Malt1 modulators and uses thereof

Abstract

Provided herein are compounds, compositions, and methods useful for modulating MALT1 and for treating related diseases, disorders, and conditions.

Description

[0001] This application is a divisional application of Chinese invention patent application (application date: October 15, 2021; application number: 202180083881.6 (international application number: PCT / US2021 / 055173); invention title: MALT1 regulator and its use).

[0002] Cross-reference to related applications

[0003] This application claims priority and benefit to U.S. Provisional Patent Application No. 63 / 092,768, filed October 16, 2020, the entire contents of which are incorporated herein by reference. Background of the Invention

[0005] Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is an intracellular signaling protein known from both innate immune cells (such as natural killer (NK) cells, dendritic cells (DCs), and mast cells) and adaptive immune cells (such as T cells and B cells). MALT1 plays a crucial role in influencing immune responses. For example, in T cell receptor signaling, MALT1 mediates nuclear factor kappa B (NFKB) signaling, leading to T cell activation and proliferation. Therefore, MALT1 is significant for understanding the mechanisms of autoimmunity and inflammatory pathology. Furthermore, 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 could be used as potential therapeutic agents. Invention Overview

[0007] This document provides compounds designed to be used as MALT1 modulators. In some embodiments, these compounds are anticipated to be used as therapeutic agents for autoimmune and inflammatory diseases, disorders or conditions, or cancer.

[0008] On the one hand, this article provides compounds represented by formula (I) or pharmaceutically acceptable salts thereof:

[0009] (I)

[0010] in:

[0011] R 1 Selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl and 5-10 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 3-6 The cycloalkyl group and the 5-10 membered heterocyclic group may optionally be independently selected from R on one or more available carbons, consisting of one, two, three or more groups. 1aThe substituents are substituted, wherein if the 5-10 membered heterocyclic group contains a substituted cyclic nitrogen atom, the cyclic nitrogen atom may optionally be replaced by R. 1b Substitution, wherein if the 5-10 membered heterocyclic group contains a substituted cyclic sulfur atom, the cyclic sulfur atom may optionally be substituted by two O atoms;

[0012] R 2 It is CH3 or CF3;

[0013] R 3 It is hydrogen; or

[0014] R 3 Selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 cycloalkyl, 5-6 membered heterocyclic, 5-6 membered heterocyclic -C 1-3 Alkyl-, 5-6-membered heterocyclic-O-, phenyl, and 5-6-membered heteroaryl, any one of which may optionally be selected independently by one, two, or three from R 3a Substituents of the substituents;

[0015] R 4 C 1-6 alkyl;

[0016] R 1a Each time it appears, it is independently selected from 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 alkoxy, 5-6 membered heterocyclic and 5-6 membered heteroaryl, wherein the C 1-6 Alkyl groups are optionally coated with -N(R) A )2 substitution, and wherein if the 5-6 membered heterocyclic group contains a substituted cyclic nitrogen atom, then the cyclic nitrogen atom may optionally be replaced by R B replace;

[0017] R 1b Selected from 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;

[0018] R 3a Each time it appears, it is independently selected from halogens and C. 1-4 Alkyl, C 1-4 Haloalkyl, C1-4 Alkoxy, C 1-4 Halogenated alkoxy, hydroxyl, C 1-4 alkenyl, cyano, azide, -NR C R D C 3-6 cycloalkyl, C 1-4 Alkoxy C 1-4 Alkoxy, 5-6 membered heterocyclic -O-, 5-6 membered heterocyclic and phenyl, wherein C 3-6 The cycloalkyl group, the 5-6 membered heterocyclic group -O-, the 5-6 membered heterocyclic group, and the phenyl group are optionally selected by one, two, or three independently from R. p Substituents of the substituents;

[0019] R p Each time it appears, it is independently selected from halogens and C. 1-4 Alkyl, C 1-4 Halogenated alkyl, hydroxyl, C 1-4 Alkoxy, C 1-4 Alkoxy C 1-4 Alkyl, NR C R D and amino C 1-3 alkyl;

[0020] R A Each time it appears, it is independently selected from hydrogen and C. 1-6 Alkyl, -C(O)C 1-6 Alkyl groups and -C(O)OC 1-6 alkyl;

[0021] R B Selected from C 1-6 Alkyl, C 3-6 cycloalkyl and -C(O)OC 1-6 alkyl;

[0022] R C and R D Each time it appears, it is independently selected from hydrogen and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl and C 3-4 cycloalkyl, or

[0023] R C and R D Together with the nitrogen atoms to which they are attached, they form 4-6 membered heterocyclic groups or 4-6 membered heteroaryl groups, wherein the 4-6 membered heterocyclic group or 4-6 membered heteroaryl group may contain additional nitrogen or oxygen atoms and optionally be substituted with one or two fluorine atoms; and

[0024] t is 0 or 1.

[0025] On the other hand, this article provides compounds represented by formula (Ib) or pharmaceutically acceptable salts thereof:

[0026] (Ib)

[0027] in:

[0028] R 1 C 1-6 Alkyl, C 3-6 Cycloalkyl or 5-10 membered heterocyclic group, wherein the C 3-6 The cycloalkyl group may optionally be formed on one or more available carbons by one, two, three or more atoms, each independently selected from R. 1a The substituents are substituted, wherein if the 5-10 membered heterocyclic group contains a substituted cyclic nitrogen atom, the cyclic nitrogen atom may optionally be replaced by R. 1b Substitution, wherein if the 5-10 membered heterocyclic group contains a substituted cyclic sulfur atom, the cyclic sulfur atom may optionally be substituted by two O atoms;

[0029] R 1a Each time it appears, it is independently selected from 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 5-6 heteroaryl groups, wherein the C 1-6 Alkyl groups are optionally coated with -N(R) A )2 replaces;

[0030] R 1b Selected from 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; and

[0031] R A Each time it appears, it is independently selected from hydrogen and C. 1-6 Alkyl, -C(O)C 1-6 Alkyl groups and -C(O)OC 1-6 alkyl.

[0032] In some embodiments, the compounds provided herein are selected from the compounds listed in Table 1 or pharmaceutically acceptable salts thereof.

[0033] On the other hand, this document provides pharmaceutical compositions comprising the compounds disclosed herein and pharmaceutically acceptable carriers.

[0034] On the other hand, this article provides a method for treating cancer in subjects who require this treatment, the method comprising administering to the subject a therapeutically effective amount of the compound or pharmaceutical composition disclosed herein.

[0035] On the other hand, this article provides a method for treating autoimmune or inflammatory conditions or diseases in subjects who require such treatment, the method comprising administering to the subject a therapeutically effective amount of the compound or pharmaceutical composition disclosed herein. Invention Details

[0037] As generally described herein, the present invention provides compounds designed, for example, to function as MALT1 modulators. In some embodiments, these compounds are intended to be used as therapeutic agents for treating autoimmune and inflammatory diseases, disorders or conditions, or cancer.

[0038] definition

[0039] Chemical definition

[0040] The definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the periodic table, CAS version, Handbook of Chemistry and Physics, 75th edition (internal page), and specific functional groups are generally defined as described herein. Furthermore, see Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5 th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3 rd The book describes the general principles of organic chemistry, as well as specific functional groups and reactivity, in Edition 1987, Cambridge University Press, Cambridge.

[0041] The compounds described herein may contain one or more asymmetric 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 may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures rich in one or more stereoisomers. Isomers may be isolated from the mixture by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis. See, 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, page 268 (EL Eliel, ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). This invention further covers the compounds described herein in their single isomer form, substantially free of other isomers, and alternatively in mixtures of different isomers.

[0042] As used herein, a pure enantiomer is substantially free of other enantiomers or stereoisomers of the compound (i.e., exhibiting an enantiomeric excess). In other words, the “S” form of the compound is substantially free of the “R” form of the compound, and therefore exhibits an enantiomeric excess of the “R” form. The terms “enantiomerically pure” or “pure enantiomer” mean that the compound contains more than 75 wt%, more than 80 wt%, more than 85 wt%, more than 90 wt%, more than 91 wt%, more than 92 wt%, more than 93 wt%, more than 94 wt%, more than 95 wt%, more than 96 wt%, more than 97 wt%, more than 98 wt%, more than 98.5 wt%, more than 99 wt%, more than 99.2 wt%, more than 99.5 wt%, more than 99.6 wt%, more than 99.7 wt%, more than 99.8 wt%, or more than 99.9 wt% of enantiomers. In some implementations, the weight is based on the total weight of all enantiomers or stereoisomers of the compound.

[0043] In the compositions provided herein, the enantiomerically pure compound may be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising an enantiomerically pure R-compound may comprise, for example, about 90% excipients and about 10% enantiomerically pure R-compound. In some embodiments, the enantiomerically pure R-compound in such compositions may, for example, comprise at least about 95% by weight of the R-compound and at most about 5% by weight of the S-compound, based on the total weight of the compounds. For example, a pharmaceutical composition comprising an enantiomerically pure S-compound may comprise, for example, about 90% excipients and about 10% enantiomerically pure S-compound. In some embodiments, the enantiomerically pure S-compound in such compositions may, for example, comprise at least about 95% by weight of the S-compound and at most about 5% by weight of the R-compound, based on the total weight of the compounds. In some embodiments, the active ingredient may be formulated with or without a small amount of excipients or a carrier.

[0044] The compounds described herein may also contain one or more isotopic substitutions. For example, H can be in any isotopic form, including 1 H, 2 H (D or deuterium) and 3 H (T or tritium); C can be any isotopic form, including 12 C 13 C and 14 C and O can be in any isotopic form, including 16 O and 18 O; F can be any isotopic form, including 18 F and 19 F; etc.

[0045] The following terms are intended to have the meanings presented below and to aid in understanding the description and intended scope of the invention. When the description may include compounds and their pharmaceutically acceptable salts, pharmaceutical compositions comprising such compounds, and methods of using such compounds and compositions, the following terms, if present, shall have the following meanings unless otherwise stated. It should also be understood that, as described herein, any portion defined below may be substituted with multiple substituents, and each definition is intended to include such substituted portions within its scope as shown below. Unless otherwise stated, the term “substituted” is defined as follows. It should also be understood that the terms “group” and “base” are considered interchangeable when used herein. The articles “an” and “a” may be used herein to refer to one / a or more / a (i.e., at least one / a) of the grammatical objects of the article. By way of example, “analogy” means one or more analogs.

[0046] When listing a range of values, the intention is to cover every value within that range and its subranges. For example, "C 1–6The term "alkyl" is intended to encompass C1, C2, C3, C4, C5, C6, and C6 alkyl groups. 1–6 C 1–5 C 1–4 C 1–3 C 1–2 C 2–6 C 2–5 C 2–4 C 2–3 C 3–6 C 3–5 C 3–4 C 4–6 C 4–5 and C 5–6 alkyl.

[0047] As used herein, "alkyl" refers to, for example, a straight-chain or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C"). 1–20 Alkyl group). In some embodiments, the alkyl group has 1 to 10 carbon atoms (“C10”). 1–10 Alkyl group). In some embodiments, the alkyl group has 1 to 9 carbon atoms (“C1”). 1–9 Alkyl group). In some embodiments, the alkyl group has 1 to 8 carbon atoms (“C1”). 1–8 Alkyl group). In some embodiments, the alkyl group has 1 to 7 carbon atoms (“C1”). 1–7 Alkyl group (“C”). In some embodiments, the alkyl group has 1 to 6 carbon atoms (“C”). 1–6 Alkyl group). In some embodiments, the alkyl group has 1 to 5 carbon atoms (“C1”). 1–5 Alkyl group). In some embodiments, the alkyl group has 1 to 4 carbon atoms (“C1”). 1–4 Alkyl group). In some embodiments, the alkyl group has 1 to 3 carbon atoms (“C1”). 1–3 Alkyl group (“alkyl”). In some embodiments, the alkyl group has 1 to 2 carbon atoms (“C”). 1-2 Alkyl group (“C1 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, hexyl, etc.

[0048] As used herein, “alkenyl” refers to a straight-chain or branched hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds), and optionally one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds). 2–20 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group does not contain any triple bonds. In some embodiments, the alkenyl group has 2 to 10 carbon atoms (“C”). 2–10Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 9 carbon atoms (“C”). 2–9 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 8 carbon atoms (“C”). 2–8 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 7 carbon atoms (“C”). 2–7 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 6 carbon atoms (“C”). 2–6 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 5 carbon atoms (“C”). 2–5 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 4 carbon atoms (“C”). 2–4 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 3 carbon atoms (“C”). 2–3 The alkenyl group (“C2-alkenyl”) has two carbon atoms in some embodiments. The one or more carbon-carbon double bonds can be internal (e.g., in 2-butenyl) or terminal (e.g., in 1-butenyl). 2–4 Examples of alkenyl groups include vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), etc. 2–6 Examples of alkenyl groups include the C group mentioned above. 2–4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), and hexenyl (C6). Other examples of alkenyl groups include heptenyl (C7), octenyl (C8), and octtrienyl (C8).

[0049] As used herein, “alkynyl” refers to a straight-chain or branched hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds), and optionally one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds). 2–20 The alkynyl group (“Alynyl”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 10 carbon atoms (“C”). 2–10 The alkynyl group (“C”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 9 carbon atoms (“C”). 2–9 The alkynyl group (“acetylenic”) has 2 to 8 carbon atoms in some embodiments. 2–8 The alkynyl group (“acetylation”) has 2 to 7 carbon atoms in some embodiments. 2–7 The alkynyl group (“C”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 6 carbon atoms (“C”). 2–6 The alkynyl group (“H”) has 2 to 5 carbon atoms in some embodiments. 2–5 The alkynyl group (“C”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 4 carbon atoms (“C”). 2–4The alkynyl group (“C”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 3 carbon atoms (“C”). 2–3 The alkynyl group (“C2-alkynyl”) is used in some embodiments. The one or more carbon-carbon triple bonds can be internal (as in 2-butynyl) or terminal (as in 1-butynyl). 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 Examples of alkenyl groups include the C group mentioned above. 2–4 Alkynyl groups include pentynyl (C5), hexynyl (C6), etc. Other examples of alkynyl groups include heptynyl (C7), octynyl (C8), etc.

[0050] As used herein, “alkylene,” “alkenylene,” “alkynylene,” “cycloalkylene,” “heterocyclic,” “heteroaryl,” and “phenylene” refer to the divalent groups of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic (e.g., saturated and partially saturated), heteroaryl, and phenyl, respectively.

[0051] When a range or number of carbons is provided for a particular "alkylene", "alkenylene", or "ynyneyl" group, it should be understood that the range or number refers to the range or number of carbons in a straight-chain divalent carbon chain. "alkylene", "alkenylene", and "ynyneyl" groups may be substituted or unsubstituted by one or more substituents as described herein.

[0052] As used herein, “aryl” refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a ring array) having 6–14 ring carbon atoms and 0 heteroatoms (“C…”) in the aromatic ring system. 6–14 The aryl group (“Aryl”). In some embodiments, the aryl group has 6 ring carbon atoms (“C6 aryl”; for example, phenyl). In some embodiments, the aryl group has 10 ring carbon atoms (“C6 aryl”). 10 Aryl; for example, naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms (“C”). 14"Aryl" (e.g., anthracene). "Aryl" also includes ring systems in which an aromatic ring as defined above is fused with one or more carbocyclic or heterocyclic groups, wherein the group or linking point is on the aromatic ring, and in such cases, the number of carbon atoms continues to indicate the number of carbon atoms in the aromatic ring system. Typical aryl groups include, but are not limited to, those derived from: anthracene, acenaphthene, phenanthrene, anthracene, azurite, benzene, chrysene, coronene, fluoranthene, fluorene, and hexaphenylene. Hexalene, hexadiene, as-dicyclopentanobenzene, s-dicyclopentanobenzene, indene, indene, naphthalene, octacene, octaphene, octalene, pentyl-2,4-diene, pentanebenzene, cyclopentadiene, pentanene, perylene, phenanthracene, sepium, heptaphenene, pyrene, pyroxane, rubigin, benzophenanthrene, and trinaphthalene. Specifically, aryl groups include phenyl, naphthyl, indene, and tetrahydronaphthyl.

[0053] As used herein, “heteroaryl” refers to a 4n+2 aromatic ring system of 5-10 member monocyclic or bicyclic rings (e.g., having 6 or 10 electrons shared in the ring array), having a ring carbon atom and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, and sulfur (“5–10 member heteroaryl”). In heteroaryls containing one or more nitrogen atoms, the bonding point can be a carbon or nitrogen atom, provided the valence allows. Heteroaryl bicyclic ring systems may contain one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems in which a heteroaryl ring as defined above is fused with one or more carbocyclic or heterocyclic groups, wherein the bonding point is on the heteroaryl ring, and in such cases, the number of ring members continues to indicate the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring as defined above is fused with one or more aryl groups, wherein the linking point is on an aryl or heteroaryl ring, and in such cases, the number of ring members indicates the number of ring members in the fused (aryl / heteroaryl) ring system. In bicyclic heteroaryl groups (e.g., indolyl, quinolinyl, carbazolyl, etc.) where one ring does not contain a heteroatom, the linking point can be on either ring, i.e., the ring carrying the heteroatom (e.g., 2-indolyl) or the ring without the heteroatom (e.g., 5-indolyl).

[0054] In some embodiments, the heteroaryl group is a 5-10 membered aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, the heteroaryl group is a 5-8 membered aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, the heteroaryl group is a 5-6 membered aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, the 5-6 membered heteroaryl group has 1-3 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl group has 1-2 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl group has one cyclic heteroatom selected from nitrogen, oxygen, and sulfur.

[0055] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrole, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetraazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azircolyl, oxazircolyl, and thioazircolyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazole, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolazinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthidyl, pteridyl, quinolinyl, isoquinolinyl, cenolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0056] Representative examples of heteroaryl groups include the following:

[0057]

[0058] Each Z is selected from carbonyl, N, NR 65 O and S; and R 65 Independently hydrogen, C1-8 alkyl, C3-10 Carbocyclic group, 4-10 membered heterocyclic group, C6-C 10 Aryl and 5-10 heteroaryl compounds.

[0059] As used herein, "carbocyclic group" or "carbocyclic ring" refers to a non-aromatic ring system having 3 to 10 ring carbon atoms ("C"). 3–10 A group consisting of a carbocyclic group (“C”) and a non-aromatic cyclic hydrocarbon group with zero heteroatoms. In some embodiments, the carbocyclic group has 3 to 8 cyclic carbon atoms (“C”). 3–8 Carbocyclic group (“CCR”). In some embodiments, the carbocyclic group has 3 to 7 cyclic carbon atoms (“C”). 3-7 Carbocyclic group (“CCR”). In some embodiments, the carbocyclic group has 3 to 6 cyclic carbon atoms (“C”). 3–6 (Carbocyclic group). In some embodiments, the carbocyclic group has 5 to 10 cyclic carbon atoms (“C”). 5–10 (Carbocyclic group). Example C 3–6 Carbocyclic groups include, but are not limited to, cyclopropyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), and cyclohexadienyl (C6). Example C 3-8 Carbocyclic groups include, but are not limited to, the C groups mentioned above. 3-6 Carbocyclic groups, including cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cyclohepttrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), etc. Example C 3–10 Carbocyclic groups include, but are not limited to, the C groups mentioned above. 3–8 Carbocyclic groups and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9) 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C9) 10 ), spiro[4.5]decyl (C 10 As illustrated in the foregoing examples, in some embodiments, the carbocyclic group is monocyclic (“monocyclic carbocyclic”) or contains fused, bridged, or spirocyclic systems, such as bicyclic systems (“bicyclic carbocyclic”), and may be saturated or partially unsaturated. “Carbocyclic” also includes ring systems in which the carbocyclic ring as defined above is fused with one or more aryl or heteroaryl groups, wherein the connection point is on the carbocyclic ring, and in such cases, the number of carbons continues to indicate the number of carbons in the carbocyclic system.

[0060] The term "cycloalkyl" refers to hydrocarbons derived from cycloalkanes, referred to herein as, for example, "C". 4-8"Cycloalkyl" refers to a monovalent saturated cyclic, bicyclic, or bridged (e.g., adamantyl) hydrocarbon group with 3-12, 3-8, 4-8, or 4-6 carbons. Exemplary cycloalkyl groups include, but are not limited to, cyclohexane, cyclopentane, cyclobutane, and cyclopropane.

[0061] As used herein, “C3-6 monocyclic cycloalkyl” or “monocyclic C3-6 cycloalkyl” refers to a saturated 3- to 7-membered monocyclic hydrocarbon ring system. 3- to 7-membered monocyclic cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Where specified as optional substituted or substituted, the substituent on the cycloalkyl group (e.g., in the case of an optionally substituted cycloalkyl group) may be present at any substituted position, including, for example, the position connecting to the cycloalkyl group.

[0062] As used herein, "heterocyclic group" or "heterocycle" refers to a group having a 3- to 10-membered nonaromatic ring system having a ring carbon atom and one to four ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 10-membered heterocyclic group"). In a heterocyclic group containing one or more nitrogen atoms, the linking point can be a carbon or nitrogen atom, provided the valence allows. Heterocyclic groups can be monocyclic ("monocyclic heterocyclic group") or fused, bridged, or spirocyclic systems (such as bicyclic systems ("bicyclic heterocyclic group")), and can be saturated or partially unsaturated. A heterocyclic bicyclic ring system may contain one or more heteroatoms in one or both rings. "Heterocyclic group" also includes ring systems in which a heterocyclic ring as defined above is fused with one or more carbocyclic groups, wherein the connection point is on the carbocyclic or heterocyclic ring; or ring systems in which a heterocyclic ring as defined above is fused with one or more aryl or heteroaryl groups, wherein the connection point is on the heterocyclic ring. In such cases, the number of ring members continues to indicate the number of ring members in the heterocyclic ring system. The terms "heterocyclic," "heterocyclic group," "heterocyclic ring," "heterocyclic group," "heterocyclic moiety," and "heterocyclic radical" are used interchangeably.

[0063] In some embodiments, the heterocyclic group is a 4-7 membered non-aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“4-7 membered heterocyclic group”). In some embodiments, the heterocyclic group is a 5-10 membered non-aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5-10 membered heterocyclic group”). In some embodiments, the heterocyclic group is a 5-8 membered non-aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclic group”). In some embodiments, the heterocyclic group is a 5-6 membered non-aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclic group”). In some embodiments, the 5-6 membered heterocyclic group has 1-3 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclic group has 1-2 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclic group has 1 cyclic heteroatom selected from nitrogen, oxygen, and sulfur.

[0064] Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to, aziridinyl, ethylene oxide, and cyclothioethane. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to, aziridine, oxadiazolinyl, and thiohexacyclobutane. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxopranyl, oxadiazolinyl, dithiohexacyclopentane, and oxazolidinyl-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithiaalkyl, and dioxalyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirheptanyl, oxeheptanyl, and thioheptanyl. Exemplary 8-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirheptanyl, oxeheptanyl, and thioheptanyl. Exemplary 5-membered heterocyclic groups fused to a C6 aromatic ring (also referred to herein as 5,6-bicyclic heterocycles) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinone, etc. Exemplary 6-membered heterocyclic groups fused to an aromatic ring (also referred to herein as 6,6-bicyclic heterocycles) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0065] Examples of saturated or partially unsaturated heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, pyrrolylyl, pyridoneyl, pyrrolidoneyl, piperidinyl, oxazolyl, piperazineyl, dioxalyl, dioxopentyl, morpholinyl, dihydrofuranyl, dihydropyranyl, dihydropyridyl, tetrahydropyridyl, dihydropyrimidinyl, oxobutyl, azahexacyclic butyl, and tetrahydropyrimidinyl. Where specified as optional substitution or substituted, the substituent on the heterocyclic group (e.g., in the case of optionally substituted heterocyclic groups) may be present at any substituted position, including, for example, positions connecting to the heterocyclic group.

[0066] 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 have been replaced by nitrogen, oxygen, or sulfur heteroatoms. "Hetero" can be applied to any of the above-mentioned hydrocarbon groups having 1 to 5, and particularly 1 to 3, heteroatoms, such as alkyl groups (e.g., heteroalkyl groups); carbocyclic groups (e.g., heterocyclic groups); aryl groups (e.g., heteroaryl groups), etc.

[0067] As used in this article, "cyano" refers to -CN.

[0068] As used herein, the terms "halogenated" and "halogen" refer to an atom selected from fluorine (fluorinated, -F), chlorine (chlorinated, -Cl), bromine (brominated, -Br), and iodine (iodinated, -I). In some embodiments, the halogen group is fluorine or chlorine.

[0069] As used herein, the term "alkoxy" refers to an alkyl group (-O(alkyl)) that is attached to another part by an oxygen atom. Non-limiting examples include, for example, methoxy, ethoxy, propoxy, and butoxy.

[0070] "Haloalkoxy" refers to a haloalkyl group that is attached to another part by an oxygen atom, such as, but not limited to, -OCHCF2 or -OCF3.

[0071] The term "haloalkyl" includes mono-, poly-, and per-haloalkyl groups substituted with one or more halogen atoms, wherein the halogen is independently selected from fluorine, chlorine, bromine, and iodine. For the C1-4 haloalkyl group -O-C1-4 alkyl, the connecting point appears on the halogenated alkyl moiety.

[0072] As used in this article, "oxo" refers to -C=O.

[0073] Generally, the term "substituted," whether or not preceded by the term "optionally," means that at least one hydrogen atom present on a group (e.g., a carbon or nitrogen atom) is replaced by a permissible substituent, such as a substituent that, upon substitution, yields a stable compound, such as a compound that is not spontaneously transformed, for example, by rearrangement, cyclization, elimination, or other reactions. Unless otherwise stated, a "substituted" group has substituents at one or more substituted positions of the group, and when more than one position in any given structure is substituted, the substituents are either the same or different at each position.

[0074] Where valence permits, the nitrogen atom may be substituted or unsubstituted, and may include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen substituents include, but are not limited to, 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 All-halogenated alkyl, C 2–10 alkenyl, C 2–10 alkynyl group, C 3–10 Carbocyclic groups, 3–14 membered heterocyclic groups, C 6–14 aryl and 5–14 heteroaryl groups, or two R groups bonded to a nitrogen atom cc The groups combine to form a 3-14 membered heterocyclic group or a 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution, and wherein R aa R bb R cc and R dd The definition is as above.

[0075] These and other exemplary substituents are described in more detail in the detailed description of the invention, embodiments, and claims. The invention is not intended to be limited in any way to the above list of exemplary substituents.

[0076] Other definitions

[0077] As used herein, "pharmaceuticalally acceptable carrier" means a non-toxic carrier, adjuvant, or mediator that does not impair the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants, or mediators that can be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffering substances such as phosphates, glycine, sorbic acid, potassium sorbate, mixtures of saturated vegetable fatty acids in the form of glycerides, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.

[0078] As used herein, a “pharmaceutically acceptable salt” means that, within reasonable medical judgment, it is suitable for contact with human and lower animal tissues without excessive toxicity, irritation, allergic reactions, etc., and is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are those formed by reacting amino groups with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, disaccharide, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucono-heptahydrate, glyceryl phosphate, gluconate, hemisulfate, heptahydrate, hexanoate, hydroiodate, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, dodecyl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, neopentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Pharmaceutically acceptable salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N. + (C 1–4 Alkyl salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium salts. Other pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxyl, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate ions.

[0079] As used herein, the “subject” intended to be administered includes, but is not limited to, humans (i.e., men or women of any age group, such as pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and / or non-human animals, such as mammals like primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms “human,” “patient,” and “subject” are used interchangeably herein.

[0080] Disease, obstacle, and symptom are used interchangeably in this article.

[0081] As used herein, and unless otherwise stated, the terms “treat,” “treating,” and “treatment” refer to actions that occur when a subject has the specified disease, disorder, or condition, which reduce the severity of the disease, disorder, or condition, or delay or slow the progression of the disease, disorder, or condition (“therapeutic treatment”), and also to actions that occur before the subject begins to have the specified disease, disorder, or condition (“preventive treatment”).

[0082] As used herein, an "effective amount" of a compound means an amount sufficient to elicit the desired biological response. Those skilled in the art will understand that the effective amount of the compounds of the present invention can vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the route of administration, and the age, health, and condition of the subject. Effective amounts include both therapeutic and prophylactic treatments.

