MALT1 modulator and its usage

Abstract

To provide a MALT1 modulator and its use. [Solution] Compounds, compositions, and methods useful for modulating MALT1 and treating related diseases, disorders, and conditions are provided herein. In some embodiments, the compounds of the compositions described herein may be administered simultaneously with, before, or after one or more other therapeutic agents. In some embodiments, the compounds of the compositions described herein may be administered separately by the same or different routes of administration, or together with other agents in the same pharmaceutical composition.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority and benefit of U.S. Provisional Patent Application No. 63 / 092,768, filed on 16 October 2020, the contents of which are incorporated herein by reference in their entirety. [Background technology]

[0002] background Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is a known intracellular signaling protein from innate immune cells (e.g., natural killer cells (NK), dendritic cells (DC), and mast cells) and adaptive immune cells (e.g., T cells and B cells). MALT1 plays an essential role in influencing immune responses. For example, in T cell receptor signaling, MALT1 mediates nuclear factor κB (NFKB) signaling, leading to T cell activation and proliferation. Therefore, MALT1 is of interest in the mechanisms of autoimmune and inflammatory pathology. In addition, constitutive (dysregulated) MALT1 activity is associated with cancers such as MALT lymphoma and activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL). Modulators of MALT1 activity may be useful as potentially promising therapeutic agents. [Overview of the Initiative] [Means for solving the problem]

[0003] overview Compounds designed to act as MALT1 modulators are provided herein. In some embodiments, such compounds are envisioned to be useful as therapeutic agents for treating autoimmune and inflammatory diseases, disorders or conditions, or cancer.

[0004] In one embodiment, the compound represented by formula (I) is used herein. [ka] or a pharmaceutically acceptable salt thereof [wherein, R 1 is selected from the group consisting of C 1~6 alkyl, C 1~6 alkoxy, C 3~6 cycloalkyl, and 5- to 10-membered heterocyclyl, and C 1~6 alkyl, C 3~6 cycloalkyl, and 5- to 10-membered heterocyclyl are each independently selected from 1, 2, 3, or more substituents selected from R 1a and may be optionally substituted on one or more available carbons, where when the 5- to 10-membered heterocyclyl contains a ring nitrogen atom that can be substituted, the ring nitrogen atom may be optionally substituted by R 1b , and when the 5- to 10-membered heterocyclyl contains a ring sulfur atom that can be substituted, the ring sulfur atom may be optionally substituted by 2 O atoms, R 2 is CH3 or CF3, R 3 is hydrogen or R 3 is selected from the group consisting of C 1~6 alkyl, C 1~6 alkoxy, C 3~7 cycloalkyl, 5- to 6-membered heterocyclyl, 5- to 6-membered heterocyclyl-C 1~3 alkyl-, 5- to 6-membered heterocyclyl-O-, phenyl, and 5- to 6-membered heteroaryl, and any of them may be optionally substituted by 1, 2 or 3 substituents each independently selected from R 3a , R 4 is C 1~6 alkyl, R 1a is, each time it appears, cyano, halogen, hydroxyl, oxo, C 1~6 alkyl, -C(O)OR A , -C(O)N(R A )2, -N(R A )2, C 1~6Independently selected from the group consisting of alkoxys, 5-6 membered heterocyclyls, and 5-6 membered heteroaryls, C 1~6 Alkyl is -N(R A )2 is substituted as needed, and here, if a 5-6 member heterocyclyl contains a substituteable ring nitrogen atom, that ring nitrogen atom is R B This may be replaced as needed, R 1b C 1~6 Alkyl, -C(O)OR A , -C(O)C 1~6 Alkyl, -C(O)C 3~6 Cycloalkyl, -C(O)N(R A )2, and -S(O)2C 1~6 Selected from the group consisting of alkyl groups, R 3a Each time it appears, halogen, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, Hydroxy, C 1~4 Alkenil, Cyano, Azid, -NR C R D , C 3~6 Cycloalkyl, C 1~4 Alkoxy C 1~4 Independently selected from the group consisting of alkoxy, 5-6 membered heterocyclyl-O-, 5-6 membered heterocyclyl, and phenyl, C 3~6 Cycloalkyl groups, 5-6 membered heterocyclyl-O- groups, 5-6 membered heterocyclyl groups, and phenyl groups are R p They are optionally substituted with one, two, or three substituents independently selected from each of the following: R p Each time it appears, halogen, C 1~4 Alkyl, C 1~4 Haloalkyl, hydroxy, C 1~4 Alkoxy, C 1~4 Alkoxy C 1~4 Alkyl, NR C R D , and aminoC 1~3 Independently selected from the group consisting of alkyls, R A Each time it appears, hydrogen, C 1~6 Alkyl, -C(O)C 1~6 Alkyl and -C(O)OC 1~6 Independently selected from the group consisting of alkyls, R B C 1~6 Alkyl, C 3~6 Cycloalkyl and -C(O)OC 1~6 Selected from the group consisting of alkyl groups, R C and R D Each time it appears, hydrogen, C 1~6 Alkyl, Halo C 1~6 Alkyl, and C 3~4 Independently selected from the group consisting of cycloalkyls, or R C and R D These, together with the nitrogen atom to which they are bonded, form a 4-6 membered heterocycline or 4-6 membered heteroaryl, which may contain further nitrogen or oxygen atoms and may be substituted as needed with one or two fluorocarbons. t is either 0 or 1. It will be provided.

[0005] In another embodiment, the compound represented by formula (Ib) as used herein [ka] or a pharmaceutically acceptable salt thereof [in the formula, R 1 C 1~6 Alkyl, C 3~6 A cycloalkyl or 5-10 membered heterocycline, C 3~6 Cycloalkyl is R 1aIt may be optionally substituted on one or more available carbons by one, two, three, or more substituents each independently selected from, where when a 5- to 10-member heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom is R 1b It may be optionally substituted by, and when a 5- to 10-member heterocyclyl contains a substitutable ring sulfur atom, the ring sulfur atom may be optionally substituted by two O atoms. R 1a is, each time it appears, independently selected from the group consisting of cyano, halogen, hydroxyl, C 1~6 alkyl, -C(O)OR A , -C(O)N(R A )2, -N(R A )2, C 1~6 alkoxy, and 5- to 6-member heteroaryl, and C 1~6 alkyl is optionally substituted by -N(R A )2. R 1b is selected from the group consisting of C 1~6 alkyl, -C(O)OR A , -C(O)C 1~6 alkyl, -C(O)C 3~6 cycloalkyl, -C(O)N(R A )2, and -S(O)2C 1~6 alkyl. R A is, each time it appears, independently selected from the group consisting of hydrogen, C 1~6 alkyl, -C(O)C 1~6 alkyl, and -C(O)OC 1~6 alkyl. is provided.

[0006] In some embodiments, the compounds provided herein are selected from the compounds listed in Table 1 or pharmaceutically acceptable salts thereof.

[0007] In another aspect, provided herein is a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable carrier.

[0008] In another aspect, provided herein is a method of treating cancer in a subject that requires treatment of cancer, the method comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition disclosed herein.

[0009] In another aspect, provided herein is a method of treating an autoimmune or inflammatory disorder or disease in a subject that requires treatment of an autoimmune or inflammatory disorder or disease, the method comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition disclosed herein.

Mode for Carrying Out the Invention

[0010] Detailed Description As generally described herein, the present invention provides compounds designed to act as MALT1 modulators. In certain embodiments, such compounds are envisioned to be useful as therapeutic agents for treating autoimmune and inflammatory diseases, disorders or conditions, or cancer. Definitions Chemical Definitions

[0011] The definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Ed, front and back covers, and specific functional groups are generally defined as described herein. In addition, general principles of organic chemistry, as well as specific functionality and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999, Smith and March, March's Advanced Organic Chemistry, 5 thEdition, John Wiley & Sons, Inc., New York, 2001, Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989. and Carruthers, Some Modern Methods of Organic Synthesis, 3 rd Edition, This is described in Cambridge University Press, Cambridge, 1987.

[0012] 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 be in the form of individual enantiomers, diastereomers or geometric isomers, or in the form of a mixture of stereoisomers, including racemic mixtures and mixtures in which one or more stereoisomers are concentrated. Isomers can 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 can be prepared by asymmetric synthesis. For example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981), Wilen et al., Tetrahedron 33:2725 (1977), Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962), and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, See Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972. The present invention additionally encompasses the compounds described herein as individual isomers substantially free of other isomers and, alternatively, as mixtures of various isomers.

[0013] As used herein, a pure enantiomeric compound is substantially free of other enantiomers or stereoisomers of the compound (i.e., is enantiomerically pure). In other words, the "S" form of the compound is substantially free of the "R" form of the compound and is thus enantiomerically pure with respect to the "R" form. The terms "enantiomerically pure" or "pure enantiomer" indicate that the compound contains more than 75%, more than 80%, more than 85%, more than 90%, more than 91%, more than 92%, more than 93%, more than 94%, more than 95%, more than 96%, more than 97%, more than 98%, more than 98.5%, more than 99%, more than 99.2%, more than 99.5%, more than 99.6%, more than 99.7%, more than 99.8%, or more than 99.9% enantiomer. In certain embodiments, the weight is based on the total weight of all enantiomers or stereoisomers of the compound.

[0014] In the compositions provided herein, an enantiomerically pure compound may be present with other active or inactive ingredients. For example, a pharmaceutical composition containing an enantiomerically pure R-compound can contain, for example, about 90% excipient and about 10% enantiomerically pure R-compound. In certain embodiments, an enantiomerically pure R-compound in such a composition can contain, for example, at least about 95% by weight of the R-compound and up to about 5% by weight of the S-compound, based on the total weight of the compound. For example, a pharmaceutical composition containing an enantiomerically pure S-compound can contain, for example, about 90% excipient and about 10% enantiomerically pure S-compound. In certain embodiments, an enantiomerically pure S-compound in such a composition can contain, for example, at least about 95% by weight of the S-compound and up to about 5% by weight of the R-compound, based on the total weight of the compound. In certain embodiments, the active ingredient can be formulated without or with little excipient or carrier.

[0015] The compounds described herein may also contain one or more isotope substitutions. For example, H can be 1 H, 2 H (D or deuterium), and 3 H (T or tritium) in any isotopic form, C can be 12 C, 13 C, and 14 C in any isotopic form, O can be 16 O and 18 O in any isotopic form, F can be 18 F and 19 F in any isotopic form, and so on.

[0016] The following terms are intended to have the meanings presented below and are useful for understanding this description and the 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 following meanings unless otherwise indicated. It should also be understood that any part defined below may be substituted with various substituents where described herein, and that each definition is intended to include such substituted parts within the scope described below. Unless otherwise stated, the term “substituted” shall be defined as described below. Furthermore, it should be understood that the terms “group” and “radical” may be considered interchangeable where used herein. The articles “a” and “an” may be used herein to refer to one or more (i.e., at least one) of the grammatical objects of the article. For example, “a analog” means one analog or more analogs.

[0017] When a range of values ​​is listed, it is intended to include each value and subrange within that range. For example, "C 1~6 "Alkyl" refers to C1, C2, C3, C4, C5, C6, C 1~6 , C 1~5 , C 1~4 , C 1~3 , C 1~2 , C 2~6 , C 2~5 , C 2~4 , C 2~3 , C 3~6 , C 3~5 , C 3~4 , C 4~6 , C 4~5 , and C 5~6 It is intended to include alkyl groups.

[0018] As used herein, “alkyl” refers to, for example, a radical of a linear or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C"). 1~20 This refers to an alkyl group. 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.

[0019] 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., one, two, three, or four carbon-carbon double bonds), and optionally one or more carbon-carbon triple bonds (e.g., one, two, three, or four carbon-carbon triple bonds). 2~20 This refers to an alkenyl group. In certain embodiments, the alkenyl group 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. possesses ("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., in 2-butenyl) or terminal (e.g., in 1-butenyl). C 2~4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), and butadienyl (C4). 2~6 As an example of an alkenyl group, the aforementioned C 2~4 Examples of alkenyl groups include pentenyl (C5), pentadienyl (C5), and hexenyl (C6). Further examples of alkenyls include heptenyl (C7), octenyl (C8), and octatrienyl (C8).

[0020] As used herein, "alkynyl" refers to a radical of a linear or branched hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., one, two, three, or four carbon-carbon triple bonds), and optionally one or more carbon-carbon double bonds (e.g., one, two, three, or four carbon-carbon double bonds).2~20 This refers to an "alkynyl" group. In certain embodiments, the alkynyl group does not contain any double bonds. In some embodiments, the alkynyl group has 2 to 10 carbon atoms ("C"). 2~10 ("Alkynyl"). In some embodiments, the alkynyl group has 2 to 9 carbon atoms ("C"). 2~9 ("Alkynyl"). In some embodiments, the alkynyl group has 2 to 8 carbon atoms ("C"). 2~8 ("Alkynyl"). In some embodiments, the alkynyl group has 2 to 7 carbon atoms ("C"). 2~7 ("Alkynyl"). In some embodiments, the alkynyl group has 2 to 6 carbon atoms ("C"). 2~6 ("Alkynyl"). In some embodiments, the alkynyl group has 2 to 5 carbon atoms ("C"). 2~5 ("Alkynyl"). In some embodiments, the alkynyl group has 2 to 4 carbon atoms ("C"). 2~4 ("Alkynyl"). In some embodiments, the alkynyl group has 2 to 3 carbon atoms ("C"). 2~3 "Alkynyl"). In some embodiments, the alkynyl group has two carbon atoms ("C2 alkynyl"). One or more carbon-carbon triple bonds may be internal (e.g., in 2-butynyl) or terminal (e.g., in 1-butynyl). C 2~4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), and 2-butynyl (C4). 2~6 As an example of an alkenyl group, the aforementioned C 2~4 Examples include alkynyl groups, as well as pentynyl (C5), hexynyl (C6), and the like. Further examples of alkynyls include heptynyl (C7) and octinyl (C8).

[0021] As used herein, “alkylene,” “alkenylene,” “alkylylene,” “cycloalkylene,” “heterocyclylene,” “heteroarylene,” and “phenylene” refer to divalent radicals of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl (e.g., saturated and partially saturated), heteroaryl, and phenyl groups, respectively.

[0022] When a range or number of carbon atoms is provided for a particular "alkylene," "alkenylene," or "alkynylene" group, it is understood that this range or number refers to a range or number of carbon atoms in a divalent chain of straight carbon atoms. The "alkylene," "alkenylene," and "alkynylene" groups may or may not be substituted with one or more substituents as described herein.

[0023] As used herein, "aryl" refers to a ring with 6 to 14 carbon atoms in an aromatic ring system. A radical ("C") of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., where 6, 10, or 14 π electrons are shared in the cyclic arrangement) is provided, with an atom and zero heteroatoms. 6~14 This refers to "aryl". 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" (e.g., naphthyl, e.g., 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 a ring system in which an aryl ring, as defined above, is fused with one or more carbocyrillic or heterocyclyl groups, where the radical or bond site is located on the aryl ring, and in such cases the number of carbon atoms still specifies 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, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiaden, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. In particular, aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl.

[0024] As used herein, “heteroaryl” refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., 6 or 10 electrons shared in the cyclic arrangement) where the aromatic ring system provides a ring carbon atom and 1-4 ring heteroatoms (each heteroatom independently selected from nitrogen, oxygen, and sulfur). In a heteroaryl group containing one or more nitrogen atoms, the bond site may be a carbon atom or a nitrogen atom, as permitted by valence. A heteroaryl bicyclic ring system may contain one or more heteroatoms in one or both rings. “Heteroaryl” includes a ring system in which the previously defined heteroaryl ring is fused with one or more carbocykryl or heterocyclyl groups, where the bond site is located on the heteroaryl ring, and in such cases the number of ring members still specifies the number of ring members in the heteroaryl ring system. A "heteroaryl" also includes a ring system in which a previously defined heteroaryl ring is fused with one or more aryl groups, where the bond site is located on an aryl ring or a heteroaryl ring, and in such cases 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, etc.), the bond site can be located on either ring, i.e., on a ring supporting a heteroatom (e.g., 2-indolyl) or on a ring not containing a heteroatom (e.g., 5-indolyl).

[0025] In some embodiments, the heteroaryl group is a 5-10 membered aromatic ring system ("5-10 membered heteroaryl") in which a ring carbon atom and 1-4 ring heteroatoms (each heteroatom independently selected from nitrogen, oxygen, and sulfur) are provided in the aromatic ring system. In some embodiments, the heteroaryl group is a 5-8 membered aromatic ring system ("5-8 membered heteroaryl") in which a ring carbon atom and 1-4 ring heteroatoms (each heteroatom independently selected from nitrogen, oxygen, and sulfur) are provided in the aromatic ring system. In some embodiments, the heteroaryl group is a 5-6 membered aromatic ring system ("5-6 membered heteroaryl") in which a ring carbon atom and 1-4 ring heteroatoms (each heteroatom independently selected from nitrogen, oxygen, and sulfur) are provided in the aromatic ring system. Some embodiments In some embodiments, a 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0026] Examples of five-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Examples of five-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Examples of five-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Examples of five-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Examples of six-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Examples of six-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Examples of six-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetradinyl, respectively. Examples of seven-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Examples of 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranil, benzoisofuranil, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl (benzthiadiazolyl), indolidinyl, and prinyl. Examples of 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthylidinyl, pteridinyl, quinolinyl, isoquinolinyl, sinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0027] Typical examples of heteroaryls include the following: [ka] [In the formula, each Z is a carbonyl, N, or NR.] 65 Selected from O and S, R 65 These are, independently, hydrogen and C 1~8 Alkyl, C 3~10 Carbocyclyl, 4-10 member heterocyclyl, C6-C 10 [Aryls, and heteroaryls with 5 to 10 members.]

[0028] As used herein, "carbocykrill" or "carbocyclic" refers to a non-aromatic cyclic carbon having 3 to 10 ring carbon atoms and 0 heteroatoms in a non-aromatic ring system. Hydrogen radical ("C 3~10 This refers to a "carbocyclyl" group. In some embodiments, the carbocyclyl 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 Examples of carbocyclyl groups include, but are not limited to, cyclopropyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), and cyclohexadienyl (C6). 3~8 As a carbocyric group, the aforementioned C 3~6 Examples include, but are not limited to, carbocyclyl groups, and 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. 3~10As a carbocyric group, the aforementioned C 3~8 Carbocyclyl group, and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9) 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C9) 10 ), spiro[4.5]decanil(C 10 Examples include, but are not limited to, the above. As the above examples show, in certain embodiments, the carbocyclyl group is either monocyclic ("monocyclic carbocyclyl") or contains a condensed, bridged, or spirocyclic system, such as a bicyclic system ("bicyclic carbocyclyl"), and may be saturated or partially unsaturated. "Carbocyclyl" also includes a cyclic system in which the previously defined carbocyclyl ring is fused with one or more aryl or heteroaryl groups, where the bond site is located on the carbocyclyl ring, and in such cases the number of carbons still specifies the number of carbons in the carbocyclic system.

[0029] The term "cycloalkyl" in this specification refers, for example, to "C" derived from cycloalkanes. 4~8 A "cycloalkyl" refers to a monovalent saturated, bicyclic, or bridged (e.g., adamantyl) hydrocarbon group consisting of 3 to 12, 3 to 8, 4 to 8, or 4 to 6 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclohexane, cyclopentane, cyclobutane, and cyclopropane.

[0030] When used herein, "C 3~6 "Monocyclic cycloalkyl" or "Monocyclic C 3~6"Cycloalkyl" refers to a saturated 3- to 7-membered monocyclic hydrocarbon ring system. 3- to 7-membered monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Substituents on the cycloalkyl (e.g., in the case of optionally substituted cycloalkyls), if optionally substituted or specified as substituted, can be located at any substituted position, including, for example, the position to which the cycloalkyl group is attached.

[0031] As used herein, “heterocyclyl” or “heterocyclic” refers to a 3- to 10-membered non-aromatic cyclic radical (“3- to 10-membered heterocyclyl”) having a ring carbon atom and 1 to 4 ring heteroatoms (each heteroatom independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon). In a heterocyclyl group containing one or more nitrogen atoms, the bond site may be a carbon atom or a nitrogen atom, as permitted by valence. A heterocyclyl group may be monocyclic (“monocyclic heterocyclyl”) or condensed, bridging, or spirocyclic, such as a bicyclic system (“bicyclic heterocyclyl”), and may be saturated or partially unsaturated. A heterocyclyl bicyclic system may have one or more heteroatoms on one or both rings. It may include: “heterocyclyl” also includes a ring system in which a previously defined heterocyclyl ring is fused with one or more carbocyrill groups (where the bond site is located on either the carbocyrill or heterocyclyl ring), or a ring system in which a previously defined heterocyclyl ring is fused with one or more aryl or heteroaryl groups (where the bond site is located on the heterocyclyl ring), in which case the number of ring members still specifies the number of ring members in the heterocyclyl ring system. The terms “heterocyclyl,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical” may be used interchangeably.

[0032] In some embodiments, the heterocyclyl group is a 4-7 member non-aromatic ring system ("4-7 member heterocyclyl") having a ring carbon atom and 1-4 ring heteroatoms (each heteroatom independently selected from nitrogen, oxygen, and sulfur). In some embodiments, the heterocyclyl group is a 5-10 member non-aromatic ring system ("5-10 member heterocyclyl") having a ring carbon atom and 1-4 ring heteroatoms (each heteroatom independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon). In some embodiments, the heterocyclyl group is a 5-8 member non-aromatic ring system ("5-8 member heterocyclyl") having a ring carbon atom and 1-4 ring heteroatoms (each heteroatom independently selected from nitrogen, oxygen, and sulfur). In some embodiments, the heterocyclyl group is a 5-6 member non-aromatic ring system ("5-6 member heterocyclyl") having a ring carbon atom and 1-4 ring heteroatoms (each heteroatom independently selected from nitrogen, oxygen, and sulfur). In some embodiments, the 5-6 member heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 member heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 member heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0033] Examples of three-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxyranyl, and thiorenyl. Examples of four-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Examples of five-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Examples of five-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranil, disulfuranil, and oxazolidine-2-one. Examples of five-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Examples of six-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranil, dihydropyridinyl, and thianil. Examples of six-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianil, and dioxanil. Examples of six-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinyl. Examples of seven-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Examples of eight-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azokanyl, oxecanyl, and thiokanyl. Examples of five-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclic rings) include indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, etc. is not limited thereto. Exemplary 6-membered heterocyclyl groups (also referred to herein as 6,6-bicyclic heterocyclic rings) fused to an aryl ring include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0034] Examples of saturated or partially unsaturated heterocyclic radicals include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, pyrrolidinyl, pyridinonyl, pyrrolidonyl, piperidinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, morpholinyl, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, oxetanyl, azetidinyl, and tetrahydropyrimidinyl. When substituted as necessary or specified as substituted, substituents on the heterocyclyl (e.g., in the case of a heterocyclyl substituted as necessary) can be present at any substitutable position, including, for example, the position to which the heterocyclyl group is attached.

[0035] When used to describe a compound or a group present on a compound, "hetero" means that one or more carbon atoms in the compound or group are replaced by nitrogen, oxygen, or sulfur heteroatoms. Hetero can be applied to any of the above-described hydrocarbyl groups having 1 to 5, particularly 1 to 3 heteroatoms, and can be, for example, applied to alkyl to give, for example, heteroalkyl, applied to carbocyclyl to give, for example, heterocyclyl, applied to aryl to give, for example, heteroaryl, etc.

[0036] As used herein, "cyano" refers to -CN.

[0037] The terms "halo" and "halogen," as used herein, refer to an atom selected from fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), and iodine (iodo, -I). In certain embodiments, the halo group is either fluoro or chloro.

[0038] As used herein, the term "alkoxy" refers to an alkyl group (-O(alkyl)) bonded to another part via an oxygen atom. Non-limiting examples include, for example, methoxy, ethoxy, propoxy, and butoxy.

[0039] A "haloalkoxy" is a haloalkyl group bonded to another part via an oxygen atom, such as -OCHCF2 or -OCF3, but is not limited to these.

[0040] The term "haloalkyl" includes monohaloalkyl, polyhaloalkyl, and perhaloalkyl groups substituted with one or more halogen atoms, where the halogen is independently selected from fluorine, chlorine, bromine, and iodine. 1~4 Haloalkyl-OC 1~4 Regarding alkyl groups, their bonding sites occur on the halogenated alkyl moiety.

[0041] As used herein, "oxo" refers to -C=O.

[0042] Generally, the term “substituted” means that at least one hydrogen atom on a group (e.g., a carbon or nitrogen atom) is replaced by an acceptable substituent, such as a substituent that results in a stable compound upon substitution, such as a compound 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 that group and can be substituted in any given structure. If more than one position is substituted, the substituents are either the same or different at each position.

[0043] Nitrogen atoms may be substituted or unsubstituted, as long as their valence allows, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary substituents on nitrogen atoms include 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(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc -SOR aa -C(=S)N(R cc )2, -C(=O)SR cc -C(=S)SR cc -P(=O)2R aa -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenil, C 2~10 Alkinyl, C 3~10 Carbocyclyl, 3-14 member heterocyclyl, C 6~14 Examples include, but are not limited to, aryls and 5- to 14-membered heteroaryls, or two Rs bonded to a nitrogen atom. cc The groups combine to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyryl, heterocyclyl, aryl, and heteroaryl has 0, 1, 2, 3, 4, or 5 R groups.dd They are independently substituted at the base, R aa , R bb , R cc and R dd This is as previously defined.

[0044] These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and Claims. The present invention is by no means intended to be limited by the prior list of exemplary substituents. Other definitions

[0045] As used herein, “pharmaceutically acceptable carrier” means a non-toxic carrier, adjuvant, or vehicle that does not impair the pharmacological activity of the compound formulated with it. 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, e.g., human serum albumin, buffers, e.g., phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts, or electrolytes, e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.

[0046] As used herein, “pharmaceutically acceptable salt” refers to a salt that is suitable for use in contact with human and lower animal tissues without excessive toxicity, irritation, allergic reactions, etc., within the bounds of sound medical judgment, and that is commensurate with a reasonable cost-benefit 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. Compounds of the present invention pharmaceutically acceptable salts include salts derived from suitable inorganic and organic acids, as well as inorganic and organic bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed using inorganic acids, e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids, e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipines, alginates, ascorbic acid, aspartates, benzenesulfonates, and benzoates. This includes bicarbonate, borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. pharmaceutically acceptable salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium and N + (C 1~4 Alkyl) tetrasalts are included. Typical alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations, formed, where appropriate, using counterions such as halide ions, hydroxide ions, carboxylate ions, sulfate ions, phosphate ions, nitrate ions, lower alkyl sulfonate ions, and aryl sulfonate ions.

[0047] 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, e.g., mammals, e.g., primates (e.g., crab-eating 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.

[0048] Diseases, disorders, and conditions are used interchangeably in this specification.

[0049] As used herein, unless otherwise specified, the terms “to treat,” “to treat,” and “treatment” refer to actions that reduce the severity of a disease, disorder, or condition, or delay or slow the progression of such disease, disorder, or condition, while the subject is suffering from the specified disease, disorder, or condition ("therapeutic treatment"), and also refer to actions that occur before the subject begins to suffer from the specified disease, disorder, or condition ("preventive treatment").

[0050] As used herein, “effective dose” of a compound refers to an amount sufficient to elicit 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 method of administration, and the age, health, and condition of the subject. The effective dose includes both therapeutic and prophylactic treatments.

[0051] As used herein, unless otherwise specified, the “therapeutic dose” of a compound is an amount sufficient to produce a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with that disease, disorder, or condition. The therapeutic dose of a compound means the amount of the therapeutic agent that, alone or in combination with other treatments, produces a therapeutic benefit in the treatment of a disease, disorder, or condition. The term “therapeutic dose” may include an amount that improves the overall treatment, reduces or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic effect of another therapeutic agent. compound

[0052] In one embodiment, the compound represented by formula (I) is used herein. [ka] or a pharmaceutically acceptable salt thereof [in the formula, R 1 C 1~6 Alkyl, C 1~6 Alkoxy, C 3~6 Selected from the group consisting of cycloalkyls and 5-10 membered heterocyclines, C 1~6 Alkyl, C 3~6 Cycloalkyls and 5-10 membered heterocyclines are R 1a One or more available carbon atoms may be optionally substituted by one, two, three, or more substituents independently selected from each of the following, where if the 5-10 membered heterocyclyl contains a substituteable ring nitrogen atom, the ring nitrogen atom is R 1b If a 5-10 member heterocycline contains a substituteable ring sulfur atom, that ring sulfur atom may be substituted with two oxygen atoms as needed. R 2 It is CH3 or CF3, R 3 is hydrogen, or R 3 C 1~6Alkyl, C 1~6 Alkoxy, C 3~7 Cycloalkyl, 5-6 member heterocyclyl, 5-6 member heterocyclyl-C 1~3 Selected from the group consisting of alkyl-, 5-6 member heterocyclyl-O-, phenyl, and 5-6 member heteroaryl, any of which is R 3a They may be substituted as needed with one, two, or three substituents independently selected from each of the following: R 4 C 1~6 It is alkyl, R 1a Each time it appears, it is cyano, halogen, hydroxyl, oxo, C 1~6 Alkyl, -C(O)OR A ,-C(O)N(R A )2, -N(R A )2, C 1~6 Independently selected from the group consisting of alkoxys, 5-6 membered heterocyclyls, and 5-6 membered heteroaryls, C 1~6 Alkyl is -N(R A )2 is substituted as needed, and here, if a 5-6 member heterocyclyl contains a substituteable ring nitrogen atom, that ring nitrogen atom is R B This may be replaced as needed, R 1b C 1~6 Alkyl, -C(O)OR A , -C(O)C 1~6 Alkyl, -C(O)C 3~6 Cycloalkyl, -C(O)N(R A )2, and -S(O)2C 1~6 Selected from the group consisting of alkyl groups, R 3a Each time it appears, halogen, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, Hydroxy, C 1~4 Alkenil, Cyano, Azid, -NR C R D , C 3~6 Cycloalkyl, C1~4 Alkoxy C 1~4 Independently selected from the group consisting of alkoxy, 5-6 membered heterocyclyl-O-, 5-6 membered heterocyclyl, and phenyl, C 3~6 Cycloalkyl groups, 5-6 membered heterocyclyl-O- groups, 5-6 membered heterocyclyl groups, and phenyl groups are R p They are optionally substituted with one, two, or three substituents independently selected from each of the following: R p Each time it appears, halogen, C 1~4 Alkyl, C 1~4 Haloalkyl, hydroxy, C 1~4 Alkoxy, C 1~4 Alkoxy C 1~4 Alkyl, NR C R D , and aminoC 1~3 Independently selected from the group consisting of alkyls, R A Each time it appears, hydrogen, C 1~6 Alkyl, -C(O)C 1~6 Alkyl and -C(O)OC 1~6 Independently selected from the group consisting of alkyls, R B C 1~6 Alkyl, C 3~6 Cycloalkyl and -C(O)OC 1~6 Selected from the group consisting of alkyl groups, R C and R D Each time it appears, hydrogen, C 1~6 Alkyl, Halo C 1~6 Alkyl, and C 3~4 Independently selected from the group consisting of cycloalkyls, or R C and R D These, together with the nitrogen atom to which they are bonded, form a 4-6 membered heterocycline or 4-6 membered heteroaryl, which may contain further nitrogen or oxygen atoms and may be substituted as needed with one or two fluorocarbons. t is either 0 or 1. It will be provided.

[0053] In another embodiment, the compound represented by formula (I) as used herein [ka] or a pharmaceutically acceptable salt thereof [in the formula, R 1 C 1~6 Alkyl, C 3~6 A cycloalkyl or 5-10 membered heterocycline, C 3~6 Cycloalkyl is R 1a One or more available carbon atoms may be optionally substituted by one, two, three, or more substituents independently selected from each of the following, where if the 5-10 membered heterocyclyl contains a substituteable ring nitrogen atom, the ring nitrogen atom is R 1b If a 5-10 member heterocycline contains a substituteable ring sulfur atom, that ring sulfur atom may be substituted with two oxygen atoms as needed. R 2 It is CH3 or CF3, R 3 C 1~6 It is alkyl, C 1~6 Alkyl is C 1~4 They may be substituted with alkoxy as needed. R 4 C 1~6 It is alkyl, R 1a Each time it appears, it is cyano, halogen, hydroxyl, C 1~6 Alkyl, -C(O)OR A ,-C(O)N(R A )2, -N(R A )2, C 1~6 Independently selected from the group consisting of alkoxys and 5-6 member heteroaryls, C 1~6 Alkyl is -N(R A )2 is replaced as needed, R1b C 1~6 Alkyl, -C(O)OR A , -C(O)C 1~6 Alkyl, -C(O)C 3~6 Cycloalkyl, -C(O)N(R A )2, and -S(O)2C 1~6 Selected from the group consisting of alkyl groups, R A Each time it appears, hydrogen, C 1~6 Alkyl, -C(O)C 1~6 Alkyl and -C(O)OC 1~6 Independently selected from the group consisting of alkyls, t is either 0 or 1. It will be provided.

[0054] In some embodiments, t=0. In some embodiments, t=1.

[0055] In some embodiments, R 4 C 1~6 It is alkyl. In some embodiments, R 4 This is CH3.

[0056] In another embodiment, the compound represented by formula (Ia) as used herein [ka] or a pharmaceutically acceptable salt thereof [in the formula, R 1 C 1~6 Alkyl, C 1~6 Alkoxy, C 3~6 Selected from the group consisting of cycloalkyls and 5-10 membered heterocyclines, C 1~6 Alkyl, C 3~6 Cycloalkyls and 5-10 membered heterocyclines are R 1aOne or more available carbon atoms may be optionally substituted by one, two, three, or more substituents independently selected from each of the following, where if the 5-10 membered heterocyclyl contains a substituteable ring nitrogen atom, the ring nitrogen atom is R 1b If a 5-10 member heterocycline contains a substituteable ring sulfur atom, that ring sulfur atom may be substituted with two oxygen atoms as needed. R 2 It is CH3 or CF3, R 3 is hydrogen, or R 3 C 1~6 Alkyl, C 1~6 Alkoxy, C 3~7 Cycloalkyl, 5-6 member heterocyclyl, 5-6 member heterocyclyl-C 1~3 Selected from the group consisting of alkyl-, 5-6 member heterocyclyl-O-, phenyl, and 5-6 member heteroaryl, any of which is R 3a They may be substituted as needed with one, two, or three substituents independently selected from each of the following: R 1a Each time it appears, it is cyano, halogen, hydroxyl, oxo, C 1~6 Alkyl, -C(O)OR A ,-C(O)N(R A )2, -N(R A )2, C 1~6 Independently selected from the group consisting of alkoxys, 5-6 membered heterocyclyls, and 5-6 membered heteroaryls, C 1~6 Alkyl is -N(R A )2 is substituted as needed, and here, if a 5-6 member heterocyclyl contains a substituteable ring nitrogen atom, that ring nitrogen atom is R B This may be replaced as needed, R 1b C 1~6 Alkyl, -C(O)OR A , -C(O)C 1~6 Alkyl, -C(O)C3~6 Cycloalkyl, -C(O)N(R A )2, and -S(O)2C 1~6 Selected from the group consisting of alkyl groups, R 3a Each time it appears, halogen, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, Hydroxy, C 1~4 Alkenil, Cyano, Azid, NR C R D , C 3~6 Cycloalkyl, C 1~4 Alkoxy C 1~4 Independently selected from the group consisting of alkoxy, 5-6 membered heterocyclyl-O-, 5-6 membered heterocyclyl, and phenyl, C 3~6 Cycloalkyl groups, 5-6 membered heterocyclyl-O- groups, 5-6 membered heterocyclyl groups, and phenyl groups are R p They are optionally substituted with one, two, or three substituents independently selected from each of the following: R p is halogen, C 1~4 Alkyl, C 1~4 Haloalkyl, hydroxy, C 1~4 Alkoxy, C 1~4 Alkoxy C 1~4 Alkyl, NR C R D , and aminoC 1~3 Selected from the group consisting of alkyl groups, R A Each time it appears, hydrogen, C 1~6 Alkyl, -C(O)C 1~6 Alkyl and -C(O)OC 1~6 Independently selected from the group consisting of alkyls, R B C 1~6 Alkyl, C 3~6 Cycloalkyl and -C(O)OC 1~6 Selected from the group consisting of alkyl groups, R C and R D Each time it appears, hydrogen, C1~6 Alkyl, Halo C 1~6 Alkyl, and C 3~4 Independently selected from the group consisting of cycloalkyls, or R C and R D These, together with the nitrogen atom to which they are bonded, form a 4-6 membered heterocycline or 4-6 membered heteroaryl, which may contain further nitrogen or oxygen atoms and may be substituted as needed with one or two fluorocarbons. It will be provided.

