Ion channel modulator

Abstract

To provide an ion channel modulator. [Solution] The present invention relates in part to condensed heteroaryl compounds and compositions useful for preventing and / or treating diseases or conditions associated with abnormal function of voltage-opening sodium ion channels, such as abnormal delayed / sustained sodium currents. Methods for treating diseases or conditions associated with abnormal function of sodium ion channels, including neurological disorders (e.g., Dravet syndrome, epilepsy), pain, and neuromuscular disorders, are also provided herein.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority and interest to U.S. Provisional Patent Application No. 62 / 677,903, filed on 30 May 2018, and U.S. Provisional Patent Application No. 62 / 738,508, filed on 28 September 2018, each of which is incorporated herein by reference in whole. [Background technology]

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

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

[0004] This specification describes condensed heteroaryl compounds and compositions useful for preventing and / or treating a disease, disorder, or condition, such as an abnormal function of a sodium ion channel, such as a disease, disorder, or condition associated with an abnormal late sodium current (INaL). In one aspect, the disclosure features a compound of formula (I). In one aspect, the invention provides a compound having formula I,

Chemical formula

Chemical formula

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

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

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

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

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

[0010] In another aspect, the present disclosure relates to a compound having formula Id, [ka] or provide a pharmaceutically acceptable salt thereof, in the formula, R 1 teeth, [ka] The cycloalkyl group is a monocyclic C3-6 cycloalkyl group, or a 4-7 member monocyclic heterocycline, wherein the cycloalkyl group and heterocycline group may optionally contain one or more R groups. a Replaced by, R 2 This is a C1-4 haloalkyl, phenyl, or one or more R components of any choice. b It is a monocyclic C3-6 cycloalkyl substituted with, R 3 is hydrogen, C1-4 alkyl, or C1-4 haloalkyl, R 4 is hydrogen or C1-4 alkyl, R 5 It is a halo, R 6 is a C1-4 alkyl or C1-4 haloalkyl, and the C1-4 alkyl or C1-4 haloalkyl is, respectively, OR c Replaced by, t is 0, 1, or 2. R a and R b Each of these is independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy. R c This can be optionally C3-6 cycloalkyl or C 1-4These are C1-4 alkyl or C3-6 cycloalkyl groups substituted with alkoxy. R d It is hydrogen or a C1-4 alkyl group.

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

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

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

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

[0015] In another embodiment, the crystalline compound provided herein is of the following formula: [ka] The crystalline compound exhibits an X-ray powder diffraction pattern that includes peaks at the following diffraction angles (2θ): 6.9±0.2, 16.5±0.2, and 20.8±0.2.

[0016] In another embodiment, the crystalline compound provided herein is of the following formula: [ka] The crystalline compound exhibits an X-ray powder diffraction pattern that includes peaks at the following diffraction angles (2θ): 16.7±0.2, 19.0±0.2, and 20.4±0.2.

[0017] In another aspect, the present invention provides a crystalline compound of the following formula: [ka] The crystalline compound exhibits an X-ray powder diffraction pattern that includes peaks at the following diffraction angles (2θ): 7.3±0.2, 14.5±0.2, and 21.9±0.2.

[0018] In another aspect, the present disclosure provides a crystalline compound of the following formula: [ka] The crystalline compound exhibits an X-ray powder diffraction pattern that includes peaks at the following diffraction angles (2θ): 12.6±0.2, 15.8±0.2, and 18.6±0.2.

[0019] In another aspect, the present invention provides a crystalline compound of the following formula: [ka] The crystalline compound exhibits an X-ray powder diffraction pattern that includes peaks at the following diffraction angles (2θ): 5.8±0.2, 19.7±0.2, and 21.0±0.2.

[0020] In another aspect, the present invention provides a crystalline compound of the following formula: [ka] The crystalline compound exhibits an X-ray powder diffraction pattern that includes peaks at the following diffraction angles (2θ): 7.3±0.2, 16.6±0.2, and 18.4±0.2.

[0021] In another aspect, the present invention provides a crystalline compound of the following formula: [ka] The crystalline compound exhibits an X-ray powder diffraction pattern that includes peaks at the following diffraction angles (2θ): 6.9±0.2, 16.4±0.2, and 19.5±0.2.

[0022] In another aspect, the present invention provides a crystalline compound of the following formula: [ka] The crystalline compound exhibits an X-ray powder diffraction pattern that includes peaks at the following diffraction angles (2θ): 9.9±0.2, 19.8±0.2, and 23.7±0.2.

[0023] In another aspect, the present disclosure provides a crystalline compound of the following formula: [ka] The crystalline compound exhibits an X-ray powder diffraction pattern that includes peaks at the following diffraction angles (2θ): 9.3±0.2, 18.8±0.2, and 21.4±0.2.

[0024] In another embodiment, provided herein are pharmaceutical compositions comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0025] In another aspect of this disclosure, a composition is provided comprising a compound disclosed herein (e.g., a compound of formula I, I', Ia, Ib, Ic, Id, II, III, V, VII, VIII, or IX) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0026] Also provided herein are pharmaceutical compositions for pharmaceutical use 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.

[0027] In another embodiment, the foregoing provides a method for treating a condition related to abnormal function of sodium ion channels in a subject, comprising administering a therapeutically effective amount of one of the compounds disclosed herein (e.g., compounds of formulas I, I', Ia, Ib, Ic, Id, II, III, V, VII, VIII, or IX), or a pharmaceutically acceptable salt thereof, or one of the compositions or pharmaceutical compositions disclosed herein, to the subject.

[0028] In some embodiments, the condition is a neurological or 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 childhood epilepsy or a childhood epileptic 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.

[0029] In some embodiments, the condition is selected from the group consisting of epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, and 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-infant seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutation, childhood partial epilepsy of unknown cause with SCN3A mutation, 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.

[0030] In another aspect, what is provided herein is a method for treating neurological or psychiatric disorders. The method involves administering 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, to a subject requiring it.

[0031] In another embodiment, the present invention provides a method for treating pain, the method comprising administering 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, to a subject in need thereof.

[0032] This disclosure also provides compounds disclosed herein (e.g., compounds of formulas I, I', Ia, Ib, Ic, Id, II, III, V, VII, VIII, or IX), or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable compositions disclosed herein, or compositions disclosed herein for treating conditions associated with abnormal function of sodium ion channels in a subject.

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

[0034] In some embodiments, the condition is selected from the group consisting of epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, and 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-infant seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutation, childhood partial epilepsy of unknown cause with SCN3A mutation, 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.

[0035] In another aspect, the Disclosure provides a compound disclosed herein (e.g., a compound of formula I, I', Ia, Ib, Ic, Id, II, III, V, VII, VIII, or IX), or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable composition disclosed herein, or a composition disclosed herein for the treatment of a neurological or psychiatric disorder.

[0036] Other purposes and advantages will become apparent to those skilled in the art from consideration of the modes, examples, and claims for carrying out the invention. [Brief explanation of the drawing]

[0037] [Figure 1] (Figure 1A) XRPD patterns of compound 10 raw materials are shown. (Figure 1B) DSCs of compound 10 are shown. [Figure 2] (Figure 2A) XRPD pattern of compound 62 starting material. (Figure 2B) DSC of compound 62. [Figure 3] (Figure 3A) XRPD pattern of compound 6B starting material. (Figure 3B) DSC of compound 6B. [Figure 4] (Figure 4A) XRPD pattern of compound 56 starting material. (Figure 4B) DSC of compound 56. [Figure 5] (Figure 5A) XRPD pattern of compound 3 raw material. (Figure 5B) DSC of compound 3. [Figure 6] (Figure 6A) XRPD pattern of compound 11 raw material. (Figure 6B) DSC of compound 11. [Figure 7] (Figure 7A) XRPD pattern of compound 53 starting material. (Figure 7B) DSC of compound 53. [Figure 8] (Figure 8A) shows the XRPD pattern of compound 59. (Figure 8B) shows the DSC of compound 59. [Figure 9] (Figure 9A) XRPD patterns of compound 48 are shown. (Figure 9B) DSCs of compound 48 are shown. [Modes for carrying out the invention]

[0038] Where described herein, the present invention provides compounds and compositions useful for preventing and / or treating diseases, disorders, or conditions described herein, such as diseases, disorders, or conditions related to abnormal function of sodium ion channels, such as abnormal delayed sodium current (INaL). Exemplary diseases, disorders, or conditions include neurological disorders (e.g., epilepsy or epileptic syndromes, neurodevelopmental disorders or neuromuscular disorders), psychiatric disorders, pain, or gastrointestinal disorders.

[0039] definition chemical definition Definitions of specific functional groups and chemical terms are described in detail below. Chemical elements are from Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75. th Identified according to the ed. return, specific functional groups are generally defined as described herein. In addition, general principles of organic chemistry, as well as specific functional groups and reactivity, are as follows: Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5 th Edition, John Wiley & Sons, Inc., New York, 2001, Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989, and Carruthers, Some Modern Methods. of Organic Synthesis, 3 rd This is described in Edition, Cambridge University Press, Cambridge, 1987.

[0040] The compounds described herein may contain one or more chiral centers and therefore may exist in various isomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may exist in the form of individual enantiomers, diastereomers or geometric isomers, or in the form of a racemic mixture and a mixture of stereoisomers including one or more stereoisomer-rich mixtures. The isomers may be isolated from the mixture by methods known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts, or preferred isomers may be prepared by asymmetric synthesis. For example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New Y ork, 1981), Wilen et al., Tetrahedron 33:2725(1977), Eliel, Stereochemistry of Carbon See Compounds (McGraw-Hill, NY, 1962) and Wilen, Tables of Resolving Agents and Optical Resolutions, p. 268 (ELEliel, 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 alternatively as mixtures of various isomers.

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

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

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

[0044] The following terms are intended to have the meanings presented below and are useful for understanding the description and intended scope of the invention. When describing the invention, which may include compounds and pharmaceutically acceptable salts thereof, pharmaceutical compositions containing such compounds, and methods of using such compounds and compositions, the following terms, where present, have the meanings below unless otherwise indicated. It should also be understood that, when described herein, any of the parts defined below may be substituted with various substituents, and that each definition is intended to include the substituted parts within those scopes set forth below. Unless otherwise specified, the term “substituted” is defined as set forth below. It should also be understood that the terms “group” and “radical” may be considered interchangeable when used herein. The articles “a” and “an” may be used to refer to one or more (i.e., at least one) of the grammatical objects of the articles. For example, “analog” is This refers to one analogue or two or more analogues.

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

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

[0047] As used herein, “alkenyl” refers to a radical of a linear or branched hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds), and optionally one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds) ("C2-20 ("Alkenyl"). In certain embodiments, the alkenyl does not contain any triple bonds. In some embodiments, the alkenyl group has 2 to 10 carbon atoms ("C"). 2-10 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 9 carbon atoms ("C"). 2-9 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 8 carbon atoms ("C"). 2-8 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 7 carbon atoms ("C"). 2-7 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 6 carbon atoms ("C"). 2-6 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 5 carbon atoms ("C"). 2-5 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 4 carbon atoms ("C"). 2-4 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 3 carbon atoms ("C"). 2-3 "Alkenyl"). In some embodiments, the alkenyl group has two carbon atoms ("C2 alkenyl"). One or more carbon-carbon double bonds may be internal (e.g., 2-butenyl) or terminal (e.g., 1-butenyl). C 2-4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), and butadienyl (C4). 2-6 An example of an alkenyl group is the aforementioned C 2-4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), and others. Additional examples of alkenyls include heptenyl (C7), octenyl (C8), octatrienyl (C8), and others.

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

[0049] As used herein, “alkylene,” “alkenylene,” and “alkynylene” refer to the 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” group, it is understood that the range or number refers to the range or number of carbon atoms in a linear divalent carbon chain. The “alkylene,” “alkenylene,” and “alkynylene” groups may be substituted with one or more substituents as described herein, or they may be unsubstituted.

[0050] As used herein, “aryl” refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14π electrons shared in a cyclic arrangement) having 6 to 14 ring carbon atoms and 0 heteroatoms provided to the aromatic ring system ("C"). 6-14 In some embodiments, the aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl group has ten ring carbon atoms ("C6 aryl"). 10 "Aryl"; for example, naphthyl (such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms ("C"). 14"Aryl" (e.g., anthracyl). "Aryl" also includes ring systems, where the aryl ring defined above is condensed with one or more carbocyryl or heterocyclyl groups, and the radical or bond site is on the aryl ring, in such examples 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 acetantrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluorantene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indan, indene, naphthalene, octacene, octafen, octalen, ovalen, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. In particular, the aryl group includes phenyl, naphthyl, indenyl, and tetrahydronaphthyl.

[0051] As used herein, “heteroaryl” refers to a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 electrons shared in a cyclic arrangement) having a ring carbon atom and 1-4 ring heteroatoms provided to the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In a heteroaryl group containing one or more nitrogen atoms, the bond site can be a carbon or nitrogen atom, as long as the valence allows. A heteroaryl bicyclic ring system may contain one or more heteroatoms in one or both rings. "Hyperaryl" includes a ring system in which the heteroaryl ring defined above is fused with one or more carbocyclyl or heterocyclyl groups, and the bond site is on the heteroaryl ring, in which case the number of ring members continues to specify the number of ring members in the heteroaryl ring system. "Hyperaryl" also includes a ring system in which the heteroaryl ring defined above is fused with one or more aryl groups, and the bond site is on either the aryl or heteroaryl ring, in which case the number of ring members specifies the number of ring members in the fused (aryl / heteroaryl) ring system. In a bicyclic heteroaryl group in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl), the bond site can be on either ring, i.e., the ring containing a heteroatom (e.g., 2-indolyl) or the ring not containing a heteroatom (e.g., 5-indolyl).

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

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

[0054] Examples of representative heteroaryls include the following,

Chemical formula

[0055] As used herein, "carbocyrill" or "carbocyclic" refers to a non-aromatic ring system with 3 to 10 ring carbon atoms ("C"). 3-10 This refers to a radical of a non-aromatic cyclic hydrocarbon group having 0 heteroatoms ("carbocyrill"). In some embodiments, the carbocyrill group has 3 to 8 ring carbon atoms ("C"). 3-8 Carbocyclyl). In some embodiments, the carbocyclyl group has 3 to 7 ring carbon atoms ("C"). 3-7 Carbocyclyl). In some embodiments, the carbocyclyl group has 3 to 6 ring carbon atoms ("C"). 3-6 Carbocyclyl). In some embodiments, the carbocyclyl group has 5 to 10 ring carbon atoms ("C"). 5-10 Carbocyclyl). Exemplary C 3-6 The carbocyclyl group includes, without limitation, cyclopropyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C 3-8 The carbocyclyl group is without limitation, as mentioned above. 3-6 Carbocyclyl groups, similarly including cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), etc. Exemplary C 3-10 The carbocyclyl group is without limitation, as mentioned above. 3-8 Carbocyclyl group, similarly cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9) 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C9) 10 ), spiro[4.5]decanil(C 10) and so on. When the above examples illustrate, in certain embodiments the carbocyclyl group may be monocyclic ("monocyclic carbocyclyl") or may include condensed, bridging, or spirocyclic systems such as bicyclic systems ("bicyclic carbocyclyl"), and may be saturated or partially unsaturated. "Carbocyclyl" also includes cyclic systems, where the carbocyclyl ring as defined above is condensed with one or more aryl or heteroaryl groups, and the bonding site is on the carbocyclyl ring, in such examples the number of carbons continues to specify the number of carbons in the carbocyclic system.

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

[0057] As used herein, “C3-6 monocyclic cycloalkyl” or “monocyclic C3-6 cycloalkyl” refers to a saturated 3- to 7-membered monocyclic hydrocarbon ring system. 3- to 7-membered monocyclic cycloalkyls include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Where optionally substituted or designated as substituted, substituents on the cycloalkyl (e.g., in the case of optionally substituted cycloalkyls) may be located at any substituted position, including, for example, the position to which the cycloalkyl group is attached.

[0058] As used herein, “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 10-membered non-aromatic ring system having a ring carbon atom and 1- to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3- to 10-membered heterocyclyl”). In heterocyclyl groups containing one or more nitrogen atoms, the bond sites can be carbon or nitrogen atoms, as long as the valence allows. Heterocyclyl groups can be monocyclic (“monocyclic heterocyclyl”) or bicyclic (“bicyclic heterocyclyl”) systems, or condensed, bridging, or spirocyclic systems, and can be saturated or partially unsaturated. A heterocyclyl bicyclic ring system may contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes a ring system, where the heterocyclyl ring defined above is fused with one or more carbocykyl groups, with the bond point located on either the carbocykyl or heterocyclyl ring or ring system, or where the heterocyclyl ring defined above is fused with one or more aryl or heteroaryl groups, with the bond point located on the heterocyclyl ring, in which case the number of ring members continues to specify the number of ring members in the heterocyclyl ring system. The terms "heterocyclyl," "heterocyclyl," "heterocyclyl ring," "heterocyclic group," "heterocyclic part," and "heterocyclic radical" may be used interchangeably.

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

[0060] Exemplary three-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxylanyl, and thiorenyl. Exemplary four-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl. Exemplary five-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary five-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidine-2-one. Exemplary five-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary six-membered heterocyclyl groups containing one heteroatom include, The following are examples of heterocyclyl groups fused to a C6 aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring): exemplified six-membered heterocyclyl groups containing two heteroatoms include, without limitation, piperadinyl, morpholinyl, dithianyl, and dioxanyl. exemplified six-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinyl. exemplified seven-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl, and thiepanyl. exemplified eight-membered heterocyclyl groups containing one heteroatom include, without limitation, azokanyl, oxekanyl, and thiokanyl. exemplified five-membered heterocyclyl groups fused to a C6 aryl ring (also referred herein as a 5,6-bicyclic heterocyclic ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Examples of six-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, but are not limited to, tetrahydroquinolinyl and tetrahydroisoquinolinyl.

[0061] Examples of saturated or partially unsaturated heterocyclic radicals include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, terahydropyranyl, pyrrolidinyl, pyridinonyl, pyrrolidonyl, piperidinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, morpholinyl, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, oxetanyl, azetidinyl, and tetrahydropyrimidinyl. Where optionally substituted or designated as substituted, substituents on the heterocyclyl (e.g., in the case of optionally substituted heterocyclyls) may be located at any substituted position, including, for example, the position to which the heterocyclyl group is attached.

[0062] When "hetero" is used to describe a compound or a group present in a compound, it means that one or more carbon atoms in the compound or group are replaced by heteroatoms of nitrogen, oxygen, or sulfur. Hetero can be applied to any of the above hydrocarbyl groups, such as alkyl, e.g., heteroalkyl; carbocykryl, e.g., heterocyclyl; and aryl, e.g., heteroaryl, which have 1 to 5, and especially 1 to 3, heteroatoms.

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

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

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

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

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

[0068] As used herein, "nitro" refers to -NO2.

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

[0070] In general, the term “substitution,” whether preceded by the term “optionally,” means that at least one hydrogen atom present on a group (e.g., a carbon or nitrogen atom) is replaced by an acceptable substituent, such as a substituent that, upon substitution, produces a stable compound, such as one that does not spontaneously undergo transformation by rearrangement, cyclization, elimination, or other reactions. Unless otherwise indicated, a “substituted” group has substituents at one or more substituted positions on the group, and when two or more positions of any given structure are substituted, the substituents are either the same or different at each position.

[0071] Nitrogen atoms can be substituted or unsubstituted as long as their valence allows, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents are hydrogen, -OH, and -OR. aa , -N(R cc )2, -CN, -C(=O)R aa -C(=O)N(R cc )2, -CO2R aa , -SO2R aa -C(=NR bb )R aa -C(=NR cc )OR aa -C(=NR cc )N(Rcc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc -SOR aa -C(=S)N(R cc )2, -C(=O)SR cc -C(=S)SR cc -P(=O)2R aa -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenil, C 2-10 Alkinyl, C 3-10 Carbocyclyl, 3-14 member heterocyclyl, C 6-14 This includes, but is not limited to, aryls and 5-14 member heteroaryls, or two Rs bonded to a nitrogen atom. cc The groups bond to form a 3-14 membered heterocyclyl or 5-14 heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyryl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R groups. dd Substituted with R aa , R bb , R cc、 and R dd This is defined above.

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

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

[0074] As used herein, “pharmaceutically acceptable salts” refers to salts that, within reasonable medical judgment, are suitable for use in contact with human and lower animal tissues without excessive toxicity, irritation, allergic reactions, etc., and that balance with a reasonable benefit / risk ratio. pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts include salts These are salts of an amino group formed by using an inorganic acid such as an acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or by using an organic acid such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipine, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, and 2-hydroxyethanesulfonate. This includes 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, etc. Pharmaceutically acceptable salts derived from appropriate bases include alkali metals, alkaline earth metals, ammonium, and N + (C 1-4 This includes alkyl) tetrasalts. Typical alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfons, and aryl sulfons, where appropriate.

[0075] As used herein, the “subject” to which 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 adults)) and / or non-human animals, including mammals such as primates (e.g., cynomolgus macaques, rhesus macaques), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the subject is human. In certain embodiments, the subject is a non-human animal. The terms “human,” “patient,” and “subject” are used interchangeably herein.

[0076] Diseases, disorders, and conditions are used interchangeably in this specification.

[0077] As used herein, unless otherwise specified, the terms “to treat,” “to treat,” and “treatment” mean an action that occurs while the subject is suffering from a specified disease, disorder, or condition and is intended to reduce the severity of the disease, disorder, or condition, or to delay or slow the progression of the disease, disorder, or condition ("therapeutic treatment"), and also an action that occurs before the subject begins to suffer from a specified disease, disorder, or condition ("preventive treatment").

[0078] As used herein, “effective dose” of a compound refers to an amount sufficient to induce a desired biological response. As will be understood by those skilled in the art, the effective dose of a compound in the present invention may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mechanism of administration, and the age, health, and condition of the subject. The effective dose encompasses both therapeutic and prophylactic treatments.

[0079] As used herein, and unless otherwise specified, the “therapeutic dose” of a compound is the amount sufficient to provide 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. The therapeutic dose of a compound means the amount of the drug alone or in combination with other therapies that provide therapeutic benefit in the treatment of a disease, disorder, or condition. The term “therapeutic dose” refers to the overall therapeutic dose. It may include amounts that improve the law, reduce or avoid the symptoms or etiology of a disease or condition, or enhance the therapeutic effect of another drug.

[0080] compound In one embodiment, the present invention relates to a compound having formula I, [ka] or provide a pharmaceutically acceptable salt thereof, in the formula, X and Y are independent of each other, CR d or N, R 1 teeth, [ka] The cycloalkyl group is a monocyclic C3-6 cycloalkyl group, or a 4-7 member monocyclic heterocycline, wherein the cycloalkyl group and heterocycline group may optionally contain one or more R groups. a Replaced by, R 2 This is a C1-4 haloalkyl, phenyl, or one or more R components of any choice. b It is a monocyclic C3-6 cycloalkyl substituted with, R 3 is hydrogen, C1-4 alkyl, or C1-4 haloalkyl, R 4 is hydrogen or C1-4 alkyl, R 5 It is a halo, R 6 is a C1-4 alkyl or C1-4 haloalkyl, and the C1-4 alkyl or C1-4 haloalkyl is, respectively, ORc Replaced by, t is 0, 1, or 2. R a and R b Each of these is independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy. R c This can be optionally C3-6 cycloalkyl or C 1-4 These are C1-4 alkyl or C3-6 cycloalkyl groups substituted with alkoxy. R d is hydrogen or C1-4 alkyl, However, the compound has the formula: [ka] Not a compound having [the specified compound], or a pharmaceutically acceptable salt thereof.

[0081] In one embodiment, the present invention relates to a compound having formula I', [ka] , or provide a pharmaceutically acceptable salt thereof, in the formula, X and Y are independent of each other, CR d or N, R 1 teeth, [ka] The cycloalkyl group is a monocyclic C3-6 cycloalkyl group, or a 4-7 member monocyclic heterocycline, wherein the cycloalkyl group and heterocycline group may optionally contain one or more R groups. a Replaced by, R 2 This is a C1-4 haloalkyl, phenyl, or one or more R components of any choice. b It is a monocyclic C3-6 cycloalkyl substituted with, R 3 is hydrogen, C1-4 alkyl, or C1-4 haloalkyl, R 4is hydrogen or C1-4 alkyl, R 5 It is a halo, R 6 is a C1-4 alkyl or C1-4 haloalkyl, and the C1-4 alkyl or C1-4 haloalkyl is, respectively, OR c Replaced by, t is 0, 1, or 2. R a and R b Each of these is independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy. R c This can be optionally C3-6 cycloalkyl or C 1-4 These are C1-4 alkyl or C3-6 cycloalkyl groups substituted with alkoxy. R d is hydrogen or C1-4 alkyl, or a pharmaceutically acceptable salt thereof.

[0082] In some embodiments, the compound is of formula Ia: [ka] or a pharmaceutically acceptable salt thereof, where the variables are as defined herein.

[0083] In some embodiments, the compound is of formula Ib: [ka] or a pharmaceutically acceptable salt thereof, where the variables are as defined herein.

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

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

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

[0087] In another aspect, the present disclosure relates to a compound having formula Id: [ka] or provide a pharmaceutically acceptable salt thereof, in the formula, R 1 teeth, [ka] The cycloalkyl group is a monocyclic C3-6 cycloalkyl group, or a 4-7 member monocyclic heterocycline, wherein the cycloalkyl group and heterocycline group may optionally contain one or more R groups. a Replaced by, R 2 This is a C1-4 haloalkyl, phenyl, or one or more R components of any choice. b It is a monocyclic C3-6 cycloalkyl substituted with, R 3 is hydrogen, C1-4 alkyl, or C1-4 haloalkyl, R 4 is hydrogen or C1-4 alkyl, R 5 It is a halo, R 6 is a C1-4 alkyl or C1-4 haloalkyl, and the C1-4 alkyl Or C1-4 haloalkyls are, respectively, OR c Replaced by, t is 0, 1, or 2. R a and R b Each of these is independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy. R c This can be optionally C3-6 cycloalkyl or C 1-4 These are C1-4 alkyl or C3-6 cycloalkyl groups substituted with alkoxy. R d It is either hydrogen or a C1-4 alkyl group.

[0088] In some embodiments, the compound is of formula V: [ka] or a pharmaceutically acceptable salt thereof, where the variables are as defined herein.

[0089] In some embodiments, the compound is of formula VII: [ka] or a pharmaceutically acceptable salt thereof, where the variables are as defined herein.

[0090] In some embodiments, the compound is of formula VIII: [ka] or a pharmaceutically acceptable salt thereof, where the variables are as defined herein.

[0091] In some embodiments, the compound is of formula VIII: [ka] or a pharmaceutically acceptable salt thereof, where the variables are defined herein. It is.

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

[0093] In some embodiments, R 1 This is an optional selection of one or more R a It is cyclobutyl substituted with [a specific compound].

[0094] In some embodiments, R 2 is a C1-4 haloalkyl. In some embodiments, R 2 is CF3. In some embodiments, R 2 It is phenyl.

[0095] In some embodiments, R 3 It is a C1-4 alkyl group, and R 4 R is hydrogen or a C1-4 alkyl group. In some embodiments, R 3 and R 4 Each of these is a C1-4 alkyl group. In some embodiments, R 3 and R 4 Each of these is methyl. In some embodiments, R 3 is methyl, and R 4 is hydrogen. In some embodiments, R 3 and R 4 Each of these is hydrogen.

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

[0097] In some embodiments, R c is a C1-4 alkyl group optionally substituted with cyclopropyl. In some embodiments, R cIt is cyclopropyl.

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

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

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

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

[0102] In some embodiments, R a is a C1-4 haloalkyl. In some embodiments, R a is CF3. In some embodiments, R a It is fluoro.

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

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

[0105] In some embodiments, the compound is [ka] [ka] [ka] [ka] [ka] [ka] A selection from the group consisting of, or a pharmaceutically acceptable salt thereof.

[0106] In some embodiments, the compound is [ka] A selection from the group consisting of, or a pharmaceutically acceptable salt thereof.

[0107] In another aspect, the present invention provides a crystalline compound of the following formula: [ka] The crystalline compound exhibits an X-ray powder diffraction pattern that includes peaks at the following diffraction angles (2θ): 6.9±0.2, 16.5±0.2, and 20.8±0.2.

[0108] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern that includes peaks at the following diffraction angles (2θ): 6.9±0.2, 13.9±0.2, 16.5±0.2, 19.5±0.2, and 20.8±0.2.

[0109] In some embodiments, the crystalline compound includes peaks at the following diffraction angles (2θ): 6.9±0.2, 11.2±0.2, 13.9±0.2, 16.5±0.2, 17.4±0.2, 18.1±0.2, 19.1±0.2, 19.5±0.2, and 20.8±0.2. It exhibits an X-ray powder diffraction pattern.

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

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

[0112] In some embodiments, the crystalline compound has substantially the same differential scanning calorimetry curve as shown in Figure 2B.

[0113] In another embodiment, the crystalline compound provided herein is of the following formula: [ka] The crystalline compound exhibits an X-ray powder diffraction pattern containing peaks at the following diffraction angles (2θ): 16.7±0.2, 19.0±0.2, and 20.4±0.2.

[0114] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern that includes peaks at the following diffraction angles (2θ): 7.2±0.2, 14.4±0.2, 16.7±0.2, 19.0±0.2, 20.4±0.2, and 25.7±0.2.

[0115] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern that includes peaks at the following diffraction angles (2θ): 7.2±0.2, 14.4±0.2, 16.7±0.2, 17.9±0.2, 19.0±0.2, 20.4±0.2, 20.8±0.2, 23.2±0.2, 25.7±0.2, and 28.0±0.2.

[0116] In some embodiments, the crystalline compound exhibits substantially the same X-ray powder diffraction pattern as shown in Figure 3A.

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

[0118] In some embodiments, the crystalline compound has substantially the same differential scanning calorimetry curve as shown in Figure 3B.