[0083] As used herein, and unless otherwise stated, a "therapeuticly effective amount" of a compound is an amount sufficient to provide therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with said disease, disorder, or condition. A therapeutically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other therapies, that provides therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeuticly effective amount" may also encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of a disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0084] compound

[0085] On the one hand, this article provides compounds represented by formula (I) or pharmaceutically acceptable salts thereof:

[0086] (I)

[0087] in:

[0088] R1 Selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl and 5-10 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 3-6 The cycloalkyl group and the 5-10 membered heterocyclic group may optionally be independently selected from R on one or more available carbons, consisting of one, two, three or more groups. 1a The substituents are substituted, wherein if the 5-10 membered heterocyclic group contains a substituted cyclic nitrogen atom, the cyclic nitrogen atom may optionally be replaced by R. 1b Substitution, wherein if the 5-10 membered heterocyclic group contains a substituted cyclic sulfur atom, the cyclic sulfur atom may optionally be substituted by two O atoms;

[0089] R 2 It is CH3 or CF3;

[0090] R 3 It is hydrogen; or

[0091] R 3 Selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 cycloalkyl, 5-6 membered heterocyclic, 5-6 membered heterocyclic -C 1-3 Alkyl-, 5-6-membered heterocyclic-O-, phenyl, and 5-6-membered heteroaryl, any one of which may optionally be selected independently by one, two, or three from R 3a Substituents of the substituents;

[0092] R 4 C 1-6 alkyl;

[0093] R 1a Each time it appears, it is independently selected from 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 alkoxy, 5-6 membered heterocyclic and 5-6 membered heteroaryl, wherein the C 1-6 Alkyl groups are optionally coated with -N(R) A )2 substitution, and wherein if the 5-6 membered heterocyclic group contains a substituted cyclic nitrogen atom, then the cyclic nitrogen atom may optionally be replaced by R B replace;

[0094] R 1b Selected from C 1-6 Alkyl, -C(O)OR A -C(O)C 1-6Alkyl, -C(O)C 3-6 Cycloalkyl, -C(O)N(R) A )2 and -S(O)2C 1-6 alkyl;

[0095] R 3a Each time it appears, it is independently selected from halogens and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, hydroxyl, C 1-4 alkenyl, cyano, azide, -NR C R D C 3-6 cycloalkyl, C 1-4 Alkoxy C 1-4 Alkoxy, 5-6 membered heterocyclic -O-, 5-6 membered heterocyclic and phenyl, wherein C 3-6 The cycloalkyl group, the 5-6 membered heterocyclic group -O-, the 5-6 membered heterocyclic group, and the phenyl group are optionally selected by one, two, or three independently from R. p Substituents of the substituents;

[0096] R p Each time it appears, it is independently selected from halogens and C. 1-4 Alkyl, C 1-4 Halogenated alkyl, hydroxyl, C 1-4 Alkoxy, C 1-4 Alkoxy C 1-4 Alkyl, NR C R D and amino C 1-3 alkyl;

[0097] R A Each time it appears, it is independently selected from hydrogen and C. 1-6 Alkyl, -C(O)C 1-6 Alkyl groups and -C(O)OC 1-6 alkyl;

[0098] R B Selected from C 1-6 Alkyl, C 3-6 cycloalkyl and -C(O)OC 1-6 alkyl;

[0099] R C and R D Each time it appears, it is independently selected from hydrogen and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl and C 3-4 cycloalkyl, or

[0100] R C and R DTogether with the nitrogen atoms to which they are attached, they form 4-6 membered heterocyclic groups or 4-6 membered heteroaryl groups, wherein the 4-6 membered heterocyclic group or 4-6 membered heteroaryl group may contain additional nitrogen or oxygen atoms and optionally be substituted with one or two fluorine atoms; and

[0101] t is 0 or 1.

[0102] On the other hand, this article provides compounds represented by formula (I) or pharmaceutically acceptable salts thereof:

[0103] (I)

[0104] in:

[0105] R 1 C 1-6 Alkyl, C 3-6 Cycloalkyl or 5-10 membered heterocyclic group, wherein the C 3-6 The cycloalkyl group may optionally be formed on one or more available carbons by one, two, three or more atoms, each independently selected from R. 1a The substituents are substituted, wherein if the 5-10 membered heterocyclic group contains a substituted cyclic nitrogen atom, the cyclic nitrogen atom may optionally be replaced by R. 1b Substitution, wherein if the 5-10 membered heterocyclic group contains a substituted cyclic sulfur atom, the cyclic sulfur atom may optionally be substituted by two O atoms;

[0106] R 2 It is CH3 or CF3;

[0107] R 3 C 1-6 Alkyl, wherein the C 1-6 Alkyl groups may optionally be C 1-4 Alkyl substitution;

[0108] R 4 C 1-6 alkyl;

[0109] R 1a Each time it appears, it is independently selected from 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 5-6 heteroaryl groups, wherein the C 1-6 Alkyl groups are optionally coated with -N(R) A )2 replaces;

[0110] R 1b Selected from 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;

[0111] R A Each time it appears, it is independently selected from hydrogen and C. 1-6 Alkyl, -C(O)C 1-6 Alkyl groups and -C(O)OC 1-6 Alkyl; and

[0112] t is 0 or 1.

[0113] In some implementations, t = 0. In some implementations, t = 1.

[0114] In some implementation schemes, R 4 C 1-6 Alkyl group. In some embodiments, R 4 It is CH3.

[0115] On the other hand, this article provides compounds represented by formula (Ia) or pharmaceutically acceptable salts thereof:

[0116] (Ia)

[0117] in:

[0118] R 1 Selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl and 5-10 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 3-6 The cycloalkyl group and the 5-10 membered heterocyclic group may optionally be independently selected from R on one or more available carbons, consisting of one, two, three or more groups. 1a Substituents; wherein if the 5-10 membered heterocyclic group contains a substituted cyclic nitrogen atom, the cyclic nitrogen atom may optionally be replaced by R. 1b Substitution, wherein if the 5-10 membered heterocyclic group contains a substituted cyclic sulfur atom, the cyclic sulfur atom may optionally be substituted by two O atoms;

[0119] R 2 It is CH3 or CF3;

[0120] R 3 It is hydrogen; or

[0121] R 3 Selected from C 1-6 Alkyl, C 1-6 Alkoxy, C3-7 cycloalkyl, 5-6 membered heterocyclic, 5-6 membered heterocyclic -C 1-3 Alkyl-, 5-6-membered heterocyclic-O-, phenyl, and 5-6-membered heteroaryl, any one of which may optionally be selected independently by one, two, or three from R 3a Substituents of the substituents;

[0122] R 1a Each time it appears, it is independently selected from 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 alkoxy, 5-6 membered heterocyclic and 5-6 membered heteroaryl, wherein the C 1-6 Alkyl groups are optionally coated with -N(R) A )2 substitution, and wherein if the 5-6 membered heterocyclic group contains a substituted cyclic nitrogen atom, then the cyclic nitrogen atom may optionally be replaced by R B replace;

[0123] R 1b Selected from 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;

[0124] R 3a Each time it appears, it is independently selected from halogens and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, hydroxyl, C 1-4 alkenyl, cyano, azide, NR C R D C 3-6 cycloalkyl, C 1-4 Alkoxy C 1-4 Alkoxy, 5-6 membered heterocyclic -O-, 5-6 membered heterocyclic and phenyl, wherein C 3-6 The cycloalkyl group, the 5-6 membered heterocyclic group -O-, the 5-6 membered heterocyclic group, and the phenyl group are optionally selected by one, two, or three independently from R. p Substituents of the substituents;

[0125] R p Selected from halogens, C 1-4 Alkyl, C 1-4 Halogenated alkyl, hydroxyl, C1-4 Alkoxy, C 1-4 Alkoxy C 1-4 Alkyl, NR C R D and amino C 1-3 alkyl;

[0126] R A Each time it appears, it is independently selected from hydrogen and C. 1-6 Alkyl, -C(O)C 1-6 Alkyl groups and -C(O)OC 1-6 alkyl;

[0127] R B Selected from C 1-6 Alkyl, C 3-6 cycloalkyl and -C(O)OC 1-6 Alkyl; and

[0128] R C and R D Each time it appears, it is independently selected from hydrogen and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl and C 3-4 cycloalkyl, or

[0129] R C and R D Together with the nitrogen atoms to which they are attached, they form 4-6 membered heterocyclic groups or 4-6 membered heteroaryl groups, wherein the 4-6 membered heterocyclic group or 4-6 membered heteroaryl group may contain additional nitrogen or oxygen atoms and optionally be substituted with one or two fluorine atoms.

[0130] On the other hand, this article provides compounds represented by formula (Ia) or pharmaceutically acceptable salts thereof:

[0131] (Ia)

[0132] in:

[0133] R 1 C 1-6 Alkyl, C 3-6 Cycloalkyl and 5-10 membered heterocyclic groups, wherein the C 3-6 The cycloalkyl group may optionally be formed on one or more available carbons by one, two, three or more atoms, each independently selected from R. 1a Substituents; wherein if the 5-10 membered heterocyclic group contains a substituted cyclic nitrogen atom, the cyclic nitrogen atom may optionally be replaced by R. 1b Substitution, wherein if the 5-10 membered heterocyclic group contains a substituted cyclic sulfur atom, the cyclic sulfur atom may optionally be substituted by two O atoms;

[0134] R 2It is CH3 or CF3;

[0135] R 3 C 1-6 Alkyl, wherein the C 1-6 Alkyl groups may optionally be C 1-4 Alkyl substitution;

[0136] R 1a Each time it appears, it is independently selected from 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 5-6 heteroaryl groups, wherein the C 1-6 Alkyl groups are optionally coated with -N(R) A )2 replaces;

[0137] R 1b Selected from 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; and

[0138] R A Each time it appears, it is independently selected from hydrogen and C. 1-6 Alkyl, -C(O)C 1-6 Alkyl groups and -C(O)OC 1-6 alkyl;

[0139] In some implementation schemes, R 2 For CH3. In some implementations, R 2 It is CF3.

[0140] In some implementation schemes, R 3 C 1-6 Alkyl, wherein R 3 Optional C 1-4 Alkyl-substituted.

[0141] In some implementation schemes, R 3 C 1-6 Alkyl group. In some embodiments, R 3 for .

[0142] In some implementation schemes, R 3 C 1-6 Alkyl, wherein R 3 C 1-4Alkyl substitution. In some embodiments, R 3 for .

[0143] On the other hand, this article provides compounds represented by formula (Ib) or pharmaceutically acceptable salts thereof:

[0144] (Ib)

[0145] in:

[0146] R 1 C 1-6 Alkyl, C 3-6 Cycloalkyl or 5-10 membered heterocyclic group, wherein the C 3-6 The cycloalkyl group may optionally be formed on one or more available carbons by one, two, three or more atoms, each independently selected from R. 1a The substituents are substituted, wherein if the 5-10 membered heterocyclic group contains a substituted cyclic nitrogen atom, the cyclic nitrogen atom may optionally be replaced by R. 1b Substitution, wherein if the 5-10 membered heterocyclic group contains a substituted cyclic sulfur atom, the cyclic sulfur atom may optionally be substituted by two O atoms;

[0147] R 1a Each time it appears, it is independently selected from 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 5-6 heteroaryl groups, wherein the C 1-6 Alkyl groups are optionally coated with -N(R) A )2 replaces;

[0148] R 1b Selected from C 1-6 Alkyl, -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 Alkyl; and

[0149] R A Each time it appears, it is independently selected from hydrogen and C. 1-6 Alkyl, -C(O)C 1-6 Alkyl groups and -C(O)OC 1-6 alkyl.

[0150] In some implementation schemes, R 1 C 1-6Alkyl group. In some embodiments, R 1 It is CH3.

[0151] In some implementation schemes, R 1 C 3-6 cycloalkyl, wherein R 1 Optionally, one, two, three, or more carbon atoms may be independently selected from R on one or more available carbons. 1a Substituents are substituted.

[0152] In some implementation schemes, R 1 C 3-6 Cycloalkyl. In some embodiments, R 1 Selected from , , and .

[0153] In some implementation schemes, R 1 C 3-6 cycloalkyl, wherein R 1 One, two, three or more carbon atoms are independently selected from R on one or more available carbons. 1a Substituents are substituted.

[0154] In some implementation schemes, R 1 for , or In some implementations, R 1a Selected from cyano, fluorine, hydroxyl, -O-CH3, -C(O)OH, -C(O)NH2, , , , , , , , , and .

[0155] In some implementation schemes, R 1 Selected from , , , , , , , , , , , , , , , and .

[0156] In some implementation schemes, R 1 Selected from , , , , , , , , , , , , , , , , , , , and .

[0157] In some implementation schemes, R 1 It is a 5-10 member heterocyclic group, where if R 1 If it contains a substituted cyclic nitrogen atom, then the cyclic nitrogen atom can be optionally replaced by R. 1b The 5-10 membered heterocyclic group may be substituted with a substituted cyclic sulfur atom, which may optionally be substituted with two O atoms.

[0158] In some implementation schemes, R 1 It is a 5-10 membered heterocyclic group. In some implementations, R 1 Selected from , , , , , and .

[0159] In some implementation schemes, R 1 for In some implementations, R 1 for .

[0160] In some implementation schemes, R 1 Selected from , , and In some implementations, R 1b Selected from CH3 , , , , , and .

[0161] In some implementation schemes, R 1 Selected from , , , , , , , , , , , , , , , , , , and .

[0162] In some implementation schemes, R 1 Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , and .

[0163] In some implementation schemes, R 1 Selected from CH3 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

[0164] In some implementation schemes, R 1 Selected from CH3 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

[0165] In some embodiments, the compounds provided herein are selected from the compounds listed in Table 1 or pharmaceutically acceptable salts thereof.

[0166] In some embodiments, the compound is selected from:

[0167] N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ 6 -Thiazide-4-carboxamide;

[0168] N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methylacetamide;

[0169] N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methyloxane-2-carboxamide;

[0170] (1r,4r)-4-{[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl](methyl)carbamoyl}methyl cyclohexane-1-carboxylate;

[0171] N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methylthiazide-4-carboxamide;

[0172] N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methyloxacyclopentane-3-carboxamide;

[0173] N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methyl-1,4-dioxaspiro[4.5]decane-8-carboxamide;

[0174] N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-4,4-difluoro-N-methylcyclohexane-1-carboxamide;

[0175] (1r,3S)-N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-3-cyano-N-methylcyclobutane-1-carboxamide;

[0176] 4-{[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl](methyl)carbamoyl}piperidine-1-carboxylic acid tert-butyl ester;

[0177] 3-{[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl](methyl)carbamoyl}piperidine-1-carboxylic acid tert-butyl ester;

[0178] 3-{[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl](methyl)carbamoyl}pyrrolidine-1-carboxylic acid tert-butyl ester;

[0179] N-[(4-{[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl](methyl)carbamoyl}cyclohexyl)methyl]tert-butyl carbamate;

[0180] (1r,4S)-N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-4-methoxy-N-methylcyclohexane-1-carboxamide;

[0181] 1-Acetyl-N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methylazacyclobutane-3-carboxamide;

[0182] N-(4-{[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl](methyl)carbamoyl}cyclohexyl)carbamate;

[0183] N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-4-acetamido-N-methylcyclohexane-1-carboxamide;

[0184] N-[(1S)-1-(4-{[2-chloro-7-(propyl-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]amino}phenyl)-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ 6 -Thiazide-4-carboxamide;

[0185] 1-Acetyl-N-[(1S)-1-(4-{[2-chloro-7-(propyl-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]amino}phenyl)-2,2,2-trifluoroethyl]-N-methylpiperidine-4-carboxamide;

[0186] N-{1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]ethyl}-N-methylcyclobutaneformamide;

[0187] N-{1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]ethyl}-N-methylcyclohexaneformamide;

[0188] N-{1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]ethyl}-N-methylcyclopentaneformamide;

[0189] N-{1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]ethyl}-N-methylcyclopropaneformamide;

[0190] N-{1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]ethyl}-N-methylacetamide;

[0191] N-{1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl}-N-methylacetamide;

[0192] N-[(1R)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ 6 -Thiazide-4-carboxamide;

[0193] N-[(1R)-1-[4-({2-chloro-7-[(1R)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ 6 -Thiazide-4-carboxamide;

[0194] N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)-2-methylphenyl]-2,2,2-trifluoroethyl]-N-methylcyclobutaneformamide;

[0195] N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)-2-methylphenyl]-2,2,2-trifluoroethyl]-N-methylcyclopropaneformamide;

[0196] N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)-2-methylphenyl]-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ 6 -Thiazide-4-carboxamide;

[0197] N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)-3-methylphenyl]-2,2,2-trifluoroethyl]-N-methylcyclobutaneformamide;

[0198] N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)-3-methylphenyl]-2,2,2-trifluoroethyl]-N-methylcyclopropaneformamide;

[0199] N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)-3-methylphenyl]-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ 6 -Thiazide-4-carboxamide;

[0200] N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylpiperidine-4-carboxamide;

[0201] N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methylpiperidin-3-carboxamide;

[0202] N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylpyrrolidine-3-carboxamide;

[0203] 4-(aminomethyl)-N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methylcyclohexane-1-carboxamide;

[0204] 1-Acetyl-N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylpiperidine-4-carboxamide;

[0205] N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methyl-1-(propane-2-sulfonyl)piperidine-4-carboxamide;

[0206] 4-{[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl](methyl)carbamoyl}piperidine-1-carboxylic acid methyl ester;

[0207] N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-1-methanesulfonyl-N-methylpiperidine-4-carboxamide;

[0208] 1-Acetyl-N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methylpiperidine-3-carboxamide;

[0209] N 3 -[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N 1 N 3 -Dimethylpiperidine-1,3-dicarboxamide;

[0210] N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-1-methanesulfonyl-N-methylpiperidine-3-carboxamide;

[0211] 1-Acetyl-N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methylpyrrolidine-3-carboxamide;

[0212] N 3 -[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N 1 N 3 -Dimethylpyrrolidine-1,3-dicarboxamide;

[0213] N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-1-methanesulfonyl-N-methylpyrrolidine-3-carboxamide;

[0214] N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-4-(acetamidomethyl)-N-methylcyclohexane-1-carboxamide;

[0215] N-[(4-{[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl](methyl)carbamoyl}cyclohexyl)methyl]carbamate;

[0216] N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-1-(cyclopropanecarbonyl)-N-methylpiperidine-4-carboxamide;

[0217] N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-1-cyclopropanecarbonyl-N-methylpiperidine-3-carboxamide;

[0218] N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-1-cyclopropanecarbonyl-N-methylpyrrolidine-3-carboxamide;

[0219] N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N,1-dimethylpiperidine-4-carboxamide;

[0220] N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N,1-dimethylpiperidin-3-carboxamide

[0221] N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N,1-dimethylpyrrolidine-3-carboxamide;

[0222] (1r,4S)-N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-4-hydroxy-N-methylcyclohexane-1-carboxamide;

[0223] (1S,4r)-4-(((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexane-1-carboxylic acid;

[0224] (1S,4r)-4-(((S)-1-(4-((2-chloro-7-isopropyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexane-1-carboxylic acid;

[0225] (1S,3r)-3-(((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclobutane-1-carboxylic acid;

[0226] (1r,4S)-N 1 -((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N 1 -Methylcyclohexane-1,4-dicarboxamide;

[0227] (1r,4S)-N 1 -((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N 1 N 4 -Dimethylcyclohexane-1,4-dicarboxamide;

[0228] (1r,4S)-N 1 -((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N 1 N 4 N 4 -Trimethylcyclohexane-1,4-dicarboxamide;

[0229] (1r,3S)-N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyl-3-(1H-tetrazol-5-yl)cyclobutane-1-carboxamide;

[0230] N-((S)-1-(4-((2-chloro-7-((R)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiaran-4-carboxamide;

[0231] 1-Acetyl-N-((S)-1-(4-((2-chloro-7-((R)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylpiperidine-4-carboxamide; and pharmaceutically acceptable salts thereof.

[0232] Pharmaceutical Compositions and Routes of Administration

[0233] The compounds provided according to the present invention are typically administered in the form of pharmaceutical compositions. Therefore, the present invention provides pharmaceutical compositions comprising one or more of the said compounds as active ingredients, or pharmaceutically acceptable salts or esters thereof, and one or more pharmaceutically acceptable excipients, carriers including 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 a manner well known in the pharmaceutical industry (see, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (GS Banker & CT Rhodes, Eds.)).

[0234] The pharmaceutical composition may be administered in single or multiple doses via any of the accepted routes of administration of the pharmaceutical agent having similar efficacy, such as those described by reference in those patents and patent applications, including rectal, sublingual, nasal and transdermal routes, intra-arterial injection, intravenous administration, intraperitoneal administration, parenteral administration, intramuscular administration, subcutaneous administration, oral administration, local administration, as an inhaler, or via an impregnation or coating device, such as a stent, like a cylindrical polymer inserted into an artery.

[0235] One mode of administration is parenteral administration, particularly by injection. The novel compositions of the present invention can be incorporated into forms for injection administration including aqueous or oily suspensions or emulsions containing sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or sterile aqueous solutions and similar vehicle media. Saline solutions are also commonly 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. Suitable flowability can be maintained, for example, by using a coating such as lecithin, in the case of dispersions by maintaining the desired particle size, and by using surfactants. Microbial action can be prevented by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc.

[0236] Sterile injectable solutions are prepared by incorporating the required amount of the compound according to the invention, along with various other components listed above, into a suitable solvent, followed by filtration sterilization if necessary. Typically, dispersions are prepared by incorporating various sterilized active ingredients into a sterile carrier containing a basic dispersion medium and the other desired components listed above. In the case of sterile powders used to prepare sterile injectable solutions, preferred methods of preparation include vacuum drying and freeze-drying techniques, which produce powders of the active ingredient plus any additional desired components derived from their previously sterile filtered solutions.

[0237] Oral administration is another route of administration for the compounds of the present invention. Administration may be via capsules or enteric-coated tablets, etc. In the preparation of pharmaceutical compositions comprising at least one of the compounds described herein, the active ingredient is typically diluted with an excipient and / or encapsulated within a carrier to present in the form of capsules, sachet, paper, or other containers. When the excipient is used as a diluent, it can be a solid, semi-solid, or liquid material (as above), which acts as a medium, carrier, or medium for the active ingredient. Thus, the composition can be in the form of tablets, pills, powders, lozenges, sachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injections, and sterile packaged powders.

[0238] Some examples of suitable excipients include lactose, glucose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth gum, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. Formulations may also include: lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifiers and suspending agents; preservatives such as methyl benzoate and hydroxypropyl benzoate; sweeteners; and flavoring agents.

[0239] The compositions of the present invention can be formulated using methods known in the art to provide rapid, sustained, or delayed release of the active ingredient after administration to a patient. Controlled-release drug delivery systems for oral administration include osmotic pump systems and dissolution systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled-release systems are given in U.S. Patent Nos. 3,845,770; 4,326,525; 4,902,514; and 5,616,345. Another formulation used in the methods of the present invention employs a transdermal drug delivery device (“patch”). Such transdermal patches can be used to provide continuous or discontinuous infusions of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for drug delivery are well known in the art. See, for example, U.S. Patent Nos. 5,023,252, 4,992,445, and 5,001,139. ​​Such patches can be constructed for continuous, pulsed, or on-demand drug delivery.

[0240] The composition is preferably formulated as a unit dosage form. The term "unit dosage form" refers to a physically separated unit suitable as a single dose for human subjects and other mammals, each unit containing a predetermined amount of active substance calculated to produce the desired therapeutic effect, and suitable pharmaceutical excipients (e.g., tablets, capsules, and ampoules). These compounds are typically administered in an effective amount. Preferably, for oral administration, each dose unit contains 1 mg to 2 g of the compound described herein, and for parenteral administration, preferably 0.1 to 700 mg of the compound described herein. However, it should be understood that the actual amount of compound administered is usually determined by the physician based on relevant circumstances, including the condition to be treated, the chosen route of administration, the compound actually administered and its relative activity, the individual patient's age, weight and response, the severity of the patient's symptoms, etc.

[0241] To prepare solid compositions, such as tablets, the main active ingredient is mixed with a pharmaceutical excipient to form a solid preformed composition containing a homogeneous mixture of the compounds of the present invention. When these preformed 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 equivalent unit dosage forms, such as tablets, pills, and capsules.

[0242] The tablets or pills of the present invention can be coated or otherwise compounded to provide a dosage form with the advantage of prolonged action, or to protect them from the acidic conditions of the stomach. For example, the tablets or pills may comprise an inner dose component and an outer dose component, the latter covering the former in an encapsulated form. These two components may be separated by an enteric coating, which prevents the components from disintegrating in the stomach and allows the inner component to be delivered intact into the duodenum or to delay release. A wide variety of materials can be used for such an enteric coating or coating, including many polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.

[0243] Compositions for inhalation or inhalation include solutions and suspensions in pharmaceutically acceptable water or organic solvents, or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients, as described above. Preferably, the composition can be administered via oral or nasal inhalation to produce a local or systemic effect. Compositions in preferred pharmaceutically acceptable solvents can be nebulized using an inert gas. The nebulized solution can be inhaled directly from a nebulizing device, or the nebulizing device can be connected to a face mask inhaler or an intermittent positive pressure ventilator. Solution, suspension, or powder compositions can be administered from a device that delivers the formulation in a suitable manner, preferably orally or intranasally.

[0244] In some embodiments, a pharmaceutical composition comprising the disclosed compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier is included.

[0245] How to use

[0246] The compounds and compositions described herein are generally used to modulate MALT1 and can be used to treat diseases or disorders, particularly those sensitive to the proteolytic and / or autoproteolytic activities that regulate MALT1. In some embodiments, the compounds and compositions described herein can be used to inhibit MALT1. In some embodiments, the compounds and compositions of the present invention are contemplated for use in treating diseases, disorders, or conditions characterized by dysregulated NF-κB activation, such as autoimmune or immune and inflammatory disorders, allergic disorders, respiratory disorders, and tumor disorders.

[0247] In typical embodiments, the present invention is intended to cover the compounds disclosed herein, as well as pharmaceutically acceptable salts, pharmaceutically acceptable esters, tautomer forms, polymorphs, and prodrugs of such compounds. In some embodiments, the present invention includes pharmaceutically acceptable addition salts, pharmaceutically acceptable esters, solvates (e.g., hydrates) of addition salts, tautomer forms, polymorphs, enantiomers, mixtures of enantiomers, stereoisomers, or mixtures of stereoisomers (pure or as racemic or non-racemic mixtures) of the compounds described herein (e.g., compounds of formula (I); such general formulas named herein).

[0248] In some implementations, autoimmune and inflammatory disorders are selected from 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 transplant rejection, acute or chronic graft-versus-host disease, chronic allogeneic graft rejection, Behcet'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 and bullous diseases (e.g., pemphigus vulgaris), antibody-mediated vasculitis syndromes, including ANCA-associated vasculitis, Henoch-Schonlein purpura, and immune complex vasculitis (primary or secondary infection or cancer).

[0249] In some implementations, the tumor barrier is selected from carcinoma, sarcoma, lymphoma, leukemia and germ cell tumors, adenocarcinoma, bladder cancer, clear cell carcinoma, skin cancer, brain cancer, cervical cancer, colon cancer, colorectal cancer, endometrial cancer, brain tumors, breast cancer, gastric cancer, germ cell tumors, glioblastoma, hepatic adenoma, Hodgkin lymphoma, liver cancer, kidney cancer, lung cancer, pancreatic cancer, head / neck / laryngeal cancer, ovarian cancer, skin tumors, prostate cancer, renal cell carcinoma, gastric cancer, hematologic malignancies, 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 Cezari syndrome, mycosis fungoides, cutaneous T-cell lymphoma, T-cell acute lymphoblastic leukemia, melanoma, mucosa-associated lymphoid tissue (MALT). MALT lymphoma, multiple myeloma, plasma cell tumor, malignant lentigines melanoma, acral melanoma, squamous cell carcinoma, chronic myeloid leukemia, myeloid leukemia, superficial diffuse melanoma, acral lentigines melanoma, mucosal melanoma, nodular melanoma, polypoid melanoma, fibroproliferative melanoma, amelanoma, soft tissue melanoma, melanoma with nevus-like cells, and so on. Spitz nevus is a characteristic melanoma, uveal melanoma, precursor T-cell lymphoma, leukemia / lymphoma, acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, follicular lymphoma, chronic lymphocytic leukemia / lymphoma, Burkitt lymphoma, mycosis fungoides, peripheral T-cell lymphoma, nodular sclerosis of Hodgkin lymphoma, mixed cell subtype of Hodgkin lymphoma, non-small cell lung cancer, large cell carcinoma, and small cell lung cancer.

[0250] In some embodiments, the tumor disorder is cancer in the form of a tumor or a hematogenous cancer. 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 selected from adenomas, adenocarcinomas, blastomas (e.g., hepatoblastoma, glioblastoma, neuroblastoma, and retinoblastoma), carcinomas (e.g., colorectal cancer or hepatocellular carcinoma, pancreatic cancer, prostate cancer, gastric cancer, esophageal cancer, cervical cancer, head and neck cancer, and adenocarcinoma), desmoidomas, fibroblastic small round cell tumors, endocrine tumors, germ cell tumors, lymphomas, leukemias, sarcomas (e.g., Ewing sarcoma, osteosarcoma, rhabdomyosarcoma, or any other soft tissue sarcoma), nephroblastomas, lung tumors, colon tumors, lymphomas, breast tumors, or melanomas.

[0251] In some implementations, allergic disorders are selected from contact dermatitis, celiac disease, asthma, hypersensitivity to house dust mites, pollen and related allergens, and beryllium poisoning.

[0252] In some implementations, the respiratory disorder is selected from asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pulmonary edema, pulmonary embolism, pneumonia, pulmonary sarcoidosis, silicosis, pulmonary fibrosis, respiratory failure, acute respiratory distress syndrome, primary pulmonary hypertension, and emphysema.

[0253] In some embodiments, the compounds and compositions of the present invention can be used to treat rheumatoid arthritis, systemic lupus erythematosus, vasculitis, allergic diseases, asthma, chronic obstructive pulmonary disease (COPD), acute or chronic transplant rejection, graft-versus-host disease, hematopoietic cancer or solid tumors, chronic myeloid leukemia, myeloid leukemia, non-Hodgkin lymphoma or other B-cell lymphomas.

[0254] Combination therapy

[0255] The compounds or compositions described herein may be administered in combination with another drug or therapy. Subjects to be given the compounds disclosed herein may have a disease, disorder, or condition or symptoms thereof that would benefit from treatment with another drug or therapy.

[0256] In some embodiments, the compounds of the compositions described herein may be administered simultaneously, before, or after one or more other therapeutic agents. In some embodiments, the compounds of the compositions described herein may be administered alone via the same or different routes of administration, or together with other pharmaceutical agents in the same pharmaceutical composition.

[0257] In some embodiments, the compounds described herein may be administered as the sole active ingredient or, for example, as an adjuvant, in combination with other drugs such as immunosuppressants or immunomodulators or other anti-inflammatory agents (e.g., for the treatment or prevention of acute or chronic rejection or inflammation or autoimmune diseases of allogeneic or xenografts), or chemotherapeutic agents (e.g., antiproliferative agents of malignant cells). For example, the compounds of the present invention may be used in combination with neurotrophic inhibitors such as cyclosporine A or FK506; rmTOR inhibitors such as rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, biolimus-7, or biolimus-9; ascomycins with immunosuppressive properties such as ABT-281, ASM981; corticosteroids; cyclophosphamide; azathioprine; methotrexate; leflunomide; imidazolidinedione; mycophenolic acid or its salt; mycophenolate mofetil; or IL-1β inhibitors.