[0057] In another embodiment, the compound represented by formula (Ia) as used herein [ka] or a pharmaceutically acceptable salt thereof [in the formula, R 1 C 1~6 Alkyl, C 3~6 Cycloalkyl and 5-10 membered heterocyclyl, C 3~6 Cycloalkyl is R 1a One or more available carbon atoms may be optionally substituted by one, two, three, or more substituents independently selected from each of the following, where if the 5-10 membered heterocyclyl contains a substituteable ring nitrogen atom, the ring nitrogen atom is R 1b If a 5-10 member heterocycline contains a substituteable ring sulfur atom, that ring sulfur atom may be substituted with two oxygen atoms as needed. R 2 It is CH3 or CF3, R 3 C 1~6 It is alkyl, C 1~6 Alkyl is C 1~4 They may be substituted with alkoxy as needed. R 1aEach time it appears, it is cyano, halogen, hydroxyl, C 1~6 Alkyl, -C(O)OR A ,-C(O)N(R A )2, -N(R A )2, C 1~6 Independently selected from the group consisting of alkoxys and 5-6 member heteroaryls, C 1~6 Alkyl is -N(R A )2 is replaced as needed, R 1b C 1~6 Alkyl, -C(O)OR A , -C(O)C 1~6 Alkyl, -C(O)C 3~6 Cycloalkyl, -C(O)N(R A )2, and -S(O)2C 1~6 Selected from the group consisting of alkyl groups, R A Each time it appears, hydrogen, C 1~6 Alkyl, -C(O)C 1~6 Alkyl and -C(O)OC 1~6 [Independently selected from the group consisting of alkyl groups] It will be provided.

[0058] In some embodiments, R 2 This is CH3. In some embodiments, R 2 This is CF3.

[0059] In some embodiments, R 3 C 1~6 It is alkyl, R 3 C 1~4 It is replaced with alkoxy as needed.

[0060] In some embodiments, R 3 C 1~6 It is alkyl. In some embodiments, R 3 teeth, [ka] That is the case.

[0061] In some embodiments, R 3 C 1~6 It is alkyl, R 3 C 1~4 It is substituted with alkoxy. In some embodiments, R 3 teeth, [ka] That is the case.

[0062] In another embodiment, the compound represented by formula (Ib) as used herein [ka] or a pharmaceutically acceptable salt thereof [in the formula, R 1 C 1~6 Alkyl, C 3~6 A cycloalkyl or 5-10 membered heterocycline, C 3~6 Cycloalkyl is R 1a One or more available carbon atoms may be optionally substituted by one, two, three, or more substituents independently selected from each of the following, where if the 5-10 membered heterocyclyl contains a substituteable ring nitrogen atom, the ring nitrogen atom is R 1b If a 5-10 member heterocycline contains a substituteable ring sulfur atom, that ring sulfur atom may be substituted with two oxygen atoms as needed. R 1a Each time it appears, it is cyano, halogen, hydroxyl, C 1~6 Alkyl, -C(O)OR A ,-C(O)N(R A )2, -N(R A )2, C 1~6 Independently selected from the group consisting of alkoxys and 5-6 member heteroaryls, C 1~6 Alkyl is -N(R A )2 is replaced as needed, R 1b C 1~6Alkyl, -C(O)OR A , -C(O)C 1~6 Alkyl, -C(O)C 1~6 Cycloalkyl, -C(O)N(R A )2, and -S(O)2C 1~6 Selected from the group consisting of alkyl groups, R A Each time it appears, hydrogen, C 1~6 Alkyl, -C(O)C 1~6 Alkyl and -C(O)OC 1~6 [Independently selected from the group consisting of alkyl groups] It will be provided.

[0063] In some embodiments, R 1 C 1~6 It is alkyl. In some embodiments, R 1 This is CH3.

[0064] In some embodiments, R 1 C 3~6 It is cycloalkyl, R 1 R 1a One or more available carbon atoms may be optionally substituted by one, two, three, or more substituents independently selected from each of the following.

[0065] In some embodiments, R 1 C 3~6 It is cycloalkyl. In some embodiments, R 1 teeth, [ka] It is selected from the group consisting of the following.

[0066] In some embodiments, R 1 C 3~6 It is cycloalkyl, R 1 R 1a One or more available carbon atoms are substituted by one, two, three, or more substituents, each independently selected from the available substituents.

[0067] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1a cyano, fluoro, hydroxyl, -O-CH3, -C(O)OH, -C(O)NH2, [ka] It is selected from the group consisting of the following.

[0068] In some embodiments, R 1 teeth, [ka] [ka] It is selected from the group consisting of the following.

[0069] In some embodiments, R 1 teeth, [ka] [ka] It is selected from the group consisting of the following.

[0070] In some embodiments, R 1 R is a heterocyclyl with 5-10 members, where R 1 but, If it contains a replaceable ring nitrogen atom, that ring nitrogen atom is R 1b They may be substituted as needed, and if a 5-10 membered heterocycline contains a substituteable ring sulfur atom, that ring sulfur atom may be substituted as needed with two oxygen atoms.

[0071] In some embodiments, R 1is a 5-10 member heterocycline. In some embodiments, R 1 teeth, [ka] It is selected from the group consisting of the following.

[0072] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] That is the case.

[0073] In some embodiments, R 1 teeth, [ka] Selected from the group consisting of R 1b CH3, [ka] It is selected from the group consisting of the following.

[0074] In some embodiments, R 1 teeth, [ka] [ka] It is selected from the group consisting of the following.

[0075] In some embodiments, R 1 teeth, [ka] [ka] It is selected from the group consisting of the following.

[0076] In some embodiments, R 1 CH3, [ka] [ka] [ka] It is selected from the group consisting of the following.

[0077] In some embodiments, R 1 CH3, [ka] [ka] [ka] It is selected from the group consisting of the following.

[0078] In some embodiments, the compounds provided herein are selected from the compounds listed in Table 1 or pharmaceutically acceptable salts thereof.

[0079] In some embodiments, the compound is N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ 6 -Chiang-4-carboxamide; N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methylacetamide; N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methyloxan-2-carboxamide; Methyl(1r,4r)-4-{[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl](methyl)carbamoyl}cyclohexane-1-carboxylate; N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methylthian-4-carboxamide; N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methyloxolane-3-carboxamide; N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methyl-1,4-dioxaspiro[4.5]decane-8-carboxamide; N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}aminophenyl]- 2,2,2-trifluoroethyl]-4,4-difluoro-N-methylcyclohexane-1-carboxamide; (1r,3S)-N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-3-cyano-N-methylcyclobutane-1-carboxamide; tert-butyl4-{[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl](methyl)carbamoyl}piperidine-1-carboxylate; tert-butyl3-{[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl](methyl)carbamoyl}piperidine-1-carboxylate; tert-butyl3-{[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl](methyl)carbamoyl}pyrrolidine-1-carboxylate; tert-butyl N-[(4-{[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl](methyl)carbamoyl}cyclohexyl)methyl]carbamate; (1r,4S)-N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-4-methoxy-N-methylcyclohexane-1-carboxamide; 1-Acetyl-N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methylazetidine-3-carboxamide; N-(4-{[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine6-yl}amino)phenyl]-2,2,2-trifluoroethyl](methyl)carbamoyl}cyclohexyl)carbamate; N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-4-acetamide-N-methylcyclohexane-1-carboxamide; N-[(1S)-1-(4-{[2-chloro-7-(propan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl]amino}phenyl)-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ 6 -Chiang-4-carboxamide; 1-Acetyl-N-[(1S)-1-(4-{[2-chloro-7-(propan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl]amino}phenyl)-2,2,2-trifluoroethyl]-N-methylpiperidine-4-carboxamide; N-{1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]ethyl}-N-methylcyclobutanecarboxamide; N-{1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]ethyl}-N -Methylcyclohexanecarboxamide; N-{1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]ethyl}-N-methylcyclopentanecarboxamide; N-{1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]ethyl}-N-methylcyclopropanecarboxamide; N-{1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]ethyl}-N-methylacetamide; N-{1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl}-N-methylacetamide; N-[(1R)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ 6 -Chiang-4-carboxamide; N-[(1R)-1-[4-({2-chloro-7-[(1R)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ 6 -Chiang-4-carboxamide; N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)-2-methylphenyl]-2,2,2-trifluoroethyl]-N-methylcyclobutanecarboxamide; N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)-2-methylphenyl]-2,2,2-trifluoroethyl]-N-methylcyclopropanecarboxamide; N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)-2-methylphenyl]-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ 6 -Chiang-4-carboxamide; N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)-3-methylphenyl]-2,2,2-trifluoroethyl]-N-methylcyclobutanecarboxamide; N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)-3-methylphenyl]-2,2,2-trifluoroethyl]-N-methylcyclopropanecarboxamide; N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)-3-methylphenyl]-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ 6 -Chiang-4-carboxamide; N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylpiperidine-4-carboxamide; N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}aminophenyl]- 2,2,2-trifluoroethyl]-N-methylpiperidine-3-carboxamide; N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylpyrrolidine-3-carboxamide; 4-(aminomethyl)-N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methylcyclohexane-1-carboxamide; 1-Acetyl-N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylpiperidine-4-carboxamide; N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methyl-1-(propane-2-sulfonyl)piperidine-4-carboxamide; Methyl 4-{[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl](methyl)carbamoyl}piperidine-1-carboxylate; N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-1-methanesulfonyl-N-methylpiperidine-4-carboxamide; 1-Acetyl-N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methylpiperidine-3-carboxamide; N 3 -[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N 1 ,N 3 -Dimethylpiperidine 1,3-dicarboxamide; N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-1-methanesulfonyl-N-methylpiperidine-3-carboxamide; 1-Acetyl-N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methylpyrrolidine-3-carboxamide; N 3 -[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N 1 ,N 3 -Dimethylpyrrolidine-1,3-dicarboxamide; N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-1-methanesulfonyl-N-methylpyrrolidine-3-carboxamide; N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}aminophenyl]- 2,2,2-trifluoroethyl]-4-(acetamidomethyl)-N-methylcyclohexane-1-carboxamide; Methyl N-[(4-{[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl](methyl)carbamoyl}cyclohexyl)methyl]carbamate; N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-1-(cyclopropanecarbonyl)-N-methylpiperidine-4-carboxamide; N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-1-cyclopropanecarbonyl-N-methylpiperidine-3-carboxamide; N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-1-cyclopropanecarbonyl-N-methylpyrrolidine-3-carboxamide; N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N,1-dimethylpiperidine-4-carboxamide; N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N,1-dimethylpiperidine-3-carboxamide N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N,1-dimethylpyrrolidine-3-carboxamide; (1r,4S)-N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-4-hydroxy-N-methylcyclohexane-1-carboxamide; (1S,4r)-4-(((S)-1-(4((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexane-1-carboxylic acid; (1S,4r)-4-(((S)-1-(4((2-chloro-7-isopropyl-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexane-1-carboxylic acid; (1S,3r)-3-(((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclobutane-1-carboxylic acid; (1r,4S)-N 1 -((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N 1 -Methylcyclohexane-1,4-dicarboxamide; (1r,4S)-N 1 -((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino )phenyl)-2,2,2-trifluoroethyl)-N 1 ,N 4 -Dimethylcyclohexane-1,4-dicarboxamide; (1r,4S)-N 1 -((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N 1 ,N 4 ,N 4 -Trimethylcyclohexane-1,4-dicarboxamide; (1r,3S)-N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyl-3-(1H-tetrazole-5-yl)cyclobutan-1-carboxamide; N-((S)-1-(4-((2-chloro-7-((R)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide; Selected from the group consisting of 1-acetyl-N-((S)-1-(4-((2-chloro-7-((R)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylpiperidine-4-carboxamide; and pharmaceutically acceptable salts thereof. Pharmaceutical composition and route of administration

[0080] The compounds provided in accordance with the present invention are typically administered in the form of pharmaceutical compositions. Accordingly, the present invention provides pharmaceutical compositions containing, as active ingredients, one or more of the described compounds, or pharmaceutically acceptable salts or esters thereof, as well as carriers including one or more pharmaceutically acceptable excipients, inert solid diluents and fillers, diluents including sterile aqueous solutions and various organic solvents, permeation enhancers, solubilizers, and adjuvants. The pharmaceutical compositions may be administered alone or in combination with other therapeutic agents. Such compositions are prepared in methods well known in the field of pharmaceutical preparation (e.g., Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th). Ed. (1985), and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (See GS Banker & CT Rhodes, Eds.).

[0081] The pharmaceutical composition may be administered in single or multiple doses by any of the accepted methods of administration of drugs having similar utility as described in the patents and patent applications incorporated by reference, including, for example, rectally, intraoral buccal, intranasal and transdermal routes, 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 via a cylindrical polymer inserted into an artery.

[0082] One method of administration is parenteral, particularly by injection. Forms into which the novel compositions of the present invention may be incorporated for injection include aqueous or oily suspensions or emulsions (including sesame oil, corn oil, cottonseed oil, or peanut oil), as well as elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical vehicles. Aqueous solutions in saline are also conventionally used for injection, 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. Appropriate fluidity can be maintained, for example, by the use of coatings such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. Prevention of microbial action can be achieved by various antimicrobial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc.

[0083] Injectable sterile solutions are prepared by incorporating the required amount of compounds according to the present invention, along with various other components listed above as needed, into a suitable solvent, followed by sterilization by filtration. Generally, dispersions are prepared by incorporating various sterilized active ingredients into a sterile vehicle containing a basic dispersion medium and other components as needed from those listed above. In the case of sterile powders for the preparation of injectable sterile solutions, preferred preparation methods are vacuum drying and freeze-drying techniques, which yield a powder in which the active ingredient is combined with any additional desired components obtained from a pre-sterilized filtered solution thereof.

[0084] Oral administration is another route of administration of compounds according to the present invention. Administration may be via capsules or enteric-coated tablets, etc. In the preparation of a pharmaceutical composition comprising at least one compound described herein, the active ingredient is usually diluted with an excipient and / or encapsulated in a carrier, which may be in the form of a capsule, sachet, paper or other container. Where the excipient acts as a diluent, the excipient may be in the form of a solid, semi-solid, or liquid material (as described above) acting as a vehicle, carrier or medium for the active ingredient. Accordingly, the composition may be in the form of tablets, pills, powders, licks, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solid or in a liquid medium), ointments containing up to 10% by weight of the active compound, for example, soft and hard gelatin capsules, injectable sterile solutions, and packaged sterile powders.

[0085] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. In addition, the formulation may contain lubricants, such as talc, magnesium stearate, and mineral oil, humectants, emulsifiers and suspending agents, preservatives, such as methyl hydroxybenzoate and propyl hydroxybenzoate, sweeteners, and flavoring agents.

[0086] The compositions of the present invention can be formulated to produce rapid, sustained, or delayed release of the active ingredient after administration to a patient by using procedures known in the art. Controlled-release drug delivery systems for oral administration include osmotic pump systems and dissolution systems containing polymer-coated reservoirs or drug polymer matrix formulations. Examples of controlled-release systems are shown in U.S. Patents 3,845,770, 4,326,525, 4,902,514 and 5,616,345. Another formulation for use in the methods of the present invention is a transdermal delivery device ("patch"). Such transdermal patches can be used to deliver the compounds of the present invention in controlled amounts, either continuously or discontinuously. 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.

[0087] The composition is preferably formulated into unit dosage forms. The term "unit dosage form" refers to a physically distinct unit (e.g., tablet, capsule, ampoule) suitable as a unit dose for human subjects and other mammals, in which each unit contains a predetermined amount of the active substance calculated to produce the desired therapeutic effect in conjunction with appropriate pharmacokinetic excipients. The compound is generally administered in a pharmaceutically effective dose. Preferably, each dose unit contains 1 mg to 2 g of the compound described herein for oral administration, and preferably 0.1 to 700 mg of the compound described herein for parenteral administration. However, in practice It should be understood that the amount of compound administered is usually determined by a physician, taking into account the 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.

[0088] To prepare a solid composition, such as a tablet, the main active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of the compounds of the present invention. When these preformulation compositions are referred to as homogeneous, it means that the active ingredient is uniformly dispersed throughout the composition so that the composition can be easily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules.

[0089] The tablets or pills of the present invention may be coated or otherwise formulated to provide a dosage form that offers the benefit of long-term action or to protect from the acidic conditions of the stomach. For example, the tablets or pills may contain inner and outer dosage components, the latter in the form of an outer coating over the former. These two components may be separated by an enteric coating, which works to withstand disintegration in the stomach and allow the inner component to pass intact into the duodenum or to delay its release. Various materials, including several polymer acids, as well as mixtures of polymer acids with materials such as shellac, cetyl alcohol, and cellulose acetate, can be used for such enteric coatings or coatings.

[0090] 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 the above-mentioned suitable pharmaceutically acceptable excipients. Preferably, compositions are administered orally or via nasal respiratory routes for topical or systemic effects. Compositions in preferably pharmaceutically acceptable solvents may be sprayed using an inert gas. The sprayed solutions may be absorbed directly from the spraying device, or the spraying device may be attached to a face mask tent or an intermittent positive pressure respirator. The solutions, suspensions, or powder compositions may be administered preferably orally or nasally from a device that delivers the formulation in an appropriate manner.

[0091] In some embodiments, the pharmaceutical composition comprises a disclosed compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. How to use

[0092] The compounds and compositions described herein are generally useful for modulating MALT1 and for treating diseases or disorders, particularly those susceptible to modulation of MALT1's proteolytic and / or autoproteolytic activity. In some embodiments, the compounds and compositions described herein are useful for inhibiting MALT1. In some embodiments, the compounds and compositions of the present invention are intended to be useful in treating diseases, disorders, or conditions characterized by dysregulated NF-κB activation, such as autoimmune or immunological and inflammatory disorders, allergic disorders, respiratory disorders, and oncological disorders.

[0093] 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 encompasses pharmaceutically acceptable addition salts, pharmaceutically acceptable esters, solvates (e.g., hydrates), tautomers, polymorphs, enantiomers, and enantiomer mixtures of compounds described herein, e.g., compounds of formula I, e.g., compounds of the formula named herein. This includes substances, stereoisomers, or mixtures of stereoisomers (either pure or as racemic or non-racemic mixtures).

[0094] In some embodiments, autoimmune and inflammatory disorders are selected from antibody-mediated vasculitis syndromes, including arthritis, ankylosing spondylitis, inflammatory bowel disease, ulcerative colitis, gastritis, pancreatitis, Crohn's disease, celiac disease, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, rheumatoid arthritis, rheumatic fever, gout, organ or graft rejection, acute or chronic graft-versus-host disease, chronic allograft rejection, Behçet's disease, uveitis, psoriasis, psoriatic arthritis, BENTA disease, polymyositis, dermatitis, atopic dermatitis, dermatomyositis, acne vulgaris, myasthenia gravis, hidradenitis suppurativa, Graves' disease, Hashimoto's thyroiditis, Sjögren's syndrome, as well as bullous disorders (e.g., pemphigus vulgaris), ANCA-associated vasculitis, Henoch-Schönlein purpura, and immune complex vasculitis (either primary or secondary to infection or cancer).

[0095] In some embodiments, oncological disorders include carcinomas, sarcomas, lymphomas, leukemias and germ cell tumors, adenocarcinomas, bladder cancers, clear cell carcinomas, skin cancers, brain cancers, cervical cancers, colon cancers, colorectal cancers, endometrial cancers, brain tumors, breast cancers, gastric cancers, germ cell tumors, and neuromas. Glioblastoma, hepatic adenoma, Hodgkin lymphoma, liver cancer, kidney cancer, lung cancer, pancreatic cancer, head / neck / pharyngeal cancer, ovarian cancer, skin tumors, prostate cancer, renal cell carcinoma, stomach cancer, hematological cancer, medulloblastoma, non-Hodgkin lymphoma, diffuse large B-cell lymphoma ( DLBCL), activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL), mantle cell lymphoma, marginal zone lymphoma, T-cell lymphoma, especially Sézary syndrome, mycosis fungoides, cutaneous T-cell lymphoma, T-cell acute lymphoblastic leukemia, melanoma, mucosa-associated lymphoid tissue (MALT) lymphoma, multiple myeloma, plasma cell neoplasm, malignant lentigo melanoma, acral lentiginous melanoma, squamous cell carcinoma, chronic myelogenous leukemia The following are selected from leukemia, myeloid leukemia, superficial spreading melanoma, acral lentiginous melanoma, mucosal melanoma, nodular melanoma, polypoid melanoma, fibroplastic melanoma, chromosomal malignant melanoma, soft tissue melanoma, melanoma with small nevus-like cells, melanoma with Spitz nevus characteristics, uveal melanoma, progenitor T cell leukemia / lymphoma, acute myeloid leukemia, chronic myeloid leukemia (chronic myeloid leukemia), acute lymphoblastic leukemia, follicular lymphoma, chronic lymphoblastic leukemia / lymphoma, Burkitt lymphoma, mycosis fungoides, peripheral T cell lymphoma, nodular sclerosing type of Hodgkin lymphoma, mixed cell type subtype of Hodgkin lymphoma, non-small cell lung cancer, large cell carcinoma, and small cell lung cancer.

[0096] In some embodiments, the oncological disorder is cancer or bloodborne cancer in the form of a tumor. In some embodiments, the tumor is a solid tumor. In some embodiments, the tumor is malignant and / or metastatic. In some embodiments, the tumor is an adenoma, adenocarcinoma, blastoma (e.g., hepatoblastoma, glioblastoma, neuroblastoma, and retinoblastoma), carcinoma (e.g., colorectal cancer or hepatocellular carcinoma, pancreatic, prostate, stomach, esophageal, cervical, and head cancer). A selection from cancers of the neck and cervix, as well as adenocarcinomas, tendonoids, fibrous round cell tumors, endocrine tumors, germ cell tumors, lymphomas, leukemias, sarcomas (e.g., Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, or any other soft tissue sarcoma), Wilms' tumor, lung tumors, colon tumors, lymphomas, mammary gland tumors, or melanoma.

[0097] In some embodiments, the allergic disorder is selected from contact dermatitis, celiac disease, asthma, hypersensitivity to dust mites, pollen and related allergens, and beryllium poisoning.

[0098] In some embodiments, respiratory disorders include asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pulmonary edema, pulmonary embolism, pneumonia, pulmonary sarcoidosis, silicosis, pulmonary fibrosis, and respiratory disorders. The diagnosis is selected from insufficiency, acute respiratory distress syndrome, primary pulmonary hypertension, and emphysema.

[0099] In some embodiments, the compounds and compositions of the present invention may be useful in the treatment of rheumatoid arthritis, systemic lupus erythematosus, vasculitic conditions, allergic diseases, asthma, chronic obstructive pulmonary disease (COPD), acute or chronic graft rejection, graft-versus-host disease, hematopoietic cancer or solid tumors, chronic myeloid leukemia, myeloleukemia, non-Hodgkin lymphoma or other B-cell lymphomas. Combination therapy

[0100] The compounds of the compositions described herein may be administered in combination with other drugs or treatments. Subjects who would be administered the compounds disclosed herein may have a disease, disorder, or condition, or symptoms thereof, that could benefit from treatment using other drugs or treatments.

[0101] In some embodiments, the compounds of the compositions described herein may be administered simultaneously with, before, or after one or more other therapeutic agents. In some embodiments, the compounds of the compositions described herein may be administered separately or together with other agents in the same pharmaceutical composition by the same or different routes of administration.

[0102] In some embodiments, the compounds described herein may be administered as sole active ingredients or, for example, in combination with other drugs for the treatment or prevention of acute or chronic rejection of allografts or xenografts, or inflammatory or autoimmune disorders, such as immunosuppressants or immunomodulators, or other anti-inflammatory agents, or chemotherapeutic agents, such as malignant cell antiproliferative agents, for example, as adjuvants to them. For example, the compounds of the present invention may be used in combination with calcineurin inhibitors, such as cyclosporine A or FK 506; rmTOR inhibitors, such as rapamycin, 40-0-(2-hydroxyethyl)-rapamycin, biolimus-7 or biolimus-9; ascomycin with immunosuppressive properties, such as ABT-281, ASM981; corticosteroids; cyclophosphamide; azathioprene; methotrexate; leflunomide; mizoribine; mycophenolic acid or salt; mycophenolate mofetil; or IL-1 beta inhibitors.

[0103] In some embodiments, the compounds described herein are combined with a co-agent that is a PI3K inhibitor.

[0104] In some embodiments, the compounds described herein are combined with concomitant agents that affect BTK (Bruton's tyrosine kinase).

[0105] For the treatment of oncological diseases, the compounds described herein may be used in combination with B-cell modulators, such as rituximab, ofatumumab, BTK or SYK inhibitors, inhibitors of PKC, PI3K, PDK, PIM, JAK, and rmTOR, as well as BH3 mimetic agents. [Examples]

[0106] The following representative examples are intended to illustrate the present invention and are not intended to limit the scope of the invention, nor should they be construed as such.

[0107] The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. Unless otherwise stated, typical or preferred processing conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given. It should be noted that other processing conditions may be used unless otherwise specified. Optimal reaction conditions may vary with the specific reactants or solvents used, but such conditions can be determined by those skilled in the art through conventional optimization.

[0108] In addition, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesirable reactions. The selection of suitable protecting groups for specific functional groups, as well as the conditions suitable for protection and deprotection, are well known in the art. For example, numerous protecting groups, as well as their introduction and removal, are described in TW Greene and PGM Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New This is described in York, 1991 and the references cited therein.

[0109] The compounds provided herein can be isolated and purified by known standard procedures. Such procedures include recrystallization, filtration, flash chromatography, grinding, high-pressure liquid chromatography (HPLC), or supercritical fluid chromatography (SFC). It should be noted 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 prepared using methods well known to those skilled in the art. List of abbreviations: HCl ethyl acetate THF (Tetrahydrofuran) PE (Petroleum Ether) DMA (dimethylacetamide) MeOH methanol EtOH Ethanol DMF (N,N-dimethylformamide) DMSO (Dimethyl Sulfoxide) xphos 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl FA Formic Acid DCM Dichloromethane MTBE methyl tert-butyl ether TFA (Trifluoroacetic Acid) MeCN, ACN Acetonitrile i-PrMgCl Isopropyl Magnesium Chloride xantphos 4,5-bis(diphenylphosphin)-9,9-dimethylxanthene i-PrOH Isopropyl Alcohol TMSCF3 Trifluoromethyltrimethylsilane MeI iodomethane LiHMDS (Lithium Bis(Trimethylsilyl)amide) h, hr, hrs time Calcd Calculated value UV ultraviolet light rt room temperature DIEA, DIPEA N,N-diisopropylethylamine HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate CDI 1,1'-Carbonyldiimidazole ee enantiomer excess TMS (trimethylsilyl) Pd2(dba)3 Tris(dibenzylideneacetone) Dipalladium(0) Et3N,TEA Triethylamine Cesium carbonate (Cs2CO3) INT intermediate EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride HOBT, HOBt 1-hydroxybenzotriazole TLC (Thin-Layer Chromatography) Conc. Boc tert-butyloxycarbonyl AcCl (Acty chloride) NaBH3CN Sodium borocyanohydride HO(CH2O)nH Paraformaldehyde LiOH,H2O (Lithium Hydroxide Monohydrate) NH4Cl (Ammonium Chloride) MeNH2.HCl methylamine hydrochloride Me2NH.HCl Dimethylamine hydrochloride TMSN3 Trimethylsilyl azide (C4H9)2SnO Dibutyltin oxide NH2NH2.H2O Hydrazine hydrate t-BuOH tert-butyl alcohol t-BuOK potassium tert-butoxide DPPA (Diphenylphosphoryl Azide) NaOH (Sodium Hydroxide) (n-Bu)4OAc Tetrabutylammonium acetate (COCl)2 oxalyl chloride Na2CO3 (sodium carbonate) POCl3 phosphorus oxychloride TBSCl tert-butyldimethylsilyl chloride TBS tert-butyldimethylsilyl NaH (sodium hydride) Ti(OEt)4 Titanium Ethoxide TBAT Tetrabutylammonium difluorotriphenyl silicate on overnight EDTA (Ethylenediaminetetraacetic acid) (Example 1) Preparation of compounds

[0110] Methods for preparing the compounds described herein are illustrated in the following synthesis schemes. These schemes are provided for illustrative purposes and should not be considered to limit the scope or spirit of the invention. The starting materials shown in the schemes can be obtained from commercial sources or prepared from commercially available sources based on procedures described in the literature. 1. Compounds prepared using Scheme 1 Scheme 1: [ka]

[0111] R 3 Triazolopyrimidine G-1a containing R 1 and R 2 The compound of formula (I) is provided by reacting it with carboxamide G-1b containing [the specified substance]. N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ 6 Synthesis of -thian-4-carboxamide (also known as N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide) (Compound 1.1) [ka]

[0112] Dioxane (6 mL) contains 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine hydrochloride [INT1.1] (460 mg, 1.74 mmol), N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ 6 A mixture of -thian-4-carboxamide [INT5.1] (779 mg, 1.82 mmol), Pd2(dba)3 (159 mg, 174 μmol), xanthophos (201 mg, 348 μmol), and Cs2CO3 (1.70 g, 5.22 mmol) was stirred at 100°C for 4 hours. The mixture was concentrated under reduced pressure to obtain the crude product, which was then purified by silica gel flash chromatography (methanol / dichloromethane = 0 / 1~1 / 10) and preparative HPLC (column: YMC Triart C18 250×50mm×7μm, table: 29~58%B (A = water (0.05v / v% ammonia hydroxide)), B = acetonitrile), flow rate: 60mL / min, UV detector 220nm), and then N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ 6 -Chiane-4-carboxamide [Compound 1.1] (211 mg, 368 μmol) was obtained as a dry powder. m / z: C23H27ClF3N6O4S [M+H]+ Calculated value 575.2, measured value 575.3. 1 HNMR (400 MHz, DMSO-d6) δ = 8.80 (s, 1H), 8.02 - 7.94 (m,1H), 7.26 -7.12 (m, 2H), 6.99 - 6.89 (m, 2H), 6.45 - 6.02 (m, 1H), 5.12 (q, J=6.8 Hz, 1H), 3.25 - 3.14 (m, 3H), 3.12 (s, 3H), 3.10 - 3.05 (m, 2H), 2.86 (s, 3H), 2.08 - 1.94 (m, 4H), 1.55 (d, J=6.8 Hz, 3H). Compound 1.1 was determined to have at least 89% chiral purity. Synthesis of N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methylacetamide (compound 1.2) [ka]

[0113] A mixture of 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine hydrochloride [INT1.1] (100 mg, 378 μmol), N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methylacetamide [INT5.2] (117 mg, 378 μmol), Pd2(dba)3 (34.6 mg, 37.8 μmol), xanthophos (43.7 mg, 75.6 μmol), and Cs2CO3 (368 mg, 1.13 mmol) in dioxane (3 mL) was stirred at 100°C for 3 hours under an N2 atmosphere. The mixture was concentrated under reduced pressure to obtain the crude product, which was then subjected to preparative HPLC (column: YMC Triart C18). The compound was purified using a 250×50mm×7μm table (31~71%B (A = water (0.05v / v% ammonia hydroxide)), B = acetonitrile), flow rate: 60mL / min, UV detector 220nm) to obtain N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methylacetamide [compound 1.2] (20.0 mg, 43.7 μmol, yield 11.6%) as a yellow dry powder. m / z: [M+H]+ of C19H21ClF3N6O2 (calculated value 457.1, measured value 457.2). 1 HNMR (400 MHz, CD3OD) δ = 8.90 - 8.85 (m, 1H), 7.40 -7.27 (m, 2H),7.11 - 7.01 (m, 2H), 6.50 (q, J=9.2 Hz, 1H), 5.36 (q, J=6.4 Hz,1H), 3.37 - 3.35 (m, 3H), 2.95 - 2.72 (m, 3H), 2.36 - 2.19 (m, 3H), 1.64 (d,J=6.8 Hz,3H). Synthesis of N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methyloxane-2-carboxamide (compound 1.3) [ka]

[0114] Dioxane (2 mL) contains 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine hydrochloride [INT1.1] (80 mg, 302 μmol), N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methyloxane-2-carboxamide [INT5.3] (114 mg, 302 μmol), xanthophos (34.9 mg, 60.4 μmol), Pd2(dba)3 (27.6 mg, 30.2 μmol), and Cs2CO3 (196 The mixture (mg, 604 μmol) was stirred at 100°C for 3 hours under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure to obtain the crude product, which was then analyzed by silica gel flash chromatography (siRNA / petroleum ether = 1 / 10 to 1 / 1) and preparative HPLC (column: YMC). The compound was purified using a Triart C18 250×50mm×7μm table (table: 26~66%B (A = water (0.05v / v% ammonia hydroxide)), B = acetonitrile), flow rate: 60mL / min, UV detector 220nm) to obtain N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methyloxan-2-carboxamide [compound 1.3] (30.1 mg, 57.1 μmol, yield 18.9%) as a yellow dry powder. m / z: [M+H]+ of C23H27ClF3N6O3 (calculated value 527.2, measured value 527.3). 1 HNMR (400 MHz, CD3OD) δ = 8.91 - 8.83 (m, 1H), 7.47 -7.26 (m, 2H),7.06 (d, J=8.4 Hz, 2H), 6.54 - 6.04 (m, 1H), 5.36 (q, J=6.8 Hz,1H), 4.41 - 4.25(m, 1H), 4.08 - 3.95 (m, 1H), 3.71 - 3.51 (m, 1H), 3.36 (s,3H), 2.98 - 2.69 (m, 3H), 1.98 - 1.90 (m, 1H), 1.85 -1.66 (m, 3H), 1.64 (d,J=6.8 Hz, 3H), 1.63 - 1.54 (m, 2H). Synthesis of methyl(1r,4r)-4-{[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl](methyl)carbamoyl}cyclohexane-1-carboxylate (compound 1.4) [ka]

[0115] A mixture of 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine hydrochloride [INT1.1] (50 mg, 189 μmol), methyl(1r,4r)-4-{[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)carbamoyl}cyclohexane-1-carboxylate [INT5.4] (82.4 mg, 189 μmol), xanthophos (21.8 mg, 37.8 μmol), Pd2(dba)3 (17.3 mg, 18.9 μmol), and Cs2CO3 (123 mg, 378 μmol) in dioxane (2 mL) was stirred at 100°C for 3 hours under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel flash chromatography (SiO2 / petroleum ether = 1 / 10 to 1 / 1) and preparative HPLC (column: YMC Triart C18 250 × 50 mm × 7 μm, table: 27 to 67% B (A = water (0.05 v / v% ammonia hydroxide)), B = acetonitrile), flow rate: 60 mL / min, UV detector 220 nm) to obtain methyl (1r,4r)-4-{[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl](methyl)carbamoyl}cyclohexane-1-carboxylate [compound 1.4] (14.2 mg, 24.3 μmol, yield 12.9%) as a yellow dry powder. m / z: C26H31ClF3N6O4 [M+H]+ Calculated value 583.2, measured value 583.3. 1 HNMR (400 MHz, CDCl3) δ = 8.90 (s, 1H), 7.32 (d, J=8.4Hz, 2H), 7.13 -7.09 (m, 1H), 7.04 (d, J=8.4 Hz, 2H), 6.63 (q, J=8.2 Hz, 1H),5.48 (q, J=6.8 Hz,1H), 3.69 (s, 3H), 3.49 (s, 3H), 2.92 (s, 3H), 2.63 - 2.54(m, 1H), 2.44 - 2.35(m, 1H), 2.17 - 2.06 ( m, 2H), 2.00 - 1.92 (m, 1H), 1.91 -1.83 (m, 1H), 1.72 - 1.63 (m, 2H), 1.61 (d,J=6.8 Hz, 3H), 1.54 - 1.42 (m, 2H). Synthesis of N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methylthian-4-carboxamide (compound 1.5) [ka]

[0116] A mixture of 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine hydrochloride [INT1.1] (100 mg, 378 μmol), N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methylthian-4-carboxamide [INT5.5] (149 mg, 378 μmol), xanthophos (43.7 mg, 75.6 μmol), Pd2(dba)3 (34.6 mg, 37.8 μmol), and Cs2CO3 (246 mg, 756 μmol) in 5 mL of dioxane was stirred at 100°C for 3 hours under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure to obtain the crude product, which was then subjected to silica gel flash chromatography (¼ / petroleum ether = 1 / 10 to 1 / 1) and preparative HPLC (column: YMC). The compound was purified using a Triart C18 250×50mm×7μm table (table: 35~75%B (A = water (0.05v / v% ammonia hydroxide)), B = acetonitrile), flow rate: 60mL / min, UV detector 220nm) to obtain N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methylthian-4-carboxamide [compound 1.5] (26.9 mg, 49.5 μmol, yield 13.1%) as a yellow dry powder. m / z: [M+H]+ of C23H27ClF3N6O2S (calculated value 543.1, measured value 543.4). 1 HNMR (400 MHz, CDCl3) δ = 8.89 (s, 1H), 7.31 (d, J=8.4Hz, 2H), 7.11(s, 1H), 7.04 (d, J=8.4 Hz, 2H), 6.62 (q, J=8.4 Hz, 1H), 5.48 (q,J=6.8 Hz, 1H),3.49 (s, 3H), 2.90 (s, 3H), 2.81 - 2.70 (m, 4H), 2.70 - 2.62 (m,1H), 2.17 -2.11 (m, 1H), 2.08 - 1.99 (m, 3H), 1.61 (d, J=6.8 Hz, 3H). Synthesis of N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methyloxolane-3-carboxamide (compound 1.6) [ka]

