF6N5O[M+H] + 426.0, experimental value 426.1.

[0705] Synthesis of Compound 60: A mixture of 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridinyl]-5-methyl-[1,2,4]triazolo[4,3-a]pyrazine (140 mg, 0.33 mmol), AgOTf (1267.44 mg, 4.93 mmol) in DMF (2 mL) and methanol (2 mL, 0.33 mmol) was stirred at 90 ° C for 2 days. After cooling to room temperature, the reaction was diluted with EtOAc (10 mL) and saturated NaCl (10 mL), and the mixture was filtered through celite and eluted with EtOAc (10 mL). The combined organic phases were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by Prep-TLC (silica gel, PE:EtOAc=2:1) ​​to give an impure product. The impure product was triturated from n-hexane / DCM (2:1, 3 mL) to give the product as a solid (11.92 mg, 28.3 μmol, 9% yield). 1 H NMR (CDCl3, 400MHz)δ H =9.39 (s, 1H), 8.11 (d, 1H), 7.69 (dd, 1H), 5.96-5.85 (m, 1H), 3.92 (s, 3H), 2.88 (s, 3H), 1.60 (d, 3H). LCMS chromatogram in 2.0 min R t =1.28 min, 10-80 AB, MS ESI calculated value C 16 H 14 F6N5O2[M+H] + 422.1, experimental value 422.2.

[0706] Example 59: 3-[Difluoro(methoxy)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridinyl]-5-methyl-[1,2,4]triazolo[4,3-a]pyrazine

[0707]

[0708] Synthesis of A71:NBS (34.35 g, 192.98 mmol) was added to a solution of 5-chloropyrazine-2-amine (25 g, 192.98 mmol) in DCM (250 mL). The resulting mixture was stirred at 40 ° C for 1 hour. After cooling to room temperature and concentrating, water (200 mL) was added to produce a residue, which was extracted with EtOAc (150 mL × 2). The combined organic phases were washed with brine (150 mL), dried over Na2SO4, filtered and concentrated to produce a crude product. The crude product was purified by column chromatography on silica gel (EtOAc in PE = 0% to 15% to 30%) to produce a solid product (31 g, 148.72 mmol, 77% yield). 1 H NMR (DMSO-d6, 400 MHz) δ H =8.09(s,1H),6.96(s,2H).

[0709] Synthesis of A72: 3-bromo-5-chloro-pyrazin-2-amine (31 g, 148.72 mmol), Pd(dppf)Cl2 (16.32 g, 22.31 mmol), methyl A mixture of 1,4-dioxane (300 mL) and 1,4-dioxane (13.35 g, 223.09 mmol) was stirred at 90°C for 16 hours. After cooling to room temperature, the mixture was concentrated to yield a residue. Water (100 mL) was added to the residue and extracted with EtOAc (100 mL x 2). The combined organic phases were washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated to yield 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 yield the product as a solid (13 g, 90.548 mmol, 61% yield). 1 H NMR (DMSO-d6, 400 MHz) δ H =7.83(s,1H),6.40(s,2H),2.26(s,3H).

[0710] Synthesis of A73: A mixture of 5-chloro-3-methyl-pyrazin-2-amine (3 g, 20.9 mmol), isoamyl nitrite (3.67 g, 31.34 mmol), and CuBr (3 g, 20.9 mmol) in MeCN (30 mL) was stirred at 50°C for 12 hours. The mixture was diluted with H2O (30 mL) and extracted with EtOAc (70 mL x 2). The combined organic phases were washed with water (30 mL x 2) and brine (30 mL), dried over Na2SO4, and concentrated to yield the crude product. The crude product was purified by flash column chromatography on silica gel (DCM in PE = 0% to 2%) to yield the product as an oil (1.2 g, 5.78 mmol, 28% yield). 1 HNMR (CDCl3, 400MHz)δ H =8.22 (s, 1H), 2.68 (s, 3H). LCMS in 2.0min chromatogram R t =1.10 min, 10-80 AB, MS ESI calculated for C5H5BrClN2 [M+H] + 208.9, experimental value 208.7.

[0711] Synthesis of A74: A mixture of 2-bromo-5-chloro-3-methyl-pyrazine (1.2 g, 5.78 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (1.3 g, 4.05 mmol), CsCO (3.77 g, 11.57 mmol) and Pd(dppf)Cl (634.85 mg, 0.87 mmol) in 1,4-dioxane (30 mL) and water (3 mL) was stirred at 60° C. under N for 16 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 separating the filtrate, the organic phase was washed with brine (30 mL), dried over anhydrous NaSO, filtered and concentrated to give the crude product. The crude product was purified by flash column chromatography on silica gel (EtOAc in PE = 0% to 1% to 2%) to give the product as a solid (580 mg, 1.71 mmol, 30% yield). 1 H NMR (CDCl3, 400MHz)δ H =8.52 (s, 1H), 8.19 (d, 1H), 7.73 (dd, 1H), 4.91 (q, 2H), 2.69 (s, 3H). LCMS in 1.5min chromatogram R t = 0.93 min, 5-95 AB, MS ESI calculated value C 12 H9ClF4N3O[M+H]+ 322.0, experimental value 322.0.

[0712] Synthesis of A75: A solution of 5-chloro-2-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridinyl]-3-methyl-pyrazine (640 mg, 1.89 mmol) and hydrazine (605.42 mg, 18.89 mmol) in MeCN (20 mL) was stirred at 90° C. for 16 hours. After cooling to room temperature, the mixture was concentrated, water (20 mL) was added, and the mixture was extracted with EtOAc (20 mL×3). The combined organic phases were washed with brine (20 mL×2), dried over anhydrous Na 2 SO 4 , filtered, and concentrated to give the crude product as a solid (530 mg, 1.30 mmol, 69% yield). 1 H NMR (DMSO-d6, 400 MHz) δ H =8.18 (d, 1H), 8.08 (s, 1H), 8.06 (s, 1H), 7.97 (dd, 1H), 5.13 (q, 2H), 4.32 (br s, 2H), 2.41 (s, 3H). LCMS in 1.5min chromatogram R t = 0.72 min, 5-95 AB, MS ESI calculated value C 12 H 12 F4N5O[M+H] + 318.1, experimental value 318.1.

[0713] Synthesis of A76: A solution of [5-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridinyl]-6-methyl-pyrazin-2-yl]hydrazine (530 mg, 1.67 mmol), 2-chloro-2,2-difluoro-acetic acid (2-chloro-2,2-difluoro-acetyl) ester (1.22 g, 5.01 mmol) and 4A molecular sieves (3 g) in toluene (30 mL) was stirred at 120° C. for 6 days. After cooling to room temperature, the mixture was concentrated to give a residue. Water (50 mL) was added to the residue, followed by extraction with EtOAc (50 mL×2). The combined organic phases were washed with water (50 mL) and brine (50 mL×2), dried over anhydrous Na 2 SO 4 , 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 as an oil (180 mg, 426.2 μmol, 26% yield). LCMS R t =3.64 min, 10-80 AB, MS ESI calculated value C 14 H9ClF6N5O[M+H] + 412.0, experimental value 412.1.

[0714] Synthesis of compound 61: A solution of 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridinyl]-5-methyl-[1,2,4]triazolo[4,3-a]pyrazine (180 mg, 0.44 mmol) and AgOTf (1.69 g, 6.56 mmol) in methanol (5 mL) and DMF (5 mL) was stirred at 90 ° C. under N 2 for 16 hours. After cooling to room temperature, saturated NaCl (50 mL) and EtOAc (50 mL) were added to the mixture and the mixture was filtered through celite. After separation, the organic phase was washed with brine (30 mL), dried over anhydrous Na 2 SO 4, 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 as a solid (38.62 mg, 94.1 μιηοΐ, 22% yield). 1 H NMR (CDCl3, 400MHz)δ H =9.39 (s, 1H), 8.12 (d, 1H), 7.71 (dd, 1H), 4.93 (q, 2H), 3.92 (s, 3H), 2.88 (s, 3H). LCMS in 2.0min chromatogram R t =1.20 min, 10-80 AB, MS ESI calculated value C 15 H 12 F6N5O2[M+H] + 408.1, experimental value 407.9.

[0715] Example 60: 3-[Difluoro(methoxy)methyl]-6-[6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyrazine

[0716]

[0717] To a suspension of 3-[bromo(difluoro)methyl]-6-[6-[rac-(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridinyl]-[1,2,4]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 filtrate was extracted with EtOAc (20 mL x 2). The combined organic phases were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash column chromatography on silica gel (EtOAc in PE = 0% to 10% to 20%) to give the product as a solid (1.96 g, ee = 92.28%). Analytical SFC: Analysis by SFC (Chiralpak OJ-3 150×4.6 mm ID, 3 μm mobile phase: A: CO 2 , B: ethanol (0.05% DEA); gradient: 5% to 40% B in 5 min and 40% to 5% B in 0.5 min, holding 5% B for 1.5 min; flow rate: 2.5 mL / min, column temperature: 35° C.) showed two peaks at = 2.71 min and 2.96 min. The product was isolated by SFC (DAICEL CHIRALCEL OJ (250 mm×50 mm, 10 mm); A=CO 2 and B=0.1% NH 3 H 2 O EtOH; 35° C.; 200 mL / min; 25% B; 8 min run; 100 injections, Rt=4.2 min for peak 1 and Rt=4.7 min for peak 2) to give the product as a solid (1415.6 mg, 3.64 mmol, 55% yield). 1 H NMR (400 MHz, CD3CN) δH=9.45 (d, 1H), 8.80 (d, 1H), 8.66 (d, 1H), 8.35 (dd, 1H), 6.99 (d, 1H), 5.97-5.90 (m, 1H), 3.94 (s, 3H), 1.53 (d, 3H). LCMS chromatogram in 2.0 min R t = 1.27 min, 10-80 AB, MS ESI calculated value C 15 H 13 F5N5O2[M+H] + 389.1, experimental value 390.0.