[0258] In some implementations, the compounds described herein are combined with adjuvants that act as PI3K inhibitors.

[0259] In some embodiments, the compounds described herein are combined with adjuvants that affect BTK (Brutton's tyrosine kinase).

[0260] For the treatment of cancer, the compounds described herein can be used in combination with B-cell modulators such as rituximab, ofamumab, BTK or SYK inhibitors, PKC, PI3K, PDK, PIM, JAK and rmTOR inhibitors and BH3 mimics. Example

[0261] The following representative embodiments are intended to help illustrate the invention, and are not intended to, nor should they be construed as, limiting the scope of the invention.

[0262] The compounds described herein can be prepared from readily available starting materials using the following general methods and procedures. It should be understood that other process conditions may be used, unless otherwise stated, provided that typical or preferred operating conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given. Optimal reaction conditions may vary depending on the specific reactants or solvents used, but such conditions can be determined by those skilled in the art through routine optimization.

[0263] Furthermore, it will be apparent to those skilled in the art that conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesirable reactions. The selection of appropriate protecting groups for specific functional groups, as well as suitable conditions for protection and deprotection, is well known in the art. For example, many protecting groups and their introduction and removal are described in, for example, TW Greene and PGM Wuts, Protecting Groups in Organic Synthesis, 2nd ed., Wiley, New York, 1991, and the references cited therein.

[0264] The compounds described herein can be separated and purified using known standard procedures. These procedures include recrystallization, filtration, rapid chromatography, grinding, high-performance liquid chromatography (HPLC), or supercritical fluid chromatography (SFC). Note that rapid chromatography can be performed manually or using an automated system. The compounds described herein can be characterized using 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 generated using methods well known to those skilled in the art.

[0265] List of abbreviations:

[0266] EtOAc (ethyl acetate)

[0267] THF Tetrahydrofuran

[0268] PE petroleum ether

[0269] DMA dimethylacetamide

[0270] MeOH (methanol)

[0271] EtOH (ethanol)

[0272] DMF N,N-dimethylformamide

[0273] DMSO (dimethyl sulfoxide)

[0274] xphos 2-Dicyclohexylphosphine-2′,4′,6′-Triisopropylbiphenyl

[0275] FA Formic acid

[0276] DCM dichloromethane

[0277] MTBE (methyl tert-butyl ether)

[0278] TFA (trifluoroacetic acid)

[0279] MeCN, ACN acetonitrile

[0280] i-PrMgCl isopropyl magnesium chloride

[0281] Xantphos 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene

[0282] i-PrOH isopropanol

[0283] TMSCF3 Trifluoromethyltrimethylsilane

[0284] MeI iodomethane

[0285] LiHMDS bis(trimethylsilyl)aminolithium

[0286] h, hr, hrs hours

[0287] Calcd (calculated value)

[0288] UV ultraviolet rays

[0289] rt room temperature

[0290] DIEA, DIPEA N,N-diisopropylethylamine

[0291] HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0292] CDI 1,1'-carbonyldiimidazole

[0293] ee enantiomer excess

[0294] TMS trimethylsilyl

[0295] Pd2(dba)3 tris(dibenzylacetone)dipalladium(0)

[0296] Et3N, TEA Triethylamine

[0297] Cs2CO3 (cesium carbonate)

[0298] INT intermediate

[0299] EDCI 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

[0300] HOBT, HOBt 1-hydroxybenzotriazole

[0301] TLC (Thin Layer Chromatography)

[0302] Conc. (thick / rich)

[0303] Boc tert-butoxycarbonyl

[0304] AcCl (acetyl chloride)

[0305] NaBH3CN Sodium cyanoborohydride

[0306] HO(CH2O)nH Paraformaldehyde

[0307] LiOH.H2O Lithium hydroxide monohydrate

[0308] NH4Cl ammonium chloride

[0309] MeNH2.HCl methylamine hydrochloride

[0310] Me2NH.HCl dimethylamine hydrochloride

[0311] TMSN3 Trimethylsilyl Azide

[0312] (C4H9)2SnO Dibutyltin Oxide

[0313] NH2NH2.H2O hydrazine hydrate

[0314] t-BuOH tert-butanol

[0315] t-BuOK potassium tert-butoxide

[0316] DPPA diphenylphosphohydride

[0317] NaOH (sodium hydroxide)

[0318] (n-Bu)4OAc Tetrabutylacetic acid ammonium

[0319] (COCl)2 oxalyl chloride

[0320] Na2CO3 (Sodium carbonate)

[0321] POCl3 Phosphorus oxychloride

[0322] TBSCl tert-butyldimethylchlorosilane

[0323] TBS tert-butyldimethylsilyl

[0324] Sodium hydride (NaH)

[0325] Ti(OEt)4 titanium ethanol

[0326] TBAT Tetrabutylammonium difluorotriphenylsilicate

[0327] overnight

[0328] EDTA (ethylenediaminetetraacetic acid)

[0329] Example 1. Preparation of the compound

[0330] The methods for preparing the compounds described herein are illustrated in the following synthetic embodiments. These embodiments are given to illustrate the invention and should not be construed as limiting the scope or spirit of the invention in any way. The starting materials shown in the embodiments can be obtained from commercial sources or prepared from commercial sources according to the operations described in the literature.

[0331] 1. Compounds prepared using Scheme 1

[0332] Option 1:

[0333]

[0334] Contains R 3 Triazolopyrimidine G-1a and R-containing 1 and R 2 The reaction of formamide G-1b yields compound (I).

[0335] N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6- [[2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ] 6 -Thiazide-4-carboxamide (also known as N-thiazide-4-carboxamide) ((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)benzene The synthesis of (2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiaran-4-carboxamide (1,1-dioxide) (compound 1.1) become

[0336]

[0337] 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 thiazide-4-carboxamide [INT 5.1] (779 mg, 1.82 mmol), Pd2(dba)3 (159 mg, 174 µmol), Xantphos (201 mg, 348 µmol), and Cs2CO3 (1.70 g, 5.22 mmol) in dioxane (6 mL) was stirred at 100 °C for 4 hours. The mixture was concentrated under reduced pressure to obtain a crude product, which was then purified by silica gel rapid chromatography (methanol / dichloromethane = 0 / 1 to 1 / 10) and preparative HPLC (column: YMC Triart C18 250*50mm*7μm, table: 29-58% B (A = water (0.05% ammonium hydroxide v / v)), B = acetonitrile), flow rate: 60 mL / min, UV detector 220nm) to obtain N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ 6 1,4-thiazide-4-carboxamide [compound 1.1] (211 mg, 368 µmol), as a dry powder. m / z: [M + H] + The calculated value of C23H27ClF3N6O4S is 575.2; the measured value is 575.3. 1 ¹H NMR (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=6.8Hz, 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 a chiral purity of at least 89%.

[0338] N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6- Synthesis of [[amino]phenyl]-2,2,2-trifluoroethyl]-N-methylacetamide (compound 1.2)

[0339]

[0340] Under a nitrogen atmosphere, a mixture of 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine hydrochloride [INT 1.1] (100 mg, 378 µmol), N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methylacetamide [INT 5.2] (117 mg, 378 µmol), Pd2(dba)3 (34.6 mg, 37.8 µmol), Xantphos (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. The mixture was concentrated under reduced pressure to obtain a crude product, which was purified by preparative HPLC (column: YMC TriartC18 250*50mm*7μm, table: 31-71% B (A = water (0.05% ammonium hydroxide v / v)), B = acetonitrile), flow rate: 60mL / min, UV detector 220 nm) to obtain N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methylacetamide [compound 1.2] (20.0 mg, 43.7 µmol, 11.6% yield), as a yellow dry powder. m / z: [M + H] + C19H21ClF3N6O2 Calculated value: 457.1; Measured value: 457.2. 1 H NMR (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).

[0341] N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6- Synthesis of [[amino]phenyl]-2,2,2-trifluoroethyl]-N-methyloxane-2-carboxamide (compound 1.3)

[0342]

[0343] Under a nitrogen atmosphere, a mixture of 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine hydrochloride [INT 1.1] (80 mg, 302 µmol), N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methyloxane-2-carboxamide [INT 5.3] (114 mg, 302 µmol), Xantphos (34.9 mg, 60.4 µmol), Pd2(dba)3 (27.6 mg, 30.2 µmol), and Cs2CO3 (196 mg, 604 µmol) in dioxane (2 mL) was stirred at 100 °C for 3 hours. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel rapid chromatography (EtOAc / petroleum ether = 1 / 10 to 1 / 1) and preparative HPLC (column: YMC Triart C18 250*50mm*7μm, table: 26-66% B (A = water (0.05% ammonium hydroxide v / v)), B = acetonitrile), flow rate: 60 mL / min, UV detector 220nm) to obtain N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methyloxane-2-carboxamide [compound 1.3] (30.1 mg, 57.1 µmol, 18.9% yield), as a yellow dry powder. m / z: [M + H]+ C23H27ClF3N6O3 Calculated value 527.2; Measured value 527.3. 1 H NMR (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).

[0344] (1r,4r)-4-{[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5- [a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl](methyl)carbamoyl}methyl cyclohexane-1-carboxylate (compound) Synthesis of compound 1.4)

[0345]

[0346] Under a nitrogen atmosphere, a mixture of 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine hydrochloride [INT 1.1] (50 mg, 189 µmol), (1r,4r)-4-{[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)carbamoyl}cyclohexane-1-carboxylate [INT 5.4] (82.4 mg, 189 µmol), Xantphos (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. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel rapid chromatography (EtOAc / petroleum ether = 1 / 10 to 1 / 1) and preparative HPLC (column: YMCTriart C18 250*50mm*7μm, table: 27-67% B (A = water (0.05% ammonium hydroxide v / v)), B = acetonitrile), flow rate: 60 mL / min, UV detector 220 nm) to obtain (1r,4r)-4-{[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl](methyl)carbamoyl}methyl cyclohexane-1-carboxylate [compound 1.4] (14.2 mg, 24.3 µmol, (12.9% yield), a yellow dry powder. m / z: [M + H] + C26H31ClF3N6O4 Calculated value 583.2; measured value 583.3. 1HNMR (400 MHz, CDCl3) δ = 8.90 (s, 1H), 7.32 (d, J=8.4 Hz, 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).

[0347] N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6- Synthesis of [[amino]phenyl]-2,2,2-trifluoroethyl]-N-methylthiazide-4-carboxamide (compound 1.5)

[0348]

[0349] Under a nitrogen atmosphere, a mixture of 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine hydrochloride [INT 1.1] (100 mg, 378 µmol), N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methylthiazide-4-carboxamide [INT 5.5] (149 mg, 378 µmol), Xantphos (43.7 mg, 75.6 µmol), Pd2(dba)3 (34.6 mg, 37.8 µmol), and Cs2CO3 (246 mg, 756 µmol) in dioxane (5 mL) was stirred at 100 °C for 3 hours. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel rapid chromatography (EtOAc / petroleum ether = 1 / 10 to 1 / 1) and preparative HPLC (column: YMC Triart C18 250*50mm*7μm, table: 35-75% B (A = water (0.05% ammonium hydroxide v / v)), B = acetonitrile), flow rate: 60 mL / min, UV detector 220nm) to obtain N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methylthiamide-4-carboxamide [compound 1.5] (26.9 mg, 49.5 µmol, 13.1% yield), as a yellow dry powder. m / z: [M + H]+ C23H27ClF3N6O2S Calculated value 543.1; Measured value 543.4. 1 H NMR (400 MHz, CDCl3) δ = 8.89 (s, 1H), 7.31 (d, J=8.4Hz, 2H), 7.11 (s, 1H), 7.04 (d, J=8.4 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).

[0350] N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6- Synthesis of [[amino]phenyl]-2,2,2-trifluoroethyl]-N-methyloxacyclopentane-3-carboxamide (compound 1.6)

[0351]

[0352] Pd2(dba)3 (19.9 mg, 21.8 µmol), Cs2CO3 (213 mg, 654 µmol), and xantphos (12.6 mg, 21.8 µmol) were added to a mixture of N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methyloxacyclopentane-3-carboxamide [INT 5.6] (80 mg, 218 µmol) and 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine hydrochloride [INT 1.1] (68.9 mg, 261 µmol) in dioxane (2 mL). The reaction mixture was stirred at 100 °C for 3 h under N2, then diluted with brine (20 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to obtain a crude product, which was purified by preparative HPLC (column: Boston Prime C18 150*25mm*5μmμm, table: 32-62% B (A = water (0.05% ammonium 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]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methyloxacyclopentane-3-carboxamide [compound 1.6] (2.20 mg, 4.28 µmol, 2.0% yield), as a grayish-white dry powder. m / z: [M + H]+ C22H25ClF3N6O3 Calculated value 513.2; Measured value 513.3. 1 H NMR(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).

[0353] N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6- [[4,2,2-trifluoroethyl]-N-methyl-1,4-dioxane[4,5]decane-8-carboxamide (compound)] Synthesis of 1.7)

[0354]

[0355] Under a nitrogen atmosphere, a mixture of 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine hydrochloride [INT 1.1] (60.4 mg, 229 µmol), N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methyl-1,4-dioxaspiro[4.5]decane-8-carboxamide [INT 5.7] (100 mg, 229 µmol), Xantphos (26.5 mg, 45.8 µmol), Pd2(dba)3 (20.9 mg, 22.9 µmol), and Cs2CO3 (149 mg, 458 µmol) in dioxane (5 mL) was stirred at 100 °C for 3 hours. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel rapid chromatography (EtOAc / petroleum ether = 1 / 5 to 1 / 3) and preparative HPLC (column: YMC Triart C18250*50mm*7μm, table: 33-73% B (A = water (0.05% ammonium hydroxide v / v)), 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]pyrimidin-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, (24.2% yield), a yellow dry powder. m / z: [M + H] + C26H31ClF3N6O4 Calculated value 583.2; measured value 583.4. 1H NMR (400 MHz, CDCl3) δ= 8.89 (s, 1H), 7.32 (d, J=8.4 Hz, 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=6.8 Hz, 3H), 1.57 - 1.52 (m, 2H).

[0356] N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6- Synthesis of [[amino]phenyl]-2,2,2-trifluoroethyl]-4,4-difluoro-N-methylcyclohexane-1-carboxamide (compound 1.8)

[0357]

[0358] Under a nitrogen atmosphere, a mixture of 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine hydrochloride [INT 1.1] (100 mg, 378 µmol), N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-4,4-difluoro-N-methylcyclohexane-1-carboxamide [INT 5.8] (156 mg, 378 µmol), Xantphos (43.7 mg, 75.6 µmol), Pd2(dba)3 (34.6 mg, 37.8 µmol), and Cs2CO3 (368 mg, 1.13 mmol) in dioxane (5 mL) was stirred at 100 °C for 3 hours. The reaction mixture was filtered through diatomaceous earth. The filter cake was washed with EtOAc (20 mL x 2). The filtrate was concentrated under reduced pressure to obtain a crude product, which was then purified by preparative HPLC (column: Welch Ultimate C18 150*25mm*5μmμm, table: 49-79% B (A = water (10 mM NH4HCO3), 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]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-4,4-difluoro-N-methylcyclohexane-1-carboxamide [compound 1.8] (61.5 mg, 109 µmol, 29.0% yield), as a yellow solid. m / z: [M + H] + C24H27ClF5N6O2 Calculated value 561.2; Measured value 561.2. 1 H NMR (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).

[0359] (1r,3S)-N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]) Pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-3-cyano-N-methylcyclobutane-1-carboxamide (compound 1.9) Synthesis

[0360]

[0361] (1r,3S)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-3-cyano-N-methylcyclobutane-1-carboxamide [INT 5.9] (0.1 g, 0.2665 mmol), 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine [INT 1.1 free base] (60.5 mg, 266 µmol), xantphos (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 min. Pd2(dba)3 (12.1 mg, 13.3 µmol) was added, followed by degassing of the reaction mixture with argon for 5 min and stirring at 100 °C for 10 h. The reaction mixture was cooled to room temperature and the solid was filtered off. The filtrate was purified by HPLC (see conditions below) to give (1r,3S)-N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-3-cyano-N-methylcyclobutane-1-carboxamide [compound 1.9] (14.9 mg, 0.02857 mmol, 10.7% yield), as a yellow oil. m / z: [M + H] + C23H24ClF3N7O2 Calculated value 522.2; Measured value 522.2. 1 H NMR (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=9.1Hz, 1H), 5.37 (q, J=6.7 Hz, 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).

[0362] HPLC conditions; System: Agilent 1260 Infinity II LC coupled with Agilent 6120B single quadrupole LC / MS system • Column description: Chromatorex SBM 100-5T 5 μm C18(2) 100 Å, LC column 100 x 19 mm, Waters, Sun Fire; Stationary phase: C18; Solid support: Fully porous silica; Separation method: Reversed phase; Mobile phase A: Water; Mobile phase B: Acetonitrile; Flow rate: 30 ml / min; Loading pump: 4 ml / min B; Gradient conditions: 20-40-55-100% (B) 0-2-10-11.2 min.

[0363] 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-carboxylic acid tert-butyl ester (compound 1.10) Synthesis

[0364]

[0365] Under a nitrogen atmosphere, a mixture of 4-{[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)carbamoyl}piperidin-1-carboxylic acid tert-butyl ester [INT 7.1] (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 [INT 1.1] (82.4 mg, 312 µmol) and xantphos (18.0 mg, 31.2 µmol) in dioxane was heated at 100 °C. oStir at C for 4 hours. Add brine (20 mL) and extract the mixture with EtOAc (30 mL x 2). Wash the combined organic layers with brine (20 mL x 2), dry with anhydrous Na2SO4, filter, and concentrate 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 (0.05% ammonium hydroxide v / v)-ACN), B = acetonitrile), flow rate: 30 mL / min, UV detector 220 nm) to obtain 4-{[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl](methyl)carbamoyl}piperidine-1-carboxylic acid tert-butyl ester [compound 1.10] (9.10 mg, 14.5 µmol, 4.7% yield), as a yellow dry powder. m / z: [M + H - 100] + C28H36ClF3N7O4 Calculated value 526.2; Measured value 526.3. 1 H NMR (400 MHz, CDCl3) d = 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).

[0366] 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-carboxylic acid tert-butyl ester (compound 1.11) Synthesis

[0367]

[0368] Pd2(dba)3 (133 mg, 146 µmol) was added to a solution of 3-{[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)carbamoyl}piperidin-1-carboxylic acid tert-butyl ester [INT 7.2] (700 mg, 1.46 mmol), 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine hydrochloride [INT 1.1] (332 mg, 1.46 mmol), Cs2CO3 (1.42 g, 4.38 mmol), and xantphos (168 mg, 292 µmol) in dioxane (5 mL). The reaction mixture was then heated in 100 mL of water. o Stirring at C for 2 hours. The reaction mixture was concentrated under reduced pressure to give a crude product, which was purified by silica gel rapid chromatography (EtOAc / PE = 0 / 1 to 1 / 1) to give 3-{[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl](methyl)carbamoyl}piperidine-1-carboxylic acid tert-butyl ester [compound 1.11] (480 mg, 766 µmol, 52.5% yield). 60.6 mg of the product was purified by preparative HPLC (column: YMC Triart C18 250*50mm*7μm, table: 47-87% B (A = water (water (0.225% FA), B = acetonitrile), flow rate: 60 mL / min, UV detector 220 nm) to obtain 3-{[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl](methyl)carbamoyl}piperidine-1-carboxylic acid tert-butyl ester [compound 1.11] (10.6 mg, 16.9 µmol), as a grayish-white solid. m / z: [M + H]+ The calculated value of C28H36ClF3N7O4 is 626.2; the measured value is 626.3. 1H NMR (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 (brs, 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).

[0369] 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-carboxylic acid tert-butyl ester (compound) Synthesis of 1.12)

[0370]

[0371] Pd2(dba)3 (27.4 mg, 30.0 µmol) was added to a mixture of 3-{[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)carbamoyl}pyrrolidine-1-carboxylic acid tert-butyl ester [INT 7.3] (140 mg, 300 µmol), 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine hydrochloride [INT 1.1] (95.0 mg, 360 µmol), xantphos (17.3 mg, 30.0 µmol), and Cs2CO3 (390 mg, 1.20 mmol) in dioxane (2 mL), and the mixture was incubated at 100 °C under N2. oStir at C for 3 hours. Dilute the reaction mixture with brine (20 mL) and extract with EtOAc (20 mL × 3). Dry the combined organic layers over anhydrous sodium sulfate and filter. Concentrate the filtrate to give the crude product, which is purified by silica gel rapid chromatography (methanol / dichloromethane = 1 / 20). The product was then purified by preparative HPLC (column: Boston Prime C18 150*30mm*5μm, table: 44-74% B (A = water (0.05% ammonium hydroxide v / v)-ACN), B = acetonitrile), flow rate: 25 mL / min, UV detector 220 nm) to obtain 3-{[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl](methyl)carbamoyl}pyrrolidine-1-carboxylic acid tert-butyl ester [compound 1.12] (2.70 mg, 4.41 µmol, 1.5% yield), as a yellow dry powder. m / z: [M + H] + C27H34ClF3N7O4 Calculated value 612.2; Measured value 612.4. 1 H NMR (400 MHz, CDCl3) d = 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).

[0372] N-[(4-{[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine] [Pyridine-6-yl]amino)phenyl]-2,2,2-trifluoroethyl](methyl)carbamoyl]cyclohexyl)methyl]tert-butyl carbamate Synthesis of (Compound 1.13)

[0373]

[0374] Pd2(dba)3 (75.7 mg, 82.7 µmol) was added to a suspension of N-[(4-{[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)carbamoyl}cyclohexyl)methyl]carbamate [INT 7.4] (420 mg, 827 µmol), 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine hydrochloride [INT 1.1] (282 mg, 1.07 mmol), Cs2CO3 (537 mg, 1.65 mmol), and xantphos (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 rapid chromatography (MeOH / dichloromethane = 0 / 1 to 1 / 99) to give N-[(4-{[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl](methyl)carbamoyl}cyclohexyl)methyl]tert-butyl carbamate [compound 1.13] (500 mg, 765 µmol, 92.5% yield), as a yellow solid. 100 mg of the product was further purified by preparative HPLC (column: Phenomenex Gemini-NX 80*40mm*3μm, table: 39-79% B (A=water (0.05% ammonium hydroxide v / v), B=MeOH), flow rate: 25 mL / min, UV detector 220 nm) to obtain N-[(4-{[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl](methyl)carbamoyl}cyclohexyl)methyl]tert-butyl carbamate [compound 1.13] (500 mg, 39.1 µmol), as a yellow dry powder. m / z: [M + H]+ C30H40ClF3N7O4 Calculated value 654.3; Measured value 654.6. 1H NMR (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=6.4 Hz, 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).

[0375] (1r,4S)-N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]) (pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-4-methoxy-N-methylcyclohexane-1-carboxamide (compound) Synthesis of 1.14)

[0376]

[0377] Under N2, Pd2(dba)3 (20.1 mg, 22.0 µmol) was added to a mixture of (1r,4S)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-methoxy-N-methylcyclohexane-1-carboxamide [INT 7.5] (90 mg, 220 µmol), 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine hydrochloride [INT 1.1] (50.0 mg, 220 µmol), Cs2CO3 (143 mg, 440 µmol), and Xantphos (25.4 mg, 44.0 µmol) in dioxane (1 mL), and the reaction mixture was heated to 100 mL. oStir at C for 1 hour. Quench the reaction by adding water (10 mL) and extract with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain a crude product. This crude product was purified by preparative HPLC (column: YMC-Actus TriartC18 150*30mm*5μm, table: 48-68% water (0.05% ammonium hydroxide v / v)-ACN, flow rate: 35 mL / min, UV detector 220 nm) to obtain (1r,4S)-N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-4-methoxy-N-methylcyclohexane-1-carboxamide [compound 1.14] (8.60 mg, 15.4 µmol, 7.0% yield), as a yellow dry powder. m / z: [M + H] + C25H31ClF3N6O3 Calculated value 555.2; Measured value 555.3. 1 H NMR (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=6.7 Hz, 3H), 1.49 - 1.32 (m, 2H), 1.25 - 1.08 (m, 2H).

[0378] 1-Acetyl-N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5- [a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methylazacyclobutane-3-carboxamide (compound 1.15) Synthesis

[0379]

[0380] Pd2(dba)3 (23.2 mg, 25.4 µmol) was added to a solution of 1-acetyl-N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methylazacyclobutane-3-carboxamide [INT 5.10] (100 mg, 254 µmol), 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine hydrochloride [INT 1.1] (73.6 mg, 279 µmol), Cs2CO3 (248 mg, 762 µmol), and xantphos (29.3 mg, 50.8 µmol) in dioxane (3 mL), and the reaction mixture was stirred at 100 °C for 16 hours under N2. 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: 24-64% B (A = water (0.05% ammonium 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]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methylazacyclobutane-3-carboxamide [compound 1.15] (21.2 mg, 39.2 µmol, 15.4% yield), as a yellow dry powder. m / z: [M + H] + C23H26ClF3N7O3 Calculated value 540.2; Measured value 540.2. 1 H NMR (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, , 3H), 1.62 - 1.58 (m,3H).

[0381] N-(4-{[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine [Pyridine-6-ylamino)phenyl]-2,2,2-trifluoroethyl](methyl)carbamoyl]cyclohexyl)carbamate (also known as (4-) (((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)benzene Synthesis of (methyl)carbamoyl)cyclohexyl)methyl carbamate (compound 1.16)

[0382]

[0383] At 20 °C, Pd2(dba)3 (8.11 mg, 8.86 µmol) was added to a mixture of N-(4-{[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)carbamoyl}cyclohexyl)carbamate [INT 9.1] (40 mg, 88.6 µmol), 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine hydrochloride [INT 1.1] (20.1 mg, 88.6 µmol), Cs2CO3 (57.6 mg, 177 µmol), and Xantphos (10.2 mg, 17.7 µmol) in dioxane (1 mL), 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 (INT 9.1 at a scale of 44.3 µmol). Water (10 mL) was added, and the mixture was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain a crude product. This crude product was purified by preparative HPLC (column: YMC-Actus TriartC18 150*30mm*5μm, table: 46-66% water (0.05% ammonium hydroxide v / v)-ACN, flow rate: 35 mL / min, UV detector 220 nm) to obtain N-(4-{[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl](methyl)carbamoyl}cyclohexyl)carbamate [compound 1.16] (12.2 mg, 20.4 µmol, 15.3% yield), as a yellow dry powder. m / z: [M + H] + C26H32ClF3N7O4 Calculated value 598.2; Measured value 598.3. 1H NMR (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).

[0384] N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6- The synthesis of [[amino]phenyl]-2,2,2-trifluoroethyl]-4-acetamido-N-methylcyclohexane-1-carboxamide (compound 1.17) become

[0385]

[0386] At 20 °C, Pd2(dba)3 (4.20 mg, 4.59 µmol) was added to a mixture of N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-4-acetamido-N-methylcyclohexane-1-carboxamide [INT 9.2] (20 mg, 45.9 µmol), 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine hydrochloride [INT 1.1] (10.4 mg, 45.9 µmol), Cs2CO3 (29.9 mg, 91.8 µmol), and Xantphos (5.31 mg, 9.18 µmol) in dioxane (2 mL), and the mixture was stirred at 100 °C for 1 hour under N2. The reaction was combined with another batch of the same reaction (22.9 µmol scale) and concentrated under reduced pressure to obtain a crude product. This crude product was purified by preparative HPLC (column: YMCActus Triart C18 150*30mm*5μm, table: 42-62% water (0.05% ammonium hydroxide v / v)-ACN, flow rate: 35mL / min, UV detector 220 nm) to obtain N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-4-acetamido-N-methylcyclohexane-1-carboxamide [compound 1.17] (8.50 mg, 14.6 µmol, 21.2% yield), as a yellow dry powder. m / z: [M + H]+ C26H32ClF3N7O3 Calculated value 582.2; Measured value 582.2. 1 H NMR (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=6.6 Hz, 3H), 1.51 - 1.31 (m, 2H), 1.29 - 1.11 (m, 2H).

[0387] N-[(1S)-1-(4-{[2-chloro-7-(propyl-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]amino}benzene [2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ 6 -Thiazide-4-carboxamide (also known as (S)-N-(1-(4-) ((2-Chloro-7-isopropyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyl Synthesis of tetrahydro-2H-thiaran-4-carboxamide (1,1-dioxide) (compound 1.18)

[0388]

[0389] To 2-chloro-7-(propyl-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine hydrochloride [INT 1.2] (30 mg, 120 µmol), N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ 6 Pd2(dba)3 (10.9 mg, 12.0 µmol) was added to a dioxane (5 mL) solution of thiazide-4-carboxamide [INT 5.1] (51.3 mg, 120 µmol), xantphos (13.8 mg, 24.0 µmol), and Cs2CO3 (117 mg, 360 µmol). The reaction was stirred at 100 °C for 2 h under N2. The reaction was combined with another batch of the same reaction (120 µmol scale), quenched by adding water (30 mL), and extracted with EtOAc (30 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain a crude product. This crude product was purified by preparative HPLC (column: YMC-Actus Triart C18 150*30mm*5μm, table: 40-60% B (A=water (0.05% ammonium hydroxide), B=ACN), flow rate: 35 mL / min, UV detector 220nm) to obtain N-[(1S)-1-(4-{[2-chloro-7-(propyl-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]amino}phenyl)-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ 6 Thiane-4-carboxamide [compound 1.18] (22.1 mg, 39.5 µmol, 16.5% yield), is a white, dry powder. m / z: [M + H]+ C23H27ClF3N6O3S Calculated value 559.1; Found value 559.1. 1H NMR (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).