[0119] In another aspect, the present invention provides a crystalline compound of the following formula: [ka] The crystalline compound exhibits an X-ray powder diffraction pattern that includes peaks at the following diffraction angles (2θ): 7.3±0.2, 14.5±0.2, and 21.9±0.2.

[0120] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern that includes peaks at the following diffraction angles (2θ): 7.3±0.2, 14.5±0.2, 17.9±0.2, 19.0±0.2, and 21.9±0.2.

[0121] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern that includes peaks at the following diffraction angles (2θ): 7.3±0.2, 13.7±0.2, 14.5±0.2, 17.9±0.2, 19.0±0.2, 20.3±0.2, 21.9±0.2, 24.7±0.2, and 25.4±0.2.

[0122] In some embodiments, the crystalline compound exhibits substantially the same X-ray powder diffraction pattern as shown in Figure 4A.

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

[0124] In some embodiments, the crystalline compound has substantially the same differential scanning calorimetry curve as shown in Figure 4B.

[0125] In another embodiment, the crystalline compound provided herein is of the following formula: [ka] The crystalline compound exhibits an X-ray powder diffraction pattern that includes peaks at the following diffraction angles (2θ): 12.6±0.2, 15.8±0.2, and 18.6±0.2.

[0126] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern that includes peaks at the following diffraction angles (2θ): 10.7±0.2, 12.3±0.2, 12.6±0.2, 15.8±0.2, 18.6±0.2, and 22.6±0.2.

[0127] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern that includes peaks at the following diffraction angles (2θ): 10.7±0.2, 12.3±0.2, 12.6±0.2, 14.9±0.2, 15.8±0.2, 16.6±0.2, 16.8±0.2, 18.6±0.2, 21.0±0.2, and 22.6±0.2.

[0128] In some embodiments, the crystalline compound exhibits substantially the same X-ray powder diffraction pattern as shown in Figure 5A.

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

[0130] In some embodiments, the crystalline compound has substantially the same differential scanning calorimetry curve as shown in Figure 5B.

[0131] In another embodiment, the crystalline compound provided herein is of the following formula: [ka] The crystalline compound exhibits an X-ray powder diffraction pattern that includes peaks at the following diffraction angles (2θ): 5.8±0.2, 19.7±0.2, and 21.0±0.2.

[0132] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern that includes peaks at the following diffraction angles (2θ): 5.8±0.2, 14.5±0.2, 15.3±0.2, 19.7±0.2, 21.0±0.2, and 24.2±0.2.

[0133] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern that includes peaks at the following diffraction angles (2θ): 5.8±0.2, 11.6±0.2, 12.0±0.2, 14.5±0.2, 15.3±0.2, 19.1±0.2, 19.7±0.2, 21.0±0.2, 22.4±0.2, and 24.2±0.2.

[0134] In some embodiments, the crystalline compound exhibits substantially the same X-ray powder diffraction pattern as shown in Figure 6A.

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

[0136] In some embodiments, the crystalline compound has substantially the same differential scanning calorimetry curve as shown in Figure 6B.

[0137] In another aspect, the present invention provides a crystalline compound of the following formula: [ka] The crystalline compound exhibits an X-ray powder diffraction pattern that includes peaks at the following diffraction angles (2θ): 7.3±0.2, 16.6±0.2, and 18.4±0.2.

[0138] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern that includes peaks at the following diffraction angles (2θ): 7.3±0.2, 13.8±0.2, 16.6±0.2, 18.4±0.2, 20.3±0.2, and 24.3±0.2.

[0139] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern that includes peaks at the following diffraction angles (2θ): 7.3±0.2, 10.8±0.2, 13.8±0.2, 16.6±0.2, 17.8±0.2, 18.4±0.2, 19.5±0.2, 20.3±0.2, 21.2±0.2, and 24.3±0.2.

[0140] In some embodiments, the crystalline compound exhibits substantially the same X-ray powder diffraction pattern as shown in Figure 7A.

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

[0142] In some embodiments, the crystalline compound has substantially the same differential scanning calorimetry curve as shown in Figure 7B.

[0143] In another aspect, the present invention provides a crystalline compound of the following formula: [ka] The crystalline compound exhibits an X-ray powder diffraction pattern that includes peaks at the following diffraction angles (2θ): 6.9±0.2, 16.4±0.2, and 19.5±0.2.

[0144] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern that includes peaks at the following diffraction angles (2θ): 6.9±0.2, 16.4±0.2, 17.4±0.2, 18.0±0.2, 19.5±0.2, and 20.8±0.2.

[0145] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern that includes peaks at the following diffraction angles (2θ): 6.9±0.2, 11.2±0.2, 13.6±0.2, 13.9±0.2, 16.4±0.2, 17.4±0.2, 18.0±0.2, 19.5±0.2, and 20.8±0.2.

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

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

[0148] In some embodiments, the crystalline compound has substantially the same differential scanning calorimetry curve as shown in Figure 8B.

[0149] In another aspect, the present disclosure provides a crystalline compound of the following formula: [ka] The crystalline compound exhibits an X-ray powder diffraction pattern that includes peaks at the following diffraction angles (2θ): 9.9±0.2, 19.8±0.2, and 23.7±0.2.

[0150] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern that includes peaks at the following diffraction angles (2θ): 9.9±0.2, 12.3±0.2, 14.1±0.2, 19.8±0.2, 20.7±0.2, and 23.7±0.2.

[0151] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern that includes peaks at the following diffraction angles (2θ): 7.3±0.2, 9.9±0.2, 12.3±0.2, 14.1±0.2, 16.5±0.2, 17.2±0.2, 19.8±0.2, 20.7±0.2, 23.7±0.2, 24.8±0.2, 27.7±0.2, and 29.1±0.2.

[0152] In some embodiments, the crystalline compound exhibits substantially the same X-ray powder diffraction pattern as shown in Figure 9A.

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

[0154] In some embodiments, the crystalline compound has substantially the same differential scanning calorimetry curve as shown in Figure 9B.

[0155] In another embodiment, the crystalline compound provided herein is of the following formula: [ka] The crystalline compound exhibits an X-ray powder diffraction pattern that includes peaks at the following diffraction angles (2θ): 9.3±0.2, 18.8±0.2, and 21.4±0.2.

[0156] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern that includes peaks at the following diffraction angles (2θ): 9.3±0.2, 16.1±0.2, 18.8±0.2, 21.1±0.2, 21.4±0.2, and 21.6±0.2.

[0157] In some embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern that includes peaks at the following diffraction angles (2θ): 9.3±0.2, 16.1±0.2, 18.8±0.2, 21.1±0.2, 21.4±0.2, 21.6±0.2, 22.6±0.2, 23.9±0.2, 26.0±0.2, and 26.4±0.2.

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

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

[0160] In some embodiments, the crystalline compound has substantially the same differential scanning calorimetry curve as shown in Figure 1B.

[0161] In some embodiments, X-ray powder diffraction patterns were obtained using Cu Kα radiation.

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

[0163] The pharmaceutical composition may be administered in single or multiple doses by any of the acceptable mechanisms of administration of similarly useful drugs described in the patents and patent applications incorporated by reference, for example, by rectal, buccal, intranasal and subcutaneous routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, as an inhalant, or via an impregnated or coated device such as a stent or arterial insertion cylindrical polymer.

[0164] One mechanism for administration is parenteral administration, particularly by injection. Forms into which the novel compositions of the present invention may be incorporated for administration by injection include aqueous or oily suspensions, or emulsions having 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 physiological saline can also be used for injection as before, but are less preferred in the context of the present invention. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, etc. (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be used. Adequate fluidity can be maintained, for example, by the use of coatings such as lecithin, by maintaining the particle size required in the case of dispersion, and by the use of surfactants. Prevention of microbial action can be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc.

[0165] Sterile injectable solutions can be prepared by incorporating the compound according to the present invention in the required amount into a suitable solvent having various other components as described above, and then sterilizing by filtration as necessary. Generally, dispersions are prepared by incorporating various sterilized active ingredients into a sterile vehicle containing a basic dispersion medium and other required components from those described 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 yield a powder of the active ingredient plus any additional desired components from its pre-sterilized filtered solution.

[0166] Oral administration is another route for administering compounds according to the present invention. Administration may be via capsules or enteric-coated tablets, etc. When preparing a pharmaceutical composition comprising at least one compound described herein, the active ingredient is usually diluted with an excipient and / or encapsulated in such a carrier, which may be in the form of a capsule, pouch, paper, or other container. When the excipient serves as a diluent, it may be a solid, semi-solid, or liquid material (as described above) that acts as a vehicle, carrier, or culture medium for the active ingredient. Thus, the composition may be in the form of tablets, pills, powders, licks, pouches, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solid or in liquid culture medium), for example, ointments, soft and hard gelatin capsules, sterile injection solutions, and sterile packaging powders containing up to 10% by weight of the active compound.

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

[0168] The compositions of the present invention can be formulated to provide rapid, sustained, or delayed release of the active ingredient after administration to a patient by using procedures known in the art. Controlled-release drug delivery systems for oral administration include an osmotic pump system and a dissolution system comprising a polymer-coated reservoir or drug-polymer matrix formulation. Examples of controlled-release systems are described in U.S. Patents 3,845,770, 4,326,525, 4,902,514, and 5,616,345. Another formulation for use in the method of the present invention utilizes a transdermal delivery device ("patch"). Such transdermal patches can be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The configuration and use of transdermal patches for drug delivery are well known in the art. See, for example, U.S. Patents 5,023,252, 4,992,445, and 5,001,139. Such patches can be constructed for continuous, pulsatile, or on-demand delivery of pharmaceuticals.

[0169] The composition is preferably formulated in unit dosage forms. The term “unit dosage form” refers to a physically distinct unit suitable as a unit dose for human subjects and other mammals, each unit containing a predetermined amount of active material calculated to produce the desired therapeutic effect in relation to a suitable pharmaceutically effective excipient (e.g., tablet, capsule, ampoule). The compound is generally administered in a pharmaceutically effective dose. Preferably, for oral administration, each dose unit contains 1 mg to 2 g of the compound described herein, and for parenteral administration, preferably 0.1 to 700 mg of the compound described herein. However, it will be understood that the actual amount of compound administered is usually determined by a physician in consideration of relevant circumstances, including the condition being treated, the chosen route of administration, the actual compound administered and its relative activity, the individual patient’s age, weight, and response, and the severity of the patient’s symptoms.

[0170] For example, to prepare a solid composition such as a tablet, the main active ingredient is mixed with a pharmaceutical excipient to form a solid preliminary formulation composition containing a homogeneous mixture of the compounds of the present invention. When these preliminary formulation compositions are referred to as homogeneous, it means that the active ingredient is uniformly dispersed throughout the composition, and therefore the composition can be easily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules.

[0171] The tablets or pills of the present invention may be formulated to provide a dosage form that offers the benefit of long-term action, or to be coated or otherwise formulated to protect from the acidic conditions of the stomach. For example, the tablets or pills may comprise an inner dosage component and an outer dosage component, the latter in the form of a coating covering the former. The two components may be separated by an enteric coating that helps withstand disintegration in the stomach and allows the inner component to enter the duodenum intact or be released with delayed release. Various materials may be used for such enteric coatings or coatings, and such materials include many polymer acids, as well as mixtures of polymer acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0172] Compositions for inhalation or inhalation include solutions and suspensions in pharmaceutically acceptable aqueous solvents or organic solvents, or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. Preferably, compositions are administered orally or via nasal respiration for topical or systemic effects. Compositions in preferably pharmaceutically acceptable solvents may be sprayed using an inert gas. The liquid may be inhaled directly from a spray device, or the spray device may be attached to a facial mask tent or an intermittent positive airway pressure (PAP) respiration machine. The solution, suspension, or powder composition may be administered orally or nasally from a device that delivers the formulation in an appropriate manner.

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

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

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

[0176] Epilepsy and epileptic syndromes The compounds described herein are useful in the treatment of epilepsy and epileptic syndromes. Epilepsy is a CNS disorder in which the activity of nerve cells in the brain is disrupted, causing seizures or periods of abnormal behavior, sensation, and sometimes loss of consciousness. Seizure symptoms can vary widely, from simple, expressionless staring for a few seconds to repetitive, single contractions of one's own arms or legs during a seizure.

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

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

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

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

[0181] In some embodiments, epilepsy or epileptic syndrome is hereditary epilepsy or hereditary epileptic syndrome. In some embodiments, epilepsy or epileptic syndrome is 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-infant seizures, SCN2A mutation This includes epileptic encephalopathy, focal epilepsy with SCN3A mutation, partial epilepsy of unknown etiology in children with SCN3A mutation, 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, or KCNT1 epileptic encephalopathy.

[0182] In some embodiments, the methods described herein involve administering a compound described herein (e.g., a compound of formula I, I', Ia, Ib, Ic, Id, II, III, V, VII, VIII, or IX) before treating epilepsy or epileptic syndrome (e.g., epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutation, generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures) This further includes identifying subjects having epilepsy, infantile spasms, benign familial neonatal-infant seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutation, partial epilepsy of unknown etiology in children with SCN3A mutation, 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, or KCNT1 epileptic encephalopathy.

[0183] In one embodiment, the present invention relates to epilepsy or epileptic syndromes (e.g., epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infant 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-infant seizures, SCN2A epileptic encephalopathy, SCN3A sudden epilepticus). The present invention features a method for treating focal epilepsy with mutations, unexplained childhood partial epilepsy with SCN3A mutation, 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, or KCNT1 epileptic encephalopathy, and provides a compound of formula (I) to patients in need of such treatment. [ka] This includes administering either a pharmaceutically acceptable salt thereof, where the variables are as defined herein.

[0184] The compounds of the present invention (for example, compounds of formulas I, I', Ia, Ib, Ic, Id, II, III, V, VII, VIII, or IX) may also be used to treat epileptic encephalopathy, targeting ALDH7A1, ALG13, ARHGEF9, ARX, ASAH1, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLN8, CNTNAP2, CPA6, CSTB, DEPDC5, DNM1, EEF1A2, EPM2A, EPM2B, GABRA1, GABRB3, GABRG2, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, HCN1, IER3IP1, KCNA2, KCNB1, KCNC1 It has mutations in one or more of the following: KCNMA1, KCNQ2, KCNQ3, KCNT1, KCTD7, LGI1, MEF2C, NHLRC1, PCDH19, PLCB1, PNKP, PNPO, PRICKLE1, PRICKLE2, PRRT2, RELN, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SCN9A, SIAT9, SIK1, SLC13A5, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SNIP1, SPTAN1, SRPX2, ST3GAL3, STRADA, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, and WWOX.

[0185] In some embodiments, the methods described herein involve administering ALDH7A1, ALG13, ARHGEF9, ARX, ASAH1, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLN8, CNTNAP2, CPA6, CSTB, DEPDC5, DNM1, EEF1A2, EPM2A, EPM2B, GABRA1, GABRB3, GABRG2, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, HCN1, IER3IP1, KCNA2, KCNB1, KCNC1, KCNM This further includes identifying subjects having mutations in one or more of the following: A1, KCNQ2, KCNQ3, KCNT1, KCTD7, LGI1, MEF2C, NHLRC1, PCDH19, PLCB1, PNKP, PNPO, PRICKLE1, PRICKLE2, PRRT2, RELN, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SCN9A, SIAT9, SIK1, SLC13A5, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SNIP1, SPTAN1, SRPX2, ST3GAL3, STRADA, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, and WWOX.

[0186] Neurodevelopmental disorders The compounds described herein may be useful in the treatment of neurodevelopmental disorders. In some embodiments, neurodevelopmental disorders include autism, autism with epilepsy, tuberous sclerosis, fragile X syndrome, Rett syndrome, Angelman syndrome, Dup15q syndrome, 22q13.3 deletion syndrome, Prader-Willi syndrome, palatine-cardiafacial syndrome, Smith-Lemli-Opitz syndrome, or neurodevelopmental disorders with epilepsy. In some embodiments, the methods described herein involve the compounds described herein (e.g., formulas I, I', Ia) This further includes identifying subjects with neurodevelopmental disorders (e.g., autism, autism with epilepsy, tuberous sclerosis, fragile X syndrome, Rett syndrome, Angelman syndrome, Dup15q syndrome, 22q13.3 deletion syndrome, Prader-Willi syndrome, palatocardiofacial syndrome, Smith-Lemli-Opitz syndrome, or neurodevelopmental disorders with epilepsy) before administering compounds Ib, Ic, Id, II, III, V, VII, VIII, or IX.

[0187] In one embodiment, the present invention features a method for treating neurodevelopmental disorders (e.g., autism, autism with epilepsy, tuberous sclerosis, fragile X syndrome, Rett syndrome, Angelman syndrome, Dup15q syndrome, 22q13.3 deletion syndrome, Prader-Willi syndrome, palatocardiofacial syndrome, Smith-Lemli-Opitz syndrome, or neurodevelopmental disorders with epilepsy), wherein the compound (I) is applied to a subject in need of the treatment. [ka] This includes administering either a pharmaceutically acceptable salt thereof, where the variables are as defined herein.

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

[0189] In one embodiment, the present invention features a method for treating pain (e.g., neuropathic pain, trigeminal neuralgia, migraine, hemiplegic migraine, familial hemiplegic migraine, familial hemiplegic migraine type 3, cluster headache, trigeminal neuralgia, cerebellar ataxia, or related headache disorders), wherein the compound (I) is used in a subject requiring the treatment. [ka] This includes administering either a pharmaceutically acceptable salt thereof, where the variables are as defined herein.

[0190] Neuromuscular disorders The compounds described herein may be useful in the treatment of neuromuscular disorders. In some embodiments, neuromuscular disorders include amyotrophic lateral sclerosis, multiple sclerosis, myotonia, congenital paramyotonia, potassium-exacerbated myotonia, periodic paralysis, hyperkalemic periodic paralysis, hypokalemic periodic paralysis, or laryngospasm associated with SCN4A mutations. In some embodiments The methods described herein further include identifying subjects having neuromuscular disorders (e.g., amyotrophic lateral sclerosis, multiple sclerosis, myotonia, congenital paramyotonia, potassium-exacerbated myotonia, periodic paralysis, hyperkalemic periodic paralysis, hypokalemic periodic paralysis, or laryngospasm with SCN4A mutation) before administering any of the compounds described herein (e.g., compounds of formula I, I', Ia, Ib, Ic, Id, II, III, V, VII, VIII, or IX).

[0191] In one embodiment, the present invention features a method for treating neuromuscular disorders (e.g., amyotrophic lateral sclerosis, multiple sclerosis, myotonia, congenital paramyotonia, potassium-exacerbated myotonia, periodic paralysis, hyperkalemic periodic paralysis, hypokalemic periodic paralysis, or laryngospasm associated with SCN4A mutation), wherein the compound (I) is used in a subject requiring the treatment. [ka] This includes administering either a pharmaceutically acceptable salt thereof, where the variables are as defined herein.

[0192] Other disabilities In some embodiments, the compounds of the present invention (e.g., compounds of formulas I, I', Ia, Ib, Ic, Id, II, III, V, VII, VIII, or IX) may have suitable pharmacokinetic properties so that they may be active with respect to the central and / or peripheral nervous system. In some embodiments, the compounds provided herein are used to treat cardiovascular diseases such as atrial and ventricular arrhythmias including atrial fibrillation, Prinzmetal (variant) angina, stable angina, unstable angina, ischemia and reperfusion injury in the heart, kidneys, liver, and brain, exercise-induced angina, pulmonary hypertension, congestive heart disease including diastolic and systolic heart failure, recurrent ischemia, cerebral ischemia, stroke, renal ischemia, ischemia associated with organ transplantation, acute coronary syndrome, peripheral artery disease, intermittent claudication, and myocardial infarction. In some embodiments, the compounds provided herein may be used in the treatment of diseases affecting the neuromuscular system that cause itching, spasms, or paralysis, or in the treatment of diabetes or reduced insulin sensitivity, and diabetes-related disease conditions such as diabetic neuropathy. In some embodiments, the disclosed method involves administering a pharmaceutical composition.

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

[0194] Combination therapy The compounds or compositions described herein (for example, for use in modulating sodium ion channels, e.g., delayed sodium (INaL) currents) may be administered in combination with other drugs or therapies. Subjects receiving the compounds disclosed herein may have diseases, disorders, conditions, or symptoms thereof that would benefit from treatment with other drugs or therapies. These diseases or conditions may be associated with epilepsy or epileptic syndromes, neurodevelopmental disorders, pain, or neuromuscular disorders.

[0195] Antiepileptic drugs Antiepileptic drugs include brivalacetam, carbamazepine, clobazam, clonazepam, and di This product contains azepam, divalproex, eslicarbazepine, ethosuximide, ezogavine, ferbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, lorazepam, oxcarbazepine, permpanel, phenobarbital, phenytoin, pregabalin, primidone, rufinamide, tigabin, topiramate, valproic acid, vigabatrin, zonisamide, and cannabidiol.

[0196] Cardiovascular drug combination therapy Cardiovascular diseases or conditions that may benefit from combination therapy with other therapeutic agents of the sodium channel blocker of the present invention include, but are not limited to, angina including stable angina, unstable angina (UA), exercise-induced angina, variant angina, arrhythmias, intermittent claudication, myocardial infarction including non-STE myocardial infarction (NSTEMI), pulmonary hypertension including pulmonary arterial hypertension, congestive (or chronic) heart failure and diastolic heart failure and heart failure with preserved ventricular capacity (diastolic dysfunction), heart failure such as acute heart failure, or recurrent ischemia.

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

[0198] The co-administration of the sodium channel blocker of this invention with a suitable therapeutic agent for treating cardiovascular conditions allows for the enhancement of the standard treatment the patient is currently receiving.

[0199] Antiangin medication Antianginal drugs include beta-blockers, calcium channel blockers, and nitrates. Beta-blockers reduce the heart's oxygen needs by reducing its workload, resulting in a decreased heart rate and less vigorous cardiac contractions. Examples of beta-blockers include acebutolol (Sectral), atenolol (Tenormin), betaxolol (Kerlone), bisoprolol / hydrochlorothiazide (Ziac), bisoprolol (Zebeta), carteolol (Cartrol), esmolol (Brevibloc), labetalol (Normodyne, Trendate), metoprolol (Lopressor, Toprol XL), nadolol (Corgard), propranolol (Inderal), sotalol (Betapace), and timolol (Blocadren).

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

[0201] Calcium channel blockers prevent the normal flow of calcium to heart and blood vessel cells, causing vasodilation and thereby increasing the supply of blood and oxygen to the heart. Examples of calcium channel blockers include amlodipine (Norvasc, Lotrel), bepridil (Vascor), diltiazem (Cardizem, Tiazac), felodipine (Plendil), nifedipine (Adalat, Procardia), nimodipine (Nimotop), nisoldipine (Sular), verapamil (Calan, Isoptin, Verelan), and nicardipine.

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

[0203] Angiotensin-converting enzyme (ACE) inhibitors reduce the workload on the heart by dilating blood vessels and decreasing resistance to blood flow. Examples of ACE inhibitors include benazepril (Lotensin), captopril (Capoten), enalapril (Vasotec), fosinopril (Monopril), lisinopril (Prinivil, Zestril), moexipril (Univasc), perindopril (Aceon), quinapril (Accupril), ramipril (Altace), and trandolapril (Mavik).

[0204] Vasodilators reduce pressure on blood vessels by relaxing and dilating them. Examples of vasodilators include hydralazine, diazoxide, prazosin, clonidine, and methyldopa. ACE inhibitors, nitrates, potassium channel activators, and calcium channel blockers also act as vasodilators.

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

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

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

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

[0209] Thrombolytic agents work by breaking down existing blood clots. Examples of thrombolytic agents include streptokinase, urokinase, tenecteplase (TNK), and tissue plasminogen activator (t-PA).

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

[0211] The combination of amiodarone and doronedarone is particularly interesting, given the recently discovered synergistic effects of the sodium channel blocker lanolazine, amiodarone, and doronedarone.

[0212] Antihypertensive drugs Antihypertensive drugs are used to treat hypertension, a condition in which blood pressure is consistently higher than normal. Hypertension is associated with many aspects of cardiovascular disease, including congestive heart failure, atherosclerosis, and blood clots for reason. Examples of antihypertensive drugs include alpha-1-adrenergic antagonists such as prazosin (Minipress), doxazosin mesylate (Cardura), prazosin hydrochloride (Minipress), prazosin, polythiazide (Minizide), and terazosin hydrochloride (Hytrin), and beta-adrenergic antagonists such as propranolol (Inderal), nadolol (Corgard), timolol (Blocadren), metoprolol (Lopressor), and pindolol (Visken). Sex antagonists and central alpha-adrenergic receptor agonists such as clonidine hydrochloride (Catapres), clonidine hydrochloride and chlorthalidone (Clorpres, Combipres), guanabenz acetate (Wytensin), guanfacine hydrochloride (Tenex), methyldopa (Aldomet), methyldopa and chlorothiazide (Aldoclor), methyldopa and hydrochlorothiazide (Aldoril), and labetalol (Normodyne, Trendate) and carvedilol (Coreg ) and other combinations of alpha / beta adrenergic antagonists, adrenergic neuron blockers such as guanethidine (ismelin) and reserpine (Serpasil), central nervous system-acting antihypertensives such as clonidine (Catapres), methyldopa (Aldomet), and guanabenz (Wytensin), and anti-angiotensin II agents, as well as perindopril (Aceon), captopril (Capoten), enalapril (Vasotec), lisinopril (Prinivil, Zestri l) ACE inhibitors such as, angiotensin II receptor antagonists such as candesartan (Atacand), eprosartan (Teveten), irbesartan (Avapro), losartan (Cozaar), telmisartan (Micardis), and valsartan (Diovan), calcium channel blockers such as verapamil (Calan, Isoptin), diltiazem (Cardizem), and nifedipine (Adalat, Procardia), diuretics, and nitroprusside (Nipride),It includes direct vasodilators such as diazoxide (Hyperstat IV), hydralazine (Apresoline), minoxidil (Loniten), and verapamil, as well as potassium channel activators such as apricarim, bimalim, chromalim, emacalimm, nicorandil, and pinacidil.

[0213] Lipid-lowering drugs Lipid-lowering drugs are used to reduce the amount of cholesterol or fatty sugar present in the blood. Examples of lipid-lowering drugs include bezafibrate (Bezalip), ciprofibrate (Modalim), and statins such as atorvastatin (Lipitor), fluvastatin (Lescol), lovastatin (Mevacor, Altocor), mevastatin, pitavastatin (Livalo, Pitava), pravastatin (Lipostat), rosuvastatin (Crestor), and simvastatin (Zocor).

[0214] In this invention, patients presenting with acute coronary events often suffer from secondary medical conditions such as metabolic disorders, pulmonary disorders, peripheral vascular disorders, or gastrointestinal disorders, one or more of which are present. Such patients may benefit from combination therapy, which includes administering lanolazine to the patient in combination with at least one therapeutic agent.

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

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

[0217] Combination therapy for dysphagia Examples of metabolic disorders include, but are not limited to, diabetes mellitus, including type 1 and type 2 diabetes mellitus, metabolic syndrome, dyslipidemia, obesity, impaired glucose tolerance, hypertension, elevated serum cholesterol, and elevated triglycerides.

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

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

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

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

[0222] Combination therapy of antibiotics, analgesics, antidepressants, and anti-anxiety medications Patients presenting with acute coronary events may benefit from the administration of lanolazine in combination with antibiotics, analgesics, antidepressants, and anxiolytics.

[0223] antibiotics Antibiotics are therapeutic drugs that kill or stop the growth of microorganisms, including both bacteria and fungi. Examples of antibiotics include penicillin (amoxicillin), cephalosporins such as cefazolin, cefuroxime, cefadroxil (Duricef), cephalexin (Keflex), cefradin (Velosef), cefaclor (Ceclor), cefuroxime axtel (Ceftin), cefprodil (Cefzil), loracalbef (Lorabid), cefixime (Suprax), cefpodoxime proxetil (Vantin), ceftibuten (Cedax), ceftidinir (Omnicef), ceftriaxone (Rocephin), carbapenems, and monobactams, and tetracyclines such as tetracycline. It also contains macrolide antibiotics such as erythromycin, aminoglycosides such as gentamicin, tobramycin, and amikacin, quinolones such as ciprofloxacin, cyclic peptides such as vancomycin, streptogramin, and polymyxin, lincosamides such as clindamycin, oxazolidinos such as linezolid, and sulfonamide antibiotics such as sulfisoxazole, as well as beta-lactam antibiotics.

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

[0225] Antidepressants and anti-anxiety drugs Antidepressants and anxiolytics include those used to treat anxiety disorders and depression, as well as those used as sedatives and tranquilizers. Examples of antidepressants and anxiolytics include benzodiazepines such as diazepam, lorazepam, and midazolam, as well as barbiturates, glutethimid, chloral hydrate, meprobamate, sertraline (Zoloft, Lustral, Apo-Sertral, Asentra, Gladem, Serlift, Stimuloton), escitalopram (Lexapro, Cipralex), fluoxetine (Prozac, Sarafem, Fluctin, Fontex, Prodep, Fludep, Lovan), and venlafaxine (Effexor). This includes XR (Efexor), citalopram (Celexa, Cipramil, Talohexane), paroxetine (Paxil, Seroxat, Aropax), trazodone (Desyrel), amitriptyline (Elavil), and bupropion (Wellbutrin, Zyban). Antidepressants and anxiolytics may include neuroactive steroids and ketamine, as well as related NMDA receptor antagonists.

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

[0227] The combination therapy method includes the simultaneous administration of two or more formulations containing the sodium channel blocker and therapeutic agent(s) of the present invention, as well as the simultaneous administration of a single formulation containing the sodium channel blocker and therapeutic agent(s) of the present invention, which is substantially the simultaneous administration of two or more formulations containing the sodium channel blocker and therapeutic agent(s) of the present invention, and the sequential administration of the sodium channel blocker and therapeutic agent(s) of the present invention in any order, preferably including a period during which the sodium channel blocker and therapeutic agent(s) of the present invention exert their therapeutic effects simultaneously. [Examples]

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

[0229] The compounds provided herein are readily available using the following general methods and procedures. It can be prepared from suitable starting materials. Naturally, if typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, it will be understood that other process conditions may also be used unless otherwise indicated. Optimal reaction conditions may vary depending on the specific reactants or solvent used, but such conditions can be determined by those skilled in the art through routine optimization.