[0718] Example 61: 3-[Cyclopropyloxy(difluoro)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyrazine

[0719]

[0720] To a mixture of cyclopropanol (84.65 mg, 1.46 mmol), 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridinyl]-[1,2,4]triazolo[4,3-a]pyrazine (300 mg, 0.73 mmol) in DMF (5 mL) was added potassium tert-butoxide (163.54 mg, 1.46 mmol). The reaction mixture was stirred at 20 ° C for 1 hour. The mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL×2). The combined organic phases were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 30%) to give an impure product. The impure product was triturated from n-hexane / DCM (2:1, 3 mL) to afford the product (33.18 mg, 76.6 μιηοΐ, 11% yield). 1 H NMR (CDCl3, 400MHz)δ H =9.52 (d, 1H), 8.49 (d, 1H), 8.43 (d, 1H), 8.05 (dd, 1H), 5.96-5.86 (m, 1H), 4.21-4.16 (m, 1H), 1.61 (d, 3H), 1.04-0.99 (m, 2H), 0.87-0.81 (m, 2H). LCMS chromatogram in 2.0min R t = 1.34 min, 10-80 AB. MS ESI calculated value C 17 H 14 F6N5O2[M+H] + 434.1, experimental value 434.1.

[0721] Example 62: 6-(6-Benzyloxy-5-fluoro-3-pyridyl)-3-[ethoxy(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyrazine

[0722]

[0723] Synthesis of A84: To a solution of phenylmethanol (10.5 g, 97.1 mmol) in THF (100 mL) was added portionwise NaH (7 g, 175 mmol) at 0°C over 0.5 hours. After the addition, the mixture was stirred at 20°C for 1 hour. 5-Bromo-2,3-difluoro-pyridine (18.83 g, 97.1 mmol) was then added to the mixture. The resulting mixture was stirred at 20°C for 3 hours. The mixture was poured into a saturated NH4Cl solution (100 mL) and extracted with EtOAc (100 mL x 2). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give an oily crude product (27 g, 89.52 mmol).

[0724] Synthesis of A85: A mixture of 2-benzyloxy-5-bromo-3-fluoro-pyridine (27 g, 95.71 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (29.16 g, 114.85 mmol), KOAc (18.79 g, 191.41 mmol), and Pd(dppf)Cl (10.5 g, 14.36 mmol) in 1,4-dioxane (300 mL) was stirred at 90° C. under N for 16 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 as a solid (20 g, 60.75 mmol, 63% yield). 1 HNMR (400MHz, CDCl3)δ H =8.30(d,1H),7.66(dd,1H),7.50(d,2H),7.41-7.31(m,3H),5.52(s,2H),1.35(s,12H).

[0725] Synthesis of A86: A mixture of 2-bromo-5-chloro-pyrazine (4 g, 20.68 mmol), 2-benzyloxy-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (6.81 g, 20.68 mmol), CsCO (13.47 g, 41.36 mmol) and Pd(dppf)Cl (2.27 g, 3.1 mmol) in 1,4-dioxane (30 mL) and water (3 mL) was stirred at 50° C. under N for 16 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated. Water (50 mL) was added and the aqueous layer was extracted with EtOAc (50 mL×2). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 15% to 30%) to give the product as a solid (5.5 g, 17.42 mmol, 84% yield). 1 H NMR (400 MHz, DMSO-d6) δ H =9.15(s,1H),8.85(s,1H),8.77(s,1H),8.37(d,1H),7.52-7.46(m,2H),7.44-7.32(m,3H),5.51(s,2H).

[0726] Synthesis of A87: A mixture of 2-(6-benzyloxy-5-fluoro-3-pyridyl)-5-chloro-pyrazine (4.2 g, 13.3 mmol) and hydrazine (4.26 g, 133.03 mmol) in MeCN (20 mL) was stirred at 90 ° C for 16 hours. After cooling to room temperature, the solution was concentrated under reduced pressure. Water (30 mL) was added and the aqueous layer was extracted with EtOAc (30 mL×2). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated to give a solid crude product (4 g, 7.38 mmol). LCMS chromatogram in 1.5 min R t = 0.76 min, 5-95 AB, MS ESI calculated value C 16 H 15 FN5O[M+H] + 312.1, experimental value 311.9.

[0727] Synthesis of A88: To a 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×2). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated to give the crude product as a solid (900 mg, 1.92 mmol). 1 H NMR (400 MHz, DMSO-d6) δ H =11.40(s,1H),9.52(s,1H),8.78(d,1H),8.63(d,1H),8.24(dd,1H),8.14(d,1H),7.49(d,2H),7.43-7.32(m,3H),5.49(s,2H).

[0728] 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 Tf2O (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 phases were washed with saturated NaHCO3 solution (30 mL) and brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 30% to 50%) to give the product as a solid (240 mg, 533.1 μmol, 55% yield). 1 H NMR (400 MHz, CDCl3) δ H =9.57(d,1H),8.55(d,1H),8.41(s,1H),8.01(dd,1H),7.52(d,2H),7.44-7.32(m,3H),5.57(s,2H).

[0729] Synthesis of Compound 64: A mixture of 6-(6-benzyloxy-5-fluoro-3-pyridinyl)-3-[bromo(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyrazine (240 mg, 0.53 mmol) and AgBF4 (207.55 mg, 1.07 mmol) in ethanol (5 mL) was stirred 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 as a solid (31.09 mg, 74.8 μmol, 14% yield). 1 H NMR (400 MHz, CDCl3) δ H =9.51 (d, 1H), 8.50 (d, 1H), 8.46 (s, 1H), 8.00 (dd, 1H), 7.55-7.48 (m, 2H), 7.44-7.33 (m, 3H), 5.56 (s, 2H), 4.37 (q, 2H), 1.51 (t, 3H). LCMS R in 2.0 min chromatogram t =1.38 min, 10-80 AB, MS ESI calculated value C 20 H 17 F3N5O2[M+H] + 416.1, experimental value 416.0.

[0730] Example 63: 3-[Difluoro(methoxy)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridinyl]-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine

[0731]

[0732] Synthesis of A100: A mixture of 3-[bromo(difluoro)methyl]-6-chloro-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine (900 mg, 3.03 mmol) and AgBF4 (1.17 g, 6.05 mmol) in methanol (10 mL) was stirred at 60° C. in the 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 Na2SO4, 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 as a solid (180 mg, 724.0 μmol, 23% yield). 1 H NMR (400 MHz, CDCl3) δ H=7.99 (s, 1H), 3.90 (s, 3H), 2.53 (s, 3H). LCMS in 1.5min chromatogram R t =0.78 min, 5-95 AB, MS ESI calculated value C8H8ClF2N4O[M+H] + 249.0, experimental value 248.9.

[0733] Synthesis of Compound 65: A mixture of 6-chloro-3-[difluoro(methoxy)methyl]-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine (100 mg, 0.40 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (193.72 mg, 0.60 mmol), K3PO4 (170.78 mg, 0.80 mmol), and Pd(t-Bu3P)2 (30.83 mg, 0.06 mmol) in 1,4-dioxane (5 mL) and water (0.50 mL) was stirred at 80°C under N2 for 3 hours. After cooling to room temperature, water (20 mL) was added to the mixture, and the aqueous layer was extracted with EtOAc (20 mL x 2). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, 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 as a solid (64.84 mg, 158.9 μmol, 39% yield). 1 H NMR (400 MHz, CDCl3) δ H =8.20 (d, 1H), 8.06 (s, 1H), 7.69 (dd, 1H), 4.94 (q, 2H), 3.88 (s, 3H), 2.48 (s, 3H). LCMS in 2.0min chromatogram R t = 1.18 min, 10-80 AB, MS ESI calculated value C 15 H 12 F6N5O2[M+H] + 408.1, experimental value 408.0.

[0734] Example 64: 3-[Difluoro(methoxy)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridinyl]-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine

[0735]

[0736] A mixture of 3-fluoro-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (121.31 mg, 0.36 mmol), 6-chloro-3-[difluoro(methyloxy)methyl]-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine (75 mg, 0.3 mmol), Pd(t-Bu3P)2 (23.13 mg, 0.05 mmol), K3PO4 (128.09 mg, 0.6 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was stirred at 80°C for 3 hours. After cooling to room temperature, the mixture was concentrated and diluted with H2O (20 mL). The aqueous layer was extracted with EtOAc (20 mL x 2). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (EtOAc 100%) to give the product as a solid (70.46 mg, 0.17 mmol, 55% yield). 1 H NMR (400 MHz, CDCl3) δ H =8.18 (d, 1H), 8.06 (d, 1H), 7.67 (dd, 1H), 5.97-5.86 (m, 1H), 3.88 (s, 3H), 2.49 (s, 3H), 1.61 (d, 3H). LCMS Rt = 1.24 min in 2 min chromatography, 10-80 AB, MS ESI calculated value C 16 H 14 F6N5O2[M+H] + 422.1, experimental value 422.0.

[0737] Example 65: 3-[Ethoxy(difluoro)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridinyl]-5-methyl-[1,2,4]triazolo[4,3-a]pyrazine

[0738]

[0739] A mixture of 3-[bromo(difluoro)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridinyl]-5-methyl-[1,2,4]triazolo[4,3-a]pyrazine (100 mg, 0.21 mmol) and AgBF4 (82.81 mg, 0.43 mmol) in ethanol (1 mL) was stirred at 60 ° C in the dark for 1 hour. After cooling to room temperature, EtOAc (30 mL) and saturated aqueous NaCl solution (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 phases were washed with brine (30 mL), dried over anhydrous Na2SO4, 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 impure product as a solid (55 mg).The impure product was triturated from EtOH (1 mL) to give the product as a solid (19.57 mg, 21% yield). 1 H NMR (400 MHz, CDCl3) δ H =9.39 (s, 1H), 8.11 (d, 1H), 7.69 (dd, 1H), 5.96-5.85 (m, 1H), 4.32 (q, 2H), 2.90 (s, 3H), 1.60 (d, 3H), 1.45 (t, 3H). LCMS R in 2.0 min chromatogram t =1.34 min, 10-80 AB, MS ESI calculated value C 17 H 16 F6N5O2[M+H] + 436.1, experimental value 436.0.

[0740] Example 66: 3-[Difluoro(methoxy)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridinyl]-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine

[0741]

[0742] Synthesis of A103: A mixture of 3,6-dichloro-4-methyl-pyridazine (14 g, 85.89 mmol) and N2H4·H2O (4.29 g, 85.89 mmol) in ethanol (200 mL) was stirred at 70°C for 30 hours. After cooling to room temperature, the suspension was filtered. The filter cake was washed with EtOH (50 mL x 3) and dried in an oven to produce a mixture of two regioisomers (A103, A103-2) in a ratio of about 1:1 (by 1H NMR analysis) to obtain a solid product (8 g, 50.45 mmol, 58% yield).