[0390] 1-Acetyl-N-[(1S)-1-(4-{[2-chloro-7-(propyl-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidine-6- Synthesis of [[amino]phenyl]-2,2,2-trifluoroethyl]-N-methylpiperidine-4-carboxamide (compound 1.19)

[0391]

[0392] Under a nitrogen atmosphere, a mixture of 2-chloro-7-(propyl-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-methylpiperidin-4-carboxamide [INT 5.11] (93.0 mg, 221 µmol), xantphos (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. 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 (0.05% ammonium hydroxide v / v)-ACN), B = acetonitrile), flow rate: 25 mL / min, UV detector 220 nm) to obtain 1-acetyl-N-[(1S)-1-(4-{[2-chloro-7-(prop-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]amino}phenyl)-2,2,2-trifluoroethyl]-N-methylpiperidin-4-carboxamide [compound 1.19] (19.1 mg, 34.6 µmol, 17.3% yield), as a white dry powder. m / z: [M+H]+ C25H30ClF3N7O2 Calculated value 552.2; Measured value 552.2. 1H NMR (400MHz, CDCl3) d =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=13.6 Hz, 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=2.4Hz, 3H), 1.91 - 1.81 (m, 2H), 1.80 - 1.69 (m, 2H), 1.54 (s, 3H), 1.53 (s, 3H).

[0393] N-{1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino Synthesis of [N-methylcyclobutaneformamide](compound 1.20)

[0394]

[0395] Pd2(dba)3 (18.4 mg, 20.2 µmol) was added to a solution of N-[1-(4-bromophenyl)ethyl]-N-methylcyclobutanecarboxamide [INT 11.1] (60 mg, 202 µmol), 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine hydrochloride [INT 1.1] (45.9 mg, 202 µmol), Cs2CO3 (197 mg, 606 µmol), and xantphos (23.3 mg, 40.4 µmol) in dioxane (2 mL), and the reaction mixture was stirred at 100 °C for 2 hours under N2. The mixture was concentrated under vacuum to obtain a crude product, which was then purified by preparative HPLC (column: Phenomenex Gemini-NX 80*40mm*3μm, table: 20-60% B (A = water (0.05% ammonium hydroxide v / v), B = acetonitrile), flow rate: 25 mL / min, UV detector 220nm) to obtain N-{1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]ethyl}-N-methylcyclobutaneformamide [compound 1.20] (5.60 mg, 12.6 µmol, 6.3% yield), as a yellow dry powder. m / z: [M + H]+ C22H28ClN6O2 Calculated value 443.2; Measured value 443.3.1 H NMR (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).

[0396] N-{1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino Synthesis of [N-methylcyclohexaneformamide](compound 1.21)

[0397]

[0398] Pd2(dba)3 (14.1 mg, 15.4 µmol) was added to a solution of N-[1-(4-bromophenyl)ethyl]-N-methylcyclohexaneformamide [INT 11.2] (50 mg, 154 µmol), 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine hydrochloride [INT 1.1] (35.0 mg, 154 µmol), Cs2CO3 (150 mg, 462 µmol), and xantphos (17.8 mg, 30.8 µmol) in dioxane (3 mL), and the reaction mixture was stirred at 100 °C for 2 hours under N2. The mixture was concentrated under vacuum to obtain a crude product, which was then purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30mm*3μm, table: 35-75% B (A = water (0.05% ammonium hydroxide v / v), B = acetonitrile), flow rate: 25 mL / min, UV detector 220 nm) to obtain N-{1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]ethyl}-N-methylcyclohexaneformamide [compound 1.21] (9.30 mg, 19.7 µmol, 12.8% yield), as a yellow dry powder. m / z: [M + H]+ C24H32ClN6O2 Calculated value 471.2; Measured value 471.3. 1 H NMR (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 (br d, 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).

[0399] N-{1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino Synthesis of [N-methylcyclopentaneformamide](compound 1.22)

[0400]

[0401] To a solution of N-[1-(4-bromophenyl)ethyl]-N-methylcyclopentaneformamide [INT 11.3] (50 mg, 161 µmol) and 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine hydrochloride [INT 1.1] (36.6 mg, 161 µmol) in dioxane (3 mL), Cs₂CO₃ (157 mg, 482 µmol), xantphos (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 under vacuum to obtain a crude product, which was then purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30mm*3μm, table: 35-75% B (A = water (0.05% ammonium hydroxide v / v), B = acetonitrile), flow rate: 25 mL / min, UV detector 220 nm) to obtain N-{1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]ethyl}-N-methylcyclopentanecarboxamide [compound 1.22] (10.0 mg, 21.8 µmol, 13.6% yield), as a yellow dry powder. m / z: [M + H]+ C23H30ClN6O2 Calculated value 457.2; Measured value 457.3. 1 H NMR (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).

[0402] N-{1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino Synthesis of [N-methylcyclopropaneformamide](compound 1.23)

[0403]

[0404] At 25 °C, Pd2(dba)3 (16.2 mg, 17.7 µmol), Cs2CO3 (173 mg, 531 µmol), and xantphos (20.4 mg, 35.4 µmol) were added to a mixture of N-[1-(4-bromophenyl)ethyl]-N-methylcyclopropaneformamide [INT 12.2] (50 mg, 177 µmol) and 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine hydrochloride [INT 1.1] (40.2 mg, 177 µmol) in dioxane (2 ml). The mixture was stirred at 100 °C under N2 for 12 hours. The mixture was concentrated under vacuum to obtain a crude product, which was then purified by preparative HPLC (column: YMCTriart C18 250*50mm*7μm, table: 25-65% B (A = water (0.05% ammonium hydroxide v / v), 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]pyrimidin-6-yl}amino)phenyl]ethyl}-N-methylcyclopropaneformamide [compound 1.23] (16.9 mg, 39.4 µmol, 22.2% yield), as a yellow dry powder. m / z: [M + H]+ C21H26ClN6O2 Calculated value 429.2; Measured value 429.3. 1 H NMR (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 (br d, J=6.4 Hz, 1H), 1.43 (br d, J=7.2 Hz, 2H), 0.85 - 0.76 (m,4H).

[0405] N-{1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino Synthesis of [N-methylacetamide](compound 1.24)

[0406]

[0407] To a solution of N-[1-(4-bromophenyl)ethyl]-N-methylacetamide [INT 12.1] (30 mg, 117 µmol) and 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine hydrochloride [INT 1.1] (26.6 mg, 117 µmol) in dioxane (2 mL), Pd2(dba)3 (10.7 mg, 11.7 µmol), Cs2CO3 (114 mg, 351 µmol), and xantphos (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 a crude product, which was purified by preparative HPLC (column: YMC-ActusTriart C18 150*30mm*5μm, table: 37-57% B (A = water (0.05% ammonium hydroxide)), B = acetonitrile), flow rate: 35 mL / min, UV detector 220 nm) to obtain N-{1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]ethyl}-N-methylacetamide [compound 1.24] (2.50 mg, 6.20 µmol, 5.3% yield), as a yellow dry powder. m / z: [M + H]+ C19H24ClN6O2 Calculated value 403.2; Measured value 403.2. 1 H NMR (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).

[0408] N-{1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino Synthesis of [[2,2,2-trifluoroethyl]-N-methylacetamide (compound 1.25)]

[0409]

[0410] Pd2(dba)3 (80 mg, 0.08736 mmol) was added to 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), xantphos (80 mg, 0.1382 mmol), and Cs2CO3 (500 mg, 1.53 mmol) in dioxane (2 mL), and the mixture was stirred at 100 °C for 12 hours under N2. The reaction mixture was diluted with EtOAc (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 aqueous solution (0.05% ammonium hydroxide v / v), flow rate: 25 mL / min) to obtain N-{1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl}-N-methylacetamide [compound 1.25] (10.2 mg, 0.02232 mmol, 4.6% yield), as a yellow dry powder. m / z: [M + H]+ C19H21ClF3N6O2 Calculated value 457.1; Measured value 457.1. 1 H NMR (400MHz, DMSO-d6) d= 8.84 (s, 1H), 8.07 - 7.90 (m, 1H), 7.34 - 7.13 (m, 2H), 6.97 (br d, J=8.6Hz, 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).

[0411] N-[(1R)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6- [[2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ] 6 -Thiazide-4-carboxamide (also known as N-thiazide-4-carboxamide) ((R)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)benzene The synthesis of (2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiaran-4-carboxamide (1,1-dioxide) (compound 1.26) become

[0412]

[0413] To N-[(1R)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ 6 Pd2(dba)3 (10.6 mg, 11.6 µmol), Cs2CO3 (113 mg, 348 µmol), and xantphos (13.4 mg, 23.2 µmol) were added to a dioxane (2 mL) solution of thiazide-4-carboxamide [INT 14.1] (50 mg, 116 µmol) and 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine hydrochloride [INT 1.1] (31.6 mg, 139 µmol). The reaction mixture was stirred at 100 °C for 2 h under N2. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was then purified by preparative HPLC (column: Boston Green ODS 150*30mm*5μm, table: 24-64% B (A = water (0.05% ammonium hydroxide)), B = acetonitrile), flow rate: 30 mL / min, UV detector 220 nm) to obtain N-[(1R)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ 6 Thiane-4-carboxamide [compound 1.26] (16.4 mg, 28.5 µmol, 24.6% yield), is a yellow dry powder. m / z: [M + H]+ C23H27ClF3N6O4S Calculated value 575.1; Found value 575.3. 1 H NMR (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=6.8 Hz, 3H).

[0414] N-[(1R)-1-[4-({2-chloro-7-[(1R)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6- [[2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ] 6 -Thiazide-4-carboxamide (also known as N-thiazide-4-carboxamide) ((R)-1-(4-((2-chloro-7-((R)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)benzene The synthesis of (2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiaran-4-carboxamide (1,1-dioxide) (compound 1.27) become

[0415]

[0416] Under a nitrogen atmosphere, 2-chloro-7-[(1R)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine hydrochloride [INT 1.3] (60 mg, 227 µmol), N-[(1R)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ 6 A mixture of thiazide-4-carboxamide [INT 14.1] (97.2 mg, 227 µmol), Pd2(dba)3 (20.7 mg, 22.7 µmol), Xantphos (26.2 mg, 45.4 µmol), and Cs2CO3 (221 mg, 681 µmol) in dioxane (2 mL) was stirred at 100 °C for 3 h. The mixture was concentrated under reduced pressure to give a crude product, which was purified by silica gel rapid chromatography (methanol / dichloromethane = 0 / 1 to 1 / 20). The generated product was purified by preparative HPLC (column: YMC Triart C18 250*50mm*7μm, table: 26-66% B (A = water (0.05% ammonium hydroxide v / v)), B = acetonitrile), flow rate: 60 mL / min, UV detector 220 nm) and preparative TLC (SiO2, dichloromethane:methanol = 20:1) to obtain N-[(1R)-1-[4-({2-chloro-7-[(1R)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ 6 Thiane-4-carboxamide [compound 1.27] (5.20 mg, 9.04 µmol, 4.0% yield), is a white, dry powder. m / z: [M+H]+C23H27ClF3N6O4S Calculated value 575.1; Found value 575.3. 1H NMR (400 MHz, CD3OD) δ = 8.86 (s,1H), 7.30 (d, J=8.4 Hz, 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=6.8 Hz, 3H).

[0417] N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6- Synthesis of [[[[amino]-2-methylphenyl]-2,2,2-trifluoroethyl]-N-methylcyclobutaneformamide (compound 1.28)]

[0418]

[0419] N-[(1S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethyl]-N-methylcyclobutaneformamide [INT 16.1] (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 INT 1.1] (62.3 mg, 274 µmol), Cs₂CO₃ (268 mg, 823 µmol), and xantphos (15.8 mg, 27.4 µmol) were mixed in dioxane (2 mL), and the reaction mixture was degassed with argon for 5 min. Pd₂(dba)₃ (12.5 mg, 13.7 µmol) was added, followed by degassed with argon for 5 min, and the mixture was stirred at 100 °C for 10 h. The reaction mixture was then cooled to room temperature. The solid was filtered off. The filtrate was purified by HPLC (see conditions below) to give N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)-2-methylphenyl]-2,2,2-trifluoroethyl]-N-methylcyclobutanecarboxamide [compound 1.28] (44.7 mg, 0.08757 mmol, 31.9% yield), as a yellow solid. m / z: [M + H]+ C23H27ClF3N6O2 Calculated value 511.2; Found value 511.2. 1H NMR (400 MHz, DMSO-d6 ) δ = 8.83 (d, J=1.4 Hz, 1H), 7.91 (s,1H), 7.29 (d, J=8.4 Hz, 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).

[0420] HPLC conditions; System: Agilent 1260 Infinity II LC coupled with Agilent 6120B single quadrupole LC / MS system; Column description: Chromatorex SBM 100-5T 5 μm C18(2) 100 Å, LC column 100 x 19 mm, Waters, Sun Fire; Stationary phase: C18; Solid support: fully porous silica; Separation method: reversed phase; Mobile phase A: water.

[0421] N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6- Synthesis of [[[[amino]-2-methylphenyl]-2,2,2-trifluoroethyl]-N-methylcyclopropaneformamide (compound 1.29)]

[0422]

[0423] N-[(1S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethyl]-N-methylcyclopropaneformamide [INT 16.2] (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 INT 1.1] (64.8 mg, 0.2846 mmol), Cs₂CO₃ (277 mg, 853 µmol), and xantphos (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 room temperature. The solid was filtered off, and the filtrate was purified by HPLC (see conditions below) to give N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)-2-methylphenyl]-2,2,2-trifluoroethyl]-N-methylcyclopropaneformamide [compound 1.29] (15.7 mg, 0.03173 mmol, 11.1% yield), as a yellow solid. m / z: [M + H]+ C22H25ClF3N6O2 Calculated value 497.2; Found value 497.2. 1 H NMR (400MHz, 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, , 1.03 - 0.86 (m, 4H).

[0424] HPLC conditions; System: Agilent 1260 Infinity II LC coupled with Agilent 6120B single quadrupole LC / MS system; Column description: Chromatorex SBM 100-5T 5 μm C18(2) 100 Å, LC column 100 x 19 mm, Waters, Sun Fire; Stationary phase: C18; Solid support: fully porous silica; Separation method: 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) 0-2-10-11.2 min.

[0425] N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6- [[[[[[[[[[[[[[] ...]][[[[[[[[[[[[[[[[]][[[[[[ 6 -Thiazide-4-carboxamide (also known as N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino (2-methylphenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiaran-4-carboxamide 1,1-dioxide (Chemical) Synthesis of compound 1.30

[0426]

[0427] N-[(1S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ 6 A mixture of thiazide-4-carboxamide [INT 16.3] (100 mg, 0.2260 mmol), 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine [INT 1.1 free base] (51.4 mg, 226 µmol), Cs₂CO₃ (220 mg, 678 µmol), and dioxane (3 mL) was purged with argon. Then xantphos (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 EtOAc (30 mL) and concentrated under reduced pressure. The resulting residue was purified by HPLC (see conditions below) to give N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)-2-methylphenyl]-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ 6 4-Thiamidine-4-carboxamide [compound 1.30] (12.5 mg, 0.02128 mmol, 9.4% yield), as a yellow solid. m / z: [M+H]+C24H29ClF3N6O4S Calculated value 589.2; Found value 589.0.1 H NMR (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=6.7 Hz, 3H).

[0428] HPLC conditions; System: Agilent 1260 Infinity II LC coupled with Agilent 6120B single quadrupole LC / MS system; Column description: Chromatorex SBM 100-5T 5 μm C18(2) 100 Å, LC column 100 x 19 mm, Waters, Sun Fire; Stationary phase: C18; Solid support: fully porous silica; Separation method: 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) 0-2-10-11.2 min.

[0429] N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6- Synthesis of [[[[amino]-3-methylphenyl]-2,2,2-trifluoroethyl]-N-methylcyclobutaneformamide (compound 1.31)]

[0430]

[0431] 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 INT 1.1] (74.8 mg, 329 µmol), Cs₂CO₃ (321 mg, 988 µmol), and xantphos (19.0 mg, 32.9 µmol) were mixed in dioxane (2 mL), and the reaction mixture was degassed with argon for 5 min. Pd₂(dba)₃ (15.0 mg, 16.4 µmol) was added, and the reaction mixture was then degassed with argon for 5 min and stirred at 100 °C for 10 h. The reaction mixture was cooled to room temperature and the solid was filtered off. The filtrate was purified by HPLC (see conditions below) to give N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)-3-methylphenyl]-2,2,2-trifluoroethyl]-N-methylcyclobutaneformamide [compound 1.31] (7.31 mg, 0.01431 mmol, 4.4% yield), as a yellow solid. m / z: [M + H]+ C23H27ClF3N6O2 Calculated value 511.2; Found value 511.2. 1 H NMR (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).

[0432] HPLC conditions; System: Agilent 1260 Infinity II LC coupled with Agilent 6120B single quadrupole LC / MS system; Column description: Chromatorex SBM 100-5T 5 μm C18(2) 100 Å, LC column 100 x 19 mm, Waters, Sun Fire; Stationary phase: C18; Solid support: fully porous silica; Separation method: 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) 0-2-10-11.2 min.

[0433] N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6- Synthesis of [[[[[[[[[[[] ...[[]][[[[[[[]][[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[

[0434]

[0435] N-[(1S)-1-(4-bromo-3-methylphenyl)-2,2,2-trifluoroethyl]-N-methylcyclopropaneformamide [INT 17.2] (50 mg, 0.1427 mmol), 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine [INT 1.1 free base] (32.3 mg, 142 µmol), and Cs₂CO₃ (139 mg, 428 µmol) were mixed in dioxane (5 mL). Argon gas was bubbled through the reaction mixture for 15 min. Then xantphos (16.4 mg, 28.5 µmol) and Pd₂(dba)₃ (13.0 mg, 14.2 µmol) were added, and the reaction mixture was stirred at 100 °C for 14 h. The reaction mixture was cooled, filtered, and concentrated under vacuum. The resulting residue was purified by HPLC (see conditions below) to give N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)-3-methylphenyl]-2,2,2-trifluoroethyl]-N-methylcyclopropaneformamide [compound 1.32] (21.6 mg, 0.04358 mmol, 30.6% yield), as a yellow solid. m / z: [M + H]+ C22H25ClF3N6O2 Calculated value 497.2; Found value 497.0. 1H NMR (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=9.5 Hz, 1H), 5.17 (q, J=6.6 Hz, 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).

[0436] HPLC conditions; System: Agilent 1260 Infinity II LC coupled with Agilent 6120B single quadrupole LC / MS system; Column description: Chromatorex SBM 100-5T 5 μm C18(2) 100 Å, LC column 100 x 19 mm, Waters, Sun Fire; Stationary phase: C18; Solid support: fully porous silica; Separation method: 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) 0-2-10-11.2 min.

[0437] N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6- [[[[amino]-3-methylphenyl]-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ] 6 -Thiazide-4-carboxamide (also known as N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino (3-methylphenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiaran-4-carboxamide 1,1-dioxide (Chemical) Synthesis of compound 1.33

[0438]

[0439] N-[(1S)-1-(4-bromo-3-methylphenyl)-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ 6Thiane-4-carboxamide [INT 17.3] (0.1 g, 0.2260 mmol), 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine [INT 1.1 free base] (51.4 mg, 226 µmol), Cs₂CO₃ (220 mg, 678 µmol), and xantphos (13.0 mg, 22.6 µmol) were mixed in dioxane (2 mL), and the reaction mixture was degassed with argon for 5 min. Pd₂(dba)₃ (10.3 mg, 11.3 µmol) was added. The reaction mixture was then degassed with argon for 5 min and stirred at 100 °C for 10 h. The reaction mixture was cooled to room temperature, and the solids were filtered off. The filtrate was purified by HPLC (see below conditions) to give N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)-3-methylphenyl]-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ 6 4-Thiamidine-4-carboxamide [compound 1.33] (20.7 mg, 0.03515 mmol, 15.5% yield), as a yellow solid. m / z: [M+ H]+ C24H29ClF3N6O4S Calculated 589.2; Found 589.0. 1 H NMR (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=9.4 Hz, 1H), 5.16 (q, J=6.7 Hz, 1H), 3.21 (d, J=13.9Hz, 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).

[0440] HPLC conditions; System: Agilent 1260 Infinity II LC coupled with Agilent 6120B single quadrupole LC / MS system; Column description: Chromatorex SBM 100-5T 5 μm C18(2) 100 Å, LC column 100 x 19 mm, Waters, Sun Fire; Stationary phase: C18; Solid support: fully porous silica; Separation method: 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) 0-2-10-11.2 min.

[0441] 2. Compounds prepared using scheme 2

[0442] Option 2:

[0443]

[0444] The starting material G-2a was treated with acid to obtain compound (I). G2a For Boc (for cyclic carbamates) or HBoc (for acyclic carbamates). R G2b It is H (for secondary amines) or H2 (for primary amines).

[0445] N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6- Synthesis of (N-methylpiperidine-4-carboxamide trifluoroacetate) (compound 2.1)

[0446]

[0447] The mixture of 4-(((S)-1-(4-(((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)piperidine-1-carboxylic acid tert-butyl ester [compound 1.10] (300 mg, 479 µmol) in 4 M HCl / dioxane (10 mL, 40.0 mmol) was stirred at 25 °C for 4 hours. The mixture was concentrated under reduced pressure to give N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylpiperidine-4-carboxamide hydrochloride [compound 2.1, HCl salt] (250 mg, 444 µmol, 92.9% yield), as a yellow solid. 50 mg (95.0 mmol) of the crude product was purified by preparative HPLC (column: Boston Green ODS 150*30mm*5um, 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]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylpiperidin-4-carboxamide trifluoroacetate [compound 2.1] (17.6 mg, 27.5 µmol), as a yellow dry powder. m / z: [M + H]+ C23H28ClF3N7O2 Calculated value 526.2; Measured value 526.3. 1 H NMR(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 (br d, J=5.2 Hz, 2H), 2.99 (brs, 1H), 2.93 (s, 3H), 2.23 - 1.94 (m, 4H), 1.61 (d, J=6.8 Hz, 3H).

[0448] N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6- Synthesis of [[amino]phenyl]-2,2,2-trifluoroethyl]-N-methylpiperidine-3-carboxamide (compound 2.2)

[0449]

[0450] A solution of 3-{[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl](methyl)carbamoyl}piperidine-1-carboxylic acid tert-butyl ester [compound 1.11] (200 mg, 319 µmol) in 4 M HCl / dioxane (6 mL) was stirred at 20 °C for 16 hours. The reaction mixture was concentrated under reduced pressure to give N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methylpiperidine-3-carboxamide hydrochloride [compound 2.2, HCl salt] (140 mg, 266 µmol, 83.4% yield), as a yellow solid. 45.3 mg of the crude product was purified by preparative HPLC (column: Phenomenex Gemini-NX 80*40mm*3μm, table: 22-62% B (A = water (0.05% ammonium 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]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methylpiperidin-3-carboxamide [compound 2.2] (5.30 mg, 10.0 µmol, 11.7% yield), as a yellow solid. m / z: [M + H]+ C23H28ClF3N7O2 Calculated value 526.2; Measured value 526.3. 1H NMR (400 MHz, CDCl3) δ = 8.89 (s, 1H), 7.31 (d, J=8.4 Hz, 2H), 7.11 (s, 1H), 7.04 (d, J=8.8Hz, 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).

[0451] N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6- Synthesis of (N-methylpyrrolidine-3-carboxamide hydrochloride) (compound 2.3)

[0452]

[0453] The mixture of 3-{[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl](methyl)carbamoyl}pyrrolidine-1-carboxylic acid tert-butyl ester [compound 1.12] (200 mg, 326 µmol) in 4 M 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]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylpyrrolidine-3-carboxamide hydrochloride [compound 2.3] (31.3 mg, 57.1 µmol, 17.5% yield). m / z: [M + H] + C22H26ClF3N7O2 Calculated values: 512.1, 514.1; Measured values: 512.3, 514.2. 1H NMR (400 MHz, CDCl3)d = 10.16 (br s, 1H), 9.42 (br s, 1H), 8.90 (br s, 1H), 7.47 - 7.27 (m, 2H),7.14 - 7.00 (m, 2H), 6.62 - 6.43 (m, 1H), 5.48 (br d, J=6.0 Hz, 1H), 3.68 (brd, 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).

[0454] 4-(aminomethyl)-N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolidine] [1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methylcyclohexane-1-carboxamide; formic acid (compound) Synthesis of 2.4)

[0455]

[0456] A solution of N-[(4-{[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl](methyl)carbamoyl}cyclohexyl)methyl]tert-butyl carbamate [compound 1.13] (450 mg, 625 µmol) in 4 N HCl / dioxane (5 mL) was stirred at 20 °C for 12 hours. The mixture was concentrated under reduced pressure to give 4-(aminomethyl)-N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methylcyclohexane-1-carboxamide hydrochloride [compound 2.4, HCl salt] (370 mg, 616 µmol, 98.6% yield), as a yellow solid. 100 mg of the product was further purified by preparative HPLC (column: YMC Triart C18 250*50mm*7μm, 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]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methylcyclohexane-1-carboxamide; formic acid [compound 2.4] (21.7 mg, 36.1 µmol, 21.7% yield), as a yellow dry powder. m / z: [M + H] + C25H32ClF3N7O2 Calculated value 554.2; Measured value 554.4. 1 H NMR (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).

[0457] 3. Compounds prepared using scheme 3

[0458] Option 3:

[0459]

[0460] The starting material G-3a was used with R... G3b Treatment with G-3b yielded compound (I). G3a For NH (for cyclic amines) or NH2 (for primary amines); X is CO or SO2; R G3b For CH3, iPr, OMe, or NHMe; and R G3c It is N (for cyclic amides, ureas, or carbamates) or NH (for acyclic amides, ureas, or carbamates).

[0461] 1-Acetyl-N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]) Synthesis of pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylpiperidine-4-carboxamide (compound 3.1)

[0462]

[0463] Acetyl chloride (29.1 mg, 371 µmol) was added to a mixture of N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylpiperidin-4-carboxamide hydrochloride [compound 2.1, HCl salt] (60 mg, 106 µmol) and triethylamine (53.6 mg, 530 µmol) in DCM (2 mL), and the mixture was stirred at 25 °C for 12 hours. The mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5μm, table: 35-65%B (A = water (0.05% ammonium hydroxide v / v), B = acetonitrile), flow rate: 30 mL / min, UV detector 220 nm) to obtain 1-acetyl-N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylpiperidin-4-carboxamide [compound 3.1] (17.7 mg, 31.1 µmol, 29.4% yield), as a yellow dry powder. m / z: [M + H]+ C25H30ClF3N7O3 Calculated value 568.2; Measured value 568.4. 1H NMR (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).

[0464] N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6- [[amino]phenyl]-2,2,2-trifluoroethyl]-N-methyl-1-(propane-2-sulfonyl)piperidine-4-carboxamide (compound) Synthesis of 3.2)

[0465]

[0466] At 25 °C, propane-2-sulfonyl chloride (40.4 mg, 284 µmol) was added to a mixture of N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methylpiperidin-4-carboxamide hydrochloride [compound 2.1, HCl salt] (80 mg, 142 µmol) and triethylamine (57.4 mg, 568 µmol) in DCM (5 mL), and the mixture was stirred at 25 °C for 12 hours. The mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5μm, table: 40-70% B (A = water (0.05% ammonium hydroxide v / v)-ACN), B = acetonitrile), flow rate: 30 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]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methyl-1-(propane-2-sulfonyl)piperidine-4-carboxamide [compound 3.2] (9.10 mg, 14.3 µmol, 10.1% yield), as a yellow dry powder. m / z: [M + H] + C26H34ClF3N7O4S Calculated value: 632.2; Measured value: 632.3. 1H NMR (400 MHz, CDCl3) d = 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).

[0467] 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-carboxylic acid methyl ester (compound 3.3) synthesis

[0468]

[0469] Methyl chloroformate (329 mg, 3.48 mmol) was added to a mixture of N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methylpiperidin-4-carboxamide hydrochloride [compound 2.1, HCl salt] (100 mg, 177 µmol) and triethylamine (71.6 mg, 708 µmol) in DMF (3 mL), 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 (0.05% ammonium hydroxide v / v)- ACN), B = acetonitrile), flow rate: 25 mL / min, UV detector 220 nm) to obtain methyl piperidine-1-carboxylate [compound 3.3] (46.0 mg, 78.7 µmol, 44.6% yield). m / z: [M + H] + C25H30ClF3N7O4 Calculated value 584.2; Measured value 584.5.1 H NMR(400 MHz, CDCl3) d = 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 (brs, 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).

[0470] N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6- Synthesis of [[amino]phenyl]-2,2,2-trifluoroethyl]-1-methanesulfonyl-N-methylpiperidine-4-carboxamide (compound 3.4)

[0471]

[0472] At 0 °C, methanesulfonyl chloride (120 mg, 1.04 mmol) was added to a mixture of N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-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, 708 µmol) in DMF (3 mL), 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 (0.05% ammonium hydroxide v / v)- ACN, 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]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-1-methanesulfonyl-N-methylpiperidine-4-carboxamide [compound 3.4] (21.0 mg, 34.7 µmol, 19.8% yield), as a yellow dry powder. m / z: [M + H]+ C24H30ClF3N7O4S Calculated value 604.2; Measured value 604.3. 1H NMR (400 MHz, CDCl3) d = 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=8.8 Hz, 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).

[0473] 1-Acetyl-N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5- Synthesis of [a]pyrimidin-6-yl]amino]phenyl]-2,2,2-trifluoroethyl]-N-methylpiperidine-3-carboxamide (compound 3.5)

[0474]

[0475] At 25 °C, triethylamine (38.4 mg, 380 µmol) was added to a mixture of N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methylpiperidin-3-carboxamide [compound 2.2] (40 mg, 76.0 µmol) and acetyl chloride (20.8 mg, 266 µmol) in DCM (2 mL), 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 (0.05% ammonium hydroxide v / v)), 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]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methylpiperidin-3-carboxamide [compound 3.5] (8.90 mg, 15.6 µmol, 20.6% yield), as a yellow dry powder. m / z: [M + H]+ C25H30ClF3N7O3 Calculated value 568.2; Measured value 568.3. 1H NMR (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=6.8Hz, 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).