[0230] Additionally, as will become apparent to those skilled in the art, conventional protecting groups may need to be used to protect certain functional groups from undesirable reactions. The selection of suitable protecting groups for specific functional groups, as well as suitable conditions for protection and deprotection, are well known in the art. For example, numerous protecting groups, as well as their introduction and removal, are described by TW Greene and PGMWuts,Protecting Groups in Organic This is described in Synthesis, Second Edition, Wiley, New York, 1991, and the references cited herein.

[0231] The compounds provided herein can be isolated and purified by known standard procedures. Such procedures include recrystallization, filtration, flash chromatography, polishing, 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.

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

[0233] List of abbreviations Pd(dppf)Cl2[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride Pd(t-Bu3P)2bis(tri-tert-butylphosphine)palladium(0) Pd(OAc)2 Palladium(II) acetate SPhos 2-dicyclohexylphosphino-2',6'-dimethoxybiphenylEt3N triethylamine AgOTf Silver Trifluoromethanesulfonate DMF (N,N-dimethylformamide) MeOH methanol EtOH Ethanol i-Pr2O Diisopropyl Ether THF (Tetrahydrofuran) DCM Dichloromethane AcN or MeCN acetonitrile EA or alkyl ethyl acetate PE (Petroleum Ether) DMSO (Dimethyl Sulfoxide) Acetic acid (ACOH) NBS N-bromosuccinimide NaOMe Sodium Methoxy EtONa sodium ethoxide TsOH p-toluenesulfonic acid DEA N,N-diethylaniline DIPEA N,N-Diisopyruethylamine TFA (Trifluoroacetic Acid) KOAc Potassium Acetate T3P Propanephosphonic Acid Anhydride

[0234] Example 1: 3-[cyclopropylmethoxy(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyridine [ka] Synthesis of B: To a suspension of NaH (2.94 g, 73.56 mmol) in THF (50 mL), 2,2,2-trifluoroethanol (7.36 g, 73.56 mmol) was slowly added at 20°C, and the mixture was stirred for 1 hour. Then, 5-chloro-2,3-difluoropyridine (10 g, 66.88 mmol) was added, and the mixture was stirred for a further 4 hours at 20°C. The mixture was quenched with saturated NH4Cl (50 mL) and extracted with RINKAN (100 mL x 2). The combined organic phase was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to obtain B (15000 mg, 65.34 mmol) as oil. 1 1H NMR (400 MHz, CDCl3)δ H=7.83(d, 1H), 7.38(dd, 1H), 4.73(q, 2H).

[0235] Synthesis of A3: A mixture of B (8 g, 34.85 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (26.55 g, 104.55 mmol), K3PO4 (14.79 g, 69.7 mmol), SPhos (4.29 g, 10.45 mmol), and Pd(OAc)2 (782.4 mg, 3.48 mmol) in 1,4-dioxane (250 mL) was stirred at 85°C for 16 hours. After cooling to room temperature, the mixture was filtered through Celite and eluted with SiO2 (50 mL x 2). The filtrate was concentrated, diluted with alkyl hydroxide (200 mL), washed with water (100 mL x 2) and brine (100 mL), dried on Na2SO4, filtered, and concentrated to obtain the crude product. This crude product was purified by flash chromatography on silica gel (alkyl hydroxide in PE = 0 to 10% to 40%) to obtain the product (3 g, 4.6021 mmol) as oil. 1 1H NMR (400 MHz, CDCl3)δ H =8.26(d, 1H), 7.72(dd, 1H), 4.87(q, 2H), 1.35(s, 12H). Using Method B, LCMS R t =0.94 min, C 13 H 17 BF4NO3[M+H] + MS ES Calculated value: 322.1, measured value: 322.3. [ka]

[0236] Synthesis of A2: To a mixture of cyclopropylmethanol (382.93 mg, 5.31 mmol) in THF (10 mL), NaH (212.41 mg, 5.31 mmol) was added, and the mixture was stirred at 20°C for 0.5 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 reaction was quenched with saturated NH4Cl (10 mL), and the mixture was extracted with ethyl acetate (10 mL × 2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by flash chromatography on silica gel (ethyl acetate in PE = 10% to 40%) to obtain the product (240 mg, 0.73 mmol) as a solid. LCMS chromatography with Rt=4 minutes yielded 2.29 minutes.

[0237] Synthesis of Compound 1: A mixture of 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (111.02 mg, 0.35 mmol), Pd(dppf)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) is prepared in 90 ml. ℃ The mixture was stirred under N2 for 16 hours. After cooling to room temperature, the mixture was filtered through Celite and eluted with siRNA (10 mL x 2). The filtrate was concentrated to obtain the crude product. The crude product was purified by preparative HPLC (Waters Xbridge 150 mm x 25 mm, 5 μm) using A=H2O (10 mM NH4HCO3) and B=CH3CN (50-70% B over 7 minutes) to obtain the product (100.49 mg, 0.23 mmol) as a solid. 1 1H NMR (400MHz, DMSO-d6)δ H=8.75(s, 1H), 8.46(d, 1H), 8.34(dd, 11.2Hz, 1H), 8.14-8.09(m, 1H), 7.97(dd, 1H), 5.18(q, 2H), 4.09(d, 2H), 1.31-1.21(m, 1H), 0.61-0.55(m, 2H), 0.43-0.37(m, 2H). LCMS R t = 1.31 minutes in chromatography at 2.0 minutes, C 18 H 15 F6N4O2[M+H] + The MS ESI calculated value for this is 433.1, and the measured value is 433.0.

[0238] Example 2: 3-[difluoro(isobutoxy)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-[1,2,4]triazolo[4, 3-a] Pyridine [ka] Synthesis of A4: To a mixture of 2-methylpropan-1-ol (393.6 mg, 5.31 mmol) in THF (10 mL), NaH (212.41 mg, 5.31 mmol) was added, and the mixture was stirred at 20°C for 0.5 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 reaction was quenched with saturated NH4Cl (10 mL), and the mixture was extracted with RINKAN (20 mL × 2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by flash chromatography on silica gel (RINKAN in PE = 10% to 40%) to obtain the product (100 mg, 0.30 mmol) as a solid. LCMS chromatography with Rt=1.5 minutes, 0.86 minutes, MS ESI calculated value C 11 H 13 BrF2N3O[M+H+2] + 320.0, measured value 320.2.

[0239] Synthesis of Compound 2: A mixture of 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (110.33 mg, 0.34 mmol), Pd(dppf)Cl2 (34.28 mg, 0.05 mmol), 6-bromo-3-[difluoro(isobutoxy)methyl]-[1,2,4]triazolo[4,3-a]pyridine (100 mg, 0.31 mmol), and K2CO3 (86.35 mg, 0.62 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was stirred under N2 at 90°C for 16 hours. After cooling to room temperature, the mixture was filtered through Celite, eluted with ELISA (10 mL × 2), and the filtrate was concentrated to obtain the crude product. The crude product was purified by preparative HPLC (Waters Xbridge 150mm x 25mm, 5μm) using A=H2O (10mM NH4HCO3) and B=CH3CN, taking 8 minutes to remove 50-70% of B), to obtain the solid product (53.41 mg, 0.12 mmol). 1 1H NMR (400MHz, DMSO-d6)δ H =8.70(s, 1H), 8.44(d, 1H), 8.33(dd, 1H), 8.12(dd, 1H), 7.96(dd, 1H), 5.18(q, 2H), 4.02(d, 2H), 2.09-1.98(m, 1H), 0.96(d, 6H). LCMS R t = 1.34 minutes in chromatography with a 2.0 minute interval, C 18 H 17 F6N4O2[M+H] + The MS ESI calculated value for this is 435.1, and the measured value is also 435.1.

[0240] Example 3: 3-[ethoxy(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyridine [ka] Synthesis of A5: A mixture of 6-bromo-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyridine (300 mg, 1.06 mmol) and EtONa (361.37 mg, 5.31 mmol) in ethanol (10 mL) was stirred at 80 °C for 24 hours. After cooling to room temperature, the reaction was quenched with saturated NH₄Cl (10 mL), and the mixture was extracted with SiO₂ (20 mL × 2). The combined organic phase was washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated to obtain the crude product. The crude product was purified by flash chromatography on silica gel (SiO₂ in PE = 10% to 40%) to obtain the product (70 mg, 0.17 mmol) as a solid. LCMS R t = 1.97 minutes after 4 minutes of chromatography, MS ESI calculated value C9H9BrF2N3O[M+H+2] + 294.0, actual measured value 293.8.

[0241] Synthesis of Compound 3: A mixture of 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (84.65 mg, 0.26 mmol), Pd(dppf)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 under N2 at 90°C for 16 hours. After cooling to room temperature, the mixture was filtered through Celite, eluted with ELISA (10 mL × 2), and the filtrate was concentrated to obtain the crude product. The crude product was purified by preparative HPLC (Waters Xbridge 150mm × 25mm 5μm) using A=H2O (10mM NH4HCO3) and B=CH3CN, taking 8 minutes to obtain 42-62% of B), and the product (44.33 mg, 0.11 mmol) was obtained as a solid. 1 1H NMR (400MHz, DMSO-d6)δ H=8.73 (s, 1H), 8.46 (d, 1H), 8.35 (br d, 1H), 8.11 (d, 1H), 7.96 (d, 1H), 5.18 (q, 2H), 4.29 (q, 2H), 1.36 (t, 3H) t = Chromatography for 2.0 minutes, then 1.25 minutes, C 16 H 13 F6N4O2[M+H] + The MS ESI calculated value for this is 407.1, and the measured value is 407.0.

[0242] Example 4: 3-[difluoro(isopropoxy)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyridine [ka] Synthesis of A6: To a mixture of propan-2-ol (319.15 mg, 5.31 mmol) in THF (10 mL), NaH (127.45 mg, 3.19 mmol) was added, and the mixture was stirred at 20°C for 0.5 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 reaction was quenched with saturated NH4Cl (10 mL), and the mixture was extracted with ethyl acetate (10 mL x 2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by flash chromatography on silica gel (ethyl acetate in PE = 10% to 40%) to obtain the product (240 mg, 0.72 mmol) as a solid. LCMS chromatography with Rt=4 minutes, 2.18 minutes, MS ESI calculated value C 10 H 11 BrF2N3O[M+H+2] + 306.0, actual measured value 305.9.

[0243] Synthesis of Compound 4: A mixture of 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (115.38 mg, 0.36 mmol), Pd(dppf)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 under N2 at 90°C for 16 hours. After cooling to room temperature, the mixture was filtered through Celite, eluted with ELISA (10 mL x 2), and the filtrate was concentrated to obtain the crude product. The crude product was purified by preparative HPLC (Waters Xbridge 150mm × 25mm 5μm) using A=H2O (10mM NH4HCO3) and B=CH3CN (45-65% B) over 8 minutes to obtain the solid product (80.25 mg, 0.19 mmol). 1 1H NMR (400MHz, DMSO-d6)δ H =8.60(s, 1H), 8.43(d, 1H), 8.32(dd, 1H), 8.11(d, 1H), 7.95(dd, 1H), 5.17(q, 2H), 4.90(spt, 1H), 1.41(d, 6H). LCMS R t = 1.29 minutes in chromatography for 2.0 minutes, C 17 H 15 F6N4O2[M+H] + The MS ESI calculated value for this is 421.1, and the measured value is 421.0.

[0244] Example 5: 3-[difluoro(methoxy)methyl]-6-[5-fluoro-6-(2,2,2-trifluoro-1,1-dimethylethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyridazine [ka] Synthesis of A7: (2-chloro-2,2-difluoroacetyl)2-chloro-2,2-difluoroacetate (5.55 g, 22.83 mmol) was added to a mixture of (6-chloropyridazin-3-yl)hydrazine (3 g, 20.75 mmol) in toluene (40 mL). The reaction mixture was stirred at 110 °C for 4 hours. After cooling to room temperature, the reaction mixture was concentrated. The residue was diluted with saturated NaHCO3 (50 mL), and the mixture was extracted with ELISA (50 mL x 2). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product as a solid. 1 1H NMR (400MHz, DMSO-d6)δ H =8.67(d, 1H), 7.78(d, 1H).

[0245] Synthesis of A9: A mixture of 6-chloro-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-b]pyridazine (200 mg, 0.84 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoro-1,1-dimethylethoxy)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 ethyl acetate (10 mL), filtered through silica gel, and eluted with ethyl acetate (20 mL). The combined filtrate was concentrated to obtain the crude product. The crude product was purified by flash chromatography on silica gel (ethyl acetate in PE = 20%, 50%, and 80%) to obtain the product (260 mg, 0.50 mmol) as a solid. LCMS R t = 1.5 minutes chromatography followed by 0.96 minutes, C 15 H 11 ClF6N5O[M+H] + The MS ESI calculated value for this was 426.1, while the measured value was 425.9.

[0246] Synthesis of Compound 5: To a mixture of 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoro-1,1-dimethylethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyridazine (150 mg, 0.35 mmol) in MeCN (1 mL), AgOTf (905.31 mg, 3.52 mmol) and MeOH (8 mL, 0.35 mmol) were added. The mixture was stirred at 90°C for 10 days. After cooling to room temperature, the mixture was concentrated to obtain a residue. The residue was diluted with water (30 mL) and extracted with RINKAN (30 mL x 2). The combined organic phase was washed with water (20 mL x 2) and brine (30 mL x 2), dried on anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by preparative HPLC (Waters Xbridge 150mm × 25mm, 5μm) using A=H2O (0.05% NH4OH) and B=CH3CN (57-87% B) over 9 minutes to obtain the product as a solid. 1 1H NMR (CDCl3, 400MHz)δ H =8.55(d, 1H), 8.29(d, 1H), 8.09(dd, 1H), 7.65(d, 1H), 3.94(s, 3H), 1.90(s, 6H). LCMS R t = 1.32 minutes in chromatography with 2.0 minutes, C 16 H 14 F6N5O2[M+H] + The MS ESI calculated value for this is 422.1, and the measured value is 422.0.

[0247] Example 6: 3-[difluoro(methoxy)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyridine [ka] A mixture of 6-bromo-3-[difluoro(methoxy)methyl]-[1,2,4]triazolo[4,3-a]pyridine (100 mg, 360 μmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methylethoxy]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 for 12 hours under N2. After cooling to room temperature, the mixture was diluted with H2O (10 mL) and extracted with ELISA (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 obtain the crude product. The crude product was then separated by preparative HPLC (Boston). The product was purified using Prime C18 (150 × 30 mm, 5 μm), A=H2O (0.05% NH4OH), and B=CH3CN, with 53-83% of B removed over 8 minutes, to obtain the product as a solid. 1 1H NMR (400MHz, DMSO-d6)δ H =8.73(s, 1H), 8.45(d, 1H), 8.33(dd, 1H), 8.10(d, 1H), 7.94(d, 1H), 6.01(spt, 1H), 3.89(s, 3H), 1.54(d, 3H). LCMS R t = 1.27 minutes in 2.0 minutes chromatography, MS ESI calculated value C 18 H 13 F6N4O2[M+H] + 407.09, measured value 406.9.

[0248] Example 7: 3-[difluoro(methoxy)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyridine [ka] 1,4-Dioxane (5 mL) and 6-bromo-3-[difluo A mixture of [(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-methylethoxy]pyridine (144.62 mg, 430 μmol), K2CO3 (99.41 mg, 720 μmol), and Pd(dppf)Cl2 (39.47 mg, 50 μmol) was stirred under N2 at 80°C for 12 hours. After cooling to room temperature, the mixture was diluted with H2O (10 mL) and extracted with ELISA (20 mL x 2). The combined organic phase was washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by preparative HPLC (Boston Prime C18 (150 mm × 30 mm, 5 μm), A=H2O (0.05% NH4OH) and B=CH3CN, 53-83% B over 8 minutes) to obtain 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 t = 1.27 minutes in 2.0 minutes chromatography, MS ESI calculated value C 18 H 13 F6N4O2[M+H] + 407.1, measured value 406.9.

[0249] Example 8: 3-[Cyclopropylmethoxy(difluoro)methyl]-6-[5-Fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine [ka] A mixture of 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine (300 mg, 0.75 mmol) and AgOTf (1938.39 mg, 7.54 mmol) in cyclopropylmethanol (15 mL, 0.75 mmol) and CH3CN (15 mL) was stirred at 90°C for 14 days. After cooling to room temperature, the reaction product was diluted with Depositphotos (40 mL), saturated NaCl (40 mL) was added to the mixture, the mixture was filtered through Celite, eluted with Depositphotos (20 mL x 2), and the filtrate was concentrated to obtain the crude product. The crude product was purified by preparative TLC ( Depositphotos:PE = 1:1) to obtain an impure product. The impure product was purified by preparative HPLC (Waters Xbridge 150mm x 25mm, 5μm) using A=H2O (10mM NH4HCO3) and B=CH3CN (48-68% B) over 8 minutes to obtain the product as a solid. 1 1H-NMR (CDCl3, 400MHz)δ H =9.52(d, 1H), 8.57(d, 1H), 8.50(d, 1H), 8.07(dd, 1H), 4.93(q, 2H), 4.13(d, 2H), 1.40-1.30(m, 1H), 0.79-0.73(m, 2H), 0.49-0.42(m, 2H). LCMS R t = 1.33 minutes in chromatography at 2.0 minutes, C 17 H 14 F6N5O2[M+H] + The MS ESI calculated value for this is 434.1, and the measured value is 434.0.

[0250] Example 9: 3-[Cyclopropylmethoxy(difluoro)methyl]-6-[5-Fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine [ka] Synthesis of A19: A mixture of 1,4-dioxane (1 L) and water (150 mL) containing 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-chloropyrazine (80 g, 413.59 mmol) was stirred at 35°C for 2 hours. 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 on anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was redissolved in EA / PE=1 / 3 (500 mL) and then filtered through a silica gel mat. The cake was washed with EA / PE=1 / 3 (500 mL). The combined organic phase was concentrated to obtain the residue as oil. PE (500 mL) was slowly added to the oil to obtain several solids. The solids were collected and dried in an oven to obtain the product (100 g, 242.4 mmol, 58% yield) as a solid. LCMS R t = 1.28 minutes of chromatography in 2.0 minutes, 10⁻⁸⁰AB, C 11 H7ClF4N3O[M+H] + The MS ESI calculated value for this was 308.0, while the measured value was 307.9.

[0251] Synthesis of A20: A mixture of 2-chloro-5-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]pyrazine (140 g, 339.36 mmol) and hydrazine hydrate (169.88 g, 3393.6 mmol) in MeCN (1.4 L) was stirred at 100°C for 16 hours. After cooling to room temperature, the mixture was poured into water (4.5 L). Several solids were observed, and the solids were collected by filtration. The cakes were washed with water (500 mL x 2). The solids were redissolved in RINKAN (3 L), washed with brine (500 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product (100 g, 329.8 mmol, 97% yield) as a solid. LCMS Rt = Chromatography for 1.5 minutes, 0.74 minutes, 5-95AB, C 11 H 10 F4N5O[M+H] + The MS ESI calculated value for this was 304.1, while the measured value was 303.9.

[0252] Synthesis of A13: To a solution of 2-bromo-2,2-difluoroacetic acid (87 g, 497.34 mmol) in THF (1 L), one drop of DMF and (COCl)2 (50.5 mL, 596.81 mmol) were added. 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-difluoroacetyl chloride (95.66 g, 494.69 mmol) in THF (1 L), [5-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyri [Zyl]pyrazine-2-yl]hydrazine (100 g, 329.79 mmol) was added. The resulting mixture was stirred at 20°C for 2 hours. Water (1 L) was added to the solution and extracted with siRNA (1 L x 2). The combined organic phase was washed with brine (500 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product (150 g, 326.0 mmol, 98% yield, mixture of mono and bis-alkylated products) as a solid. LCMS R t = 1.5 minutes chromatography for 0.92 minutes, 5-95AB, C 13 H9BrF6N5O2[M+H] + The MS ESI calculated value for this is 460.1, while the measured value is 459.8.

[0253] Synthesis of A14: A solution of 2-bromo-2,2-difluoro-N'-[5-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]pyrazine-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 ethyl acetate (2 L x 2). The combined organic phase was washed with brine (1 L x 2), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by chromatographic flash on silica gel (ethyl acetate in PE = 0% to 15% to 30%) to obtain the product (80 g, 181.0 mmol, 55% yield) as oil. 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).

[0254] Synthesis of Compound 10: A mixture of 3-[bromo(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine (76 g, 171.9 mmol) and AgBF4 (66.93 g, 343.81 mmol) in ethanol (760 mL) was stirred at 60 °C for 1 hour. After cooling to room temperature, the mixture was poured into saturated aqueous NaCl (1 L) and SiO4 (2 L). The mixture was filtered through Celite. After separation, the aqueous layer was extracted with SiO4 (500 mL x 2). The combined organic phases were washed with brine (500 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by chromatographic flash column on silica gel (with ethyl acetate in PE ranging from 0% to 30% to 50%), and then polished with EtOH (50 mL) to obtain the product (44.45 g, 109.01 mmol, 63% yield) as a solid. 1 1H NMR (CDCl 3400MHz) δ H=9.52(d, 1H), 8.49(dd, 2H), 8.07(dd, 1H), 4.93(q, 2H), 4.37(q, 2H), 1.51(t, 3H). LCMS R t = Chromatography for 2.0 minutes, 1.25 minutes, 10⁻⁸ AB, C 15 H 12 F6N5O2[M+H] + The MS ESI calculated value for this is 408.1, and the measured value is 408.0.

[0255] Example 10: 3-[difluoro(methoxy)methyl]-6-[5-fluoro-6-[1-(trifluoromethyl)cyclobutoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine [ka] 3-[chloro(difluoro) in a mixed solvent of methanol (14 mL) and DMF (14 mL) A mixture of [methyl]-6-[5-fluoro-6-[1-(trifluoromethyl)cyclobutoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine (1.4 g, 3.2 mmol) and AgOTf (8.22 g, 31.98 mmol) 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 SiO2 (40 mL x 2). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, and concentrated to obtain the crude product. The crude product was purified by preparative HPLC (Waters Xbridge (150 mm x 25 mm, 5 μm), A=H2O (10 mM NH4HCO3) and B=CH3CN, 57-67% B over 8 minutes) to obtain the product (240 mg). Another batch was started with 1.2 g of A24, and approximately 110 mg of the product was obtained by preparative HPLC (Boston Prime C18 (150 mm × 30 mm, 5 μm) A=H2O (0.05% NH4OH) and B=CH3CN, 50-80% B over 9 minutes). The two batches of product were combined and freeze-dried to obtain the product as a solid.1 1H NMR (CDCl3, 400MHz)δ H =9.51(d, 1H), 8.49(d, 1H), 8.47(d, 1H), 8.05(dd, 1H), 3.98(s, 3H), 2.98-2.86(m, 2H), 2.81-2.72(m, 2H), 2.11-1.93(m, 2H). LCMS R t = 2 minutes chromatography followed by 1.30 minutes, 10⁻⁸ AB, C 17 H 14 F6N5O2[M+H] + The MS ESI calculated value for this is 434.1, while the measured value is 433.9.

[0256] Example 11: 3-[difluoro(methoxy)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyridazine [ka] Synthesis of A25: A mixture of 6-chloro-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-b]pyridazine (120 mg, 0.50 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methylethoxy]pyridine (201.9 mg, 0.60 mmol), K3PO4 (319.74 mg, 1.51 mmol), and Pd(t-Bu3P)2 (25.66 mg, 0.05 mmol) in 1,4-dioxane (12 mL) and H2O (4 mL) was stirred at 90°C for 16 hours. After cooling to room temperature, the reaction mixture was concentrated, diluted with water (20 mL), and extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with brine (40 mL) and then placed on Na2SO4. The mixture was dried and concentrated to obtain a residue. The residue was purified by flash chromatography on silica gel (siRNA in PE = 0% to 60%) to obtain the product (120 mg, 0.29 mmol) as a solid. 1 1H-NMR (CDCl3, 400MHz)δH =8.57(d, 1H), 8.35(d, 1H), 8.15(dd, 1H), 7.74(d, 1H), 5.93(m, 1H)1.61(d, 3H).

[0257] Synthesis of Compound 12: A mixture of AgOTf (599.15 mg, 2.33 mmol) and 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methylethoxy]-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 x 2). The combined organic phase was washed with brine (40 mL), dried over Na2SO4, and concentrated to obtain the residue. The residue was subjected to preparative HPLC (Boston). The product (5.12 mg, 13 μmol) was purified over 8 minutes using a Prime C18 150 × 30 mm 5 μm substrate with A = H2O (0.05% NH4OH) and B = CH3CN, resulting in 52-82% B. 1 1H-NMR (CDCl3, 400MHz)δ H =8.55(d, 1H), 8.30(d, 1H), 8.14(dd, 1H), 7.66(d, 1H), 5.92(m, 1H), 3.94(s, 3H), 1.61(d, 3H). LCMS R t = 1.28 minutes in chromatography for 2.0 minutes, C 15 H 12 F6N5O2[M+H] + The MS ESI calculated value for this is 408.1, and the measured value is 408.0.

[0258] Example 12: 3-[difluoro(methoxy)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methylethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyridazine [ka] Synthesis of A26: Mixture of 6-chloro-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-b]pyridazine (120 mg, 0.50 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methylethoxy]pyridine (201.9 mg, 0.60 mmol), K3PO4 (319.74 mg, 1.51 mmol), and Pd(t-Bu3P)2 (25.66 mg, 0.05 mmol) in 1,4-dioxane (12 mL) and H2O (4 mL) was incubated 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 x 2). The combined organic phase was washed with brine (40 mL), dried on Na2SO4, and concentrated to obtain the crude product. The crude product was purified by flash chromatography on silica gel (ethyl acetate in PE = 0% to 60%) to obtain the product (140 mg, 0.34 mmol) as a solid. 1 1H-NMR (CDCl3, 400MHz)δ H =8.57(d, 1H), 8.35(d, 1H), 8.14(dd, 1H), 7.74(d, 1H), 5.93(m, 1H), 1.61(d, 3H).

[0259] Synthesis of Compound 13: A mixture of 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methylethoxy]-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, diluted with water (20 mL), and then extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with brine (40 mL), dried over Na2SO4, and concentrated to obtain the residue. The residue was purified by preparative HPLC (Boston Prime C18 150×30mm 5μM) using A=H2O (0.05% NH4OH) and B=CH3CN (52-82% B) over 8 minutes to obtain the product (5 mg, 12.2 μmol). 1 1H-NMR (CDCl3, 400MHz)δ H =8.55(d, 1H), 8.30(d, 1H), 8.14(dd, 1H), 7.66(d, 1H), 5.92(m, 1H), 3.94(s, 3H), 1.61(d, 3H). LCMS R t = 1.26 minutes C in 2.0 minutes chromatography 15 H 12 F6N5O2[M+H] + The MS ESI calculated value for this is 408.1, and the measured value is 408.0.

[0260] Example 13: 3-[cyclopropylmethoxy(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyridazine [ka] Synthesis of A27: 6-chloro-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-b]pyridazine (500 mg, 2.09 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (2015.06 mg, 6.28 mmol), Pd(t-Bu3P)2 (160.37 mg, 0.31 mmol), and K3PO4 (888.25 mg, 4) in 1,4-dioxane (15 mL) and water (1.5 mL). A mixture of 0.18 mmol was stirred under N2 at 90°C for 16 hours. The mixture was filtered through Celite and eluted with ethylacetate (10 mL x 2). The filtrate was concentrated to obtain the crude product. The crude product was purified by flash chromatography on silica gel (ethylacetate in PE = 20% to 60%) to obtain the product (900 mg, 1.90 mmol) as a solid. LCMS chromatography Rt = 1.5 min for 0.85 min, MS ESI calculated value C 13 H7ClF6N5O[M+H] + 398.0, actual measured value 398.0.

[0261] Synthesis of Compound 14: A mixture of 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyridazine (200 mg, 0.50 mmol) and AgOTf (1292.26 mg, 5.03 mmol) in cyclopropylmethanol (10 mL, 0.50 mmol) and CH3CN (10 mL) was stirred at 90°C for 13 days. After cooling to room temperature, the reaction product was diluted with ethyl acetate (40 mL) and brine (40 mL). The mixture was filtered through Celite, eluted with ethyl acetate (20 mL x 2), and the filtrate was concentrated to obtain the crude product. The crude product was purified by preparative HPLC (Boston Prime C18 150mm×30mm 5μm) using A=H2O (0.05% NH4OH volume / volume) and B=CH3CN (58-88% B) over 8 minutes to obtain an impure product. The impure product was polished with n-hexane / i-Pr2O (volume / volume = 1:1, 2 mL) to obtain the product (9.82 mg, 22.2 μmol) as a solid. 1 1H NMR (DMSO-d6, 400MHz)δ H =8.83(d, 1H), 8.67(d, 1H), 8.45(dd, 1H), 8.21(d, 1H), 5.22(q, 2H), 4.03(d, 2H), 1.26-1.18(m, 1H), 0.62-0.54(m, 2H), 0.43-0.33(m, 2H). LCMS R t = 2.87 minutes in chromatography for 4.0 minutes, C 17 H 14 F6N5O2[M+H] + The MS ESI calculated value for this is 434.1, and the measured value is 434.0.

[0262] Example 14: 3-[difluoro(methoxy)methyl]-6-[5-fluoro-6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine [ka] Synthesis of A29: A solution of [5-[5-fluoro-6-(2,2,2-trifluoro-1,1-dimethylethoxy)-3-pyridyl]pyrazine-2-yl]hydrazine (300 mg, 0.91 mmol) and (2-chloro-2,2-difluoroacetyl)2-chloro-2,2-difluoroacetate (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 obtain a residue. Water (50 mL) was added to the residue, and the mixture was converted to ELISA (50 mL x 2). Extraction was performed using [method]. The combined organic phase was washed with water (50 mL) and brine (50 mL x 2), dried on anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified using a flash chromatography column on silica gel (ethyl acetate in PE = 0%, 10%, and 20%) to obtain the product (150 mg, 346.3 μmol) as a solid. LCMS R t = 3.06 minutes in chromatography at 4.0 minutes, C 15 H 11 ClF6N5O[M+H] + The MS ESI calculated value for this is 426.0, and the measured value is also 426.0.