[0117] Dioxane (2 mL) contains N-[(1S)-1-(4-bromophenyl)-2,2,2 A mixture of [-trifluoroethyl]-N-methyloxolane-3-carboxamide [INT5.6] (80 mg, 218 μmol) and 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine hydrochloride [INT1.1] (68.9 mg, 261 μmol) was mixed with Pd2(dba)3 (19.9 mg, 21.8 μmol), Cs2CO3 (213 mg, 654 μmol), and xanthophos (12.6 mg, 21.8 μmol). The reaction mixture was stirred at 100°C for 3 hours under N2, then diluted with brine (20 mL) and extracted with SiO2 (10 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to obtain the crude product, which was purified by preparative HPLC (column: Boston Prime C18 150×25mm×5μm, table: 32~62%B (A=water (0.05% ammonia hydroxide), B=acetonitrile), flow rate: 25mL / min, UV detector 220nm) to obtain N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methyloxolane-3-carboxamide [compound 1.6] (2.20 mg, 4.28 μmol, yield 2.0%) as an off-white dry powder. m / z: C22H25ClF3N6O3 [M+H]+ Calculated value 513.2, measured value 513.3. 1 HNMR (400MHz, CDCl3) δ = 8.90 (s, 1H), 7.37 - 7.31 (m,2H), 7.12 (s,1H), 7.05 (d, J=8.4 Hz, 2H), 6.62 (q, J=8.8 Hz, 1H), 5.49 (q,J=6.8 Hz, 1H), 4.18 - 4.01 (m, 1H), 4.00 - 3.86 (m, 3H), 3.49(s, 3H), 3.40 -3.28 (m, 1H), 2.97 - 2.82 (m, 3H), 2.32 - 2.09 (m, 2H), 1.62 (d,J=6.8 Hz, 3H). Synthesis of N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methyl-1,4-dioxaspiro[4.5]decane-8-carboxamide (compound 1.7) [ka]

[0118] A mixture of 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine hydrochloride [INT1.1] (60.4 mg, 229 μmol), N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methyl-1,4-dioxaspiro[4.5]decane-8-carboxamide [INT5.7] (100 mg, 229 μmol), xanthophos (26.5 mg, 45.8 μmol), Pd2(dba)3 (20.9 mg, 22.9 μmol), and Cs2CO3 (149 mg, 458 μmol) in 5 mL of dioxane was stirred at 100°C for 3 hours under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure to obtain the crude product, which was then purified by silica gel flash chromatography (siRNA / petroleum ether = 1 / 5~1 / 3) and preparative HPLC (column: YMC Triart C18 250×50mm×7μm, table: 33~73%B (A = water (0.05v / v% ammonia hydroxide)), B = acetonitrile), flow rate: 60mL / min, UV detector 220nm) to obtain N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methyl-1,4-dioxaspiro[4.5]decane-8-carboxamide [compound 1.7] (32.3 mg, 55.4 μmol, yield 24%). 0.2% was obtained as a yellow dry powder. m / z: C26H31ClF3N6O4 [M+H]+ calculated value 583.2, measured value 583.4. 1H NMR(400 MHz, CDCl3) δ = 8.89 (s, 1H), 7.32 (d, J=8.4Hz, 2H), 7.10 (s,1H), 7.03 (d, J=8.4 Hz, 2H), 6.65 (q, J=8.8 Hz, 1H), 5.48 (q,J=6.8 Hz, 1H), 3.97 (s, 4H), 3.49 (s, 3H), 2.92 (s, 3H), 2.66- 2.55 (m, 1H),1.97 - 1.93 (m, 1H), 1.93 - 1.83 (m, 4H), 1.83 - 1.75 (m, 1H),1.61 (d, J=6.8Hz, 3H), 1.57 - 1.52 (m, 2H). Synthesis of N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-4,4-difluoro-N-methylcyclohexane-1-carboxamide (compound 1.8) [ka]

[0119] A mixture of 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine hydrochloride [INT1.1] (100 mg, 378 μmol), N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-4,4-difluoro-N-methylcyclohexane-1-carboxamide [INT5.8] (156 mg, 378 μmol), xanthophos (43.7 mg, 75.6 μmol), Pd2(dba)3 (34.6 mg, 37.8 μmol), and Cs2CO3 (368 mg, 1.13 mmol) was stirred at 100°C for 3 hours under an N2 atmosphere. The reaction mixture was filtered through Celite. The filtered cake was washed with SiO2 (20 mL x 2). The filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by preparative HPLC (column: Welch Xtimate C18 150×25mm×5μm, table: 49~79%B (A=water (10mM NH4HCO3), B=acetonitrile), flow rate: 25mL / min, UV detector 220nm) to obtain N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-4,4-difluoro-N-methylcyclohexane-1-carboxamide [compound 1.8] (61.5 mg, 109 μmol, yield 29.0%) as a yellow solid. m / z: C24H27ClF5N6O2 [M+H]+ Calculated value 561.2, measured value 561.2. 1 HNMR (400MHz, DMSO-d6) δ = 8.84 (s, 1H), 8.08 - 7.95 (m,1H), 7.29 - 7.13 (m,2H), 7.04 - 6.90 (m, 2H), 6.71 - 6.10 (m, 1H), 5.15 (q, J= 6.8 Hz, 1H), 3.16 (s, 3H), 2.90 (s, 4H), 2.13 - 1.62 (m, 8H), 1.59 (d, J =6.8 Hz,3H). Synthesis of (1r,3S)-N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-3-cyano-N-methylcyclobutane-1-carboxamide (compound 1.9) [ka]

[0120] (1r,3S)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-3-cyano-N-methylcyclobutane-1-carboxamide [INT5.9] (0.1 g, 0.2665 mmol), 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine [free base of INT1.1] (60.5 mg, 266 μmol), xanthophos (15.3 mg, 26.6 μmol), and Cs2CO3 (260 mg, 799 μmol) were mixed in dioxane (3 mL), and the reaction mixture was degassed with argon for 5 minutes. Pd2(dba)3 (12.1 mg, 13.3 μmol) was added, and the reaction mixture was degassed with argon for 5 minutes and stirred at 100°C for 10 hours. The reaction mixture was cooled to rt and the solid was filtered off. The filtrate was purified by HPLC (see conditions below) to obtain (1r,3S)-N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-3-cyano-N-methylcyclobutan-1-carboxamide [compound 1.9] (14.9 mg, 0.02857 mmol, yield 10.7%) as a yellow oil. m / z: C23H24ClF3N7O2 [M+H]+ Calculated value 522.2, measured value 522.2. 1HNMR (400 MHz, CD3OD ) δ 8.87 (d, J=1.7 Hz, 1H), 7.31 (d,J=8.4 Hz,2H), 7.07 (d, J=8.4 Hz, 2H), 6.49 (q, J=9.1 Hz, 1H), 5.37 (q, J=6.7Hz, 1H),3.76 (h, J=7.3, 6.7 Hz, 1H), 3.37 - 3.24 (m, 2H), 2.82 (s, 3H), 2.77 -2.58 (m,7H), 1.65 (d, J=6.7 Hz, 3H).

[0121] HPLC conditions, system: Agilent 1260 Infinity II LC connected to Agilent 6120B single quadrupole LC / MS system. Column description: Chromatorex SBM 100-5T 5μm C18(2) 100Å, LC column 100×19mm, Waters, Sun Fire, stationary phase: C18, solid support: fully porous silica, separation mode: reversed phase, mobile phase A: water, mobile phase B: acetonitrile, flow rate: 30 ml / min, loading pump: 4 ml / min for B, gradient conditions: 20%~40%~55%~100% (B) over 0 min~2 min~10 min~11.2 min. Synthesis of tert-butyl 4-{[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl](methyl)carbamoyl}piperidine-1-carboxylate (compound 1.10) [ka]

[0122] In dioxane, tert-butyl 4-{[(1S)-1-(4-bromophenyl)-2 A mixture of ,2,2-trifluoroethyl](methyl)carbamoyl}piperidine-1-carboxylate [INT7.1] (150 mg, 312 μmol), Pd2(dba)3 (28.5 mg, 31.2 μmol), Cs2CO3 (304 mg, 936 μmol), 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine hydrochloride [INT1.1] (82.4 mg, 312 μmol), and xanthophos (18.0 mg, 31.2 μmol) was stirred at 100°C for 4 hours under an N2 atmosphere. Brine (20 mL) was added, and the mixture was extracted with SiO2 (30 mL x 2). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (column: Boston Prime C18 150×30mm×5μm, table: 49~79%B (A=water (0.05v / v% ammonia hydroxide)-ACN), B=acetonitrile), flow rate: 30mL / min, UV detector 220nm) to obtain tert-butyl 4-{[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl](methyl)carbamoyl}piperidine-1-carboxylate [compound 1.10] (9.10 mg, 14.5 μmol, yield 4.7%) as a yellow dry powder. m / z: C28H36ClF3N7O4 [M+H-100]+ Calculated value 526.2, Measured value 526.3. 1 HNMR (400 MHz, CDCl3) δ = 8.90 (s,1H), 7.32 (d, J=8.8 Hz, 2H), 7.19 - 7.08 (m, 1H), 7.04 (d, J=8.8 Hz,2H), 6.63(q, J=8.8 Hz, 1H), 5.48 (q, J=6.8 Hz, 1H), 4.19 (br d, J=13.2 Hz, 2H),3.49 (s,3H), 3.00 - 2.91 (m, 3H), 2.85 - 2.69 (m, 3H), 1.82 - 1.68 (m, 4H),1.62 (s, 3H), 1.47 (s, 9H). Synthesis of tert-butyl 3-{[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl](methyl)carbamoyl}piperidine-1-carboxylate (compound 1.11) [ka]

[0123] In a solution of tert-butyl 3-{[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)carbamoyl}piperidine-1-carboxylate [INT7.2] (700 mg, 1.46 mmol), 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine hydrochloride [INT1.1] (332 mg, 1.46 mmol), Cs2CO3 (1.42 g, 4.38 mmol), and xanthophos (168 mg, 292 μmol), Pd2(dba)3 (133 mg, 146 μmol) was added to dioxane (5 mL), and the reaction mixture was stirred at 100 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel flash chromatography (SiO2 / PE = 0 / 1 to 1 / 1) to obtain tert-butyl3-{[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl](methyl)carbamoyl}piperidine-1-carboxylate [compound 1.11] (480 mg, 766 μmol, yield 52.5%) as a yellow oil. 60.6 mg of this product was subjected to preparative HPLC (column: YMC Triart C18 250 × 50 mm × 7 μm, tetrafluoroethylene The compound was purified using a 47-87% B solution (A = water (0.225% FA), B = acetonitrile), flow rate: 60 mL / min, UV detector 220 nm) to obtain tert-butyl 3-{[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl](methyl)carbamoyl}piperidine-1-carboxylate [compound 1.11] (10.6 mg, 16.9 μmol) as an off-white solid. m / z: [M+H]+ of C28H36ClF3N7O4 calculated value 626.2, measured value 626.3. 1 HNMR (400 MHz, DMSO-d6) δ = 8.84 (s, 1H), 8.07 - 7.92 (m,1H), 7.31 - 7.14 (m, 2H), 6.97 (br d, J=8.4 Hz, 2H), 6.43 (q, J=9.6 Hz, 1H),5.16 (q, J=6.8 Hz, 1H), 4.08 - 3.84 (m, 2H), 3.17 (s, 3H), 2.91 (s, 3H), 2.77(br s, 2H), 2.68 (br s, 1H), 1.82 (br d, J=12.4 Hz, 1H), 1.69 - 1.54 (m, 5H),1.40 (s, 10H). Synthesis of tert-butyl 3-{[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl](methyl)carbamoyl}pyrrolidine-1-carboxylate (compound 1.12) [ka]

[0124] In 2 mL of dioxane, a mixture of tert-butyl 3-{[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)carbamoyl}pyrrolidine-1-carboxylate [INT7.3] (140 mg, 300 μmol), 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine hydrochloride [INT1.1] (95.0 mg, 360 μmol), xanthophos (17.3 mg, 30.0 μmol), and Cs2CO3 (390 mg, 1.20 mmol) was mixed with Pd2(dba)3 (27.4 mg, 30.0 μmol), and the mixture was stirred at 100°C for 3 hours under N2. The reaction mixture was diluted with brine (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to obtain the crude product, which was purified by silica gel flash chromatography (methanol / dichloromethane = 1 / 20). Next, the product was purified by preparative HPLC (column: Boston Prime C18 150×30mm×5μm, table: 44~74%B (A=water (0.05v / v% ammonia hydroxide)-ACN), B=acetonitrile), flow rate: 25mL / min, UV detector 220nm) to obtain tert-butyl3-{[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl](methyl)carbamoyl}pyrrolidine-1-carboxylate [compound 1.12] (2.70 mg, 4.41 μmol, yield 1.5%) as a yellow dry powder. m / z: C27H34ClF3N7O4 [M+H]+ Calculated value 612.2, measured value 612.4. 1HNMR (400 MHz, CDCl3) δ = 8.90 (d,J=3.2 Hz, 1H), 7.32 (br d, J=8.0Hz, 2H), 7.13 (s, 1H), 7.04 (br d, J=8.4 Hz,2H), 6.66 - 6.55 (m, 1H), 5.48 (q,J=6.8 Hz, 1H), 3.84 - 3.51 (m, 3H), 3.49 (s,3H), 3.45 - 3.25 (m, 2H), 2.97 -2.78 (m, 3H), 2.36 - 2.05 (m, 2H), 1.62 (d,J=6.8 Hz, 3H), 1.49 - 1.45 (m, 9H). tert-butyl N-[(4-{[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6 Synthesis of [-ylamino)phenyl]-2,2,2-trifluoroethyl](methyl)carbamoyl]cyclohexyl)methyl]carbamate (compound 1.13) [ka]

[0125] Pd2(dba)3 (75.7 mg, 82.7 μmol) was added to a suspension of tert-butyl N-[(4-{[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)carbamoyl}cyclohexyl)methyl]carbamate[INT7.4] (420 mg, 827 μmol), 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine hydrochloride[INT1.1] (282 mg, 1.07 mmol), Cs2CO3 (537 mg, 1.65 mmol), and xanthophos (95.4 mg, 165 μmol) in dioxane (3 mL). The resulting mixture was stirred at 100 °C for 3 hours under N2. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was purified by silica gel flash chromatography (MeOH / dichloromethane = 0 / 1 to 1 / 99) to obtain tert-butyl N-[(4-{[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl](methyl)carbamoyl}cyclohexyl)methyl]carbamate [compound 1.13] (500 mg, 765 μmol, yield 92.5%) as a yellow solid. Furthermore, 100 mg of the product was purified by preparative HPLC (column: Phenomenex Gemini-NX 80 × 40 mm × 3 μm, table: 39~79%B (A = water (0.05 v / v% ammonia hydroxide), B = MeOH), flow rate: 25 mL / min, UV detector 220 nm) to obtain tert-butyl N-[(4-{[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl](methyl)carbamoyl}cyclohexyl)methyl]carbamate [compound 1.13] (500 mg, 39.1 μmol) as a yellow dry powder. m / z: C30H40ClF3N7O4 [M+H]+ Calculated value 654.3, measured value 654.6. 1 HNMR (400 MHz, DMSO-d6) δ = 8.85 (s, 1H), 8.05 - 7.97 (m,1H), 7.26 - 7.10 (m, 2H), 7.04 - 6.92 (m, 2H), 6.82 (br t, J=5.6 Hz, 1H), 6.51- 6.07 (m, 1H), 5.16 (q, J=6.8 Hz, 1H), 3.16 (s, 3H), 2.87 (s, 3H), 2.78 (br t,J=6.4Hz, 2H), 2.70 - 2.56 (m, 1H), 1.83 - 1.64 (m, 4H), 1.59 (d, J=6.8 Hz, 3H), 1.37(s, 12H), 1.04 - 0.83 (m, 2H). Synthesis of (1r,4S)-N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-4-methoxy-N-methylcyclohexane-1-carboxamide (compound 1.14) [ka]

[0126] In 1 mL of dioxane, a mixture of (1r,4S)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-methoxy-N-methylcyclohexane-1-carboxamide [INT7.5] (90 mg, 220 μmol), 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine hydrochloride [INT1.1] (50.0 mg, 220 μmol), Cs2CO3 (143 mg, 440 μmol), and xanthophos (25.4 mg, 44.0 μmol) was added, to which Pd2(dba)3 (20.1 mg, 22.0 μmol) was added under N2 conditions, and the reaction mixture was stirred at 100°C for 1 hour. The reaction was quenched by adding water (10 mL) and extracted with dimethyl (2 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous sodium 2SO4, and concentrated under reduced pressure to obtain the crude product, which was then subjected to preparative HPLC (column: YMC-Actus Triart C18). The compound was purified using a 150×30mm×5μm table (48-68% water (0.05v / v% ammonia hydroxide)-ACN, flow rate: 35mL / min, UV detector 220nm) to obtain (1r,4S)-N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-4-methoxy-N-methylcyclohexane-1-carboxamide [compound 1.14] (8.60 mg, 15.4 μmol, yield 7.0%) as a yellow dry powder. m / z: [M+H]+ of C25H31ClF3N6O3 calculated value 555.2, measured value 555.3. 1 HNMR (400 MHz, DMSO-d6) δ = 8.84 (s, 1H), 7.98 (s, 1H),7.16 (br d, J=8.4 Hz,2H), 6.96 (d, J=8.7 Hz, 2H), 6.50 - 6.09 (m, 1H), 5.15(q, J=6.7 Hz, 1H), 3.23(s, 3H), 3.16 (s, 3H), 3.10 (br s, 1H), 2.91 - 2.59 (m,4H), 2.11 - 1.93 (m,2H), 1.84 - 1.66 (m, 2H), 1.59 (d, J=6.7Hz, 3H), 1.49 -1.32 (m, 2H), 1.25 - 1.08 (m, 2H). Synthesis of 1-acetyl-N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methylazetidine-3-carboxamide (compound 1.15) [ka]

[0127] In 3 mL of dioxane, a solution of 1-acetyl-N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methylazetidine-3-carboxamide [INT5.10] (100 mg, 254 μmol), 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine hydrochloride [INT1.1] (73.6 mg, 279 μmol), Cs2CO3 (248 mg, 762 μmol), and xanthophos (29.3 mg, 50.8 μmol) was prepared. Pd2(dba)3 (23.2 mg, 25.4 μmol) was added, and the reaction mixture was stirred at 100°C for 16 hours under N2. The reaction mixture was concentrated under reduced pressure to obtain the crude product, which was then purified by preparative HPLC (column: YMC Triart C18 250×50mm×7μm, table: 24~64%B (A=water (0.05% ammonia hydroxide)), B=acetonitrile), flow rate: 60 mL / min, UV detector 220 nm) to obtain 1-acetyl-N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl ]-2,2,2-trifluoroethyl]-N-methylazetidine-3-carboxamide [compound 1.15] (21.2 mg, 39.2 μmol, yield 15.4%) was obtained as a yellow dry powder. m / z: C23H26ClF3N7O3 [M+H]+ calculated value 540.2, measured value 540.2. 1 HNMR (400 MHz, DMSO-d6) δ = 8.85 (s, 1H), 8.02 (s, 1H),7.33 - 7.15 (m, 2H), 6.97(br d, J=8.4 Hz, 2H), 6.42 (q, J=9.2 Hz, 1H), 5.16(q, J=6.8 Hz, 1H), 4.38 -4.17 (m, 2H), 4.10 - 3.99 (m, 1H), 3.92 - 3.81 (m,2H), 3.17 (s, 3H), 2.76 -2.69 (m, 3H), 1.76 (d, J=2.8 Hz, 3H), 1.62 - 1.58 (m,3H). Synthesis of N-(4-{[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine6-yl}amino)phenyl]-2,2,2-trifluoroethyl](methyl)carbamoyl}cyclohexyl)carbamate (also known as methyl(4-(((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine6-yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexyl)carbamate) (Compound 1.16) [ka]

[0128] In 1 mL of dioxane, a mixture of methyl N-(4-{[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)carbamoyl}cyclohexyl)carbamate [INT9.1] (40 mg, 88.6 μmol), 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine hydrochloride [INT1.1] (20.1 mg, 88.6 μmol), Cs2CO3 (57.6 mg, 177 μmol), and xanthophos (10.2 mg, 17.7 μmol) was added to Pd2(dba)3 (8.11 mg, 8.86 μmol) at 20°C, and the mixture was stirred at 100°C for 1 hour under N2. The reaction mixture was cooled to 25°C and combined with another batch of the same reaction (INT9.1 on a 44.3 μmol scale). Water (10 mL) was added, and the mixture was extracted with HCl (2 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to obtain the crude product. This crude product was purified by preparative HPLC (column: YMC-Actus Triart C18 150 × 30 mm × 5 μm, table: 46-66% water (0.05 v / v% ammonia hydroxide)-ACN, flow rate: 35 mL / min, UV detector 220 nm) to obtain methyl N-(4-{[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine 6-yl}amino)phenyl]-2,2,2-trifluoroethyl](methyl)carbamoyl}cyclohexyl)carbamate [compound 1.16] (12.2 mg, 20.4 μmol, yield 15.3%) as a yellow dry powder. m / z: C26H32ClF3N7O4 [M+H]+ Calculated value 598.2, measured value 598.3. 1 HNMR (400 MHz, DMSO-d6) δ = 8.83 (s, 1H), 7.98 (s, 1H),7.16 (br d, J=8.4 Hz,2H), 6.96 (d, J=8.7 Hz, 3H), 6.55 - 6.07 (m, 1H), 5.15(q, J=6.7 Hz, 1H), 3.50 (s, 3H), 3.28 - 3.20 (m, 1H), 3.16 (s,3H), 2.87 (s,3H), 2.61 (br s, 1H), 1.90 - 1.66 (m, 4H), 1.59 (d, J=6.7 Hz, 3H),1.51 - 1.32(m, 2H), 1.31 - 1.13 (m, 2H). N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-4-acetamido-N-methylcyclohexane1 - Synthesis of carboxamide (compound 1.17) [ka]

[0129] In 2 mL of dioxane, a mixture of N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-4-acetamide-N-methylcyclohexane-1-carboxamide [INT9.2] (20 mg, 45.9 μmol), 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine hydrochloride [INT1.1] (10.4 mg, 45.9 μmol), Cs2CO3 (29.9 mg, 91.8 μmol), and xanthophos (5.31 mg, 9.18 μmol) was added to Pd2(dba)3 (4.20 mg, 4.59 μmol) at 20°C, and the mixture was stirred at 100°C for 1 hour under N2. The reaction products were combined with another batch of the same reaction (22.9 μmol scale), concentrated under reduced pressure to obtain the crude product, which was purified by preparative HPLC (column: YMCActus Triart C18 150×30 mm×5 μm, table: 42-62% water (0.05 v / v% ammonia hydroxide)-ACN, flow rate: 35 mL / min, UV detector 220 nm) to obtain N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-4-acetamide-N-methylcyclohexane1-carboxamide [compound 1.17] (8.50 mg, 14.6 μmol, yield 21.2%) as a yellow dry powder. m / z: C26H32ClF3N7O3 [M+H]+ Calculated value 582.2, measured value 582.2. 1HNMR (400 MHz, DMSO-d6) δ = 8.83 (s, 1H), 7.98 (s, 1H),7.72 (d, J=7.6 Hz, 1H),7.17 (br d, J=8.4 Hz, 2H), 6.96 (d, J=8.7 Hz, 2H), 6.45(br d, J=9.5 Hz, 1H),5.15 (q, J=6.7 Hz, 1H), 3.46 (br s, 1H), 3.16 (s, 3H),2.88 (s, 3H), 2.63 (br d,J=7.2 Hz, 1H), 1.91 - 1.66 (m, 7H), 1.59 (d, J=6.6Hz, 3H), 1.51 - 1.31 (m, 2H),1.29 - 1.11 (m, 2H). N-[(1S)-1-(4-{[2-chloro-7-(propan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl]amino}phenyl)-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ 6 Synthesis of -thian-4-carboxamide (also known as (S)-N-(1-(4-((2-chloro-7-isopropyl-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide) (Compound 1.18) [ka]

[0130] Dioxane (5 mL) contains 2-chloro-7-(propan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine hydrochloride [INT1.2] (30 mg, 120 μmol), N-[(1S)-1-(4-bromophenyl)-2,2,2-triph [Luoroethyl]-N-methyl-1,1-dioxo-1λ 6Pd2(dba)3 (10.9 mg, 12.0 μmol) was added to a solution of -thian-4-carboxamide [INT5.1] (51.3 mg, 120 μmol), xanthophos (13.8 mg, 24.0 μmol), and Cs2CO3 (117 mg, 360 μmol). The reaction mixture was stirred at 100°C for 2 hours under N2. The reaction mixture was combined with another of the same reaction (120 μmol scale), quenched by adding water (30 mL), and extracted with HCl (30 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude product, which was then purified by preparative HPLC (column: YMC-Actus Triart C18 150×30mm×5μm, table: 40~60%B (A=water (0.05% ammonia hydroxide), B=ACN), flow rate: 35mL / min, UV detector 220nm) to N-[(1S)-1-(4-{[2-chloro-7-(propan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl]amino}phenyl)-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ 6 -Chiane-4-carboxamide [compound 1.18] (22.1 mg, 39.5 μmol, yield 16.5%) was obtained as a white, dry powder. m / z: C23H27ClF3N6O3S [M+H]+ calculated value 559.1, measured value 559.1. 1 HNMR (400 MHz, DMSO-d6) δ = 8.77 - 8.66 (m, 1H), 8.20 -8.10 (m, 1H), 7.26 - 7.10(m, 2H), 6.86 - 6.74 (m, 2H), 6.46 - 6.04 (m, 1H),3.71 (q, J=7.2 Hz, 1H), 3.26- 3.05 (m, 5H), 2.94 - 2.61 (m, 3H), 2.08 - 1.90(m, 4H), 1.42 (d, J=7.2 Hz, 6H). Synthesis of 1-acetyl-N-[(1S)-1-(4-{[2-chloro-7-(propan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl]amino}phenyl)-2,2,2-trifluoroethyl]-N-methylpiperidine-4-carboxamide (compound 1.19) [ka]

[0131] A mixture of 2-chloro-7-(propan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine hydrochloride [INT1.2] (50 mg, 201 μmol), 1-acetyl-N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methylpiperidine-4-carboxamide [INT5.11] (93.0 mg, 221 μmol), xanthophos (11.6 mg, 20.1 μmol), Pd2(dba)3 (18.4 mg, 20.1 μmol), and Cs2CO3 (196 mg, 602 μmol) in dioxane (1 mL) was stirred at 100°C for 3 hours under an N2 atmosphere. The mixture was concentrated under reduced pressure to obtain a crude product, which was purified by preparative HPLC (column: Boston Prime C18 150×30mm×5μm, table: 25~65%B (A=water (0.05v / v% ammonia hydroxide)-ACN), B=acetonitrile), flow rate: 25mL / min, UV detector 220nm) to obtain 1-acetyl-N-[(1S)-1-(4-{[2-chloro-7-(propan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl]amino}phenyl)-2,2,2-trifluoroethyl]-N-methylpiperidine-4-carboxamide [compound 1.19] (19.1 mg, 34.6 μmol, yield 17.3%) as a white dry powder. m / z: C25H30ClF3N7O2 [M+H]+ Calculated value 552.2, measured value 552.2. 1HNMR (400MHz, CDCl3) δ = 8.68 (s,1H), 7.24 (br t, J=7.6 Hz, 2H), 6.66(d, J=8.4 Hz, 2H), 6.57 (q, J=9.2 Hz, 1H),5.47 (br s, 1H), 4.61 (br d, J=13.6Hz, 1H), 3.97 - 3.86 (m, 2H), 3.22 - 3.08(m, 1H), 2.92 (s, 3H), 2.85 - 2.62 (m, 2H), 2.11 (d, J=2.4 Hz, 3H), 1.91 - 1.81(m, 2H), 1.80 - 1.69 (m, 2H), 1.54 (s, 3H), 1.53 (s,3H). Synthesis of N-{1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]ethyl}-N-methylcyclobutanecarboxamide (compound 1.20) [ka]

[0132] In 2 mL of dioxane, a solution of N-[1-(4-bromophenyl)ethyl]-N-methylcyclobutanecarboxamide [INT11.1] (60 mg, 202 μmol), 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine hydrochloride [INT1.1] (45.9 mg, 202 μmol), Cs2CO3 (197 mg, 606 μmol), and xanthophos (23.3 mg, 40.4 μmol) was added, to which Pd2(dba)3 (18.4 mg, 20.2 μmol). The reaction mixture was stirred at 100°C for 2 hours under N2. The mixture was concentrated in vacuum to obtain a crude product, which was purified by preparative HPLC (column: Phenomenex Gemini-NX 80×40mm×3μm, table: 20~60%B (A=water (0.05v / v% ammonia hydroxide), B=acetonitrile), flow rate: 25mL / min, UV detector 220nm) to obtain N-{1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]ethyl}-N-methylcyclobutanecarboxamide [compound 1.20] (5.60 mg, 12.6 μmol, yield 6.3%) as a yellow dry powder. m / z: [M+H]+ of C22H28ClN6O2 calculated value 443.2, measured value 443.3. 1 HNMR (400MHz, DMSO-d6) δ = 8.80 (s, 1H), 7.81 - 7.69 (m,1H), 7.11 - 7.05 (m,2H), 6.94 - 6.89 (m, 2H), 5.73 (q, J=6.8 Hz, 0.7H), 5.17(q, J=6.8 Hz, 1H), 4.92(q, J=6.4 Hz, 0.3H), 3.53 - 3.35 (m, 1H), 3.17 (s, 3H),2.52 (s, 2H), 2.48 (s,1H), 2.34 - 2.07 (m, 4H), 1.97 - 1.85 (m, 1H), 1.80 -1.71 (m, 1H), 1.58 (d,J=6.8 Hz, 3H), 1.46 - 1.32 (m, 3H). Synthesis of N-{1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]ethyl}-N-methylcyclohexanecarboxamide (compound 1.21) [ka]

[0133] Dioxane (3 mL) contains N-[1-(4-bromophenyl)ethyl]-N-methylcyclohexanecarboxamide [INT11.2] (50 mg, 154 μmol), 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine hydrochloride [INT1.1] (35.0 mg, 154 μmol), Cs2CO3 (150 mg, 462 μmol), and xanthophos (17.8 mg, 3 Pd2(dba)3 (14.1 mg, 15.4 μmol) was added to a 0.8 μmol solution, and the reaction mixture was stirred at 100°C for 2 hours under N2. The mixture was concentrated in vacuum to obtain a crude product, which was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75×30mm×3μm, table: 35~75%B (A=water (0.05v / v% ammonia hydroxide), B=acetonitrile), flow rate: 25mL / min, UV detector 220nm) to obtain N-{1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]ethyl}-N-methylcyclohexanecarboxamide [compound 1.21] (9.30 mg, 19.7 μmol, yield 12.8%) as a yellow dry powder. m / z: [M+H]+ of C24H32ClN6O2 calculated value 471.2, measured value 471.3. 1HNMR (400MHz, DMSO-d6) δ = 8.79 (s, 1H), 7.79 - 7.70 (m,1H), 7.11 - 7.03 (m,2H), 6.96 - 6.88 (m, 2H), 5.83 - 5.12 (m, 2H), 3.17 (s,3H), 2.75 - 2.53 (m,3H), 1.74 - 1.60 (m, 5H), 1.58 (d, J=6.8 Hz, 3H), 1.49 (brd, J=6.8 Hz, 1H),1.42 (br s, 1H), 1.34 (br d, J=7.2 Hz, 3H), 1.27 (br d,J=12.8 Hz, 2H), 1.24 -1.09 (m, 2H). Synthesis of N-{1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]ethyl}-N-methylcyclopentanecarboxamide (compound 1.22) [ka]

[0134] In 3 mL of dioxane, a solution of N-[1-(4-bromophenyl)ethyl]-N-methylcyclopentanecarboxamide [INT11.3] (50 mg, 161 μmol) and 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine hydrochloride [INT1.1] (36.6 mg, 161 μmol) was prepared. To this solution, Cs2CO3 (157 mg, 482 μmol), xanthophos (18.5 mg, 32.1 μmol), and Pd2(dba)3 (14.6 mg, 16.0 μmol) were added. The reaction mixture was stirred at 100°C for 2 hours under N2. The mixture was concentrated in vacuum to obtain a crude product, which was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75×30mm×3μm, table: 35~75%B (A=water (0.05v / v% ammonia hydroxide), B=acetonitrile), flow rate: 25mL / min, UV detector 220nm) to obtain N-{1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]ethyl}-N-methylcyclopentanecarboxamide [compound 1.22] (10.0 mg, 21.8 μmol, yield 13.6%) as a yellow dry powder. m / z: [M+H]+ of C23H30ClN6O2 calculated value 457.2, measured value 457.3. 1 HNMR (400MHz, DMSO-d6) δ = 8.80 (s, 1H), 7.80 - 7.70 (m,1H), 7.14 - 7.04 (m, 2H), 6.99 - 6.87 (m, 2H), 5.81 - 5.13 (m, 2H), 3.17 (s,3H), 3.13 -2.91 (m, 1H), 2.70 - 2.51 (m, 3H), 1.86 - 1.62 (m, 6H), 1.58 (d, J=6.8 Hz, 3H),1.55 - 1.45 (m, 3H), 1.35 (d, J=7.2 Hz, 2H). Synthesis of N-{1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]ethyl}-N-methylcyclopropanecarboxamide (compound 1.23) [ka]

[0135] To a mixture of N-[1-(4-bromophenyl)ethyl]-N-methylcyclopropanecarboxamide [INT12.2] (50 mg, 177 μmol) and 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine hydrochloride [INT1.1] (40.2 mg, 177 μmol) in 2 ml of dioxane, Pd2(dba)3 (16.2 mg, 17.7 μmol), Cs2CO3 (173 mg, 531 μmol), and xanthophos (20.4 mg, 35.4 μmol) were added at 25°C. The mixture was stirred at 100°C for 12 hours under N2. The mixture was concentrated under vacuum to obtain the crude product, which was then subjected to preparative HPLC (column: YMC Triart). The compound was purified using a C18 250×50mm×7μm table with a 25-65% B (A = water (0.05 v / v% ammonia hydroxide), B = acetonitrile), flow rate: 60 mL / min, UV detector 220 nm) to obtain N-{1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]ethyl}-N-methylcyclopropanecarboxamide [compound 1.23] (16.9 mg, 39.4 μmol, yield 22.2%) as a yellow dry powder. m / z: [M+H]+ of C21H26ClN6O2 calculated value 429.2, measured value 429.3. 1 HNMR (400MHz, DMSO-d6) δ = 8.86 (s, 1H), 7.92 - 7.74 (m,1H), 7.46 - 6.96 (m,4H), 5.86 - 5.52 (m, 1H), 5.23 (q, J=6.8 Hz, 1H), 3.24 (s,3H), 2.87 - 2.58 (m, 3H), 2.19 - 1.89 (m, 1H), 1.64 (d, J=6.8 Hz, 3H), 1.59 (brd, J=6.4 Hz, 1H),1.43 (br d, J=7.2 Hz, 2H), 0.85 - 0.76 (m, 4H). Synthesis of N-{1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]ethyl}-N-methylacetamide (compound 1.24) [ka]