[0476] N3-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine- Synthesis of [6-yl]amino]phenyl]-2,2,2-trifluoroethyl]-N1,N3-dimethylpiperidine-1,3-dicarboxamide (compound 3.6)

[0477]

[0478] At 0 °C, triethylamine (38.4 mg, 380 µmol) was added to a mixture of N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methylpiperidin-3-carboxamide [compound 2.2] (50 mg, 95.0 µmol) in CH2Cl2 (3 mL), followed by N-methylcarbamoyl chloride (10.5 mg, 113 µmol). 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% ammonium hydroxide)), B = acetonitrile), flow rate: 25 mL / min, UV detector 220nm) to obtain N3-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N1,N3-dimethylpiperidine-1,3-dicarboxamide [compound 3.6] (8.00 mg, 13.7 µmol, 14.4% yield), as a yellow solid. m / z: [M + H]+ C25H31ClF3N8O3 Calculated value 583.2; Measured value 583.4. 1 H NMR (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).

[0479] N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6- Synthesis of [[amino]phenyl]-2,2,2-trifluoroethyl]-1-methanesulfonyl-N-methylpiperidine-3-carboxamide (compound 3.7)

[0480]

[0481] At 0 °C, triethylamine (38.4 mg, 380 µmol) was added to a mixture of N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methylpiperidin-3-carboxamide [compound 2.2] (50 mg, 95.0 µmol) in CH2Cl2 (2 mL), followed by methanesulfonyl chloride (90 mg, 785 µmol). 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: 34-64% B (water (0.05% ammonium hydroxide v / v), 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]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-1-methanesulfonyl-N-methylpiperidine-3-carboxamide [compound 3.7] (4.30 mg, 7.11 µmol, 7.5% yield), as a white dry powder. m / z: [M + H]+ C24H30ClF3N7O4S Calculated value 604.2; Measured value 604.3. 1 H NMR (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).

[0482] 1-Acetyl-N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5- Synthesis of [a]pyrimidin-6-yl]amino]phenyl]-2,2,2-trifluoroethyl]-N-methylpyrrolidine-3-carboxamide (compound 3.8)

[0483]

[0484] Acetyl chloride (74.9 mg, 955 µmol) was added to a mixture of N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-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) in DCM (2 mL), 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 (0.05% ammonium hydroxide v / v)-ACN), B = acetonitrile), flow rate: 30 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]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methylpyrrolidine-3-carboxamide [compound 3.8] (8.40 mg, 15.1 µmol, 5.6% yield), as a yellow dry powder. m / z: [M + H] + C24H28ClF3N7O3 Calculated value 554.2; Measured value 554.4. 1 H NMR (400 MHz, CDCl3) d = 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=6.8 Hz, 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).

[0485] N3-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine- [6-ylamino)phenyl]-2,2,2-trifluoroethyl]-N1,N3-dimethylpyrrolidine-1,3-dicarboxamide (compound 3.9) synthesis

[0486]

[0487] At 0 °C, triethylamine (110 mg, 1.09 mmol) was added to a mixture of N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methylpyrrolidine-3-carboxamide hydrochloride [compound 2.3] (150 mg, 273 µmol) in CH2Cl2 (3 mL), followed by N-methylcarbamoyl chloride (30.5 mg, 327 µmol). 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 (0.05% ammonium hydroxide v / v)-ACN)), 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]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N1,N3-dimethylpyrrolidine-1,3-dicarboxamide [compound 3.9] (11.4 mg, 20.0 µmol, 7.4% yield), as a yellow dry powder. m / z: [M + H] + C24H29ClF3N8O3 Calculated value 569.1; Measured value 569.4. 1 H NMR (400MHz, CDCl3) d = 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=4.4 Hz, 3H), 2.84 (dd, J=2.4, 4.8 Hz, 3H), 2.42 - 2.11 (m,2H), 1.63 (br s, 3H).

[0488] N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6- [[amino]phenyl]-2,2,2-trifluoroethyl]-1-methanesulfonyl-N-methylpyrrolidine-3-carboxamide (compound 3.10) synthesis

[0489]

[0490] At 0 °C, methanesulfonyl chloride (310 mg, 2.70 mmol) was added to a mixture of N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-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) in DMF (2 mL). 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) to obtain N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-1-methanesulfonyl-N-methylpyrrolidine-3-carboxamide [compound 3.10] (22.5 mg, 35.9 µmol, 12.2% yield), as a yellow dry powder. m / z: [M + H]+ C23H28ClF3N7O4S Calculated value 590.1; Measured value 590.4. 1 H NMR (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).

[0491] N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6- [[[amino]phenyl]-2,2,2-trifluoroethyl]-4-(acetamidomethyl)-N-methylcyclohexane-1-carboxamide (compound) Synthesis of 3.11)

[0492]

[0493] Et3N (49.0 mg, 485 µmol) and acetyl chloride (63.5 mg, 810 µmol) were added to a CH2Cl2 (1.5 mL) solution of 4-(aminomethyl)-N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methylcyclohexane-1-carboxamide [the free base of compound 2.4] (90 mg, 162 µmol). The resulting mixture was stirred at 20 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to give the residue. The residue was purified by preparative HPLC (column: YMC Triart C18 250*50mm*7μm, table: 26-66% B (A=water (0.05% ammonium hydroxide v / v), B=acetonitrile), flow rate: 60 mL / min, UV detector 220nm) to obtain N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-4-(acetamidomethyl)-N-methylcyclohexane-1-carboxamide [compound 3.11] (23.8 mg, 39.9 µmol, 24.6% yield), as a yellow dry powder. m / z: [M + H] + C27H34ClF3N7O3 Calculated value 596.2; Measured value 596.2. 1 H NMR (400 MHz, CDCl3) δ = 8.81 (s,1H), 7.23 (br d, 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=6.8 Hz, 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).

[0494] N-[(4-{[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine] [Pyridine-6-yl]amino)phenyl]-2,2,2-trifluoroethyl](methyl)carbamoyl]cyclohexyl)methyl]carbamate methyl ester Synthesis of (compound 3.12)

[0495]

[0496] Et3N (49.0 mg, 485 µmol) and methyl chloroformate (75.7 mg, 810 µmol) were added to a CH2Cl2 (1.5 mL) solution of 4-(aminomethyl)-N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methylcyclohexane-1-carboxamide [the free base of compound 2.4] (90 mg, 162 µmol). The resulting mixture was stirred at 20 °C for 2 hours. The reaction mixture was poured into water (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (15 mL x 2) and concentrated under reduced pressure to give the residue. The residue was purified by preparative HPLC (column: YMC Triart C18 250*50mm*7μm, table: 31-71% B (A=water (0.05% ammonium hydroxide v / v), B=acetonitrile), flow rate: 60 mL / min, UV detector 220 nm) to obtain N-[(4-{[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl](methyl)carbamoyl}cyclohexyl)methyl]carbamate [compound 3.12] (19.3 mg, 31.5 µmol, 19.4% yield), as a yellow dry powder. m / z: [M +H]+ C27H34ClF3N7O4 Calculated value 612.2; Measured value 612.2. 1H NMR (400 MHz, CDCl3) δ =8.81(s, 1H), 7.23 (br d, J=8.0 Hz, 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 (br s, 1H), 3.59 (s,3H), 3.41 (s, 3H), 3.08 - 2.92 (m, 2H), 2.83 (s, 3H), 2.46 (br t, 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).

[0497] 4. Compounds prepared using scheme 4

[0498] Option 4:

[0499]

[0500] The starting material G-4a was treated with G-4b to obtain compound (I).

[0501] N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6- (2,2,2-trifluoroethyl)-1-(cyclopropanecarbonyl)-N-methylpiperidine-4-carboxamide (compound 4.1) synthesis

[0502] Cyclopropanecarboxylic acid (36.5 mg, 425 µmol) was added to a mixture of N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylpiperidin-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) in DCM (3 mL). 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 (0.05% ammonium hydroxide v / v), B = acetonitrile), flow rate: 25 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]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-1-(cyclopropanecarbonyl)-N-methylpiperidin-4-carboxamide [compound 4.1] (20.5 mg, 34.5 µmol, 24.3% yield), as a yellow dry powder. m / z: [M + H] + C27H32ClF3N7O3 Calculated value 594.2; Measured value 594.5. 1 H NMR (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).

[0503] N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6- The synthesis of [[amino]phenyl]-2,2,2-trifluoroethyl]-1-cyclopropanecarbonyl-N-methylpiperidine-3-carboxamide [compound 4.2] become

[0504]

[0505] 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]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methylpiperidin-3-carboxamide [compound 2.2] (50 mg, 95.0 µmol) was added, and the mixture was stirred at 25 °C under N2 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-NXC18 75*30mm*3μm, table: 34-74% B (A = water (0.225% FA), 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]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-1-cyclopropanecarbonyl-N-methylpiperidine-3-carboxamide [compound 4.2] (2.80 mg, 4.71 µmol, 5.0% yield), as a yellow solid. m / z: [M + H] + C27H32ClF3N7O3 Calculated value 594.2; Measured value 594.4. 1 H NMR (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 (br d, J=6.4Hz, 3H), 1.24 (br s, 1H), 0.72 (br s, 4H).

[0506] N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6- [[amino]phenyl]-2,2,2-trifluoroethyl]-1-cyclopropanecarbonyl-N-methylpyrrolidine-3-carboxamide (compound 4.3) synthesis

[0507]

[0508] Cyclopropanecarboxylic acid (70.4 mg, 818 µmol) was added to a mixture of N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-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) in DCM (3 mL). 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 (0.05% ammonium hydroxide v / v)-ACN), B = acetonitrile), flow rate: 30 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]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-1-cyclopropanecarbonyl-N-methylpyrrolidine-3-carboxamide [compound 4.3] (14.7 mg, 25.3 µmol, 9.3% yield), as a yellow dry powder. m / z: [M + H] + C26H30ClF3N7O3 Calculated value 580.2; Measured value 580.5. 1H NMR (400 MHz, CDCl3) d = 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=5.4Hz, 1H), 1.63 (s, 3H), 1.09 - 0.96 (m, 2H), 0.79 (br d, J=7.6 Hz, 2H).

[0509] 5. Compounds prepared using scheme 5

[0510] Option 5:

[0511]

[0512] The starting material G-5a was treated with HO(CH2O)nH (paraformaldehyde) and NaBH3CN to obtain compound (I).

[0513] N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6- Synthesis of (N,1-dimethylpiperidine-4-carboxamide) (compound 5.1)

[0514]

[0515] A mixture of N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylpiperidin-4-carboxamide hydrochloride [compound 2.1, HCl salt] (80 mg, 152 µmol), sodium cyanoborohydride (14.2 mg, 227 µmol), and triethylamine (30.7 mg, 304 µmol) in MeOH (3 mL) was stirred at 25 °C for 0.5 h. Paraformaldehyde (22.8 mg, 760 µmol) was added, and the mixture was stirred at 25 °C for 12 h. The crude product was purified by preparative HPLC (column: Phenomenex Gemini-NX 80*40mm*3μm, table: 39-79% B (A = water (0.05% ammonium hydroxide v / v), B = acetonitrile), flow rate: 25 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]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N,1-dimethylpiperidin-4-carboxamide [compound 5.1] (22.0 mg, 40.7 µmol, 26.8% yield), as a yellow dry powder. m / z: [M + H]+ C24H30ClF3N7O2 Calculated value 540.2; Measured value 540.5. 1 H NMR (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).

[0516] N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6- Synthesis of (N,1-dimethylpiperidine-3-carboxamide) (compound 5.2)

[0517]

[0518] Triethylamine (19.2 mg, 190 µmol) and sodium cyanoborohydride (8.92 mg, 142 µmol) were added to a mixture of N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methylpiperidin-3-carboxamide [compound 2.2] (50 mg, 95.0 µmol) and paraformaldehyde (14.2 mg, 474 µmol) in MeOH (1 mL). The mixture was stirred at 25 °C under N2 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]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N,1-dimethylpiperidin-3-carboxamide [compound 5.2] (4.70 mg, 8.70 µmol, 9.2% yield), as a yellow dry powder. m / z: [M + H]+ C24H30ClF3N7O2 Calculated value 540.2; Measured value 540.3. 1 H NMR (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).

[0519] N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6- The synthesis of [[amino]phenyl]-2,2,2-trifluoroethyl]-N,1-dimethylpyrrolidine-3-carboxamide hydrochloride (compound 5.3) become

[0520]

[0521] A mixture of N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methylpyrrolidine-3-carboxamide hydrochloride [compound 2.3] (150 mg, 273 µmol), sodium cyanoborohydride (25.7 mg, 409 µmol), and triethylamine (55.2 mg, 546 µmol) in MeOH (3 mL) was stirred at 25 °C for 0.5 h. Then paraformaldehyde (40.8 mg, 1.36 mmol) was added, and the reaction was stirred at 25 °C for 12 h. The crude product 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-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N,1-dimethylpyrrolidine-3-carboxamide hydrochloride [compound 5.3] (14.3 mg, 25.4 µmol, 9.3% yield), as a yellow dry powder. m / z: [M + H] + C23H28ClF3N7O2 Calculated value 526.2; Measured value 526.3. 1 H NMR (400MHz, CDCl3) d = 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(br d, 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 (brs, 1H), 1.60 (s, 3H).

[0522] 6. Compounds prepared using scheme 6

[0523] Option 6:

[0524]

[0525] (1r,4S)-N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]) Pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-4-hydroxy-N-methylcyclohexane-1-carboxamide (Compound 6.1) Synthesis

[0526] 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]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylcyclohexane-1-carboxamide [INT 18.1] (100 mg, 152 µmol) in TFA (0.5 mL) and CH2Cl2 (0.5 mL) was stirred at 20 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to give 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: 30 mL / min, UV detector 220 nm) to give (1r,4S)-N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-4-hydroxy-N-methylcyclohexane-1-carboxamide [compound 6.1] (6.50 mg, 12.0 µmol, 7.9% yield), as a yellow dry powder. m / z: [M + H] + C24H29ClF3N6O3 Calculated value 541.2; Measured value 541.3. 1H NMR (400MHz, 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=6.4 Hz, 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).

[0527] 7. Compounds prepared using scheme 7

[0528] Option 7:

[0529]

[0530] The starting material G-7a was treated with a hydrolysis reagent to obtain compound (I).

[0531] (1S,4r)-4-(((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]) Pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexane-1-carboxylic acid (compound 7.1) Synthesis

[0532]

[0533] To a mixture of (1S,4r)-4-(((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexane-1-carboxylate [compound 1.4] (100 mg, 171 µmol) in THF (2 mL) and H₂O (1 mL), 1 N HCl (1 mL, 1 mmol) was added, and the mixture was stirred at 70 °C for 6 hours. Water (10 mL) was added, and the mixture was extracted with EtOAc (10 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product. This crude product was purified by preparative HPLC (column: Boston Green ODS 150*30mm*5μm, table: 28-68% B (A = water (0.05% HCl v / v)), B = acetonitrile), flow rate: 30 mL / min, UV detector 220 nm) and lyophilized to obtain (1S,4r)-4-(((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexane-1-carboxylic acid [compound 7.1] (42.5 mg, 74.6 µmol, 43.7% yield), as a yellow dry powder. m / z: [M + H]+ C25H29ClF3N6O4 Calculated value 569.2; Measured value 569.2. 1 H NMR (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=6.8 Hz, 3H), 1.49 - 1.29 (m, 4H).

[0534] (1S,4r)-4-(((S)-1-(4-((2-chloro-7-isopropyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino Synthesis of (methyl)carbamoyl)-2,2,2-trifluoroethyl(methyl)carbamoyl)cyclohexane-1-carboxylic acid amino salt (compound 7.2)

[0535]

[0536] At 20 °C, a mixture of (1S,4r)-4-(((S)-1-(4-((2-chloro-7-isopropyl-[1,2,4]triazolo[1,5-a]pyrimidin-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) in H2O (2 mL) and THF (2 mL) was stirred for 12 hours. The mixture was concentrated under reduced pressure to give a residue, which was diluted with water (5 mL). The resulting mixture was adjusted to pH = 4 with 1 N HCl and extracted with EtOAc (5 mL x 2). The combined organic layers were washed with brine (10 mL) and concentrated to give a yellow solid. The solid was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5μm, table: 15 - 45% B (A = water (0.05% ammonium hydroxide v / v), B = acetonitrile), flow rate: 30 mL / min, UV detector 220 nm) to obtain (1S,4r)-4-(((S)-1-(4-((2-chloro-7-isopropyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexane-1-carboxylic acid amino salt [compound 7.2] (2.80 mg, 4.91 µmol, 5.6% yield), as a white dry powder. m / z: [M + H] + C25H29ClF3N6O3 Calculated value 553.2; Measured value 553.1. 1 H NMR (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).

[0537] (1S,3r)-3-(((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]) Pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclobutane-1-carboxylic acid (compound 7.3) Synthesis

[0538]

[0539] Methyl (1S,3r)-3-(((S)-1-(4-(((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-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 the mixture was stirred for 10 hours. The pH of the reaction mixture was adjusted to 7 with a dilute aqueous HCl solution. The solvent was distilled off, and the residue was purified by HPLC (see conditions below) to give (1S,3r)-3-(((S)-1-(4-(((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclobutane-1-carboxylic acid [compound 7.3] (5.70 mg, 0.01053 mmol, 4.3% yield), as a yellow solid. m / z: [M + H]+ C23H25ClF3N6O4 Calculated value 541.2; Found value 541.0. 1 H NMR (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).

[0540] HPLC conditions; System: Agilent 1260 Infinity II LC coupled with Agilent 6120B single quadrupole LC / MS system; Column description: Chromatorex SBM 100-5T C18 100 Å, LC column 100 x 19 mm, Waters, Sun Fire; Stationary phase: C18; Solid support: fully porous silica; Separation method: reversed phase; Mobile phase A: water; Mobile phase B: acetonitrile; Flow rate: 30 ml / min; Loading pump: 4 ml / min B; Gradient conditions: 0-0-25-100% (B) 0-2-10-11.2 min.

[0541] 8. Compounds prepared using scheme 8

[0542] Option 8:

[0543]

[0544] The starting material G-8a was treated with an amine-containing compound to obtain compound (I). G8 and R G8’ It can be H or Me.

[0545] (1r,4S)-N1-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]) Pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-1-methylcyclohexane-1,4-dicarboxamide (compound 8.1) synthesis

[0546]

[0547] To a mixture of (1S,4r)-4-(((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexane-1-carboxylic acid [compound 7.1] (50 mg, 87.8 µmol) in DMF (1 mL), 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 h. Then NH4Cl (9.36 mg, 175 µmol) was added, and the mixture was stirred at 25 °C for 12 h. The mixture was purified by preparative HPLC (column: YMC Triart C18250*50mm*7μm, table: 25-65% B (A = water (0.05% ammonium hydroxide v / v)), B = acetonitrile), flow rate: 60 mL / min, UV detector 220 nm) to give (1r,4S)-N1-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N1-methylcyclohexane-1,4-dicarboxamide [compound 8.1] (4.00 mg, 7.04 µmol, 8.0% yield), as a yellow dry powder. m / z: [M +H]+ C25H30ClF3N7O3 Calculated value 568.2; Measured value 568.1. 1 H NMR (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).

[0548] (1r,4S)-N1-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]) (pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N1,N4-dimethylcyclohexane-1,4-dicarboxamide (compound) Synthesis of 8.2)

[0549]

[0550] To a mixture of (1S,4r)-4-(((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexane-1-carboxylic acid [compound 7.1] (50 mg, 87.8 µmol) in DMF (1 mL), 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 h. Then, methylamine hydrochloride (8.84 mg, 131 µmol) was added, and the mixture was stirred at 25 °C for 12 h. The mixture was purified by preparative HPLC (column: YMC TriartC18 250*50mm*7μm, table: 26-66% B (A = water (0.05% ammonium hydroxide v / v)), B = acetonitrile), flow rate: 60mL / min, UV detector 220 nm) to give (1r,4S)-N1-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N1,N4-dimethylcyclohexane-1,4-dicarboxamide [compound 8.2] (19.8 mg, 34.0 µmol, 38.7% yield), as a yellow dry powder. m / z: [M + H]+ C26H32ClF3N7O3 Calculated value 582.2; Measured value 582.2. 1 H NMR (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=8.8Hz, 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=6.8Hz, 3H), 1.62 - 1.51 (m, 4H).

[0551] (1r,4S)-N1-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]) (Pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N1,N4,N4-trimethylcyclohexane-1,4-dicarboxamide (compound) Synthesis of substance 8.3)

[0552]

[0553] To a mixture of (1S,4r)-4-(((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexane-1-carboxylic acid [compound 7.1] (50 mg, 87.8 µmol) in DMF (1 mL), 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 h. Then dimethylamine hydrochloride (10.6 mg, 131 µmol) was added, and the mixture was stirred at 25 °C for 12 h. The mixture was purified by preparative HPLC (column: YMCTriart C18 250*50mm*7μm, table: 30-70% B (A = water (0.05% ammonium hydroxide v / v)), B = acetonitrile), flow rate: 60 mL / min, UV detector 220 nm) to give (1r,4S)-N1-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N1,N4,N4-trimethylcyclohexane-1,4-dicarboxamide [compound 8.3] (12.4 mg, 20.8 µmol, 23.7% yield), as a yellow dry powder. m / z: [M + H]+ C27H34ClF3N7O3 Calculated value 596.2; Measured value 596.2. 1 H NMR (400MHz, 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).

[0554] 9. Compounds prepared using scheme 9

[0555] Option 9:

[0556]

[0557] (1r,3S)-N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]) (Pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyl-3-(1H-tetrazol-5-yl)cyclobutane-1-carboxamide Synthesis of (Compound 9.1)

[0558] (1r,3S)-N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-3-cyano-N-methylcyclobutane-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. EtOAc (10 mL) and H2O (5 mL) were added, and the organic phase was evaporated under vacuum at 45 °C. The residue was purified by HPLC (see conditions below) to give (1r,3S)-N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyl-3-(1H-tetrazol-5-yl)cyclobutane-1-carboxamide [compound 9.1] (16.3 mg, 0.029 mmol, 50.3% yield), as a yellow solid. m / z: [M + H]+C23H25ClF3N10O2 Calculated value 565.2; Found value 565.0. 1 H NMR (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).

[0559] HPLC conditions; System: Agilent 1260 Infinity II LC coupled with Agilent 6120B single quadrupole LC / MS system; Column: Chromatorex SBM 100-5T 5 µm C18(2) 100 Å, LC column 100 x 19 mm, Waters, Sun Fire; Stationary phase: C18; Solid support: fully porous silica; Separation method: 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) 0-2-10-11.2 min.

[0560] 10. Compounds 1.1 and N-((S)-1-(4-((2-chloro-7-((R)-1-methoxyethyl)-[1,2,4]triazolo) [1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiaran-4-carboxamide 1,1-di Separation and individualization of oxides (compound 10.1)

[0561] Option 10:

[0562]

[0563] N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiaran-4-carboxamide 1,1-dioxide [Compound 1.1] could be further purified by chiral SFC (column: DAICEL CHIRALPAK AD 250mm*50mm, 10 μm, surface: 30-30% 0.1% NH3H2O ​​ETOH), flow rate: 200 mL / min, UV detector 220 nm), resulting in [Compound 1.1] Separation and isolation of compound 10.1 (>98% chiral purity) and N-((S)-1-(4-((2-chloro-7-((R)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiaran-4-carboxamide 1,1-dioxide [compound 10.1] (>98% chiral purity). For compound 10.1; m / z: [M + H]+C23H27ClF3N6O4S Calculated value 575.1; Found value 575.0. 1H NMR (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).

[0564] 11. Compounds 3.1 and 1-acetyl-N-((S)-1-(4-((2-chloro-7-((R)-1-methoxyethyl)-[1,2, 4] Triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylpiperidine-4-carboxamide (compound) Separation and isolation of material 11.1)

[0565] Option 11:

[0566]

[0567] 1-Acetyl-N-((1S)-1-(4-((2-chloro-7-(1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylpiperidin-4-carboxamide [compound 3.1] could be further purified by chiral SFC (column: DAICEL CHIRALPAK IG (250mm*50mm, 10um), table: 50-50% B (A = water (0.1% ammonium hydroxide), B = MeOH), flow rate: 200 mL / min), resulting in compound 3.1. Separation and isolation of compound 11.1 (100% chiral purity) and 1-acetyl-N-((S)-1-(4-((2-chloro-7-((R)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylpiperidin-4-carboxamide [compound 11.1] (97% chiral purity). For compound 11.1; m / z: [M + H]+ C25H30ClF3N7O3 Calculated value 568.2; Found value 568.1. 1H NMR (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).

[0568] 12. Synthesis of intermediates

[0569] The following intermediates were synthesized and used in the synthesis of the compounds in the examples.

[0570] 2-Chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine hydrochloride (intermediate) Synthesis of 1.1):

[0571]

[0572] Synthesis of (S)-4-methoxy-3-oxovalerate tert-butyl ester (INT 1-b):

[0573] A solution of (S)-2-methoxypropionic acid [INT 1-a] (20 g, 192 mmol) in anhydrous tetrahydrofuran (342 mL) was cooled to 0 °C. At 0 °C, carbonyl diimidazole (30.6 g, 189 mmol) was added in several portions, and the mixture was stirred at this temperature for 1.25 h. At 0 °C, in a separate flask, 1-methylethyl magnesium chloride (1+) (249 mL, 499 mmol, 2 M THF solution) was added to a solution of 3-(tert-butoxy)-3-oxopropionic acid (46.1 g, 288 mmol) in anhydrous tetrahydrofuran (342 mL), and the mixture was stirred at room temperature for 1.25 h. This solution was then added to the acyl imidazolium solution through a sleeve at 0 °C, and the resulting mixture was stirred overnight at room temperature. The reaction mixture was cooled to 0°C and quenched by adding 10% citric acid aqueous solution. It was extracted with EtOAc, washed with saturated NaHCO3 aqueous solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give crude product. It was purified by silica gel rapid chromatography (acetone / hexane = 0 / 1 to 1 / 9) to give oily (S)-4-methoxy-3-oxovalerate tert-butyl ester [INT 1-b] (30.0 g, 148 mmol, 55.6%).

[0574] (S)-2-amino-7-(1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-carboxylic acid tert-butyl ester (INT) Synthesis of 1-c):

[0575] A solution of (S)-4-methoxy-3-oxovalerate tert-butyl ester [INT 1-b] (25 g, 123 mmol) and (dimethoxymethyl)dimethylamine (11.1 mL, 83.6 mmol) was heated at 120 °C for 1.5 h. The mixture was cooled to room temperature, and 4H-1,2,4-triazol-3,5-diamine (12.1 g, 123 mmol) was added, followed by ethanol (123 mL), and the mixture was heated at 85 °C for 1 h. After completion, the mixture was concentrated under reduced pressure and recrystallized from EtOH / water (1:1, 600 mL), filtered, and the filter cake was washed with 30% EtOH / water, followed by MTBE, to give solid tert-butyl 2-amino-7-(1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylate (12.7 g, 43.2 mmol, 52%). The filtrate was concentrated under reduced pressure to remove MTBE, and the solid was filtered and washed with hexane to give further (S)-2-amino-7-(1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylate [INT 1-c] (5.3 g, 18.0 mmol, 23%) as solid. Total 18.0 g, 75% yield. Chiral HPLC showed 96.9% ee. 1 H NMR (400 MHz, CDCl3) δ = 8.75(s, 1H), 5.40 (q, J=6.8 Hz, 1H), 4.95 (br s, 2H), 3.30 (s, 3H), 1.75 (d, J=6.8 Hz, 3H), 1.62 (s, 9H).

[0576] 2-Chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid (INT 1-d) synthesis:

[0577] Under ice bath conditions, at 5°C, a solution of sodium nitrite (338 mg, 4.90 mmol) in H₂O (5 mL) was added to a mixture of 2-amino-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid tert-butyl ester [INT 1-c] (1.2 g, 4.09 mmol) and copper(II) chloride dihydrate (173 mg, 1.02 mmol) in concentrated HCl (20 mL), and the mixture was stirred at 5°C for 30 minutes. The mixture was then warmed to 25°C and stirred for 16 hours. Water (100 mL) was added, and a 1 N NaOH aqueous solution was added to adjust the pH to 3–4. The mixture was extracted with CHCl3:i-PrOH = 3:1 (100 mL × 3), and the combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give solid 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid [INT 1-d] [INT 1-d] (962 mg, 92.4% yield). m / z: [M+H]+ C9H10ClN4O3 Calculated value 257.0; Found value 256.9. 1 H NMR (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).

[0578] N-{2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}carbamic acid Synthesis of tert-butyl ester (INT 1-e):

[0579] To a solution of 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-carboxylic acid [INT 1-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 ºC for 2 hours under N2 atmosphere. The mixture was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel rapid chromatography (EtOAc / petroleum ether = 1 / 10 to 1 / 5) to give solid N-{2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl} tert-butyl carbamate [INT 1-e] (420 mg, 25.4% yield). m / z: [M+H]+ C13H19ClN5O3 Calculated value 328.1; Found value 328.0.1 H NMR (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).

[0580] 2-Chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine hydrochloride (INT) Synthesis of 1.1):

[0581] A mixture of N-{2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}carbamate tert-butyl [INT 1-e] (420 mg, 1.28 mmol) in 4N HCl / dioxane (5 mL) was stirred at 25 °C for 2 h. LC-MS showed that the reaction was complete and a 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 give solid 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-amine hydrochloride [INT 1.1] (400 mg, crude).