[0263] Synthesis of Compound 15: To a solution of 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine (150 mg, 0.35 mmol) in methanol (5 mL) and MeCN (5 mL), AgOTf (1.81 g, 7.05 mmol) was added. The resulting mixture was stirred in a sealed tube at 90°C under N2 for 5 days. The mixture was cooled to room temperature, then brine (20 mL) and siRNA (30 mL) were added, and the mixture was filtered. After separating the filtrate, the organic phase was washed with water (20 mL x 2) and brine (20 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by preparative TLC (PE:Â=4:1) to obtain the product (14.23 mg, 33.2 mmol) as a solid. 11H NMR (CDCl3, 400MHz)δ H= 9.52(d, 1H), 8.51(d, 1H), 8.45(d, 1H), 8.02(dd, 1H), 3.98(s, 3H), 1.89(s, 6H). LCMS R t = 1.33 minutes in chromatography at 2.0 minutes, C 16 H 14 F6N5O2[M+H] + The MS ESI calculated value for this is 422.1, and the measured value is 422.0.

[0264] Example 15: 3-[ethoxy(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyridazine [ka] A mixture of 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyridazine (200 mg, 0.50 mmol) and AgOTf (1292.26 mg, 5.03 mmol) in ethanol (10 mL, 0.50 mmol) and CH3CN (10 mL) was stirred at 90°C for 13 days. After cooling to room temperature, the reaction product was diluted with ethyl acetate (40 mL) and brine (40 mL). The mixture was filtered through Celite, eluted with ethyl acetate (20 mL x 2), and the filtrate was concentrated to obtain the crude product. The crude product was purified by preparative TLC (ethyl acetate:DCM:PE = 1:1:1) to obtain the impure product. The impure product was purified with n-hexane / CH2Cl2 (volume / volume = 1:2, 6 mL) to obtain the product (15.95 mg, 39.2 mmol) as a solid. 1 1H NMR (DMSO-d6, 400MHz)δ H =8.81(d, 1H), 8.68(d, 1H), 8.43(dd, 1H), 8.21(d, 1H), 5.22(q, 2H), 4.24(q, 2H), 1.36(t, 3H). LCMS R t= 1.26 minutes in chromatography for 2.0 minutes, C 15 H 12 F6N5O2[M+H] + The MS ESI calculated value for this is 408.1, and the measured value is 408.0.

[0265] Example 16: 3-[difluoro(methoxy)methyl]-6-[5-fluoro-6-[1- [(trifluoromethyl)cyclobutoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyridazine [ka] Synthesis of A7-a: (2-chloro-2,2-difluoroacetyl)-2-chloro-2,2-difluoroacetate (7.56 g, 31.13 mmol) was added to a mixture of (6-chloropyridazin-3-yl)hydrazine (3.0 g, 20.75 mmol) in toluene (40 mL). The reaction mixture was stirred at 110 °C for 4 hours. After cooling to room temperature, the reaction mixture was concentrated. The residue was diluted with saturated NaHCO3 (50 mL), and the mixture was extracted with ELISA (50 mL x 2). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product (4700 mg, 19.66 mmol) as a solid. 1 1H NMR (400 MHz, CDCl3) δ H =7.35(d, 1H), 8.23(d, 1H).

[0266] Synthesis of A30: A mixture of 6-chloro-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-b]pyridazine (150 mg, 0.63 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[1-(trifluoromethyl)cyclobutoxy]pyridine (362.64 mg, 1 mmol), K3PO4 (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. New spots (Rf=0.45, UV) were observed by TLC, and no traces of the starting material (Rf=0.8, UV) remained. After cooling to room temperature, the reaction mixture was concentrated to remove the solvent, diluted with water (20 mL), and extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with brine (40 mL), dried on Na2SO4, and concentrated to obtain the crude product. The crude product was purified by flash chromatography on silica gel (ethyl acetate in PE = 0% to 60%) to obtain the product (120 mg, 0.27 mmol) as a solid. 1 1H NMR (CDCl3, 400MHz)δ H =8.57(d, 1H), 8.33(d, 1H), 8.15-8.06(m, 1H), 7.73(d, 1H), 2.82-2.96(m, 2H), 2.78-2.81(m, 2H), 2.00-2.08(m, 2H).

[0267] Synthesis of Compound 17: A mixture of 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[1-(trifluoromethyl)cyclobutoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyridazine (120 mg, 0.27 mmol) and silver trifluoromethanesulfonate (0.7 g, 2.74 mmol) in a mixed solvent of methanol (12 mL) and MeCN (4 mL) was stirred at 80°C for 72 hours. After cooling to room temperature, the mixture was reconstituted. The 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 x 2). The combined organic phase was washed with brine (40 mL), dried over Na2SO4, and concentrated to obtain the residue. The crude product was purified by preparative HPLC (Boston Prime C18 150 mm x 30 mm 5 μm) A=H2O (0.05% NH4OH) and B=ACN (52-82% B over 8 minutes) to obtain the product (27.93 mg, 64.5 μmol) as a solid. 1 1H NMR (CDCl3, 400MHz)δ H =8.54(d, 1H), 8.28(d, 1H), 8.11(dd, 1H), 7.64(d, 1H), 3.93(s, 3H), 2.82-2.96(m, 2H), 2.76-2.81(m, 2H), 1.57-2.07(m, 2H). LCMS R t = 1.32 minutes in chromatography with 2.0 minutes, C 17 H 14 F6N5O2[M+H] + The MS ESI calculated value for this is 434.1, and the measured value is 434.0.

[0268] Example 17: 3-[difluoro(methoxy)methyl]-6-[5-fluoro-6-[1-(trifluoromethyl)cyclobutoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyridine [ka] Synthesis of A1: A mixture of (5-bromo-2-pyridyl)hydrazine (2.6 g, 13.83 mmol) and (2-chloro-2,2-difluoroacetyl)2-chloro-2,2-difluoroacetate (5.04 g, 20.74 mmol) in toluene (100 mL) was stirred at 10 °C for 1 hour, then the mixture was heated to 120 °C and stirred for 36 hours. After cooling to room temperature, the reaction was quenched with saturated NaHCO3 (50 mL), and the mixture was extracted with siRNA (50 mL x 2). The organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by flash chromatography on silica gel (siRNA in PE = 0% to 20% to 30%) to obtain the product (3900 mg, 13.81 mmol) as a solid. 1 1H NMR (400 MHz, CDCl3)δ H =8.42(s, 1H), 7.84(d, 1H), 7.53(dd, 1H). LCMS R t = Chromatography for 7.0 minutes yielded C7H4BrClF2N3[M+H+2] at 3.19 minutes. + The MS ESI calculated value for this was 283.9, while the measured value was 283.6.

[0269] Synthesis of A15: A mixture of 6-bromo-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyridine (1 g, 3.54 mmol) and NaOMe (956.21 mg, 17.7 mmol) in methanol (20 mL) was stirred at 80°C for 24 hours. After cooling to room temperature, the reaction was quenched with saturated NH4Cl (50 mL), and the mixture was extracted with SiO2 (50 mL x 2). The combined organic layer was extracted with brine (5 The solution was washed with 0 mL of water, dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by flash chromatography on silica gel (with HCl in PE ranging from 0% to 30% to 40%) to obtain the solid product (380 mg, 127.56 μmol). 1 1H-NMR (CDCl3, 400MHz)δ H =8.43(s, 1H), 7.77(d, 1H), 7.47-7.41(m, 1H), 3.92(s, 3H). LCMS R t = Chromatography for 7.0 minutes followed by 2.95 minutes, C8H7BrF2N3O[M+H+2] + The MS ESI calculated value for this is 280.0, while the measured value is 279.7.

[0270] Synthesis of compound 18: A mixture of 6-bromo-3-[difluoro(methoxy)methyl]-[1,2,4]triazolo[4,3-a]pyridine (100 mg, 0.36 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[1-(trifluoromethyl)cyclobutoxy]pyridine (155.86 mg, 0.43 mmol), K2CO3 (99.41 mg, 0.72 mmol), and Pd(dppf)Cl2 (39.47 mg, 0.05 mmol) in 1,4-dioxane (5 mL) and water (0.50 mL) was stirred at 80°C for 12 hours. After cooling to room temperature, the mixture was diluted with H2O (10 mL) and extracted with ELISA (20 mL x 2). The combined organic phases were washed with water (30 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by preparative HPLC (Boston Prime C18 (150 mm × 30 mm, 5 μm), A=H2O (0.05% NH4OH) and B=CH3CN, 58-88% B over 8 minutes) to obtain the product (66.89 mg, 15.47 μmol) as a solid. 1 1H NMR (DMSO-d6, 400MHz)δ H =8.75(s, 1H), 8.46(d, 1H), 8.33(dd, 1H), 8.10(d, 1H), 7.96(dd, 1H), 3.89(s, 3H), 2.97-2.85(m, 2H), 2.72-2.62(m, 2H), 2.07-1.95(m, 1H), 1.93-1.81(m, 1H). LCMS R t = 1.32 minutes in a 2.0 minute chromatography, MS ESI calculated value C 18 H 15 F6N4O2[M+H]+ 433.1, measured value 432.9.

[0271] Example 18: Synthesis of 3-[cyclopropylmethoxy(difluoro)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methylethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyridine [ka] A mixture of 6-bromo-3-[cyclopropylmethoxy(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyridine (65 mg, 200 μmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methylethoxy]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 under N2 at 80°C for 12 hours. After cooling to room temperature, the mixture was diluted with H2O (10 mL) and extracted with ELISA (20 mL x 2). Wash the combined organic phases with water (20 mL) and brine (30 mL), then N The crude product was dried over a2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by preparative HPLC (Boston Prime C18 (150 × 30 mm, 5 μm) A=H2O (0.05% NH4OH) and B=CH3CN, 62-92% of B over 8 minutes) to obtain the product (43.42 mg, 97.3 μmol, 48% yield) as a solid. 1 1H NMR (DMSO-d6, 400MHz)δ H =8.74(s, 1H), 8.44(d, 1H), 8.32(dd, 1H), 8.11(dd, 1H), 7.95(dd, 1H), 6.02(spt, 1H), 4.09(d, 2H), 1.54(d, 3H), 1.32-1.21(m, 1H), 0.62-0.52(m, 2H), 0.44-0.33(m, 2H). LCMS R t = 1.37 minutes in chromatography at 2.0 minutes, 10⁻⁸ AB, MS ESI calculated value C 19 H 17 F6N4O2[M+H] + 447.1, measured value 447.0.

[0272] Example 19: 3-[difluoro(isopropoxy)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methylethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyridine [ka] A mixture of 6-bromo-3-[difluoro(isopropoxy)methyl]-[1,2,4]triazolo[4,3-a]pyridine (70 mg, 230 μmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methylethoxy]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 under N2 at 80°C for 12 hours. After cooling to room temperature, the mixture was diluted with H2O (10 mL) and extracted with ELISA (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 obtain the crude product. The crude product was purified by preparative HPLC (Boston Prime C18 (150 × 30 mm, 5 μm), A=H2O (0.05% NH4OH) and B=CH3CN, 60-90% B over 8 minutes) to obtain the product (33.94 mg, 78.1 μmol, 34% yield) as a solid. 1 1H NMR (DMSO-d6, 400MHz)δ H=8.61(s, 1H), 8.43(d, 1H), 8.31(dd, 1H), 8.11(dd, 1H), 7.95(dd, 1H), 6.02(spt, 1H), 4.90(spt, 1H), 1.54(d, 3H), 1.41(d, 6H). LCMS R t = 1.35 min chromatography in 2.0 mins, 10⁻⁸ AB, MS ESI calculated value C 18 H 17 F6N4O2[M+H] + 435.1, measured value 435.0.

[0273] Example 20: 3-[difluoro(isopropoxy)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methylethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyridine [ka] A mixture of 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methylethoxy]pyridine (84.29 mg, 0.25 mmol), Pd(dppf)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 under N2 at 90°C for 16 hours. After cooling to room temperature, the mixture was filtered through Celite, eluted with ELISA (10 mL x 2), and the filtrate was concentrated to obtain the crude product. The crude product was purified by preparative HPLC (Boston Prime C18 (150 mm × 30 mm, 5 μm) A=H2O (0.05% ammonia hydroxide, volume / volume) and B=CH3CN, 60-90% of B over 8 minutes) to obtain the product (24.78 mg, 57.1 μmol, 25% yield) as a solid. 1 1H NMR (DMSO-d6, 400MHz)δ H=8.61(s, 1H), 8.43(d, 1H), 8.32(dd, 1H), 8.12(d, 1H), 7.95(dd, 1H), 6.03(spt, 1H), 4.95-4.85(m, 1H), 1.54(d, 3H), 1.41(d, 6H). LCMS R t = 1.37 minutes in chromatography at 2.0 minutes, 10⁻⁸ AB, C 18 H 17 F6N4O2[M+H] + The MS ESI calculated value for this is 435.1, and the measured value is also 435.1.

[0274] Example 21: 3-[difluoro(isobutoxy)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methylethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyridine [ka] Synthesis of A1-a: A mixture of (5-bromo-2-pyridyl)hydrazine (5 g, 26.59 mmol) and (2-chloro-2,2-difluoroacetyl)2-chloro-2,2-difluoroacetate (9690.21 mg, 39.89 mmol) in toluene (200 mL) was stirred at 10°C for 1 hour, and then the mixture was heated at 120°C for 36 hours. After cooling to room temperature, the reaction was quenched with saturated NaHCO3 (200 mL), and then mixed. The substance was extracted with siRNA (80 mL x 2). The organic layer was washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by flash chromatography on silica gel (siRNA in PE = 0%, 5%, and 20%) to obtain the product (5700 mg, 20.18 mmol, 76% yield) as a solid. 1 1H NMR (CDCl3, 400MHz)δ H =8.43(s, 1H), 7.84(dd, 1H), 7.54(dd, 1H).

[0275] Synthesis of A4-a: To a mixture of 2-methylpropan-1-ol (1312 mg, 17.7 mmol) in THF (40 mL), NaH (708.04 mg, 17.7 mmol) was added, 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 (1000 mg, 3.54 mmol) was 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 RINKAN (30 mL x 2). The combined organic phase was washed with brine (70 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by flash chromatography on silica gel (10% to 40% siRNA in PE) to obtain the product (750 mg, 2.34 mmol, 66% yield) as oil. 1 1H NMR (CDCl3, 400MHz)δ H =8.44(s, 1H), 7.77(d, 1H), 7.44(dd, 1H), 4.00(d, 2H), 2.16-2.06(m, 1H), 1.04(d, 6H).

[0276] Synthesis of compound 22: A mixture of 6-bromo-3-[difluoro(isobutoxy)methyl]-[1,2,4]triazolo[4,3-a]pyridine (100 mg, 310 μmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methylethoxy]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 under N2 at 80 °C for 12 hours. After cooling to room temperature, the mixture was diluted with H2O (10 mL) and then extracted with ELISA (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 obtain the crude product. The crude product was purified by preparative HPLC (Boston Prime C18 (150 × 30 mm, 5 μm), A=H2O (0.05% NH4OH) and B=CH3CN, 65-95% of B over 8 minutes) to obtain the product (47.11 mg, 105.1 μmol, 34% yield) as a solid. 1 1H NMR (DMSO-d6, 400MHz)δ H= 8.70(s, 1H), 8.43(d, 1H), 8.31(dd, 1H), 8.11(dd, 1H), 7.95(dd, 1H), 6.02(spt, 1H), 4.01(d, 2H), 2.10-1.95(m, 1H), 1.54(d, 3H), 0.96(d, 6H). LCMS R t = 1.41 minutes in 2.0 minutes chromatography, 10⁻⁸ AB, MS ESI calculated value C 19 H 19 F6N4O2[M+H] + 449.1, measured value 449.1.

[0277] Example 22: 3-[difluoro(isobutoxy)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methylethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyridine [ka] A mixture of 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methylethoxy]pyridine (115.14 mg, 0.34 mmol), Pd(dppf)Cl2 (34.28 mg, 0.05 mmol), 6-bromo-3-[difluoro(isobutoxy)methyl]-[1,2,4]triazolo[4,3-a]pyridine (100 mg, 0.31 mmol), and K2CO3 (86.35 mg, 0.62 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was stirred under N2 at 90°C for 16 hours. After cooling to room temperature, the mixture was filtered through Celite, eluted with ELISA (10 mL x 2), and the filtrate was concentrated to obtain the crude product. The crude product was purified by preparative HPLC (Boston Prime The product (68.11 mg, 0.15 mmol, 48% yield) was obtained as a solid by purifying the C18 (150 mm × 30 mm, 5 μm) with A=H2O (0.05% ammonia hydroxide volume / volume) and B=CH3CN over 8 minutes to obtain 61-91% of B). 1 H NMR (DMSO-d6, 400MHz)δ H =8.70(s, 1H), 8.43(d, 1H), 8.31(dd, 1H), 8.15-8.09(m, 1H), 7.95(dd, 1H), 6.08-5.96(m, 1H), 4.02(d, 2H), 2.09-1.96(m, 1H), 1.54(d, 3H), 0.96(d, 6H). LCMS R t = 1.42 minutes in chromatography at 2.0 minutes, 10⁻⁸⁰ AB C 19 H 19 F6N4O2[M+H] + The MS ESI calculated value for this is 449.1, and the measured value is also 449.1.

[0278] Example 23: 3-[difluoro(methoxy)methyl]-6-[5-fluoro-6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyridine [ka] Synthesis of A15-a: A mixture of 6-bromo-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyridine (1000 mg, 3.54 mmol) and NaOMe (956.21 mg, 17.7 mmol) in methanol (20 mL) was stirred at 80°C for 24 hours. After cooling to room temperature, the reaction was quenched with saturated NH4Cl (50 mL), and the mixture was extracted with ethyl acetate (50 mL x 2). The organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by flash chromatography on silica gel (ethyl acetate in PE = 0% to 30% to 40%) to obtain the product (230 mg, 754.3 μmol, 21% yield) as oil. LCMS R t = 1.41 minutes after 1.5 minutes of chromatography, 5-95AB, MS ESI calculated value C8H8BrF2N3O[M+H+2] + 280.0, actual measured value 279.9.

[0279] Synthesis of Compound 24: A mixture of 6-bromo-3-[difluoro(methoxy)methyl]-[1,2,4]triazolo[4,3-a]pyridine (70 mg, 250 μmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoro-1,1-dimethylethoxy)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 under N2 at 80°C for 12 hours. After cooling to room temperature, the mixture was diluted with H2O (20 mL) and extracted with ELISA (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 obtain the crude product. The crude product was purified by preparative HPLC (Boston Prime C18 (150 × 30 mm, 5 μm), A=H2O (0.05% NH4OH) and B=CH3CN; 56-86% of B over 8 minutes) to obtain the product (22.72 mg, 54.1 μmol, 21% yield) as a solid. 1 1H NMR (DMSO-d6, 400MHz)δ H =8.75(s, 1H), 8.47(d, 1H), 8.31(dd, 1H), 8.14-8.05(m, 1H), 7.95(dd, 1H), 3.89(s, 3H), 1.82(s, 6H). LCMS R t = 1.31 minutes in chromatography at 2.0 minutes, 10⁻⁸ AB, MS ESI calculated value C 17 H 15 F6N4O2[M+H] + 421.1, measured value 421.1.

[0280] Example 24: 3-[Cyclopropylmethoxy(difluoro)methyl]-6-[5-Fluoro-6-[(1R)-2,2,2-trifluoro-1-methylethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyridine [ka] A mixture of 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methylethoxy]pyridine (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 under N2 at 90°C for 16 hours. After cooling to room temperature, the mixture was filtered through Celite, eluted with ELISA (10 mL x 2), and the filtrate was concentrated to obtain the crude product. The crude product was purified by preparative HPLC (Boston Prime C18 150mm×30mm 5μm) using A=H2O (0.05% ammonia hydroxide volume / volt) and B=CH3CN (60-90% of B) over 8 minutes, and the product (51.82 mg, 0.12 mmol, 62% yield) was obtained as a solid. 1 H NMR (DMSO-d6, 400MHz)δ H =8.74(s, 1H), 8.45(d, 1H), 8.32(dd, 1H), 8.11(dd, 1H), 7.96(dd, 1H), 6.02(spt, 1H), 4.09(d, 2H), 1.54(d, 3H), 1.32-1.21(m, 1H), 0.62-0.54(m, 2H), 0.43-0.36(m, 2H). LCMS R t = 1.39 minutes in chromatography at 2.0 minutes, 10⁻⁸⁰AB C 19 H 17 F6N4O2[M+H] + The MS ESI calculated value for this is 447.1, and the measured value is also 447.1.

[0281] Example 25: 3-[ethoxy(difluoro)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methylethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine [ka] A mixture of 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methylethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine (500 mg, 1.21 mmol) and AgOTf (3120.55 mg, 12.15 mmol) in ethanol (7 mL) and MeCN (7 mL) was stirred at 90°C for 5 days. The mixture was cooled to room temperature, then ethyl acetate (20 mL) and brine (50 mL) were added to the mixture, and the resulting suspension was filtered through Celite. The filtrate was separated, and the aqueous phase was extracted with ethyl acetate (50 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by chromatographic flashing on silica gel (with alkyl groups of 10%, 30%, and 50% in PE), and then polished with DCM (3 mL) and n-hexane (4 mL) to obtain the product (31.35 mg, 74 μmol, 6% yield) as a solid. 1 1H NMR (CDCl3, 400MHz)δ H =9.52(d, 1H), 8.48(dd, 2H), 8.04(dd, 1H), 5.95-5.87(m, 1H), 4.37(q, 2H), 1.60(d, 3H), 1.51(t, 3H). LCMS R t = 2 minutes chromatography followed by 1.35 minutes, 10⁻⁸ AB, C 16 H 14 F6N5O2[M+H] + The MS ESI calculated value for this is 422.1, and the measured value is also 422.1.

[0282] Example 26: 6-[5-fluoro-6-(2,2,2-trifluoro-1,1-dimethylethoxy)-3-pyridyl]-3-(methoxymethyl)-[1,2,4]triazolo[4,3-b]pyridazine [ka] A mixture of 6-chloro-3-(methoxymethyl)-[1,2,4]triazolo[4,3-b]pyridazine (100 mg, 0.5 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoro-1,1-dimethylethoxy)pyridine (210.94 mg, 0.6 mmol), K3PO4 (213.79 mg, 1.01 mmol), and Pd(t-Bu3P)2 (38.6 mg, 0.08 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was stirred under N2 at 80°C for 16 hours. After cooling to room temperature, the mixture was diluted with H2O (10 mL) and extracted with ELISA (20 mL x 2). The phase was washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by preparative HPLC (Boston Prime C18 (150 mm × 30 mm, 5 μm; mobile phase: [water (0.05% NH4OH)-ACN]; B%: 40-70%, 9 min) to obtain the product (47.66 mg, 0.12 mmol, 25% yield) as a solid. 1 1H NMR (CDCl3, 400MHz)δ H =8.54(d, 1H), 8.24(d, 1H), 8.09(dd, 1H), 7.57(d, 1H), 5.11(s, 2H), 3.53(s, 3H), 1.90(s, 6H). LCMS R t = 1.21 minutes in chromatography at 2.0 minutes, 10⁻⁸ AB, C 16 H 16 F4N5O2[M+H] + The MS ESI calculated value for this is 386.1, and the measured value is 386.0.

[0283] Example 27: 6-[5-fluoro-6-(2,2,2-trifluoro-1,1-dimethylethoxy)-3-pyridyl]-3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyridine [ka] Synthesis of A33: To a solution of (5-bromo-2-pyridyl)hydrazine (8.5 g, 45.21 mmol) in toluene (80 mL), 2-methoxyacetyl chloride (5.4 g, 49.73 mmol) was added dropwise at 25°C. The solution was stirred at 25°C for 30 minutes, and then refluxed at 120°C for 48 hours. After cooling to room temperature, the reaction mixture was concentrated to obtain a residue. The residue was rinsed off with DCM (100 mL) to obtain the product (3.0 g, 10.01 mmol, 22% yield) as a solid. 1 H NMR (MeOD-d4, 400MHz) δ=9.15(s, 1H), 8.19-8.32(m, 1H), 8.11-7.96(m, 1H), 5.09(s, 2H), 3.49(s, 3H).

[0284] Synthesis of Compound 28: A mixture of 6-bromo-3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyridine (150 mg, 0.62 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoro-1,1-dimethylethoxy)pyridine (259.61 mg, 0.74 mmol), K2CO3 (171.29 mg, 1.24 mmol), and Pd(dppf)Cl2 (68.01 mg, 0.09 mmol) in a mixed solvent of 1,4-dioxane (15 mL) and water (3 mL) was heated at 85 °C for 16 hours. After cooling to room temperature, the reaction product was concentrated, diluted with H2O (20 mL), and then extracted with DCM (20 mL x 2). The combined organic phases were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was subjected to preparative HPLC (YMC-Actus). Triart C18 (100 mm × 30 mm, 5 μm) A=H2O (0.05% HCl) and B=CH3CN were used to purify the product over 8 minutes with 50-75% B), and the product was obtained in CH3CN / H2O (approximately 150 mL). The solution was concentrated to remove most of the CH3CN, and the pH was basicized to approximately 9 with NaHCO3 (solid), followed by extraction with DCM (50 mL × 3). The combined organic phase was concentrated to obtain the product (121.16 mg, 0.32 mmol, 51% yield) as a solid. 1 H NMR(CDCl3, 400MHz)δ=8.34(s, 1H), 8.16(d, 1H), 7.89(d, 1H), 7.60(dd, 1H), 7.47(dd, 1H), 5.08(s, 2H), 3.42(s, 3H), 1.87(s, 6H). LCMS R t = Chromatography for 2.0 minutes, 1.25 minutes, 10⁻⁸ AB, C 17 H 17 F4N4O2[M+ H] + The MS ESI calculated value for this was 385.1, while the measured value was 384.9.

[0285] Example 28: 6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyridine [ka] A mixture of 6-bromo-3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyridine (150 mg, 0.62 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (238.75 mg, 0.74 mmol), K2CO3 (171.29 mg, 1.24 mmol), and Pd(dppf)Cl2 (68.01 mg, 0.09 mmol) in a mixed solvent of 1,4-dioxane (15 mL) and water (3 mL) was stirred at 85°C for 16 hours. After cooling to room temperature, the reaction product was concentrated, diluted with H2O (20 mL), and then extracted with DCM (20 mL x 2). The combined organic phases were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by preparative HPLC (Boston Prime C18 (150 mm × 30 mm, 5 μm) A=H2O (0.05% NH4OH) and B=CH3CN, 40-70% B in 8 mins) to obtain the product (141.29 mg, 0.39 mmol, 64% yield) as a solid. 1 H NMR(CDCl3, 400MHz)δ=8.35(s, 1H), 8.17(d, 1H), 7.90(d, 1H), 7.65(dd, 1H), 7.47(dd, 1H), 5.09(s, 2H), 4.91(q, 2H), 3.43(s, 3H). LCMS R t = Chromatography for 2.0 minutes, 1.17 minutes, 10⁻⁸ AB, C 15 H 13 F4N4O2[M+H] + MS ESI calculated value: 357.1, measured value: 356.9.

[0286] Example 29: 3-[difluoro(methoxy)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyridine [ka] A mixture of 6-bromo-3-[difluoro(methoxy)methyl]-[1,2,4]triazolo[4,3-a]pyridine (70 mg, 250 μmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (97 mg, 300 μmol), K2CO3 (69.59 mg, 0.50 mmol), and Pd(dppf)Cl2 (27.63 mg, 0.04 mmol) in 1,4-dioxane (5 mL) and water (0.50 mL) was heated at 80°C. The mixture was stirred under N2 for 12 hours. After cooling to room temperature, the mixture was diluted with H2O (10 mL) and extracted with SiO2 (20 mL x 2). The combined organic phase was washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was first purified by preparative HPLC (Boston Prime C18 (150 mm x 30 mm, 5 μm), A=H2O (0.05% NH4OH) and B=CH3CN, 43-73% B over 8 minutes), and then purified by preparative HPLC (Boston Green ODS (150 mm x 30 mm, 5 μm), A=H2O (0.075% TFA) and B=CH3CN, 49-63% B over 10 minutes). The combined fractions were concentrated to remove ACN, basicized to approximately pH 8 with saturated NaHCO3, and the mixture was extracted with HCl (30 mL x 2). The combined organic phase was washed with brine (40 mL), dried over Na2SO4, filtered, and concentrated to obtain the product (41.36 mg, 105.4 μmol, 42% yield) as a solid. 1 1H NMR (DMSO-d6, 400MHz)δ H= 8.74(s, 1H), 8.47(d, 1H), 8.36(dd, 1H), 8.11(dd, 1H), 7.96(dd, 1H), 5.18(q, 2H), 3.89(s, 3H). LCMS R t = 1.19 minutes in chromatography at 2.0 minutes, 10⁻⁸ AB, MS ESI calculated value C 15 H 11 F6N4O2[M+H] +393.1, actual measured value 393.0.