[0743] 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 phases were washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 20% to 40% to 60%) to yield A99 (400 mg, 1.34 mmol, 10% yield) and A99-2 (600 mg, 2.01 mmol, 14% yield) as solids. A99 1 H NMR (400 MHz, CDCl3) δ H =8.08(s,1H),2.58(s,3H). A99-2 1 HNMR (400MHz, CDCl3)δ H =7.14(s,1H),2.81(s,3H).

[0744] Synthesis of A100-a: A mixture of 3-[bromo(difluoro)methyl]-6-chloro-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine (400 mg, 1.34 mmol) and 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, saturated aqueous 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 phases were washed with brine (20 mL), dried over anhydrous Na2SO4, 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 as a solid (230 mg, 0.93 mmol, 68% yield). 1 H NMR (400 MHz, CDCl 3) δ H =7.98 (d, 1H), 3.89 (s, 3H), 2.53 (s, 3H). LCMS Rt = 0.73 min in 1.5 min chromatography, 10-80 AB, MS ESI calculated value C8H8ClF2N4O [M+H] +249.0, experimental value 248.8.

[0745] Synthesis of compound 68: A mixture of 6-chloro-3-[difluoro(methoxy)methyl]-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine (70 mg, 0.28 mmol), 3-fluoro-2-(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (113.22 mg, 0.34 mmol), K 3 PO 4 (119.55 mg, 0.56 mmol) and Pd(t-Bu 3 P) 2 (21.58 mg, 0.04 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was stirred at 80° C. under N 2 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 mixture was extracted with EtOAc (20 mL x 2). The combined organic phases were washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by prep-TLC (silica gel, EtOAc) to give the product as a solid (65 mg, 154.3 μmol, 54% yield). 1 H NMR (400 MHz, CDCl3) δ H =8.18 (d, 1H), 8.06 (d, 1H), 7.67 (dd, 1H), 5.96-5.87 (m, 1H), 3.88 (s, 3H), 2.49 (s, 3H), 1.61 (d, 3H). LCMS chromatogram in 2.0 min R t = 1.31 min, 10-80 AB, MS ESI calculated value C 16 H 14 F6N5O2[M+H] + 422.1, experimental value 422.2.

[0746] Example 67: 6-[5-Fluoro-6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridinyl]-3-(methoxymethyl)-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine

[0747]

[0748] A mixture of 6-chloro-3-(methoxymethyl)-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine (80 mg, 0.38 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)pyridine (197.03 mg, 0.56 mmol), K 3 PO 4 (159.74 mg, 0.75 mmol) and Pd(t-Bu 3 P) 2 (28.84 mg, 0.06 mmol) in 1,4-dioxane (5 mL) and H 2 O (0.5 mL) was stirred at 80° C. under N 2 for 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×2). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by prep-HPLC (Waters XBridge BEH C18 (150 mm x 25 mm, 5 μm) A = H2O (0.075% NH4HCO3) and B = CH3CN; 50-60% B in 9.5 min) to give the product as a solid (21.64 mg, 0.05 mmol, 14% yield). 1 HNMR (400MHz, CDCl3)δ H =8.15 (d, 1H), 8.00 (d, 1H), 7.62 (dd, 1H), 5.04 (s, 2H), 3.48 (s, 3H), 2.45 (s, 3H), 1.90 (s, 6H). LCMS R in 2.0 min chromatography t =1.28 min, 10-80 AB, MS ESI calculated value C 17 H 18 F4N5O2[M+H] + 400.1, experimental value 400.1.

[0749] Example 68: 6-[5-Fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridinyl]-3-(methoxymethyl)-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine

[0750]

[0751] A mixture of 6-chloro-3-(methoxymethyl)-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine (70 mg, 0.33 mmol), 3-fluoro-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (132.38 mg, 0.40 mmol), K 3 PO 4 (139.78 mg, 0.66 mmol) and Pd(t-Bu 3 P) 2 (25.24 mg, 0.05 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was stirred at 80 ° C under N 2 for 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 phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 10% to 20%) to give the product as a solid (33.02 mg, 0.09 mmol, 26% yield). 1 H NMR (400 MHz, CDCl3) δ H =8.16 (d, 1H), 8.00 (d, 1H), 7.65 (dd, 1H), 5.96-5.86 (m, 1H), 5.04 (s, 2H), 3.49 (s, 3H), 2.46 (s, 3H), 1.61 (d, 3H). LCMS chromatogram in 2.0 min R t =1.24 min, 10-80 AB, MS ESI calculated value C 16 H 16 F4N5O2[M+H] + 386.1, experimental value 385.9.

[0752] Example 69: 6-[5-Fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridinyl]-3-(methoxymethyl)-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine

[0753]

[0754] Synthesis of A105: The corresponding pinacol ester was dissolved in MeCN and aqueous HCl was added. The mixture was stirred at room temperature for 2 hours and then concentrated to give A105, which was used crude.

[0755] Synthesis of compound 71: 6-chloro-3-(methoxymethyl)-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine (70 mg, 0.33 mmol), [5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl] A mixture of 1,4-dioxane (5 mL) and water (0.5 mL) was stirred at 80 ° C under N 2 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×2). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na 2 SO 4, filtered and concentrated. The crude product was purified by prep-TLC (silica gel, EtOAc) to give the product as a solid (9.8 mg, 0.03 mmol, 8% yield). 1 H NMR (400 MHz, CDCl3) δ H =8.17 (d, 1H), 8.01 (s, 1H), 7.68 (dd, 1H), 5.04 (s, 2H), 4.93 (q, 2H), 3.49 (s, 3H), 2.45 (s, 3H). LCMS chromatogram in 2.0 min R t = 1.19 min, 10-80 AB, MS ESI calculated value C 15 H 14 F4N5O2[M+H] + 372.1, experimental value 372.0.

[0756] Example 70: 6-[5-Fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridinyl]-3-(methoxymethyl)-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine

[0757]

[0758] 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 room temperature, the mixture was concentrated, and the residue was diluted with H2O (30 mL). The mixture was extracted with EtOAc (50 mL x 2). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (EtOAc) three times to give A104 (250 mg, 1.17 mmol, 9% yield) and A104-2 (500 mg, 2.35 mmol, 19% yield) as solids.1 H NMR (400 MHz, CDCl3) δ H =7.94(d,1H),5.02(s,2H),3.50(s,3H),2.51(s,3H).

[0759] Synthesis of compound 72: A mixture of 6-chloro-3-(methoxymethyl)-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine (60 mg, 0.28 mmol), 3-fluoro-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (113.47 mg, 0.34 mmol), K 3 PO 4 (119.81 mg, 0.56 mmol) and Pd(t-Bu 3 P) 2 (21.63 mg, 0.04 mmol) in 1,4-dioxane (5 mL) and H 2 O (0.5 mL) was stirred at 80° C. under N 2 for 1 hour. 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 phases were washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by prep-TLC (silica gel, EtOAc) to give the product as a solid (23.22 mg, 59.2 μmol, 21% yield). 1 H NMR (400 MHz, CDCl3) δ H =8.16 (d, 1H), 8.01 (s, 1H), 7.65 (dd, 1H), 5.96-5.85 (m, 1H), 5.04 (s, 2H), 3.49 (s, 3H), 2.45 (s, 3H), 1.61 (d, 3H). LCMS chromatogram in 2.0 min R t =1.24 min, 10-80 AB, MS ESI calculated value C 16 H 16 F4N5O2[M+H] + 386.1, experimental value 386.1.

[0760] Example 71: 3-(Difluoro(methoxy)methyl)-6-(6-(3,3-difluorocyclobutyloxy)pyridine-3-

[0761] 1,2,4]triazolo[4,3-a]pyrazine

[0762]

[0763] Synthesis of A107: To a stirred solution of 6-chloro-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyrazine (1.0 g, 4.18 mmol) and 2-(3,3-difluorocyclobutyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.43 g, 4.6 mmol) in 1,4-dioxane (27.0 mL) was added water (3.0 mL) and CsCO (2.73 g, 8.37 mmol). Pd(dppf)Cl·DCM (0.34 g, 0.42 mmol) was added to the reaction mixture under a nitrogen atmosphere and heated at 80° C. for 16 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 give the product (430 mg, 1.11 mmol, 26% yield). LCMS: 388.1 (M+H), Rt 2.4 min, column: ZORBAX XDB C-18 (50×4.6 mm), 3.5 μm, mobile phase: A: 0.1% HCOOH:ACN (95:5) in water, B: ACN; flow rate: 1.5 mL / min.

[0764] Synthesis of Compound 73: To a stirred solution of 3-(chlorodifluoromethyl)-6-(6-(3,3-difluorocyclobutyloxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine (100 mg, 0.26 mmol) in MeCN (4.5 mL) was added CsCO (515 mg, 1.58 mmol) and methanol (0.21 mL, 5.2 mmol). The reaction was stirred at room temperature for 1 h. 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 NaSO, and concentrated. The crude compound was purified by preparative HPLC to give a solid (32 mg, 0.08 mmol, 32% yield). Prep-HPLC method: Rt = 16.1; Column: XBridge C8 (150 x 19 mm), 5.0 μm; Mobile phase: 0.1% TFA / acetonitrile in water; Flow rate: 15.0 mL / min. HPLC: Rt 4.49 min, Column: XBridge C8 (50 x 4.6 mm), 3.5 μm, Mobile phase: A: 0.1% TFA in water, B: 0.1% TFA in ACN; Flow rate: 2.0 mL / min. LCMS: 384.1 (M+H), Rt 2.22 min, Column: ZORBAX XDB C-18 (50 x 4.6 mm), 3.5 μm, Mobile phase: A: 0.1% HCOOH:ACN (95:5) in water, B: ACN; Flow rate: 1.5 mL / min. 1 H NMR (400MHz, CD3OD): δ9.54(d,1H),8.86(d,1H),8.78(s,1H),8.39(dd,1H),6.9 9(d,1H),5.25-5.22(m,1H),3.99(s,3H),3.23-3.13(m,2H),2.82-2.70(m,2H).

[0765] Example 72: 3-(Cyclopropyloxydifluoromethyl)-6-(6-(2,2,2-trifluoroethoxy)pyridine-3-

[0766] 1,2,4]triazolo[4,3-a]pyrazine

[0767]

[0768] 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 dropwise to the reaction mixture and stirred for 2 hours. The reaction mixture was cooled to 10°C and treated with ice water (50 mL). The reaction mixture was extracted with ethyl acetate (2 x 60 mL). The organic layer was washed with brine (50 mL), dried over anhydrous NaSO, and concentrated. The crude compound was purified by column chromatography on silica gel with 5% ethyl acetate / PE to give the product (5.0 g, 19.5 mmol, 68% yield). LCMS: 256.0 (M+H) and 258 (M+2+H), Rt 2.59 min, column: ZORBAX XDB C-18 (50X 4.6 mm), 3.5 μm, mobile phase: A: 0.1% HCOOH:ACN in water (95:5), B: ACN; flow rate: 1.5 mL / min.