[0136] In 2 mL of dioxane, a solution of N-[1-(4-bromophenyl)ethyl]-N-methylacetamide [INT12.1] (30 mg, 117 μmol) and 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine hydrochloride [INT1.1] (26.6 mg, 117 μmol) was added. Pd2(dba)3 (10.7 mg, 11.7 μmol), Cs2CO3 (114 mg, 351 μmol), and xanthophos (13.5 mg, 23.4 μmol) were added. The reaction mixture was stirred at 100°C for 2 hours under N2. The reaction mixture was concentrated under reduced pressure to obtain the crude product, which was then subjected to preparative HPLC (column: YMC-Actus Triart C18). 150 x 30 mm x 5 μm, Table: 37-57% B (A = water (0.05% ammonium hydroxide)), B = acetonitrile), Flow rate: 35 mL / min, UV detector 220 nm) Therefore, purification was performed to obtain N-{1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]ethyl}-N-methylacetamide [compound 1.24] (2.50 mg, 6.20 μmol, yield 5.3%) as a yellow dry powder. m / z: C19H24ClN6O2 [M+H]+ calculated value 403.2, measured value 403.2. 1HNMR (400MHz, DMSO-d6) δ = 8.85 - 8.53 (m, 1H), 7.89 -7.72 (m, 1H), 7.49 - 6.91(m, 4H), 5.80 - 5.01 (m, 2H), 3.18 (s, 3H), 2.65 -2.54 (m, 3H), 2.16 - 2.01 (m,3H), 1.59 (d, J=6.8 Hz, 3H), 1.50 - 1.34 (m, 3H). Synthesis of N-{1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl}-N-methylacetamide (compound 1.25) [ka]

[0137] In 2 mL of dioxane, a mixture of 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine hydrochloride [INT1.1] (120 mg, 0.5271 mmol), N-[1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methylacetamide [INT13.1] (150 mg, 0.4836 mmol), xanthophos (80 mg, 0.1382 mmol), and Cs2CO3 (500 mg, 1.53 mmol) was mixed with Pd2(dba)3 (80 mg, 0.08736 mmol). The mixture was stirred at 100°C for 12 hours under N2. The reaction product was diluted with RINKAN (30 mL), filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: Boston Prime C18 150×30mm×5μm, conditions: 40%~60% CH3CN in water (0.05v / v% ammonia hydroxide), flow rate: 25mL / min) to obtain N-{1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl}-N-methylacetamide [compound 1.25] (10.2 mg, 0.02232 mmol, yield 4.6%) as a yellow dry powder. m / z: [M+H]+ of C19H21ClF3N6O2 calculated value 457.1, measured value 457.1. 1 HNMR (400MHz, DMSO-d6) δ = 8.84 (s, 1H), 8.07 -7.90 (m, 1H), 7.34 - 7.13 (m,2H), 6.97 (br d, J=8.6 Hz, 2H), 6.50 - 5.82 (m,1H), 5.16 (q, J=6.7 Hz, 1H),3.17 (s, 3H), 2.90 - 2.59 (m, 3H), 2.31 - 2.10 (m,3H), 1.60 (d, J=6.7 Hz, 3H). N-[(1R)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ 6Synthesis of -thian-4-carboxamide (also known as N-((R)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide) (Compound 1.26) [ka]

[0138] Dioxane (2 mL) contains N-[(1R)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ 6 To a solution of -thian-4-carboxamide [INT14.1] (50 mg, 116 μmol) and 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine hydrochloride [INT1.1] (31.6 mg, 139 μmol), Pd2(dba)3 (10.6 mg, 11.6 μmol), Cs2CO3 (113 mg, 348 μmol), and xanthophos (13.4 mg, 23.2 μmol) were added. The reaction mixture was stirred at 100°C for 2 hours under N2. The reaction mixture was concentrated under reduced pressure to obtain the crude product, which was then purified by preparative HPLC (column: Boston Green ODS 150×30mm×5μm, table: 24~64%B (A=water (0.05% ammonia hydroxide)), B=acetonitrile), flow rate: 30 mL / min, UV detector 220 nm) and N-[(1R)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ 6 -Chiane-4-carboxamide [Compound 1.26] (16.4 mg, 28.5 μmol, yield 24.6%) was obtained as a yellow dry powder. m / z: C23H27ClF3N6O4S [M+H]+ Calculated value 575.1, measured value 575.3. 1HNMR (400MHz, DMSO-d6) δ = 8.83 (s, 1H), 8.07 - 7.97 (m,1H), 7.29 - 7.17 (m,2H), 7.03 - 6.92 (m, 2H), 6.49 - 6.05 (m, 1H), 5.16 (q,J=6.8 Hz, 1H), 3.26 - 3.19 (m, 2H), 3.16 (s, 3H), 3.13 -3.08 (m, 2H), 2.90 (s,3H), 2.65 (s, 1H), 2.10 - 1.95 (m, 4H), 1.59 (d, J=6.8Hz, 3H). N-[(1R)-1-[4-({2-chloro-7-[(1R)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ 6 Synthesis of -thian-4-carboxamide (also known as N-((R)-1-(4-((2-chloro-7-((R)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide) (Compound 1.27) [ka]

[0139] Dioxane (2 mL) contains 2-chloro-7-[(1R)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine hydrochloride [INT1.3] (60 mg, 227 μmol), N-[(1R)-1-(4-bromophenyl)-2,2, 2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ 6A mixture of -thian-4-carboxamide [INT14.1] (97.2 mg, 227 μmol), Pd2(dba)3 (20.7 mg, 22.7 μmol), xanthophos (26.2 mg, 45.4 μmol), and Cs2CO3 (221 mg, 681 μmol) was stirred at 100°C for 3 hours under an N2 atmosphere. The mixture was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel flash chromatography (methanol / dichloromethane = 0 / 1 to 1 / 20). The resulting product was purified by preparative HPLC (column: YMC Triart C18 250×50mm×7μm, table: 26~66%B (A=water (0.05v / v% ammonia hydroxide)), B=acetonitrile), flow rate: 60mL / min, UV detector 220nm) and preparative TLC (SiO2, dichloromethane:methanol=20:1), and then N-[(1R)-1-[4-({2-chloro-7-[(1R)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ 6 -Chiane-4-carboxamide [Compound 1.27] (5.20 mg, 9.04 μmol, yield 4.0%) was obtained as a white, dry powder. m / z: C23H27ClF3N6O4S [M+H]+ Calculated value 575.1, measured value 575.3. 1 HNMR (400 MHz, CD3OD) δ = 8.86 (s, 1H), 7.30 (d, J=8.4Hz, 2H), 7.06(d, J=8.4 Hz, 2H), 6.52 (q, J=9.2 Hz, 1H), 5.36 (q, J=6.8 Hz,1H), 3.36 (s, 3H),3.25 - 3.10 (m, 5H), 3.02 - 2.75 (m, 3H), 2.35 - 2.12 (m,4H), 1.64 (d, J=6.8Hz, 3H). Synthesis of N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)-2-methylphenyl]-2,2,2-trifluoroethyl]-N-methylcyclobutanecarboxamide (compound 1.28) [ka]

[0140] N-[(1S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethyl]-N-methylcyclobutanecarboxamide [INT16.1] (0.1 g, 0.2745 mmol), 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine [free base of INT1.1] (62.3 mg, 274 μmol), Cs2CO3 (268 mg, 823 μmol), and xanthophos (15.8 mg, 27.4 μmol) were mixed in dioxane (2 mL), and the reaction mixture was degassed with argon for 5 minutes. Pd2(dba)3 (12.5 mg, 13.7 μmol) was added, and the reaction mixture was then degassed with argon for 5 minutes and stirred at 100°C for 10 hours. The reaction mixture was cooled to rt. The solid was filtered off. The filtrate was purified by HPLC (see conditions below) to obtain N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)-2-methylphenyl]-2,2,2-trifluoroethyl]-N-methylcyclobutanecarboxamide [compound 1.28] (44.7 mg, 0.08757 mmol, yield 31.9%) as a yellow solid. m / z: C23H27ClF3N6O2 [M+H]+ calculated value 511.2, measured value 511.2. 1 HNMR (400 MHz, DMSO-d6 ) δ = 8.83 (d, J=1.4 Hz, 1H), 7.91(s, 1H), 7.29 (d, J=8.4Hz, 1H), 6.85 - 6.78 (m, 2H), 6.43 (q, J=9.3 Hz, 1H),5.14 (q, J=6.6 Hz, 1H), 3.46 (p,J=8.5 Hz, 1H), 3.16 (s, 3H), 2.63 (s, 3H),2.14 (dp, J=24.5, 8.1, 7.5 Hz, 4H),2.05 (s, 3H), 1.93 (dt, J=18.4, 9.2 Hz,1H), 1.76 (s, 1H), 1.58 (d, J=6.7 Hz, 3H).

[0141] HPLC conditions, system: Agilent 1260 Infinity II LC connected to Agilent 6120B single quadrupole LC / MS system, column description: Chromatorex SBM 100-5T 5μm C18(2) 100Å, LC column 100×19mm, Waters, Sun Fire, stationary phase: C18, solid support: fully porous silica, separation mode: reversed phase, mobile phase A: water. Synthesis of N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)-2-methylphenyl]-2,2,2-trifluoroethyl]-N-methylcyclopropanecarboxamide (compound 1.29) [ka]

[0142] N-[(1S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethyl]-N-methylcyclopropanecarboxamide [INT16.2] (0.1 g, 0.2855 mmol), 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine [free base of INT1.1] (64.8 mg, 0.2846 mmol), Cs2CO3 (277 mg, 853 μmol), and xanthophos (16.4 mg, 28.4 μmol) were mixed in dioxane (2 mL). Pd2(dba)3 (13.0 mg, 14.2 μmol) was added under an inert atmosphere. The mixture was stirred at 100°C for 10 hours, and then the reaction mixture was cooled to rt. The solid was filtered off, and the filtrate was purified by HPLC (see conditions below) to obtain N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)-2-methylphenyl]-2,2,2-trifluoroethyl]-N-methylcyclopropanecarboxamide [compound 1.29] (15.7 mg, 0.03173 mmol, yield 11.1%) as a yellow solid. m / z: C22H25ClF3N6O2 [M+H]+ calculated value 497.2, measured value 497.2. 1 HNMR (400 MHz, CD3OD) δ = 8.89 (d, J=2.4 Hz, 1H), 7.48 (d, J=8.4 Hz,1H), 6.94 (dt,J=8.7, 4.3 Hz, 2H), 6.51 (q, J=8.9 Hz, 1H), 5.38 (q, J=6.7 Hz,1H), 3.38 (s,3H), 3.01 (s, 3H), 2.71 - 2.58 (m, 1H), 2.33 - 2.11 (m, 3H), 2.07 - 1.95 (m,1H), 1.65 (d, J=6.7 Hz, 3H), 1.03 - 0.86 (m, 4H).

[0143] HPLC conditions, system: Agilent 1260 Infinity II LC connected to Agilent 6120B single quadrupole LC / MS system, column description: Chromatorex SBM 100-5T 5μm C18(2) 100Å, LC column 100×19mm, Waters, Sun Fire, stationary phase: C18, solid support: fully porous silica, separation mode: reversed phase, mobile phase A: water, mobile phase B: acetonitrile, flow rate: 30 ml / min, loading pump: 4 ml / min B, gradient conditions: 20%~40%~50%~100% (B) over 0 min~2 min~10 min~11.2 min. N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)-2-methylphenyl]-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ 6 -Cian-4-carboxamide (also, N-((S)-1-(4-((2-chloro- Synthesis of 7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)-2-methylphenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide) (compound 1.30) [ka]

[0144] N-[(1S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ 6A mixture of -thian-4-carboxamide [INT16.3] (100 mg, 0.2260 mmol), 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine [free base of INT1.1] (51.4 mg, 226 μmol), Cs2CO3 (220 mg, 678 μmol), and dioxane (3 mL) was purged with argon. Next, xanthophos (26.1 mg, 45.2 μmol) and Pd2(dba)3 (20.6 mg, 22.6 μmol) were added, and the reaction mixture was stirred at 100 °C for 10 hours. After cooling, the reaction mixture was diluted with ELISA (30 mL) and concentrated under reduced pressure. The resulting residue is purified by HPLC (see conditions below) to obtain N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)-2-methylphenyl]-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ 6 -Chiane-4-carboxamide [compound 1.30] (12.5 mg, 0.02128 mmol, yield 9.4%) was obtained as a yellow solid. m / z: C24H29ClF3N6O4S [M+H]+ calculated value 589.2, measured value 589.0. 1 HNMR (500 MHz, DMSO-d6) δ = 8.80 (s, 1H), 7.90 (s, 1H),7.29 (d, J=8.3 Hz, 1H), 6.87 - 6.75 (m, 2H), 6.43(q, J=9.1 Hz, 1H), 5.13 (q,J=6.8 Hz, 1H), 3.27 - 3.14 (m, 2H), 3.15 (s, 3H),3.12 - 3.04 (m, 3H), 2.79 (s,3H), 2.15 - 2.03 (m, 2H), 2.01 (s, 3H), 1.99 -1.94 (m, 2H), 1.57 (d, J=6.7Hz,3H).

[0145] HPLC conditions, system: Agilent 1260 Infinity II LC connected to Agilent 6120B single quadrupole LC / MS system, column description: Chromatorex SBM 100-5T 5μm C18(2) 100Å, LC column 100×19mm, Waters, Sun Fire, stationary phase: C18, solid support: fully porous silica, separation mode: reversed phase, mobile phase A: water, mobile phase B: acetonitrile, flow rate: 30 ml / min, loading pump: 4 ml / min B, gradient conditions: 20%~35%~50%~100% (B) over 0 min~2 min~10 min~11.2 min. Synthesis of N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)-3-methylphenyl]-2,2,2-trifluoroethyl]-N-methylcyclobutanecarboxamide (compound 1.31) [ka]

[0146] N-[(1S)-1-(4-bromo-3-methylphenyl)-2,2,2-trifluoroethyl]-N-methylcyclobutanecarboxamide [INT17.1] (0.12 g, 0.3294 mmol), 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine [free base of INT1.1] (74.8 mg, 329 μmol), Cs2CO3 (321 mg, 988 μmol), and xanthophos (19.0 mg, 32.9 μmol) were mixed in dioxane (2 mL), and the reaction mixture was degassed with argon for 5 minutes. Pd2(dba)3 (15.0 mg, 16.4 μmol) was added, and the reaction mixture was then degassed with argon for 5 minutes and stirred at 100°C for 10 hours. The reaction mixture was cooled to rt and the solid was filtered off. The filtrate was purified by HPLC (see conditions below) to obtain N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)-3-methylphenyl]-2,2,2-trifluoroethyl]-N-methylcyclobutanecarboxamide [compound 1.31] (7.31 mg, 0.01431 mmol, yield 4.4%) as a yellow solid. m / z: C23H27ClF3N6O2 [M+H]+ calculated value 511.2, measured value 511.2. 1 HNMR (500 MHz, DMSO-d6) δ = 8.74 (s, 1H), 7.23 (s, 1H),7.14 (s, 1H), 7.02 (d, J=8.5 Hz, 1H),6.83 (d, J=8.4 Hz, 1H), 6.40 (q, J=9.5Hz, 1H), 5.15 (q, J=6.7 Hz, 1H), 3.50 -3.43 (m, 1H), 3.23 (s, 3H), 2.71 (s,3H), 2.30 (s, 3H), 2.21 - 2.06 (m, 4H),1.91 (q, J=9.5 Hz, 1H), 1.79 - 1.73 (m,1H), 1.54 (d, J = 6.7 Hz, 3H).

[0147] HPLC conditions, system: Agilent 1260 Infinity II LC connected to Agilent 6120B single quadrupole LC / MS system, column description: Chromatorex SBM 100-5T 5μm C18(2) 100Å, LC column 100×19mm, Waters, Sun Fire, stationary phase: C18, solid support: fully porous silica, separation mode: reversed phase, mobile phase A: water, mobile phase B: acetonitrile, flow rate: 30 ml / min, loading pump: 4 ml / min B, gradient conditions: 30%~45%~60%~100% (B) over 0 min~2 min~10 min~11.2 min. Synthesis of N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)-3-methylphenyl]-2,2,2-trifluoroethyl]-N-methylcyclopropanecarboxamide (compound 1.32) [ka]

[0148] N-[(1S)-1-(4-bromo-3-methylphenyl)-2,2,2-trifluor Roethyl-N-methylcyclopropanecarboxamide [INT17.2] (50 mg, 0.1427 mmol), 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine [free base of INT1.1] (32.3 mg, 142 μmol), and Cs2CO3 (139 mg, 428 μmol) were mixed in dioxane (5 mL). Argon was blown over the reaction mixture for 15 minutes. Xanthophos (16.4 mg, 28.5 μmol) and Pd2(dba)3 (13.0 mg, 14.2 μmol) were then added, and the reaction mixture was stirred at 100°C for 14 hours. The reaction mixture was cooled, filtered, and concentrated under vacuum. The resulting residue was purified by HPLC (see conditions below) to obtain N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)-3-methylphenyl]-2,2,2-trifluoroethyl]-N-methylcyclopropanecarboxamide [compound 1.32] (21.6 mg, 0.04358 mmol, yield 30.6%) as a yellow solid. m / z: C22H25ClF3N6O2 [M+H]+ calculated value 497.2, measured value 497.0. 1 HNMR (400 MHz, DMSO-d6) δ = 8.81 - 8.75 (m, 1H), 7.26 (s,1H), 7.17 (s, 1H), 7.05(d, J=8.4 Hz, 1H), 6.90 - 6.83 (m, 1H), 6.43 (q, J=9.5Hz, 1H), 5.17 (q, J=6.6Hz, 1H), 3.25 (s, 3H), 3.01 (s, 3H), 2.32 (s, 3H), 2.06- 1.97 (m, 1H), 1.56 (d,J=6.7 Hz, 3H), 0.90 - 0.81 (m, 4H).

[0149] HPLC conditions, system: Agilent 1260 Infinity II LC connected to Agilent 6120B single quadrupole LC / MS system, column description: Chromatorex SBM 100-5T 5μm C18(2) 100Å, LC column 100×19mm, Waters, Sun Fire, stationary phase: C18, solid support: fully porous silica, separation mode: reversed phase, mobile phase A: water, mobile phase B: acetonitrile, flow rate: 30 ml / min, loading pump: 4 ml / min B, gradient conditions: 20%~40%~65%~100% (B) over 0 min~2 min~10 min~11.2 min. N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)-3-methylphenyl]-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ 6 Synthesis of -thian-4-carboxamide (also known as N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)-3-methylphenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide) (Compound 1.33) [ka]

[0150] N-[(1S)-1-(4-bromo-3-methylphenyl)-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ 6 -Thiane-4-carboxamide [INT17.3] (0.1 g, 0.2260 mmol), 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine [free base of INT1.1] (51.4 mg, 226 μmol), Cs2CO3 (220 mg, 678 μmol), and xanthophos (13.0 mg, 22.6 μmol) were mixed in dioxane (2 mL), and the reaction mixture was degassed with argon for 5 minutes. Pd2(d ba)3 (10.3 mg, 11.3 μmol) was added. Next, the reaction mixture was degassed with argon for 5 minutes and stirred at 100°C for 10 hours. The reaction mixture was cooled to rt and the solid was filtered off. The filtrate was purified by HPLC (see conditions below) to obtain N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)-3-methylphenyl]-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ 6 -Chiane-4-carboxamide [compound 1.33] (20.7 mg, 0.03515 mmol, yield 15.5%) was obtained as a yellow solid. m / z: C24H29ClF3N6O4S [M+H]+ calculated value 589.2, measured value 589.0. 1 HNMR (600 MHz, DMSO-d6) δ = 8.74 (s, 1H), 7.24 (s, 1H),7.15 (s, 1H), 7.03 (d,J=8.6 Hz, 1H), 6.84 (d, J=8.4 Hz, 1H), 6.41 (q, J=9.4Hz, 1H), 5.16 (q, J=6.7Hz, 1H), 3.21 (d, J=13.9 Hz, 3H), 3.18 - 3.05 (m, 5H),2.89 (s, 3H), 2.34 - 2.28 (m, 3H), 2.11 - 1.95 (m, 4H), 1.54 (d, J = 6.7 Hz, 3H).

[0151] HPLC conditions, system: Agilent 1260 Infinity II LC connected to Agilent 6120B single quadrupole LC / MS system, column description: Chromatorex SBM 100-5T 5μm C18(2) 100Å, LC column 100×19mm, Waters, Sun Fire, stationary phase: C18, solid support: fully porous silica, separation mode: reversed phase, mobile phase A: water, mobile phase B: acetonitrile, flow rate: 30 ml / min, loading pump: 4 ml / min B, gradient conditions: 10%~30%~55%~100% (B) over 0 min~2 min~10 min~11.2 min. 2. Compounds prepared using Scheme 2 Scheme 2: [ka]

[0152] The starting material G-2a is treated with acid to provide the compound of formula (I). G2a This is either Boc (for cyclic carbamates) or HBoc (for acyclic carbamates). G2b This is either H (for secondary amines) or H2 (for primary amines). Synthesis of N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylpiperidine-4-carboxamide trifluoroacetate (Compound 2.1) [ka]

[0153] 4M HCl / Dioxane (10 mL, 40.0 mmol) contains tert-butyl 4- A mixture of (((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)piperidine-1-carboxylate [compound 1.10] (300 mg, 479 μmol) was stirred at 25°C for 4 hours. The mixture was concentrated under reduced pressure to obtain N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylpiperidine-4-carboxamide hydrochloride [compound 2.1, HCl salt] (250 mg, 444 μmol, yield 92.9%) as a yellow solid. 50 mg (95.0 μmol) of the crude product was purified by preparative HPLC (column: Boston Green ODS 150 × 30 mm × 5 μm, table: 10-50% B (A = water (0.1% TFA)-ACN), B = acetonitrile), flow rate: 30 mL / min, UV detector 220 nm) to obtain N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylpiperidine-4-carboxamide trifluoroacetate [compound 2.1] (17.6 mg, 27.5 μmol) as a yellow dry powder. m / z: C23H28ClF3N7O2 [M+H]+ Calculated value 526.2, measured value 526.3. 1 HNMR (400 MHz, CDCl3) δ = 9.66 (br s, 1H), 9.16 (br s,1H), 8.89 (s, 1H), 7.31 (d, J=8.4 Hz, 2H), 7.14 (s, 1H), 7.05 (d, J=8.8 Hz,2H), 6.57 (q,J=8.8 Hz, 1H), 5.48 (q, J=6.8 Hz, 1H), 3.57 (br s, 5H), 3.14 (brd, J=5.2 Hz,2H), 2.99 (br s, 1H), 2.93 (s, 3H), 2.23 - 1.94 (m, 4H), 1.61 (d,J=6.8 Hz, 3H). Synthesis of N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methylpiperidine-3-carboxamide (compound 2.2) [ka]

[0154] A solution of tert-butyl 3-{[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl](methyl)carbamoyl}piperidine-1-carboxylate [compound 1.11] (200 mg, 319 μmol) was stirred in 4 M HCl / dioxane (6 mL) at 20°C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methylpiperidine-3-carboxamide hydrochloride [compound 2.2, HCl salt] (140 mg, 266 μmol, yield 83.4%) as a yellow solid. 45.3 mg of this crude product was purified by preparative HPLC (column: Phenomenex Gemini-NX 80 × 40 mm × 3 μm, table: 22-62% B (A = water (0.05% ammonia hydroxide)), B = acetonitrile), flow rate: 25 mL / min, UV detector 220 nm) to obtain N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methylpiperidine-3-carboxamide [compound 2.2] (5.30 mg, 10.0 μmol, yield 11.7%) as a yellow solid. m / z: C2 The calculated [M+H]+ value for 3H28ClF3N7O2 is 526.2, and the measured value is 526.3. 1 1H NMR (400 MHz, CDCl3) δ = 8.89 (s, 1H), 7.31 (d, J=8.4Hz, 2H), 7.11 (s,1H), 7.04 (d, J=8.8 Hz, 2H), 6.61 (q, J=9.2 Hz, 1H), 5.48 (q,J=6.8 Hz, 1H),3.51 - 3.45 (m, 3H), 3.15 - 2.98 (m, 2H), 2.93 (s, 3H), 2.85 -2.67 (m, 2H), 2.62 (s, 2H), 2.05- 1.96 (m, 1H), 1.82 - 1.70 (m, 2H), 1.61 (d,J=6.8 Hz, 3H), 1.59 - 1.50 (m,1H). Synthesis of N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylpyrrolidine-3-carboxamide hydrochloride (compound 2.3) [ka]

[0155] A mixture of tert-butyl 3-{[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl](methyl)carbamoyl}pyrrolidine-1-carboxylate [compound 1.12] (200 mg, 326 μmol) in 4M HCl / dioxane (10 mL, 40.0 mmol) was stirred at 25°C for 2 hours. The mixture was concentrated under reduced pressure to obtain a crude product, which was purified by preparative HPLC (column: Boston Green ODS 150×30mm×5μm, table: 16~56%B (A=water (0.05%HCl)-ACN), B=acetonitrile), flow rate: 30 mL / min, UV detector 220 nm) to obtain N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylpyrrolidine-3-carboxamide hydrochloride [compound 2.3] (31.3 mg, 57.1 μmol, yield 17.5%) as a yellow powder. m / z: For C22H26ClF3N7O2, the calculated [M+H]+ values ​​are 512.1, 514.1, and the measured values ​​are 512.3, 514.2. 1HNMR (400 MHz, CDCl3) δ = 10.16 (brs, 1H), 9.42 (br s, 1H), 8.90 (brs, 1H), 7.47 - 7.27 (m, 2H), 7.14 - 7.00 (m,2H), 6.62 - 6.43 (m, 1H), 5.48 (brd, J=6.0 Hz, 1H), 3.68 (br d, J=14.8 Hz,4H), 3.49 (s, 3H), 3.04 - 2.79 (m, 3H),2.47 (br s, 1H), 2.22 - 2.09 (m, 2H),1.61 (br d, J=6.0 Hz, 3H). 4-(aminomethyl)-N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methylcyclohexane-1-carboxamide; synthesis of formic acid (compound 2.4) [ka]

[0156] In 4N HCl / dioxane (5 mL), tert-butyl N-[(4-{[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2- A solution of [[Lifluoroethyl](methyl)carbamoyl)cyclohexyl)methyl]carbamate [Compound 1.13] (450 mg, 625 μmol) was stirred at 20°C for 12 hours. The mixture was concentrated under reduced pressure to obtain 4-(aminomethyl)-N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methylcyclohexane-1-carboxamide hydrochloride [Compound 2.4, HCl salt] (370 mg, 616 μmol, yield 98.6%) as a yellow solid. Furthermore, 100 mg of the product was purified by preparative HPLC (column: YMC Triart C18 250 × 50 mm × 7 μm, table: 12-52% B (A = water (0.225% FA), B = acetonitrile), flow rate: 60 mL / min, UV detector 220 nm) to obtain 4-(aminomethyl)-N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methylcyclohexane-1-carboxamide; formic acid [compound 2.4] (21.7 mg, 36.1 μmol, yield 21.7%) as a yellow dry powder. m / z: C25H32ClF3N7O2 [M+H]+ Calculated value 554.2, measured value 554.4. 1 HNMR (400 MHz, DMSO-d6) δ = 8.84 (s, 1H), 8.43 (s, 1H),8.13 - 8.00 (m, 1H), 7.29- 7.12 (m, 2H), 7.02 - 6.93 (m, 2H), 6.52 - 6.08 (m,1H), 5.16 (q, J = 6.8 Hz, 1H), 3.16 (s, 3H), 2.87 (s, 3H), 2.67- 2.56 (m, 2H),1.88 - 1.67 (m, 4H), 1.59 (d, J=6.4 Hz, 3H), 1.55 - 1.21 (m,4H), 1.10 - 0.91 (m, 2H). 3. Compounds prepared using Scheme 3 Scheme 3: [ka]

[0157] Starting material G-3a, R G3b The compound of formula (I) is provided by treating with G-3b, which contains R. G3a is either NH (for cyclic amines) or NH2 (for primary amines), X is CO or SO2, and R G3b is CH3, iPr, OMe, or NHMe, and R G3c This is either N (for cyclic amides, ureas, or carbamates) or NH (for acyclic amides, ureas, or carbamates). Synthesis of 1-acetyl-N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylpiperidine-4-carboxamide (compound 3.1) [ka]

[0158] In 2 mL of DCM, a mixture of N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylpiperidine-4-carboxamide hydrochloride [compound 2.1, HCl salt] (60 mg, 106 μmol) and triethylamine (53.6 mg, 530 μmol) was added with acetyl chloride (29.1 mg, 371 μmol) at 25°C, and the mixture was stirred at 25°C for 12 hours. The mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (column: Boston Prime C18 150×30mm×5μm, table: 35~65%B (A=water (0.05v / v% ammonia hydroxide), B=acetonitrile), flow rate: 30mL / min, UV detector 220nm) to obtain 1-acetyl-N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylpiperidine-4-carboxamide [compound 3.1] (17.7 mg, 31.1 μmol, yield 29.4%) as a yellow dry powder. m / z: C25H30ClF3N7O3 [M+H]+ Calculated value 568.2, measured value 568.4. 1 HNMR (400MHz, CDCl3) δ = 8.90 (s, 1H), 7.35 - 7.29 (m,2H), 7.17 -7.01 (m, 3H), 6.68 - 6.58 (m, 1H), 5.49 (q, J=6.8 Hz, 1H), 4.71 -4.54 (m, 1H),3.93 (br d, J=13.6 Hz, 1H), 3.49 (s, 3H), 3.20 - 3.09 (m, 1H),2.95 (s, 3H), 2.88 - 2.66 (m, 2H), 2.12(s, 3H), 1.95 - 1.67 (m, 4H), 1.62 (d,J=6.7 Hz, 3H). Synthesis of N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methyl-1-(propane-2-sulfonyl)piperidine-4-carboxamide (compound 3.2) [ka]

[0159] In 5 mL of DCM, a mixture of N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methylpiperidine-4-carboxamide hydrochloride [compound 2.1, HCl salt] (80 mg, 142 μmol) and triethylamine (57.4 mg, 568 μmol) was added at 25°C, and the mixture was stirred at 25°C for 12 hours. The mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (column: Boston Prime C18 150×30mm×5μm, table: 40~70%B (A=water (0.05v / v% ammonia hydroxide)-ACN), B=acetonitrile), flow rate: 30mL / min, UV detector 220nm) to obtain N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methyl-1-(propan-2-sulfonyl)piperidine-4-carboxamide [compound 3.2] (9.10 mg, 14.3 μmol, yield 10.1%) as a yellow dry powder. m / z: C26H34ClF3N7O4S [M+H]+ Calculated value 632.2, measured value 632.3. 1HNMR (400 MHz, CDCl3) δ = 8.89 (s,1H), 7.32 (br d, J=8.4 Hz, 2H),7.18 - 7.01 (m, 3H), 6.62 (q, J=9.2 Hz, 1H),5.48 (q, J=6.8 Hz, 1H), 3.85 (dt,J=4.4, 8.8 Hz, 2H), 3.49 (s, 3H), 3.19 (td,J=6.8, 13.6 Hz, 1H), 3.08 - 2.99 (m,2H), 2.93 (s, 3H), 2.85 - 2.67 (m, 1H),1.98 - 1.87 (m, 3H), 1.87 - 1.79 (m, 1H), 1.62 (s, 3H), 1.37 (d, J=6.8 Hz, 6H). Synthesis of methyl 4-{[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl](methyl)carbamoyl}piperidine-1-carboxylate (compound 3.3) [ka]

[0160] In 3 mL of DMF, a mixture of N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methylpiperidine-4-carboxamide hydrochloride [compound 2.1, HCl salt] (100 mg, 177 μmol) and triethylamine (71.6 mg, 708 μmol) was mixed with methyl chloroformate (329 mg, 3.48 mmol), and the mixture was stirred at 25°C for 12 hours. The crude product was purified by preparative HPLC (column: YMC Triart C18 250×50mm×7μm, table: 33~73%B (A=water (0.05v / v% ammonia hydroxide)-ACN), B=acetonitrile), flow rate: 25mL / min, UV detector 220nm) to obtain methyl 4-{[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl](methyl)carbamoyl}piperidine-1-carboxylate [compound 3.3] (46.0 mg, 78.7 μmol, yield 44.6%) as a yellow dry powder. m / z: C25H30ClF3N7O4 [M+H]+ Calculated value 584.2, measured value 584.5. 1 HNMR (400 MHz, CDCl3) δ = 8.89 (s,1H), 7.32 (d, J=8.4 Hz, 2H), 7.12(s, 1H), 7.04 (d, J=8.8 Hz, 2H), 6.62 (q,J=9.2 Hz, 1H), 5.48 (q, J=6.8 Hz, 1H),4.22 (br s, 2H), 3.72 (s, 3H), 3.49 (s,3H), 2.94 (s, 3H), 2.91 - 2.69 (m, 3H),1.89 - 1.69 (m, 4H), 1.62 (d, J=6.7 Hz,3H). Synthesis of N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-1-methanesulfonyl-N-methylpiperidine-4-carboxamide (compound 3.4) [ka]

[0161] In 3 mL of DMF, N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methylpiperidine-4-carboxamide hydrochloride [compound 2.1, HCl salt] (100 mg, 177 μmol), DIPEA (91.5 mg, 708 μmol), and triethylamine (71.6 mg) To a mixture of 708 μmol, methanesulfonyl chloride (120 mg, 1.04 mmol) was added at 0°C, and the mixture was stirred at 25°C for 12 hours. The crude product was purified by preparative HPLC (column: YMC Triart C18 250×50mm×7μm, table: 30~70%B (A=water (0.05v / v% ammonia hydroxide)-ACN, B=acetonitrile), flow rate: 60mL / min, UV detector 220nm) to obtain N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-1-methanesulfonyl-N-methylpiperidine-4-carboxamide [compound 3.4] (21.0 mg, 34.7 μmol, yield 19.8%) as a yellow dry powder. m / z: C24H30ClF3N7O4S [M+H]+ Calculated value 604.2, measured value 604.3. 1HNMR (400 MHz, CDCl3) δ = 8.89 (s,1H), 7.35 - 7.29 (m, 2H), 7.12 (s,1H), 7.05 (d, J=8.8 Hz, 2H), 6.62 (q, J=8.8Hz, 1H), 5.49 (q, J=6.8 Hz, 1H), 3.91 - 3.75 (m, 2H), 3.54 - 3.47 (m, 3H), 3.16- 2.86 (m, 5H), 2.83 (s, 3H), 2.78 - 2.71 (m, 1H), 2.05 - 1.91 (m, 3H), 1.91 -1.84 (m, 1H), 1.62 (d,J=6.8 Hz, 3H). Synthesis of 1-acetyl-N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methylpiperidine-3-carboxamide (compound 3.5) [ka]

[0162] In 2 mL of DCM, a mixture of N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methylpiperidine-3-carboxamide [compound 2.2] (40 mg, 76.0 μmol) and acetyl chloride (20.8 mg, 266 μmol) was mixed with triethylamine (38.4 mg, 380 μmol) at 25°C, and the mixture was stirred at 25°C for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was purified by preparative HPLC (column: YMC Triart C18 250×50mm×7μm, table: 31~71%B (A=water (0.05v / v% ammonia hydroxide)), B=acetonitrile), flow rate: 60mL / min, UV detector 220nm) to obtain 1-acetyl-N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methylpiperidine-3-carboxamide [compound 3.5] (8.90 mg, 15.6 μmol, yield 20.6%) as a yellow dry powder. m / z: C25H30ClF3N7O3 [M+H]+ Calculated value 568.2, measured value 568.3. 1 HNMR (400 MHz, CDCl3) δ = 8.97 - 8.88 (m, 1H), 7.38 -7.29 (m, 2H), 7.15 - 7.10 (m, 1H), 7.08 - 7.02 (m,2H), 6.66 - 6.51 (m, 1H),5.48 (q, J=6.8 Hz, 1H), 4.73 - 4.55 (m, 1H), 3.90 -3.78 (m, 1H), 3.49 (s, 3H),3.22 - 3.03 (m, 1H), 2.94 (s, 3H), 2.82 - 2.64 (m, 2H),2.11 (s, 3H), 2.07 -1.99 (m, 1H), 1.96 - 1.82 (m, 2H), 1.81 - 1.66 (m, 1H),1.63 - 1.60 (m, 2H), 1.58- 1.45 (m, 1H). N3-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N1,N3-dimethylpiperidine 1,3-dica Synthesis of Ruboxamide (Compound 3.6) [ka]