[0287] Example 30: 6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methylethoxy]-3-pyridyl]-3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyrazine [ka] A mixture of 6-chloro-3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyrazine (70 mg, 0.35 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methylethoxy]pyridine (141.73 mg, 0.42 mmol), Cs2CO3 (229.66 mg, 0.70 mmol), and Pd(dppf)Cl2 (38.68 mg, 0.05 mmol) in 1,4-dioxane (5 mL) and water (0.50 mL) was stirred under N2 at 70°C for 5 hours. After cooling to room temperature, the mixture was diluted with H2O (20 mL) and extracted with ELISA (30 mL x 2). The combined organic phases were washed with water (30 mL) and brine (30 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was first purified by preparative TLC (silica gel, PE:siRNA = 1:1). The resulting product was purified by preparative HPLC (Boston Prime C18 (150 mm × 30 mm, 5 μm), A=H2O (0.05% NH4OH) and B=CH3CN, 38-68% B over 9 minutes) to obtain the product (4.43 mg, 11.9 μmol, 3% yield) as a solid. 1 1H NMR (CDCl3, 400MHz)δ H =9.44(d, 1H), 8.49(dd, 1H), 8.47(s, 1H), 8.05(dd, 1H), 5.95-5.83(m, 1H), 5.14(s, 2H), 3.47(s, 3H), 1.60 (d, 3H). LCMS R t = 1.18 min chromatography in 2.0 mins, 10⁻⁸ AB, MS ESI calculated value C15 H 14 F4N5O2[M+H] + 372.1, actual measured value 371.9.

[0288] Example 31: 3-[ethoxy(difluoro)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methylethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyridine [ka] A mixture of 6-bromo-3-[ethoxy(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyridine (100 mg, 0.34 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methylethoxy]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 under N2 at 80°C for 12 hours. After cooling to room temperature, the mixture was diluted with H2O (10 mL) and extracted with ELISA (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 obtain the crude product. The crude product was purified by preparative HPLC (Boston Prime C18 (150 mm × 30 mm, 5 μm), A=H2O (0.05% NH4OH) and B=CH3CN, 60-90% B over 9 minutes) to obtain the product (39.75 mg, 93.5 μmol, 27% yield) as a solid. 1 1H NMR (DMSO-d6, 400MHz)δ H =8.72(s, 1H), 8.44(d, 1H), 8.33(dd, 1H), 8.10(d, 1H), 7.94(dd, 1H), 6.02(spt, 1H), 4.29(q, 2H), 1.54(d, 3H), 1.36(t, 3H). LCMS R t= 1.28 minutes in chromatography at 2.0 minutes, 10⁻⁸ AB MS ESI calculated value C 17 H 15 F6N4O2[M+H] + 421.1, measured value 421.0.

[0289] Example 32: 3-[ethoxy(difluoro)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methylethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine [ka] A mixture of 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methylethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine (200 mg, 0.49 mmol) and AgOTf (1.25 g, 4.86 mmol) in ethanol (10 mL) and MeCN (10 mL) was stirred at 90°C for 5 days. The mixture was cooled to room temperature. SiO (50 mL) and brine (50 mL) were added to the mixture, and the mixture was filtered through Celite. The liquid was separated, and the aqueous layer was extracted with alkylammonium sulfate (50 mL). The combined organic phase was dried over anhydrous sodium 2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by flash chromatography on silica gel (alkylammonium sulfate in PE = 10%, 30%, and 50%), and then polished with n-hexane (5 mL) to obtain the product (41.27 mg, 98.0 μmol, 20% yield) as a solid. 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 t = 1.29 minutes of chromatography in 2.0 minutes, 10⁻⁸⁰AB, C 16 H 14 F6N5O2[M+H]+ The MS ESI calculated value for this is 422.1, and the measured value is 422.0.

[0290] Example 33: 3-[ethoxy(difluoro)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methylethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyridine [ka] A mixture of 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methylethoxy]pyridine (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 under N2 at 90°C for 16 hours. After cooling to room temperature, the mixture was filtered through Celite, eluted with ELISA (10 mL x 2), and the filtrate was concentrated to obtain the crude product. The crude product was purified by preparative HPLC (Boston Prime C18 (150 mm × 30 mm, 5 μm) A=H2O (0.05% NH4OH) and B=CH3CN, 45-75% of B over 9 minutes) to obtain the product (62.87 mg, 0.15 mmol, 43% yield) as a solid. 1 1H NMR (DMSO-d6, 400MHz)δ H =8.72(s, 1H), 8.44(d, 1H), 8.33(dd, 1H), 8.14-8.06(m, 1H), 7.94(dd, 1H), 6.01(spt, 1H), 4.28(q, 2H), 1.54(d, 3H), 1.36(t, 3H). LCMS R t = 1.26 minutes in chromatography at 2.0 minutes, 10⁻⁸ AB, C 17 H 15 F6N4O2[M+H] +The MS ESI calculated value for this is 421.1, and the measured value is 421.0.

[0291] Example 34: 6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-3-(methoxymethyl)-[1,2,4]triazolo[4,3-b]pyridazine [ka] A mixture of 6-chloro-3-(methoxymethyl)-[1,2,4]triazolo[4,3-b]pyridazine (100 mg, 0.50 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (194 mg, 0.60 mmol), K3PO4 (213.79 mg, 1.01 mmol), and Pd(t-Bu3P)2 (38.6 mg, 0.08 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was stirred for 3 hours at 80°C under N2. After cooling to room temperature, water (20 mL) and ethyl acetate (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 on anhydrous Na₂SO₄, filtered, and concentrated to obtain the crude product. The crude product was purified by preparative HPLC (Boston Prime C18 (150 mm × 30 mm, 5 μm) A=H₂O (0.05% NH₄OH) and B=CH₃CN, 33-63% B over 8 minutes) to obtain the product (49 mg, 137.2 μmol, 27% yield) as a solid. 1 1H NMR (CDCl3, 400MHz)δ H =8.54(d, 1H), 8.25(d, 1H), 8.17(dd, 1H), 7.58(d, 1H), 5.11(s, 2H), 4.94(q, 2H), 3.54(s, 3H). LCMS R t = 1.08 min chromatography in 2.0 mins, 10⁻⁸ AB, C 14 H 12 F4N5O2[M+H] + The MS ESI calculated value for this was 358.1, while the measured value was 357.9.

[0292] Example 35: 3-[cyclopropoxy(difluoro)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methylethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyridine [ka] A mixture of 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methylethoxy]pyridine (121.22 mg, 0.36 mmol), Pd(dppf)Cl2 (36.09 mg, 0.05 mmol), 6-bromo-3-[cyclopropoxy(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyridine (100 mg, 0.33 mmol), and K2CO3 (90.9 mg, 0.66 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was stirred under N2 at 90°C for 16 hours. After cooling to room temperature, the mixture was filtered through Celite, eluted with ELISA (10 mL x 2), and the filtrate was concentrated to obtain the crude product. The crude product was analyzed by preparative HPLC (Boston Prime C18 (150 mm x 30 mm, 5 μm) A=H2O (0.05% NH4OH) and The product was purified by 47-77% of the solution (B=CH3CN) over 9 minutes to obtain the solid product (54.98 mg, 0.13 mmol, 39% yield). 1 1H NMR (DMSO-d6, 400MHz)δ H =8.65(s, 1H), 8.44(d, 1H), 8.33(dd, 1H), 8.11(d, 1H), 7.94(dd, 1H), 6.07-5.97(m, 1H), 4.25-4.15(m, 1H), 1.54(d, 3H), 0.95-0.86(m, 2H), 0.77-0.69(m, 2H). LCMS R t = 1.33 minutes in chromatography with 2.0 minutes, 10⁻⁸⁰ AB C 18 H 15 F6N4O2[M+H] +The MS ESI calculated value for this is 433.1, and the measured value is also 433.1.

[0293] Example 36: 3-[cyclopropoxy(difluoro)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyridine [ka] Synthesis of A36: To a mixture of cyclopropanol (246.74 mg, 4.25 mmol) and 6-bromo-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyridine (600 mg, 2.12 mmol) in DMF (10 mL), potassium tert-butoxide (476.69 mg, 4.25 mmol) was added. The reaction mixture was stirred at 20°C for 2 hours. The reaction was quenched with saturated NH4Cl (40 mL), and the mixture was then extracted with ELISA (50 mL x 2). The combined organic phase was washed with water (80 mL) and brine (80 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by flash chromatography on silica gel (ethyl acetate in PE = 0%, 20%, and 40%) to obtain the product (270 mg, 0.89 mmol, 42% yield) as a solid. LCMS R t = 3.74 minutes in chromatography at 7.0 minutes, 0-60 AB MS ESI calculated value C 10 H9BrF2N3O[M+H+2] + 306.0, measured value 305.8.

[0294] Synthesis of compound 37: A mixture of 6-bromo-3-[cyclopropoxy(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyridine (100 mg, 0.33 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methylethoxy]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 under N2 at 80°C for 12 hours. After cooling to room temperature, the mixture was diluted with H2O (10 mL) and extracted with siRNA (20 mL x 2). The combined organic phase was washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by preparative HPLC (Boston Prime C18 (150 mm x 30 mm, 5 μm), A=H2O (0.05% NH4OH) and B=CH3CN; 50-70% B over 9 minutes) to obtain the product (35.99 mg, 83.2 μmol, 25% yield) as a solid. 1 1H NMR (DMSO-d6, 400MHz)δ H =8.65(s, 1H), 8.44(d, 1H), 8.33(dd, 1H), 8.11(dd, 1H), 7.94(dd, 1H), 6.09-5.95(m, 1H), 4.25-4.14(m, 1H), 1.54(d, 3H), 0.95-0.86(m, 2H), 0.79-0.67(m, 2H). LCMS R t = 1.29 minutes in 2.0 minutes chromatography, 10⁻⁸ AB, MS ESI calculated value C 18 H 15 F6N4O2[M+H] + 433.1, measured value 433.0.

[0295] Example 37: 6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methylethoxy]-3-pyridyl]-3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyrazine [ka] Synthesis of A37: A mixture of 1,1,2-trimethoxyethane (1.25 g, 10.38 mmol) and (5-chloropyrazine-2-yl)hydrazine (1 g, 6.92 mmol) in ethanol (20 mL) was mixed with 12 N 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, and the pH was then basicized to approximately 9 with Na₂CO₃ (solid), and extracted with siRNA (50 mL × 4). The combined organic phase was washed with brine (30 mL), dried over Na₂SO₄, filtered, and concentrated to obtain the crude product. The crude product was polished with siRNA / PE (2 / 10 mL), dried in an oven to obtain 5-chloro-N-(2-methoxyethylideneamino)pyrazine-2-amine (1050 mg, 3.73 mmol, 54% yield) as a solid. LCMS R t = Chromatography for 1.5 minutes, 0.70 minutes, 5-95AB, C7H 10 ClN4O[M+H] + MS ESI calculated value: 201.0, measured value: 201.0.

[0296] Synthesis of A38: To a mixture of 5-chloro-N-(2-methoxyethylideneamino)pyrazine-2-amine (1 g, 4.98 mmol) in DMF (10 mL), a solution of NBS (1.24 g, 6.98 mmol) in DMF (7 mL) was added dropwise over 0.5 hours, and the mixture was then stirred at 20°C for 1 hour. The mixture was diluted with H₂O (50 mL) and extracted with SiO₂ (50 mL x 4). The combined organic phase was washed with brine (50 mL), dried over Na₂SO₄, filtered, and concentrated to obtain the crude product (1000 mg, 3.58 mmol, 72% yield) as a solid, which was used directly without any further purification. LCMS R t= Chromatography for 1.5 minutes, followed by 0.80 minutes, 5-95AB, C7H9BrClN4O[M+H+2] + The MS ESI calculated value for this was 281.0, and the measured value was 280.9.

[0297] Synthesis of A34: To a mixture of N-(5-chloropyrazine-2-yl)-2-methoxyethanehydrazonoyl bromide (1 g, 3.58 mmol) in toluene (15 mL), Et3N (0.99 mL, 7.16 mmol) was added, and the mixture was stirred at 20°C for 1 hour. The mixture was diluted with H2O (30 mL) and extracted with siRNA (50 mL × 2). The combined organic phase was washed with water (20 mL × 2) and brine (20 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by flash chromatography on silica gel (siRNA in PE = 0% to 40% to 80%) to obtain the product (380 mg, 1.87 mmol, 52% yield) as a solid. 1 1H NMR (CDCl3, 400MHz)δ H= 9.21(d, 1H), 8.28(d, 1H), 5.07(s, 2H), 3.45(s, 3H). LCMS R t = Chromatography for 1.5 minutes followed by 0.30 minutes, 5-95AB, C7H8ClN4O[M+H] + The MS ESI calculated value for this is 199.0, and the measured value is also 199.0.

[0298] Synthesis of compound 38: A mixture of 6-chloro-3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyrazine (70 mg, 0.35 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methylethoxy]pyridine (177.16 mg, 0.53 mmol), Pd(dppf)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 under N2 at 75 °C for 12 hours. After cooling to room temperature, the mixture was diluted with H2O (30 mL) and extracted with ELISA (50 mL x 2). The combined organic phases were washed with water (20 mL x 2) and brine (20 mL), dried on Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was first purified by preparative TLC (silica gel, PE:siRNA = 1:1), and then purified by preparative HPLC [Boston Prime C18 (150 mm x 30 mm, 5 μm) A=H2O (0.05% NH4OH) and B=CH3CN, 38-68% B over 9 minutes] to obtain the product (12.63 mg, 34.0 μmol, 10% yield) as a solid. 1 1H NMR (CDCl3, 400MHz)δ H= 9.44 (d, 1H), 8.50(d, 1H), 8.47(d, 1H), 8.05(dd, 1H), 5.97-5.84(m, 1H), 5.14(s, 2H), 3.47(s, 3H), 1.60(d, 3H). LCMS R t = 1.17 minutes in chromatography at 2.0 minutes, 10⁻⁸⁰AB C 15 H 14 F4N5O2[M+H] + The MS ESI calculated value for this is 372.1, while the measured value is 371.9.

[0299] Example 38: 6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyrazine [ka] A mixture of 6-chloro-3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyrazine (70 mg, 0.35 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (169.75 mg, 0.53 mmol), Pd(dppf)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 under N2 at 75°C for 12 hours. After cooling to room temperature, the mixture was diluted with H2O (20 mL) and extracted with ELISA (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 obtain the crude product. The crude product was purified by preparative TLC (silica gel, PE:siRNA = 1:1) to obtain the product (14.65 mg, 40.7 μmol, 12% yield) as a solid. 1 1H NMR (CDCl3, 400MHz)δ H= 9.44(d, H), 8.52(d, 1H), 8.48(d, 1H), 8.07(dd, 1H), 5.14(s, 2H), 4.92(q, 2H), 3.47(s, 3H) ) LCMS R t = 1.19 minutes in chromatography at 2.0 minutes, 10⁻⁸⁰AB C 14 H 12 F4N5O2[M+H] + The MS ESI calculated value for this was 358.1, while the measured value was 357.9.

[0300] Example 39: 6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methylethoxy]-3-pyridyl]-3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyridine [ka] A mixture of 6-bromo-3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyridine (200 mg, 0.83 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methylethoxy]pyridine (332.23 mg, 0.99 mmol), K2CO3 (228.38 mg, 1.65 mmol), and Pd(dppf)Cl2 (90.68 mg, 0.12 mmol) in 1,4-dioxane (15 mL) and water (5 mL) was incubated at 85°C for 16 hours. After cooling to room temperature, the reaction mixture was concentrated, diluted with H2O (20 mL), and then extracted with DCM (20 mL x 2). The combined organic phases were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified using preparative HPLC (Boston Prime C18 (150 mm × 30 mm 5 μm) A=H2O (0.05% NH4OH) and B=CH3CN, 35-65% B over 9 minutes) to obtain the product (104.44 mg, 0.28 mmol, 34% yield) as a solid. 1 1H NMR (DMSO-d6, 400MHz)δ H =8.85(s, 1H), 8.49(d, 1H), 8.35(dd, 1H), 7.89-8.05(m, 1H), 7.77-7.88(m, 1H), 6.05-5.87(m, 1H), 5.02(s, 2H), 3.35(s, 3H), 1.55(d, 3H). LCMS R t = Chromatography for 2.0 minutes, 1.150 minutes, 10⁻⁸ AB, C 16 H 15 F4N4O2[M+H] + The MS ESI calculated value for this is 371.1, and the measured value is also 371.1.

[0301] Example 40: 3-[ethoxy(difluoro)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methylethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyridazine [ka] 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methylethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyridazine (300 mg, 0.73 mmol) and AgOTf (1872.33 mg, 7.29 mmol) in ethanol (10 mL) and MeCN (10 mL). The mixture of l) was stirred at 90°C for 9 days. After cooling to room temperature, the reaction was diluted with Â(60 mL), and brine(20 mL) was added to the mixture. The mixture was filtered through Celite and extracted with Â(50 mL × 2). The combined organic layer was washed with water(50 mL) and brine(50 mL), dried over Na₂SO₄, filtered, and concentrated to obtain the crude product. The crude product was purified by flash chromatography on silica gel (Â in PE = 0% to 70%). The product was then rinsed with n-hexane(1 mL) and i-Pr₂O(1 mL) to obtain the product (28.86 mg, 67.3 μmol, 9% yield) as a solid. 1 1H NMR (CDCl3, 400MHz)δ H =8.54(d, 1H), 8.29(d, 1H), 8.13(dd, 1H), 7.65(d, 1H), 5.92(spt, 1H), 4.33(q, 2H), 1.61(d, 3H), 1.48(t, 3H). LCMS R t = 1.27 minutes in 2.0 minutes chromatography, 10⁻⁸ AB, MS ESI calculated value C 16 H 14 F6N5O2[M+H] + 422.1, measured value 422.0.

[0302] Example 41: 3-[ethoxy(difluoro)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methylethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyridazine [ka] Synthesis of A26-a: A mixture of 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methylethoxy]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 under N2 at 80°C for 16 hours. After cooling to room temperature, the mixture was filtered through Celite, eluted with SiO2 (20 mL x 2), and the filtrate was concentrated to obtain the crude product. The crude product was purified by flash chromatography on silica gel (acetyl in PE = 30% to 60%) to obtain the product (1000 mg, 2.12 mmol, 51% yield) as a solid. LCMS R t = 1.5 minutes chromatography for 0.93 minutes, 5-95AB, C 14 H9ClF6N5O[M+H] + The MS ESI calculated value for this is 412.0, and the measured value is 412.1.

[0303] Synthesis of Compound 42: A mixture of 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methylethoxy]-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 mixture was diluted with SiO2 (40 mL), and the mixture was saturated with NaCl ( The mixture was added to 40 mL, filtered through Celite, eluted with siRNA (20 mL x 2), and the filtrate was concentrated to obtain the crude product. The crude product was purified by flash chromatography on silica gel (siRNA in PE = 0%, 50%, and 100%). The product was further purified by preparative HPLC (Boston Prime C18 (150 mm x 30 mm, 5 μm) A=H2O (0.05% NH4OH volume / volt) and B=CH3CN, 51-81% of B over 9 minutes) to obtain the product (8.12 mg, 19.3 μmol, 3% yield) as a solid. 1 1H NMR (CDCl3, 400MHz)δ H =8.54(d, 1H), 8.30(d, 1H), 8.13(dd, 1H), 7.66(d, 1H), 5.96-5.88(m, 1H), 4.33(q, 2H), 1.62(s, 3H), 1.48(t, 3H). LCMS R t = 1.29 minutes of chromatography in 2.0 minutes, 10⁻⁸⁰AB, C 16 H 14 F6N5O2[M+H] + The MS ESI calculated value for this is 422.1, and the measured value is 422.0.

[0304] Example 42: 6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methylethoxy]-3-pyridyl]-3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyridine [ka] A mixture of 6-bromo-3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyridine (100 mg, 0.41 mmol), Pd(dppf)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-methylethoxy]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 under N2 at 80°C for 16 hours. After cooling to room temperature, the mixture was filtered through Celite, eluted with ELISA (10 mL × 2), and the filtrate was concentrated to obtain the crude product. The crude product was purified by flash chromatography on silica gel (50% to 100% Â in PE). The product was then polished with n-hexane / DCM (5:1, 10 mL) to obtain the product (46.5 mg, 0.13 mmol, 30% yield) as a solid. 1 1H NMR (DMSO-d6, 400MHz)δ H =8.84(s, 1H), 8.49(d, 1H), 8.35(dd, 1H), 7.97-7.90(m, 1H), 7.87-7.80(m, 1H), 6.01(spt, 1H), 5.01(s, 2H), 3.34(s, 3H), 1.54(d, 3H). LCMS R t = 1.13 minutes in chromatography at 2.0 minutes, 10⁻⁸ AB, C 16 H 15 F4N4O2[M+H] + The MS ESI calculated value for this was 371.1, while the measured value was 370.9.

[0305] Example 43: 6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methylethoxy]-3-pyridyl]-3-(methoxymethyl)-[1,2,4]triazolo[4,3-b]pyridazine [ka] A mixture of 6-chloro-3-(methoxymethyl)-[1,2,4]triazolo[4,3-b]pyridazine (100 mg, 0.50 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methylethoxy]pyridine (202.47 mg, 0.60 mmol), K3PO4 (213.79 mg, 1.01 mmol), and Pd(t-Bu3P)2 (38.6 mg, 0.08 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was stirred for 3 hours at 80°C under N2. After cooling to room temperature, water (20 mL) and ethyl acetate (20 mL) were added to the mixture and filtered through Celite. After separation, the organic phase was washed with brine (20 mL), dried on anhydrous Na₂SO₄, filtered, and concentrated to obtain the crude product. The crude product was purified by preparative HPLC (Boston Prime C18 (150 mm × 30 mm, 5 μm) A=H₂O (0.05% NH₄OH) and B=CH₃CN, 33-63% B over 8 minutes) to obtain the product (38 mg, 102.3 μmol, 20% yield) as a solid. 1 1H NMR (CDCl3, 400MHz)δ H =8.53(d, 1H), 8.25(d, 1H), 8.14(dd, 1H), 7.57(d, 1H), 5.98-5.85(m, 1H), 5.11(s, 2H), 3.54(s, 3H), 1.61(d, 3H). LCMS R t = 1.13 minutes in chromatography at 2.0 minutes, 10⁻⁸ AB, C 15 H 14 F4N5O2[M+H] + The MS ESI calculated value for this is 372.1, while the measured value is 371.9.

[0306] Example 44: 3-[difluoro(isobutoxy)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methylethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine [ka] A mixture of 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methylethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine (200 mg, 0.49 mmol) and AgOTf (1.25 g, 4.86 mmol) in isobutyl alcohol (10 mL) and MeCN (10 mL) was stirred at 90°C for 7 days. SiO (50 mL) and brine (50 mL) were added to the mixture, and several solids were observed. The mixture was filtered through Celite. The filtrate was separated, and the aqueous layer was extracted with SiO (50 mL). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain the crude product. The crude product was purified by flash chromatography on silica gel (with  in PE = 10%, 30%, and 50%) to obtain the product (80 mg) as oil.

[0307] The impure product (80 mg, 0.18 mmol) was subjected to preparative HPLC (Boston Group). The organic phase was purified using an ODS (150 mm × 30 mm, 5 μm) with A=H₂O (0.075% TFA) and B=CH₃CN (66-96% B) over 8 minutes, and concentrated to obtain the residue. Saturated NaHCO₃ aqueous solution (10 mL) was added to the residue, and the mixture was extracted with RINKAN (15 mL × 2). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain the product (55.97 mg, 124.6 μmol, 70% yield) as a solid. 1 1H NMR (CDCl3 + D2O, 400MHz)δ H =9.52(d, 1H), 8.53-8.43(m, 2H), 8.04(dd, 1H), 5.98-5.84(m, 1H), 4.06(d, 2H), 2.21-2.06(m, 1H), 1.60(d, 3H), 1.08(d, 6H). LCMS R t = 1.37 minutes in chromatography at 2.0 minutes, 10⁻⁸ AB, C 18 H 18 F6N5O2[M+H] +The MS ESI calculated value for this is 450.1, and the measured value is 450.0.

[0308] Example 45: 6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methylethoxy]-3-pyridyl]-3-(methoxymethyl)-[1,2,4]triazolo[4,3-b]pyridazine [ka] Synthesis of A32: To a solution of (6-chloropyridazin-3-yl)hydrazine (3 g, 20.75 mmol) in toluene (80 mL), 2-methoxyacetyl chloride (2.48 g, 22.83 mmol) was added dropwise at 25°C. The solution was stirred at 25°C for 30 minutes and refluxed at 120°C for 24 hours. After cooling to room temperature, the mixture was diluted with H2O (40 mL) and extracted with siRNA (40 mL x 2). The combined organic phase was washed with brine (40 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was rinsed with i-Pr2O (10 mL) to obtain the product (1500 mg, 7.31 mmol, 35% yield) as a solid. LCMS R t = Chromatography for 1.5 minutes, 0.43 minutes, 5-95AB, C7H8ClN4O[M+H] + The MS ESI calculated value for this is 198.0, and the measured value is 199.0.

[0309] Synthesis of compound 46: A mixture of 6-chloro-3-(methoxymethyl)-[1,2,4]triazolo[4,3-b]pyridazine (100 mg, 0.5 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methylethoxy]pyridine (202.47 mg, 0.6 mmol), K3PO4 (213.79 mg, 1.01 mmol), and Pd(t-Bu3P)2 (38.6 mg, 0.08 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was stirred under N2 at 80°C for 12 hours. After cooling to room temperature, the mixture was diluted with H2O (10 mL) and extracted with ELISA (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 obtain the crude product. The crude product was purified by preparative HPLC (column: Boston Prime (150 mm × 30 mm, 5 μm; mobile phase: A = H2O (0.05% NH4OH); B = CH3CN, 35-65% B over 9 minutes) to obtain the product (43.29 mg, 0.12 mmol, 23% yield) as a solid. 1 1H NMR (CDCl3, 400MHz)δ H =8.53(d, 1H), 8.25(d, 1H), 8.14(dd, 1H), 7.57(d, 1H), 5.98-5.5.85(m, 1H), 5.11(s, 2H), 3.54(s, 3 H), 1.61(d, 3H). LCMS R t = Chromatography for 2.0 minutes, 1.17 minutes, 10⁻⁸ AB, C 15 H 14 F4N5O2[M+H] + The MS ESI calculated value for this is 372.1, and the measured value is also 372.1.

[0310] Example 46: 3-[difluoro(isobutoxy)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methylethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyridazine [ka] A mixture of 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methylethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyridazine (300 mg, 0.73 mmol) and AgOTf (1872.33 mg, 7.29 mmol) in 2-methylpropan-1-ol (10 mL, 0.73 mmol) and MeCN (10 mL) was stirred at 90°C for 9 days. After cooling to room temperature, the reaction product was diluted with Depositphotos (60 mL) and brine (20 mL), filtered through Celite, and extracted with Depositphotos (50 mL x 2). The combined organic layer was washed with water (50 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by flash chromatography on silica gel (ethyl acetate in PE = 0% to 70%). The isolated product was further purified by preparative HPLC (Boston Prime C18 (150 mm × 30 mm, 5 μm), A=H2O (0.05% NH4OH) and B=CH3CN, 60–90% of B in 9 minutes) to obtain the product (7.42 mg, 16.5 μmol, 2% yield) as a solid. 1 1H NMR (CDCl3, 400MHz)δ H= 8.54(d, 1H), 8.30(d, 1H), 8.14(dd, 1H), 7.66(d, 1H), 5.98-5.85(m, 1H), 4.01(d, 2H), 2.15-2.01(m, 1H), 1.61(d, 3H), 1.05(d, 6H). LCMS R t = 1.39 minutes in chromatography at 2.0 minutes, 10⁻⁸ AB, MS ESI calculated value C 18 H 18 F6N5O2[M+H] + 450.1, measured value 450.1.

[0311] Example 47: 3-[ethoxy(difluoro)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methylethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyridazine [ka] 6-chloro-3-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyrazine (150 mg, 0.76 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxane (8 mL) and water (0.80 mL) A mixture of sabororan-2-yl)-2-(2,2,2-trifluoro-1,1-dimethylethoxy)pyridine (527.36 mg, 1.51 mmol), Cs2CO3 (738.18 mg, 2.27 mmol), and Pd(dppf)Cl2 (110.52 mg, 0.15 mmol) was stirred under N2 at 75°C for 9 hours. After cooling to room temperature, the mixture was diluted with H2O (20 mL) and extracted with  (30 mL × 2). The combined organic phase was washed with water (30 mL × 1) and brine (30 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by preparative HPLC (Boston Prime C18 (150 mm × 30 mm, 5 μm), A=H2O (0.05% NH4OH) and B=CH3CN, 49-59% of B over 9 minutes) to obtain the product (90.56 mg, 235 μmol, 31% yield) as a solid. 1 1H NMR (CDCl3, 400MHz)δ H= 9.43(s, 1H), 8.57-8.40(m, 2H), 8.01(d, 1H), 5.13(s, 2H), 3.46(s, 3H), 1.88(s, 6H). LCMS R t = 1.24 min chromatography in 2.0 mins, 10⁻⁸ AB, MS ESI calculated value C 16 H 16 F4N5O2[M+H] + 386.1 (Measured value: 386.1)

[0312] Example 48: 3-[difluoro(isobutoxy)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methylethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyridazine [ka] A mixture of 2-methylpropan-1-ol (10 mL, 1.21 mmol) and CH3CN (10 mL) containing 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methylethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-b]pyridazine (500 mg, 1.21 mmol) and AgOTf (3120.6 mg, 12.15 mmol) was stirred at 90°C for 8 days. After cooling to room temperature, the reaction mixture was diluted with siRNA (40 mL), brine (40 mL) was added to the mixture, the mixture was filtered through Celite, eluted with siRNA (20 mL x 2), and the filtrate was concentrated to obtain the crude product. The crude product was purified by flash chromatography on silica gel (siRNA in PE = 0% to 50% to 100%) to obtain the impure product. The impure product was purified by preparative HPLC (Waters Xbridge 150 mm x 25 mm, 5 μm) A=H2O (10 mM NH4HCO3) and B=CH3CN (54-84% B over 8 minutes) to obtain the product (53.85 mg, 0.12 mmol, 10% yield) as a solid. 1 1H NMR (CDCl3, 400MHz)δ H =8.54(d, 1H), 8.30(d, 1H), 8.13(dd, 1H), 7.66(d, 1H), 5.92(spt, 1H), 4.01(d, 2H), 2.16-2.04(m, 1H), 1.61(d, 3H), 1.05(d, 6H). LCMS R t = 1.42 minutes in chromatography at 2.0 minutes, 10⁻⁸ AB, C 18 H 18 F6N5O2[M+H] + The MS ESI calculated value for this is 450.1, and the measured value is also 450.1.