[0769] Synthesis of A110: To a stirred solution of 5-bromo-2-(2,2,2-trifluoroethoxy)pyridine (5.0 g, 19.53 mmol) and bis(pinacolato)diboron (6.45 g, 25.39 mmol) in 1,4-dioxane (50.0 mL) was added potassium acetate (3.83 g, 39.0 mmol). Pd(dppf)Cl2·DCM (1.59 g, 1.95 mmol) was added to the reaction mixture under a nitrogen atmosphere and heated at 80°C for 12 hours. The reaction mixture was cooled to room temperature, filtered through celite, and concentrated under reduced pressure. The crude compound was purified by column chromatography on silica gel with 5% ethyl acetate / PE to give the product (4.32 g, 14.3 mmol, 73% yield). LCMS: 304.1 (M+H), Rt 2.85 min, column: ZORBAX XDB C-18 (50X 4.6 mm), 3.5 μm, mobile phase: A: 0.1% HCOOH:ACN in water (95:5), B: ACN; flow rate: 1.5 mL / min.

[0770] Synthesis of A112: To a stirred solution of 6-chloro-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyrazine (1.3 g, 5.44 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (1.5 g, 4.95 mmol) in 1,4-dioxane (25.0 mL) 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 a nitrogen atmosphere and heated at 80°C for 12 hours. The reaction mixture was cooled to room temperature, filtered through celite, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel with 30% ethyl acetate / PE to give the product (500 mg, 1.3 mmol, 26% yield). LCMS: 380.0 (M+H), Rt 2.45 min, column: ZORBAX XDB C-18 (50×4.6 mm), 3.5 μm, mobile phase: A: 0.1% HCOOH:ACN (95:5) in water, B: ACN; flow rate: 1.5 mL / min.

[0771] Synthesis of Compound 74: To a stirred solution of 3-(chlorodifluoromethyl)-6-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine (100 mg, 0.26 mmol) in MeCN (10 mL) was added CsCO (514 mg, 1.58 mmol) and cyclopropanol (0.21 mL, 3.29 mmol). The reaction was stirred at room temperature for 1 hour. The reaction mixture was treated with water (15.0 mL) and extracted with ethyl acetate (2×20 mL). The organic layer was washed with brine (15 mL), dried over anhydrous NaSO, and concentrated. The crude compound was purified by preparative HPLC to give a solid (10 mg, 0.024 mmol, 9% yield). Prep-HPLC method: Rt = 14.2; Column: XBridge C8 (150 x 19 mm), 5.0 μm; Mobile phase: 0.1% TFA / acetonitrile in water; Flow rate: 15.0 mL / min. HPLC: Rt 5.01 min, Column: XBridge C8 (50 x 4.6 mm), 3.5 μm, Mobile phase: A: 0.1% TFA in water, B: 0.1% TFA in ACN; Flow rate: 2.0 mL / min. LCMS: 402.1 (M+H), Rt 2.30 min, Column: XBridge C8 (50 x 4.6 mm), 3.5 μm, Mobile phase: A: 0.1% TFA in water:ACN (95:5), B: 0.1% TFA in ACN; Flow rate: 1.5 mL / min. 1 H NMR (400MHz, CD3OD): δ9.55(d,1H),8.89(d,1H),8.75(s,1H),8.43(dd,1H), 7.09(d,1H),4.98(q,2H),4.26-4.23(m,1H),0.99(m,2H),0.85-0.81(m,2H).

[0772] Example 73: 3-(Cyclopropyloxydifluoromethyl)-6-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine

[0773]

[0774] 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 dropwise. 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 Na2SO4, and concentrated. The crude compound was purified by column chromatography on silica gel with 2% ethyl acetate / PE to give the product (10.5 g, 38.1 mmol, 73% yield). LCMS: 273.9 (M+H) and 276.0 (M+2+H), Rt 2.53 min, column: ZORBAX XDB C-18 (50X 4.6 mm), 3.5 μm, mobile phase: A: 0.1% HCOOH:ACN in water (95:5), B: ACN; flow rate: 1.5 mL / min.

[0775] Synthesis of A3-a: To a stirred solution of 5-bromo-3-fluoro-2-(2,2,2-trifluoroethoxy)pyridine (3.0 g, 10.95 mmol) and bis(pinacolato)diboron (3.61 g, 14.23 mmol) in 1,4-dioxane (30.0 mL) was added potassium acetate (2.15 g, 21.9 mmol). Pd(dppf)Cl2·DCM (0.89 g, 1.09 mmol) was added to the reaction mixture under a nitrogen atmosphere and heated at 80°C for 12 hours. The reaction mixture was cooled to room temperature, filtered through celite, and concentrated under reduced pressure. The crude compound was purified by column chromatography on silica gel with 15% ethyl acetate / PE to give the product (2.0 g, 6.2 mmol, 56% yield). LCMS: 322.1 (M+H), Rt 2.97 min, column: Atlantis dC18 (50X 4.6 mm), 5 μm, mobile phase: A: 0.1% HCOOH:ACN in water (95:5), B: ACN; flow rate: 1.5 mL / min.

[0776] Synthesis of A18-a: To a stirred solution of 6-chloro-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyrazine (2.0 g, 8.37 mmol) and 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (2.96 g, 9.2 mmol) in 1,4-dioxane (26.0 mL) was added water (4.0 mL) and K2CO3 (2.31 g, 16.74 mmol). PdCl2(PPh3)2 (0.59 g, 0.84 mmol) was added to the reaction mixture under a nitrogen atmosphere and heated at 90°C for 12 hours. The reaction mixture was cooled to room temperature, filtered through celite, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 30% ethyl acetate / PE to give the product (1.35 g, 3.4 mmol, 40% yield). LCMS: 398.0 (M+H), Rt 2.51 min, Column: Atlantis dC-18 (50 x 4.6 mm), 3.5 μm, Mobile Phase: A: 0.1% HCOOH in water: ACN (95:5), B: ACN; Flow rate: 1.5 mL / min. 1 H NMR (400MHz, DMSO-d6): δ9.77(d,1H),9.14(s,1H),8.84(d,1H),8.66(dd,1H),5.20(q,2H).

[0777] Synthesis of Compound 75: To a stirred solution of 3-(chlorodifluoromethyl)-6-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine (150.0 mg, 0.38 mmol) in MeCN (8.0 mL) was added CsCO (737 mg, 2.26 mmol) and cyclopropanol (0.48 mL, 7.54 mmol). The reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was treated with water (15.0 mL) and extracted with ethyl acetate (2×20 mL). The organic layer was washed with brine (15 mL), dried over anhydrous NaSO, and concentrated. The crude compound was purified by preparative HPLC to give a solid (15 mg, 0.035 mmol, 9% yield). Preparative HPLC method: Rt 14.8; Column: XBridge C-18 (150 x 19 mm), 5.0 μm; Mobile phase: 0.1% TFA in water / acetonitrile; Flow rate: 15.0 mL / min. HPLC: Rt 5.16 min, Column: XBridge C8 (50 x 4.6 mm), 3.5 μm, Mobile phase: A: 0.1% TFA in water, B: 0.1% TFA in ACN; Flow rate: 2.0 mL / min. LCMS: 420.0 (M+H), Rt 2.64 min, Column: Atlantis dC18 (50 x 4.6 mm), 3.5 μm, Mobile phase: A: 0.1% HCOOH in water, B: ACN; Flow rate: 1.5 mL / min. 1 H NMR (400MHz, DMSO-d6): δ9.71(d,1H),8.93(d,1H),8.78(d,1H),8.56(dd, 1H),5.19(q,2H),4.24-4.20(m,1H),0.96-0.92(m,2H),0.77-0.72(m,2H).

[0778] Example 74: 3-(Difluoro(methoxy)methyl)-6-(6-(3,3-difluorocyclobutyloxy)-5-fluoropyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine

[0779]

[0780] Synthesis of A115: To a stirred solution of 2-chloro-5-hydrazinopyrazine (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 (2×50 mL). The organic layer was washed with brine (30 mL), dried over Na2SO4, and concentrated to a solid (6 g). It was used in the next step without further purification.

[0781] Synthesis of A111: To a stirred solution of 2-chloro-N'-(5-chloropyrazin-2-yl)-2,2-difluoroacetohydrazide (6.0 mg, 23.34 mmol) in DCM (120 mL) was added trifluoromethanesulfonic anhydride (4.73 mL, 28.01 mmol) and 2-methoxypyridine (4.91 mL, 46.69 mmol) at 0°C. The reaction mixture was slowly warmed to room temperature and stirred for 2 hours. The reaction mixture was treated with 10% sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (2×50 mL). The organic layer was washed with brine (50 mL), dried over Na2SO4, and concentrated. The crude product was purified by column chromatography on silica gel with 15% EtOAc / PE to give the product as a solid (4.0 g, 16.5 mmol, 71% yield). LCMS: 239.0 (M+H), Rt 1.66 min, column: ZORBAX XDBC-18 (50X 4.6 mm), 3.5 μm, mobile phase: A: 0.1% HCOOH:ACN in water (95:5), B: ACN; flow rate: 1.5 mL / min.

[0782] 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 dropwise to the reaction mixture and stirred for 4 hours. The reaction mixture was cooled to 10°C and treated with ice water (30 mL). The reaction mixture was extracted with ethyl acetate (2 x 30 mL). The organic layer was washed with brine (50 mL), dried over anhydrous NaSO, and concentrated. The crude compound was purified by column chromatography on silica gel with 10% ethyl acetate / PE to give the product (1.0 g, 3.57 mmol, 77% yield). LCMS: 282.0 (M+H) and 284.0 (M+2+H), Rt 2.66 min, column: ZORBAX XDB C-18 (50X 4.6 mm), 3.5 μm, mobile phase: A: 0.1% HCOOH:ACN in water (95:5), B: ACN; flow rate: 1.5 mL / min.