[0163] In 3 mL of CH2Cl2, a mixture of N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methylpiperidine-3-carboxamide [compound 2.2] (50 mg, 95.0 μmol) was added, to which triethylamine (38.4 mg, 380 μmol) was added, followed by the addition of N-methylcarbamoyl chloride (10.5 mg, 113 μmol) at 0°C. The mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was purified by preparative HPLC (column: Phenomenex Gemini-NX 80×40mm×3μm, table: 22~62%B (A=water (0.05% ammonia hydroxide)), B=acetonitrile), flow rate: 25 mL / min, UV detector 220 nm) to obtain N3-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N1,N3-dimethylpiperidine 1,3-dicarboxamide [compound 3.6] (8.00 mg, 13.7 μmol, yield 14.4%) as a yellow solid. m / z: C25H31ClF3N8O3 [M+H]+ Calculated value 583.2, measured value 583.4. 1HNMR (400MHz, DMSO-d6) δ = 8.87 - 8.83 (m, 1H), 8.05 -7.94 (m, 1H), 7.37 - 7.15(m, 2H), 7.02 - 6.94 (m, 2H), 6.53 - 6.37 (m, 2H),5.15 (q, J=6.8 Hz, 1H), 4.04(br d, J=9.6 Hz, 1H), 3.91 (br d, J=13.2 Hz, 1H),3.16 (s, 3H), 2.90 (s, 3H), 2.69 (br dd, J=3.6, 11.6 Hz, 2H), 2.66 - 2.61 (m,1H), 2.57 - 2.54 (m, 3H), 1.87 - 1.72 (m, 1H), 1.59 (d, J=6.8 Hz, 3H), 1.57 -1.45 (m, 2H), 1.43- 1.30 (m, 1H). Synthesis of N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-1-methanesulfonyl-N-methylpiperidine-3-carboxamide (compound 3.7) [ka]

[0164] In 2 mL of CH2Cl2, a mixture of N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methylpiperidine-3-carboxamide [compound 2.2] (50 mg, 95.0 μmol) was added, to which triethylamine (38.4 mg, 380 μmol) was added, followed by methanesulfonyl chloride (90 mg, 785 μmol) at 0°C. The mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product, which was then subjected to preparative HPLC (column: Boston Prime C18 150 × 30 mm × 5 μm, table: 34~6). The compound was purified using 4% B (water (0.05 v / v% ammonia hydroxide), B = acetonitrile), flow rate: 25 mL / min, UV detector 220 nm) to obtain N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-1-methanesulfonyl-N-methylpiperidine-3-carboxamide [compound 3.7] (4.30 mg, 7.11 μmol, yield 7.5%) as a white dry powder. m / z: C24H30ClF3N7O4S [M+H]+ calculated value 604.2, measured value 604.3. 1 HNMR (400MHz, DMSO-d6) δ = 8.86 - 8.80 (m, 1H), 7.99 (s,1H), 7.26 - 7.14 (m,2H), 7.00 - 6.90 (m, 2H), 6.50 - 6.12 (m, 1H), 5.18 - 4.94(m, 1H), 3.64 - 3.52(m, 2H), 3.33 - 3.30 (m, 3H), 3.16 - 3.07 (m, 3H), 2.90(s, 3H), 2.88 - 2.84 (m, 1H), 2.82 - 2.65 (m, 2H), 1.88 - 1.71 (m, 2H), 1.58(d, J=6.8 Hz, 3H), 1.55- 1.49 (m, 1H), 1.48 - 1.36 (m, 1H). Synthesis of 1-acetyl-N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methylpyrrolidine-3-carboxamide (compound 3.8) [ka]

[0165] In 2 mL of DCM, a mixture of N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methylpyrrolidine-3-carboxamide hydrochloride [compound 2.3] (150 mg, 273 μmol) and triethylamine (137 mg, 1.36 mmol) was mixed with acetyl chloride (74.9 mg, 955 μmol) at 25°C, and the mixture was stirred at 25°C for 12 hours. The mixture was concentrated under reduced pressure to obtain a crude product, which was purified by preparative HPLC (column: Boston Prime C18 150×30mm×5μm, table: 22~52%B (A=water (0.05v / v% ammonia hydroxide)-ACN), B=acetonitrile), flow rate: 30mL / min, UV detector 220nm) to obtain 1-acetyl-N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methylpyrrolidine-3-carboxamide [compound 3.8] (8.40 mg, 15.1 μmol, yield 5.6%) as a yellow dry powder. m / z: C24H28ClF3N7O3 [M+H]+ Calculated value 554.2, measured value 554.4. 1 HNMR (400 MHz, CDCl3) δ = 8.94 -8.88 (m, 1H), 7.35 - 7.29 (m, 2H),7.14 (s, 1H), 7.05 (dd, J=4.0, 8.4 Hz, 2H),6.65 - 6.53 (m, 1H), 5.48 (q, J=6.8Hz, 1H), 4.01 - 3.51 (m, 4H), 3.49 (s, 3H),3.44 - 3.25 (m, 1H), 3.00 - 2.91 (m,3H), 2.53 - 2.11 (m, 2H), 2.11 - 2.06 (m,3H), 1.62 (br s, 3H). Synthesis of N3-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N1,N3-dimethylpyrrolidine-1,3-dicarboxamide (compound 3.9) [ka]

[0166] In 3 mL of CH2Cl2, a mixture of N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methylpyrrolidine-3-carboxamide hydrochloride [Compound 2.3] (150 mg, 273 μmol) was added, to which triethylamine (110 mg, 1.09 mmol) was added, followed by the addition of N-methylcarbamoyl chloride (30.5 mg, 327 μmol) at 0°C. The mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was purified by preparative HPLC (column: Boston Prime C18 150×30mm×5μm, table: 22~52%B (A=water (0.05v / v% ammonia hydroxide)-ACN)), B=acetonitrile), flow rate: 25mL / min, UV detector 220nm) to obtain N3-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N1,N3-dimethylpyrrolidine-1,3-dicarboxamide [compound 3.9] (11.4 mg, 20.0 μmol, yield 7.4%) as a yellow dry powder. m / z: C24H29ClF3N8O3 [M+H]+ Calculated value 569.1, measured value 569.4. 1 HNMR (400MHz, CDCl3) δ = 8.91 (d,J=5.6 Hz, 1H), 7.35 - 7.29 (m, 2H),7.13 (s, 1H), 7.05 (d, J=8.4 Hz, 2H), 6.64- 6.54 (m, 1H), 5.48 (q, J=6.8 Hz, 1H), 4.21 (br d, J=4.0 Hz, 1H), 3.81 - 3.68(m, 1H),3.63 - 3.54 (m, 2H), 3.49 (d, J=1.2 Hz, 3H), 3.44 - 3.28 (m, 2H), 2.94(d, J=4.4Hz, 3H), 2.84 (dd, J=2.4, 4.8 Hz, 3H), 2.42 - 2.11 (m, 2H), 1.63 (brs, 3H). Synthesis of N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-1-methanesulfonyl-N-methylpyrrolidine-3-carboxamide (compound 3.10) [ka]

[0167] In 2 mL of DMF, a mixture of N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methylpyrrolidine-3-carboxamide hydrochloride [Compound 2.3] (150 mg, 293 μmol), DIPEA (151 mg, 1.17 mmol), and triethylamine (118 mg, 1.17 mmol) was mixed with methanesulfonyl chloride (310 mg, 2.70 mmol) at 0°C. The mixture was stirred at 15°C for 12 hours. The crude product was purified by preparative HPLC (column: Boston Green ODS 150×30mm×5μm, table: 28~68%B (A=water (0.05%HCl)-ACN, B=acetonitrile), flow rate: 30 mL / min, UV detector 220 nm), and then N-[(1S)-1-[4-({2- Chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-1-methanesulfonyl-N-methylpyrrolidine-3-carboxamide [Compound 3.10] (22.5 mg, 35.9 μmol, yield 12.2%) was obtained as a yellow dry powder. m / z: C23H28ClF3N7O4S [M+H]+ Calculated value 590.1, measured value 590.4. 1 HNMR (400MHz, CDCl3) δ = 8.90 (s, 1H), 7.35 - 7.29 (m,2H), 7.14 (s,1H), 7.05 (d, J=8.4 Hz, 2H), 6.57 (q, J=9.2 Hz, 1H), 5.49 (q,J=6.8 Hz, 1H),3.78 - 3.53 (m, 3H), 3.49 (s, 3H), 3.46 - 3.35 (m, 2H), 2.97 -2.91 (m, 6H),2.37 - 2.15 (m, 2H), 1.62 (s, 3H). Synthesis of N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-4-(acetamidomethyl)-N-methylcyclohexane-1-carboxamide (compound 3.11) [ka]

[0168] In 1.5 mL of CH2Cl2, a solution of 4-(aminomethyl)-N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methylcyclohexane-1-carboxamide [free base of compound 2.4] (90 mg, 162 μmol) was added to Et3N (49.0 mg, 485 μmol) and acetyl chloride (63.5 mg, 810 μmol). The resulting mixture was stirred at 20°C for 2 hours. The reaction product was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: YMC Triart C18 250×50mm×7μm, table: 26~66%B (A=water (0.05v / v% ammonia hydroxide), B=acetonitrile), flow rate: 60mL / min, UV detector 220nm) to obtain N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-4-(acetamidomethyl)-N-methylcyclohexane-1-carboxamide [compound 3.11] (23.8 mg, 39.9 μmol, yield 24.6%) as a yellow dry powder. m / z: C27H34ClF3N7O3 [M+H]+ Calculated value 596.2, measured value 596.2. 1 HNMR (400 MHz, CDCl3) δ = 8.81 (s, 1H), 7.23 (brd, J=8.4 Hz, 2H),7.04 (s, 1H), 6.96 (d, J=8.4 Hz, 2H),6.55 (q, J=9.2 Hz, 1H), 5.64 - 5.52 (m, 1H), 5.40 (q, J=6.8Hz, 1H), 3.41 (s, 3H), 3.13 - 3.00 (m,2H), 2.83 (s, 3H), 2.52 - 2.41 (m, 1H),1.96 - 1.90 (m, 3H), 1.80 - 1.66 (m,3H), 1.60 - 1.41 (m, 6H), 1.06 - 0.85 (m,2H). Synthesis of methyl N-[(4-{[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl](methyl)carbamoyl}cyclohexyl)methyl]carbamate (compound 3.12) [ka]

[0169] In 1.5 mL of CH2Cl2, a solution of 4-(aminomethyl)-N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methylcyclohexane-1-carboxamide [free base of compound 2.4] (90 mg, 162 μmol) was added to Et3N (49.0 mg, 485 μmol) and methyl chloroformate (75.7 mg, 810 μmol). The resulting mixture was stirred at 20°C for 2 hours. The reaction mixture was poured into water (10 mL) and extracted with SiO2 (10 mL x 2). The combined organic layers were washed with brine (15 mL x 2) and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: YMC Triart C18 250×50mm×7μm, table: 31~71%B (A=water (0.05v / v% ammonia hydroxide), B=acetonitrile), flow rate: 60mL / min, UV detector 220nm) to obtain methyl N-[(4-{[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl](methyl)carbamoyl}cyclohexyl)methyl]carbamate [compound 3.12] (19.3 mg, 31.5 μmol, yield 19.4%) as a yellow dry powder. m / z: C27H34ClF3N7O4 [M+H]+ Calculated value 612.2, measured value 612.2. 1 HNMR (400 MHz, CDCl3) δ =8.81 (s, 1H), 7.23 (br d, J=8.0Hz, 2H), 7.04 (s,1H), 6.96 (br d, J=8.4 Hz, 2H), 6.55 (q, J=8.8 Hz, 1H), 5.40(q, J=6.8 Hz, 1H), 4.72 (brs, 1H), 3.59 (s, 3H), 3.41 (s, 3H), 3.08 - 2.92 (m,2H), 2.83 (s, 3H), 2.46 (brt, J=11.6 Hz, 1H), 1.83 - 1.67 (m, 4H), 1.65 - 1.38(m, 6H), 0.95 (br t, J=11.2 Hz, 2H). 4. Compounds prepared using Scheme 4 Scheme 4: [ka]

[0170] The starting material G-4a is treated with G-4b to provide the compound of formula (I). Synthesis of N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-1-(cyclopropanecarbonyl)-N-methylpiperidine-4-carboxamide (compound 4.1) [ka]

[0171] In 3 mL of DCM, a mixture of N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylpiperidine-4-carboxamide hydrochloride [compound 2.1, HCl salt] (80 mg, 142 μmol), EDCI (54.4 mg, 284 μmol), hydroxybenzotriazole (19.1 mg, 142 μmol), and triethylamine (43.0 mg, 425 μmol) was mixed with cyclopropanecarboxylic acid (36.5 mg, 425 μmol). The mixture was stirred at 25°C for 12 hours. The crude product was purified by preparative HPLC (column: Phenomenex Gemini-NX 80×40mm×3μm, table: 21~61%B (A=water (0.05v / v% ammonia hydroxide), B=acetonitrile), flow rate: 25mL / min, UV detector 220nm) to obtain N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-1-(cyclopropanecarbonyl)-N-methylpiperidine-4-carboxamide [compound 4.1] (20.5 mg, 34.5 μmol, yield 24.3%) as a yellow dry powder. m / z: C27H32ClF3N7O3 [M+H]+ Calculated value 594.2, measured value 594.5. 1 HNMR (400 MHz, CDCl3) δ = 8.89 (s, 1H), 7.32(br d, J=8.0 Hz, 2H),7.17 - 7.02 (m, 3H), 6.63 (q, J=9.2 Hz, 1H), 5.48 (q,J=6.8 Hz, 1H), 4.62 (br s,1H), 4.32 (br s, 1H), 3.49 (s, 3H), 3.29 - 3.10 (m,1H), 2.95 (s, 3H), 2.90 -2.70 (m, 2H), 1.98 - 1.67 (m, 5H), 1.62 (d, J=6.8 Hz,3H), 0.99 (br s, 2H), 0.78 (br d,J=7.8 Hz, 2H). Synthesis of N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-1-cyclopropanecarbonyl-N-methylpiperidine-3-carboxamide [Compound 4.2] [ka]

[0172] To a mixture of cyclopropanecarboxylic acid (12.2 mg, 142 μmol), EDCI (27.2 mg, 142 μmol), and HOBt (19.1 mg, 142 μmol) in CH2Cl2 (3 mL), N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methylpiperidine-3-carboxamide [compound 2.2] (50 mg, 95.0 μmol) was added, and the mixture was stirred at 25°C for 16 hours under N2. The reaction product was concentrated under reduced pressure to obtain the crude product, which was then subjected to preparative HPLC (column: Phenomenex Gemini-NX C18). The compound was purified using a 75×30mm×3μm table with 34-74% B (A = water (0.225% FA), B = acetonitrile), a flow rate of 25 mL / min, and a 220 nm UV detector to obtain N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-1-cyclopropanecarbonyl-N-methylpiperidine-3-carboxamide [compound 4.2] (2.80 mg, 4.71 μmol, yield 5.0%) as a yellow solid. m / z: [M+H]+ of C27H32ClF3N7O3 calculated value 594.2, measured value 594.4. 1HNMR (400 MHz, DMSO-d6) δ = 8.85 (s, 1H), 8.02 (br s, 1H),7.30 - 7.16 (m, 2H),6.97 (br d, J=8.0 Hz, 2H), 6.44 (br d, J=8.8 Hz, 1H), 5.16(br d, J=6.4 Hz, 1H),4.47 - 4.19 (m, 2H), 3.16 (s, 3H), 2.89 (br s, 3H), 2.70(br d, J=18.8 Hz, 1H), 2.62(br s, 2H), 2.00 (br s, 1H), 1.91 - 1.72 (m, 2H),1.71 - 1.63 (m, 1H), 1.59 (brd, J=6.4 Hz, 3H), 1.24 (br s, 1H), 0.72 (br s,4H). Synthesis of N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-1-cyclopropanecarbonyl-N-methylpyrrolidine-3-carboxamide (compound 4.3) [ka]

[0173] In 3 mL of DCM, a mixture of N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methylpyrrolidine-3-carboxamide hydrochloride [compound 2.3] (150 mg, 273 μmol), EDCI (104 mg, 546 μmol), hydroxybenzotriazole (36.8 mg, 273 μmol), and triethylamine (82.7 mg, 818 μmol) was mixed with cyclopropanecarboxylic acid (70.4 mg, 818 μmol). The mixture was stirred at 25°C for 12 hours. The crude product was purified by preparative HPLC (column: Boston Prime C18 150×30mm×5μm, table: 39~69%B (A=water (0.05v / v% ammonia hydroxide)-ACN), B=acetonitrile), flow rate: 30mL / min, UV detector 220nm) to obtain N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-1-cyclopropanecarbonyl-N-methylpyrrolidine-3-carboxamide [compound 4.3] (14.7 mg, 25.3 μmol, yield 9.3%) as a yellow dry powder. m / z: C26H30ClF3N7O3 [M+H]+ Calculated value 580.2, measured value 580.5. 1 HNMR (400 MHz, CDCl3) δ = 8.92 -8.90 (m, 1H), 7.37 - 7.30 (m, 2H),7.13 (s, 1H), 7.08 - 7.02 (m, 2H), 6.67 -6.55 (m, 1H), 5.48 (q, J=6.8 Hz, 1H), 4.09 -3.53 (m, 4H), 3.49 (s, 3H), 3.45 -3.26 (m, 1H), 3.00 - 2.92 (m, 3H), 2.55 -2.02 (m, 2H), 1.64 (br d, J=5.4 Hz,1H), 1.63 (s, 3H), 1.09 - 0.96 (m, 2H), 0.79(br d, J = 7.6 Hz, 2H). 5. Compounds prepared using Scheme 5 Scheme 5: [ka]

[0174] The starting material G-5a is treated with HO(CH2O)nH(paraformaldehyde) and NaBH3CN to provide the compound of formula (I). Synthesis of N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N,1-dimethylpiperidine-4-carboxamide (compound 5.1) [ka]

[0175] In 3 mL of MeOH, a mixture of N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylpiperidine-4-carboxamide hydrochloride [compound 2.1, HCl salt] (80 mg, 152 μmol), sodium borohydride (14.2 mg, 227 μmol), and triethylamine (30.7 mg, 304 μmol) was stirred at 25°C for 0.5 hours. Paraformaldehyde (22.8 mg, 760 μmol) was added, and the mixture was stirred at 25°C for 12 hours. The crude product was purified by preparative HPLC (column: Phenomenex Gemini-NX 80×40mm×3μm, table: 39~79%B (A=water (0.05v / v% ammonia hydroxide), B=acetonitrile), flow rate: 25mL / min, UV detector 220nm) to obtain N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N,1-dimethylpiperidine-4-carboxamide [compound 5.1] (22.0 mg, 40.7 μmol, yield 26.8%) as a yellow dry powder. m / z: C24H30ClF3N7O2 [M+H]+ Calculated value 540.2, measured value 540.5. 1 HNMR (400MHz, CDCl3) δ = 8.90 (s, 1H), 7.33(br d, J=8.4 Hz, 2H), 7.11(s, 1H), 7.04 (d, J=8.4 Hz, 2H), 6.64 (q, J=9.2 Hz,1H), 5.48 (q, J=6.8 Hz, 1H),3.49 (s, 3H), 3.03 - 2.85 (m, 5H), 2.54 (br s,1H), 2.30 (s, 3H), 2.07 - 1.89(m, 4H), 1.87 - 1.79 (m, 1H), 1.78 - 1.70 (m,1H), 1.62 (s, 3H). Synthesis of N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N,1-dimethylpiperidine-3-carboxamide (compound 5.2) [ka]

[0176] In 1 mL of MeOH, a mixture of N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methylpiperidine-3-carboxamide [compound 2.2] (50 mg, 95.0 μmol) and paraformaldehyde (14.2 mg, 474 μmol) was mixed with triethylamine (19.2 mg, 190 μmol) and sodium borohydride cyanohydride (8.92 mg, 142 μmol). The mixture was stirred under N2 at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was purified by preparative HPLC (column: YMC Triart C18 250×50mm×7μm, table: 11~51%B (A=water (0.225%FA), B=acetonitrile), flow rate: 60 mL / min, UV detector 220 nm) to obtain N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N,1-dimethylpiperidine-3-carboxamide [compound 5.2] (4.70 mg, 8.70 μmol, yield 9.2%) as a yellow dry powder. m / z: C24H30ClF3N7O2 [M+H]+ Calculated value 540.2, measured value 540.3. 1HNMR (400 MHz, DMSO-d6) δ = 8.83 (s, 1H), 8.20 (s, 1H),8.04 - 7.94 (m, 1H), 7.28- 7.12 (m, 2H), 6.97 (br d, J=8.4 Hz, 2H), 6.43 (q,J=9.2 Hz, 1H), 5.15 (q,J=6.8 Hz, 1H), 3.16 (s, 3H), 3.00 - 2.78 (m, 6H), 2.25(s, 3H), 2.19 - 1.91 (m,2H), 1.87 - 1.74 (m, 1H), 1.73 - 1.60 (m, 2H), 1.59(d, J=6.8 Hz, 3H), 1.40 - 1.24 (m, 1H). Synthesis of N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N,1-dimethylpyrrolidine-3-carboxamide hydrochloride (compound 5.3) [ka]

[0177] In 3 mL of MeOH, a mixture of N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methylpyrrolidine-3-carboxamide hydrochloride [compound 2.3] (150 mg, 273 μmol), sodium borohydride (25.7 mg, 409 μmol), and triethylamine (55.2 mg, 546 μmol) was stirred at 25°C for 0.5 hours. Next, paraformaldehyde (40.8 mg, 1.36 mmol) was added, and the reaction mixture was stirred at 25°C for 12 hours. The crude product was subjected to preparative HPLC (column: Boston Green ODS). (150 x 30 mm x 5 μm, Table: 16-56%B (A = Water (0.05% HCl)-ACN), B = Acetonitrile), Flow rate: 30 mL / min, UV detector 220 nm) The compound was purified to obtain N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N,1-dimethylpyrrolidine-3-carboxamide hydrochloride [compound 5.3] (14.3 mg, 25.4 μmol, yield 9.3%) as a yellow dry powder. m / z: C23H28ClF3N7O2 [M+H]+ calculated value 526.2, measured value 526.3. 1 HNMR (400MHz, CDCl3) δ = 12.84 (brs, 1H), 8.91 (s, 1H), 7.33 - 7.28(m, 2H), 7.15 (br d, J=3.6 Hz, 1H), 7.05 (brd, J=8.4 Hz, 2H), 6.58 - 6.43 (m,1H), 5.48 (q, J=6.8 Hz, 1H), 4.04 - 3.87 (m,1H), 3.80 (br s, 2H), 3.49 (s, 3H), 3.48 - 3.36 (m, 1H), 3.04 (br s, 1H), 3.00- 2.96 (m,3H), 2.94 (s, 3H), 2.71 (br d, J=17.2 Hz, 1H), 2.11 (br s, 1H), 1.60(s, 3H). 6. Compounds prepared using Scheme 6 Scheme 6: [ka] Synthesis of (1r,4S)-N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-4-hydroxy-N-methylcyclohexane-1-carboxamide (compound 6.1)

[0178] A solution of (1r,4S)-4-((tert-butyldimethylsilyl)oxy)-N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylcyclohexane-1-carboxamide [INT18.1] (100 mg, 152 μmol) was stirred in TFA (0.5 mL) and CH2Cl2 (0.5 mL) at 20°C for 0.5 hours. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Boston Green ODS 150×30mm×5μm, table: 23~63%B (A=water (0.05%HCl), B=acetonitrile), flow rate: 30mL / min, UV detector 220nm) to obtain (1r,4S)-N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-4-hydroxy-N-methylcyclohexane-1-carboxamide [compound 6.1] (6.50 mg, 12.0 μmol, yield 7.9%) as a yellow dry powder. m / z: C24H29ClF3N6O3 [M+H]+ Calculated value 541.2, measured value 541.3. 1 HNMR (400 MHz, CDCl3) δ = 9.05 (s, 1H), 7.47 (br d,J=8.0 Hz, 2H),7.43 (s, 1H), 7.20 (br d, J=8.4 Hz, 2H), 6.78 (q, J=8.8 Hz, 1H),5.64 (q, J=6.4Hz, 1H), 3.93 - 3.81 (m, 1H), 3.65 (s, 3H), 3.08 (s, 3H), 2.78 -2.64 (m, 1H), 2.27 (br dd, J=3.6, 8.4 Hz, 2H), 2.13 - 2.05 (m, 1H),2.03 - 1.96(m, 1H), 1.91 - 1.85 (m, 2H), 1.77 (d, J=6.8 Hz, 3H), 1.57 - 1.42(m, 2H). 7. Compounds prepared using Scheme 7 Scheme 7: [ka]

[0179] The starting material G-7a is treated with a hydrolyzing agent to provide the compound of formula (I). Synthesis of (1S,4r)-4-(((S)-1-(4((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexane-1-carboxylic acid (compound 7.1) [ka]

[0180] A mixture of methyl(1S,4r)-4-(((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexane-1-carboxylate [compound 1.4] (100 mg, 171 μmol) was added to THF (2 mL) and H2O (1 mL), and the mixture was stirred at 70°C for 6 hours. Water (10 mL) was added, and the mixture was extracted with SiO (10 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by preparative HPLC (column: Boston Green ODS 150×30mm×5μm, table: 28~68%B (A=water (0.05v / v%HCl)), B=acetonitrile), flow rate: 30mL / min, UV detector 220nm) and lyophilization to obtain (1S,4r)-4-(((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexane-1-carboxylic acid [compound 7.1] (42.5 mg, 74.6 μmol, yield 43.7%) as a yellow dry powder. m / z: C25H29ClF3N6O4 [M+H]+ Calculated value 569.2, measured value 569.2. 1 HNMR (400 MHz, DMSO-d6) δ = 12.06 (br s, 1H), 8.84 (s,1H), 8.03 - 7.97 (m, 1H), 7.25 - 7.13 (m, 2H), 7.01 - 6.93 (m, 2H), 6.51 - 6.10(m, 1H),5.15 (q, J=6.4 Hz, 1H), 3.16 (s, 3H), 2.90 - 2.68 (m, 3H), 2.49 - 2.38(m, 1H),2.27 - 2.13 (m, 1H), 2.01 - 1.87 (m, 2H), 1.84 - 1.68 (m, 2H), 1.59(d, J=6.8Hz, 3H), 1.49 - 1.29 (m, 4H). Synthesis of (1S,4r)-4-(((S)-1-(4-((2-chloro-7-isopropyl-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexane-1-carboxylate ammonia salt (compound 7.2) [ka]

[0181] A mixture of methyl(1S,4r)-4-(((S)-1-(4-((2-chloro-7-isopropyl-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexane-1-carboxylate [INT18.2] (50 mg, 88.1 μmol) and lithium hydroxide monohydrate (7.38 mg, 176 μmol) was stirred in H2O (2 mL) and THF (2 mL) for 12 hours at 20°C. The mixture was concentrated under reduced pressure to obtain a residue, which was diluted with water (5 mL). The resulting mixture was adjusted to pH=4 with 1N HCl and extracted with SiO2 (5 mL × 2). The combined organic layers were washed with brine (10 mL) and concentrated to obtain a yellow solid. The solid was purified by preparative HPLC (column: Boston Prime C18 150×30mm×5μm, table: 15~45%B (A=water (0.05v / v% ammonia hydroxide), B=acetonitrile), flow rate: 30mL / min, UV detector 220nm) to obtain (1S,4r)-4-(((S)-1-(4-((2-chloro-7-isopropyl-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexane-1-carboxylate ammonia salt [compound 7.2] (2.80 mg, 4.91 μmol, yield 5.6%) as a white dry powder. m / z: [M+H]+ of C25H29ClF3N6O3 calculated value 553.2, measured value 553.1. 1HNMR (400 MHz, DMSO-d6) δ = 8.73 (s, 1H), 8.13 (s, 1H),7.13 (br d, J=8.4 Hz,2H), 6.79 (br d, J=8.8 Hz, 2H), 6.51 - 6.36 (m, 1H), 3.72(td, J=7.2, 14.0 Hz, 1H),2.87 (s, 2H), 2.71 - 2.66 (m, 2H), 2.20 (br s, 1H),1.98 - 1.86 (m, 2H), 1.83 -1.68 (m, 2H), 1.52 - 1.32 (m, 10H). Synthesis of (1S,3r)-3-(((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclobutane-1-carboxylic acid (compound 7.3) [ka]

[0182] Methyl(1S,3r)-3-(((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclobutane-1-carboxylate[INT18.3] (0.136 g, 0.2450 mmol) was dissolved in a mixture of tetrahydrofuran (0.9 mL) and water (0.1 mL). Lithium hydroxide monohydrate (10.2 mg, 245 μmol) was added to the reaction mixture and stirred for 10 hours. The pH of the reaction mixture was adjusted to 7 with dilute aqueous HCl. The solvent is removed by distillation, and the residue is purified by HPLC (see conditions below) to obtain (1S,3r)-3-(((S)-1-(4-((2-chloro-7-((S)-1-methyl (Ciethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclobutane-1-carboxylic acid [Compound 7.3] (5.70 mg, 0.01053 mmol, yield 4.3%) was obtained as a yellow solid. m / z: C23H25ClF3N6O4 [M+H]+ Calculated value 541.2, measured value 541.0. 1 HNMR (400 MHz, CD3CN) δ = 8.81 (s, 1H), 7.32 - 7.20 (m, 2H), 7.09 -7.00 (m, 3H),6.59 - 6.47 (m, 1H), 5.39 - 5.30 (m, 1H), 3.46 - 3.32 (m, 4H),2.97 - 2.84 (m,1H), 2.71 (s, 3H), 2.54 (s, 1H), 2.37 - 2.32 (m, 2H), 2.13 (s,2H), 1.58 - 1.52(m, 3H).

[0183] HPLC conditions, system: Agilent 1260 Infinity II LC connected to Agilent 6120B single quadrupole LC / MS system, column description: Chromatorex SBM 100-5T C18 100Å, LC column 100×19mm, Waters, Sun Fire, stationary phase: C18, solid support: fully porous silica, separation mode: reversed phase, mobile phase A: water, mobile phase B: acetonitrile, flow rate: 30 ml / min, loading pump B: 4 ml / min, gradient conditions: 0%~0%~25%~100% (B) over 0 min~2 min~10 min~11.2 min. 8. Compounds prepared using Scheme 8 Scheme 8: [ka]

[0184] The starting material G-8a is treated with an amine-containing compound to produce the compound of formula (I). G8 and R G8’ It is either H or Me. Synthesis of (1r,4S)-N1-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N1-methylcyclohexane-1,4-dicarboxamide (compound 8.1) [ka]

[0185] In 1 mL of DMF, a mixture of (1S,4r)-4-(((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexane-1-carboxylic acid [compound 7.1] (50 mg, 87.8 μmol) was added, to which HATU (49.8 mg, 131 μmol) and DIEA (33.9 mg, 263 μmol) were added, and the mixture was stirred at 25°C for 0.5 hours. Next, NH4Cl (9.36 mg, 175 μmol) was added, and the mixture was stirred at 25°C for 12 hours. The mixture was purified by preparative HPLC (column: YMC Triart C18 250×50mm×7μm, table: 25~65%B (A=water (0.05v / v% ammonia hydroxide)), B=acetonitrile), flow rate: 60mL / min, UV detector 220nm). This yielded (1r,4S)-N1-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N1-methylcyclohexane-1,4-dicarboxamide [compound 8.1] (4.00 mg, 7.04 μmol, yield 8.0%) as a yellow dry powder. m / z: [M+H]+ of C25H30ClF3N7O3 calculated value 568.2, measured value 568.1. 1 HNMR (400 MHz, MeOD) δ = 8.87 (s, 1H), 7.29 (d, J=8.4 Hz,2H), 7.06 (d, J=8.8 Hz, 2H), 6.59 - 6.48 (m, 1H), 5.36(q, J=6.8 Hz, 1H), 3.36(s, 3H), 2.96 (s, 3H), 2.79 - 2.74 (m, 1H), 2.35 - 2.23(m, 1H), 1.98 - 1.83(m, 4H), 1.64 (d, J=6.8 Hz, 3H), 1.61 - 1.51 (m, 4H). Synthesis of (1r,4S)-N1-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N1,N4-dimethylcyclohexane-1,4-dicarboxamide (compound 8.2) [ka]

[0186] In 1 mL of DMF, a mixture of (1S,4r)-4-(((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexane-1-carboxylic acid [compound 7.1] (50 mg, 87.8 μmol) was added, to which HATU (49.8 mg, 131 μmol) and DIPEA (51.1 mg, 396 μmol) were added, and the mixture was stirred at 25°C for 0.5 hours. Next, methanamine hydrochloride (8.84 mg, 131 μmol) was added, and the mixture was stirred at 25°C for 12 hours. The mixture was purified by preparative HPLC (column: YMC Triart C18 250×50mm×7μm, table: 26~66%B (A=water (0.05v / v% ammonia hydroxide)), B=acetonitrile), flow rate: 60mL / min, UV detector 220nm) to obtain (1r,4S)-N1-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N1,N4-dimethylcyclohexane-1,4-dicarboxamide [compound 8.2] (19.8 mg, 34.0 μmol, yield 38.7%) as a yellow dry powder. m / z: C26H32ClF3N7O3 [M+H]+ Calculated value 582.2, measured value 582.2. 1 HNMR (400 MHz, CD3OD) δ = 8.87 (s, 1H), 7.38 - 7.25 (m,2H), 7.06 (d, J=8.8 Hz, 2H),6.53 (q, J=8.8 Hz, 1H), 5.36 (q, J=6.8 Hz, 1H),3.36 (s, 3H), 2.96 (s, 3H), 2.82- 2.72 (m, 1H), 2.70 (s, 3H), 2.29 - 2.17 (m, 1H), 1.96 - 1.78 (m, 4H), 1.64 (d,J=6.8 Hz, 3H), 1.62 - 1.51 (m, 4H). Synthesis of (1r,4S)-N1-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N1,N4,N4-trimethylcyclohexane-1,4-dicarboxamide (compound 8.3) [ka]

[0187] In 1 mL of DMF, a mixture of (1S,4r)-4-(((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexane-1-carboxylic acid [compound 7.1] (50 mg, 87.8 μmol) was added, to which HATU (49.8 mg, 131 μmol) and DIPEA (51.1 mg, 396 μmol) were added, and the mixture was stirred at 25°C for 0.5 hours. Next, dimethylamine hydrochloride (10.6 mg, 131 μmol) was added, and the mixture was stirred at 25°C for 12 hours. The mixture was purified by preparative HPLC (column: YMC Triart C18 250×50mm×7μm, table: 30~70%B (A=water (0.05v / v% ammonia hydroxide)), B=acetonitrile), flow rate: 60mL / min, UV detector 220nm) to obtain (1r,4S)-N1-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N1,N4,N4-trimethylcyclohexane-1,4-dicarboxamide [compound 8.3] (12.4 mg, 20.8 μmol, yield 23.7%) as a yellow dry powder. m / z: C27H34ClF3N7O3 [M+H]+ Calculated value 596.2, measured value 596.2. 1 HNMR (400 MHz, CD3OD) δ = 8.87 (s, 1H), 7.40 - 7.25 (m,2H), 7.13 - 7.01(m, 2H), 6.53 (q, J=8.8 Hz, 1H), 5.36 (q, J=6.8 Hz, 1H), 3.36(s, 3H), 3.12 (s,3H), 2.98 - 2.95 (m, 3H), 2.93 (s, 3H), 2.82 - 2.73 (m, 2H),1.97 - 1.80 (m,4H), 1.64 (d, J=6.8 Hz, 3H), 1.63 - 1.51 (m, 4H). 9. Compounds prepared using Scheme 9 Scheme 9: [ka] Synthesis of (1r,3S)-N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyl-3-(1H-tetrazole-5-yl)cyclobutane-1-carboxamide (compound 9.1)

[0188] (1r,3S)-N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-3-cyano-N-methylcyclobutan-1-carboxamide [compound 1.9] (0.03 g, 0.0575 mmol) was dissolved in benzene (2 mL). Trimethylsilyl azide (26.3 mg, 229 μmol) and dibutyltin oxide (28.3 mg, 114 μmol) were added. The mixture was stirred at 50°C for 10 hours. HCl (10 mL) and H2O (5 mL) were added, and the organic phase was evaporated in vacuum at 45°C. The residue was subjected to HPLC (see conditions below). Purified by (a method), (1r,3S)-N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyl-3-(1H-tetrazole-5-yl)cyclobutan-1-carboxamide [compound 9.1] (16.3 mg, 0.029 mmol, yield 50.3%) was obtained as a yellow solid. m / z: C23H25ClF3N10O2 [M+H]+ calculated value 565.2, measured value 565.0. 1 HNMR (400 MHz, CD3OD) δ = 8.90 - 8.88 (m, 1H), 7.36 -7.32 (m, 2H),7.10 - 7.05 (m, 2H), 6.60 - 6.51 (m, 1H), 5.37 (q, J=6.6 Hz, 1H),3.92 - 3.70(m, 2H), 3.37 (s, 3H), 2.91 - 2.79 (m, 4H), 2.73 - 2.59 (m, 3H),1.67 - 1.63 (m,3H).