[0313] Example 49: 3-(ethoxymethyl)-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methylethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine [ka] Synthesis of A40: A mixture of [5-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methylethoxy]-3-pyridyl]pyrazine-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 into a residue, the residue was redissolved in siRNA (20 mL), washed with water (10 mL x 2) and brine (10 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the product (150 mg, 0.13 mmol, 20% yield) as a solid. LCMS R t = Chromatography for 1.5 minutes, 0.84 minutes, 5-95AB, C 16 H 18 F4N5O3[M+H] + MS ESI calculated value: 404.1, measured value: 404.2.

[0314] Synthesis of Compound 50: A mixture of 2-ethoxy-N'-[5-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methylethoxy]-3-pyridyl]pyrazine-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 obtain a solid. The solid was redissolved in siRNA (20 mL), basicized to approximately pH 9 with saturated Na₂CO₃, washed with water (10 mL x 2) and brine (10 mL x 2), dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain the crude product. The crude product was subjected to preparative HPLC (Boston The product (48.08 mg, 0.12 mmol, 34% yield) was obtained as a solid by purifying with 45-75% of B) in a 5 μM solution of A=H2O (0.05% ammonia hydroxide) and B=CH3CN over 9 minutes. 1 H NMR (DMSO-d6, 400MHz)δ H =9.55(d, 1H), 9.15(d, 1H), 8.77(d, 1H), 8.49(dd, 1H), 6.08-5.98(m, 1H), 5.08(s, 2H), 3.61(q, 2H), 1.55(d, 3H), 1.15(t, 3H). LCMS R t = 1.23 minutes in chromatography at 2.0 minutes, 10⁻⁸ AB, C 16 H 16 F4N5O2[M+H] + The MS ESI calculated value for this is 386.1, and the measured value is 386.0.

[0315] Example 50: 3-[cyclopropoxy(difluoro)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methylethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine [ka] To a mixture of cyclopropanol (28.22 mg, 0.49 mmol) and 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methylethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine (100 mg, 0.24 mmol) in DMF (2 mL), potassium tert-butoxide (54.51 mg, 0.49 mmol) was added 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 ELISA (10 mL x 2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by preparative HPLC (Waters Xbridge (150 mm × 25 mm, 5 μm) A=H2O (10 mM NH4HCO3) and B=CH3CN, 57-67% of B over 8 minutes) to obtain the product (3.98 mg, 0.01 mmol, 4% yield) as oil. 1 1H NMR (CD3CN, 400MHz) δ H =9.46(s, 1H), 8.67-8.56(m, 2H), 8.20(dd, 1H), 6.01-5.92(m, 1H), 4.21-4.14(m, 1H), 1.58(d, 3H), 1.00-0.91(m, 2H), 0.81-0.73(m, 2H). LCMS R t = 2 minutes chromatography, 1.31 minutes, 10⁻⁸ AB, C 17 H 14 F6N5O2[M+H] + The MS ESI calculated value for this is 434.1, while the measured value is 433.9.

[0316] Example 51: 3-(ethoxymethyl)-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methylethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine [ka] Synthesis of A41: A mixture of (5-chloropyrazine-2-yl)hydrazine (500 mg, 3.46 mmol) and 2-ethoxyacetyl chloride (551.03 mg, 4.5 mmol) in toluene (7 mL) was stirred at 20 °C for 2 hours, and then heated at 130 °C for 3 days. Most of the toluene was then removed, acetic acid (40 mL) was added, and the mixture was stirred at 120 °C for 16 hours. After cooling to room temperature, the mixture was concentrated to obtain a residue. The residue was redissolved in siRNA (40 mL), basicized to approximately pH 9 with saturated Na₂CO₃, washed with water (20 mL x 2) and brine (20 mL x 2), dried on anhydrous Na₂SO₄, filtered, and concentrated to obtain the crude product. The crude product was purified by flash chromatography on silica gel (siRNA = 40% to 70% in PE) to obtain the product (240 mg, 1.11 mmol, 32% yield) as a solid. LCMS R t = Chromatography for 1.5 minutes, 0.60 minutes, 5-95AB, C8H 10 ClN4O[M+H] + The MS ESI calculated value for this is 213.0, and the measured value is also 213.0.

[0317] Synthesis of compound 52: 3-fluorinated in 1,4-dioxane (10 mL) and water (2 mL) A mixture of ro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methylethoxy]pyridine (453.86 mg, 1.35 mmol), 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) was stirred under N2 at 75°C for 16 hours. After cooling to room temperature, the mixture was filtered through Celite, eluted with ELISA (10 mL x 2), and the filtrate was concentrated to obtain the crude product. The crude product was purified by flash chromatography on silica gel (siRNA in PE = 30%, 60%, and 100%) to obtain an impure product. The impure product was purified by preparative HPLC (Waters Xbridge 150mm × 25mm, 5μm) A=H2O (10mM NH4HCO3) and B=CH3CN (40-70% B over 8 minutes) to obtain the product (37.8 mg, 98.1 μmol, 9% yield) as a solid. 1 1H NMR (DMSO-d6, 400MHz)δ H =9.56(d, 1H), 9.15(d, 1H), 8.77(d, H), 8.49(dd, 1H), 6.09-5.97(m, 1H), 5.08(s, 2H), 3.61(q, 2H), 1.55(d, 3H), 1.14(t, 3H). LCMS R t = 1.24 minutes in chromatography at 2.0 minutes, 10⁻⁸ AB, C 16 H 16 F4N5O2[M+H] + The MS ESI calculated value for this is 386.1, and the measured value is also 386.1.

[0318] Example 52: 3-[difluoro(methoxy)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine [ka] Synthesis of A19-a: A mixture of 2-bromo-5-chloropyrazine (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), Cs2CO3 (10.11 g, 31.02 mmol), and Pd(dppf)Cl2 (1.7 g, 2.33 mmol) in 1,4-dioxane (50 mL) and water (5 mL) was stirred for 5 hours at 55 °C under N2. The reaction mixture was cooled to room temperature and concentrated to obtain a residue. Water (50 mL) and ethyl acetate (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 on anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by chromatographic flashing on silica gel (siRNA in PE = 0%, 5%, and 10%) to obtain the product (3700 mg, 10.69 mmol, 69% yield) as a solid. 1 1H NMR (DMSO-d6, 400MHz)δ H =9.19(d, 1H), 8.88(d, 1H), 8.80(d, 1H), 8.49(dd, 1H ), 5.18(q, 2H). LCMS R t = 1.5 minutes chromatography for 0.93 minutes, 5-95AB, C 11 H7ClF4N3O[M+H] + The MS ESI calculated value for this is 308.0, and the measured value is also 308.0.

[0319] Synthesis of A20-a: Hydrazine (3.85 g, 120.27 mmol) was added to a mixture of 2-chloro-5-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]pyrazine (3.7 g, 12.03 mmol) in MeCN (50 mL), and the mixture was stirred at 90°C for 16 hours. The reaction product was cooled to room temperature and concentrated to obtain a residue. Water (30 mL) was added to the residue and extracted with RINKAN (30 mL x 2). The combined organic phase was washed with brine (30 mL), dried on anhydrous Na2SO4, filtered, and concentrated to obtain the crude product (3500 mg, 9.60 mmol, 80% yield) as a solid. 1 1H NMR (DMSO-d6, 400MHz)δ H =8.62(d, 1H), 8.58(d, 1H), 8.30-8.24(m, 2H), 8.19(d, 1H), 5.12(q, 2H), 4.36(s, 2H). LCMS R t = Chromatography for 1.5 minutes, 0.73 minutes, 5-95AB, C 11 H 10 F4N5O[M+1H] + The MS ESI calculated value for this is 304.1, and the measured value is 304.0.

[0320] Synthesis of A18: A solution of [5-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]pyrazine-2-yl]hydrazine (3 g, 9.89 mmol) and (2-chloro-2,2-difluoroacetyl)2-chloro-2,2-difluoroacetate (7.21 g, 29.68 mmol) in toluene (60 mL) was stirred at 110 °C for 96 hours. Then, a molecular sieve (3 g) was added to the mixture, and the mixture was stirred at 130 °C for a further 16 hours. After cooling to room temperature, the mixture was concentrated to obtain a residue. Water (20 mL) was added to the residue and extracted with siRNA (30 mL × 2). The combined organic phase was washed with water (20 mL) and brine (20 mL × 2), dried on anhydrous Na₂SO₄, filtered, and concentrated to obtain the crude product. The crude product was purified by flash chromatography column on silica gel (0% to 10% to 20% Â in PE) to obtain the product (1300 mg, 3.24 mmol, 33% yield) as oil. LCMS R t = 4 minutes chromatography, 2.63 minutes, 10⁻⁸⁰AB, C 13 H7ClF6N5O[M+H] + The MS ESI calculated value for this was 398.0, while the measured value was 397.9.

[0321] Synthesis of Compound 53: A mixture of 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine (600 mg, 1.51 mmol) and AgOTf (3.88 g, 15.09 mmol) in methanol (12 mL) and DMF (4 mL) was stirred at 90°C for 48 hours. After cooling to room temperature, the reaction mixture was treated with brine (20 mL), and the precipitate was filtered. The filtrate was concentrated, diluted with water (20 mL), and then extracted with ELISA (20 mL x 3). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, concentrated, and the crude product was obtained. The crude product was purified by flash chromatography on silica gel (with alkyl groups of 0%, 10%, and 30% in PE) to obtain the product (247.53 mg, 0.63 mmol, 42% yield) as a solid.1 1H NMR (CDCl3, 400MHz)δ H =9.52(d, 1H), 8.52(d, 1H), 8.46(d, 1H), 8.07(dd, 1H), 4.93(q, 2H), 3.98(s, 3H). LCMS R t = 1.23 minutes of chromatography in 1.5 minutes, 5-95AB, C 14 H 10 F6N5O2[M+H] + The MS ESI calculated value for this is 394.1, and the measured value is 394.0.

[0322] Example 53: 3-[difluoro(methoxy)methyl]-6-[6-(2,2,2-trifluoro-1,1-dimethylethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine [ka] A mixture of 3-[chloro(difluoro)methyl]-6-[6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine (1.9 g, 4.66 mmol) and AgOTf (11.97 g, 46.59 mmol) in solvents DMF (15 mL) and methanol (15 mL) was stirred at 90°C for 96 hours. After cooling to room temperature, the reaction mixture was treated with brine (50 mL), and the precipitate was filtered. The filtrate was concentrated, diluted with water (40 mL), and then extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with brine (50 mL), dried over Na2SO4, and concentrated to obtain the crude product. The crude product was purified by flash chromatography on silica gel (ethyl acetate in PE = 0% to 40%) to obtain the product (170 mg). Another 88 mg of the product was obtained from a different batch. The three batches of product were combined and lyophilized to obtain the product (193.0 mg, 0.48 mmol) as a solid. 1H NMR (400MHz, CDCl3)δ=9.52(d, 1H), 8.72(d, 1H), 8.43(s, 1H), 8.19(dd, 1H), 6.94(d, 1H), 3.98(s, 3H), 1.87 ppm(s, 6H). LCMS R t = 1.235 minutes by chromatography at 2.0 minutes, 10⁻⁸ AB, C 16 H 15 F5N5O2[M+H] + The MS ESI calculated value for this was 404.1, while the measured value was 403.9.

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

[0324] Synthesis of A55: A mixture of 5-bromo-2-[1-(trifluoromethyl)cyclobutoxy]pyridine (2.5 g, 8.44 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-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 under N2 at 90°C for 12 hours. After cooling to room temperature, the mixture was concentrated to obtain a residue. The residue was diluted with H2O (40 mL), and the mixture was extracted with ELISA (40 mL x 2). The combined organic phases were washed with water (40 mL) and brine (40 mL), dried on Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by flash chromatography on silica gel (ethyl acetate in PE = 0% to 1%) to obtain the crude product (2.65 g, 3.92 mmol, 46% yield) as oil. 1 1H NMR (CDCl3, 400MHz)δ H =8.54(d, 1H), 7.95(dd, 1H), 6.74(d, 1H), 2.99-2.81(m, 2H), 2.75-2.53(m, 2H), 2.13-1.78(m, 2H), 1.34(s, 12H).

[0325] Synthesis of A56: A mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[1-(trifluoromethyl)cyclobutoxy]pyridine (2.1 g, 6.12 mmol), 2-bromo-5-chloropyrazine (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 under N2 at 60 °C for 6 hours. After cooling to room temperature, the mixture was concentrated to obtain a residue. The residue was diluted with H2O (20 mL), and the mixture was extracted with ELISA (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 obtain the crude product. The crude product was purified by flash chromatography on silica gel (siRNA in PE = 0%, 1%, and 10%) to obtain the product (1.5 g, 4.263 mmol, 70% yield) as oil. 1 1H NMR (CDCl3, 400MHz)δ H =8.80-8.72(m, 2H), 8.63(d, 1H), 8.25(dd, 1H), 6.91(d, 1H), 3.01-2.83(m, 2H), 2.78-2.62(m, 2H), 2.18-1.84(m, 2H).

[0326] Synthesis of A57: A mixture of 2-chloro-5-[6-[1-(trifluoromethyl)cyclobutoxy]-3-pyridyl]pyrazine (1.2 g, 3.64 mmol) and hydrazine (1.17 g, 36.4 mmol) in MeCN (20 mL) was heated to 90 °C and stirred for 16 hours. After cooling to room temperature, the reaction mixture was concentrated, diluted with H2O (30 mL), and extracted with SiO2 (30 mL x 2). The combined organic phase was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product (950 mg, 2.48 mmol, 68% yield) as a solid. LCMS R t = 2.0 minutes chromatography for 0.99 minutes, 10⁻⁸⁰AB, C 14 H 15 F3N5O[M+H]+ The MS ESI calculated value for this is 326.1, and the measured value is 326.0.

[0327] Synthesis of A58: A mixture of [5-[6-[1-(trifluoromethyl)cyclobutoxy]-3-pyridyl]pyrazine-2-yl]hydrazine (1.13 g, 3.47 mmol), 4A molecular weight sieve (1 g, 3.47 mmol), and (2-chloro-2,2-difluoro-acetyl)2-chloro-2,2-difluoroacetate (1.69 g, 6.95 mmol) in toluene (15 mL) was heated to 130 °C and stirred for 16 hours. After cooling to room temperature, the reaction mixture was filtered, diluted with H₂O (50 mL), and extracted with SiO₂ (50 mL × 2). The combined organic phase was washed with brine (50 mL), dried over Na₂SO₄, filtered, and concentrated to obtain the crude product (820 mg, 1.13 mmol, 33% yield) as a solid. LCMS R t = 1.38 minutes in chromatography at 2.0 minutes, 10⁻⁸ AB, C 16 H 12 ClF5N5O[M+H] + The MS ESI calculated value for this is 420.1, and the measured value is 420.0.

[0328] Synthesis of Compound 57: A mixture of 3-[chloro(difluoro)methyl]-6-[6-[1-(trifluoromethyl)cyclobutoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine (600 mg, 1.43 mmol) 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 SiO2 (30 mL x 2). The organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by flash chromatography on silica gel (PE = 0% to 40% to 70% siRNA) to obtain the product (194.76 mg, 0.47 mmol, 33% yield) as a solid. 1 1H NMR (CDCl3, 400MHz)δH =9.52(d, 1H), 8.72(d, 1H), 8.44(d, 1H), 8.23(dd, 1H), 7.0-6.89(m, 1H), 3.97(s, 3H), 3.00-2.85(m, 2H), 2.80-2.63(m, 2H), 2.13-1.89(m, 2H). LCMS R t = 1.33 minutes in chromatography at 2.0 minutes, 10⁻⁸ AB, C 17 H 15 F5N5O2[M+H] + The MS ESI calculated value for this is 416.1, and the measured value is also 416.1.

[0329] Example 56: 3-[difluoro(methoxy)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-5-methyl-[1,2,4]triazolo[4,3-a]pyrazine [ka] Synthesis of A59: 2-bromo-5-chloro-3-methylpyrazine (900 mg, 4.34 mmol) in 1,4-dioxane (40 mL) and water (8 mL), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methylethoxy]pyridine (1.31 g) A mixture of 3.9 mmol, Pd(dppf)Cl2 (0.48 g, 0.65 mmol), and Cs2CO3 (2.83 g, 8.68 mmol) was stirred at 50°C under N2 for 5 hours. The mixture was cooled to room temperature, diluted with HCl (30 mL), filtered through silica gel, eluted with HCl (20 mL), and the filtrate was concentrated to obtain the crude product. The product was purified by flash chromatography on silica gel (HCl in PE = 0% to 3%) to obtain the product (1100 mg, 2.83 mmol, 65% yield) as a solid. LCMS R t = 1.41 minutes of chromatography in 1.5 minutes, 10⁻⁸ AB, C 13 H 11ClF4N3O[M+H] + The MS ESI calculated value for this is 336.0, and the measured value is also 336.0.

[0330] Synthesis of A60: A mixture of 5-chloro-2-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methylethoxy]-3-pyridyl]-3-methylpyrazine (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 siRNA (20 mL x 2). The combined organic phase was washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated to obtain the crude product. The crude product was rinsed with PE (5 mL) to obtain the product (800 mg, 2.41 mmol, 68% yield) as a solid. The crude product was used in the next step without further purification. LCMS R t = Chromatography for 1.5 minutes, 0.75 minutes, 5-95AB, C 13 H 14 F4N5O[M+H] + The MS ESI calculated value for this is 332.1, and the measured value is also 332.1.

[0331] Synthesis of A61: To a mixture of [5-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methylethoxy]-3-pyridyl]-6-methylpyrazine-2-yl]hydrazine (500 mg, 1.51 mmol) in toluene (10 mL), (2-chloro-2,2-difluoro-acetyl)2-chloro-2,2-difluoroacetate (366.68 mg, 1.51 mmol) and a 4A molecular sieve (1 g) were added. The reaction mixture was stirred at 110 °C for 5 days. After cooling to room temperature, the reaction mixture was concentrated. The residue was diluted with saturated NaHCO3 (30 mL) and the mixture was extracted with ELISA (30 mL x 2). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated to obtain the residue. The residue was purified by flash column on silica gel (ethyl acetate in PE = 0% to 20%) to obtain the product (105 mg, 0.16 mmol, 11% yield) as a solid. LCMS R t = 1.5 minutes chromatography for 0.92 minutes, 5-95AB, C 15 H 11 ClF6N5O[M+H] + The MS ESI calculated value for this is 426.0, and the measured value is 426.2.

[0332] Synthesis of Compound 58: A mixture of 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methylethoxy]-3-pyridyl]-5-methyl-[1,2,4]triazolo[4,3-a]pyrazine (105 mg, 0.25 mmol) and AgOTf (633.7 mg, 2.47 mmol) in a mixed solvent of methanol (1 mL) and DMF (1 mL) was stirred at 90°C for 48 hours. After cooling to room temperature, the reaction mixture was treated with brine (15 mL), and the precipitate was filtered. The filtrate was extracted with ethyl acetate (15 mL x 2). The combined organic phase was dried over Na2SO4 and concentrated to obtain the crude product. The crude product was purified by flash chromatography on silica gel (ethyl acetate in PE = 0%, 30%, and 50%). Next, product e was rinsed with DCM (0.5 mL) and n-hexane (0.5 mL) to obtain the product (2.05 mg, 4.90 μmol, 2% yield). 1 1H NMR (CDCl3, 400MHz)δ H =9.39(s, 1H), 8.11(d, 1H), 7.69(dd, 1H), 5.94-5.86(m, 1H), 3.92(s, 3H), 2.88(s, 3H), 1.60(d, 3H). LCMS R t = 2 minutes chroma 1.24 minutes in tography, 10-80AB, C 16 H 14 F6N5O2[M+H] + The MS ESI calculated value for this is 422.1, and the measured value is 422.0.

[0333] Example 57: 3-[difluoro(methoxy)methyl]-6-[6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine [ka] Synthesis of A62: To a mixture of (2S)-2-(trifluoromethyl)oxirane (3 g, 26.77 mmol) in THF (25 mL), LiAlH4 (0.5 g, 13.2 mmol) was added under N2 at 0°C for 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, eluted with THF (20 mL x 2), the organic phase was washed with brine (20 mL x 2), dried over Na2SO4, and filtered to obtain 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.

[0334] Synthesis of A63: To a solution of (2S)-1,1,1-trifluoropropan-2-ol in THF (50 mL), NaH (0.8 g, 19.94 mmol) was added over 20 minutes at 0°C, and the mixture was stirred at 0°C for 40 minutes. Then, 5-bromo-2-fluoropyridine (2.7 g, 15.34 mmol) was added to the mixture, and the mixture was stirred at 50°C for 2 hours. The mixture was quenched with saturated NH4Cl (40 mL), extracted with siRNA (60 mL), the combined organic phase was washed with brine (40 mL x 2), dried over Na2SO4, filtered, and concentrated to obtain the crude product (3.48 g, 9.29 mmol, 61% yield) as oil. LCMS R t = Chromatography for 1.5 minutes, 0.95 minutes, 5-95AB, C8H8BrF3NO[M+H] + The MS ESI calculated value for this was 270.0, while the measured value was 269.9.

[0335] Synthesis of A64: A mixture of 5-bromo-2-[(1S)-2,2,2-trifluoro-1-methylethoxy]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 under N2 at 85 °C for 12 hours. After cooling to room temperature, the mixture was concentrated to obtain a residue. The residue was diluted with H2O (30 mL), and the mixture was extracted with ELISA (40 mL x 2). The combined organic phases were washed with water (40 mL) and brine (40 mL), dried on Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by flash chromatography on silica gel (SiO in PE = 0% to 1%) to obtain the product (3 g, 5.72 mmol (44% yield) was obtained as oil. 1 1H NMR (DMSO-d6, 400MHz)δ H =8.42(d, 1H), 7.96(dd, 1H), 6.93(d, 1H), 6.00-5.93(m, 1H), 1.45(d, 3H), 1.30(s, 12H). LCMS R t = 1.02 minutes of chromatography in 1.5 minutes, 5-95AB, C 14 H 20 BF3NO3[M+H] + The MS ESI calculated value for this is 318.1, and the measured value is also 318.1.

[0336] Synthesis of A65: A mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methylethoxy]pyridine (600 mg, 1.89 mmol), 2-bromo-5-chloropyrazine (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 under N2 at 60°C for 5 hours. After cooling to room temperature, the mixture was concentrated to obtain a residue. The residue was diluted with H2O (20 mL), and the mixture was extracted with  (30 mL × 2). The combined organic phases were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by flash chromatography on silica gel (ethyl acetate in PE = 0% to 3%) to obtain the product (350 mg, 1.15 mmol, 61% yield) as oil. LCMS R t = Chromatography for 1.5 minutes, 0.95 minutes, 5-95AB, C 12 H 10 ClF3N3O[M+H] + The MS ESI calculated value for this is 304.0, while the measured value is 304.1.

[0337] Synthesis of A66: A mixture of 2-chloro-5-[6-[(1S)-2,2,2-trifluoro-1-methylethoxy]-3-pyridyl]pyrazine (351.14 mg, 1.16 mmol) and hydrazine (741.21 mg, 23.13 mmol) in CH3CN (5 mL) was stirred at 90°C for 16 hours. After cooling to room temperature, the reaction was quenched with saturated NH4Cl (30 mL), and the mixture was extracted with ELISA (20 mL x 2). The combined organic phase was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product (350 mg, 1.05 mmol, 91% yield) as a solid. LCMS R t = Chromatography for 1.5 minutes, 0.74 minutes, 5-95AB, C 12 H 13 F3N5O[M+H] +The MS ESI calculated value for this is 300.1, and the measured value is also 300.1.

[0338] Synthesis of A67: A mixture of [5-[6-[(1S)-2,2,2-trifluoro-1-methylethoxy]-3-pyridyl]pyrazine-2-yl]hydrazine (350 mg, 1.17 mmol), (2-chloro-2,2-difluoroacetyl)2-chloro-2,2-difluoroacetate (852.42 mg, 3.51 mmol), and 4A molecular sieve (500 mg, 1.17 mmol) in toluene (8 mL) was stirred at 120 °C for 2 days. After cooling to room temperature, the reaction was quenched with saturated NaHCO3 (20 mL), and the mixture was extracted with ELISA (20 mL x 2). The combined organic phase was washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated to obtain the product (420 mg, 1.01 mmol, 86% yield) as a solid. LCMS R t = 1.5 minutes chromatography for 0.92 minutes, 5-95AB C 14 H 10 ClF5N5O[M+H] + The MS ESI calculated value for this is 394.0, and the measured value is 394.1.

[0339] Synthesis of compound 59: A mixture of 3-[chloro(difluoro)methyl]-6-[6-[(1S)-2,2,2-trifluoro-1-methylethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine (420 mg, 1.07 mmol) and AgOTf (3289.25 mg, 12.8 mmol) in DMF (6 mL) and methanol (6 mL, 1.07 mmol) was stirred at 90°C for 24 hours. After cooling to room temperature, the reaction mixture was diluted with SiO (30 mL) and quenched with saturated NaCl (30 mL). The solution was filtered through Celite and eluted with Â10 mL. The filtrate was washed with water (30 mL) and brine (30 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by flash chromatography on silica gel (Â1 in PE = 0%, 15%, and 30%) to obtain the impure product. The impure product was polished with n-hexane / DCM (2:1, 6 mL) to obtain the product (118.39 mg, 0.30 mmol, 29% yield) as a solid. 1 1H NMR (CD3CN, 400MHz) δ H =9.46(d, 1H), 8.81(d, 1H), 8.66(d, 1H), 8.35(dd, 1H), 6.99(d, 1H), 5.99-5.88(m, 1H), 3.94(s, 3H), 1.53(d, 3H). LCMS R t = 1.28 minutes of chromatography in 2.0 minutes, 10⁻⁸⁰AB, C 15 H 13 F5N5O2[M+H] + The MS ESI calculated value for this is 390.1, and the measured value is 390.0.

[0340] Example 58: 3-[difluoro(methoxy)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-5-methyl-[1,2,4]triazolo[4,3-a]pyrazine [ka] Synthesis of A68: A mixture of 2-bromo-5-chloro-3-methylpyrazine (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-methylethoxy]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 ethyl acetate (50 mL), filtered through silica gel, eluted with ethyl acetate (20 mL), and concentrated to obtain the crude product. The product was purified by flash chromatography on silica gel (acetyl-35% to 20% of PE) to obtain the product (930 mg, 2.62 mmol, 60% yield) as a colorless oil. LCMS R t = Chromatography for 1.5 minutes, 0.95 minutes, 5-95AB, C 13 H 11 ClF4N3O[M+H] + The MS ESI calculated value for this is 336.0, while the measured value is 336.1.

[0341] Synthesis of A69: A mixture of hydrazine (1775.89 mg, 55.41 mmol) and 5-chloro-2-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methylethoxy]-3-pyridyl]-3-methylpyrazine (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 RINKAN (40 mL x 2). The combined organic phase was washed with water (30 mL) and brine (30 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product (980 mg, 2.45 mL). A solid (mol, 89% yield) was obtained. LCMS R t = Chromatography for 1.5 minutes, 0.75 minutes, 5-95AB, C 13 H 14 F4N5O[M+H] +The MS ESI calculated value for this is 332.1, and the measured value is 332.2.

[0342] Synthesis of A70: A mixture of [5-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methylethoxy]-3-pyridyl]-6-methylpyrazine-2-yl]hydrazine (600 mg, 1.81 mmol), (2-chloro-2,2-difluoroacetyl)2-chloro-2,2-difluoroacetate (1320.05 mg, 5.43 mmol), and 4A molecular sieve (600 mg, 1.81 mmol) in toluene (10 mL) was stirred at 120 °C for 5 days. After cooling to room temperature, the reaction was quenched with saturated NaHCO3 (20 mL), and the mixture was extracted with ELISA (20 mL x 2). The combined organic phase was washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by flash chromatography on silica gel (ethyl acetate in PE = 0% to 40%) to obtain the product (140 mg, 0.22 mmol, 12% yield) as a solid. LCMS R t = 1.5 minutes chromatography for 0.92 minutes, 5-95AB, C 15 H 11 ClF6N5O[M+H] + The MS ESI calculated value for this is 426.0, and the measured value is 426.1.

[0343] Synthesis of Compound 60: A mixture of 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methylethoxy]-3-pyridyl]-5-methyl-[1,2,4]triazolo[4,3-a]pyrazine (140 mg, 0.33 mmol) and AgOTf (1267.44 mg, 4.93 mmol) in DMF (2 mL) and methanol (2 mL, 0.33 mmol) was stirred at 90°C for 2 days. After cooling to room temperature, the reaction product was diluted with SiO (10 mL) and saturated NaCl (10 mL). The mixture was filtered through Celite and eluted with SiO (10 mL). The combined organic phase was washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by preparative TLC (silica gel, PE:Â=2:1) ​​to obtain an impure product. The impure product was rinsed with n-hexane / DCM (2:1, 3 mL) to obtain the product (11.92 mg, 28.3 μmol, 9% yield) as a solid. 1 1H NMR (CDCl3, 400MHz)δ H =9.39(s, 1H), 8.11(d, 1H), 7.69(dd, 1H), 5.96-5.85(m, 1H), 3.92(s, 3H), 2.88(s, 3H), 1.60(d, 3H). LCMS R t = 1.28 minutes of chromatography in 2.0 minutes, 10⁻⁸⁰AB, C 16 H 14 F6N5O2[M+H] + The MS ESI calculated value for this is 422.1, and the measured value is 422.2.