[0783] Synthesis of A117: To a stirred solution of 5-bromo-2-(3,3-difluorocyclobutyloxy)-3-fluoropyridine (1.1 g, 3.91 mmol) and bis(pinacolato)diboron (1.29 g, 5.09 mmol) in 1,4-dioxane (20.0 mL) was added potassium acetate (0.77 g, 7.83 mmol). Pd(dppf)Cl2·DCM (0.32 g, 0.39 mmol) was added to the reaction mixture under a nitrogen atmosphere and heated at 90°C for 16 hours. The reaction mixture was cooled to room temperature, filtered through celite, and concentrated under reduced pressure. The crude compound was purified by column chromatography on silica gel with 5% ethyl acetate / PE to give the product (1.2 g, 3.6 mmol, 93% yield). LCMS: 330.1 (M+H), Rt 2.97 min, column: ZORBAX XDB C-18 (50X 4.6 mm), 3.5 μm, mobile phase: A: 0.1% HCOOH:ACN in water (95:5), B: ACN; flow rate: 1.5 mL / min.

[0784] Synthesis of A118: To a stirred solution of 6-chloro-3-(chlorodifluoromethyl)-[1,2,4]triazolo[4,3-a]pyrazine (0.91 g, 3.83 mmol) and 2-(3,3-difluorocyclobutyloxy)-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.17 g, 3.55 mmol) in 1,4-dioxane (15.0 mL) was added water (3.0 mL) and Cs2CO3 (2.31 g, 7.13 mmol). Pd(dppf)Cl2·DCM (0.29 g, 0.36 mmol) was added to the reaction mixture under a 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 give the product (1.11 g, 2.75 mmol, 77% yield). LCMS: 405.9 (M+H), Rt 2.30 min, column: ZORBAX XDB C-18 (50×4.6 mm), 3.5 μm, mobile phase: A: 0.1% HCOOH:ACN (95:5) in water, B: ACN; flow rate: 1.5 mL / min.

[0785] Synthesis of Compound 76: To a stirred solution of 3-(chlorodifluoromethyl)-6-(6-(3,3-difluorocyclobutyloxy)-5-fluoropyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine (140 mg, 0.34 mmol) in MeCN (7.5 mL) was added CsCO (668 mg, 2.06 mmol) and methanol (0.14 mL, 3.4 mmol). The reaction was stirred at room temperature for 1 h. 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 NaSO, and concentrated. The crude compound was purified by preparative HPLC to give a solid (18 mg, 0.04 mmol, 13% yield). Prep. HPLC method: Rt 12.9; Column: YMC Phenyl (150 x 19 mm), 5.0 μm; Mobile phase: 0.1% TFA / acetonitrile in water; Flow rate: 15.0 mL / min. HPLC: Rt 5.01 min, 97.3%; Column: XBridge C8 (50 x 4.6 mm), 3.5 μm; Mobile phase: A: 0.1% TFA in water, B: 0.1% TFA in ACN; Flow rate: 2.0 mL / min. LCMS: 402.0 (M+H), Rt 2.48 min; Column: Atlantis dC18 (50 x 4.6 mm), 5.0 μm; Mobile phase: A: 0.1% HCOOH:ACN (95:5) in water, B: ACN; Flow rate: 1.5 mL / min. 1 H NMR (400MHz, DMSO-d6): δ9.70(d,1H),8.97(s,1H),8.77(d,1H),8.49(dd, 1H),5.30-5.26(m,1H),3.92(s,3H),3.26-3.19(m,2H),2.89-2.84(m,2H).

[0786] Example 75: 6-(6-(3,3-difluorocyclobutyloxy)-5-fluoropyridin-3-yl)-3-(ethoxydifluoromethyl)-[1,2,4]triazolo[4,3-a]pyrazine

[0787]

[0788] To a stirred solution of 3-(chlorodifluoromethyl)-6-(6-(3,3-difluorocyclobutyloxy)-5-fluoropyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine (150 mg, 0.34 mmol)) in MeCN (7.5 mL) was added CsCO (668 mg, 2.06 mmol) and ethanol (0.2 mL, 3.4 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was treated with water (20.0 mL) and extracted with ethyl acetate (2 x 25 mL). The organic layer was washed with brine (20 mL), dried over anhydrous NaSO, and concentrated. The crude compound was purified by preparative HPLC to give a solid (22 mg, 0.05 mmol, 15% yield). Prep. HPLC method: Rt 13.1; Column: XBridge C-18 (150 x 19 mm), 5.0 μm; Mobile phase: 0.1% TFA / acetonitrile in water; Flow rate: 15.0 mL / min. HPLC: Rt 5.08 min, 94.8%; Column: XBridge C8 (50 x 4.6 mm), 3.5 μm; Mobile phase: A: 0.1% TFA in water, B: 0.1% TFA in ACN; Flow rate: 2.0 mL / min. LCMS: 416.1 (M+H), Rt 2.44 min; Column: ZORBAX XDB C-18 (50 x 4.6 mm), 3.5 μm; Mobile phase: A: 0.1% HCOOH:ACN (95:5) in water, B: ACN; Flow rate: 1.5 mL / min. 1 H NMR (400MHz, CD3OD): δ9.54(d,1H),8.83(d,1H),8.67(d,1H),8.26(dd,1H),5.3 2-5.30(m,1H),4.40(q,2H),3.25-3.15(m,2H),2.90-2.77(m,2H),1.49(t,3H).

[0789] Example 76: 3-(Cyclopropyloxydifluoromethyl)-6-(6-(3,3-difluorocyclobutyloxy)pyridine-3-

[0790] 1,2,4]triazolo[4,3-a]pyrazine

[0791]

[0792] To a stirred solution of 3-(chlorodifluoromethyl)-6-(6-(3,3-difluorocyclobutyloxy)-5-fluoropyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine (100 mg, 0.26 mmol) in MeCN (9.0 mL) was added CsCO (504 mg, 1.55 mmol) and cyclopropanol (0.33 mL, 5.16 mmol). The reaction mixture was stirred at room temperature for 4 h. 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 NaSO, and concentrated. The crude compound was purified by preparative HPLC to give a solid (14 mg, 0.034 mmol, 13% yield). Prep. HPLC method: Rt 10.67; Column: Sunfire C-18 (150 x 19 mm), 5.0 μm; Mobile phase: 0.1% TFA / acetonitrile in water; Flow rate: 15.0 mL / min. HPLC: Rt 5.19 min, Column: XBridge C8 (50 x 4.6 mm), 3.5 μm, Mobile phase: A: 0.1% TFA in water, B: 0.1% TFA in ACN; Flow rate: 2.0 mL / min. LCMS: 410.1 (M+H), Rt 2.36 min, Column: XBridge C8 (50 x 4.6 mm), 3.5 μm, Mobile phase: A: 0.1% TFA in water:ACN (95:5), B: 0.1% TFA in ACN; Flow rate: 1.5 mL / min. 1 H NMR (400MHz, CD3OD): δ9.54(d,1H),8.84(d,1H),8.71(s,1H),8.37(dd,1H),7.00(d,1 H),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),

[0793] 0.84-0.79 (m, 2H).

[0794] Example 77: 3-(Ethoxymethyl)-6-(5-fluoro-6-((1,1,1-trifluoro-2-methylprop-2-yl)oxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine

[0795]

[0796] Synthesis of A119: To a stirred solution of 1,1,1-trifluoro-2-methylpropan-2-ol (0.57 g, 4.43 mmol) in THF (20 mL) at 0°C 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 dropwise to the reaction mixture and stirred for 16 h. The reaction mixture was cooled to 10°C and treated with ice water (30 mL). The reaction mixture was extracted with ethyl acetate (2 x 50 mL). The organic layer was washed with brine (30 mL), dried over anhydrous NaSO, and concentrated. The crude compound was purified by column chromatography on silica gel with 2% ethyl acetate / PE to give the product (765 mg, 2.54 mmol, 49% yield). 1 H NMR (400MHz, CDCl3): δ7.99(d,1H),7.54(dd,1H),1.80(s,6H).

[0797] Synthesis of A8: To a stirred solution of 5-bromo-3-fluoro-2-((1,1,1-trifluoro-2-methylprop-2-yl)oxy)pyridine (765 mg, 2.54 mmol) and bis(pinacolato)diboron (0.71 g, 2.79 mmol) in 1,4-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 a nitrogen atmosphere and heated at 80°C for 16 hours. The reaction mixture was cooled to room temperature, filtered through celite, and concentrated under reduced pressure. The crude compound was purified by column chromatography on silica gel with 30% ethyl acetate / PE to give the product (300 mg, 0.86 mmol, 33% yield). LCMS: 350.1 (M+H), Rt 3.31 min, column: Atlantis dC18 (50X4.6 mm), 3.5 μm, mobile phase: A: 0.1% HCOOH:ACN in water (95:5), B: ACN; flow rate: 1.5 mL / min.

[0798] 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) at 0°C, followed by 2-ethoxyacetyl chloride (2.36 mL, 13.53 mmol). 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 (2×25 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4 and concentrated. The crude product was purified by column chromatography on silica gel with 22% EtOAc / PE to give the product (0.8 g, 3.47 mmol, 25% yield). LCMS: 231.1 (M+H), Rt 1.07 min, column: ZORBAX XDB C-18 (50X 4.6 mm), 3.5 μm, mobile phase: A: 0.1% HCOOH:ACN (95:5) in water, B: ACN; flow rate: 1.5 mL / min.

[0799] Synthesis of A41-a: To a stirred solution of N'-(5-chloropyrazin-2-yl)-2-ethoxyacetohydrazide (400 mg, 1.73 mmol) in DCM (15.0 mL) was added trifluoromethanesulfonic anhydride (0.38 mL, 2.25 mmol) and 2-methoxypyridine (377 mg, 3.46 mmol) at 0°C. The reaction mixture was slowly warmed to room temperature and stirred for 16 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 Na2SO4, and concentrated. The crude product was purified by column chromatography on silica gel with 35% EtOAc / PE to give the product (100 mg, 0.47 mmol, 27% yield). LCMS: 213.1 (M+H), Rt 1.46 min. Column: Atlantis dC18 (50×4.6 mm), 5.0 μm, mobile phase: A: 0.1% HCOOH:ACN (95:5) in water, B: ACN; flow rate: 1.5 mL / min.