[0189] HPLC conditions, system: Agilent 1260 Infinity II LC connected to Agilent 6120B single quadrupole LC / MS system, column: Chromatorex SBM 100-5T 5μm C18(2) 100Å, LC column 100×19mm, Waters, Sun Fire, stationary phase: C18, solid support: fully porous silica, separation mode: reversed phase, mobile phase A: water, mobile phase B: acetonitrile, flow rate: 30 ml / min, loading pump: 4 ml / min B, gradient conditions: 20%~30%~70%~100% (B) over 0 min~2 min~10 min~11.2 min. 10. Separation and isolation of compound 1.1 and N-((S)-1-(4-((2-chloro-7-((R)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide (compound 10.1) Scheme 10: [ka]

[0190] N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide [compound 1.1] was subjected to chiral SFC (column: DAIEL CHIRALPAK AD 250mm×50mm, 10μm, table: 30~30% 0.1% NH3H2O) Further purification by ETOH (flow rate: 200 mL / min, UV detector 220 nm) allows for the separation and isolation of [Compound 1.1] (>98% chiral purity) and N-((S)-1-(4-((2-chloro-7-((R)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide [Compound 10.1] (>98% chiral purity). For Compound 10.1, the m / z [M+H]+ of C23H27ClF3N6O4S is calculated at 575.1 and measured at 575.0. 1 HNMR (400 MHz, DMSO) δ = 8.83 (s, 1H), 7.99 (s, 1H),7.19 (d, J=8.0 Hz, 2H), 6.97(d, J=8.0 Hz, 2H), 6.43 (q, J=8.0 Hz, 1H), 5.15(q, J=8.0 Hz, 1H), 3.26 - 3.05(m, 8H), 2.90 (s, 3H), 2.14 - 1.93 (m, 4H), 1.59(d, J=8.0 Hz, 3H). 11. Compound 3.1 and 1-acetyl-N-((S)-1-(4-((2-chloro-7-((R)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyl Isolation and isolation of piperidine-4-carboxamide (compound 11.1) Scheme 11: [ka]

[0191] 1-Acetyl-N-((1S)-1-(4-((2-chloro-7-(1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylpiperidine-4-carboxamide [Compound 3.1] was subjected to chiral SFC (column: DAIEL CHIRALPAK). Further purification by IG (250mm x 50mm, 10um), table: 50-50%B (A = water (0.1% ammonia hydroxide), B = MeOH), flow rate: 200 mL / min) allows for the separation and isolation of compound 3.1 (100% chiral purity) and 1-acetyl-N-((S)-1-(4-((2-chloro-7-((R)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylpiperidine-4-carboxamide [compound 11.1] (97% chiral purity). For compound 11.1, the m / z [M+H]+ of C25H30ClF3N7O3 is calculated at 568.2 and measured at 568.1. 1 HNMR (400MHz, CDCl3) δ = 8.90 (s, 1H), 7.35 - 7.29 (m,2H), 7.11 (s,1H), 7.04 (d, J=8.8 Hz, 2H), 6.62 (q, J=8.8 Hz, 1H), 5.48 (q,J=6.8 Hz, 1H),4.69 - 4.55 (m, 1H), 3.99 - 3.87 (m, 1H), 3.49 (s, 3H), 3.22 -3.08 (m, 1H),2.95 (s, 3H), 2.88 - 2.66 (m, 2H), 2.12 (s, 3H), 1.96 - 1.70 (m,4H), 1.63 -1.61 (m, 3H). 12. Synthesis of intermediates

[0192] The following intermediates were synthesized and used for the synthesis of the exemplified compounds. Synthesis of 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine hydrochloride (intermediate 1.1): [ka] Synthesis of tert-butyl(S)-4-methoxy-3-oxopentanoate (INT1-b):

[0193] A solution of (S)-2-methoxypropanoic acid [INT1-a] (20 g, 192 mmol) in anhydrous tetrahydrofuran (342 mL) was cooled to 0°C. Carbonyl diimidazole (30.6 g, 189 mmol) was added in several portions at 0°C, and the mixture was stirred at this temperature for 1.25 hours. In a separate flask, magnesium (1+)1-methylethyl chloride (249 mL, 499 mmol, 2 M in THF) was added at 0°C to a solution of 3-(tert-butoxy)-3-oxopropanoic acid (46.1 g, 288 mmol) in anhydrous tetrahydrofuran (342 mL), and the mixture was stirred at room temperature for 1.25 hours. Next, this solution was added to the acylimidazole solution at 0°C via a cannula, and the resulting mixture was stirred overnight at room temperature. The reaction mixture was cooled to 0°C, quenched by adding a 10% aqueous citric acid solution, extracted with toluene, washed with saturated aqueous NaHCO3 solution, dried over anhydrous Na2SO4, concentrated under reduced pressure to obtain the crude product, which was purified by silica gel flash chromatography (acetone / hexane = 0 / 1 to 1 / 9) to obtain tert-butyl(S)-4-methoxy-3-oxopentanoate [INT1-b] (30.0 g, 148 mmol, 55.6%) as an oily substance. Synthesis of tert-butyl(S)-2-amino-7-(1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylate(INT1-c):

[0194] A solution of tert-butyl(S)-4-methoxy-3-oxopentanoate [INT1-b] (25 g, 123 mmol) and (dimethoxymethyl)dimethylamine (11.1 mL, 83.6 mmol) was heated at 120°C for 1.5 hours. The mixture was cooled to room temperature, 4H-1,2,4-triazole-3,5-diamine (12.1 g, 123 mmol) was added, followed by the addition of ethanol (123 mL), and the mixture was heated at 85°C for 1 hour. After completion, the mixture was concentrated under reduced pressure, recrystallized from EtOH / water (1:1, 600 mL), filtered, the filtered cake was washed with 30% EtOH / water, and then washed with MTBE to obtain tert-butyl 2-amino-7-(1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylate (12.7 g, 43.2 mmol, 52%) as a solid. The filtrate was concentrated under reduced pressure to remove MTBE, the solid was filtered, and washed with hexane to obtain a further tert-butyl(S)-2-amino-7-(1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylate [INT1-c] (5.3 g, 18.0 mmol, 23%) as a solid. Total 18.0 g, yield 75%. Chiral HPLC showed 96.9% ee. 1 HNMR (400 MHz, CDCl3) δ = 8.75 (s, 1H), 5.40 (q, J=6.8Hz, 1H), 4.95(br s, 2H), 3.30 (s, 3H), 1.75 (d, J=6.8 Hz, 3H), 1.62 (s, 9H). Synthesis of 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid (INT1-d):

[0195] To a mixture of tert-butyl 2-amino-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylate[INT1-c] (1.2 g, 4.09 mmol) and copper(II) chloride dihydrate (173 mg, 1.02 mmol) in concentrated HCl (20 mL), a solution of sodium nitrite (338 mg, 4.90 mmol) in H2O (5 mL) was added at 5°C using an ice bath, and the mixture was stirred at 5°C for 30 minutes. Next, the mixture was heated to 25°C and stirred for 16 hours. Water (100 mL) was added, and then 1N NaOH aqueous solution was added to adjust the pH to 3-4. The mixture was extracted with CHCl3:i-PrOH=3:1 (100 mL x 3), and the combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid[INT1-d] (962 mg, yield 92.4%) as a solid. m / z: [M+H]+ of C9H10ClN4O3: calculated value 257.0, measured value 256.9. 1 HNMR (400 MHz, DMSO-d6) δ = 14.00 (br s, 1H), 9.07 (s,1H), 5.39 (q,J=6.4 Hz, 1H), 3.21 (s, 3H), 1. 63 (d, J=6.4 Hz, 3H). Synthesis of tert-butyl N-{2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}carbamate (INT1-e):

[0196] To a solution of 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid [INT1-d] (1.3 g, 5.06 mmol) in t-BuOH (10 mL), {[azido(phenoxy)phosphoryl]oxy}benzene (2.08 g, 7.58 mmol) and triethylamine (1.02 g, 10.1 mmol) were added, and the mixture was stirred at 100°C for 2 hours under an N2 atmosphere. The mixture was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel flash chromatography (siRNA / petroleum ether = 1 / 10 to 1 / 5) to obtain tert-butyl N-{2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}carbamate [INT1-e] (420 mg, yield 25.4%) as a solid. m / z: C13H19ClN5O3 [M+H]+ calculated value 328.1, measured value 328.0. 1 HNMR (400 MHz, CDCl3) δ = 9.62 (br s, 1H), 8.05 (s, 1H),5.45 (q, J=6.8 Hz, 1H),3.48 (s, 3H), 1.63 (d, J=6.8 Hz, 3H), 1.56 (s, 9H). Synthesis of 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine hydrochloride (INT1.1):

[0197] A mixture of tert-butyl N-{2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl}carbamate [INT1-e] (420 mg, 1.28 mmol) was stirred in 4N HCl / dioxane (5 mL) at 25°C for 2 hours. LC-MS indicated that the reaction was complete, and one new peak with the desired MS was detected (Rt = 0.611 min, m / z: 227.8 [M + H]+). The mixture was concentrated under reduced pressure to obtain 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine hydrochloride [INT1.1] (400 mg, crude) as a solid. Synthesis of 2-chloro-7-isopropyl-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine hydrochloride (intermediate 1.2): [ka] Synthesis of methyl 2-amino-7-isopropyl-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylate (INT1-g):

[0198] A mixture of methyl 4-methyl-3-oxopentanoate [INT1-f] (23.2 g, 160 mmol) and DMF-DMA (19.0 g, 160 mmol) was subjected to an N2 atmosphere. The mixture was stirred at 120°C for 2 hours under gas. Next, a mixture of 1H-1,2,4-triazole-3,5-diamine (15.8 g, 160 mmol) was added to EtOH (30 mL), and the mixture was stirred at 85°C for 2 hours. The mixture was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel flash chromatography (siRNA / petroleum ether = 1 / 10 to 3 / 2) to obtain methyl 2-amino-7-isopropyl-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylate [INT1-g] (20.6 g, 87.7 mmol, yield 54.7%) as an off-white solid. m / z: [M+H]+ of C10H14N5O2, calculated value 236.1, measured value 236.2. 1 HNMR (400 MHz, CDCl3) δ = 8.88 (s, 1H), 4.93 (br s, 2H),4.48 - 4.39(m, 1H), 3.89 (s, 3H), 1.49 (s, 3H), 1.47 (s, 3H). Synthesis of methyl 2-chloro-7-isopropyl-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylate (INT1-h):

[0199] A mixture of methyl 2-amino-7-isopropyl-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylate [INT1-g] (10.17 g, 34.5 mmol) and copper(II) chloride dihydrate (1.46 g, 8.62 mmol) was added to a solution of sodium nitrite (2.85 g, 41.4 mmol) in H2O (5 mL) at 5°C. The mixture was stirred at 5°C (cooled in an ice bath) for 30 minutes. Next, the mixture was heated to 25°C and stirred for 12 hours. The pH was adjusted to 7 by adding 2N NaOH aqueous solution, and the mixture was extracted with ELISA (200 mL x 2). The combined organic layers were washed with brine (200 mL x 3), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. This crude product was purified by silica gel flash chromatography (siRNA / petroleum ether = 0 / 1 to 1 / 1) to obtain methyl 2-chloro-7-isopropyl-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylate[INT1-h] (3.00 g, 11.7 mmol, yield 34.1%) as a yellow solid. m / z: [M+H]+ of C10H12ClN4O2, calculated value 255.1, measured value 255.0. 1 H NMR (400 MHz, CDCl3) δ = 9.16 (d, J=1.2 Hz, 1H), 4.60 -4.44 (m, 1H),4.03 (d, J = 0.4 Hz, 3H), 1.61 (dd, J = 1.2, 7.2 Hz, 6H). Synthesis of 2-chloro-7-isopropyl-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid (INT1-i):

[0200] To a mixture of methyl 2-chloro-7-isopropyl-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylate[INT1-h] (1 g, 3.92 mmol) in THF (10 mL), lithium(1+) hydroxide hydrate (2 M in H2O, 2.94 mL, 5.88 mmol) was added, and the mixture was stirred at 25°C for 3 hours. The THF was removed under reduced pressure, and water (10 mL) was added. 1N HCl was added to adjust the pH to 3-4, and the mixture was filtered. The filtered cake was washed with water (20 mL x 2), collected, and concentrated under reduced pressure to obtain a solid. The solid was purified by preparative HPLC (column: Boston Green ODS 150×30mm×5μm, table: 8~48%B (A=water (0.05%HCl), B=acetonitrile), flow rate: 30mL / min, UV detector 220nm) to obtain 2-chloro-7-isopropyl-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid [INT1-i] (300 mg, 1.24 mmol, yield 31.8%) as a white dry powder. m / z: [M+H]+ of C9H10ClN4O2, calculated value 241.1, measured value 241.0. 1 HNMR (400 MHz, DMSO-d6) δ = 14.14 (br s, 1H), 9.14 (s,1H), 4.48 (spt, J = 6.8Hz, 1H), 1.51 (s, 3H), 1.49 (s, 3H). Synthesis of tert-butyl(2-chloro-7-isopropyl-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)carbamate (INT1-j):

[0201] In toluene (5 mL), 2-chloro-7-isopropyl-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid [INT1-i] (150 mg, 623 μmol) To the solution of (1), diphenyl phosphoryl azide (257 mg, 934 μmol), t-BuOH (2 mL), and potassium tert-butoxide (208 mg, 1.86 mmol) were added. The reaction mixture was stirred at 100°C for 16 hours under N2. The mixture was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel flash chromatography (0-50% ethyl acetate in PE) to obtain tert-butyl (2-chloro-7-isopropyl-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)carbamate [INT1-j] (80.0 mg, 256 μmol, yield 41.2%) as a yellow solid. m / z: [M+H]+ of C13H19ClN5O2, calculated value 312.1, measured value 312.1. Synthesis of 2-chloro-7-isopropyl-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine hydrochloride (INT1.2):

[0202] A solution of tert-butyl(2-chloro-7-isopropyl-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)carbamate [INT1-j] (80 mg, 256 μmol) in 4 M HCl / dioxane (10 mL) was stirred at 15°C for 16 hours. The reaction product was concentrated under reduced pressure to obtain 2-chloro-7-isopropyl-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine hydrochloride [INT1.2] (63.0 mg, 253 μmol, yield 99.2%) as a white solid. m / z: C8H11ClN5 [M+H]+ calculated value 212.1, measured value 211.7. Synthesis of (R)-2-chloro-7-(1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine hydrochloride (intermediate 1.3): [ka]

[0203] (R)-2-chloro-7-(1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine [INT1.3] can be prepared using (2R)-2-methoxypropanoic acid as a starting material by the same synthetic route outlined for INT1.1. m / z: [M+H]+ of C8H11ClN5O: calculated 228.1, experimental 228.1. Synthesis of (R)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide (intermediate 2.1): [ka] Synthesis of (R,E)-N-(4-bromobenzylidene)-2-methylpropane-2-sulfinamide (INT2-b):

[0204] To a solution of 4-bromobenzaldehyde [INT2-a] (100 g, 541 mmol, 1.0 equivalent) in toluene (500 mL), (R)-2-methylpropane-2-sulfinamide (72.1 g, 595 mmol, 1.1 equivalent) was added at 25°C. The mixture was stirred at 25°C for 15 minutes. Next, NaOH (21.6 g, 541 mmol, 1.0 equivalent) was added to the reaction mixture, and the mixture was stirred at 25°C for 12 hours. Na2SO4 (50 g) The mixture was mixed with the added ) and stirred for 20 minutes. The four reaction mixtures were combined and filtered through Celite to obtain the filtrate, which was concentrated under vacuum to obtain the crude product as an oil. The crude product was dissolved in petroleum ether (1.0 L), stirred at -50°C for 1.0 hour, and filtered to obtain (R,E)-N-(4-bromobenzylidene)-2-methylpropane-2-sulfinamide [INT2-b] (620 g, 2.15 mol, yield 99.5%) as a solid. Synthesis of (R)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide (INT2.1):

[0205] In 1.4 L of DMF, a solution of (R,E)-N-(4-bromobenzylidene)-2-methylpropane-2-sulfinamide [INT2-b] (206 g, 715 mmol, 1.0 equivalent) and tetrabutylammonium acetate (216 g, 715 mmol, 218 mL, 1.0 equivalent) was prepared, to which TMSCF3 (259 g, 1.82 mol, 2.5 equivalents) was added at 0°C. The mixture was stirred at 5°C for 1.5 hours. This process was repeated twice, and the three reaction mixtures were combined for workup. The mixture was poured into a saturated NH4Cl solution (13.0 L) and stirred for 10 minutes to obtain a suspension. The suspension was filtered to obtain a filter cake, which was eluted with water (5.0 L). The filtered cake was ground with MTBE / petroleum ether (v / v=1:4, 2.0 L) to obtain the product as a solid, the mother liquor was concentrated under vacuum to obtain the crude product as an oily substance, and this was purified by silica gel column chromatography using petroleum ether / ethyl acetate (10 / 1~1 / 1) to obtain (R)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide [INT2.1] (389 g, 1.09 mol, yield 50.6%) as a solid. 1 HNMR (400 MHz, CDCl3) δ = 1.25 (s, 9H), 3.64 (d, J =6.40 Hz, 1H),4.79-4.83 (m, 1H), 7.32 (d, J = 8.40 Hz, 2H), 7.56 (d, J = 6.40Hz, 2H). Synthesis of (S)-1-(4-bromophenyl)-2,2,2-trifluoro-N-methylethane-1-amine hydrochloride (intermediate 3.1): [ka] Synthesis of (R)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N,2-dimethylpropane-2-sulfinamide [INT3-b]:

[0206] To a solution of LiHMDS (1.0 M, 838 mL, 3.0 equivalents), (R)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide [INT2.1] (100 g, 279 mmol, 1.0 equivalent) was added at 0-10°C and the mixture was stirred at 0-10°C for 0.5 hours. To the above mixture, MeI (119 g, 838 mmol, 52.1 mL, 3.0 equivalents) was added at 0-10°C and the mixture was stirred at 25°C for 1 hour. This process was repeated twice, and the three combined reaction mixtures were poured into saturated NH4Cl (3.0 L) and diluted with HCl (1.0 L). The mixture was separated to obtain the organic layer, and the aqueous layer was extracted with HCl (500 mL). The combined organic layers were washed with saturated NaCl (1.0 L), dried over Na2SO4, filtered, and concentrated under vacuum to obtain the crude product as an oil. The crude product was purified by silica gel column chromatography using petroleum ether / ethyl acetate (15 / 1~1 / 1) to obtain (R)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N,2-dimethylpropane-2-sulfinamide [INT3-b] (161 g, 432.5 mmol, yield 51.6%) as an oil. (S)-1-(4-bromophenyl)-2,2,2-trifluoro-N-methylethane Synthesis of -1-amine hydrochloride [INT3.1]:

[0207] To a mixture of (R)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N,2-dimethylpropane-2-sulfinamide [INT3-b] (202 g, 543 mmol, 1.0 equivalent) in HCl / siRNA (4.0 M, 2.02 L, 14.9 equivalents) was slowly added. The mixture was stirred at 20°C for 1 hour. The reaction mixture was filtered to obtain a solid, which was eluted with siRNA (200 mL), and the mother liquor was concentrated under vacuum to obtain a solid. The solid was purified by silica gel column chromatography using petroleum ether / ethyl acetate (10 / 1 to 1 / 0), and combined with the filtration cake. The mixture was concentrated at 45°C for 1 hour using an oil pump to remove solvent residue, yielding (S)-1-(4-bromophenyl)-2,2,2-trifluoro-N-methylethane-1-amine hydrochloride [INT3.1] (115 g, 378 mmol, yield 69.6%, purity 100%, HCl) as a solid. 1 HNMR (400 MHz, DMSO-d6) δ = 2.45 (s, 3H), 5.51 (s, 1H),7.62 (d, J =8.4 Hz, 2H), 7.78 (d, J = 8.40 Hz, 2H), 10.59 (s, 2H).

[0208] SFC: Rt=0.776 min, 99.98% ee, Column: Chiralpak AD-3, 100×4.6 mm, ID, 3 μm, Mobile phase: A: CO2, B: MeOH (0.05% IPA), Gradient: A:B=97:3, Flow rate: 3 mL / min, Column temperature: 35°C.

[0209] LC-MS: Rt = 1.755 min, purity 100.0%, m / z = 268.0, 270.0 (M+1)+. The gradient was 5% B at 0.40 min, 5-95% B from 0.4 to 3.0 min, retained at 95% B for 1.00 min, then 95-5% B at 0.01 min, with a flow rate of 1.0 mL / min. Mobile phase A was 0.037% trifluoroacetic acid in water, and mobile phase B was 0.018% trifluoroacetic acid in acetonitrile. The column used for chromatography was a Kinetex C18 50 × 2.1 mm column (5 μm particles). Detection methods were diode array (DAD) and cation electrospray ionization. The MS range was 100 to 1000. Synthesis of tetrahydro-2H-thiopyran-4-carbonyl chloride 1,1-dioxide (intermediate 4.1): [ka]

[0210] In 410 mL of DCM, a solution of tetrahydro-2H-thiopyran-4-carboxylic acid 1,1-dioxide [INT4-a] (41.0 g, 230 mmol, 1.0 equivalent) was added to (COCl)2 (58.4 g, 460 mmol, 40.3 mL, 2.0 equivalents) and DMF (168 mg, 2.30 mmol, 177 μL, 0.01 equivalents) under N2 conditions at 0°C. The mixture was heated to 20°C and stirred at 20°C for 2 hours. The suspension became clear, indicating that most of the starting material had been consumed. The reaction mixture was concentrated under vacuum to obtain the crude product as a solid, which was then concentrated using an oil pump to remove solvent residue and obtain tetrahydro-2H-thiopyran-4-carbonyl chloride 1,1-dioxide [INT4.1] (46.5 g, crude) as a solid. Synthesis of tetrahydro-2H-pyran-2-carbonyl chloride (intermediate 4.2): [ka]

[0211] To a mixture of tetrahydro-2H-pyran-2-carboxylic acid [INT4-b] (330 mg, 2.53 mmol) in dichloromethane (4 mL), oxalyl dichloride (478 mg, 3.79 mmol) and DMF (18.4 mg, 252 μmol) were slowly added, and the mixture was stirred at 40°C for 2 hours. The mixture was concentrated under reduced pressure to obtain tetrahydro-2H-pyran-2-carbonyl chloride [INT4.2] (370 mg, 2.49 mmol, yield 98.6%) as a yellow gum-like substance. Synthesis of methyl(1r,4r)-4-(chlorocarbonyl)cyclohexane-1-carboxylate (intermediate 4.3): [ka]

[0212] To a mixture of (1r,4r)-4-(methoxycarbonyl)cyclohexane-1-carboxylic acid [INT4-c] (1.45 g, 7.78 mmol) in dichloromethane (10 mL), oxalyl dichloride (2.93 g, 23.3 mmol) and DMF (56.8 mg, 778 μmol) were slowly added, and the mixture was stirred at 40°C for 2 hours. The mixture was concentrated under reduced pressure to obtain crude methyl (1r,4r)-4-(chlorocarbonyl)cyclohexane-1-carboxylate [INT4.3] (1.59 g, 7.76 mmol) as a yellow gum-like substance. Synthesis of thian-4-carbonyl chloride (intermediate 4.4): [ka]

[0213] To a mixture of thian-4-carboxylic acid [INT4-d] (370 mg, 2.53 mmol) in dichloromethane (2 mL), oxalyl dichloride (478 mg, 3.79 mmol) and DMF (18.4 mg, 252 μmol) were slowly added. The mixture was stirred at 40°C for 2 hours. The mixture was concentrated under reduced pressure to obtain crude thian-4-carbonyl chloride [INT4.4] (415 mg, 2.52 mmol) as a yellow gum-like substance. Synthesis of oxolane-3-carbonyl chloride (intermediate 4.5): [ka]

[0214] In 10 mL of CH2Cl2, a mixture of oxolane-3-carboxylic acid [INT4-e] (1 g, 8.61 mmol) was prepared by adding dichloride oxalate (2.18 g, 17.2 mmol) and N,N-dimethylformamide (62.9 mg, 861 μmol). The reaction mixture was stirred at 25°C for 1.5 hours. The reaction mixture was concentrated to obtain oxolane-3-carbonyl chloride [INT4.5] (1.10 g, 8.17 mmol) as a yellow oily substance. Synthesis of 1,4-dioxaspiro[4.5]decane-8-carbonyl chloride (intermediate 4.6): [ka]

[0215] To a mixture of 1,4-dioxaspiro[4.5]decane-8-carboxylic acid [INT4-f] (560 mg, 3.00 mmol) in dichloromethane (2 mL), oxalyl dichloride (567 mg, 4.50 mmol) and DMF (21.9 mg, 300 μmol) were slowly added, and the mixture was stirred at 40°C for 2 hours. The mixture was concentrated under reduced pressure to obtain crude 1,4-dioxaspiro[4.5]decane-8-carbonyl chloride [INT4.6] (610 mg, 2.98 mmol) as a yellow gum-like substance. Synthesis of 4,4-difluorocyclohexane-1-carbonyl chloride (intermediate 4.7): [ka]

[0216] To a mixture of 4,4-difluorocyclohexane-1-carboxylic acid [INT4-g] (1 g, 6.09 mmol) in dichloromethane (15 mL), oxalyl dichloride (2.29 g, 18.2 mmol) and DMF (44.5 mg, 609 μmol) were slowly added, and the mixture was stirred at 40°C for 2 hours. The mixture was concentrated under reduced pressure to obtain crude 4,4-difluorocyclohexane-1-carbonyl chloride [INT4.7] (1.11 g, 6.07 mmol) as a yellow gum-like substance. Synthesis of 1-acetylazetidine-3-carbonyl chloride (intermediate 4.8): [ka]

[0217] In a solution of 1-acetylazetidine-3-carboxylic acid [INT4-h] (300 mg, 2.09 mmol) in DCM (4 mL), oxalyl chloride (397 mg, 3.13 mmol) was added at 0°C. The mixture was stirred at 20°C for 1.5 hours. The reaction product was concentrated under reduced pressure to obtain 1-acetylazetidine-3-carbonyl chloride [INT4.8] (337 mg, 2.08 mmol). Synthesis of 1-acetylpiperidine-4-carbonyl chloride (intermediate 4.9): [ka]

[0218] To a mixture of 1-acetylpiperidine-4-carboxylic acid [INT4-i] (1 g, 5.84 mmol) in dichloromethane (10 mL), oxalyl dichloride (2.20 g, 17.5 mmol) and DMF (42.6 mg, 584 μmol) were slowly added, and the mixture was stirred at 40°C for 2 hours. The mixture was concentrated under reduced pressure to obtain crude 1-acetylpiperidine-4-carbonyl chloride [INT4.9] (1.10 g, 5.80 mmol) as a green oil. Synthesis of methyl(1r,3r)-3-(carbonochloridoyl)cyclobutane-1-carboxylate (intermediate 4.10): [ka]

[0219] To a mixture of (1r,3r)-3-(methoxycarbonyl)cyclobutane-1-carboxylic acid [INT4-j] (100 mg, 632 μmol) in CH2Cl2 (2 mL), one drop of DMF and dichloride oxalate (239 mg, 1.89 mmol) were added at 20°C. The mixture was stirred at 20°C for 1 hour. The reaction product was concentrated under reduced pressure to obtain crude methyl (1r,3r)-3-(carbonochloridoyl)cyclobutane-1-carboxylate [INT4.10] (111 mg, 628 μmol) as a pale yellow oil. Synthesis of (S)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide (intermediate 5.1): [ka]

[0220] In 200 mL of DCM, a solution of (S)-1-(4-bromophenyl)-2,2,2-trifluoro-N-methylethane-1-amine hydrochloride [INT3.1] (39.0 g, 128 mmol, 1.0 equivalent, HCl) and TEA (45.7 g, 451 mmol, 62.8 mL, 3.5 equivalents) was prepared by adding tetrahydro-2H-thiopyran-4-carbonyl chloride 1,1-dioxide [INT4.1] (45.3 g, 231 mmol, 1.8 equivalents) at 0-10°C. The mixture was stirred at 20°C for 12 hours. The mixture was separated to obtain the organic layer, and the aqueous layer was extracted with 100 mL of DCM. The combined organic layers were concentrated under vacuum to obtain the crude product as an oily substance. The crude product was purified by silica gel column chromatography using petroleum ether / ethyl acetate (15 / 1~3 / 1) to obtain (S)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide [INT5.1]( 26.0 g, 60.7 mmol, yield 47.4%, purity 100%) was obtained as a solid. 1 H NMR (400 MHz, CDCl3) δ 2.25-2.37 (m, 1H), 2.38-2.40 (m,3H), 2.88-3.00 (m, 6H), 3.30-3.31 (m, 1H), 3.22-3.45 (m, 1H), 6.56-6.63 (m,1H), 7.23 (d, J = 8.00 Hz,2H), 7.55 (d, J = 8.40 Hz, 2H).

[0221] SFC: Rt=1.21 min, 100.0%ee, column: Chiralpak AD-3, 50 x 4.6 mm ID, 3 um, mobile phase: A: CO2, B: MeOH (0.05% IPAm, v / v), flow rate: 3.4 mL / min, column temperature: 35 °C.

[0222] LC-MS: Rt = 2.431 min, purity 100%, m / z = 428.0, 430.0 (M+1)+. The gradient was 5% B at 0.40 min, 5-95% B from 0.4 to 3.0 min, retained at 95% B for 1.00 min, then 95-5% B at 0.01 min, with a flow rate of 1.0 ml / min. Mobile phase A was 0.037% trifluoroacetic acid in water, and mobile phase B was 0.018% trifluoroacetic acid in acetonitrile. The column used for chromatography was a Kinetex C18 50 × 2.1 mm column (5 μm particles). Detection methods were diode array (DAD) and cation electrospray ionization. The MS range was 100 to 1000. Synthesis of N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methylacetamide (intermediate 5.2): [ka]

[0223] In 10 mL of dichloromethane, a mixture of [(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)amine [free base of INT3.1] (1 g, 3.73 mmol) and Et3N (754 mg, 7.46 mmol) was mixed with acetyl chloride (396 μL, 5.59 mmol) at 0°C, and the mixture was stirred at 25°C for 16 hours. The mixture was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel flash chromatography (siRNA / petroleum ether = 0 / 1~1 / 5) to obtain N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methylacetamide [INT5.2] (750 mg, 2.41 mmol, yield 64.6%) as a colorless oil. m / z: C11H12BrF3NO [M+H]+ Calculated values ​​310.0, 312.0, Measured values ​​309.8, 311.8. 1 HNMR (400 MHz, CDCl3) δ = 7.54 (d, J=8.4 Hz, 2H), 7.28 -7.25 (m, 2H),6.61 (q, J=8.8 Hz, 1H), 2.85 (s, 3H), 2.21 (s, 3H). Synthesis of N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-pyran-2-carboxamide (intermediate 5.3): [ka]

[0224] In 2 mL of dichloromethane, a mixture of (S)-1-(4-bromophenyl)-2,2,2-trifluoro-N-methylethane-1-amine hydrochloride [INT3.1] (400 mg, 1.31 mmol) and Et3N (662 mg, 6.55 mmol) is added. A solution of tetrahydro-2H-pyran-2-carbonyl chloride [INT4.2] (370 mg, 2.49 mmol) was added to methane (2 mL). The mixture was stirred at 25°C for 16 hours. Water (10 mL) was added, and the mixture was extracted with dichloromethane (10 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel flash chromatography (siRNA / petroleum ether = 1 / 10 to 1 / 5) to obtain N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-pyran-2-carboxamide [INT5.3] (400 mg, 1.05 mmol, yield 80.3%) as a yellow oil. m / z: C15H18BrF3NO2 [M+H]+ Calculated value 380.0, 382.0, Measured value 380.0. Synthesis of methyl(1S,4r)-4-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexane-1-carboxylate (intermediate 5.4): [ka]

[0225] To a mixture of methyl(1r,4r)-4-(carbonochloridoyl)cyclohexane-1-carboxylate [INT4.3] (1.59 g, 7.76 mmol) and Et3N (2.65 g, 26.2 mmol) in 6 mL of dichloromethane, a solution of [(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)amine hydrochloride [INT3.1] (1.6 g, 5.25 mmol) in 6 mL of dichloromethane was added, and the mixture was stirred at 25°C for 16 hours. Water (30 mL) was added, and the mixture was extracted with dichloromethane (30 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. This crude product was purified by silica gel flash chromatography (siRNA / petroleum ether = 1 / 10 to 1 / 5) to obtain methyl (1S,4r)-4-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexane-1-carboxylate [INT5.4] (1.10 g, 2.52 mmol, yield 32.5%) as a yellow oil. m / z: C18H22BrF3NO3 [M+H]+ calculated value 436.1, 438.1, measured value 438.0. Synthesis of N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methylthian-4-carboxamide (intermediate 5.5): [ka]

[0226] A mixture of [(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)amine hydrochloride [INT3.1] (400 mg, 1.31 mmol) and Et3N (662 mg, 6.55 mmol) was added to dichloromethane (2 mL). A solution of thian-4-carbonyl chloride [INT4.4] (415 mg, 2.52 mmol) was added to the mixture, and the mixture was stirred at 25°C for 3 hours. The mixture was then dissolved in silica. Purification by gel flash chromatography (siRNA / petroleum ether = 1 / 10 to 1 / 5) yielded N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methylthian-4-carboxamide [INT5.5] (132 mg, 333 μmol, yield 25.4%) as a colorless oil. m / z: C15H18BrF3NOS [M+H]+ calculated values ​​396.0, 398.0, measured value 397.9. Synthesis of N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methyloxolane-3-carboxamide (intermediate 5.6): [ka]

[0227] In 10 mL of CH2Cl2, a mixture of [(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]methylamine hydrochloride [INT3.1] (1 g, 3.28 mmol) and triethylamine (1.65 g, 16.4 mmol) was mixed with oxolane-3-carbonyl chloride [INT4.5] (662 mg, 4.92 mmol) at 0°C. The reaction mixture was stirred at 25°C for 12 hours. The reaction mixture was concentrated, diluted with water (30 mL), and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous sodium 2SO4, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel flash chromatography (0-15% ethyl ether in petroleum ether) to obtain N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methyloxolane-3-carboxamide [INT5.6] (360 mg, 983 μmol, yield 30.0%) as a yellow oil. m / z: C14H16BrF3NO2 [M+H]+ calculated value 366.0, measured value 365.7. 1HNMR (400MHz, CDCl3) δ = 7.55 (d, J=8.4 Hz, 2H), 7.27 -7.23 (m, 2H),6.62 (q, J=8.8 Hz, 1H), 4.14 - 4.01 (m, 1H), 3.99 - 3.86 (m, 3H),3.38 - 3.28(m, 1H), 2.88 (s, 3H), 2.30 - 2.09 (m, 2H). Synthesis of N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methyl-1,4-dioxaspiro[4.5]decane-8-carboxamide (intermediate 5.7): [ka]

[0228] In 2 mL of dichloromethane, a mixture of [(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)amine hydrochloride [INT3.1] (450 mg, 1.47 mmol) and Et3N (743 mg, 7.35 mmol) was added. A solution of 1,4-dioxaspiro[4.5]decane-8-carbonyl chloride [INT4.6] (430 mg, 2.10 mmol) was added in 2 mL of dichloromethane, and the mixture was stirred at 25°C for 3 hours. 10 mL of water was added, and the mixture was extracted with dichloromethane (10 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel flash chromatography (siRNA / petroleum ether = 1 / 10~1 / 5) to obtain N-[(1S)-1-(4-bromophenyl] [(enyl)-2,2,2-trifluoroethyl]-N-methyl-1,4-dioxaspiro[4.5]decane-8-carboxamide[INT5.7] (210 mg, 481 μmol, yield 32.7%) was obtained as a yellow oil. m / z: [M+H]+ of C18H22BrF3NO3. Calculated values: 436.1, 438.1; measured value: 437.9. Synthesis of N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-4,4-difluoro-N-methylcyclohexane-1-carboxamide (intermediate 5.8): [ka]

[0229] A mixture of [(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)amine hydrochloride [INT3.1] (500 mg, 1.64 mmol) and Et3N (829 mg, 8.20 mmol) was added to dichloromethane (10 mL). A solution of 4,4-difluorocyclohexane-1-carbonyl chloride [INT4.7] (598 mg, 3.28 mmol) was added to dichloromethane (10 mL), and the mixture was stirred at 25°C for 16 hours. Water (10 mL) was added, and the mixture was extracted with dichloromethane (30 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel flash chromatography (siRNA / petroleum ether = 0 / 1~1 / 3) to obtain N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-4,4-difluoro-N-methylcyclohexane-1-carboxamide[INT5.8] (539 mg, 1.30 mmol, yield 79.3%) as a colorless gum-like substance. m / z: C16H18BrF5NO[M+H]+ calculated value 414.0, measured value 414.0. Synthesis of (1r,3S)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-3-cyano-N-methylcyclobutane-1-carboxamide (intermediate 5.9): [ka]