[0582] Synthesis of 2-chloro-7-isopropyl-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine hydrochloride (intermediate 1,2)

[0583]

[0584] Synthesis of methyl 2-amino-7-isopropyl-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylate (INT 1-g):

[0585] Under a nitrogen atmosphere, a mixture of methyl 4-methyl-3-oxovalerate [INT 1-f] (23.2 g, 160 mmol) and DMF-DMA (19.0 g, 160 mmol) was stirred at 120 °C for 2 hours. Then, a mixture of 1H-1,2,4-triazol-3,5-diamine (15.8 g, 160 mmol) in EtOH (30 mL) was added, and the mixture was stirred at 85 °C for 2 hours. The mixture was concentrated under reduced pressure to give a crude product, which was purified by silica gel rapid chromatography (EtOAc / petroleum ether = 1 / 10 to 3 / 2) to give methyl 2-amino-7-isopropyl-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylate [INT 1-g] (20.6 g, 87.7 mmol, 54.7% yield) as a grayish-white solid. m / z: [M+H]+ C10H14N5O2 Calculated value 236.1; Measured value 236.2. 1 H NMR (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).

[0586] Synthesis of methyl 2-chloro-7-isopropyl-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylate (INT 1-h):

[0587] At 5 °C, a solution of sodium nitrite (2.85 g, 41.4 mmol) in H₂O (5 mL) was added to a mixture of methyl 2-amino-7-isopropyl-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylate [INT 1-g] (10.17 g, 34.5 mmol) and copper(II) chloride dihydrate (1.46 g, 8.62 mmol) in concentrated HCl (30 mL). The mixture was stirred at 5 °C (ice bath cooling) for 30 min. The mixture was then warmed to 25 °C and stirred for 12 h. 2 N NaOH aqueous solution was added to adjust the pH to 7, and the mixture was extracted with EtOAc (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 a crude product. This crude product was purified by silica gel rapid chromatography (EtOAc / petroleum ether = 0 / 1 to 1 / 1) to give methyl 2-chloro-7-isopropyl-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylate [INT 1-h] (3.00 g, 11.7 mmol, 34.1% yield), as a yellow solid. m / z: [M+H]+ C10H12ClN4O2 Calculated value 255.1; Found 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).

[0588] Synthesis of 2-chloro-7-isopropyl-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid (INT 1-i):

[0589] To a mixture of methyl 2-chloro-7-isopropyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-carboxylate [INT 1-h] (1 g, 3.92 mmol) in THF (10 mL), lithium hydroxide (1+) hydrate (2 M H₂O solution, 2.94 mL, 5.88 mmol) was added, and the mixture was stirred at 25 °C for 3 h. THF was removed under reduced pressure, and water (10 mL) was added. 1 N HCl was added to adjust the pH to 3–4, and the mixture was filtered. The filter cake was washed with water (20 mL x 2), collected, and concentrated under reduced pressure to give 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: 30 mL / min, UV detector 220nm) to obtain 2-chloro-7-isopropyl-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid [INT 1-i] (300 mg, 1.24 mmol, 31.8% yield), as a white dry powder. m / z: [M+H]+ C9H10ClN4O2 Calculated value 241.1; Measured value 241.0. 1 H NMR (400 MHz, DMSO-d6) δ = 14.14 (br s, 1H), 9.14 (s, 1H), 4.48 (spt, J =6.8 Hz, 1H), 1.51 (s, 3H), 1.49 (s, 3H).

[0590] (2-Chloro-7-isopropyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)tert-butyl carbamate (INT 1-j) Synthesis:

[0591] To a toluene (5 mL) solution of 2-chloro-7-isopropyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-carboxylic acid [INT 1-i] (150 mg, 623 µmol), diphenylphosphoazide (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 give a crude product, which was purified by silica gel rapid chromatography (PE solution of 0-50% EtOAc) to give tert-butyl carbamate [INT 1-j] (80.0 mg, 256 µmol, 41.2% yield) as a yellow solid. m / z: [M + H] + C13H19ClN5O2 Calculated value 312.1; Measured value 312.1.

[0592] Synthesis of 2-chloro-7-isopropyl-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine hydrochloride (INT 1.2):

[0593] A solution of tert-butyl carbamate (2-chloro-7-isopropyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)carbamate [INT 1-j] (80 mg, 256 µmol) in 4 M HCl / dioxane (10 mL) was stirred at 15 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give 2-chloro-7-isopropyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-amine hydrochloride [INT 1.2] (63.0 mg, 253 µmol, 99.2% yield) as a white solid. m / z: [M + H]+ C8H11ClN5 Calculated value 212.1; Found value 211.7.

[0594] Synthesis of (R)-2-chloro-7-(1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine hydrochloride (intermediate 1.3):

[0595]

[0596] (R)-2-chloro-7-(1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine [INT 1.3] can be prepared using (2R)-2-methoxypropionic acid as a starting material via the same synthetic route outlined in INT 1.1. m / z: [M+H]+ C8H11ClN5O Calculated value 228.1; Found value 228.1.

[0597] Synthesis of (R)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide (intermediate 2.1):

[0598]

[0599] Synthesis of (R,E)-N-(4-bromophenylmethylene)-2-methylpropane-2-sulfinamide (INT 2-b):

[0600] At 25 °C, (R)-2-methylpropane-2-sulfinamide (72.1 g, 595 mmol, 1.1 eq) was added to a toluene (500 mL) solution of 4-bromobenzaldehyde [INT 2-a] (100 g, 541 mmol, 1.0 eq). The mixture was stirred at 25 °C for 15 minutes. Then, NaOH (21.6 g, 541 mmol, 1.0 eq) was added to the above reaction, and the mixture was stirred at 25 °C for 12 hours. Na₂SO₄ (50 g) was added to the mixture, and the mixture was stirred for 20 minutes. The four reaction mixtures were combined and filtered through diatomaceous earth. The filtrate was concentrated under vacuum to give an oily crude product. The crude product was dissolved in petroleum ether (1.0 L) and stirred at -50 °C for 1.0 h. After filtration, solid (R,E)-N-(4-bromophenylmethylene)-2-methylpropane-2-sulfinamide [INT 2-b] was obtained (620 g, 2.15 mol, 99.5% yield).

[0601] (R)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide (INT) Synthesis of 2.1):

[0602] At 0 °C, TMSCF3 (259 g, 1.82 mol, 2.5 eq) was added to a DMF (1.4 L) solution of (R,E)-N-(4-bromophenylmethylene)-2-methylpropane-2-sulfinamide [INT 2-b] (206 g, 715 mmol, 1.0 eq) and tetrabutylammonium acetate (216 g, 715 mmol, 218 mL, 1.0 eq). The mixture was stirred at 5 °C for 1.5 h. This process was repeated twice, and the three reaction mixtures were combined for post-treatment. The mixture was poured into a saturated NH4Cl solution (13.0 L) and stirred for 10 min to obtain a suspension. The suspension was filtered to obtain a filter cake, which was then eluted with water (5.0 L). The filter cake was ground with MTBE / petroleum ether (v / v = 1:4, 2.0 L) to obtain a solid product. The mother liquor was concentrated under vacuum to obtain an oily crude product, which was purified by silica gel column chromatography with petroleum ether / ethyl acetate (10 / 1~1 / 1) to obtain solid (R)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide [INT 2.1] (389 g, 1.09 mol, 50.6% yield). 1 H NMR (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).

[0603] Synthesis of (S)-1-(4-bromophenyl)-2,2,2-trifluoro-N-methylethyl-1-amine hydrochloride (intermediate 3.1):

[0604]

[0605] (R)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N,2-dimethylpropane-2-sulfinamide [INT] Synthesis of 3-b]:

[0606] At 0–10 °C, (R)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide [INT 2.1] (100 g, 279 mmol, 1.0 eq) was added to a LiHMDS (1.0 M, 838 mL, 3.0 eq) solution, and the mixture was stirred at 0–10 °C for 0.5 h. At 0–10 °C, MeI (119 g, 838 mmol, 52.1 mL, 3.0 eq) was added to the above mixture, and the mixture was stirred at 25 °C for 1 h. This process was repeated twice, and the three combined reaction mixtures were poured into saturated NH4Cl (3.0 L) and diluted with EtOAc (1.0 L). The mixture was separated to obtain the organic layer, and the aqueous layer was extracted with EtOAc (500 mL). The combined organic layers were washed with saturated NaCl (1.0 L), dried over Na2SO4, filtered, and concentrated under vacuum to give an oily crude product. The crude product was purified by silica gel column chromatography with petroleum ether / ethyl acetate (15 / 1~1 / 1) to give an oily (R)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N,2-dimethylpropane-2-sulfinamide [INT 3-b] (161 g, 432.5 mmol, 51.6% yield).

[0607] Synthesis of (S)-1-(4-bromophenyl)-2,2,2-trifluoro-N-methylethyl-1-amine hydrochloride [INT 3.1]:

[0608] HCl / EtOAc (4.0 M, 2.02 L, 14.9 eq) was slowly added to a mixture of (R)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N,2-dimethylpropane-2-sulfinamide [INT 3-b] (202 g, 543 mmol, 1.0 eq) in EtOAc (600 mL). The mixture was stirred at 20 °C for 1 hour. The reaction mixture was filtered to obtain a solid, which was eluted with EtOAc (200 mL), and the mother liquor was concentrated under vacuum to obtain a solid. The solid was purified by silica gel column chromatography with petroleum ether / ethyl acetate (10 / 1~1 / 0), combined with the filter cake, and concentrated at 45°C for 1 hour by an oil pump to remove solvent residues, yielding (S)-1-(4-bromophenyl)-2,2,2-trifluoro-N-methylethyl-1-amine hydrochloride [INT 3.1] (115 g, 378 mmol, 69.6% yield, 100% purity, HCl). 1H NMR (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).

[0609] 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 ℃.

[0610] LCMS: Rt = 1.755 min, 100.0% purity, m / z = 268.0, 270.0 (M+1)+. The gradient was 5% B over 0.40 min, 5-95% B over 0.4–3.0 min, holding at 95% B for 1.00 min, and then 95-5% B over 0.01 min, at a flow rate of 1.0 mL / min. Mobile phase A was an aqueous solution of 0.037% trifluoroacetic acid, and mobile phase B was an acetonitrile solution of 0.018% trifluoroacetic acid. The column used for chromatography was a Kinetex C18 50*2.1 mm column (5 μm particles). Detection methods included diode array (DAD) and positive electrospray ionization. The MS range was 100–1000.

[0611] Synthesis of tetrahydro-2H-thiaran-4-carbonyl chloride 1,1-dioxide (intermediate 4.1):

[0612]

[0613] Under N2 conditions at 0 °C, (COCl)2 (58.4 g, 460 mmol, 40.3 mL, 2.0 eq) and DMF (168 mg, 2.30 mmol, 177 µL, 0.01 eq) were added to a DCM (410 mL) solution of tetrahydro-2H-thiaran-4-carboxylic acid 1,1-dioxide [INT 4-a] (41.0 g, 230 mmol, 1.0 eq). 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 was consumed. The reaction mixture was concentrated under vacuum to obtain a solid crude product, which was then concentrated by an oil pump to remove solvent residues, yielding a solid tetrahydro-2H-thiaran-4-carbonyl chloride 1,1-dioxide [INT 4.1] (46.5 g, crude).

[0614] Synthesis of tetrahydro-2H-pyran-2-carbonyl chloride (intermediate 4.2):

[0615]

[0616] Oxaloyl chloride (478 mg, 3.79 mmol) and DMF (18.4 mg, 252 µmol) were slowly added to a mixture of tetrahydro-2H-pyran-2-carboxylic acid [INT 4-b] (330 mg, 2.53 mmol) in dichloromethane (4 mL), and the mixture was stirred at 40 °C for 2 hours. The mixture was concentrated under reduced pressure to give a yellow, resinous tetrahydro-2H-pyran-2-carbonyl chloride [INT 4.2] (370 mg, 2.49 mmol, 98.6% yield).

[0617] Synthesis of methyl (1r,4r)-4-(chlorocarbonyl)cyclohexane-1-carboxylate (intermediate 4.3):

[0618]

[0619] Oxaloyl chloride (2.93 g, 23.3 mmol) and DMF (56.8 mg, 778 µmol) were slowly added to a mixture of (1r,4r)-4-(methoxycarbonyl)cyclohexane-1-carboxylic acid [INT 4-c] (1.45 g, 7.78 mmol) in dichloromethane (10 mL), and the mixture was stirred at 40 °C for 2 hours. The mixture was concentrated under reduced pressure to give a yellow, resinous crude product of (1r,4r)-4-(chlorocarbonyl)cyclohexane-1-carboxylic acid methyl ester [INT 4.3] (1.59 g, 7.76 mmol).

[0620] Synthesis of thiazide-4-carbonyl chloride (intermediate 4,4):

[0621]

[0622] Oxaloyl chloride (478 mg, 3.79 mmol) and DMF (18.4 mg, 252 µmol) were slowly added to a mixture of thiazide-4-carboxylic acid [INT 4-d] (370 mg, 2.53 mmol) in dichloromethane (2 mL). The mixture was stirred at 40 °C for 2 hours. The mixture was concentrated under reduced pressure to give a yellow, resinous crude thiazide-4-carbonyl chloride [INT 4.4] (415 mg, 2.52 mmol).

[0623] Synthesis of oxacyclopentane-3-carbonyl chloride (intermediate 4.5):

[0624]

[0625] Oxaloyl chloride (2.18 g, 17.2 mmol) and N,N-dimethylformamide (62.9 mg, 861 µmol) were added to a mixture of oxepane-3-carboxylic acid [INT 4-e] (1 g, 8.61 mmol) in CH₂Cl₂ (10 mL). The reaction mixture was stirred at 25 °C for 1.5 h. The reaction mixture was concentrated to give a yellow oily oxepane-3-carbonyl chloride [INT 4.5] (1.10 g, 8.17 mmol).

[0626] Synthesis of 1,4-dioxane[4.5]decane-8-carbonyl chloride (intermediate 4.6):

[0627]

[0628] Oxaloyl chloride (567 mg, 4.50 mmol) and DMF (21.9 mg, 300 µmol) were slowly added to a mixture of 1,4-dioxaspiro[4.5]decane-8-carboxylic acid [INT 4-f] (560 mg, 3.00 mmol) in dichloromethane (2 mL), and the mixture was stirred at 40 °C for 2 hours. The mixture was concentrated under reduced pressure to give a yellow, resinous crude product of 1,4-dioxaspiro[4.5]decane-8-carbonyl chloride [INT 4.6] (610 mg, 2.98 mmol).

[0629] Synthesis of 4,4-difluorocyclohexane-1-carbonyl chloride (intermediate 4.7):

[0630]

[0631] Oxaloyl chloride (2.29 g, 18.2 mmol) and DMF (44.5 mg, 609 µmol) were slowly added to a mixture of 4,4-difluorocyclohexane-1-carboxylic acid [INT 4-g] (1 g, 6.09 mmol) in dichloromethane (15 mL), and the mixture was stirred at 40 °C for 2 hours. The mixture was concentrated under reduced pressure to give a yellow, resinous crude product of 4,4-difluorocyclohexane-1-carbonyl chloride [INT 4.7] (1.11 g, 6.07 mmol).

[0632] Synthesis of 1-acetylazetane-3-carbonyl chloride (intermediate 4,8):

[0633]

[0634] Oxaloyl chloride (397 mg, 3.13 mmol) was added to a DCM (4 mL) solution of 1-acetylazetane-3-carboxylic acid [INT 4-h] (300 mg, 2.09 mmol) at 0 °C. The mixture was stirred at 20 °C for 1.5 h. The reaction mixture was concentrated under reduced pressure to give 1-acetylazetane-3-carbonyl chloride [INT 4.8] (337 mg, 2.08 mmol).

[0635] Synthesis of 1-acetylpiperidine-4-carbonyl chloride (intermediate 4.9):

[0636]

[0637] Oxaloyl chloride (2.20 g, 17.5 mmol) and DMF (42.6 mg, 584 µmol) were slowly added to a mixture of 1-acetylpiperidin-4-carboxylic acid [INT 4-i] (1 g, 5.84 mmol) in dichloromethane (10 mL), and the mixture was stirred at 40 °C for 2 hours. The mixture was concentrated under reduced pressure to give crude 1-acetylpiperidin-4-carbonyl chloride [INT 4.9] (1.10 g, 5.80 mmol) as a green oil.

[0638] Synthesis of methyl (1r,3r)-3-(chloroformyl)cyclobutane-1-carboxylate (intermediate 4.10):

[0639]

[0640] At 20 °C, one drop of DMF and oxaloyl chloride (239 mg, 1.89 mmol) were added to a mixture of (1r,3r)-3-(methoxycarbonyl)cyclobutane-1-carboxylic acid [INT 4-j] (100 mg, 632 µmol) in CH2Cl2 (2 mL). The mixture was stirred at 20 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give crude (1r,3r)-3-(chloroformyl)cyclobutane-1-carboxylic acid methyl ester [INT 4.10] (111 mg, 628 µmol) as a pale yellow oil.

[0641] Synthesis of (S)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiaran-4-carboxamide 1,1-dioxide (intermediate 5.1):

[0642]

[0643] At 0–10 °C, tetrahydro-2H-thiaran-4-carbonyl chloride 1,1-dioxide [INT 4.1] (45.3 g, 231 mmol, 1.8 eq) was added to a solution of (S)-1-(4-bromophenyl)-2,2,2-trifluoro-N-methylethyl-1-amine hydrochloride [INT 3.1] (39.0 g, 128 mmol, 1.0 eq, HCl) and TEA (45.7 g, 451 mmol, 62.8 mL, 3.5 eq) in DCM (200 mL). The mixture was stirred at 20 °C for 12 hours. The mixture was separated to obtain an organic layer, and the aqueous layer was extracted with DCM (100 mL). The combined organic layers were concentrated under vacuum to give an oily crude product. The crude product was purified by silica gel column chromatography with petroleum ether / ethyl acetate (15 / 1~3 / 1) to give solid (S)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiaran-4-carboxamide 1,1-dioxide [INT 5.1] (26.0 g, 60.7 mmol, 47.4% yield, 100% purity). 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).

[0644] SFC: Rt = 1.21 min, 100.0% ee; Column: Chiralpak AD-3, 50×4.6 mm ID, 3µm; Mobile phase: A: CO2, B: MeOH (0.05% IPAm, v / v); Flow rate: 3.4 mL / min; Column temperature: 35℃.

[0645] LCMS: Rt = 2.431 min, 100% purity, m / z = 428.0, 430.0(M+1)+. The gradient was 5% B over 0.40 min, 5-95% B over 0.4–3.0 min, holding at 95% B for 1.00 min, and then 95-5% B over 0.01 min, at a flow rate of 1.0 mL / min. Mobile phase A was an aqueous solution of 0.037% trifluoroacetic acid, and mobile phase B was an acetonitrile solution of 0.018% trifluoroacetic acid. The column used for chromatography was a Kinetex C18 50*2.1 mm column (5 μm particles). Detection methods included diode array (DAD) and positive electrospray ionization. The MS range was 100–1000.

[0646] Synthesis of N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methylacetamide (intermediate 5.2):

[0647]

[0648] At 0 °C, acetyl chloride (396 µL, 5.59 mmol) was added to a mixture of [(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)amine [INT 3.1 free base] (1 g, 3.73 mmol) and Et3N (754 mg, 7.46 mmol) in dichloromethane (10 mL), and the mixture was stirred at 25 °C for 16 hours. The mixture was concentrated under reduced pressure to give a crude product, which was purified by silica gel rapid chromatography (EtOAc / petroleum ether = 0 / 1 to 1 / 5) to give a colorless oily N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methylacetamide [INT 5.2] (750 mg, 2.41 mmol, 64.6% yield). m / z: [M+H]+ C11H12BrF3NO 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).

[0649] Synthesis of N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-pyran-2-carboxamide (intermediate 5.3):

[0650]

[0651] A solution of tetrahydro-2H-pyran-2-carbonyl chloride [INT 4.2] (370 mg, 2.49 mmol) in dichloromethane (2 mL) was added to a mixture of (S)-1-(4-bromophenyl)-2,2,2-trifluoro-N-methylethyl-1-amine hydrochloride [INT 3.1] (400 mg, 1.31 mmol) and Et3N (662 mg, 6.55 mmol) in dichloromethane (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 a crude product. This crude product was purified by silica gel rapid chromatography (EtOAc / petroleum ether = 1 / 10 to 1 / 5) to give N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-pyran-2-carboxamide [INT 5.3] (400 mg, 1.05 mmol, 80.3% yield), a yellow oil. m / z: [M+H]+ C15H18BrF₃NO₂ Calculated values ​​380.0, 382.0; Found value 380.0.

[0652] Synthesis of methyl (1S,4r)-4-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexane-1-carboxylate (intermediate 5.4):

[0653]

[0654] A solution of [(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)amine hydrochloride [INT 3.1] (1.6 g, 5.25 mmol) in dichloromethane (6 mL) was added to a mixture of (1r,4r)-4-(chloroformyl)cyclohexane-1-carboxylate [INT 4.3] (1.59 g, 7.76 mmol) and Et3N (2.65 g, 26.2 mmol) in dichloromethane (6 mL), 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 a crude product. This crude product was purified by silica gel rapid chromatography (EtOAc / petroleum ether = 1 / 10 to 1 / 5) to give a yellow oily methyl (1S,4r)-4-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexane-1-carboxylate [INT 5.4] (1.10 g, 2.52 mmol, 32.5% yield). m / z: [M+H]+ C18H₂₂BrF₃NO₃ Calculated values ​​436.1, 438.1; Found value 438.0.

[0655] Synthesis of N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methylthiazide-4-carboxamide (intermediate 5.5):

[0656]

[0657] A solution of thiazide-4-carbonyl chloride [INT 4.4] (415 mg, 2.52 mmol) in dichloromethane (2 mL) was added to a mixture of [(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methylthiazide-4-carboxyl chloride [INT 4.4] (415 mg, 2.52 mmol) and the mixture was stirred at 25 °C for 3 h. The mixture was purified by silica gel rapid chromatography (EtOAc / petroleum ether = 1 / 10 to 1 / 5) to give a colorless oily N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methylthiazide-4-carboxamide [INT 5.5] (132 mg, 333 µmol, 25.4% yield). m / z: [M+H]+ C15H18BrF3NOS Calculated values: 396.0, 398.0; Measured value: 397.9.

[0658] Synthesis of N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methyloxacyclopentane-3-carboxamide (intermediate 5.6):

[0659]

[0660] At 0 °C, oxacyclopentane-3-carbonyl chloride [INT 4.5] (662 mg, 4.92 mmol) was added to a mixture of [(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)amine hydrochloride [INT 3.1] (1 g, 3.28 mmol) and triethylamine (1.65 g, 16.4 mmol) in CH2Cl2 (10 mL). The reaction mixture was stirred at 25 °C for 12 hours. The reaction mixture was concentrated, diluted with water (30 mL), and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (30 mL × 2), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel rapid chromatography (0-15% EtOAc in petroleum ether solution) to give N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methyloxacyclopentane-3-carboxamide [INT 5.6] (360 mg, 983 µmol, 30.0% yield), as a yellow oil. m / z: [M + H]+ C14H16BrF3NO2 Calculated value 366.0; Measured value 365.7. 1 H NMR (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).

[0661] Synthesis of N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methyl-1,4-dioxaspiro[4.5]decane-8-carboxamide (intermediate 5.7):

[0662]

[0663] A solution of 1,4-dioxaspiro[4.5]decane-8-carbonyl chloride [INT 4.6] (430 mg, 2.10 mmol) in dichloromethane (2 mL) was added to a mixture of [(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)amine hydrochloride [INT 3.1] (450 mg, 1.47 mmol) and Et3N (743 mg, 7.35 mmol) in dichloromethane (2 mL), and the mixture was stirred at 25 °C for 3 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 a crude product. This crude product was purified by silica gel rapid chromatography (EtOAc / petroleum ether = 1 / 10 to 1 / 5) to give N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methyl-1,4-dioxaspiro[4.5]decane-8-carboxamide [INT 5.7] (210 mg, 481 µmol, 32.7% yield), a yellow oil. m / z: [M+H]+ C18H22BrF3NO3 Calculated values ​​436.1, 438.1; Found value 437.9.

[0664] Synthesis of N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-4,4-difluoro-N-methylcyclohexane-1-carboxamide (intermediate 5.8):

[0665]

[0666] A solution of 4,4-difluorocyclohexane-1-carbonyl chloride [INT 4.7] (598 mg, 3.28 mmol) in dichloromethane (10 mL) was added to a mixture of [(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)amine hydrochloride [INT 3.1] (500 mg, 1.64 mmol) and Et3N (829 mg, 8.20 mmol) in 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 a crude product. This crude product was purified by silica gel rapid chromatography (EtOAc / petroleum ether = 0 / 1 to 1 / 3) to give a colorless, resinous N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-4,4-difluoro-N-methylcyclohexane-1-carboxamide [INT 5.8] (539 mg, 1.30 mmol, 79.3% yield). m / z: [M+H]+ C₁₆H₁₈BrF₅NO. Calculated value 414.0; Found value 414.0.

[0667] Synthesis of (1r,3S)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-3-cyano-N-methylcyclobutane-1-carboxamide (intermediate 5.9):

[0668]

[0669] (1r,3r)-3-cyanocyclobutane-1-carboxylic acid [ INT 5-a] (1 g, 7.99 mmol) and (S)-1-(4-bromophenyl)-2,2,2-trifluoro-N-methylethyl-1-amine hydrochloride [ INT3.1] (2.43 g, 7.99 mmol) was mixed in pyridine (10 mL). Phosphorus oxychloride (1.22 g, 7.99 mmol) was added in batches, and the reaction mixture was stirred at 60 °C for 16 h. The reaction was quenched by adding saturated sodium bicarbonate solution (20 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a brown gel (1r,3S)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-3-cyano-N-methylcyclobutane-1-carboxamide [INT 5.9] (2.06 g, 5.49 mmol, 68.7% yield). m / z: [M + H]+ C15H15BrF3N2O Calculated 375.0; Found 375.0.

[0670] Synthesis of 1-acetyl-N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methylazacyclobutane-3-carboxamide (intermediate 5.10):

[0671]

[0672] Triethylamine (561 mg, 5.55 mmol) was added to a CH2Cl2 solution of 1-acetylazetane-3-carbonyl chloride [INT 4.8] (300 mg, 1.85 mmol) and [(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)amine hydrochloride [INT 3.1] (563 mg, 1.85 mmol). The mixture was stirred at 20 °C for 4 hours. The reaction mixture was concentrated under reduced pressure to give a crude product, which was purified by silica gel rapid chromatography (EtOAc / PE = 0 / 1 to 1 / 5) to give 1-acetyl-N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methylazacyclobutane-3-carboxamide [INT 5.10] (250 mg, 635 µmol, 34.3% yield), as a yellow oil. m / z: [M + H]+C15H17BrF3N2O2 Calculated values ​​393.0, 395.0; Found value 394.8.

[0673] Synthesis of 1-acetyl-N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methylpiperidine-4-carboxamide (intermediate 5.11):

[0674]

[0675] To a mixture of [(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)amine hydrochloride [INT 3.1] (500 mg, 1.64 mmol) and Et3N (829 mg, 8.20 mmol) in dichloromethane (10 mL), 1-acetylpiperidin-4-carbonyl chloride [INT 4.9] (550 mg, 2.90 mmol) was added, and the mixture was stirred at 25 °C for 3 hours. The mixture was concentrated under reduced pressure to give a crude product, which was purified by silica gel rapid chromatography (methanol / dichloromethane = 0 / 1 to 1 / 20) to give 1-acetyl-N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methylpiperidin-4-carboxamide [INT 5.11] (680 mg, 1.61 mmol, 98.5% yield) as a yellow solid. m / z: [M+H]+ C17H21BrF3N2O2 Calculated values: 421.1, 423.1; Measured value: 423.1. 1 H NMR (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).

[0676] Synthesis of 1-acetyl-N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methylpiperidine-4-carboxamide (intermediate 5.12):

[0677]

[0678] At 0 °C, N,N-diisopropylethylamine (254 mg, 1.97 mmol) was added to a mixture of methyl (1r,3r)-3-(chloroformyl)cyclobutane-1-carboxylate [INT 4.10] (111 mg, 628 µmol) and [(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)amine hydrochloride [INT 3.1] (120 mg, 394 µmol) in CH₂Cl₂ (2 mL). The mixture was stirred at 0 °C for 1 h, and then at 20 °C for 12 h. The reaction mixture was diluted with CH₂Cl₂ (50 mL) and 1 N HCl (20 mL). The organic phase was separated, washed with brine (20 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to obtain a crude product. This crude product was purified by silica gel rapid chromatography (EtOAc / PE = 0 / 1 to 1 / 3) to give (1S,3r)-3-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclobutane-1-carboxylate [INT 5.12] (84.8 mg, 207 µmol, 53.0% yield (53% purity)), as a yellow oil. m / z: [M + H]+ C₁₆H₁₈BrF₃NO₃ Calculated value 408.0; Found value 408.0.

[0679] Synthesis of (S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl-1-amine (intermediate 6.1):

[0680]

[0681] Add 4 M HCl / dioxane (30 mL) to 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). Stir the mixture at 15ºC for 1 hour. Concentrate the mixture under reduced pressure to give a crude product. Dilute the mixture with water (50 mL) and extract with EtOAc (100 mL x 2). Wash the combined organic layers with 1 M HCl (100 mL x 2). Basicify the aqueous phase to pH 9-10 with 2N NaOH and extract with CH2Cl2 (100 mL x 2). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give an oily (S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl-1-amine [INT 6.1] (11.0 g, 43.2 mmol, 51.6% yield). m / z: [M + H]+ C₈H₈BrF₃N Calculated 254.0 256.0; Found 255.8.

[0682] Synthesis of (S)-4-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)piperidine-1-carboxylic acid tert-butyl ester (intermediate 7.1):

[0683]

[0684] (S)-4-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)carbamoyl)piperidine-1-carboxylic acid tert-butyl ester (INT) Synthesis of 7-a):

[0685] 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-trifluoroethyl-1-amine [INT 6.1] (6 g, 23.6 mmol) was added, and the mixture was stirred at 25 °C for 16 hours. The reaction mixture was concentrated under reduced pressure to give a crude product. The mixture was diluted with water (50 mL) and extracted with EtOAc (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 crude product was purified by silica gel rapid chromatography (EA / PE = 0 / 1 to 1 / 5) to obtain (S)-4-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)carbamoyl)piperidine-1-carboxylic acid tert-butyl ester [INT 7-a] (5.16 g, 11.0 mmol, 47.3% yield), as a yellow solid. 1 ¹H NMR (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 (quintet, 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).