[0800] Synthesis of compound 79: 6-chloro-3-(ethoxymethyl)-[1,2,4]triazolo[4,3-a]pyrazine (150 mg, 0.71 mmol) and 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-

[0801] To a stirred solution of 1,4-dioxane (10.0 mL) containing 2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)pyridine (271 mg, 0.78 mmol) and 1,4-dioxane (10.0 mL) was added water (1.0 mL) and CsCO (460 mg, 1.41 mmol). Pd(dppf)Cl·DCM (57 mg, 0.07 mmol) was added to the reaction mixture under a nitrogen atmosphere and heated at 80° C. for 16 hours. The reaction mixture was cooled to room temperature, filtered through celite, and concentrated under reduced pressure. The crude compound was purified by preparative HPLC to give a solid (105 mg, 0.26 mmol, 36% yield). Prep. HPLC method: Rt 12.75; Column: X-Select (150 × 19 mm), 5.0 μm; Mobile phase: 0.1% TFA / acetonitrile in water; Flow rate: 15.0 mL / min. HPLC: Rt 4.95 min, Column: XBridge C8 (50 x 4.6 mm, 3.5 μm, Mobile Phase: A: 0.1% TFA in water, B: 0.1% TFA in ACN; Flow rate: 2.0 mL / min. LCMS: 400.3 (M+H), Rt 2.41 min, Column: ZORBAX XDB C-18 (50 x 4.6 mm), 3.5 μm, Mobile Phase: A: 0.1% HCOOH:ACN (95:5) in water, B: ACN; Flow rate: 1.5 mL / min. 1 H NMR (400MHz, DMSO-d6): δ9.56(d,1H),9.17(d,1H),8.78(d,1H),8.45(dd,1H),5.09(s,2H),3.61(q,2H),1.83(s,6H),1.15(t,3H).

[0802] Example 79: 3-(Ethoxydifluoromethyl)-6-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine

[0803]

[0804] To a stirred solution of 3-(chlorodifluoromethyl)-6-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine (190 mg, 0.50 mmol)) in MeCN (10.0 mL) was added CsCO (978 mg, 3.0 mmol) and ethanol (0.58 mL, 10 mmol) at room temperature and stirred for 3 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 NaSO, and concentrated. The crude compound was purified by preparative HPLC to give a solid (10 mg, 0.025 mmol, 5.1% yield). Prep-HPLC method: Rt 9.35; Column: XBridge (150 x 19 mm), 5.0 μm; 0.1% TFA / acetonitrile in water; Flow rate: 15.0 mL / min. HPLC: Rt 4.89 min, Column: XBridge C8 (50 x 4.6 mm), 3.5 μm, Mobile phase: A: 0.1% TFA in water, B: 0.1% TFA in ACN; Flow rate: 2.0 mL / min. LCMS: 390.0 (M+H), Rt 2.70 min, Column: Atlantis dC-18 (50 x 4.6 mm), 5 μm, Mobile phase: A: 0.1% HCOOH:ACN (95:5) in water, B: ACN; Flow rate: 1.5 mL / min. 1 H NMR (400MHz, CDCl3): δ9.54(d,1H),8.74(d,1H),8.48(d,1H),8.26(dd,1H),7.06(d,1H),4.87(q,2H),4.38(q,2H),1.52(t,3H).

[0805] Example 80: 3-(Difluoro(isobutyloxy)methyl)-6-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine

[0806]

[0807] To a stirred solution of 2-methylpropan-1-ol (4.65 mL, 50.29 mmol) in MeCN (20 mL) was added CsCO (4.92 g, 15.09 mmol) and the reaction mixture was heated at 70°C for 20 min. The reaction mixture was cooled to room temperature and 3-(chlorodifluoromethyl)-6-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine (1.0 g, 2.51 mmol) was added. The reaction mixture was stirred at room temperature for 4 h and treated with water (30 mL). The reaction mixture was extracted with ethyl acetate (2 x 30 mL), washed with brine (20 mL), dried over NaSO, and concentrated. The crude compound was purified by preparative HPLC to give a solid (35 mg, 0.08 mmol, 3% yield). Prep-HPLC method: Rt 9.37; Column: XBridge C8 (150 x 19 mm), 5.0 μm; 0.1% TFA / acetonitrile in water; Flow rate: 15.0 mL / min. HPLC: Rt 5.60 min, Column: XBridge C8 (50 x 4.6 mm), 3.5 μm, Mobile phase: A: 0.1% TFA in water, B: 0.1% TFA in ACN; Flow rate: 2.0 mL / min. LCMS: 436.1 (M+H), Rt 2.63 min, Column: XBridge C8 (50 x 4.6 mm), 3.5 μm, Mobile phase: A: 0.1% TFA in water:ACN (95:5), B: 0.1% TFA in ACN; Flow rate: 1.5 mL / min. 1 H NMR (400MHz, DMSO-d6): δ9.72(d,1H),8.97(d,1H),8.77(d,1H),8.54(dd,1H),5.19(q,2H),4.04(d,2H),2.10-2.02(m,1H),0.98(d,6H).

[0808] Example 81: 5-[3-[Difluoro(methoxy)methyl]-[1,2,4]triazolo[4,3-a]pyrazin-6-yl]pyridin-2-ol and 6-(6-benzyloxy-5-fluoro-3-pyridinyl)-3-[ethoxy(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyrazine

[0809]

[0810] Synthesis of A92: To a solution of phenylmethanol (12 g, 110.97 mmol) in THF (100 mL) was added portionwise NaH (4.88 g, 122.06 mmol) at 0 ° C over 0.5 hours. After the addition, the mixture was stirred at 20 ° C for 1 hour. 5-bromo-2-fluoro-pyridine (18.55 g, 105.4 2 mmol) was then added to the mixture. The resulting mixture was stirred at 20 ° C for 3 hours. The mixture was poured into saturated NH4 aqueous solution (150 mL) and extracted with EtOAc (200 mL×2). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated to give an oily crude product (27 g, 95.62 mmol, 86% yield). LCMS chromatogram in 1.5 min R t = 0.96 min, 5-95 AB, MS ESI calculated value C 12 H 11 BrNO[M+H+2] + 266.0, experimental value 265.8.

[0811] 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-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (31.15 g, 122.67 mmol), KOAc (20.06 g, 204.45 mmol) and Pd(dppf)Cl2 (7.48 g, 10.22 mmol) in 1,4-dioxane (300 mL) was stirred at 90° C. under N2 for 16 hours. After cooling to room temperature, the mixture was filtered through celite and concentrated to give the crude product. The crude product was filtered through silica gel (about 50 g) and eluted with PE / EtOAc (5:1, 150 mL×5), and the filtrate was concentrated to give the impure product. The impure product was triturated from i-Pr2O (100 mL) to give the product as a solid (20 g, 64.27 mmol, 63% yield). LCMS chromatogram in 1.5 min R t = 0.74 min, 5-95 AB, MS ESI calculated value C 12 H 13 BNO3[M-C6H 10 +H] + 230.1, experimental value 230.0.

[0812] Synthesis of A94: A mixture of 2-bromo-5-chloro-pyrazine (4 g, 20.68 mmol), 2-benzyloxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (7.08 g, 22.75 mmol), Cs2CO3 (13.47 g, 41.36 mmol) and Pd(dppf)Cl2 (1.51 g, 2.07 mmol) in 1,4-dioxane (50 mL) and water (10 mL) was stirred at 50°C under N2 for 3 hours. After cooling to room temperature, the mixture was filtered and concentrated to give a residue. Water (100 mL) was added to the residue and extracted with EtOAc (150 mL x 2). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated to give the crude product. The crude product was filtered through silica gel (about 50 g) and eluted with DCM (150 mL×3). The filtrate was concentrated to give an impure product. The impure product was triturated from i-Pr 2 O (15 mL) to give a solid product (4 g, 13.44 mmol, 65% yield). LCMS chromatogram in 1.5 min R t =1.03 min, 5-95 AB, MS ESI calculated value C 16 H 13 ClN3O[M+H] + 298.1, experimental value 297.9.

[0813] Synthesis of A95: A mixture of 2-(6-benzyloxy-3-pyridyl)-5-chloro-pyrazine (4 g, 13.43 mmol) and N2H4·H2O (8.61 g) in MeCN (20 mL) was stirred at 90 ° C for 16 hours. After cooling to room temperature, the solution was concentrated to produce a residue. Water (30 mL) was added to the residue and extracted with EtOAc (50 mL×3). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated to produce a solid product (4 g, 7.84 mmol, 58% yield). LCMS chromatogram in 1.5 min R t = 0.74 min, 5-95 AB, MS ESI calculated value C 16 H 16 N5O[M+H] + 294.1, experimental value 293.9.

[0814] Synthesis of A96: To a solution of 2-bromo-2,2-difluoro-acetyl chloride (1.78 g, 9.2 mmol) in DCM (20 mL) was added [5-(6-benzyloxy-3-pyridyl)pyrazine-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 H2O (20 mL) and extracted with EtOAc (100 mL×2). The combined organic phases were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated to produce the product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 20% to 40% to 60% to 80%) to produce a solid product (1.5 g, 3.33 mmol, 54% yield). LCMS R in 1.5 min chromatography t = 0.88 min, 10-80 AB, MS ESI calculated value C 18 H 15 F2N5O2[M+H] + 450.0, experimental value 449.9.

[0815] 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 (10 mL) were added 2-methoxypyridine (0.67 mL, 6.35 mmol) and Tf2O (0.59 mL, 3.46 mmol), and the mixture was stirred at 20°C for 2 hours. Water (20 mL) was added to the mixture and extracted with DCM (50 mL x 2). The combined organic phases were washed with saturated aqueous NaHCO3 solution (30 mL) and brine (30 mL), dried over Na2SO4, filtered, and concentrated to give the crude product. The crude product was purified by flash column chromatography on silica gel (EtOAc in PE = 0% to 30% to 50%) to give the product as a solid (400 mg, 0.93 mmol, 32% yield). LCMS in 1.5min chromatogram R t = 0.93 min, 10-80 AB, MS ESI calculated value C 18 H 13 BrF2N5O[M+H+2] + 434.0, experimental value 434.0.

[0816] Synthesis of 83: A mixture of 6-(6-benzyloxy-3-pyridinyl)-3-[bromo(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyrazine (400 mg, 0.93 mmol) and AgBF4 (900.79 mg, 4.63 mmol) in methanol (4 mL) was stirred at 60 ° C in the dark for 2 hours. After cooling to room temperature, saturated aqueous NaCl solution (10 mL) was added to the mixture, followed by EtOAc (30 mL), and the mixture was filtered through celite. After separation of the phases of the filtrate, the organic phase was washed with brine (30 mL), dried over Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 20% to 40%) to give an impure product (150 mg), which was triturated from i-Pr2O (2 mL) to give the pure product (130 mg). The product was obtained as a solid (39.76 mg, 0.10 mmol, 11% yield). 1 H NMR (400 MHz, CDCl3) δ H =9.52 (d, 1H), 8.76 (d, 1H), 8.42 (d, 1H), 8.19 (dd, 1H), 7.53-7.47 (m, 2H), 7.45-7.32 (m, 3H), 6.98 (d, 1H), 5.48 (s, 2H), 3.97 (s, 3H). LCMS chromatogram in 2.0min R t =1.26 min, 10-80 AB, MS ESI calculated value C 19 H 16 F2N5O2[M+H] + 384.1, experimental value 384.1.