[0230] (1r,3r)-3-cyanocyclobutane-1-carboxylic acid [INT5-a] (1 g, 7.99 mmol) and (S)-1-(4-bromophenyl)-2,2,2-trifluoro-N-methylethane-1-amine hydrochloride [INT3.1] (2.43 g, 7.99 mmol) were mixed in pyridine (10 mL). Phosphorus oxychloride (1.22 g, 7.99 mmol) was added all at once, and the reaction mixture was stirred at 60°C for 16 hours. The reaction was quenched by adding saturated sodium bicarbonate solution (20 mL), and extracted with ELISA (3 × 50 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain (1r,3S)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-3-cyano-N-methylcyclobutane-1-carboxamide [INT5.9] (2.06 g, 5.49 mmol, yield 68.7%) as a brown, gum-like substance. m / z: C15H15BrF3N2O [M+H]+ Calculated value 375.0, Measured value 3 75.0. Synthesis of 1-acetyl-N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methylazetidine-3-carboxamide (intermediate 5.10): [ka]

[0231] In 3 mL of CH2Cl2, a solution of 1-acetylazetidine-3-carbonyl chloride [INT4.8] (300 mg, 1.85 mmol) and [(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)amine hydrochloride [INT3.1] (563 mg, 1.85 mmol) was prepared, to which triethylamine (561 mg, 5.55 mmol) was added. The mixture was stirred at 20°C for 4 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel flash chromatography (siRNA / PE = 0 / 1~1 / 5) to obtain 1-acetyl-N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methylazetidine-3-carboxamide [INT5.10] (250 mg, 635 μmol, yield 34.3%) as a yellow oil. m / z: C15H17BrF3N2O2 [M+H]+ Calculated values: 393.0, 395.0, Measured value: 394.8. Synthesis of 1-acetyl-N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methylpiperidine-4-carboxamide (intermediate 5.11): [ka]

[0232] In 10 mL of dichloromethane, a mixture of [(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)amine hydrochloride [INT3.1] (500 mg, 1.64 mmol) and Et3N (829 mg, 8.20 mmol) was mixed with 1-acetylpiperidine-4-carbonyl chloride [INT4.9] (550 mg, 2.90 mmol), and the mixture was stirred at 25°C for 3 hours. The mixture was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel flash chromatography (methanol / dichloromethane = 0 / 1 to 1 / 20) to obtain 1-acetyl-N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methylpiperidine-4-carboxamide [INT5.11] (680 mg, 1.61 mmol, yield 98.5%) as a yellow solid. m / z: C17H21BrF3N2O2 [M+H]+ Calculated value 421.1, 423.1, Measured value 423.1. 1 HNMR (400 MHz, CDCl3) δ = 7.55 (d, J=8.4 Hz, 2H), 7.24(d, J=8.4 Hz,2H), 6.62 (q, J=8.8 Hz, 1H), 4.05 - 3.82 (m, 1H), 3.23 - 3.04 (m, 1H), 2.90 (s, 3H), 2.87 - 2.71 (m, 2H), 2.70 - 2.43 (m, 1H),2.13 (s, 3H), 1.92- 1.63 (m, 4H). Synthesis of 1-acetyl-N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methylpiperidine-4-carboxamide (intermediate 5.12): [ka]

[0233] In 2 mL of CH2Cl2, a mixture of methyl (1r,3r)-3-(carbonochloridoyl)cyclobutane-1-carboxylate [INT4.10] (111 mg, 628 μmol) and [(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)amine hydrochloride [INT3.1] (120 mg, 394 μmol) was added to N,N-diisopropylethylamine (254 mg, 1.97 mmol) at 0°C. The mixture was stirred at 0°C for 1 hour, and then stirred at 20°C for 12 hours. The reaction product was diluted with CH2Cl2 (50 mL) and 1N HCl (20 mL). The organic phase was separated, washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. This was purified by silica gel flash chromatography (Â1 / PE = 0 / 1~1 / 3) to obtain methyl(1S,3r)-3-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclobutane-1-carboxylate [INT5.12] (84.8 mg, 207 μmol, yield 53.0% (purity 53%)) as a yellow oil. m / z: C16H18BrF3NO3 [M+H]+ calculated value 408.0, measured value 408.0. Synthesis of (S)-1-(4-bromophenyl)-2,2,2-trifluoroethane-1-amine (intermediate 6.1): [ka]

[0234] A mixture of (S)-N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-2-methylpropane-2-sulfinamide[INT2.1] (30 g, 83.7 mmol) in MeOH (100 mL) was mixed with 4 M HCl / dioxane (30 mL). The mixture was stirred at 15 °C for 1 hour. The mixture was concentrated under reduced pressure to obtain the crude product. The mixture was diluted with water (50 mL) and extracted with ELISA (100 mL x 2). The combined organic layers were washed with 1 M HCl (100 mL x 2). The aqueous phase was made basic with 2 N NaOH to pH=9-10 and extracted with CH2Cl2 (100 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain (S)-1-(4-bromophenyl)-2,2,2-trifluoroethane-1-amine [INT6.1] (11.0 g, 43.2 mmol, yield 51.6%) as an oil. m / z: C8H8BrF3N [M+H]+ calculated values ​​254.0, 256.0, measured value 255.8. Synthesis of tert-butyl(S)-4-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)piperidine-1-carboxylate (intermediate 7.1): [ka] Synthesis of tert-butyl(S)-4-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)carbamoyl)piperidine-1-carboxylate (INT7-a):

[0235] To a mixture of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (5.41 g, 23.6 mmol), EDCI (6.78 g, 35.4 mmol), and HOBT (4.78 g, 35.4 mmol) in CH2Cl2 (10 mL), (S)-1-(4-bromophenyl)-2,2,2-trifluoroethane-1-amine [INT6.1] (6 g, 23.6 mmol) was added, and the mixture was stirred at 25°C for 16 hours. The reaction product was concentrated under reduced pressure to obtain the crude product. The mixture was diluted with water (50 mL) and extracted with ELISA (100 mL x 2). The combined organic layers were washed with NaHCO3 (100 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude material was purified by silica gel flash chromatography (EA / PE = 0 / 1 to 1 / 5) to obtain tert-butyl(S)-4-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)carbamoyl)piperidine-1-carboxylate [INT7-a] (5.16 g, 11.0 mmol, yield 47.3%) as a yellow solid. 1 HNMR (400MHz, CDCl3) δ = 7.59 - 7.55 (m,2H), 7.29 (d, J=2.8 Hz, 2H),6.18 (br d, J=9.2 Hz, 1H), 5.72 (quin, J=8.4 Hz,1H), 4.16 (br d, J=7.2 Hz, 2H),2.87 - 2.72 (m, 2H), 2.37 (tt, J=3.6, 12.0 Hz,1H), 2.01 - 1.71 (m, 4H), 1.49(s, 9H). Synthesis of tert-butyl(S)-4-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)piperidine-1-carboxylate (INT7.1):

[0236] In 30 mL of DMF, a solution of tert-butyl(S)-4-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)carbamoyl)piperidine-1-carboxylate [INT7-a] (2 g, 4.29 mmol) was added, to which Cs2CO3 (2.79 g, 8.58 mmol) was added, and the reaction mixture was stirred at 25°C for 1 hour. Next, methyl iodide (1.81 g, 12.8 mmol) was added at 0°C, and the mixture was stirred at 25°C for 4 hours. Brine (50 mL) was added, and the mixture was extracted with RINKAN (100 mL x 2). The combined organic layers were washed with brine (50 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel flash chromatography (Âxy / petroleum ether = 1 / 5 to 1 / 0) to obtain tert-butyl(S)-4-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)piperidine-1-carboxylate [INT7.1] (1.20 g, 2.50 mmol, yield 58.5%) as a white solid. 1 1H NMR (400MHz, chloroform-d): Shift = 7.57 - 7.51 (m, 2H), 7.24 (d, J=8.4 Hz, 2H), 6.63 (q, J=9.2 Hz, 1H), 4.30 - 4.14 (m, 2H), 2.89 (s, 3H), 2.86 - 2.65 (m, 3H), 1.85 - 1.65 (m, 4H), 1.47 (s, 9H). Synthesis of tert-butyl 3-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)piperidine-1-carboxylate (intermediate 7.2): [ka] Synthesis of tert-butyl 3-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)carbamoyl)piperidine-1-carboxylate (INT7-b):

[0237] In 20 mL of CH2Cl2, a mixture of 1-[(tert-butoxy)carbonyl]piperidine-3-carboxylic acid (1.94 g, 8.49 mmol), EDCI (2.03 g, 10.6 mmol), and HOBT (1.43 g, 10.6 mmol) was added to (S)-1-(4-bromophenyl)-2,2,2-trifluoroethane-1-amine [INT6.1] (1.8 g, 7.08 mmol). The mixture was stirred at 25°C for 16 hours. The reaction was quenched by adding water (50 mL) and extracted with ELISA (50 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. This crude product was purified by silica gel flash chromatography (Â1 / PE = 0 / 1~1 / 5) to obtain tert-butyl 3-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)carbamoyl)piperidine-1-carboxylate [INT7-b] (1.40 g, 3.00 mmol, yield 42.5%) as a yellow solid. m / z: C19H25BrF3N2O3 [M+H-56]+ calculated value 408.9, measured value 408.8. Synthesis of tert-butyl 3-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)piperidine-1-carboxylate (INT7.2):

[0238] In 10 mL of DMF, a solution of tert-butyl 3-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)carbamoyl)piperidine-1-carboxylate [INT7-b] (1.4 g, 3.00 mmol) was added, and the reaction mixture was stirred at 25°C for 1 hour. Next, methyl iodide (1.27 g, 9.00 mmol) was added at 0°C, and the reaction mixture was stirred at 25°C for 4 hours. The reaction was quenched by adding water (50 mL), and then extracted with ELISA (50 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. This crude product was purified by silica gel flash chromatography (PE / siRNA = 1 / 0 to 5 / 1) to obtain tert-butyl 3-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)piperidine-1-carboxylate [INT7.2] (800 mg, 1.66 mmol, yield 55.9%) as a colorless oil. m / z: C20H27BrF3N2O3 [M-56+H]+ calculated value 425.1, measured value 424.7. Synthesis of tert-butyl 3-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)pyrrolidine-1-carboxylate (intermediate 7.3): [ka] Synthesis of tert-butyl 3-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)carbamoyl)pyrrolidine-1-carboxylate (INT7-c):

[0239] In 30 mL of CH2Cl2, a mixture of 1-[(tert-butoxy)carbonyl]pyrrolidine-3-carboxylic acid (1.69 g, 7.87 mmol), EDCI (2.26 g, 11.8 mmol), and HOBT (1.59 g, 11.8 mmol) was mixed with (S)-1-(4-bromophenyl)-2,2,2-trifluoroethane-1-amine [INT6.1] (2 g, 7.87 mmol), and the mixture was stirred at 15°C for 16 hours. The reaction product was concentrated under reduced pressure to obtain the crude product. This crude product was combined with materials from a separate identical reaction of the same scale. The mixture was diluted with water (50 mL) and extracted with ELISA (100 mL x 2). The combined organic layers were washed with NaHCO3 (100 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude material, which was purified by silica gel flash chromatography (EA / PE = 0 / 1~1 / 5) to obtain tert-butyl 3-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)carbamoyl)pyrrolidine-1-carboxylate [INT7-c] (4.26 g, 9.43 mmol, yield 59.9%) as a yellow oil. m / z: C18H23BrF3N2O3 [M-56+H]+ Calculated value 395.0, 397.0, Measured value 396.6. 1 HNMR (400MHz, CDCl3) δ = 7.55 (br d,J=8.0 Hz, 2H), 7.25 (br s, 2H),6.22 (br s, 1H), 5.69 (quin, J=8.0 Hz, 1H),3.72 - 3.42 (m, 3H), 3.40 - 3.29 (m,1H), 3.03 - 2.88 (m, 1H), 2.06 - 2.03 (m,2H), 1.46 (d, J=6.8 Hz, 9H). Synthesis of tert-butyl 3-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)pyrrolidine-1-carboxylate (INT7.3):

[0240] In 50 mL of DMF, a solution of tert-butyl 3-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)carbamoyl)pyrrolidine-1-carboxylate [INT7-c] (4.26 g, 9.43 mmol) was added, and Cs2CO3 (6.12 g, 18.8 mmol) was added. The reaction mixture was stirred at 25°C for 1 hour. Next, methyl iodide (4.00 g, 28.2 mmol) was added at 0°C, and the reaction mixture was stirred at 25°C for 4 hours. The reaction was quenched by adding water (50 mL), and then extracted with ELISA (100 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. This crude product was purified by silica gel flash chromatography (siRNA / petroleum ether = 1 / 5 to 1 / 0) to obtain tert-butyl 3-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)pyrrolidine-1-carboxylate [INT7.3] (2.20 g, 4.73 mmol, yield 50.2%) as a yellow oil. The [M-56+H]+ of C19H25BrF3N2O3 was calculated at 409.1 and measured at 409.1. 1 HNMR (400MHz, CDCl3) δ = 7.61 - 7.51(m, 2H), 7.24 (br d, J=6.4 Hz,2H), 6.61 (q, J=8.8 Hz, 1H), 3.77 - 3.49 (m,3H), 3.46 - 3.36 (m, 1H), 3.33 -3.21 (m, 1H), 3.14 (s, 1H), 2.89 (s, 2H), 2.25- 2.07 (m, 2H), 1.48 - 1.41 (m,9H). tert-butyl(S)-((4-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexyl)methyl)carbamate (intermediate 7.4): [ka] Synthesis of tert-butyl(S)-((4-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)carbamoyl)cyclohexyl)methyl)carbamate (INT7-d):

[0241] In 20 mL of CH2Cl2, a mixture of 4-({[(tert-butoxy)carbonyl]amino}methyl)cyclohexane-1-carboxylic acid (1.92 g, 7.47 mmol), EDCI (2.16 g, 11.2 mmol), and HOBT (1.51 g, 11.2 mmol) was mixed with (S)-1-(4-bromophenyl)-2,2,2-trifluoroethane-1-amine [INT6.1] (1.9 g, 7.47 mmol), and the mixture was stirred at 25°C for 16 hours. The reaction was quenched by adding saturated Na2CO3 (100 mL) and extracted with SiO2 (100 mL x 3). The combined organic layers were washed with brine (200 mL x 2), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. This crude product was purified by silica gel flash chromatography (siRNA / dichloromethane = 0 / 1 to 1 / 9) to obtain tert-butyl(S)-((4-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)carbamoyl)cyclohexyl)methyl)carbamate [INT7-d] (2.53 g, 5.12 mmol, yield 68.7%) as a white solid. m / z: C21H29BrF3N2O3 [M+H-56]+ calculated value 437.1, measured value 436.9. 1 HNMR (400MHz, CD3OD) δ = 7.58 (br d, J=8.4 Hz, 2H),7.40 (br d, J=8.4 Hz, 2H), 5.68 (q, J=8.0 Hz, 1H), 4.61 (br s, 1H), 2.89 (br d,J=6.4 Hz, 2H), 2.31 (br t, J=12.0 Hz, 1H), 1.97 - 1.66 (m, 5H), 1.47 - 1.40 (m,3H), 1.43 (s, 9H), 1.07 - 0.90 (m, 2H). Synthesis of tert-butyl(S)-((4-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexyl)methyl)carbamate (INT7.4):

[0242] A suspension of tert-butyl(S)-((4-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)carbamoyl)cyclohexyl)methyl)carbamate [INT7-d] (1 g, 2.02 mmol) and Cs2CO3 (1.97 g, 6.06 mmol) was stirred in DMF (15 mL) for 1 hour. Next, MeI (860 mg, 6.06 mmol) was added, and the resulting mixture was stirred for 3 hours. The reaction mixture was poured into water (100 mL) and extracted with SiO (100 mL x 2). The combined organic layers were washed with water (200 mL x 2) and brine (200 mL), dried over Na2SO4, and filtered. The filtrate was concentrated to obtain the residue, which was then subjected to preparative HPLC (column: Boston). Purified using Prime C18 150×30mm×5μm, table: 54~84%B (A=water (0.05v / v% ammonia hydroxide), B=acetonitrile), flow rate: 30mL / min, UV detector 220nm), tert-butyl(S)-((4-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexyl)methyl)carbamate [INT7.4] (400mg, 788μmol, yield 39.2%) as a white solid. m / z: C22H31BrF3N2O3 [M-56+H]+Calculated values ​​451.1, 453.1, measured value 452.9. 1 H NMR (400MHz, CDCl3) δ= 7.58 - 7.50 (m, 2H), 7.25 (d,J=8.4 Hz, 2H), 6.65 (q, J=8.8 Hz, 1H), 4.60 (brs, 1H), 3.02 (br t, J=6.4 Hz,2H), 2.87 (s, 3H), 2.53 (tt, J=3.2, 11.6 Hz, 1H), 1.96 - 1.77 (m, 4H), 1.71 -1.54 (m, 3H), 1.46 (s, 9H), 1.08 - 0.95 (m, 2H). (1r,4S)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-methoxy-N-methylcyclohexane-1-carboxamide (intermediate 7.5): [ka] Synthesis of (1r,4S)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-methoxycyclohexane-1-carboxamide (INT7-e):

[0243] In 20 mL of CH2Cl2, a mixture of (1r,4r)-4-methoxycyclohexane-1-carboxylic acid (435 mg, 2.75 mmol), EDCI (790 mg, 4.12 mmol), and HOBt (556 mg, 4.12 mmol) was mixed with (S)-1-(4-bromophenyl)-2,2,2-trifluoroethane-1-amine [INT6.1] (700 mg, 2.75 mmol), and the mixture was stirred at 25°C for 16 hours. The reaction mixture was quenched by adding water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated NaHCO3 (20 mL) and brine (10 mL x 2), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. This was purified by silica gel flash chromatography (siRNA / PE = 0 / 1~1 / 3) to obtain (1r,4S)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-methoxycyclohexane-1-carboxamide [INT7-e] (456 mg, 1.15 mmol, yield 42.2%) as a white solid. m / z: [M+H]+ of C16H20BrF3NO2: calculated 394.1, 396.1, measured 395.9. 1 HNMR (400 MHz, CD3OD) δ = 7.58 (d, J=8.6 Hz, 2H), 7.40(d, J=8.4 Hz, 2H), 5.68 (q, J=8.3 Hz, 1H), 3.34 (s, 3H), 3.24 - 3.09 (m, 1H),2.41 - 2.24 (m, 1H), 2.20 - 2.05 (m, 2H), 1.95 - 1.84 (m, 1H), 1.83 - 1.71 (m,1H),1.64 - 1.39 (m, 2H), 1.30 - 1.09 (m, 2H). Synthesis of (1r,4S)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-methoxy-N-methylcyclohexane-1-carboxamide (INT7.5):

[0244] In 1 mL of DMF, a mixture of (1r,4S)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-methoxycyclohexane-1-carboxamide [INT7-e] (455 mg, 1.15 mmol) and Cs2CO3 (749 mg, 2.30 mmol) was stirred at 25°C for 1 hour. CH3I (816 mg, 5.75 mmol) was added, and the mixture was stirred for 2 hours. The reaction was quenched by adding water (10 mL) and extracted with ethyl acetate (2 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous sodium 2SO4, concentrated under reduced pressure to obtain the crude product, which was purified by silica gel flash chromatography (ethyl acetate / PE = 0 / 1~1 / 3) to obtain the (1r,4S)-N-((S)-1-(4-bromophenyl) Phenyl)-2,2,2-trifluoroethyl)-4-methoxy-N-methylcyclohexane-1-carboxamide [INT7.5] (130 mg, 318 μmol, yield 27.7%) was obtained as a colorless oil. m / z: C17H22BrF3NO2 [M+H]+ calculated value 408.1, measured value 407.8. (1r,4S)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-((tert-butyldimethylsilyl)oxy)-N-methylcyclohexane-1-carboxamide (intermediate 8.1): [ka] Synthesis of (1r,4S)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-hydroxycyclohexane-1-carboxamide (INT8-a):

[0245] In 20 mL of CH2Cl2, a mixture of (1r,4r)-4-hydroxycyclohexane-1-carboxylic acid (1.13 g, 7.87 mmol), EDCI (2.28 g, 11.8 mmol), and HOBt (1.59 g, 11.8 mmol) was mixed with (S)-1-(4-bromophenyl)-2,2,2-trifluoroethane-1-amine [INT6.1] (2 g, 7.87 mmol), and the mixture was stirred at 25°C for 16 hours. The reaction was quenched by adding water (100 mL) and extracted with CH2Cl2 (100 mL x 3). The combined organic layers were washed with saturated NaHCO3 aqueous solution (200 mL x 2) and brine (200 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. This was purified by silica gel flash chromatography (siRNA / PE = 1 / 1 to 1 / 0) to obtain (1r,4S)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-hydroxycyclohexane-1-carboxamide [INT8-a] (1.80 g, 4.73 mmol, yield 60.1%) as a white solid. m / z: C15H18BrF3NO2 [M+H]+ calculated value 380.0, 382.0, measured value 381.7. Synthesis of (1r,4S)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-((tert-butyldimethylsilyl)oxy)-N-methylcyclohexane-1-carboxamide (INT8.1):

[0246] A suspension of (1r,4S)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-hydroxycyclohexane-1-carboxamide [INT8-a] (500 mg, 1.31 mmol), imidazole (178 mg, 2.62 mmol), and tert-butyl(chloro)dimethylsilane (295 mg, 1.96 mmol) was stirred in CH2Cl2 (5 mL) for 12 hours at 25°C. The reaction mixture was poured into water (30 mL) and extracted with ELISA (30 mL x 2). The combined organic layers were washed with saturated Na2CO3 (100 mL x 2) and brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. This crude product was purified by silica gel flash chromatography (siRNA / petroleum ether = 0 / 1~5 / 95) to obtain (1r,4r)-N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-4-[(tert-butyldimethylsilyl)oxy]cyclohexane-1-carboxamide (440 mg, 889 μmol, yield 68.0%) as a white solid. m / z: C21H32BrF3NO2Si[M+H]+ Calculated value 496.1, Measured value 49 6.0. 1 H NMR (400 MHz, CDCl3) δ = 7.54 (d, J = 8.4 Hz, 2H),7.25(d, J = 8.4 Hz, 2H), 6.09 (br d, J = 9.2 Hz, 1H), 5.75 - 5.62 (m, 1H), 3.62-3.51 (m, 1H), 2.18 - 2.05 (m, 1H), 1.98 - 1.79 (m, 4H), 1.30 - 1.22 (m,4H),0.89 (s, 9H), 0.06 (s, 6H).

[0247] In 3 mL of DMF, a suspension of (1r,4r)-N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-4-[(tert-butyldimethylsilyl)oxy]cyclohexane-1-carboxamide (1.15 g, 2.32 mmol) and Cs2CO3 (2.26 g, 6.96 mmol) was stirred at 20°C for 1 hour. Next, MeI (987 mg, 6.96 mmol) was added, and the reaction mixture was stirred at 20°C for 3 hours. The reaction mixture was combined with a mixture from a further identical reaction, poured into 30 mL of water, and extracted with RINKAN (30 mL x 2). The combined organic layers were washed with 2 x 50 mL of water and 50 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude material. This material was purified by silica gel flash chromatography (SiO2 / petroleum ether = 0 / 1~3 / 97) to obtain (1r,4S)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-((tert-butyldimethylsilyl)oxy)-N-methylcyclohexane-1-carboxamide [INT8.1] (495 mg, 973 μmol, yield 42.3%) as a white solid. m / z: C22H34BrF3NO2Si [M+H]+ Calculated value 508.1, 510.1, Measured value 510.1. 1 HNMR (400 MHz, CDCl3) δ = 7.53 (d, J=8.4 Hz, 2H), 7.23(d, J=8.4 Hz,2H), 6.63 (q, J=8.8 Hz, 1H), 3.70 - 3.55 (m, 1H) 2.86 (s, 3H),2.50 (tt, J=3.6,11.2 Hz, 1H), 2.03 - 1.93 (m, 2H), 1.93 - 1.83 (m, 1H), 1.83 -1.74 (m, 1H),1.71 - 1.60 (m, 2H), 1.41 - 1.30 (m, 2H), 0.89 (s, 9H), 0.07 (s,6H). Methyl(S)-(4-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexyl)carbamate (intermediate 9.1): [ka] Synthesis of tert-butyl(S)-(4-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)carbamoyl)cyclohexyl)carbamate (INT9-a):

[0248] In 2 mL of CH2Cl2, a mixture of 4-{[(tert-butoxy)carbonyl]amino}cyclohexane-1-carboxylic acid (1.43 g, 5.90 mmol), EDCI (1.69 g, 8.85 mmol), and HOBt (1.19 g, 8.85 mmol) was mixed with (S)-1-(4-bromophenyl)-2,2,2-trifluoroethane-1-amine [INT6.1] (2.5 g, 5.90 mmol), and the mixture was stirred at 25°C for 16 hours. The reaction mixture was quenched by adding water (30 mL) and extracted with ELISA (2 × 100 mL). The combined organic layers were washed with brine (2 × 50 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure to obtain the crude product, which was then purified by silica gel flash chromatography (Â / PE = 0 / 1~1 / 3) to obtain tert-butyl(S)-(4-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)carbamoyl)cyclohexyl)carbamate[INT9-a](2 0.70 g, 5.63 mmol, yield 95.7% was obtained as a white solid. m / z: C20H26BrF3N2O3 [M-Boc]+ calculated value 378.1, measured value 378.9. Synthesis of (S)-4-amino-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)cyclohexane-1-carboxamide hydrochloride (INT9-b):

[0249] A solution of tert-butyl(S)-(4-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)carbamoyl)cyclohexyl)carbamate [INT9-a] (3.1 g, 6.46 mmol) in 4 M HCl (30 mL) in dioxane was stirred at 25°C for 1 hour. The mixture was concentrated under reduced pressure to obtain (S)-4-amino-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)cyclohexane-1-carboxamide hydrochloride [INT9-b] (2.60 g, 6.25 mmol, yield 97.0%) as a white solid. m / z: C15H19BrF3N2O [M+H]+ calculated value 379.1, measured value 379.1. Synthesis of (S)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-(1,3-dioxoisoindorin-2-yl)cyclohexane-1-carboxamide (INT9-c):

[0250] A mixture of (S)-4-amino-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)cyclohexane-1-carboxamide hydrochloride [INT9-b] (1.35 g, 3.55 mmol), ethyl 1,3-dioxo-2,3-dihydro-1H isoindole-2-carboxylate (1.16 g, 5.32 mmol), and Na2CO3 (1.12 g, 10.6 mmol) in THF (20 mL) was stirred at 25°C for 1 hour. The reaction product was combined with a crude batch from the same reaction on the same scale and concentrated under reduced pressure to obtain the crude product. This crude product was ground with siRNA / PE (1 / 1, 50 mL) to obtain (S)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-(1,3-dioxoisoindorin-2-yl)cyclohexane-1-carboxamide [INT9-c] (3.60 g, 7.06 mmol, yield 99.4%) as a white solid. m / z: C23H20BrF3N2O3 [M+Na]+ Calculated values ​​531.1, 533.1, measured value 532.8. Synthesis of (S)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-(1,3-dioxoisoindolin-2-yl)-N-methylcyclohexane-1-carboxamide (INT9-d):

[0251] A mixture of (S)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-(1,3-dioxoisoindorin-2-yl)cyclohexane-1-carboxamide [INT9-c] (3.7 g, 7.26 mmol) and Cs2CO3 (4.72 g, 14.5 mmol) was stirred at 25°C for 1 hour in DMF (40 mL). CH3I (3.07 g, 21.7 mmol) was added, and the reaction mixture was stirred at 25°C for 1 hour. The reaction was quenched by adding water (50 mL) and extracted with ELISA (2 × 100 mL). The combined organic layers were washed with brine (2 × 50 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to obtain the crude product. This crude product was purified by silica gel flash chromatography (siRNA / PE = 0 / 1~1 / 3) to obtain (S)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-(1,3-dioxoisoindorin-2-yl)-N-methylcyclohexane-1-carboxamide [INT9-d] (996 mg, 1.90 mmol, yield 26.2%) as a white solid. m / z: C₂₄H₂₃BrF₃N₂O₃[M+H]+ Calculated value 523.1, Measured value 523.2. Synthesis of (S)-4-amino-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methylcyclohexane-1-carboxamide (INT9-e):

[0252] In 1 mL of EtOH, a mixture of (S)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-(1,3-dioxoisoindorin-2-yl)-N-methylcyclohexane-1-carboxamide [INT9-d] (300 mg, 573 μmol) was added, to which NH2NH2.H2O (143 mg, 2.86 mmol) was added, and the mixture was stirred at 20°C for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain (S)-4-amino-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methylcyclohexane-1-carboxamide [INT9-e] (220 mg, 559 μmol, yield 97.7%) as a yellow solid. m / z: C16H20BrF3N2O [M-NH2]+ Calculated value 376.1, measured value 376.1. Synthesis of methyl(S)-(4-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexyl)carbamate (INT9.1):

[0253] In 1 mL of CH2Cl2, a solution of (S)-4-amino-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methylcyclohexane-1-carboxamide [INT9-e] (90 mg, 228 μmol) and Et3N (115 mg, 1.14 mmol) was added, to which methyl chloroformate (64.6 mg, 684 μmol) was added, and the mixture was stirred for 1 hour. The reaction was quenched by adding water (10 mL), and the mixture was extracted with SiO2 (2 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to obtain the crude product, which was purified by preparative TLC (Â / PE = 1 / 2) to obtain methyl(S)-(4-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexyl)carbamate [INT9.1] (60.0 mg, 132 μmol, yield 58.8%) as a colorless oil. m / z: C18H23BrF3N₂O₃[M+H]+ Calculated values ​​451.1, 453.1, Measured value 452.9. Synthesis of (S)-4-acetamide-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methylcyclohexane-1-carboxamide (intermediate 9.2): [ka]

[0254] In 1 mL of DCM, a mixture of (S)-4-amino-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methylcyclohexane-1-carboxamide [INT9-e] (110 mg, 279 μmol) and triethylamine (140 mg, 1.39 mmol) was mixed with acetyl chloride (76.6 mg, 976 μmol) at 25°C, and the mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the crude product (S)-4-acetamide-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methylcyclohexane-1-carboxamide [INT9.2] (120 mg, 275 μmol, yield 99.1%) as a white solid. m / z: C18H23BrF3N2O2 [M+H]+ Calculated value 435.1, measured value 435.2. Synthesis of 1-(4-bromophenyl)-N-methylethane-1-amine (intermediate 10.1): [ka]

[0255] To a solution of 1-(4-bromophenyl)ethane-1-one [INT10-a] (10 g, 50.3 mmol) in MeOH (100 mL), sodium borohydride (8.79 g, 140 mmol) and methanamine hydrochloride (31.5 g, 468 mmol) were added. The mixture was stirred at 20°C for 12 hours. The reaction was quenched by adding water (100 mL) and extracted with siRNA (100 mL × 2). The combined organic layers were washed with brine (2 × 50 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel flash chromatography (siRNA / PE=0 / 1~1 / 0) to obtain 1-(4-bromophenyl)-N-methylethane-1-amine [INT10.1] (7.50 g, 32.8 mmol, yield 65.2%) as a colorless oil. m / z: C9H13BrN's [M+H]+ calculated value 214.0, measured value 213.9. Synthesis of N-(1-(4-bromophenyl)ethyl)-N-methylcyclobutanecarboxamide (intermediate 11.1): [ka]

[0256] In 15 mL of CH2Cl2, a mixture of cyclobutanecarboxylic acid [INT11-a] (389 mg, 3.89 mmol) and HATU (2.21 g, 5.83 mmol) was mixed with DIPEA (1.49 g, 11.6 mmol) and 1-(4-bromophenyl)-N-methylethane-1-amine [INT10.1] (1 g, 4.67 mmol). The reaction mixture was stirred under nitrogen at 20°C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product, which was purified by preparative HPLC (column: Phenomenex Gemini-NX 80×40mm×3um, table: 22~62%B (A=water (0.05% ammonia hydroxide)), B=acetonitrile), flow rate: 25 mL / min, UV detector 220 nm) to obtain N-(1-(4-bromophenyl)ethyl)-N-methylcyclobutanecarboxamide [INT11.1] (150 mg, 506 μmol, yield 13.0%) as an off-white dry powder. m / z: [M+H]+ of C14H19BrNO: calculated 296.1, 298.1, measured 298.1. Synthesis of N-[1-(4-bromophenyl)ethyl]-N-methylcyclohexanecarboxamide (intermediate 11.2): [ka]

[0257] In 10 mL of CH2Cl2, a mixture of [1-(4-bromophenyl)ethyl](methyl)amine [INT10.1] (500 mg, 2.33 mmol) and HATU (1.32 g, 3.49 mmol) was mixed with DIPEA (902 mg, 6.98 mmol) and cyclohexanecarboxylic acid [INT11-b] (447 mg, 3.49 mmol). The reaction mixture was stirred under nitrogen at 20°C for 16 hours. The mixture was diluted with water (50 mL) and extracted with EtOAC (50 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel flash chromatography (petroleum ether:ethyl acetate = 5:1) to obtain N-[1-(4-bromophenyl)ethyl]-N-methylcyclohexanecarboxamide [INT11.2] (700 mg, 2.15 mmol, yield 92.7%) as a colorless oil. m / z: C16H23BrNO [M+H]+ calculated value 324.1, 326.1, measured value 326.1. Synthesis of N-[1-(4-bromophenyl)ethyl]-N-methylcyclopentanecarboxamide (intermediate 11.3): [ka]

[0258] In 3 mL of CH2Cl2, a mixture of cyclopentanecarboxylic acid [INT11-c] (63.9 mg, 560 μmol) and HATU (266 mg, 700 μmol) was mixed with DIPEA (180 mg, 1.40 mmol) and [1-(4-bromophenyl)ethyl](methyl)amine [INT10.1] (100 mg, 467 μmol). The reaction mixture was stirred under nitrogen at 20°C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was diluted with water (20 mL) and extracted with ELISA (20 mL x 2). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SO4, and concentrated under reduced pressure to obtain N-[1-(4-bromophenyl)ethyl]-N-methylcyclopentanecarboxamide [INT11.3] (110 mg, 354 μmol, yield 76.3%) as a colorless oil. m / z: C15H21BrNO [M+H] + calculated value 310.1, 312.1, measured value 312.1. Synthesis of N-(1-(4-bromophenyl)ethyl)-N-methylacetamide (intermediate 12.1): [ka]

[0259] In 2 mL of DCM, a mixture of 1-(4-bromophenyl)-N-methylethane-1-amine [INT10.1] (100 mg, 467 μmol) was mixed with triethylamine (235 mg, 2.33 mmol) and acetyl chloride (127 mg, 1.63 mmol). The mixture was stirred at 25°C for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel flash chromatography (Â1 / PE = 0 / 1~1 / 3) to obtain N-(1-(4-bromophenyl)ethyl)-N-methylacetamide [INT12.1] (100 mg, 390 μmol, yield 84.0%). It was obtained as a colored oily substance. m / z: C11H15BrNO [M+H]+ calculated value 256.0, 258.0, measured value 257.9. Synthesis of N-[1-(4-bromophenyl)ethyl]-N-methylcyclopropanecarboxamide (intermediate 12.2): [ka]

[0260] In 10 mL of CH2Cl2, a mixture of [1-(4-bromophenyl)ethyl](methyl)amine [INT10.1] (740 mg, 3.45 mmol) and triethylamine (349 mg, 3.45 mmol) was mixed with cyclopropane carbonyl chloride [INT12-a] (1.25 g, 12.0 mmol) at 25°C, and the mixture was stirred at 25°C for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain N-[1-(4-bromophenyl)ethyl]-N-methylcyclopropanecarboxamide [INT12.2] (556 mg, 1.97 mmol) as a brown oily substance. m / z: C13H17BrNO [M+H]+ Calculated value 282.0, measured value 282.1. Synthesis of N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methylacetamide (intermediate 13.1): [ka] Synthesis of (E)-N-(4-bromobenzylidene)-2-methylpropane-2-sulfinamide (INT13-a):

[0261] To a solution of 4-bromobenzaldehyde [INT2-a] (5.0 g, 27.0 mmol) in toluene (30 mL), 2-methylpropane-2-sulfinamide (3.5 g, 28.8 mmol) was added. After 15 minutes, sodium hydroxide (1.1 g, 27.5 mmol) was added, and the reaction mixture was stirred at 25°C for 12 hours. Sodium sulfate (1.3 g) and Celite (1.3 g) were added, and the suspension was stirred for 15 minutes. The mixture was filtered and concentrated under reduced pressure to obtain (E)-N-(4-bromobenzylidene)-2-methylpropane-2-sulfinamide [INT13-a] (7.35 g, 25.5 mmol, yield 94.4%) as a colorless gum. 1HNMR (400MHz, DMSO-d6) δ = 8.55 (s, 1H), 7.89 (d, J=8.4Hz, 2H), 7.80 - 7.72 (m,2H), 1.18 (s, 9H). Synthesis of N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide (INT13-b):