[0686] (S)-4-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)piperidine-1-carboxylic acid tert-butyl Synthesis of esters (INT 7.1):

[0687] Cs₂CO₃ (2.79 g, 8.58 mmol) was added to a DMF (30 mL) solution of (S)-4-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)carbamoyl)piperidine-1-carboxylic acid tert-butyl ester [INT 7-a] (2 g, 4.29 mmol), and the reaction mixture was stirred at 25 °C for 1 hour. Iodomethane (1.81 g, 12.8 mmol) was then 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 EtOAc (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 a crude product. This crude product was purified by silica gel rapid chromatography (EtOAc / petroleum ether = 1 / 5 to 1 / 0) to give (S)-4-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)piperidine-1-carboxylic acid tert-butyl ester [INT 7.1] (1.20 g, 2.50 mmol, 58.5% yield) as a white solid. 1 ¹H NMR (400MHz, chloroform-d) shifts: 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).

[0688] Synthesis of tert-butyl 3-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)piperidine-1-carboxylate (intermediate 7.2):

[0689]

[0690] 3-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)carbamoyl)piperidine-1-carboxylic acid tert-butyl ester (INT) Synthesis of 7-b):

[0691] To a mixture of 1-[(tert-butoxy)carbonyl]piperidin-3-carboxylic acid (1.94 g, 8.49 mmol), EDCI (2.03 g, 10.6 mmol), and HOBT (1.43 g, 10.6 mmol) in CH2Cl2 (20 mL), (S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl-1-amine [INT 6.1] (1.8 g, 7.08 mmol) was added, and the mixture was stirred at 25 °C for 16 h. The reaction was quenched by adding water (50 mL) and extracted with EtOAc (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 a crude product. This crude product was purified by silica gel rapid chromatography (EtOAc / PE = 0 / 1 to 1 / 5) to give tert-butyl 3-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)carbamoyl)piperidine-1-carboxylic acid [INT 7-b] (1.40 g, 3.00 mmol, 42.5% yield), as a yellow solid. m / z: [M + H-56]+ C19H25BrF3N2O3 Calculated value 408.9; Found value 408.8.

[0692] 3-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)piperidine-1-carboxylic acid tert-butyl Synthesis of esters (INT 7.2):

[0693] Cs₂CO₃ (1.95 g, 6.00 mmol) was added to a DMF (10 mL) solution of tert-butyl piperidine-1-carboxylate [INT 7-b] (1.4 g, 3.00 mmol), and the reaction mixture was stirred at 25 °C for 1 h. Iodomethane (1.27 g, 9.00 mmol) was then added at 0 °C, and the reaction was stirred at 25 °C for 4 h. The reaction was quenched by adding water (50 mL) and then extracted with EtOAc (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 a crude product. This crude product was purified by silica gel rapid chromatography (PE / EtOAc = 1 / 0 to 5 / 1) to give a colorless oily tert-butyl 3-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)piperidine-1-carboxylic acid [INT 7.2] (800 mg, 1.66 mmol, 55.9% yield). m / z: [M – 56 + H]+ C20H27BrF3N2O3 Calculated 425.1; Found 424.7.

[0694] Synthesis of 3-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)pyrrolidine-1-carboxylic acid tert-butyl ester (intermediate 7.3):

[0695]

[0696] 3-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)carbamoyl)pyrrolidine-1-carboxylic acid tert-butyl ester Synthesis of (INT 7-c):

[0697] To 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) in CH2Cl2 (30 mL), (S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl-1-amine [INT 6.1] (2 g, 7.87 mmol) was added, and the mixture was stirred at 15 °C for 16 hours. The reaction mixture was concentrated under reduced pressure to give a crude product. This crude product was combined with substances obtained from the same reaction at the same scale. The mixture was diluted with water (50 mL) and extracted with EtOAc (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 a crude substance. This crude substance was purified by silica gel rapid chromatography (EA / PE = 0 / 1 to 1 / 5) to give 3-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)carbamoyl)pyrrolidine-1-carboxylic acid tert-butyl ester [INT 7-c] (4.26 g, 9.43 mmol, 59.9% yield), a yellow oil. m / z: [M - 56 + H] + C18H₂₃BrF₃N₂O₃ Calculated values ​​395.0, 397.0; Found value 396.6. 1 ¹H NMR (400MHz, CDCl₃) d = 7.55 (br d, J=8.0 Hz, 2H), 7.25 (br s, 2H), 6.22 (br s, 1H), 5.69 (quintet, 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).

[0698] 3-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)pyrrolidine-1-carboxylic acid tert- Synthesis of butyl ester (INT 7.3):

[0699] Cs₂CO₃ (6.12 g, 18.8 mmol) was added to a DMF (50 mL) solution of 3-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)carbamoyl)pyrrolidine-1-carboxylic acid tert-butyl ester [INT 7-c] (4.26 g, 9.43 mmol), and the reaction mixture was stirred at 25 °C for 1 h. Iodomethane (4.00 g, 28.2 mmol) was then added at 0 °C, and the reaction was stirred at 25 °C for 4 h. The reaction was quenched by adding water (50 mL) and then extracted with EtOAc (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 a crude product. This crude product was purified by silica gel rapid chromatography (EtOAc / petroleum ether = 1 / 5 to 1 / 0) to give 3-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)pyrrolidine-1-carboxylic acid tert-butyl ester [INT 7.3] (2.20 g, 4.73 mmol, 50.2% yield), a yellow oil. [M-56+H]+ C19H25BrF3N2O3 Calculated value 409.1 Analyzed value 409.1 1 H NMR (400MHz, CDCl3) d = 7.61 - 7.51 (m, 2H), 7.24 (br d, J=6.4Hz, 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).

[0700] (S)-((4-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexyl)methyl)tert-butyl carbamate (intermediate 7.4):

[0701]

[0702] (S)-((4-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)carbamoyl)cyclohexyl)methyl)carbamoic acid Synthesis of tert-butyl ester (INT 7-d):

[0703] To 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) in CH2Cl2 (20 mL), (S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl-1-amine [INT 6.1] (1.9 g, 7.47 mmol) was added, and the mixture was stirred at 25 °C for 16 hours. The reaction was quenched by adding saturated Na2CO3 (100 mL) and extracted with EtOAc (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 give a crude product. This crude product was purified by silica gel rapid chromatography (EtOAc / dichloromethane = 0 / 1 to 1 / 9) to give (S)-((4-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)carbamoyl)cyclohexyl)methyl)tert-butyl carbamate [INT 7-d] (2.53 g, 5.12 mmol, 68.7% yield), a white solid. m / z: [M + H-56]+ C₂₁H₂₉BrF₃N₂O₃ Calculated value 437.1; Found value 436.9. 1 H NMR (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 (brd, 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).

[0704] (S)-((4-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexyl)methyl)amino Synthesis of tert-butyl carbamate (INT 7.4):

[0705] A suspension of (S)-((4-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)carbamoyl)cyclohexyl)methyl)tert-butyl carbamate [INT 7-d] (1 g, 2.02 mmol) and Cs₂CO₃ (1.97 g, 6.06 mmol) in DMF (15 mL) was stirred for 1 hour. MeI (860 mg, 6.06 mmol) was then added, and the resulting mixture was stirred for 3 hours. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (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 purified by preparative HPLC (column: Boston Prime C18 150*30mm*5µm, table: 54-84% B (A = water (0.05% ammonium hydroxide v / v), B = acetonitrile), flow rate: 30 mL / min, UV detector 220nm) to obtain (S)-((4-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexyl)methyl)tert-butyl carbamate [INT 7.4] (400 mg, 788 µmol, 39.2% yield), as a white solid. m / z: [M - 56 + H]+ C22H31BrF3N2O3 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 (br s, 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).

[0706] (1r,4S)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-methoxy-N-methylcyclohexane-1-carboxamide (intermediate 7.5):

[0707]

[0708] (1r,4S)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-methoxycyclohexane-1-carboxamide Synthesis of (INT 7-e):

[0709] (S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl-1-amine [INT 6.1] (700 mg, 2.75 mmol) was added to 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) in CH2Cl2 (20 mL), and the mixture was stirred at 25 °C for 16 hours. The reaction mixture was quenched by adding water (10 mL) and extracted with EtOAc (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 a crude product. This crude product was purified by silica gel rapid chromatography (EtOAc / PE = 0 / 1 to 1 / 3) to give (1r,4S)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-methoxycyclohexane-1-carboxamide [INT 7-e] (456 mg, 1.15 mmol, 42.2% yield), a white solid. m / z: [M + H]+ C16H20BrF3NO2 Calculated values ​​394.1, 396.1; Found value 395.9. 1 H NMR (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).

[0710] (1r,4S)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-methoxy-N-methylcyclohexane-1- Synthesis of formamide (INT 7.5):

[0711] A mixture of (1r,4S)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-methoxycyclohexane-1-carboxamide [INT 7-e] (455 mg, 1.15 mmol) and Cs₂CO₃ (749 mg, 2.30 mmol) in DMF (1 mL) 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 EtOAc (2 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to obtain a crude product. This crude product was purified by silica gel rapid chromatography (EtOAc / PE = 0 / 1 to 1 / 3) to give a colorless oily (1r,4S)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-methoxy-N-methylcyclohexane-1-carboxamide [INT 7.5] (130 mg, 318 µmol, 27.7% yield). m / z: [M + H]+ C17H₂₂BrF₃NO₂ Calculated value 408.1; Found value 407.8.

[0712] (1r,4S)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-((tert-butyldimethylsilyl)oxy)-N-methylcyclohexane-1-carboxamide (intermediate 8.1):

[0713]

[0714] (1r,4S)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-hydroxycyclohexane-1-carboxamide (INT) Synthesis of 8-a):

[0715] (S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl-1-amine [INT 6.1] (2 g, 7.87 mmol) was added to 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) in CH2Cl2 (20 mL), and the mixture was stirred at 25 °C for 16 h. 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 aqueous NaHCO3 solution (200 mL x 2) and brine (200 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain a crude product. This crude product was purified by silica gel rapid chromatography (EtOAc / PE = 1 / 1 to 1 / 0) to give (1r,4S)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-hydroxycyclohexane-1-carboxamide [INT 8-a] (1.80 g, 4.73 mmol, 60.1% yield), a white solid. m / z: [M + H]+ C15H18BrF3NO2 Calculated values ​​380.0, 382.0; Found value 381.7.

[0716] (1r,4S)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-((tert-butyldimethylsilyl) Synthesis of (-O-)-N-methylcyclohexane-1-carboxamide (INT 8.1):

[0717] A suspension of (1r,4S)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-hydroxycyclohexane-1-carboxamide [INT 8-a] (500 mg, 1.31 mmol), imidazole (178 mg, 2.62 mmol), and tert-butyl(chloro)dimethylsilane (295 mg, 1.96 mmol) in CH2Cl2 (5 mL) was stirred at 25 °C for 12 hours. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (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 a crude product. This crude product was purified by silica gel rapid chromatography (EtOAc / petroleum ether = 0 / 1 to 5 / 95) to give (1r,4r)-N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-4-[(tert-butyldimethylsilyl)oxy]cyclohexane-1-carboxamide (440 mg, 889 µmol, 68.0% yield) as a white solid. m / z: [M + H]+ C₂₁H₃₂BrF₃NO₂Si Calculated value 496.1; Found value 496.0. 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).

[0718] 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) in DMF (3 mL) was stirred at 20 °C for 1 hour. MeI (987 mg, 6.96 mmol) was then added, and the reaction mixture was stirred at 20 °C for 3 hours. This reaction mixture was combined with a mixture obtained from another reaction of the same nature, poured into water (30 mL), and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with water (50 mL x 2) and brine (50 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the crude substance. The substance was purified by silica gel rapid chromatography (EtOAc / petroleum ether = 0 / 1 to 3 / 97) to give (1r,4S)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-((tert-butyldimethylsilyl)oxy)-N-methylcyclohexane-1-carboxamide [INT 8.1] (495 mg, 973 µmol, 42.3% yield), as a white solid. m / z: [M + H]+ C22H34BrF3NO2Si Calculated values ​​508.1, 510.1; Found value 510.1. 1 H NMR (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).

[0719] (S)-(4-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexyl)carbamate (intermediate 9.1):

[0720]

[0721] (S)-(4-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)carbamoyl)cyclohexyl)tert-butylcarbamate Synthesis of ester (INT 9-a):

[0722] To 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) in CH2Cl2 (2 mL), (S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl-1-amine [INT 6.1] (2.5 g, 5.90 mmol) was added, and the mixture was stirred at 25 °C for 16 hours. The reaction mixture was quenched by adding water (30 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to give a crude product. This crude product was purified by silica gel rapid chromatography (EtOAc / PE = 0 / 1 to 1 / 3) to give (S)-(4-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)carbamoyl)cyclohexyl)tert-butyl carbamate [INT 9-a] (2.70 g, 5.63 mmol, 95.7% yield), a white solid. m / z: [M-Boc]+ C₂₀H₂₆BrF₃N₂O₃ Calculated value 378.1; Found value 378.9.

[0723] (S)-4-amino-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)cyclohexane-1-carboxamide hydrochloride (INT) Synthesis of 9-b):

[0724] A solution of (S)-(4-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)carbamoyl)cyclohexyl)carbamate tert-butyl ester [INT 9-a] (3.1 g, 6.46 mmol) in 30 mL of 4 M HCl dioxane was stirred at 25 °C for 1 hour. The mixture was concentrated under reduced pressure to give (S)-4-amino-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)cyclohexane-1-carboxamide hydrochloride [INT 9-b] (2.60 g, 6.25 mmol, 97.0% yield), a white solid. m / z: [M+ H]+ C15H19BrF3N2O Calculated 379.1; Found 379.1.

[0725] (S)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-(1,3-dioxoisoindolin-2-yl)cyclohexane Synthesis of alkyl-1-carboxamide (INT 9-c)

[0726] 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. This reaction was combined with a crude batch of the same size and concentrated under reduced pressure to give the crude product. The crude product was ground with EtOAc / PE (1 / 1, 50 mL) to give (S)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-(1,3-dioxoisoindoline-2-yl)cyclohexane-1-carboxamide [INT 9-c] (3.60 g, 7.06 mmol, 99.4% yield), a white solid. m / z: [M + Na]+ C23H20BrF3N2O3 Calculated values ​​531.1, 533.1; Found value 532.8.

[0727] (S)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-(1,3-dioxoisoindolin-2-yl)-N-methyl Synthesis of cyclohexane-1-carboxamide (INT 9-d):

[0728] A mixture of (S)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-(1,3-dioxoisoindoline-2-yl)cyclohexane-1-carboxamide [INT 9-c] (3.7 g, 7.26 mmol) and Cs₂CO₃ (4.72 g, 14.5 mmol) in DMF (40 mL) was stirred at 25 °C for 1 hour. 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 EtOAc (2 x 100 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to give a crude product. This crude product was purified by silica gel rapid chromatography (EtOAc / PE = 0 / 1 to 1 / 3) to give (S)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-(1,3-dioxoisoindololin-2-yl)-N-methylcyclohexane-1-carboxamide [INT 9-d] (996 mg, 1.90 mmol, 26.2% yield), as a white solid. m / z: [M + H]+ C₂₄H₂₃BrF₃N₂O₃ Calculated value 523.1; Found value 523.2.

[0729] (S)-4-amino-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methylcyclohexane-1-carboxamide (INT) Synthesis of 9-e)

[0730] To a mixture of (S)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-(1,3-dioxoisoindoline-2-yl)-N-methylcyclohexane-1-carboxamide [INT 9-d] (300 mg, 573 µmol) in EtOH (1 mL), NH₂NH₂·H₂O (143 mg, 2.86 mmol) was added, and the mixture was stirred at 20 °C for 16 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give (S)-4-amino-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methylcyclohexane-1-carboxamide [INT 9-e] (220 mg, 559 µmol, 97.7% yield) as a yellow solid. m / z: [M - NH2] + C16H20BrF3N2O Calculated value 376.1; Measured value 376.1.

[0731] (S)-(4-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexyl)carbamoic acid Synthesis of methyl ester (INT 9.1):

[0732] Methyl chloroformate (64.6 mg, 684 µmol) was added to a CH₂Cl₂ (1 mL) solution of (S)-4-amino-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methylcyclohexane-1-carboxamide [INT 9-e] (90 mg, 228 µmol) and Et₃N (115 mg, 1.14 mmol), and the mixture was stirred for 1 hour. The reaction was quenched by adding water (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to obtain a crude product. This crude product was purified by preparative TLC (EtOAc / PE = 1 / 2) to give (S)-(4-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexyl)carbamate [INT 9.1] (60.0 mg, 132 µmol, 58.8% yield), a colorless oil. m / z: [M + H] + C₁₈H₂₃BrF₃N₂O₃ Calculated values ​​451.1, 453.1; Found value 452.9.

[0733] Synthesis of (S)-4-acetamido-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methylcyclohexane-1-carboxamide (intermediate 9.2):

[0734]

[0735] Acetyl chloride (76.6 mg, 976 µmol) was added to a mixture of (S)-4-amino-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methylcyclohexane-1-carboxamide [INT 9-e] (110 mg, 279 µmol) and triethylamine (140 mg, 1.39 mmol) in DCM (1 mL), and the mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give crude (S)-4-acetamido-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methylcyclohexane-1-carboxamide [INT 9.2] (120 mg, 275 µmol, 99.1% yield) as a white solid. m / z: [M +H]+ C18H23BrF3N2O2 Calculated value 435.1; Measured value 435.2.

[0736] Synthesis of 1-(4-bromophenyl)-N-methylethyl-1-amine (intermediate 10.1):

[0737]

[0738] Sodium cyanoborohydride (8.79 g, 140 mmol) and methylamine hydrochloride (31.5 g, 468 mmol) were added to a MeOH (100 mL) solution of 1-(4-bromophenyl)ethyl-1-one [INT 10-a] (10 g, 50.3 mmol). The mixture was stirred at 20 °C for 12 h. The reaction was quenched by adding water (100 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to obtain a crude product. This crude product was purified by silica gel rapid chromatography (EtOAc / PE = 0 / 1 to 1 / 0) to give 1-(4-bromophenyl)-N-methylethyl-1-amine [INT 10.1] (7.50 g, 32.8 mmol, 65.2% yield), as a colorless oil. m / z: [M + H] + C₉H₁₃BrN Calculated value 214.0; Found value 213.9.

[0739] Synthesis of N-(1-(4-bromophenyl)ethyl)-N-methylcyclobutaneformamide (intermediate 11.1):

[0740]

[0741] DIPEA (1.49 g, 11.6 mmol) and 1-(4-bromophenyl)-N-methylethyl-1-amine (1 g, 4.67 mmol) were added to a mixture of cyclobutanecarboxylic acid [INT 11-a] (389 mg, 3.89 mmol) and HATU (2.21 g, 5.83 mmol) in CH2Cl2 (15 mL). The reaction mixture was stirred at 20 °C for 16 hours under nitrogen. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was then purified by preparative HPLC (column: Phenomenex Gemini-NX80*40mm*3um, table: 22-62% B (A = water (0.05% ammonium hydroxide)), B = acetonitrile), flow rate: 25 mL / min, UV detector 220 nm) to obtain N-(1-(4-bromophenyl)ethyl)-N-methylcyclobutanecarboxamide [INT 11.1] (150 mg, 506 µmol, 13.0% yield), as a grayish-white dry powder. m / z: [M + H]+ C14H19BrNO Calculated values ​​296.1, 298.1; Measured value 298.1.

[0742] Synthesis of N-[1-(4-bromophenyl)ethyl]-N-methylcyclohexaneformamide (intermediate 11.2):

[0743]

[0744] DIPEA (902 mg, 6.98 mmol) and cyclohexanecarboxylic acid (INT 11-b) (447 mg, 3.49 mmol) were added to a mixture of [1-(4-bromophenyl)ethyl](methyl)amine [INT 10.1] (500 mg, 2.33 mmol) and HATU (1.32 g, 3.49 mmol) in CH2Cl2 (10 mL). The reaction mixture was stirred at 20 °C for 16 hours under nitrogen. The mixture was diluted with water (50 mL) and extracted with EtOAC (50 mL × 3). The combined organic layers were washed with brine (50 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by silica gel rapid chromatography (petroleum ether: ethyl acetate = 5:1) to give N-[1-(4-bromophenyl)ethyl]-N-methylcyclohexaneformamide [INT11.2] (700 mg, 2.15 mmol, 92.7% yield), as a colorless oil. m / z: [M + H]+ C16H23BrNO Calculated values ​​324.1, 326.1; Found value 326.1.

[0745] Synthesis of N-[1-(4-bromophenyl)ethyl]-N-methylcyclopentaneformamide (intermediate 11.3):

[0746]

[0747] DIPEA (180 mg, 1.40 mmol) and [1-(4-bromophenyl)ethyl](methyl)amine (INT 10.1) (100 mg, 467 µmol) were added to a mixture of cyclopentanecarboxylic acid [INT 11-c] (63.9 mg, 560 µmol) and HATU (266 mg, 700 µmol) in CH2Cl2 (3 mL). The reaction mixture was stirred at 20 °C for 16 hours under nitrogen. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was diluted with water (20 mL) and extracted with EtOAc (20 mL × 2). The combined organic layers were washed with brine (30 mL × 2), dried over Na₂SO₄, and concentrated under reduced pressure to give N-[1-(4-bromophenyl)ethyl]-N-methylcyclopentanecarboxamide [INT 11.3] (110 mg, 354 µmol, 76.3% yield), as a colorless oil. m / z: [M + H] + C₁₅H₂₁BrNO; calculated values ​​310.1, 312.1; measured value 312.1.

[0748] Synthesis of N-(1-(4-bromophenyl)ethyl)-N-methylacetamide (intermediate 12.1):

[0749]

[0750] Triethylamine (235 mg, 2.33 mmol) and acetyl chloride (127 mg, 1.63 mmol) were added to a mixture of 1-(4-bromophenyl)-N-methylethyl-1-amine [INT 10.1] (100 mg, 467 µmol) in DCM (2 mL). The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a crude product, which was purified by silica gel rapid chromatography (EtOAc / PE = 0 / 1 to 1 / 3) to give N-(1-(4-bromophenyl)ethyl)-N-methylacetamide [INT 12.1] (100 mg, 390 µmol, 84.0% yield) as a yellow oil. m / z: [M + H]+ C11H15BrNO Calculated values ​​256.0, 258.0; Found value 257.9.

[0751] Synthesis of N-[1-(4-bromophenyl)ethyl]-N-methylcyclopropaneformamide (intermediate 12.2):

[0752]

[0753] At 25 °C, cyclopropanecarboxyl chloride [INT 12-a] (1.25 g, 12.0 mmol) was added to a mixture of [1-(4-bromophenyl)ethyl](methyl)amine [INT 10.1] (740 mg, 3.45 mmol) and triethylamine (349 mg, 3.45 mmol) in CH2Cl2 (10 mL), and the mixture was stirred at 25 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to give N-[1-(4-bromophenyl)ethyl]-N-methylcyclopropanecarboxamide [INT 12.2] (556 mg, 1.97 mmol) as a brown oil. m / z: [M + H]+ C13H17BrNO Calculated value 282.0; Found value 282.1.

[0754] Synthesis of N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methylacetamide (intermediate 13.1):

[0755]

[0756] Synthesis of (E)-N-(4-bromophenylmethylene)-2-methylpropane-2-sulfinamide (INT 13-a):

[0757] To a solution of 4-bromobenzaldehyde [INT 2-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 diatomaceous earth (1.3 g) were added, and the suspension was stirred for 15 minutes. The mixture was filtered and concentrated under reduced pressure to give a colorless, resinous (E)-N-(4-bromobenzylmethyl)-2-methylpropane-2-sulfinamide [INT 13-a] (7.35 g, 25.5 mmol, 94.4% yield). 1 H NMR (400MHz, DMSO-d6) δ = 8.55 (s, 1H), 7.89 (d, J=8.4 Hz, 2H), 7.80 - 7.72 (m, 2H), 1.18 (s, 9H).

[0758] The synthesis of N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide (INT 13-b) become:

[0759] At 0 °C, purified trimethyl(trifluoromethyl)silane (4.29 g, 30.2 mmol) was added to a DMF (30 mL) solution of tetrabutylazanium acetate (3.64 g, 12.1 mmol) and (E)-N-(4-bromophenylmethylene)-2-methylpropane-2-sulfinamide [INT 13-a] (3.5 g, 12.1 mmol) under stirring. The mixture was stirred at 0–5 °C for 3 hours. The mixture was then poured into water (100 mL). The precipitate was collected by filtration and dried under reduced pressure to give N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide [INT 13-b] (3.50 g, 9.77 mmol, 80.8% yield) as a grayish-white solid. 1 ¹H NMR (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 (quintet, J=8.6 Hz, 1H), 1.14 (s, 9H).

[0760] Synthesis of 1-(4-bromophenyl)-2,2,2-trifluoroethyl-1-amine (INT 13-c):

[0761] A dioxane solution of 4 M HCl (9.75 mL, 39.0 mmol) was added to a methanol suspension of N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide [INT 13-b] (3.5 g, 9.77 mmol) in 20 mL, and the reaction mixture was stirred at 20 °C for 1 hour. The reaction was concentrated. The residue was diluted with water (20 mL) and adjusted to pH 10 with 1 N 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 give crude 1-(4-bromophenyl)-2,2,2-trifluoroethyl-1-amine [INT 13-c] (2.16 g, 8.50 mmol, 87.0% yield) as a brown oil. m / z: [M-NH2]+ C8H7BrF3N Calculated value 237.0; Measured value 237.0. 1 H NMR (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).

[0762] Synthesis of N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)acetamide [INT 13-d]:

[0763] Acetyl chloride (996 mg, 12.7 mmol) was added to a CH₂Cl₂ (30 mL) solution of 1-(4-bromophenyl)-2,2,2-trifluoroethyl-1-amine [INT 13-c] (2.7 g, 8.50 mmol) and triethylamine (1.72 g, 17.0 mmol), and the reaction mixture was stirred at 20 °C for 12 hours. The reaction mixture was diluted with CH₂Cl₂ (50 mL), washed with water (50 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to give a crude product. This crude product was purified by silica gel chromatography (PE solution of 50% ethyl acetate) to give N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)acetamide [INT 13-d] (2.50 g, 8.44 mmol, 99.6% yield) as a grayish-white solid. m / z: [M + H]+ C10H10BrF3NO Calculated values: 296.0, 298.0; Measured value: 295.8. 1 H NMR (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).

[0764] Synthesis of N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methylacetamide (INT 13.1):

[0765] The 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 [INT 13-d] (2.5 g, 8.44 mmol) was added, and the reaction mixture was stirred at 0 °C for 30 min. Iodomethane (3.59 g, 25.3 mmol) was then added, and the reaction mixture was heated to 20 °C over N2 for 12 h. The reaction was quenched by adding saturated NH4Cl (150 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to obtain a crude product. This crude product was purified by silica gel chromatography (PE solution of 20% ethyl acetate) to give N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methylacetamide [INT 13.1] (1.83 g, 5.90 mmol, 70.1% yield), a brown oily substance. m / z: [M + H] + C₁₁H₁₂BrF₃NO Calculated values ​​310.0, 312.0; Found 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).

[0766] Synthesis of (R)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiaran-4-carboxamide 1,1-dioxide (intermediate 14.1):

[0767]

[0768] (S)-N-((R)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide (INT) Synthesis of 14-a):

[0769] (S)-N-((R)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide [INT 14-a] was prepared using (S)-(-)-2-methyl-2-propanesulfinamide via the same synthetic route as (R)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide [INT 2.1].

[0770] Synthesis of (R)-1-(4-bromophenyl)-2,2,2-trifluoroethyl-1-amine (INT 14-b):

[0771] 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 added to a dioxane solution of 4 M HCl (20 mL). The mixture was stirred at 20 °C for 1.5 h. The mixture was concentrated under reduced pressure to give a crude product. The mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL × 2). The combined organic layers were washed with 1 M HCl (50 mL x 2). The aqueous phase was alkalized to pH 9-10 with 2 N NaOH and extracted with CH2Cl2 (50 mL x 2). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the crude product (R)-1-(4-bromophenyl)-2,2,2-trifluoroethyl-1-amine [INT 14-b] (3.50 g, 13.7 mmol, 61.8% yield), a yellow solid. m / z: [M + H] + C₈H₈BrF₃N Calculated values ​​254.0, 256.0; Found value 254.1.

[0772] (R)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)tetrahydro-2H-thiaran-4-carboxamide 1,1-dioxide Synthesis of (INT 14-c):

[0773] (R)-1-(4-bromophenyl)-2,2,2-trifluoroethyl-1-amine [INT 14-b] (2 g, 7.87 mmol) was added to a mixture of tetrahydro-2H-thiaran-4-carboxylic acid 1,1-dioxide [INT 4-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 h. The reaction was quenched by adding water (50 mL) and extracted with EtOAc (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 give a crude product. This crude product was purified by silica gel rapid chromatography (EtOAc / PE = 0 / 1 to 1 / 5) to give (R)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)tetrahydro-2H-thiaran-4-carboxamide 1,1-dioxide [INT 14-c] (2.20 g, 5.31 mmol, 67.4% yield), a white solid. m / z: [M + H]+ C14H16BrF3NO3S Calculated values ​​414.0, 416.0; Found value 416.2.