[0817] Example 82: 3-(Difluoro(methoxy)methyl)-6-(6-(3,3-difluorocyclobutyloxy)-5-fluoropyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyridine

[0818]

[0819] To a suspension of CsCO (928 mg, 2.85 mmol) in CHCN (2.0 mL) was added methanol (0.23 mL, 5.7 mmol) at room temperature. The reaction mixture was stirred at room temperature for 10 min, and a solution of 3-(chlorodifluoromethyl)-6-(6-(3,3-difluorocyclobutyloxy)-5-fluoropyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyridine (190 mg, 0.47 mmol) in CHCN (10.0 mL) was added dropwise. The reaction mixture was stirred at room temperature for 2 h. 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 NaSO, and concentrated. The crude product was purified by preparative HPLC to give the product as a solid (50 mg, 0.12 mmol, 26% yield). Prep. HPLC method: Rt 11.75; Column: X-Bridge (150 x 19 mm), 5.0 μm; Mobile phase: 0.1% TFA / acetonitrile in water; Flow rate: 15.0 mL / min. HPLC: Rt 4.64 min, 99.8%; Column: X-Bridge C8 (50 x 4.6 mm), 3.5 μm; Mobile phase: A: 0.1% TFA in water, B: 0.1% TFA in ACN; Flow rate: 2.0 mL / min. LCMS: 401.1 (M+H), Rt 2.22 min, 99.6%; Column: ZORBAX XDB C-18 (50 x 4.6 mm), 3.5 μm; Mobile phase: A: 0.1% HCOOH:ACN (95:5) in water, B: ACN; Flow rate: 1.5 mL / min. 1 H NMR (400MHz, CD3OD): δ8.65(s,1H),8.31(d,1H),8.00-7.97(m,2H),7.90(dd ,1H),5.32-5.28(m,1H),3.96(s,3H),3.26-3.15(m,2H),2.89-2.77(m,2H).

[0820] Example 83: 6-(6-(3,3-difluorocyclobutyloxy)-5-fluoropyridin-3-yl)-3-(ethoxydifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine

[0821]

[0822] Synthesis of A11: 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 give the product as a solid (10.7 g). It was used in the next step without further purification.

[0823] Synthesis of A127: To a stirred solution of A11 (2.0 g, 10.6 mmol) in toluene (25 mL) was added 2-chloro-2,2-difluoroacetic anhydride (2.84 g, 11.7 mmol) at 0 ° C. The reaction mixture was heated at 100 ° C for 1 hour. The reaction mixture was cooled to room temperature and concentrated. The crude reaction mixture was treated with water (50 mL) and extracted with ethyl acetate (2×50 mL). The organic layer was washed with saturated NaHCO 3 solution (20 mL) and then brine (30 mL), dried over Na 2 SO 4 and concentrated to give the product as a solid (2.7 g). It was used in the next step without further purification.

[0824] Synthesis of A128: To a stirred solution of A127 (2.7 g, 8.99 mmol) in DCM (30 mL) was added trifluoromethanesulfonic anhydride (1.66 mL, 9.88 mmol) and 2-methoxypyridine (1.96 g, 17.97 mmol) at 0°C. The reaction mixture was slowly warmed to room temperature and stirred for 1 hour. The reaction mixture was treated with 10% sodium bicarbonate solution (50 mL) and extracted with DCM (2×50 mL). The organic layer was washed with brine (50 mL), dried over Na 2 SO 4 and concentrated. The crude product was purified by column chromatography on silica gel with 20% EtOAc / PE to give 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 (50×4.6 mm), 3.5 μm, mobile phase: A: 0.1% HCOOH:ACN in water (95:5), B: ACN; flow rate: 1.5 mL / min.

[0825] Synthesis of A125: To a stirred solution of A128 (1.0 g, 3.54 mmol) and 2-(3,3-difluorocyclobutyloxy)-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.28 g, 3.89 mmol) in 1,4-dioxane (20.0 mL) was added water (4.0 mL) and K2CO3 (0.98 g, 7.08 mmol). To the reaction mixture was added Pd(PPh3)2Cl2 (0.25 g, 0.35 mmol) under a nitrogen atmosphere and heated at 80°C for 16 hours. The reaction mixture was cooled to room temperature and filtered through celite. The reaction mixture was treated with water (30 mL) and extracted with ethyl acetate (2×30 mL). The organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, and concentrated. The crude compound was purified by column chromatography on silica gel with 40% ethyl acetate / PE to give the compound as a solid (1.1 g, 2.7 mmol, 76% yield). LCMS: 405.0 (M+H), Rt 2.68 min, column: Atlantis dC-18 (50×4.6 mm), 5.0 μm, mobile phase: A: 0.1% HCOOH:ACN in water (95:5), B: ACN; flow rate: 1.5 mL / min.

[0826] Synthesis of Compound 85: To a suspension of CsCO (966 mg, 2.97 mmol) in CHCN (2.0 mL) was added ethanol (0.35 mL, 5.93 mmol) at room temperature. The reaction mixture was stirred at room temperature for 10 min, and a solution of A125 (200 mg, 0.49 mmol) in CHCN (10.0 mL) was added dropwise. The reaction mixture was stirred for 1 h, and ethanol (0.35 mL, 5.93 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for an additional 1 h. 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 NaSO, and concentrated. The crude product was purified by column chromatography on silica gel with 22% EtOAc / PE to give the product as a solid (30 mg, 0.07 mmol, 14% yield). HPLC: Rt 4.92 min, 99.9%, Column: X-Bridge C8 (50 x 4.6 mm, 3.5 μm), Mobile Phase: A: 0.1% TFA in water, B: 0.1% TFA in ACN; Flow rate: 2.0 mL / min. LCMS: 415.1 (M+H), Rt 2.53 min, 99.8%, Column: Atlantis dC-18 (50 x 4.6 mm), 5.0 μm. Mobile Phase: A: 0.1% HCOOH:ACN (95:5) in water, B: ACN; Flow rate: 1.5 mL / min. 1 H NMR (400MHz, CD3OD): δ8.65(s,1H),8.30(d,1H),8.00-7.96(m,2H),7.89(dd,1H), 5.32-5.29(m,1H),4.36(q,2H),3.26-3,16(m,2H),2.89-2.78(m,2H),1.47(t,3H).

[0827] Example 84: (R)-3-(Ethoxydifluoromethyl)-6-(6-((1,1,1-trifluoropropan-2-yl)oxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine

[0828]

[0829] Synthesis of A77: To a solution of A132 (2.2 g, 19.63 mmol) in THF (20.0 mL) was added LiAlH4 (2.0 M in THF, 4.91 mL, 9.82 mmol) dropwise at 0°C. The reaction mixture was slowly warmed to room temperature and stirred for 3 hours. The reaction mixture was cooled to 0°C and treated with saturated Na2SO4 solution (2.0 mL). The reaction mixture was filtered through celite, and the filtrate was dried over Na2SO4 and used in the next step as a solution in THF.

[0830] Synthesis of A78: To a solution of A77 (30.68 mmol) in THF was added NaH (1.84 g, 46 mmol) portionwise at 0°C and stirred for 30 min. 5-Bromo-2-fluoro-pyridine (4.32 g, 24.55 mmol) was slowly added to the reaction mixture at 0°C. The reaction mixture was slowly warmed to room temperature and stirred for 3 hours. The reaction mixture was cooled to 10°C, treated with ice water (10 mL) and extracted with ethyl acetate (2×50 mL). The organic layer was washed with brine (40 mL), dried over Na2SO4 and concentrated. The crude product was purified by column chromatography on silica gel with 20% EtOAc / PE to give the product as a colorless liquid (3.1 g, 11.5 mmol, 37% yield). LCMS: 270.0 (M+H) and 272.0 (M+2+H), Rt 2.78 min, column: ZORBAXX DB C-18 (50X 4.6 mm), 3.5 μm, mobile phase: A: 0.1% HCOOH:ACN in water (95:5), B: ACN; flow rate: 1.5 mL / min.

[0831] Synthesis of A79: To a stirred solution of A78 (3.1 g, 11.5 mmol) and bis(pinacolato)diboron (3.79 g, 14.92 mmol) in 1,4-dioxane (35.0 mL) was added potassium acetate (2.25 g, 22.96 mmol). Pd(dppf)Cl2·DCM (1.41 g, 1.72 mmol) was added to the reaction mixture under a nitrogen atmosphere and heated at 90°C for 12 hours. The reaction mixture was cooled to room temperature, filtered through celite, and concentrated under reduced pressure. The crude compound was purified by column chromatography on silica gel with 6% ethyl acetate / PE to give the product as a solid (2.8 g, 8.83 mmol, 76% yield). LCMS: 318.0 (M+H), Rt 4.04 min, column: ZORBAX Extend (50X 4.6 mm), 5 μm, mobile phase: A: 10 mM ammonium acetate in water, B: ACN; flow rate: 1.2 mL / min.

[0832] Synthesis of A82: To a stirred solution of A79 (0.5 g, 1.58 mmol) and 6-chloro-3-(chlorodifluoromethyl)-[1,2,4]triazolo[4,3-a]pyrazine (0.45 g, 1.89 mmol) in 1,4-dioxane (12.0 mL) was added water (2.0 mL) and CsCO (1.03 g, 3.15 mmol). Pd(dppf)Cl·DCM (0.11 g, 0.16 mmol) was added to the reaction mixture under a nitrogen atmosphere and heated at 90° C. for 16 hours. The reaction mixture was cooled to room temperature, filtered through celite, and concentrated under reduced pressure. The crude...