[0344] Example 59: 3-[difluoro(methoxy)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-5-methyl-[1,2,4]triazolo[4,3-a]pyrazine [ka] Synthesis of A71: To a solution of 5-chloropyrazine-2-amine (25 g, 192.98 mmol) in DCM (250 mL), NBS (34.35 g, 192.98 mmol) was added. The resulting mixture was stirred at 40°C for 1 hour. After cooling to room temperature and concentrating, water (200 mL) was added to obtain the residue, which was extracted with siRNA (150 mL × 2). The combined organic phase was washed with brine (150 mL), dried over Na₂SO₄, filtered, and concentrated to obtain the crude product. The crude product was purified by chromatography on silica gel column (siRNA in PE = 0%, 15%, and 30%) to obtain the product (31 g, 148.72 mmol, 77% yield) as a solid. 1 1H NMR (DMSO-d6, 400MHz)δ H = 8.09 (s, 1H), 6.96 (s, 2H).

[0345] Synthesis of A72: A mixture of 3-bromo-5-chloropyrazine-2-amine (31 g, 148.72 mmol), Pd(dppf)Cl2 (16.32 g, 22.31 mmol), methylboronic acid (13.35 g, 223.09 mmol), and Cs2CO3 (96.91 g, 297.45 mmol) in water (30 mL) and 1,4-dioxane (300 mL) was stirred at 90°C for 16 hours. After cooling to room temperature, the mixture was concentrated to obtain a residue. Water (100 mL) was added to the residue and extracted with siRNA (100 mL x 2). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by flash chromatography on silica gel (siRNA in PE = 20%, 40%, 60%, and 80%) to obtain the product (13 g, 90.548 mmol, 61% yield) as a solid. 1 H NMR (DMSO-d6, 400MHz)δ H =7.83(s, 1H), 6.40(s, 2H), 2.26(s, 3H).

[0346] Synthesis of A73: A mixture of 5-chloro-3-methylpyrazine-2-amine (3 g, 20.9 mmol), isopentyl nitrite (3.67 g, 31.34 mmol), and CuBr (3 g, 20.9 mmol) in MeCN (30 mL) was stirred at 50°C for 12 hours. The mixture was diluted with H2O (30 mL) and extracted with RINKAN (70 mL x 2). The combined organic phase was washed with water (30 mL x 2) and brine (30 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by flash column chromatography on silica gel (DCM in PE = 0% to 2%) to obtain the product (1.2 g, 5.78 mmol, 28% yield) as oil. 1 1H NMR (CDCl3, 400MHz)δ H =8.22(s, 1H), 2.68(s, 3H). LCMS R t Chromatography for 2.0 minutes followed by 1.10 minutes, 10⁻⁸ AB, C₅H₅BrClN₂[M+H] + MS ESI calculated value: 208.9, measured value. The value is 208.7.

[0347] Synthesis of A74: A mixture of 2-bromo-5-chloro-3-methylpyrazine (1.2 g, 5.78 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (1.3 g, 4.05 mmol), Cs2CO3 (3.77 g, 11.57 mmol), and Pd(dppf)Cl2 (634.85 mg, 0.87 mmol) in 1,4-dioxane (30 mL) and water (3 mL) was stirred for 16 hours at 60°C under N2. After cooling to room temperature, water (30 mL) and ethyl acetate (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 on anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by flash column chromatography on silica gel (siRNA in PE = 0%, 1%, and 2%) to obtain the product (580 mg, 1.71 mmol, 30% yield) as a solid.1 1H NMR (CDCl3, 400MHz)δ H =8.52(s, 1H), 8.19(d, 1H), 7.73(dd, 1H), 4.91(q, 2H), 2.69(s, 3H). LCMS R t = 1.5 minutes chromatography for 0.93 minutes, 5-95AB, C 12 H9ClF4N3O[M+H] + MS ESI calculated value: 322.0, measured value: 322.0.

[0348] Synthesis of A75: A solution of 5-chloro-2-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-3-methylpyrazine (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 RINKAN (20 mL x 3). The combined organic phase was washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product (530 mg, 1.30 mmol, 69% yield) as a solid. 1 1H NMR (DMSO-d6, 400MHz)δ H =8.18(d, 1H), 8.08(s, 1H), 8.06(s, 1H), 7.97(dd, 1H), 5.13(q, 2H), 4.32(br s, 2H), 2.41(s, 3H). LCMS R t = Chromatography for 1.5 minutes, 0.72 minutes, 5-95AB, C 12 H 12 F4N5O[M+H] + The MS ESI calculated value for this is 318.1, and the measured value is also 318.1.

[0349] Synthesis of A76: A solution of [5-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-6-methylpyrazine-2-yl]hydrazine (530 mg, 1.67 mmol), (2-chloro-2,2-difluoroacetyl)2-chloro-2,2-difluoroacetate (1.22 g, 5.01 mmol), and 4A molecular sieve (3 g) in toluene (30 mL) was stirred at 120 °C for 6 days. After cooling to room temperature, the mixture was concentrated to obtain a residue. Water (50 mL) was added to the residue, and then extracted with siRNA (50 mL × 2). The combined organic phase was washed with water (50 mL) and brine (50 mL × 2), dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain the crude product. The crude product was purified by flash chromatography column on silica gel (ethyl acetate in PE = 0%, 15%, and 30%) to obtain the product (180 mg, 426.2 μmol, 26% yield) as oil. LCMS R t = 3.64 minutes in chromatography at 7.0 minutes, 10⁻⁸ AB, C 14 H9ClF6N5O[M+H] + MS ESI calculated value: 412.0, measured value: 412.1.

[0350] Synthesis of compound 61: Solution of 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-5-methyl-[1,2,4]triazolo[4,3-a]pyrazine (180 mg, 0.44 mmol) and AgOTf (1.69 g, 6.56 mmol) in methanol (5 mL) and DMF (5 mL). The mixture was stirred at 90°C under N2 for 16 hours. After cooling to room temperature, saturated NaCl (50 mL) and ethyl acetate (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 on anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by flash column chromatography on silica gel (ethyl acetate in PE = 0%, 15%, and 30%) to obtain the product (38.62 mg, 94.1 μmol, 22% yield) as a solid.1 H NMR (CDCl3, 400MHz)δ H =9.39(s, 1H), 8.12(d, 1H), 7.71(dd, 1H), 4.93(q, 2H), 3.92(s, 3H), 2.88(s, 3H). LCMS R t = Chromatography for 2.0 minutes, 1.20 minutes, 10⁻⁸ AB, C 15 H 12 F6N5O2[M+H] + The MS ESI calculated value for this was 408.1, while the measured value was 407.9.

[0351] Example 60: 3-[difluoro(methoxy)methyl]-6-[6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine [ka] 3-[bromo(difluoro)methyl]-6-[6-[rac-(1R)-2,2,2-trifluoro-1-methylethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine (2.9 g, 6.62 mmol) was suspended in methanol (30 mL) and AgBF4 (2.58 g, 13.24 mmol) was added under N2 conditions at 25 °C. 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 ELISA (20 mL x 2). The combined organic phase was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by chromatographic flash column on silica gel (Â in PE = 0% to 10% to 20%) to obtain the product (1.96 g, ee = 92.28%) as a solid. Analysis by SFC: Analysis by SFC (Chiralpak OJ-3 150 × 4.6 mm ID, 3 μm mobile phase: A: CO2, B: ethanol (0.05% DEA); gradient: from 5% to 40% of B in 5 min and from 40% to 5% of B in 0.5 min, holding 5% of 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 separated by SFC (DAICEL CHIRALCEL OJ (250 mm × 50 mm, 10 ∝ m); A = CO2 and B = 0.1% NH3H2O ​​EtOH; 35°C; 200 mL / min; 25% B; run for 8 minutes; 100 injections, peak 1 Rt = 4.2 min and peak 2 = 4.7 min) to obtain the product (1415.6 mg, 3.64 mmol, 55% yield) as a solid. 1 H NMR(400MHz, CD3CN)δH=9.45(d, 1H), 8.80(d, 1H), 8.66(d, 1H), 8.35(dd, 1H), 6.99(d, 1H), 5.97-5.90(m, 1H), 3.94(s, 3H), 1.53(d, 3H). LCMS R t = 1.27 minutes by chromatography at 2.0 minutes, 10⁻⁸ AB, C 15 H 13 F5N5O2[M+H] + MS ESI calculated value: 389.1, measured value: 390.0.

[0352] Example 61: 3-[cyclopropoxy(difluoro)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methylethoxy]-3-pyridyl]- [1,2,4]triazolo[4,3-a]pyrazine [ka] Potassium tert-butoxide (163.54 mg, 1.46 mmol) was added to a mixture of cyclopropanol (84.65 mg, 1.46 mmol) and 3-[chloro(difluoro)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methylethoxy]-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyrazine (300 mg, 0.73 mmol) in DMF (5 mL). The reaction mixture was stirred at 20°C for 1 hour. The mixture was diluted with H2O (10 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by flash chromatography on silica gel (ethyl acetate in PE = 0% to 30%) to obtain the impure product. The impure product was purified with n-hexane / DCM (2:1, 3 mL) to obtain the product (33.18 mg, 76.6 μmol, 11% yield). 1 1H NMR (CDCl3, 400MHz)δ H =9.52(d, 1H), 8.49(d, 1H), 8.43(d, 1H), 8.05(dd, 1H), 5.96-5.86(m, 1H), 4.21-4.16(m, 1H), 1.61(d, 3H), 1.04-0.99(m, 2H), 0.87-0.81(m, 2H). LCMS R t = 1.34 minutes of chromatography in 2.0 minutes, 10⁻⁸ AB. C 17 H 14 F6N5O2[M+H] +The MS ESI calculated value for this is 434.1, and the measured value is also 434.1.

[0353] Example 62: 6-(6-benzyloxy-5-fluoro-3-pyridyl)-3-[ethoxy(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyrazine [ka] Synthesis of A84: To a solution of phenylmethanol (10.5 g, 97.1 mmol) in THF (100 mL), NaH (7 g, 175 mmol) was gradually added over 0.5 hours at 0°C. After the addition, the mixture was stirred for a further 1 hour at 20°C. Next, 5-bromo-2,3-difluoropyridine (18.83 g, 97.1 mmol) was added to the mixture. The resulting mixture was stirred for 3 hours at 20°C. The mixture was poured into a saturated NH4Cl solution (100 mL) and extracted with dimethyl phosphate (100 mL x 2). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product (27 g, 89.52 mmol) as oil.

[0354] Synthesis of A85: A mixture of 2-benzyloxy-5-bromo-3-fluoropyridine (27 g, 95.71 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (29.16 g, 114.85 mmol), KOAc (18.79 g, 191.41 mmol), and Pd(dppf)Cl2 (10.5 g, 14.36 mmol) in 1,4-dioxane (300 mL) was stirred for 16 hours at 90°C under N2. 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 obtain the product (20 g, 60.75 mmol, 63% yield) as a solid. 1 1H NMR (400 MHz, 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).

[0355] Synthesis of A86: A mixture of 2-bromo-5-chloropyrazine (4 g, 20.68 mmol), 2-benzyloxy-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (6.81 g, 20.68 mmol), Cs2CO3 (13.47 g, 41.36 mmol), and Pd(dppf)Cl2 (2.27 g, 3.1 mmol) in 1,4-dioxane (30 mL) and water (3 mL) was stirred for 16 hours at 50°C under N2. 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 RINKAN (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (with HCl in PE ranging from 0% to 15% to 30%) to obtain the product (5.5 g, 17.42 mmol, 84% yield) as a solid. 1 1H NMR (400MHz, DMSO-d6)δ H =9.15(s, 1H), 8.85(s, 1H), 8.77(s, 1H), 8.37(d, 1H), 7.52-7.46(m, 2H), 7.44-7.32(m, 3H), 5.51(s, 2H).

[0356] Synthesis of A87: A mixture of 2-(6-benzyloxy-5-fluoro-3-pyridyl)-5-chloropyrazine (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 RINKAN (30 mL x 2). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain the crude product (4 g, 7.38 mmol) as a solid. LCMS R t= Chromatography for 1.5 minutes, 0.76 minutes, 5-95AB, C 16 H 15 FN5O[M+H] + The MS ESI calculated value for this was 312.1, while the measured value was 311.9.

[0357] Synthesis of A88: To a solution of 2-bromo-2,2-difluoroacetyl chloride (1.65 g, 8.53 mmol) in THF (30 mL), [5-(6-benzyloxy-5-fluoro-3-pyridyl)pyrazine-2-yl]hydrazine (2 g, 6.42 mmol) was added. The mixture was stirred at 20°C for 1 hour. Water (30 mL) was added, and the aqueous layer was extracted with ELISA (30 mL x 2). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product (900 mg, 1.92 mmol) as a solid. 1 1H NMR (400MHz, DMSO-d6)δ H =11.40(s, 1H), 9.52(s, 1H), 8.78(d, 1H), 8.63(d, 1H), 8.24(dd, 1H), 8.14(d, 1H), 7.49(d, 2H), 7.43-7.32(m, 3H), 5.49(s, 2H).

[0358] Synthesis of A89: To a mixture of N'-[5-(6-benzyloxy-5-fluoro-3-pyridyl)pyrazine-2-yl]-2-bromo-2,2-difluoroacetohydrazide (450 mg, 0.96 mmol) in DCM (9 mL), 2-methoxypyridine (230.74 mg, 2.11 mmol) and Tf2O (0.19 mL, 1.15 mmol) were added. The mixture was stirred at 20°C for 16 hours. Water (50 mL) was added, and the aqueous layer was extracted with ELISA (50 mL x 2). The combined organic phase was 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 (with  in PE ranging from 0% to 30% to 50%) to obtain the product (240 mg, 533.1 μmol, 55% yield) as a solid. 1 1H 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).

[0359] Synthesis of compound 64: A mixture of 6-(6-benzyloxy-5-fluoro-3-pyridyl)-3-[bromo(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyrazine (240 mg, 0.53 mmol) and AgBF4 (207.55 mg, 1.07 mmol) in ethanol (5 mL) was stirred in the dark at 60 °C for 1 hour. After cooling to room temperature, the mixture was filtered through Celite and the filtrate was concentrated. The crude product was purified by flash chromatography on silica gel (siRNA in PE = 0% to 30% to 50%) to obtain the product (31.09 mg, 74.8 μmol, 14% yield) as a solid. 1 1H 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 t = 1.38 minutes in chromatography at 2.0 minutes, 10⁻⁸ AB, C 20 H 17 F3N5O2[M+H] + The MS ESI calculated value for this is 416.1, and the measured value is 416.0.

[0360] Example 63: 3-[difluoro(methoxy)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine [ka] Synthesis of A100: A mixture of 3-[bromo(difluoro)methyl]-6-chloro-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine (900 mg, 3.03 mmol) and AgBF4 (1.17 g, 6.05 mmol) in methanol (10 mL) was stirred in the dark at 60 °C for 1 hour. After cooling to room temperature, brine (50 mL) and ethyl acetate (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 (ethyl acetate in PE = 0%, 30%, and 50%) to obtain the product (180 mg, 724.0 μmol, 23% yield) as a solid. 1 1H NMR (400 MHz, CDCl3)δ H =7.99(s, 1H), 3.90(s, 3H), 2.53(s, 3H) ) LCMS R t = Chromatography for 1.5 minutes, followed by 0.78 minutes, 5-95AB, C8H8ClF2N4O[M+H] + The MS ESI calculated value for this is 249.0, and the measured value is 248.9.

[0361] Synthesis of compound 65: A mixture of 6-chloro-3-[difluoro(methoxy)methyl]-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine (100 mg, 0.40 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (193.72 mg, 0.60 mmol), 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 for 3 hours at 80°C under N2. After cooling to room temperature, water (20 mL) was added to the mixture, and the aqueous layer was extracted with ELISA (20 mL x 2). The combined organic phases were washed with brine (30 mL), dried on anhydrous Na₂SO₄, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (ethyl acetate in PE = 0%, 30%, and 50%) to obtain the product (64.84 mg, 158.9 μmol, 39% yield) as a solid. 1 1H 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 R t = 1.18 minutes of chromatography in 2.0 minutes, 10⁻⁸ AB, C 15 H 12 F6N5O2[M+H] + The MS ESI calculated value for this is 408.1, and the measured value is 408.0.

[0362] Example 64: 3-[difluoro(methoxy)methyl]-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine [ka] A mixture of 3-fluoro-2-[(1R)-2,2,2-trifluoro-1-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(methoxy)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), and K3PO4 (128.09 mg, 0.6 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was stirred at 80°C for 3 hours. After cooling to room temperature, the mixture was concentrated and diluted with H2O (20 mL). The aqueous layer was extracted with ELISA (20 mL x 2). The combined organic phases were washed with brine (20 mL), dried on anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography (100% siRNA) on silica gel to obtain the product (70.46 mg, 0.17 mmol, 55% yield) as a solid. 1 1H 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). 1.50 was obtained by LCMS chromatography with a retrieval time of 2 minutes. 24 minutes, 10-80AB, MS ESI calculation C 16 H 14 F6N5O2[M+H] + 422.1, measured value 422.0.

[0363] Example 65: 3-[ethoxy(difluoro)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methylethoxy]-3-pyridyl]-5-methyl-[1,2,4]triazolo[4,3-a]pyrazine [ka] A mixture of 3-[bromo(difluoro)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methylethoxy]-3-pyridyl]-5-methyl-[1,2,4]triazolo[4,3-a]pyrazine (100 mg, 0.21 mmol) and AgBF4 (82.81 mg, 0.43 mmol) in ethanol (1 mL) was stirred in the dark at 60 °C for 1 hour. After cooling to room temperature, SiO (30 mL) and saturated NaCl aqueous 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 SiO (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 (with ethyl acetate in PE ranging from 0% to 30% to 50%) to obtain an impure product (55 mg) as a solid. The impure product was polished with EtOH (1 mL) to obtain a solid product (19.57 mg, 21% yield). 1 1H 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 t = 1.34 minutes in chromatography at 2.0 minutes, 10⁻⁸ AB, C 17 H 16 F6N5O2[M+H] + The MS ESI calculated value for this is 436.1, and the measured value is 436.0.

[0364] Example 66: 3-[difluoro(methoxy)methyl]-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine [ka] Synthesis of A103: 3,6-dichloro-4-methylpyridazine (14g, 85.89 mmol) and N2H4 in ethanol (200 mL) . A mixture of H2O (4.29 g, 85.89 mmol) was stirred at 70°C for 30 hours. After cooling to room temperature, the suspension was filtered. The filtered cake was washed with EtOH (50 mL x 3) and dried in an oven. The resulting product is a mixture of two positional isomers (A103, A103-2) in a ratio of approximately 1:1. 1 H The solution was obtained as a solid (8 g, 50.45 mmol, 58% yield), determined by NMR.

[0365] Synthesis of A99: A mixture of 6-chloro-5-methylpyridazin-3-amine (2.0 g, 13.93 mmol), (6-chloro-4-methylpyridazin-3-yl)hydrazine, and 2-bromo-2,2-difluoroacetyl chloride (5.4 g, 27.86 mmol) in toluene (80 mL) was stirred at 120 °C for 16 hours. After cooling to room temperature, the mixture was concentrated, and the residue was diluted with H₂O (50 mL). The mixture was extracted with siRNA (100 mL x 2). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (ethyl acetate in PE = 20%, 40%, and 60%) to obtain both A99 (400 mg, 1.34 mmol, 10% yield) and A99-2 (600 mg, 2.01 mmol, 14% yield) as solids. 1 1H NMR (400 MHz, CDCl3)δ H =8.08(s, 1H), 2.58(s, 3H). A99-2 1 1H NMR (400 MHz, CDCl3)δ H = 7.14 (s, 1H), 2.81 (s, 3H).

[0366] Synthesis of A100-a: A mixture of 3-[bromo(difluoro)methyl]-6-chloro-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine (400 mg, 1.34 mmol) and AgBF4 (523.5 mg, 2.69 mmol) in methanol (5 mL) was stirred in the dark at 55 °C for 12 hours. After cooling to room temperature, saturated aqueous NaCl (30 mL) and ethyl acetate (30 mL) were added. The mixture was filtered through Celite, and the filtrate was extracted with ethyl acetate (30 mL). The combined organic phase was washed with brine (20 mL), dried on anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (ethyl acetate in PE = 0%, 30%, and 50%) to obtain the product (230 mg, 0.93 mmol, 68% yield) as a solid. 1 1H NMR (400 MHz, CDCl) 3) δ H =7.98(d, 1H), 3.89(s, 3H), 2.53(s, 3H). LCMS chromatography with Rt=1.5 min for 0.73 min, 10⁻⁸ AB, MS ESI calculated value C8H₅ClF₂N₄O[M+H] + 249.0, actual measured value 248.8.

[0367] Synthesis of compound 68: A mixture of 6-chloro-3-[difluoro(methoxy)methyl]-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine (70 mg, 0.28 mmol), 3-fluoro-2-(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (113.22 mg, 0.34 mmol), K3PO4 (119.55 mg, 0.56 mmol), and Pd(t-Bu3P)2 (21.58 mg, 0.04 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was stirred for 3 hours at 80°C under N2. 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 ethyl acetate (20 mL x 2). The combined organic phase was washed with brine (30 mL), dried on anhydrous sodium 2SO4, filtered, and concentrated. The crude product was purified by preparative TLC (silica gel, ethyl acetate) to obtain the product (65 mg, 154.3 μmol, 54% yield) as a solid. 1 1H 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 R t = 1.31 minutes in chromatography at 2.0 minutes, 10⁻⁸ AB, C 16 H 14 F6N5O2[M+H] + The MS ESI calculated value for this is 422.1, and the measured value is 422.2.

[0368] Example 67: 6-[5-fluoro-6-(2,2,2-trifluoro-1,1-dimethylethoxy)-3-pyridyl]-3-(methoxymethyl)-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine [ka] A mixture of 6-chloro-3-(methoxymethyl)-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine (80 mg, 0.38 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoro-1,1-dimethylethoxy)pyridine (197.03 mg, 0.56 mmol), K3PO4 (159.74 mg, 0.75 mmol), and Pd(t-Bu3P)2 (28.84 mg, 0.06 mmol) in 1,4-dioxane (5 mL) and H2O (0.5 mL) was stirred for 3 hours at 80°C under N2. 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 siRNA (20 mL x 2). The combined organic phase was washed with brine (30 mL), dried on anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by preparative HPLC (Waters XBridge BEH C18 (150 mm x 25 mm, 5 μm) A=H2O (0.075% NH4HCO3) and B=CH3CN, 50-60% B over 9.5 minutes) to obtain the product (21.64 mg, 0.05 mmol, 14% yield) as a solid. 1 1H NMR (400 MHz, 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 t = 1.28 minutes of chromatography in 2.0 minutes, 10⁻⁸⁰AB, C 17 H 18 F4N5O2[M+H] + The MS ESI calculated value for this is 400.1, and the measured value is also 400.1.

[0369] Example 68: 6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-3-(methoxymethyl)-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine [ka] 6-chloro-3-(methoxymethyl)-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine (70 mg, 0.33 mmol), 3-fluoro-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxane (5 mL) and water (0.5 mL) A mixture of loran-2-yl)pyridine (132.38 mg, 0.40 mmol), K3PO4 (139.78 mg, 0.66 mmol), and Pd(t-Bu3P)2 (25.24 mg, 0.05 mmol) was stirred at 80°C under N2 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 ethyl acetate (20 mL x 2). The combined organic phase was washed with brine (30 mL), dried on anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (ethyl acetate in PE = 10% to 20%) to obtain the product (33.02 mg, 0.09 mmol, 26% yield) as a solid. 1 1H 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 R t = 1.24 minutes in chromatography at 2.0 minutes, 10⁻⁸ AB, C 16 H 16 F4N5O2[M+H] + The MS ESI calculated value for this was 386.1, while the measured value was 385.9.

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

[0371] Synthesis of compound 71: A mixture of 6-chloro-3-(methoxymethyl)-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine (70 mg, 0.33 mmol), [5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]boronic acid (94.39 mg, 0.40 mmol), K3PO4 (139.78 mg, 0.66 mmol), and Pd(t-Bu3P)2 (25.24 mg, 0.05 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was stirred for 3 hours at 80°C N2. 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 ELISA (20 mL x 2). The combined organic phases were washed with brine (30 mL), dried on anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by preparative TLC (silica gel, Â) to obtain the product (9.8 mg, 0.03 mmol, 8% yield) as a solid. 1 1H 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 R t = 1.19 minutes in chromatography at 2.0 minutes, 10⁻⁸ AB, C 15 H 14 F4N5O2[M+H] + The MS ESI calculated value for this is 372.1, and the measured value is 372.0.

[0372] Example 70: 6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-3-(methoxymethyl)-7-methyl-[1,2, 4] Triazolo[4,3-b]pyridazine [ka] Synthesis of A104: To a solution of (6-chloro-5-methylpyridazin-3-yl)hydrazine and (6-chloro-4-methylpyridazin-3-yl)hydrazine (2 g, 12.61 mol) in toluene (30 mL), 2-methoxyacetyl chloride (2737.12 mg, 25.22 mmol) was added at 25 °C. The mixture was heated to 120 °C and stirred for 16 hours. After cooling to room temperature, the mixture was concentrated, and the residue was diluted with H₂O (30 mL). The mixture was extracted with siRNA (50 mL × 2). The combined organic phase was washed with brine (10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was purified three times by flash chromatography (siRNA) on silica gel to obtain both A104 (250 mg, 1.17 mmol, 9% yield) and A104-2 (500 mg, 2.35 mmol, 19% yield) as solids. 1 1H NMR (400 MHz, CDCl3)δ H =7.94(d, 1H), 5.02(s, 2H), 3.50(s, 3H), 2.51(s, 3H).

[0373] Synthesis of compound 72: A mixture of 6-chloro-3-(methoxymethyl)-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine (60 mg, 0.28 mmol), 3-fluoro-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (113.47 mg, 0.34 mmol), K3PO4 (119.81 mg, 0.56 mmol), and Pd(t-Bu3P)2 (21.63 mg, 0.04 mmol) in 1,4-dioxane (5 mL) and H2O (0.5 mL) was stirred for 1 hour at 80°C under N2. 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 ethyl acetate (20 mL x 2). The combined organic phase was washed with brine (30 mL), dried on anhydrous sodium 2SO4, filtered, and concentrated. The crude product was purified by preparative TLC (silica gel, ethyl acetate) to obtain the product (23.22 mg, 59.2 μmol, 21% yield) as a solid. 1 1H 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 R t = 1.24 minutes in chromatography at 2.0 minutes, 10⁻⁸ AB, C 16 H 16 F4N5O2[M+H] + The MS ESI calculated value for this is 386.1, and the measured value is also 386.1.

[0374] Example 71: 3-(difluoro(methoxy)methyl)-6-(6-(3,3-difluorocyclobutoxy)pyridine-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine [ka] Synthesis of A107: To a stirred solution of 6-chloro-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyrazine (1.0 g, 4.18 mmol) and 2-(3,3-difluorocyclobutoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.43 g, 4.6 mmol) in 1,4-dioxane (27.0 mL), water (3.0 mL) and Cs2CO3 (2.73 g, 8.37 mmol) were added. Pd(dppf)Cl2 . 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 using 25% ethyl acetate / PE to obtain the product (430 mg, 1.11 mmol, 26% yield). LCMS: 388.1 (M+H), Rt 2.4 min. Column: ZORBAX XDB C-18 (50 × 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.

[0375] Synthesis of Compound 73: To a stirred solution of 3-(chlorodifluoromethyl)-6-(6-(3,3-difluorocyclobutoxy)pyridine-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine (100 mg, 0.26 mmol) in MeCN (4.5 mL), Cs2CO3 (515 mg, 1.58 mmol) and methanol (0.21 mL, 5.2 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was treated with water (20.0 mL) and extracted with ethyl acetate (2 × 20 mL). The organic layer was washed with brine (15 mL), dried over anhydrous Na2SO4, and concentrated. The crude compound was purified by preparative HPLC to obtain a solid (32 mg, 0.08 mmol, 32% yield). Preparative HPLC method: Rt = 16.1; Column: XBridge C8 (150 × 19 mm), 5.0 μm; Mobile phase: 0.1% TFA in water / acetonitrile; Flow rate: 15.0 mL / min. HPLC: Rt 4.49 min, Column: XBridge C8 (50 × 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 × 4.6 mm), 3.5 μm; Mobile phase: A: 0.1% HCOOH:ACN (95:5) in water, B:ACN; Flow rate: 1.5 mL / min. 1 H NMR(400MHz, CD3OD): δ9.54(d, 1H), 8.86(d, 1H), 8.78(s, 1H), 8.39(dd, 1H), 6.99(d, 1H), 5.25-5.22(m, 1H), 3.99(s, 3H), 3.23-3.13(m, 2H), 2.82-2.70(m, 2H).

[0376] Example 72: 3-(cyclopropoxydifluoromethyl)-6-(6-(2,2,2-trifluoroethoxy)pyridine-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine [ka] Synthesis of A109: To a stirred solution of 2,2,2-trifluoroethanol (3.12 g, 31.25 mmol) in THF (25 mL) at 0°C, NaH (60% in mineral oil, 1.25 g, 31.25 mmol) was added gradually. The reaction mixture was slowly warmed to room temperature and stirred for 15 minutes. 5-bromo-2-fluoropyridine (5.0 g, 28.41 mmol) was added dropwise to the reaction mixture and stirred for 2 hours. The reaction mixture was cooled to 10°C and treated with ice water (50 mL). The reaction mixture was extracted with ethyl acetate (2 × 60 mL). The organic layer was washed with brine (50 mL), dried on anhydrous Na₂SO₄, and concentrated. The crude compound was purified by column chromatography on silica gel using 5% ethyl acetate / PE to obtain the product (5.0 g, 19.5 mmol, 68% yield). LCMS: 256.0 (M+H) and 258 (M+2+H), Rt 2.59 min. Column: ZORBAX XDB C-18 (50 × 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.