[0262] In 30 mL of DMF, 4.29 g of undiluted trimethyl(trifluoromethyl)silane (30.2 mmol) was mixed with tetrabutylazanium acetate (3.64 g of 12.1 mmol) and (E)-N-(4-bromobenzylidene)-2-methylpropane-2-sulfate. Sulfinamide [INT13-a] (3.5 g, 12.1 mmol) was added at 0°C to a stirred solution. The mixture was stirred at 0-5°C for 3 hours. The mixture was poured into water (100 mL). The precipitate was collected by filtration and dried under reduced pressure to obtain N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide [INT13-b] (3.50 g, 9.77 mmol, yield 80.8%) as an off-white solid. 1 HNMR (400MHz, DMSO-d6) δ = 7.68 - 7.62 (m, 2H), 7.61 -7.57 (m, 2H), 6.48 (d,J=9.5 Hz, 1H), 5.27 (quin, J=8.6 Hz, 1H), 1.14 (s, 9H). Synthesis of 1-(4-bromophenyl)-2,2,2-trifluoroethane-1-amine (INT13-c):

[0263] 4M HCl (9.75 mL, 39.0 mmol) in dioxane was added to a suspension of N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide [INT13-b] (3.5 g, 9.77 mmol) in methanol (20 mL), and the reaction mixture was stirred at 20°C for 1 hour. The reaction product was concentrated. The residue was diluted with water (20 mL) and adjusted to pH 10 with 1N NaOH solution. The mixture was extracted with ethyl acetate (2 × 50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude 1-(4-bromophenyl)-2,2,2-trifluoroethane-1-amine [INT13-c] (2.16 g, 8.50 mmol, yield 87.0%) as a brown oil. m / z: C8H7BrF3N's [M-NH2]+ calculated value 237.0, measured value 237.0. 1 HNMR (400MHz, DMSO-d6) δ = 7.60 (d, J=8.3 Hz, 2H), 7.47(d, J=8.3 Hz, 2H), 4.54 (q, J=8.2 Hz, 1H), 2.78 (br s, 2H). Synthesis of N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)acetamide [INT13-d]:

[0264] In 30 mL of CH2Cl2, a solution of 1-(4-bromophenyl)-2,2,2-trifluoroethane-1-amine [INT13-c] (2.7 g, 8.50 mmol) and triethylamine (1.72 g, 17.0 mmol) was added to acetyl chloride (996 mg, 12.7 mmol), and the reaction mixture was stirred at 20°C for 12 hours. The reaction mixture was diluted with 50 mL of CH2Cl2, washed with 50 mL of water, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. This crude product was purified by silica gel flash chromatography (50% ethyl acetate in PE) to obtain N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)acetamide [INT13-d] (2.50 g, 8.44 mmol, yield 99.6%) as an off-white solid. m / z: C10H10BrF3NO [M+H]+ Calculated value 296.0, 298.0, Measured value 295.8. 1 HNMR (400MHz, DMSO-d6) δ = 9.15 (d, J=9.7 Hz, 1H), 7.65(d, J=8.6 Hz, 2H), 7.53 (d,J=8.4 Hz, 2H), 5.91 - 5.74 (m, 1H), 1.96 (s, 3H). Synthesis of N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methylacetamide (INT13.1):

[0265] A mixture of sodium hydride (671 mg, 16.8 mmol) in THF (30 mL) was cooled to 0°C. N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)acetamide [INT13-d] (2.5 g, 8.44 mmol) was added, and the reaction mixture was stirred at 0°C for 30 minutes. Next, iodomethane (3.59 g, 25.3 mmol) was added, and the reaction mixture was heated to 20°C under N2 for 12 hours. The reaction was quenched by adding saturated NH4Cl (150 mL), and extracted with ELISA (2 × 100 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel flash chromatography (20% ethyl acetate in PE) to obtain N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methylacetamide [INT13.1] (1.83 g, 5.90 mmol, yield 70.1%) as a brown oily substance. m / z:C11H12BrF3NO [M+H]+Calculated values: 310.0, 312.0, Measured value: 311.7. 1 H NMR (400MHz, DMSO-d6) δ = 7.71 -7.66 (m, 2H), 7.37 -7.31 (m, 2H), 6.62 - 6.06 (m, 1H), 2.97 (s, 1H), 2.83 (s,2H), 2.16 (s, 2H),1.91 (s, 1H). Synthesis of (R)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide (intermediate 14.1): [ka] Synthesis of (S)-N-((R)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide (INT14-a):

[0266] (S)-N-((R)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide [INT14-a] was prepared using (S)-(-)-2-methyl-2-propanesulfinamide by the same synthetic route outlined for (R)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide [INT2.1]. Synthesis of (R)-1-(4-bromophenyl)-2,2,2-trifluoroethane-1-amine (INT14-b):

[0267] A mixture of (S)-N-((R)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide [INT14-a] (8 g, 22.3 mmol) in MeOH (60 mL) was mixed with 4 M HCl (20 mL) in dioxane. The mixture was stirred at 20°C for 1.5 hours. The mixture was concentrated under reduced pressure to obtain the crude product. The mixture was diluted with water (50 mL) and extracted with ELISA (50 mL x 2). The combined organic layers were washed with 1 M HCl (50 mL x 2). The aqueous phase was made basic with 2N NaOH to pH=9-10 and extracted with CH2Cl2 (50 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product (R)-1-(4-bromophenyl)-2,2,2-trifluoroethane-1-amine [INT14-b] (3.50 g, 13.7 mmol, yield 61.8%) as a yellow solid. m / z: C8H8BrF3N [M+H]+ calculated values ​​254.0, 256.0, experimental value 254.1. Synthesis of (R)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide (INT14-c):

[0268] (R)-1-(4-bromophenyl)-2,2,2-trifluoroethane-1-amine [INT14-b] (2g, 7.87 mmol) was added to a mixture of tetrahydro-2H-thiopyran-4-carboxylic acid 1,1-dioxide [INT4-a] (1.68 g, 9.44 mmol), EDCI (2.26 g, 11.8 mmol), and HOBt (1.59 g, 11.8 mmol) in CH2Cl2 (20 mL). The mixture was stirred at 25°C for 16 hours. The reaction was quenched by adding water (50 mL) and extracted with SiO2 (50 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. This crude product was purified by silica gel flash chromatography (siRNA / PE = 0 / 1~1 / 5) to obtain (R)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide [INT14-c] (2.20 g, 5.31 mmol, yield 67.4%) as a white solid. m / z: C14H16BrF3NO3S [M+H]+ calculated value 414.0, 416.0, measured value 416.2. Synthesis of (R)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide (INT14.1):

[0269] In 10 mL of DMF, a solution of (R)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide [INT14-c] (1 g, 2.41 mmol) was added, and the reaction mixture was stirred at 25°C for 1 hour. Next, methyl iodide (1.02 g, 7.23 mmol) was added at 0°C, and the reaction mixture was stirred at 25°C for 2 hours. The reaction was quenched by adding water (50 mL), and then extracted with ELISA (50 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. This crude product was purified by silica gel flash chromatography (PE / siRNA = 1 / 0 to 1 / 1) to obtain (R)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide [INT14.1] (700 mg, 1.63 mmol, yield 67.9%) as a colorless oil. m / z: C15H18BrF3NO3S [M+H]+ calculated value 428.0, 430.0, measured value 430.1. Synthesis of (S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoro-N-methylethane-1-amine hydrochloride (intermediate 15.1): [ka] Synthesis of (R,E)-N-(4-bromo-2-methylbenzylidene)-2-methylpropane-2-sulfinamide (INT15-b):

[0270] (R)-2-methylpropane-2-sulfinamide (12.1 g, 100 mmol) and 4-bromo-2-methylbenzaldehyde [INT15-a] (10 g, 50.2 mmol) were dissolved in tetrahydrofuran (50 mL), and titanium ethoxide (34.2 g, 150 mmol) was added. The mixture was stirred at 25°C for 10 hours. Next, the reaction The mixture was poured into water (500 mL) and extracted with ethyl acetate (3 × 300 mL). The organic extracts were combined, dried over Na₂SO₄, and evaporated under vacuum. The residue was purified by flash chromatography (hexane / MTBE = 1 / 0~0 / 1) to obtain (R,E)-N-(4-bromo-2-methylbenzylidene)-2-methylpropane-2-sulfinamide [INT15-b] (10.4 g, 34.5 mmol, yield 68.8%) as a yellow solid. 1 HNMR (400 MHz, CDCl3) δ 8.76 (s, 1H), 7.75 (d, J=8.7Hz, 1H), 7.46 -7.37 (m, 2H), 2.56 (s, 3H), 1.24 (s, 9H). Synthesis of (R)-N-((S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide (INT15-c):

[0271] (R,E)-N-(4-bromo-2-methylbenzylidene)-2-methylpropane-2-sulfinamide [INT15-b] (18.8 g, 62.2 mmol) and tetrabutylammonium triphenyl difluorosilicate (50.3 g, 93.3 mmol) were dissolved in THF (300 mL). Trifluoromethyltrimethylsilane (44.2 g, 311 mmol) was added dropwise at -80°C. The mixture was stirred at -30°C for 30 minutes, and then NH4Cl aqueous solution (200 mL) was added. The mixture was extracted with ELISA (2 × 200 mL). The organic phase was dried over sodium sulfate and evaporated in vacuum at 45°C. The residue was purified by flash chromatography to obtain (R)-N-((S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide [INT15-c] (19.0 g, 51.0 mmol, yield 82.2%) as a pale yellow oil. m / z: C13H18BrF3NOS [M+H]+ calculated value 372.0, measured value 372.2. 1HNMR (500 MHz, CDCl3) δ 7.39 (s, 2H), 7.27 (d, J=7.6 Hz,1H), 5.04 (p,J=7.1 Hz, 1H), 3.58 (d, J=5.8 Hz, 1H), 2.44 (s, 3H), 1.24 (s,9H). Synthesis of (R)-N-((S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethyl)-N,2-dimethylpropane-2-sulfinamide (INT15-d):

[0272] (R)-N-((S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide [INT15-c] (10 g, 26.8 mmol) was dissolved in THF (300 mL). Lithium bis(trimethylsilyl)amide (74.3 mL, 80.3 mmol) was added at 0°C. The mixture was stirred at 0°C for 20 minutes. Methyl iodide (22.7 g, 160 mmol) was added. The mixture was stirred at 20°C for 10 hours, and then NH4Cl aqueous solution (50 mL) was added. The mixture was extracted with ELISA (2 × 30 mL). The organic phase was dried with sodium sulfate and evaporated in a vacuum at 45°C to obtain crude (R)-N-((S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethyl)-N,2-dimethylpropane-2-sulfinamide [INT15-d] (8.50 g, 22.0 mmol, yield 82.5%) as a brown oily substance. m / z: C14H20BrF3NOS [M+H]+ calculated value 386.0, 388.0, measured value 388.0. 1 HNMR (400 MHz, CDCl3) δ 7.44 - 7.32 (m, 1H), 7.31 - 7.21(m, 1H), 7.18(d, J=8.2 Hz, 1H), 5.15 - 5.06 (m, 1H), 2.50 - 2.42 (m, 6H), 1.23(s, 9H). Synthesis of (S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoro-N-methylethane-1-amine hydrochloride (INT15.1):

[0273] (R)-N-((S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethyl)-N,2-dimethylpropane-2-sulfinamide [INT15-d] (10 g, 25.8 mmol) was dissolved in methanol (20 mL). Hydrogen chloride (4 M in 1,4-dioxane, 100 mL, 2.36 mol) was added. The mixture was heated to 20 The mixture was stirred at °C for 10 hours. The mixture was evaporated in a vacuum at 50 °C. MTBE (100 mL) was added. The formed solid was filtered and washed with MTBE (100 mL) to obtain (S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoro-N-methylethane-1-amine hydrochloride [INT15.1] (6.27 g, 19.6 mmol, yield 76.3%) as a white solid. m / z: C10H12BrF3N [M+H]+ calculated value 282.0, 284.0, measured value 284.0. 1 HNMR (400 MHz, DMSO-d6) δ 7.71 (d, J=8.5 Hz, 1H), 7.65 -7.55 (m, 2H), 5.51 -5.46 (m, 1H), 2.49 (s, 3H), 2.40 (s, 3H). Synthesis of (S)-1-(4-bromo-3-methylphenyl)-2,2,2-trifluoro-N-methylethane-1-amine hydrochloride (intermediate 15.2): [ka] Synthesis of (R,E)-N-(4-bromo-3-methylbenzylidene)-2-methylpropane-2-sulfinamide (INT15-f):

[0274] (R)-2-methylpropane-2-sulfinamide (18.1 g, 150 mmol) and 4-bromo-3-methylbenzaldehyde [INT15-e] (15 g, 75.3 mmol) were dissolved in tetrahydrofuran (100 mL), and titanium ethoxide (51.3 g, 225 mmol) was added. The mixture was stirred at 60°C for 10 hours. Next, the reaction mixture was poured into water (500 mL) and extracted with MTBE (3 × 300 mL). The organic extract was re-extracted with water (3 × 200 mL), dried over Na₂SO₄, and evaporated under vacuum to obtain (R,E)-N-(4-bromo-3-methylbenzylidene)-2-methylpropane-2-sulfinamide [INT15-f] (15.2 g, 50.2 mmol, yield 66.9%) as a yellow solid. 1 HNMR (400 MHz, CDCl3) δ 8.49 (s, 1H), 7.67 (d, J=2.2Hz, 1H), 7.65 -7.52 (m, 1H), 7.51 - 7.43 (m, 1H), 2.43 (s, 3H), 1.23 (s, 9H). Synthesis of (R)-N-((S)-1-(4-bromo-3-methylphenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide (INT15-g):

[0275] (R,E)-N-(4-bromo-3-methylbenzylidene)-2-methylpropane-2-sulfinamide [INT15-f] (21 g, 69.4 mmol) and tetrabutylammonium triphenyl difluorosilicate (56.1 g, 104 mmol) were dissolved in THF (500 mL). Trifluoromethyltrimethylsilane (49.3 g, 347 mmol) was added dropwise at -80°C. The mixture was stirred at -30°C for 30 minutes, and then NH4Cl aqueous solution (300 mL) was added. The mixture was extracted with ELISA (2 × 300 mL). The organic phase was dried over sodium sulfate and evaporated in vacuum at 45°C. The residue was purified by flash chromatography to obtain (R)-N-((S)-1-(4-bromo-3-methylphenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide [INT15-g] (18.5g, 49.7 mmol, yield 71.7%) as a white solid. m / z: C13H18BrF3NOS [M+H]+ calculated value 372.0, measured value 372.0. 1 HNMR (500 MHz, CDCl3) δ 7 .56 (d, J=8.2 Hz, 1H), 7.30 -7.26 (m, 1H), 7.14 - 7.08 (m, 1H), 4.75 (p, J=7.1Hz, 1H), 3.58 (d, J=6.4 Hz,1H), 2.41 (s, 3H), 1.25 (s, 9H). Synthesis of (R)-N-((S)-1-(4-bromo-3-methylphenyl)-2,2,2-trifluoroethyl)-N,2-dimethylpropane-2-sulfinamide (INT15-h):

[0276] (R)-N-((S)-1-(4-bromo-3-methylphenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide [INT15-g] (10 g, 26.8 mmol) was dissolved in THF (200 mL). Lithium (1+) bis(trimethylsilyl) azanide (74.3 mL, 80.3 mmol) was added at 0°C. The mixture was stirred at 0°C for 20 minutes. Methyl iodide (22.7 g, 160 mmol) was added. The mixture was stirred at 20°C for 10 hours, and then NH4Cl aqueous solution (200 mL) was added. The mixture was extracted with ELISA (2 × 200 mL). The organic phase was dried with sodium sulfate and evaporated in a vacuum at 45°C to obtain crude (R)-N-((S)-1-(4-bromo-3-methylphenyl)-2,2,2-trifluoroethyl)-N,2-dimethylpropane-2-sulfinamide [INT15-h] (9.09 g, 23.5 mmol, yield 88.2%) as a brown oil. m / z: C14H20BrF3NOS [M+H]+ calculated value 386.0, measured value 386.0. 1 HNMR (400 MHz, CDCl3) δ 7.57 (d, J=8.3 Hz, 1H), 7.34 (s,1H), 7.17 (d, J=8.6 Hz,1H), 5.03 (q, J=8.5 Hz, 1H), 2.50 - 2.41 (m, 6H), 1.27(s, 9H). Synthesis of (S)-1-(4-bromo-3-methylphenyl)-2,2,2-trifluoro-N-methylethane-1-amine hydrochloride (INT15.2):

[0277] (R)-N-((S)-1-(4-bromo-3-methylphenyl)-2,2,2-trifluoroethyl)-N,2-dimethylpropane-2-sulfinamide [INT15-h] (10.7 g, 27.7 mmol) was dissolved in methanol (20 mL), and then hydrogen chloride (4 M in 1,4-dioxane, 100 mL, 2.54 mol) was added. The mixture was stirred at 20 °C for 10 hours, and then evaporated under vacuum at 50 °C. MTBE (100 mL) was added. The resulting solid was filtered and washed with MTBE (50 mL) to obtain (S)-1-(4-bromo-3-methylphenyl)-2,2,2-trifluoro-N-methylethane-1-amine hydrochloride [INT15.2] (5.41 g, 16.9 mmol, yield 61.3%) as a beige solid. m / z: C10H12BrF3N [M+H]+ Calculated value 282.0, 284.0, Measured value 284.0. 1 HNMR (500 MHz, DMSO-d6 ) δ 10.51 (s, 2H), 7.76 (d, J=8.3Hz, 1H), 7.63 (d, J=2.2Hz, 1H), 7.41 (dd, J=8.3, 2.2 Hz, 1H), 5.42 (s, 1H),2.43 (s, 3H), 2.37 (s, 3H). Synthesis of (S)-N-(1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethyl)-N-methylcyclobutanecarboxamide (intermediate 16.1): [ka]

[0278] (S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoro-N-methylethane-1-amine hydrochloride [INT15.1] (0.2 g, 0.6278 mmol) and cyclobutanecarboxylic acid (125 mg, 1.25 mmol) were mixed in pyridine (2 mL), and then phosphorus oxychloride (211 mg, 1.38 mmol) was added. The mixture was stirred at 90°C for 10 hours. SiO2 (20 mL) was added, and the mixture was washed with aqueous NaHSO4 solution (3 × 5 mL). The organic phase was dried over sodium sulfate and then... Evaporation in air at 45°C yielded (S)-N-(1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethyl)-N-methylcyclobutanecarboxamide [INT16.1] (190 mg, 0.5216 mmol, yield 83.3%) as a yellow oil. m / z: C15H18BrF3NO [M+H]+ calculated value 364.1, 366.1, measured value 366.0. 1 HNMR (400 MHz, CDCl3) δ 7.37 (s, 3H), 6.53 (q, J=8.8 Hz,1H), 3.70 (q,J=7.0 Hz, 1H), 3.28 (q, J=8.5 Hz, 1H), 2.65 (s, 3H), 2.39 (q,J=9.5 Hz, 1H),2.28 (q, J=10.1 Hz, 1H), 2.21 - 2.16 (m, 4H), 2.05 - 1.86 (m,2H). Synthesis of N-[(1S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethyl]-N-methylcyclopropanecarboxamide (intermediate 16.2): [ka]

[0279] [(1S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethyl](methyl)amine hydrochloride [INT15.1] (0.2 g, 0.6278 mmol) and cyclopropanecarboxylic acid (107 mg, 1.25 mmol) were mixed in pyridine (2 mL). Next, phosphorus oxychloride (211 mg, 1.38 mmol) was added. The mixture was stirred at 90°C for 10 hours. SiO (20 mL) was added. The mixture was washed with aqueous NaHSO4 solution (3 × 5 mL). The organic phase was dried with sodium sulfate and evaporated in a vacuum at 45°C to obtain N-[(1S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethyl]-N-methylcyclopropanecarboxamide [INT16.2] (190 mg, 0.5425 mmol, yield 86.7%) as a pale yellow solid. m / z: C14H16BrF3NO [M+H]+ calculated value 350.0, measured value 350.0. 1 HNMR (400 MHz, CDCl3) δ = 7.38 (s, 3H), 6.53 (q, J=8.9Hz, 1H), 2.91(s, 3H), 2.15 (s, 3H), 1.77 - 1.72 (m, 1H), 1.11 (s, 1H), 0.99(s, 1H), 0.84 (d,J=7.1 Hz, 2H). N-[(1S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ 6 Synthesis of -thian-4-carboxamide (intermediate 16.3): [ka]

[0280] Phosphorus oxychloride (788 mg, 5.14 mmol) is mixed with pyridine (3 mL) containing [(1S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethyl](methyl)amine hydrochloride [INT15.1] (500 mg, 1.56 mmol) and 1,1-dioxo-1λ 6The mixture was added at 0°C to a solution of -thian-4-carboxylic acid [INT4-a] (833 mg, 4.68 mmol). The reaction mixture was stirred overnight. 3 mL of aqueous sodium bicarbonate solution was added, and the mixture was extracted with RINKAN (3 × 10 mL) and washed with NaHSO4 (3 × 10 mL). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was purified by HPLC (see conditions below) to N-[(1S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ 6 -Chiang-4-carboxamide[I NT16.3 (132 mg, 0.2985 mmol, yield 19.1%) was obtained as a pink solid. m / z: C16H20BrF3NO3S [M+H]+ calculated value 442.0, 444.0, measured value 444.0.

[0281] HPLC conditions: Agilent 1260 Infinity II LC connected to Agilent 6120B single quadrupole LC / MS system, Column description: Chromatorex SBM 100-5T 5μm C18(2) 100Å, LC column 100×19mm, Waters, Sun Fire, Stationary phase: C18, Solid support: All porous silica, Separation mode: Reverse phase, Mobile phase A: Water, Mobile phase B: Acetonitrile, Flow rate: 30 ml / min, Loading pump B: 4 ml / min, Gradient conditions: 20%~30%~60%~100% (B) over 0 min~2 min~10 min~11.2 min. Synthesis of (S)-N-(1-(4-bromo-3-methylphenyl)-2,2,2-trifluoroethyl)-N-methylcyclobutanecarboxamide (intermediate 17.1): [ka]

[0282] (S)-1-(4-bromo-3-methylphenyl)-2,2,2-trifluoro-N-methylethane-1-amine hydrochloride [INT15.2] (0.2 g, 0.6278 mmol) and cyclobutanecarboxylic acid (125 mg, 1.25 mmol) were mixed in pyridine (2 mL), and then phosphorus oxychloride (211 mg, 1.38 mmol) was added at 20°C. The mixture was stirred at 90°C for 10 hours. Ether (20 mL) was added, and the mixture was washed with aqueous NaHSO4 solution (3 × 5 mL). The organic extract was dried with sodium sulfate and evaporated in a vacuum at 35°C to obtain (S)-N-(1-(4-bromo-3-methylphenyl)-2,2,2-trifluoroethyl)-N-methylcyclobutanecarboxamide [INT17.1] (228 mg, 0.6260 mmol, yield 100%) as a yellow oil. m / z: C15H18BrF3NO [M+H]+ Calculated value 364.0, 366.0, Measured value 366.0. 1 HNMR (400 MHz, CDCl3) δ 7.52 (d, J=8.3 Hz, 1H),7.19 (s, 1H), 7.04 (d,J=8.6 Hz, 1H), 6.55 (q, J=8.9 Hz, 1H), 3.37 -3.27 (m, 1H), 2.71 (s, 3H), 2.40 -2.35 (m, 4H), 2.27 - 2.17 (m, 2H), 2.05 -1.88 (m, 3H). Synthesis of N-[(1S)-1-(4-bromo-3-methylphenyl)-2,2,2-trifluoroethyl]-N-methylcyclopropanecarboxamide (intermediate 17.2): [ka]

[0283] [(1S)-1-(4-bromo-3-methylphenyl)-2,2,2-trifluoroethyl](methyl)amine hydrochloride [INT15.2] (1.25 g, 3.92 mmol) and cyclopropanecarboxylic acid (674 mg, 7.84 mmol) were mixed in pyridine (20 mL). Phosphoryl chloride (1.32 g, 8.62 mmol) was added. The mixture was stirred at 90°C for 10 hours. MTBE (300 mL) was added. The mixture was washed with NaHSO4 aqueous solution (3 × 50 mL). The organic phase was dried over sodium sulfate and evaporated under vacuum to obtain N-[(1S)-1-(4-bromo-3-methylphenyl)-2,2,2-trifluoroethyl]-N-methylcyclopropanecarboxamide [INT17. 2) (480 mg, 1.37 mmol, yield 35.0%) was obtained as a yellow solid. m / z: C14H16BrF3NO [M+H]+ calculated value 350.0, measured value 350.0. Synthesis of N-[(1S)-1-(4-bromo-3-methylphenyl)-2,2,2-trifluoroethyl]-N-methylcyclopropanecarboxamide (intermediate 17.3): [ka]

[0284] [(1S)-1-(4-bromo-3-methylphenyl)-2,2,2-trifluoroethyl](methyl)amine hydrochloride [INT15.2] (0.5g, 1.56 mmol) and 1,1-dioxo-1λ 6 -Thian-4-carboxylic acid [INT4-a] (833 mg, 4.68 mmol) was mixed in pyridine (2 mL). Phosphorus oxychloride (788 mg, 5.14 mmol) was added. The mixture was stirred at 90°C for 10 hours. Ether (20 mL) was added, and the mixture was washed with NaHSO4 aqueous solution (3 × 5 mL). The organic phase was dried over sodium sulfate and evaporated in vacuum at 45°C to obtain crude N-[(1S)-1-(4-bromo-3-methylphenyl)-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ 6-Chiane-4-carboxamide [INT17.3] (656 mg, 1.48 mmol) was obtained as a yellow solid. m / z: C16H20BrF3NO3S [M+H]+ Calculated value 442.0, Measured value 442.0. Synthesis of (1r,4S)-4-((tert-butyldimethylsilyl)oxy)-N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylcyclohexane-1-carboxamide (intermediate 18.1): [ka]

[0285] Pd2(dba)3 (17.9 mg, 19.6 μmol) was added to a suspension of (1r,4S)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-((tert-butyldimethylsilyl)oxy)-N-methylcyclohexane-1-carboxamide [INT8.1] (100 mg, 196 μmol), 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine hydrochloride [INT1.1] (67.0 mg, 254 μmol), Cs2CO3 (127 mg, 392 μmol), and xanthophos (22.6 mg, 39.2 μmol) in dioxane (3 mL). The resulting mixture was stirred at 100 °C for 4 hours under N2. The reaction mixture was poured into water (20 mL) and extracted with ELISA (15 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to obtain (1r,4S)-4-((tert-butyldimethylsilyl)oxy)-N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylcyclohexane -1-Carboxamide [INT18.1] (100 mg, 152 μmol, yield 78.1%) was obtained as a yellow oily substance. m / z: C30H43ClF3N6O3Si [M+H]+ Calculated value 655.3, measured value 655.2. Synthesis of methyl(1S,4r)-4-(((S)-1-(4-((2-chloro-7-isopropyl-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexane-1-carboxylate (intermediate 18.2): [ka]

[0286] A suspension of 2-chloro-7-(propan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine hydrochloride [INT1.2] (35 mg, 141 μmol), methyl(1S,4r)-4-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexane-1-carboxylate [INT5.4] (61.5 mg, 141 μmol), cesium carbonate (137 mg, 423 μmol), tris(dibenzylideneacetone)dipalladium (6.45 mg, 7.05 μmol), and xanthophos (8.15 mg, 14.1 μmol) in dioxane (2 mL) was stirred at 100 °C for 1.5 hours under N2 conditions. The mixture was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel flash chromatography (MeOH / dichloromethane = 0 / 1 to 1 / 99) to obtain methyl(1S,4r)-4-(((S)-1-(4-((2-chloro-7-isopropyl-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexane-1-carboxylate [INT18.2] (38.5 mg, 67.9 μmol, yield 48.1%) as a yellow solid. m / z: C26H30ClF3N6O3Na[M+Na]+ Calculated value 589.2, measured value 589.3. Synthesis of methyl(1S,3r)-3-(((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclobutane-1-carboxylate (intermediate 18.3): [ka]

[0287] In 3 mL of dioxane, methyl(1S,3r)-3-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclobutane-1-carboxylate [INT5.12] (0.1 g, 0.2449 mmol), 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine [free base of INT1.1] (55.5 mg, 244 μmol) l) and a mixture of cesium carbonate (239 mg, 734 μmol) were purged with argon. Next, tris(dibenzylideneacetone)dipalladium (11.1 mg, 12.2 μmol) and xanthophos (14.1 mg, 24.4 μmol) were added under argon, and the reaction mixture was stirred at 100°C for 10 hours. After cooling the reaction mixture, it was diluted with MTBE (50 mL), filtered, and the filtrate was concentrated under reduced pressure to obtain methyl(1S,3r)-3-(((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclobutan-1-carboxylate [INT18.3] (68.0 mg, 0.1225 mmol, yield 50.3%) as a yellow oil. m / z: [M+H]+ of C24H27ClF3N6O4 calculated value 555.2, measured value 555.0. Exemplary compound of formula (I)

[0288] The compounds listed in Table 1 below were synthesized using the identified intermediates according to schemes 1 to 11 as described above. Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23 Table 1-24 Table 1-25 Table 1-26 Table 1-27 Table 1-28 Table 1-29 Table 1-30 Table 1-31 Table 1-32 Table 1-33 Table 1-34 [Table 1-35] [Table 1-36] (Example 2) MALT1 Biochemical Assay

[0289] The efficacy of the inhibitors was evaluated by measuring the enzyme activity of full-length MALT1 at various concentrations of the compound. The enzyme assay consisted of a single-substrate reaction, during which the release of a fluorescent dye was monitored as the peptide substrate was cleaved. The peptide substrate had the following sequence: Ac-Leu-Arg-Ser-Arg-Rh110-dPro (custom synthesized from WuXi AppTec, Shanghai, China). The assay buffer consisted of 50 mM Hepes, pH 7.5, 0.8 M sodium citrate, 1 mM DTT, 0.004% tween(registered trademark)-20, and 0.005% bovine serum albumin (BSA). Steady-state kinetic analysis of peptide substrate binding was performed using the Michaelis-Menten constant (K) at 150 μM. M The assay was performed in a 384-well F-bottom polypropylene black microplate (Greiner Bio_One, catalog no. 781209) with 15 nM enzyme and 30 μM peptide substrate. The reaction was quenched after 60 minutes by adding iodoacetic acid to a final concentration of 10 mM. Total fluorescence was measured using Envision (PerkinElmer) by fluorescence excitation at 485 nm and fluorescence emission at 520 nm.

[0290] To determine potency, 1 μL of serially diluted compound (in 100% DMSO) was pre-incubated with 40 μL of enzyme for 30 minutes. The reaction was induced by adding 10 μL of peptide substrate. Relative fluorescence units were converted to inhibition percentages using 0% and 100% inhibition controls as references. The 100% inhibition control was (S)-1-(5-chloro-6-(2H-1,2,3-triazole-2-yl)pyridine-3-yl)-3-(2-chloro-7-(1-methoxyethyl)pyrazolo[1,5-a]pyrimidine-6-yl)urea (IC) at a final concentration of 1 μM. 50 The IC20 inhibitor consisted of 15 nM of DMSO, while the 0% inhibitory control consisted of 2% DMSO. 50 The values ​​were calculated by fitting the concentration response curve to the four-parameter logistic equation in GraphPad Prism.

[0291] The results from this assay are summarized in Table 2 below. In this table, "A" represents an IC of less than 0.1 μM. 50 This indicates that "B" represents ICs from 0.1 μM to 1 μM. 50 This indicates that "C" represents ICs larger than 1 μM. 50 This indicates that the compound was not tested. "N / A" indicates that the compound was not tested. For compounds tested in more than one experiment, the results shown represent the average value. [Table 2-1] [Table 2-2] [Table 2-3] (Example 3) Jarcut IL-2 assay

[0292] Inhibition was determined using a Jarcutt (ATCC, clone E6.1) immortalized T cell line, which was exposed to the dose-response of the compound in a cell-based assay and assessed for viability. Il-2 inhibition was determined by ELISA. Cells were cultured in RPMI / 10% FBS (Invitrogen 11875093, Atlanta Biologicals S12450H), maintained at less than 3E6 / mL, and used in assays only for fewer than 25 passages. The compound was stamped onto a 384-well plate (PerkinElmer Culturplate, 6007680) by ECHO. Cells were seeded on top of the compound in fresh medium, incubated for 30 minutes, and then stimulated with soluble anti-CD3 / 28 / 2 (Stemcell, 10970) for 24 hours. The supernatant was collected and assessed for Il-2 (MSD, 384 wells, L21SA-1). To assess the viability of cells treated with the compound, cells were lysed with CTG reagent (Promega, G7570) and measured by luminometer. The IL-2 curve was calculated as a percentage of DMSO (100%) control and signal inhibition (0%, (S)-1-(5-chloro-6-(2H-1,2,3-triazole-2-yl)pyridine-3-yl)-3-(2-chloro-7-(1-methoxyethyl)pyrazolo[1,5-a]pyrimidine-6-yl)urea) control. IC 50 This was calculated using a 4-parameter fit in GraphPad Prism.

[0293] The results from this assay are summarized in Table 3 below. In this table, "A" represents an IC of less than 0.1 μM. 50 This indicates that "B" represents ICs from 0.1 μM to 1 μM. 50 This indicates that "C" represents ICs larger than 1 μM. 50 This indicates that the compound was not tested. "N / A" indicates that the compound was not tested. For compounds tested in more than one experiment, the results shown represent the average value. [Table 3-1] [Table 3-2] [Table 3-3] (Example 4) Human plasma protein binding assay using high-throughput dialysis (HTD)

[0294] The binding of various compounds of formula (I) to human plasma proteins was evaluated using the equilibrium dialysis method described herein. Preparation of dialysis membranes and matrices

[0295] Dialysis membrane strip (HTD96a / b, catalog number 1101, HTDialysis) The film (LLC, Gales Ferry, CT, USA) was immersed in ultrapure water at room temperature for approximately 1 hour. Each membrane strip containing two membranes was separated and immersed in 20:80 ethanol / water (v / v) for approximately 20 minutes, after which it was either ready for use or stored in the solution at 2-8°C for up to 1 month. Before the experiment, the membranes were rinsed three times and immersed in ultrapure water for 20 minutes.

[0296] On the day of the experiment, human plasma (BioIVT, catalog number HUMANPLNHPNN, sodium) was used. Multiple individuals (pooled with umheparin or EDTA-K2 anticoagulant) were thawed by running cold tap water over them and centrifuged at 3220 rpm for 5 minutes to remove any blood clots. The resulting plasma pH was confirmed to be between 7.0 and 8.0. Dialysis Procedure

[0297] The test compound and warfarin control (Stru Chem, catalog number SC-16139) were dissolved in dimethyl sulfoxide (DMSO) to obtain a 10 mM stock solution. A 400 μM DMSO solution was prepared. To prepare the loading matrix, 5 μL of the compound solution was added to 995 μL of blank human plasma in a 1:200 ratio and thoroughly mixed.

[0298] Samples at time 0 (T0), which would be used to determine the recovery rate, were prepared as follows: A fixed volume of 50 μL of loading matrix was transferred in triplicate to a sample collection plate. The samples were immediately paired with the reverse blank buffer (a basic solution (14.2 g / L Na2HPO4 and 8.77 g / L NaCl in deionized water) titrated to pH 7.4 ± 0.1 using an acidic solution (15.6 g / L NaH2PO4.2H2O and 8.77 g / L NaCl in deionized water)) to obtain a final volume of 100 μL of 1:1 matrix / dialysis buffer (v / v) in each well. 500 μL of stop solution (200 ng / mL tolbutamide and 200 ng / mL labetalol in acetonitrile) was added to these T0 samples. They were then stored at 2–8°C for further processing along with other post-dialysis samples.

[0299] To load the dialysis device (96-well equilibrium dialysis plate, Model 96b, Catalog No. 1006, HTDialysis LLC, Gales Ferry, CT, USA), a fixed volume of 150 μL of loading matrix was transferred in three consecutive units to the donor side of each dialysis well, and 150 μL of dialysis buffer was loaded to the receiver side of that well. The dialysis plate was placed in a humidified incubator at 37°C containing 5% CO2 on a s...

Claims

[Claim 1] The invention described in the specification.

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