Claims

1. A compound having formula I: or a pharmaceutically acceptable salt thereof, wherein X and Y are each independently CR d or N; R 1 yes Monocyclic C 3-6 Cycloalkyl, or 4 to 7 membered monocyclic heterocyclic group, wherein the cycloalkyl and heterocyclic group are optionally substituted by one or more R a replace; R 2 It is C 1-4 Haloalkyl, phenyl, or monocyclic C 3-6 Cycloalkyl, which is optionally substituted by one or more R b replace; R 3 It is hydrogen, C 1-4 Alkyl or C 1-4 Haloalkyl; R 4 is hydrogen or C 1-4 alkyl; R 5 It is a halogen; R 6 It is C 1-4 Alkyl or C 1-4 haloalkyl, wherein the C 1-4 Alkyl or C 1-4 The haloalkyl groups are each c replace; t is 0, 1, or 2; R a and R b are each independently selected from halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Haloalkoxy, R c Is optional 3-6 Cycloalkyl or C 1-4 Alkoxy substituted C 1-4 Alkyl, or C 3-6 cycloalkyl; and R d is hydrogen or C 1-4 alkyl; Provided that the compound is not a compound having the formula: or a pharmaceutically acceptable salt thereof.

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

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

7. A compound having formula Id: or a pharmaceutically acceptable salt thereof, wherein R 1 yes Monocyclic C 3-6 Cycloalkyl, or 4 to 7 membered monocyclic heterocyclic group, wherein the cycloalkyl and heterocyclic group are optionally substituted by one or more R a replace; R 2 It is C 1-4 Haloalkyl, phenyl, or monocyclic C 3-6 Cycloalkyl, which is optionally substituted by one or more R b replace; R 3 It is hydrogen, C 1-4 Alkyl or C 1-4 Haloalkyl; R 4 is hydrogen or C 1-4 alkyl; R 5 It is a halogen; R 6 It is C 1-4 Alkyl or C 1-4 haloalkyl, wherein the C 1-4 Alkyl or C 1-4 The haloalkyl groups are each c replace; t is 0, 1, or 2; R a and R b are each independently selected from halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Haloalkoxy; R c Is optional 3-6 Cycloalkyl or C 1-4 Alkoxy substituted C 1-4 Alkyl, or C 3-6 cycloalkyl; and R d is hydrogen or C 1-4 alkyl.

8. The compound of any one of claims 1 to 5 and 7, wherein the compound has formula 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 has 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 to 5, wherein the compound has 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 to 5, wherein the compound has formula VIII: or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 1.

12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R 1 yes 13. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R 1 is optionally passed through one or more R a Substituted cyclobutyl.

14. The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R 2 It is C 1-4 Halogenated alkyl.

15. The compound according to any one of claims 1 to 12 and 14, or a pharmaceutically acceptable salt thereof, wherein R 2 It's CF3.

16. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R 2 It is phenyl.

17. The compound of any one of claims 1 to 12 and 14 to 16, or a pharmaceutically acceptable salt thereof, wherein R 3 It is C 1-4 Alkyl and R 4 is hydrogen or C 1-4 alkyl.

18. A compound according to any one of claims 1 to 12 and 14 to 17, or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 Each is C 1-4 alkyl.

19. A compound according to any one of claims 1 to 12 and 14 to 18, or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 Each is a methyl group.

20. The compound of any one of claims 1 to 12 and 14 to 17, or a pharmaceutically acceptable salt thereof, wherein R 3 is methyl and R 4 It's hydrogen.

21. A compound according to any one of claims 1 to 12 and 14 to 16, or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 Each is hydrogen.

22. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein R 6 Yes-CF2-OR c .

23. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein R c is C optionally substituted by cyclopropyl 1-4 alkyl.

24. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein R c It is cyclopropyl.

25. The compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein R 6 It is -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 to 21, or a pharmaceutically acceptable salt thereof, wherein R 6 Yes -CH2-OR c .

27. The compound of any one of claims 1 to 21 and 26, or a pharmaceutically acceptable salt thereof, wherein R c It is C 1-4 alkyl.

28. The compound of any one of claims 1 to 21, 26 and 27, or a pharmaceutically acceptable salt thereof, wherein R 6 It is -CH2OCH3, -CH2OCH2CH3 or -CH2OCH2CH(CH3)2.

29. A compound according to any one of claims 1 to 11, 13 and 22 to 28, or a pharmaceutically acceptable salt thereof, wherein R a It is C 1-4 Halogenated alkyl.

30. A compound according to any one of claims 1 to 11, 13 and 22 to 29, or a pharmaceutically acceptable salt thereof, wherein R a It's CF3.

31. A compound according to any one of claims 1 to 11, 13 and 22 to 28, or a pharmaceutically acceptable salt thereof, wherein R a It's fluorine.

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

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

34. A compound according to any one of claims 1 to 7 and 12 to 33, or a pharmaceutically acceptable salt thereof, wherein R d It's methyl.

35. A compound according to any one of claims 1 to 7 and 12 to 33, or a pharmaceutically acceptable salt thereof, wherein R d It's hydrogen.

36. The compound of claim 1, wherein the compound is selected from: or a pharmaceutically acceptable salt thereof.

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

38. A crystalline compound of the formula, wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 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 (2θ): 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 (2θ): 6.9±0.2, 11.2±0.2, 13.9±0.2, 16.5±0.2, 17.4±0.2, 18.1±0.2, 19.1±0.2, 19.5±0.2 and 20.8±0.

2.

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

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

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

44. A crystalline compound of the formula, wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 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 (2θ): 7.2±0.2, 14.4±0.2, 16.7±0.2, 19.0±0.2, 20.4±0.2, and 25.7±0.

2.

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 (2θ): 7.2±0.2, 14.4±0.2, 16.7±0.2, 17.9±0.2, 19.0±0.2, 20.4±0.2, 20.8±0.2, 23.2±0.2, 25.7±0.2 and 28.0±0.

2.

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

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

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

50. A crystalline compound of the formula, wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 7.3±0.2, 14.5±0.2 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 (2θ): 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 (2θ): 7.3±0.2, 13.7±0.2, 14.5±0.2, 17.9±0.2, 19.0±0.2, 20.3±0.2, 21.9±0.2, 24.7±0.2, and 25.4±0.

2.

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

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

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

56. A crystalline compound of the formula, wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 12.6±0.2, 15.8±0.2 and 18.6±0.

2.

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 (2θ): 10.7±0.2, 12.3±0.2, 12.6±0.2, 15.8±0.2, 18.6±0.2, and 22.6±0.

2.

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 (2θ): 10.7±0.2, 12.3±0.2, 12.6±0.2, 14.9±0.2, 15.8±0.2, 16.6±0.2, 16.8±0.2, 18.6±0.2, 21.0±0.2, and 22.6±0.

2.

59. The crystalline compound of any one of claims 56 to 58, wherein the crystalline compound exhibits an X-ray powder diffraction pattern substantially the same as that shown in Figure 5A.

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

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

62. A crystalline compound of the formula, wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 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 (2θ): 5.8±0.2, 14.5±0.2, 15.3±0.2, 19.7±0.2, 21.0±0.2, and 24.2±0.

2.

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 (2θ): 5.8±0.2, 11.6±0.2, 12.0±0.2, 14.5±0.2, 15.3±0.2, 19.1±0.2, 19.7±0.2, 21.0±0.2, 22.4±0.2 and 24.2±0.

2.

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

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

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

68. A crystalline compound of the formula wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 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 (2θ): 7.3±0.2, 13.8±0.2, 16.6±0.2, 18.4±0.2, 20.3±0.2, and 24.3±0.

2.

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 (2θ): 7.3±0.2, 10.8±0.2, 13.8±0.2, 16.6±0.2, 17.8±0.2, 18.4±0.2, 19.5±0.2, 20.3±0.2, 21.2±0.2 and 24.3±0.

2.

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

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

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

74. A crystalline compound of the formula, wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 6.9±0.2, 16.4±0.2 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 (2θ): 6.9±0.2, 16.4±0.2, 17.4±0.2, 18.0±0.2, 19.5±0.2, and 20.8±0.

2.

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 (2θ): 6.9±0.2, 11.2±0.2, 13.6±0.2, 13.9±0.2, 16.4±0.2, 17.4±0.2, 18.0±0.2, 19.5±0.2 and 20.8±0.

2.

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

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

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

80. A crystalline compound of the formula, wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 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 (2θ): 9.9±0.2, 12.3±0.2, 14.1±0.2, 19.8±0.2, 20.7±0.2, and 23.7±0.

2.

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 (2θ): 7.3±0.2, 9.9±0.2, 12.3±0.2, 14.1±0.2, 16.5±0.2, 17.2±0.2, 19.8±0.2, 20.7±0.2, 23.7±0.2, 24.8±0.2, 27.7±0.2, and 29.1±0.

2.

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

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

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

86. A crystalline compound of the formula, wherein the crystalline compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 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 (2θ): 9.3±0.2, 16.1±0.2, 18.8±0.2, 21.1±0.2, 21.4±0.2, and 21.6±0.

2.

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 (2θ): 9.3±0.2, 16.1±0.2, 18.8±0.2, 21.1±0.2, 21.4±0.2, 21.6±0.2, 22.6±0.2, 23.9±0.2, 26.0±0.2, and 26.4±0.

2.

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

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

91. The crystalline compound of any one of claims 86 to 90, wherein the crystalline compound has a differential scanning calorimetry curve substantially the same as that shown in Figure IB.

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

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

94. A composition comprising a compound according to any one of claims 1 to 92 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

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

96. A method for treating a condition associated with abnormal function of a sodium ion channel in a subject, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 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 disorder is epilepsy or an epileptic syndrome.

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

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

101. The method of any one of claims 96 to 100, wherein the disorder 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 Regal syndrome.

103. The method of claim 101 or 102, wherein the disorder is selected from: 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, refractory childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutations, cryptogenic partial epilepsy in children with SCN3A mutations, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussen encephalitis, malignant migratory partial seizures in infancy, autosomal dominant nocturnal frontal lobe epilepsy, sudden unexpected 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 a compound of any one of claims 1 to 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 pain, wherein the method comprises administering to a subject in need thereof a compound of any one of claims 1 to 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 claims 1 to 92 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 93 or 95, or a composition of claim 94 for use in treating a condition associated with abnormal function of a sodium ion channel in a subject.

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

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

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

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

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

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

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

114. The composition or pharmaceutical composition of claim 112 or 113, wherein the disorder is selected from: 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, refractory childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutations, cryptogenic partial epilepsy in children with SCN3A mutations, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussen encephalitis, malignant migratory partial epilepsy in infancy, autosomal dominant nocturnal frontal lobe epilepsy, sudden unexpected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy.

115. A composition comprising a compound of any one of claims 1 to 92 or a pharmaceutically acceptable salt thereof, the pharmaceutical composition of claim 93 or 95, or the composition of claim 94 for use in treating a neurological disorder or a psychiatric disorder.

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