[0377] Synthesis of A110: Potassium acetate (3.83 g, 39.0 mmol) was added to a stirred solution of 5-bromo-2-(2,2,2-trifluoroethoxy)pyridine (5.0 g, 19.53 mmol) and bis(pinacolate)diborone (6.45 g, 25.39 mmol) in 1,4-dioxane (50.0 mL). Pd(dppf)Cl2 . DCM (1.59 g, 1.95 mmol) was added to the reaction mixture under a nitrogen atmosphere and heated at 80°C for 12 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and concentrated under reduced pressure. The crude compound was purified by column chromatography on silica gel using 5% ethyl acetate / PE to obtain the product (4.32 g, 14.3 mmol, 73% yield). LCMS: 304.1 (M+H), Rt 2.85 min. Column: ZORBAX XDB C-18 (50 × 4.6 mm), 3.5 μm. Mobile phase: A: 0.1% HCOOH in water:ACN (95:5), B:ACN; Flow rate: 1.5 mL / min.

[0378] Synthesis of A112: To a stirred solution of 6-chloro-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyrazine (1.3 g, 5.44 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (1.5 g, 4.95 mmol) in 1,4-dioxane (25.0 mL), water (2.5 mL) and Cs2CO3 (3.22 g, 9.9 mmol) were added. 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 analyzed by column chromatography on silica gel using 30% ethyl acetate / PE. The product was purified to obtain the product (500 mg, 1.3 mmol, 26% yield). LC-MS: 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 in water: ACN (95:5), B: ACN; flow rate: 1.5 mL / min.

[0379] Synthesis of Compound 74: To a stirred solution of 3-(chlorodifluoromethyl)-6-(6-(2,2,2-trifluoroethoxy)pyridine-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine (100 mg, 0.26 mmol) in MeCN (10 mL), Cs2CO3 (514 mg, 1.58 mmol) and cyclopropanol (0.21 mL, 3.29 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was treated with water (15.0 mL) and extracted with ethyl acetate (2 × 20 mL). The organic layer was washed with brine (15 mL), dried over anhydrous Na2SO4, and concentrated. The crude compound was purified by preparative HPLC to obtain a solid (10 mg, 0.024 mmol, 9% yield). Preparative HPLC method: Rt = 14.2; Column: XBridge C8 (150 × 19 mm), 5.0 μm; Mobile phase: 0.1% TFA in water / acetonitrile; Flow rate: 15.0 mL / min. HPLC: Rt 5.01 min, Column: XBridge C8 (50 × 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 × 4.6 mm), 3.5 μm; Mobile phase: A: 0.1% TFA in water: ACN (95:5), B: 0.1% TFA in ACN; Flow rate: 1.5 mL / min. 1 H NMR(400MHz, CD3OD): δ9.55(d, 1H), 8.89(d, 1H), 8.75(s, 1H), 8.43(dd, 1H), 7.09(d, 1H), 4.98(q, 2H), 4.26-4.23(m, 1H), 0.99(m, 2H), 0.85-0.81(m, 2H).

[0380] Example 73: 3-(cyclopropoxydifluoromethyl)-6-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridine-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine [ka] Synthesis of A113: To a stirred solution of 2,2,2-trifluoroethanol (5.67 g, 56.71 mmol) in 200 mL of THF at 0°C, NaH (60% in mineral oil, 2.26 g, 56.71 mmol) was added gradually. The reaction mixture was stirred for 15 minutes, and 5-bromo-2,3-difluoropyridine (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 × 100 mL). The organic layer was washed with brine (80 mL), dried on anhydrous Na₂SO₄, and concentrated. The crude compound was purified by column chromatography on silica gel using 2% ethyl acetate / PE to obtain the product (10.5 g, 38.1 mmol, 73% yield). LCMS: 273.9 (M+H) and 276.0 (M+2+H), Rt 2.53 min Column: ZORBAX XDB C-18 (50 × 4.6 mm), 3.5 μm; Mobile phase: A: 0.1% HCOOH in water:ACN (95:5), B:ACN; Flow rate: 1.5 mL / min.

[0381] Synthesis of A3-a: Potassium acetate (2.15 g, 21.9 mmol) was added to a stirred solution of 5-bromo-3-fluoro-2-(2,2,2-trifluoroethoxy)pyridine (3.0 g, 10.95 mmol) and bis(pinacolate)diborone (3.61 g, 14.23 mmol) in 1,4-dioxane (30.0 mL). Pd(dppf)Cl2 . DCM (0.89 g, 1.09 mmol) was added to the reaction mixture under a nitrogen atmosphere and heated at 80°C for 12 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and concentrated under reduced pressure. The crude compound was purified by column chromatography on silica gel using 15% ethyl acetate / PE to obtain the product (2.0 g, 6.2 mmol, 56% yield). LCMS: 322.1 (M+H), Rt 2.97 min. Column: Atlantis dC18 (50 × 4.6 mm), 5 μm. Mobile phase: A: 0.1% HCOOH in water:ACN (95:5), B:ACN; Flow rate: 1.5 mL / min.

[0382] Synthesis of A18-a: To a stirred solution of 6-chloro-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyrazine (2.0 g, 8.37 mmol) and 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (2.96 g, 9.2 mmol) in 1,4-dioxane (26.0 mL), water (4.0 mL) and K2CO3 (2.31 g, 16.74 mmol) were added. 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 column chromatography on silica gel using 30% ethyl acetate / PE to obtain the product (1.35 g, 3.4 mmol, 40% yield). LCMS: 398.0 (M+H), Rt 2.51 min. Column: Atlantis dC-18 (50 × 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 1H NMR (400MHz, DMSO-d6): δ9.77(d, 1H), 9.14(s, 1H), 8.84(d, 1H), 8.66(dd, 1H), 5.20(q, 2H).

[0383] Synthesis of Compound 75: To a stirred solution of 3-(chlorodifluoromethyl)-6-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridine-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine (150.0 mg, 0.38 mmol) in MeCN (8.0 mL), Cs2CO3 (737 mg, 2.26 mmol) and cyclopropanol (0.48 mL, 7.54 mmol) were added. The reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was treated with water (15.0 mL) and extracted with ethyl acetate (2 × 20 mL). The organic layer was washed with brine (15 mL), dried over anhydrous Na2SO4, and concentrated. The crude compound was purified by preparative HPLC to obtain a solid (15 mg, 0.035 mmol, 9% yield). Preparative HPLC method: Rt 14.8; Column: XBridge C-18 (150 × 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 × 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 × 4.6 mm), 3.5 μm; Mobile phase: A: 0.1% HCOOH in water, B: ACN; Flow rate: 1.5 mL / min. 1 H NM R(400MHz, DMSO-d6):δ9.71(d, 1H), 8.93(d, 1H), 8.78(d, 1H), 8.56(dd, 1H), 5.19(q, 2H), 4.24-4.20(m, 1H), 0.96-0.92(m, 2H), 0.77-0.72(m, 2H).

[0384] Example 74: 3-(difluoro(methoxy)methyl)-6-(6-(3,3-difluorocyclobutoxy)-5-fluoropyridine-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine [ka] Synthesis of A115: To a stirred solution of 2-chloro-5-hydrazinylpyrazine (5.0 g, 33.99 mmol) in toluene (50 mL), chlorodifluoroacetic anhydride (6.54 mL, 37.39 mmol) was added at 0°C. The reaction mixture was heated at 110°C for 1 hour. The reaction mixture was cooled to room temperature and concentrated. The crude reaction mixture was treated with water (50 mL) and extracted with ethyl acetate (2 × 50 mL). The organic layer was washed with brine (30 mL), dried over Na₂SO₄, and concentrated to a solid (6 g). This was used in the next step without further purification.

[0385] Synthesis of A111: To a stirred solution of 2-chloro-N'-(5-chloropyrazine-2-yl)-2,2-difluoroacetohydrazide (6.0 mg, 23.34 mmol) in DCM (120 mL), trifluoromethanesulfonic anhydride (4.73 mL, 28.01 mmol) and 2-methoxypridine (4.91 mL, 46.69 mmol) were added 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 using 15% siRNA / PE to obtain the product (4.0 g, 16.5 mmol, 71% yield) as a solid. LCMS: 239.0 (M+H), Rt 1.66 mins, Column: ZORBAX XDB C-18 (50 × 4.6 mm), 3.5 μm Mobile phase: A: 0.1% HCOOH in water:ACN (95:5), B: ACN; flow rate: 1.5 mL / min.

[0386] Synthesis of A116: 3,3-difluorocyclobutanol in THF (10 mL) at 0°C To a stirred solution of (500 mg, 4.63 mmol), NaH (60% in mineral oil, 204 mg, 5.09 mmol) was added gradually. The reaction mixture was slowly warmed to room temperature and stirred for 15 minutes. Then, 5-bromo-2,3-difluoropyridine (0.9 g, 4.63 mmol) was added dropwise to the reaction mixture and stirred for 4 hours. The reaction mixture was cooled to 10°C and treated with ice water (30 mL). The reaction mixture was extracted with ethyl acetate (2 × 30 mL). The organic layer was washed with brine (50 mL), dried on anhydrous Na₂SO₄, and concentrated. The crude compound was purified by column chromatography on silica gel using 10% ethyl acetate / PE to obtain the product (1.0 g, 3.57 mmol, 77% yield). LCMS: 282.0 (M+H) and 284.0 (M+2+H), Rt 2.66 min. Column: ZORBAX XDB C-18 (50 × 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.

[0387] Synthesis of A117: Potassium acetate (0.77 g, 7.83 mmol) was added to a stirred solution of 5-bromo-2-(3,3-difluorocyclobutoxy)-3-fluoropyridine (1.1 g, 3.91 mmol) and bis(pinacolate)diborone (1.29 g, 5.09 mmol) in 1,4-dioxane (20.0 mL). Pd(dppf)Cl2 . DCM (0.32 g, 0.39 mmol) was added to the reaction mixture under a nitrogen atmosphere and heated at 90°C for 16 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and concentrated under reduced pressure. The crude compound was purified by column chromatography on silica gel using 5% ethyl acetate / PE to obtain the product (1.2 g, 3.6 mmol, 93% yield). LCMS: 330.1 (M+H), Rt 2.97 mins. Column: ZORBAX XDB C-18 (50 × 4.6 mm), 3.5 μm Mobile phase: A: 0.1% HCOOH in water:ACN (95:5), B: ACN; flow rate: 1.5 mL / min.

[0388] Synthesis of A118: To a stirred solution of 6-chloro-3-(chlorodifluoromethyl)-[1,2,4]triazolo[4,3-a]pyrazine (0.91 g, 3.83 mmol) and 2-(3,3-difluorocyclobutoxy)-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.17 g, 3.55 mmol) in 1,4-dioxane (15.0 mL), water (3.0 mL) and Cs2CO3 (2.31 g, 7.13 mmol) were added. 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 using 30% ethyl acetate / PE to obtain the product (1.11 g, 2.75 mmol, 77% yield). LCMS: 405.9 (M+H), Rt 2.30 min. Column: ZORBAX XDB C-18 (50 × 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.

[0389] Synthesis of Compound 76: To a stirred solution of 3-(chlorodifluoromethyl)-6-(6-(3,3-difluorocyclobutoxy)-5-fluoropyridine-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine (140 mg, 0.34 mmol) in MeCN (7.5 mL), Cs2CO3 (668 mg, 2.06 mmol) and methanol (0.14 mL, 3.4 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was treated with water (20.0 mL) and extracted with ethyl acetate (2 × 20 mL). The organic layer was washed with brine (15 mL), dried over anhydrous Na2SO4, and concentrated. The crude compound was purified by preparative HPLC to obtain a solid (18 mg, 0.04 mmol, 13% yield). Preparative HPLC method: Rt 12.9; Column: YMC phenyl (150 × 19 mm), 5.0 μm; Mobile phase: 0.1% TFA in water / acetonitrile; Flow rate: 15.0 mL / min. HPLC: Rt 5.01 min, 97.3%; Column: XBridge C8 (50 × 4.6) mm, 3.5 μm; Mobile phase: A: 0.1% TFA in water, B: 0.1% TFA in ACN FA;Flow rate: 2.0mL / min. LCMS: 402.0 (M+H), Rt 2.48 min, Column: Atlantis dC18 (50 x 4.6 mm), 5.0 μm Mobile phase: A: 0.1% HCOOH in water:ACN (95:5), B: ACN; flow rate: 1.5 mL / min. 1 H NMR (400MHz, DMSO-d6): δ9.70(d, 1H), 8.97(s, 1H), 8.77(d, 1H), 8.49(dd, 1H), 5.30-5.26(m, 1H), 3.92(s, 3H), 3.26-3.19(m, 2H), 2.89-2.84(m, 2H).

[0390] Example 75: 6-(6-(3,3-difluorocyclobutoxy)-5-fluoropyridine-3-yl)-3-(ethoxydifluoromethyl)-[1,2,4]triazolo[4,3-a]pyrazine [ka] To a stirred solution of 3-(chlorodifluoromethyl)-6-(6-(3,3-difluorocyclobutoxy)-5-fluoropyridine-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine (150 mg, 0.34 mmol) in MeCN (7.5 mL), Cs2CO3 (668 mg, 2.06 mmol) and ethanol (0.2 mL, 3.4 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was treated with water (20.0 mL) and extracted with ethyl acetate (2 × 25 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated. The crude compound was purified by preparative HPLC to obtain a solid (22 mg, 0.05 mmol, 15% yield). Preparative HPLC method: Rt 13.1; Column: XBridge C-18 (150 × 19 mm), 5.0 μm; Mobile phase: 0.1% TFA in water / acetonitrile; Flow rate: 15.0 mL / min. HPLC: Rt 5.08 min, 94.8%; Column: XBridge C8 (50 × 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 × 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), 5.32-5.30(m, 1H), 4.40(q, 2H), 3.25-3.15(m, 2H), 2.90-2.77(m, 2H), 1.49(t, 3H).

[0391] Example 76: 3-(cyclopropoxydifluoromethyl)-6-(6-(3,3-difluorocyclobutoxy)pyridine-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine [ka] To a stirred solution of 3-(chlorodifluoromethyl)-6-(6-(3,3-difluorocyclobutoxy)-5-fluoropyridine-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine (100 mg, 0.26 mmol) in MeCN (9.0 mL), Cs2CO3 (504 mg, 1.55 mmol) and cyclopropanol (0.33 mL, 5.16 mmol) were added. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was treated with water (20.0 mL) and extracted with ethyl acetate (2 × 20 mL). The organic layer was washed with brine (20 mL), dried on anhydrous Na2SO4, and concentrated. The crude compound was purified by preparative HPLC to obtain a solid (14 mg, 0.034 mmol, 13% yield). Preparative HPLC method: Rt 10.67; Column: Sunfire C-18 (150 × 19 mm), 5.0 μm; Mobile phase: 0.1% TFA in water / acetonitrile; Flow rate: 15.0 mL / min. HPLC: Rt 5.19 min, Column: XBridge C8 (50 × 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 × 4.6 mm), 3.5 μm; Mobile phase: A: 0.1% TFA in water: ACN (95:5), B: 0.1% TFA in ACN; Flow rate: 1.5 mL / min. 1 H NMR(400MHz, CD3OD):δ9.54(d, 1H), 8.84(d, 1H), 8.71(s, 1H), 8.37(dd, 1H), 7.00(d, 1H), 5.25(m, 1H), 4.26-4.23(m, 1H), 3.23-3.13(m, 2H), 2.82-2.70(m, 2H), 0.99(m, 2H), 0.84-0.79(m, 2H).

[0392] Example 77: 3-(ethoxymethyl)-6-(5-fluoro-6-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)pyridine-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine [ka] Synthesis of A119: To a stirred solution of 1,1,1-trifluoro-2-methylpropan-2-ol (0.57 g, 4.43 mmol) in THF (20 mL) at 0°C, NaH (60% in mineral oil, 0.23 g, 5.67 mmol) was added gradually. The reaction mixture was slowly warmed to room temperature and stirred for 15 minutes. 5-bromo-2,3-difluoropyridine (1.0 g, 5.16 mmol) was added dropwise to the reaction mixture and stirred for 16 hours. The reaction mixture was cooled to 10°C and treated with ice water (30 mL). The reaction mixture was extracted with ethyl acetate (2 × 50 mL). The organic layer was washed with brine (30 mL), dried on anhydrous Na₂SO₄, and concentrated. The crude compound was purified by column chromatography on silica gel using 2% ethyl acetate / PE to obtain the product (765 mg, 2.54 mmol, 49% yield). 1 H NMR (400MHz, CDCl3): δ7.99(d, 1H), 7.54(dd, 1H), 1.80(s, 6H).

[0393] Synthesis of A8: 5-bromo-3-fluoro-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)pyridine (765 mg, 2.54 mmol) and bis(pinacolate)diborone (0.71 g, 2.54 mmol) in 1,4-dioxane (20.0 mL). Potassium acetate (497 mg, 5.07 mmol) was added to a 79 mmol stirred solution. 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 using 30% ethyl acetate / PE to obtain the product (300 mg, 0.86 mmol, 33% yield). LCMS: 350.1 (M+H), Rt 3.31 min. Column: Atlantis dC18 (50 × 4.6 mm), 3.5 μm. Mobile phase: A: 0.1% HCOOH in water:ACN (95:5), B:ACN, flow rate: 1.5 mL / min.

[0394] Synthesis of A120: To a stirred solution of (5-chloropyrazine-2-yl)hydrazine (2.0 g, 13.53 mmol) in DCM (15 mL), Et3N (3.78 mL, 27.07 mmol), followed by 2-ethoxyacetyl chloride (2.36 mL, 13.53 mmol), was added at 0°C. The reaction mixture was slowly warmed to room temperature and stirred for 16 hours. The reaction mixture was treated with saturated ammonium chloride solution (25 mL) and extracted with ethyl acetate (2 × 25 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4, and concentrated. The crude product was purified by column chromatography on silica gel using 22% siRNA / PE to obtain the product (0.8 g, 3.47 mmol, 25% yield). LCMS: 231.1 (M+H), Rt 1.07 min. Column: ZORBAX XDB C-18 (50 × 4.6 mm), 3.5 μm Mobile phase: A: 0.1% HCOOH in water:ACN (95:5), B: ACN; flow rate: 1.5 mL / min.

[0395] Synthesis of A41-a: To a stirred solution of N'-(5-chloropyrazine-2-yl)-2-ethoxyacethydrazide (400 mg, 1.73 mmol) in DCM (15.0 mL), trifluoromethanesulfonic anhydride (0.38 mL, 2.25 mmol) and 2-methoxypridin (377 mg, 3.46 mmol) were added 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 × 25 mL). The organic layer was washed with brine (20 mL), dried on Na₂SO₄, and concentrated. The crude product was purified by column chromatography on silica gel using 35% siRNA / PE to obtain the product (100 mg, 0.47 mmol, 27% yield). LCMS: 213.1 (M+H), Rt 1.46 min Column: Atlantis dC18 (50 × 4.6 mm), 5.0 μm; Mobile phase: A: 0.1% HCOOH in water:ACN (95:5), B:ACN; Flow rate: 1.5 mL / min.

[0396] Synthesis of compound 79: To a stirred solution of 6-chloro-3-(ethoxymethyl)-[1,2,4]triazolo[4,3-a]pyrazine (150 mg, 0.71 mmol) and 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)pyridine (271 mg, 0.78 mmol) in 1,4-dioxane (10.0 mL), water (1.0 mL) and Cs2CO3 (460 mg, 1.41 mmol) were added. Pd(dppf)Cl2 . 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 obtain a solid (105 mg, 0.26 mmol, 36% yield). Preparative HPLC method: Rt 12.75; Column: X-Select (150 × 19 mm), 5.0 μm; Mobile phase: 0.1% TFA in water / acetonitrile; Flow rate: 15.0 mL / min. HPLC: Rt 4.95 min, Column: XBridge C8 (50 × 4.6) mm, 3.5 μm; Mobile phase: A: 0.1% TFA in water, B: 0.1% TFA in ACN; Flow rate: 2.0 mL / min. LCMS: 400.3 (M+H), Rt 2.41 mins, Column: ZORBAX XDB C-18 50 × 4.6 mm), 3.5 μm Mobile phase: A: 0.1% HCOOH in water:ACN (95:5), B: ACN; flow rate: 1.5 mL / min. 1 H NMR(400MHz, DMSO-d6):δ9.56(d, 1H), 9.17(d, 1H), 8.78(d, 1H), 8.45(dd, 1H), 5.09(s, 2H), 3.61(q, 2H), 1.83(s, 6H), 1.15(t, 3H).

[0397] Example 79: 3-(ethoxydifluoromethyl)-6-(6-(2,2,2-trifluoroethoxy)pyridine-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine [ka] To a stirred solution of 3-(chlorodifluoromethyl)-6-(6-(2,2,2-trifluoroethoxy)pyridine-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine (190 mg, 0.50 mmol) in MeCN (10.0 mL), Cs2CO3 (978 mg, 3.0 mmol) and ethanol (0.58 mL, 10 mmol) were added at room temperature, and the mixture was stirred for 3 hours. The reaction mixture was treated with water (15 mL) and extracted with ethyl acetate (2 × 20 mL). The organic layer was washed with brine (15 mL), dried over anhydrous Na2SO4, and concentrated. The crude compound was purified by preparative HPLC to obtain a solid (10 mg, 0.025 mmol, 5.1% yield). Preparative HPLC method: Rt 9.35; Column: XBridge (150 × 19 mm), 5.0 μm; 0.1% TFA in water / acetonitrile; Flow rate: 15.0 mL / min. HPLC: Rt 4.89 min, Column: XBridge C8 (50 × 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 × 4.6 mm), 5 μm; Mobile phase: A: 0.1% HCOOH:ACN (95:5) in water, B:ACN; Flow rate: 1.5 mL / min. 1 H NMR(400MHz, CDCl3):δ9.54(d, 1H), 8.74(d, 1H), 8.48(d, 1H), 8.26(dd, 1H), 7.06(d, 1H), 4.87(q, 2H), 4.38(q, 2H), 1.52 (t, 3H).

[0398] Example 80: 3-(difluoro(isobutoxy)methyl)-6-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridine-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine [ka] To a stirred solution of 2-methylpropan-1-ol (4.65 mL, 50.29 mmol) in MeCN (20 mL), Cs2CO3 (4.92 g, 15.09 mmol) was added, and the reaction mixture was heated at 70°C for 20 minutes. The reaction mixture was cooled to room temperature, and 3-(chloro) was added. Difluoromethyl)-6-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridine-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine (1.0 g, 2.51 mmol) was added. The reaction mixture was stirred at room temperature for 4 hours and then treated with water (30 mL). The reaction mixture was extracted with ethyl acetate (2 × 30 mL), washed with brine (20 mL), dried over Na₂SO₄, and concentrated. The crude compound was purified by preparative HPLC to obtain a solid (35 mg, 0.08 mmol, 3% yield). Preparative HPLC method: Rt 9.37; column: XBridge C8 (150 × 19 mm), 5.0 μm; 0.1% TFA in water / acetonitrile; flow rate: 15.0 mL / min. HPLC: Rt 5.60 min, Column: XBridge C8 (50 × 4.6 mm), 3.5 μm Mobile phase: A: 0.1% TFA in water, B: 0.1% TFA in ACN; Flow rate: 2.0 mL / min. LCMS: 436.1 (M+H), Rt 2.63 min, Column: XBridge C8 (50 × 4.6 mm), 3.5 μm Mobile phase: A: 0.1% TFA in water: ACN (95:5), B: 0.1% TFA in ACN; Flow rate: 1.5 mL / min. 1 H NMR(400MHz, DMSO-d6):δ9.72(d, 1H), 8.97(d, 1H), 8.77(d, 1H), 8.54(dd, 1H), 5.19(q, 2H), 4.04(d, 2H), 2.10-2.02(m, 1H), 0.98(d, 6H).

[0399] Example 81: 5-[3-[difluoro(methoxy)methyl]-[1,2,4]triazolo[4,3-a]pyrazine-6-yl]pyridine-2-ol and 6-(6-benzyloxy-5-fluoro-3-pyridyl)-3-[ethoxy(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyrazine [ka] Synthesis of A92: To a solution of phenylmethanol (12 g, 110.97 mmol) in THF (100 mL), NaH (4.88 g, 122.06 mmol) was gradually added over 0.5 hours at 0°C. After addition, the mixture was stirred for a further 1 hour at 20°C. Next, 5-bromo-2-fluoropyridine (18.55 g, 105.42 mmol) was added to the mixture. The resulting mixture was stirred for 3 hours at 20°C. The mixture was poured into saturated NH4 aqueous solution (150 mL) and extracted with siRNA (200 mL x 2). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product (27 g, 95.62 mmol, 86% yield) as oil. LCMS R t = 1.5 minutes chromatography for 0.96 minutes, 5-95AB, C 12 H 11 BrNO[M+H+2] + The MS ESI calculated value for this was 266.0, while the measured value was 265.8.

[0400] Synthesis of A93: 2-benzyloxy-5-bromide in 1,4-dioxane (300 mL) A mixture of mopyridine (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) was stirred at 90°C under N2 for 16 hours. After cooling to room temperature, the mixture was filtered through Celite and concentrated to obtain the crude product. The crude product was filtered through silica gel (approximately 50 g), eluted with PE / siRNA (5:1, 150 mL x 5), and the filtrate was concentrated to obtain the impure product. The impure product was purified with i-Pr2O (100 mL) to obtain the product (20 g, 64.27 mmol, 63% yield) as a solid. LC-MS R t = Chromatography for 1.5 minutes, 0.74 minutes, 5-95AB, C12 H 13 BNO3[M-C6H 10 +H] + The MS ESI calculated value for this is 230.1, and the measured value is 230.0.

[0401] Synthesis of A94: A mixture of 2-bromo-5-chloropyrazine (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 for 3 hours at 50°C under N2. After cooling to room temperature, the mixture was filtered and concentrated to obtain the residue. Water (100 mL) was added to the residue and extracted with siRNA (150 mL x 2). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was filtered through silica gel (approximately 50 g) and eluted with DCM (150 mL x 3). The filtrate was concentrated to obtain the impure product. The impure product was polished with i-Pr2O (15 mL) to obtain a solid product (4 g, 13.44 mmol, 65% yield). LCMS R t = 1.03 minutes of chromatography in 1.5 minutes, 5-95AB, C 16 H 13 ClN3O[M+H] + The MS ESI calculated value for this was 298.1, while the measured value was 297.9.

[0402] Synthesis of A95: 2-(6-benzyloxy-3-pyridyl)-5-chloropyrazine (4g, 13.43 mmol) and N2H4 in MeCN (20 mL) .A mixture of H2O (8.61 g) was stirred at 90°C for 16 hours. After cooling to room temperature, the solution was concentrated to obtain a residue. Water (30 mL) was added to the residue and extracted with SiO2 (50 mL x 3). The combined organic phase was washed with brine (30 mL), dried on anhydrous Na2SO4, filtered, and concentrated to obtain the product (4 g, 7.84 mmol, 58% yield) as a solid. LCMS R t = Chromatography for 1.5 minutes, 0.74 minutes, 5-95AB, C 16 H 16 N5O[M+H] + The MS ESI calculated value for this was 294.1, while the measured value was 293.9.

[0403] Synthesis of A96: To a solution of 2-bromo-2,2-difluoroacetyl chloride (1.78 g, 9.2 mmol) in DCM (20 mL), [5-(6-benzyloxy-3-pyridyl)pyrazine-2-yl]hydrazine (1.8 g, 6.14 mmol) was added, and the suspension was stirred at 20°C for 2 hours. The mixture was diluted with H2O (20 mL) and extracted with siRNA (100 mL × 2). The combined organic phase was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to obtain the product. The crude product was purified by flash chromatography on silica gel (siRNA in PE = 20%, 40%, 60%, 80%) to obtain the product (1.5 g, 3.33 mmol, 54% yield) as a solid. LCMS R t = 1.5 minutes chromatography for 0.88 minutes, 10⁻⁸⁰AB, C 18 H 15 F2N5O2[M+H] + The MS ESI calculated value for this is 450.0, while the measured value is 449.9.

[0404] Synthesis of A97: N'-[5-(6-benzyloxy-3-pyriol] in DCM (10 mL) To a mixture of zyl)pyrazine-2-yl]-2-bromo-2,2-difluoroacetohydrazide (1.3 g, 2.89 mmol), 2-methoxypyridine (0.67 mL, 6.35 mmol) and Tf2O (0.59 mL, 3.46 mmol) were added, and the mixture was stirred at 20°C for 2 hours. Water (20 mL) was added to the mixture, and it was extracted with DCM (50 mL × 2). The combined organic phase was washed with saturated NaHCO3 aqueous solution (30 mL) and brine (30 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by chromatography flash column on silica gel (siRNA in PE = 0% to 30% to 50%) to obtain the product (400 mg, 0.93 mmol, 32% yield) as a solid. LCMS R t = 1.5 minutes chromatography followed by 0.93 minutes, 10⁻⁸ AB, C 18 H 13 BrF2N5O[M+H+2] + MS ESI calculated value: 434.0, measured value: 434.0.

[0405] Synthesis of 83: A mixture of 6-(6-benzyloxy-3-pyridyl)-3-[bromo(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyrazine (400 mg, 0.93 mmol) and AgBF4 (900.79 mg, 4.63 mmol) in methanol (4 mL) was stirred in the dark at 60°C for 2 hours. After cooling to room temperature, saturated aqueous NaCl (10 mL), followed by siRNA (30 mL), was added to the mixture, and the mixture was filtered through Celite. After separating the phase of the filtrate, the organic phase was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by flash chromatography on silica gel (siRNA = 20% to 40% PE) to obtain an impure product (150 mg), which was then polished with i-Pr2O (2 mL) to obtain a pure product (130 mg). The product (39.76 mg, 0.10 mmol, 11% yield) was obtained as a solid. 1 1H 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 R t Retention time 1.26 minutes on chromatography with a 2.0 - minute cycle, 10 - 80 AB, C 19 H 16 F2N5O2 [M + H] + Calculated MS ESI value for [M + H] is 384.1, measured value is 384.1

[0406] Example 82: 3 - (Difluoro(methoxy)methyl) - 6 - (6 - (3,3 - difluorocyclobutoxy) - 5 - fluoropyridin - 3 - yl) - [1,2,4]triazolo[4,3 - a]pyridine

Chemical Structure

Claims

[Claim 1] Neurological disorder.

Images