[0774] (R)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiaran-4-carboxamide-1,1-di Synthesis of oxides (INT 14.1):

[0775] Cs₂CO₃ (1.57 g, 4.82 mmol) was added to a DMF (10 mL) solution of (R)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)tetrahydro-2H-thiaran-4-carboxamide 1,1-dioxide [INT 14-c] (1 g, 2.41 mmol), and the reaction mixture was stirred at 25 °C for 1 h. Iodomethane (1.02 g, 7.23 mmol) was then added at 0 °C, and the reaction was stirred at 25 °C for 2 h. The reaction was quenched by adding water (50 mL) and then extracted with EtOAc (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 a crude product. This crude product was purified by silica gel rapid chromatography (PE / EtOAc = 1 / 0 to 1 / 1) to give (R)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiaran-4-carboxamide 1,1-dioxide [INT 14.1] (700 mg, 1.63 mmol, 67.9% yield), as a colorless oil. m / z: [M +H]+ C15H18BrF3NO3S Calculated values ​​428.0, 430.0; Found value 430.1.

[0776] Synthesis of (S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoro-N-methylethyl-1-amine hydrochloride (intermediate 15.1):

[0777]

[0778] Synthesis of (R,E)-N-(4-bromo-2-methylbenzylmethyl)-2-methylpropane-2-sulfinamide (INT 15-b):

[0779] (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 tetraethyl titanate (34.2 g, 150 mmol) was added. The mixture was stirred at 25 °C for 10 hours. The reaction mixture was then poured into water (500 mL) and extracted with EtOAc (3 x 300 mL). The organic extracts were combined, dried over Na2SO4, and evaporated under vacuum. The residue was purified by rapid chromatography (hexane / MTBE = 1 / 0 to 0 / 1) to give (R,E)-N-(4-bromo-2-methylbenzylmethyl)-2-methylpropane-2-sulfinamide [INT 15-b] (10.4 g, 34.5 mmol, 68.8% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 8.76 (s, 1H), 7.75 (d, J=8.7 Hz, 1H), 7.46 - 7.37 (m, 2H), 2.56 (s, 3H), 1.24 (s, 9H).

[0780] (R)-N-((S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide Synthesis of (INT 15-c):

[0781] (R,E)-N-(4-bromo-2-methylbenzyl)-2-methylpropane-2-sulfinamide [INT 15-b] (18.8 g, 62.2 mmol) and tetrabutyltriphenyl 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 min, followed by the addition of an aqueous solution of NH4Cl (200 mL). The mixture was extracted with EtOAc (2 x 200 mL). The organic phase was dried over sodium sulfate and evaporated under vacuum at 45 °C. The residue was purified by rapid chromatography to give (R)-N-((S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide [INT 15-c] (19.0 g, 51.0 mmol, 82.2% yield), a pale yellow oil. m / z: [M + H]+ C13H18BrF3NOS Calculated value 372.0; Found value 372.2. 1H NMR (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).

[0782] (R)-N-((S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethyl)-N,2-dimethylpropane-2-sulfin Synthesis of amide (INT 15-d):

[0783] (R)-N-((S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide [INT 15-c] (10 g, 26.8 mmol) was dissolved in THF (300 mL). Bis(trimethylsilyl)aminolithium (74.3 mL, 80.3 mmol) was added at 0 °C. The mixture was stirred at 0 °C for 20 min. Iodomethane (22.7 g, 160 mmol) was added. The mixture was stirred at 20 °C for 10 h, followed by the addition of an aqueous solution of NH4Cl (50 mL). The mixture was extracted with EtOAc (2 x 30 mL). The organic phase was dried over sodium sulfate and then evaporated under vacuum at 45 °C to give crude (R)-N-((S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethyl)-N,2-dimethylpropane-2-sulfinamide [INT 15-d] (8.50 g, 22.0 mmol, 82.5% yield), a brown oily substance. m / z: [M + H]+ C14H20BrF3NOS Calculated values ​​386.0, 388.0; Measured value 388.0. 1 H NMR (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).

[0784] (S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoro-N-methylethyl-1-amine hydrochloride (INT 15.1) become:

[0785] (R)-N-((S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethyl)-N,2-dimethylpropane-2-sulfinamide [INT 15-d] (10 g, 25.8 mmol) was dissolved in methanol (20 mL). Hydrogen chloride (4 M 1,4-dioxane solution, 100 mL, 2.36 mol) was added. The mixture was stirred at 20 °C for 10 h. The mixture was evaporated under vacuum at 50 °C. MTBE (100 mL) was added. The resulting solid was filtered and washed with MTBE (100 mL) to give (S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoro-N-methylethyl-1-amine hydrochloride [INT 15.1] (6.27 g, 19.6 mmol, 76.3% yield) as a white solid. m / z: [M + H]+ C10H12BrF3N Calculated values: 282.0, 284.0; Measured value: 284.0. 1 H NMR (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).

[0786] Synthesis of (S)-1-(4-bromo-3-methylphenyl)-2,2,2-trifluoro-N-methylethyl-1-amine hydrochloride (intermediate 15.2):

[0787]

[0788] Synthesis of (R,E)-N-(4-bromo-3-methylbenzylmethyl)-2-methylpropane-2-sulfinamide (INT 15-f):

[0789] (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 tetraethyl titanate (51.3 g, 225 mmol) was added. The mixture was stirred at 60 °C for 10 hours. The reaction mixture was then poured into water (500 mL) and extracted with MTBE (3 x 300 mL). The organic extract was extracted again with water (3 x 200 mL), dried over Na2SO4, and evaporated under vacuum to give (R,E)-N-(4-bromo-3-methylbenzylmethyl)-2-methylpropane-2-sulfinamide [INT 15-f] (15.2 g, 50.2 mmol, 66.9% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.49 (s, 1H), 7.67 (d, J=2.2 Hz, 1H), 7.65 - 7.52 (m, 1H), 7.51 - 7.43 (m, 1H), 2.43 (s, 3H), 1.23 (s, 9H).

[0790] (R)-N-((S)-1-(4-bromo-3-methylphenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide Synthesis of (INT 15-g):

[0791] (R,E)-N-(4-bromo-3-methylbenzyl)-2-methylpropane-2-sulfinamide [INT 15-f] (21 g, 69.4 mmol) and tetrabutyltriphenyl 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 min, followed by the addition of an aqueous solution of NH4Cl (300 mL). The mixture was extracted with EtOAc (2 x 300 mL). The organic phase was dried over sodium sulfate and evaporated under vacuum at 45 °C. The residue was purified by rapid chromatography to give (R)-N-((S)-1-(4-bromo-3-methylphenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide [INT 15-g] (18.5 g, 49.7 mmol, 71.7% yield), as a white solid. m / z: [M + H]+ C13H18BrF3NOS Calculated value 372.0; Found value 372.0. 1 H NMR (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=7.1 Hz, 1H), 3.58 (d, J=6.4 Hz, 1H), 2.41 (s, 3H),1.25 (s, 9H).

[0792] (R)-N-((S)-1-(4-bromo-3-methylphenyl)-2,2,2-trifluoroethyl)-N,2-dimethylpropane-2-sulfin Synthesis of amide (INT 15-h):

[0793] (R)-N-((S)-1-(4-bromo-3-methylphenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide [INT 15-g] (10 g, 26.8 mmol) was dissolved in THF (200 mL). Bis(trimethylsilyl)aminolithium(I+) (74.3 mL, 80.3 mmol) was added at 0 °C. The mixture was stirred at 0 °C for 20 min. Iodomethane (22.7 g, 160 mmol) was added. The mixture was stirred at 20 °C for 10 h, followed by the addition of an aqueous solution of NH4Cl (200 mL). The mixture was extracted with EtOAc (2 x 200 mL). The organic phase was dried over sodium sulfate and then evaporated under vacuum at 45 °C to give crude (R)-N-((S)-1-(4-bromo-3-methylphenyl)-2,2,2-trifluoroethyl)-N,2-dimethylpropane-2-sulfinamide [INT 15-h] (9.09 g, 23.5 mmol, 88.2% yield), a brown oily substance. m / z: [M + H]+ C14H20BrF3NOS Calculated value 386.0; Measured value 386.0. 1 H NMR (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).

[0794] (S)-1-(4-bromo-3-methylphenyl)-2,2,2-trifluoro-N-methylethyl-1-amine hydrochloride (INT 15.2) become:

[0795] (R)-N-((S)-1-(4-bromo-3-methylphenyl)-2,2,2-trifluoroethyl)-N,2-dimethylpropane-2-sulfinamide [INT 15-h] (10.7 g, 27.7 mmol) was dissolved in methanol (20 mL), followed by the addition of hydrogen chloride (4 M solution of 1,4-dioxane, 100 mL, 2.54 mol). The mixture was stirred at 20 °C for 10 h, followed by evaporation under vacuum at 50 °C. MTBE (100 mL) was added. The resulting solid was filtered and washed with MTBE (50 mL) to give (S)-1-(4-bromo-3-methylphenyl)-2,2,2-trifluoro-N-methylethyl-1-amine hydrochloride [INT 15.2] (5.41 g, 16.9 mmol, 61.3% yield) as a beige solid. m / z: [M + H]+ C10H12BrF3N Calculated values: 282.0, 284.0; Measured value: 284.0.1 H NMR (500 MHz, DMSO-d6) δ 10.51 (s, 2H), 7.76 (d, J=8.3 Hz, 1H), 7.63 (d, J=2.2 Hz, 1H), 7.41 (dd, J=8.3, 2.2 Hz, 1H), 5.42 (s, 1H), 2.43 (s,3H), 2.37 (s,3H).

[0796] Synthesis of (S)-N-(1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethyl)-N-methylcyclobutaneformamide (intermediate 16.1):

[0797]

[0798] (S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoro-N-methylethyl-1-amine hydrochloride [INT 15.1] (0.2 g, 0.6278 mmol) and cyclobutanecarboxylic acid (125 mg, 1.25 mmol) were mixed in pyridine (2 mL), followed by the addition of phosphorus oxychloride (211 mg, 1.38 mmol). The mixture was stirred at 90 °C for 10 hours. EtOAc (20 mL) was added, and the mixture was washed with aqueous NaHSO4 solution (3 x 5 mL). The organic phase was dried over sodium sulfate and then evaporated under vacuum at 45 °C to give (S)-N-(1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethyl)-N-methylcyclobutanecarboxamide [INT 16.1] (190 mg, 0.5216 mmol, 83.3% yield), as a yellow oil. m / z: [M + H]+ C15H18BrF3NO Calculated values ​​364.1, 366.1; Found value 366.0. 1 H NMR (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).

[0799] Synthesis of N-[(1S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethyl]-N-methylcyclopropaneformamide (intermediate 16.2):

[0800]

[0801] [(1S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethyl](methyl)amine hydrochloride [INT 15.1] (0.2 g, 0.6278 mmol) and cyclopropanecarboxylic acid (107 mg, 1.25 mmol) were mixed in pyridine (2 mL). Phosphorus oxychloride (211 mg, 1.38 mmol) was then added. The mixture was stirred at 90 °C for 10 hours. EtOAc (20 mL) was added. The mixture was washed with aqueous NaHSO4 solution (3 x 5 mL). The organic phase was dried over sodium sulfate and then evaporated under vacuum at 45 °C to give N-[(1S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethyl]-N-methylcyclopropaneformamide [INT 16.2] (190 mg, 0.5425 mmol, 86.7% yield), a pale yellow solid. m / z: [M + H]+ C14H16BrF3NO Calculated value 350.0; Measured value 350.0. 1 H NMR (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).

[0802] N-[(1S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ 6 Synthesis of thiazide-4-carboxamide (intermediate 16.3):

[0803]

[0804] At 0 °C, phosphorus oxychloride (788 mg, 5.14 mmol) was added to [(1S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethyl](methyl)amine hydrochloride [INT 15.1] (500 mg, 1.56 mmol) and 1,1-dioxo-1λ 6Thiane-4-carboxylic acid [INT 4-a] (833 mg, 4.68 mmol) was added to a pyridine (3 mL) solution. The reaction mixture was stirred overnight. Sodium bicarbonate aqueous solution (3 mL) was added, and the mixture was extracted with EtOAc (3 x 10 mL) and washed with NaHSO4 (3 x 10 mL). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was purified by HPLC (see below conditions) to give N-[(1S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ 6 4-Thiamidine-4-carboxamide [INT 16.3] (132 mg, 0.2985 mmol, 19.1% yield), as a pink solid. m / z: [M + H]+ C16H20BrF3NO3S Calculated 442.0, 444.0; Found 444.0.

[0805] HPLC conditions: System Agilent 1260 Infinity II LC coupled with Agilent 6120B single quadrupole LC / MS system; Column description: Chromatorex SBM 100-5T 5 μm C18(2) 100 Å, LC column 100 x 19 mm, Waters, Sun Fire; Stationary phase: C18; Solid support: fully porous silica; Separation method: reversed phase; Mobile phase A: water; Mobile phase B: acetonitrile; Flow rate: 30 ml / min; Loading pump 4 ml / min; Gradient conditions: 20-30-60-100% (B)0-2-10-11.2 min.

[0806] Synthesis of (S)-N-(1-(4-bromo-3-methylphenyl)-2,2,2-trifluoroethyl)-N-methylcyclobutaneformamide (intermediate 17.1):

[0807]

[0808] (S)-1-(4-bromo-3-methylphenyl)-2,2,2-trifluoro-N-methylethyl-1-amine hydrochloride [INT 15.2] (0.2 g, 0.6278 mmol) and cyclobutanecarboxylic acid (125 mg, 1.25 mmol) were mixed in pyridine (2 mL), followed by the addition of phosphorus oxychloride (211 mg, 1.38 mmol) at 20 °C. The mixture was stirred at 90 °C for 10 hours. EtOAc (20 mL) was added, and the mixture was washed with aqueous NaHSO4 solution (3 x 5 mL). The organic extract was dried over sodium sulfate and then evaporated under vacuum at 35 °C to give (S)-N-(1-(4-bromo-3-methylphenyl)-2,2,2-trifluoroethyl)-N-methylcyclobutanecarboxamide [INT 17.1] (228 mg, 0.6260 mmol, 100% yield), as a yellow oil. m / z: [M + H] + C15H18BrF3NO. Calculated values: 364.0, 366.0; Found value: 366.0. 1 H NMR (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).

[0809] Synthesis of N-[(1S)-1-(4-bromo-3-methylphenyl)-2,2,2-trifluoroethyl]-N-methylcyclopropaneformamide (intermediate 17.2):

[0810]

[0811] [(1S)-1-(4-bromo-3-methylphenyl)-2,2,2-trifluoroethyl](methyl)amine hydrochloride [INT 15.2] (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 h. MTBE (300 mL) was added. The mixture was washed with aqueous NaHSO4 solution (3 x 50 mL). The organic phase was dried over sodium sulfate and evaporated under vacuum to give N-[(1S)-1-(4-bromo-3-methylphenyl)-2,2,2-trifluoroethyl]-N-methylcyclopropanecarboxamide [INT 17.2] (480 mg, 1.37 mmol, 35.0% yield) as a yellow solid. m / z: [M + H] + C14H16BrF3NO Calculated value 350.0; Measured value 350.0.

[0812] Synthesis of N-[(1S)-1-(4-bromo-3-methylphenyl)-2,2,2-trifluoroethyl]-N-methylcyclopropaneformamide (intermediate 17.3):

[0813]

[0814] [(1S)-1-(4-bromo-3-methylphenyl)-2,2,2-trifluoroethyl](methyl)amine hydrochloride [INT 15.2] (0.5 g, 1.56 mmol) and 1,1-dioxo-1λ 6 Thiane-4-carboxylic acid [INT 4-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. EtOAc (20 mL) was added, and the mixture was washed with NaHSO4 aqueous solution (3 x 5 mL). The organic phase was dried over sodium sulfate and evaporated under vacuum at 45 °C to give crude N-[(1S)-1-(4-bromo-3-methylphenyl)-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ 6 Thiane-4-carboxamide [INT 17.3] (656 mg, 1.48 mmol), a yellow solid. m / z: [M + H]+ C16H20BrF3NO3S. Calculated value 442.0; measured value 442.0.

[0815] 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]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylcyclohexane-1-carboxamide (intermediate 18.1):

[0816]

[0817] 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 [INT 8.1] (100 mg, 196 µmol), 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine hydrochloride [INT 1.1] (67.0 mg, 254 µmol), Cs2CO3 (127 mg, 392 µmol), and xantphos (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 EtOAc (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 give (1r,4S)-4-((tert-butyldimethylsilyl)oxy)-N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylcyclohexane-1-carboxamide [INT 18.1] (100 mg, 152 µmol, 78.1% yield), as a yellow oil. m / z: [M + H]+ C30H43ClF3N6O3Si Calculated value 655.3; Measured value 655.2.

[0818] Synthesis of (1S,4r)-4-(((S)-1-(4-((2-chloro-7-isopropyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexane-1-carboxylic acid methyl ester (intermediate 18.2):

[0819]

[0820] Under N2, a suspension of 2-chloro-7-(propyl-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 [INT 5.4] (61.5 mg, 141 µmol), cesium carbonate (137 mg, 423 µmol), tris(dibenzylideneacetone)dipalladium (6.45 mg, 7.05 µmol), and xantphos (8.15 mg, 14.1 µmol) in dioxane (2 mL) was stirred at 100 °C for 1.5 h. The mixture was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel rapid chromatography (MeOH / dichloromethane = 0 / 1 to 1 / 99) to give (1S,4r)-4-(((S)-1-(4-((2-chloro-7-isopropyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexane-1-carboxylate [INT 18.2] (38.5 mg, 67.9 µmol, 48.1% yield), as a yellow solid. m / z: [M + Na]+ C26H30ClF3N6O3Na Calculated value 589.2; Found value 589.3.

[0821] Synthesis of (1S,3r)-3-(((S)-1-(4-(((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclobutane-1-carboxylic acid methyl ester (intermediate 18.3):

[0822]

[0823] A mixture of (1S,3r)-3-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclobutane-1-carboxylate [INT 5.12] (0.1 g, 0.2449 mmol), 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-amine [INT 1.1 free base] (55.5 mg, 244 µmol), and cesium carbonate (239 mg, 734 µmol) in dioxane (3 mL) was purged with Ar. Tris(dibenzylideneacetone)dipalladium (11.1 mg, 12.2 µmol) and xantphos (14.1 mg, 24.4 µmol) were then added under Ar, and the reaction mixture was stirred at 100 °C for 10 hours. After cooling, the reaction mixture was diluted with MTBE (50 mL), filtered, and the filtrate was concentrated under reduced pressure to give (1S,3r)-3-(((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclobutane-1-carboxylate [INT 18.3] (68.0 mg, 0.1225 mmol, 50.3% yield), as a yellow oil. m / z: [M + H]+ C24H27ClF3N6O4 Calculated value 555.2; Found value 555.0.

[0824] Exemplary compound of formula (I)

[0825] The following compounds in Table 1 were synthesized using identified intermediates according to schemes 1-11 as described above.

[0826] Table 1.

[0827]

[0828]

[0829]

[0830]

[0831]

[0832]

[0833]

[0834]

[0835]

[0836]

[0837]

[0838]

[0839]

[0840]

[0841]

[0842]

[0843]

[0844]

[0845]

[0846]

[0847]

[0848]

[0849]

[0850]

[0851]

[0852]

[0853]

[0854]

[0855]

[0856]

[0857]

[0858]

[0859]

[0860]

[0861]

[0862]

[0863]

[0864]

[0865]

[0866]

[0867]

[0868]

[0869]

[0870]

[0871]

[0872] Example 2. MALT1 Biochemical Assay

[0873] Inhibitory efficacy was assessed by measuring the enzymatic activity of full-length MALT1 (SEQ ID NO: 1) at different concentrations of the compound. The enzymatic assay consisted of a single substrate reaction that monitored the release of a fluorescent dye during peptide substrate cleavage. The peptide substrate had the following sequence: Ac-Leu-Arg-Ser-Arg-Rh110-dPro (custom-synthesized by 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-20, and 0.005% bovine serum albumin (BSA). Steady-state kinetic analysis of peptide substrate binding resulted in the Michaelis-Menten constant (K0). M The concentration was 150 µM. The assay was performed in 384-well F-bottom polypropylene black microplates (Greiner Bio_One, catalog number 781209) with 15 nM enzyme and 30 µM peptide substrate. After 60 minutes, the reaction was quenched by adding 10 mM iodoacetate. Total fluorescence was measured using an Envision (PerkinElmer) at 485 nm excitation and 520 nm emission.

[0874] To determine potency, 1 µL of serially diluted compound (in 100% DMSO) was pre-incubated with 40 µL of enzyme for 30 min. The reaction was initiated with 10 µL of peptide substrate. Relative fluorescence units were converted to percentage of inhibition using 0% and 100% inhibition controls as references. The 100% inhibition control was prepared by 1 µM final concentration of (S)-1-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-3-(2-chloro-7-(1-methoxyethyl)pyrazolo[1,5-a]pyrimidin-6-yl)urea (IC50). 50 = 15nM) was used, while the 0% inhibitory control consisted of 2% DMSO. IC 50 The values ​​are calculated by fitting the concentration-response curve to a four-parameter logic equation in GraphPadPrism.

[0875] The results of this measurement are summarized in Table 2 below. In this table, "A" indicates IC50. 50 Less than 0.1 μM; "B" indicates IC 50 From 0.1 μM to 1 μM; and “C” indicates IC 50 Greater than 1 μM. “N / A” indicates not tested. For compounds tested in multiple experiments, the results shown represent the average value.

[0876] Table 2.

[0877]

[0878]

[0879]

[0880] Example 3. Jurkat IL-2 determination

[0881] In cell-based assays, Jurkat (ATCC, clone E6.1) (immortalized T cell line) was used to determine the inhibitory effect by dose-response to the compound and assess viability, and by evaluating Il-2 inhibition via ELISA. Cells were cultured in RPMI / 10% FBS (Invitrogen 11875093, Atlanta Biologicals S12450H) at levels below 3E6 / mL and used only for assays below passage 25. The compound was labeled onto 384w plates (PerkinElmer Culturplate, 6007680) using ECHO. Cells were seeded in fresh medium on top of the compound and incubated for 30 min, followed by stimulation with soluble anti-CD3 / 28 / 2 (Stemcell, 10970) for 24 h. The supernatant was collected and Il-2 was assessed (MSD, 384w, L21SA-1). To assess cell viability after compound treatment, cells were lysed using CTG reagent (Promega, G7570) and measured using a photometer. IL-2 curves were calculated as percentages of DMSO (100%) and signal inhibition (0%, (S)-1-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-3-(2-chloro-7-(1-methoxyethyl)pyrazolo[1,5-a]pyrimidin-6-yl)urea) controls. IC50 was calculated using a four-parameter fit in GraphPad Prism. 50 .

[0882] The results of this measurement are summarized in Table 3 below. In this table, "A" indicates IC50. 50 Less than 0.1 μM; "B" indicates IC 50 From 0.1 μM to 1 μM; and “C” indicates IC 50 Greater than 1 μM. “N / A” indicates not tested. For compounds tested in multiple experiments, the results shown represent the average value.

[0883] Table 3.

[0884]

[0885]

[0886]

[0887] Example 4. High-flux dialysis (HTD) human plasma protein binding assay

[0888] The binding of various formula (I) compounds to human plasma proteins was evaluated using the balanced dialysis method described herein.

[0889] Preparation of dialysis membranes and matrices

[0890] Immerse the dialysis membrane strips (HTD 96 a / b, catalog number 1101, HTDialysis LLC, Gales Ferry, CT, USA) in ultrapure water at room temperature for approximately 1 hour. Separate each strip containing two membranes and immerse it in 20:80 ethanol / water (v / v) for approximately 20 minutes. After this, they can be used or stored in solution at 2–8°C for up to one month. Before experiments, rinse the membranes three times and immerse them in ultrapure water for 20 minutes each.

[0891] On the day of the experiment, human plasma (BioIVT, catalog number HUMANPLNHPNN, heparin sodium or EDTA-K2 anticoagulant, multiple individuals combined) was thawed under cold tap water and centrifuged at 3220 rpm for 5 minutes to remove any clots. The pH of the resulting plasma was confirmed to be 7.0-8.0.

[0892] Dialysis steps

[0893] 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 DMSO working solution was prepared at 400 μM. To prepare the loading matrix, the compound working solution (5 μL) was added to blank human plasma (995 μL) at a ratio of 1:200 and mixed thoroughly.

[0894] Time zero (T0) samples for recovery determination were prepared as follows: 50 μL of matrix-loaded aliquots were transferred in triplicate to a sample collection plate. The samples were immediately matched with the opposite blank buffer (alkaline solution (14.2 g / L Na₂HPO₄·2H₂O and 8.77 g / L NaCl in deionized water) titrated to pH 7.4 ± 0.1 with 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 together with other post-dialysis...

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof: (I) in: R 1 Selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl and 5-10 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 3-6 The cycloalkyl group and the 5-10 membered heterocyclic group may optionally be independently selected from R on one or more available carbons, consisting of one, two, three or more groups. 1a The substituents are substituted, wherein if the 5-10 membered heterocyclic group contains a substituted cyclic nitrogen atom, the cyclic nitrogen atom may optionally be replaced by R. 1b Substitution, wherein if the 5-10 membered heterocyclic group contains a substituted cyclic sulfur atom, the cyclic sulfur atom may optionally be substituted by two O atoms; R 2 It is CH3 or CF3; R 3 It is hydrogen; or R 3 Selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 cycloalkyl, 5-6 membered heterocyclic, 5-6 membered heterocyclic -C 1-3 Alkyl-, 5-6-membered heterocyclic-O-, phenyl, and 5-6-membered heteroaryl, any one of which may optionally be selected independently by one, two, or three from R 3a Substituents of the substituents; R 4 C 1-6 alkyl; R 1a Each time it appears, it is independently selected from 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 alkoxy, 5-6 membered heterocyclic and 5-6 membered heteroaryl, wherein the C 1-6 Alkyl groups are optionally coated with -N(R) A )2 substitution, and wherein if the 5-6 membered heterocyclic group contains a substituted cyclic nitrogen atom, the cyclic nitrogen atom may optionally be replaced by R B replace; R 1b Selected from 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 3a Each time it appears, it is independently selected from halogens and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, hydroxyl, C 1-4 alkenyl, cyano, azide, -NR C R D C 3-6 cycloalkyl, C 1-4 Alkoxy C 1-4 Alkoxy, 5-6 membered heterocyclic -O-, 5-6 membered heterocyclic and phenyl, wherein C 3-6 The cycloalkyl group, the 5-6 membered heterocyclic group -O-, the 5-6 membered heterocyclic group, and the phenyl group are optionally selected by one, two, or three independently from R. p Substituents of the substituents; R p Each time it appears, it is independently selected from halogens and C. 1-4 Alkyl, C 1-4 Halogenated alkyl, hydroxyl, C 1-4 Alkoxy, C 1-4 Alkoxy C 1-4 Alkyl, NR C R D and amino C 1-3 alkyl; R A Each time it appears, it is independently selected from hydrogen and C. 1-6 Alkyl, -C(O)C 1-6 Alkyl groups and -C(O)OC 1-6 alkyl; R B Selected from C 1-6 Alkyl, C 3-6 cycloalkyl and -C(O)OC 1-6 alkyl; R C and R D Each time it appears, it is independently selected from hydrogen and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl and C 3-4 cycloalkyl, or R C and R D Together with the nitrogen atoms to which they are attached, they form 4-6 membered heterocyclic groups or 4-6 membered heteroaryl groups, wherein the 4-6 membered heterocyclic group or 4-6 membered heteroaryl group may contain additional nitrogen or oxygen atoms and optionally be substituted with one or two fluorine atoms; and t is 0 or 1.

2. The compound according to claim 1, wherein R 2 It is CH3.

3. The compound according to claim 1, wherein R 2 It is CF3.

4. The compound according to any one of claims 1-3, wherein R 3 C 1-6 Alkyl, wherein R 3 Optional C 1-4 Alkyl-substituted.

5. The compound according to any one of claims 1-4, wherein R 3 C 1-6 alkyl.

6. The compound according to any one of claims 1-5, wherein R 3 for .

7. The compound according to any one of claims 1-4, wherein R 3 C 1-6 Alkyl, wherein R 3 C 1-4 Alkyl-substituted.

8. The compound according to any one of claims 1-4 and 7, wherein R 3 for .

9. The compound according to any one of claims 1-8, wherein t = 0.

10. The compound according to any one of claims 1-8, wherein t = 1.

11. The compound of claim 10, wherein R 4 C 1-6 alkyl.

12. The compound according to claim 10 or 11, wherein R 4 It is CH3.

13. The compound represented by formula (Ib) or a pharmaceutically acceptable salt thereof: (One) in: R 1 C 1-6 Alkyl, C 3-6 cycloalkyl or 5-10 membered heterocyclic group, wherein the C 3-6 The cycloalkyl group may optionally be formed on one or more available carbons by one, two, three or more atoms, each independently selected from R. 1a The substituents are substituted, wherein if the 5-10 membered heterocyclic group contains a substituted cyclic nitrogen atom, the cyclic nitrogen atom may optionally be replaced by R. 1b Substitution, wherein if the 5-10 membered heterocyclic group contains a substituted cyclic sulfur atom, the cyclic sulfur atom may optionally be substituted by two O atoms; R 1a Each time it appears, it is independently selected from 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 5-6 heteroaryl, wherein the C 1-6 Alkyl groups are optionally coated with -N(R) A )2 replaces; R 1b Selected from 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 groups; and R A Each time it appears, it is independently selected from hydrogen and C. 1-6 Alkyl, -C(O)C 1-6 Alkyl groups and -C(O)OC 1-6 alkyl.

14. The compound according to any one of claims 1-13, wherein R 1 C 1-6 alkyl.

15. The compound according to any one of claims 1-14, wherein R 1 It is CH3.

16. The compound according to any one of claims 1-13, wherein R 1 C 3-6 cycloalkyl, wherein R 1 Optionally, one, two, three, or more carbon atoms may be independently selected from R on one or more available carbons. 1a Substituents are substituted.

17. The compound according to any one of claims 1-13 and 16, wherein R 1 C 3-6 Cycloalkyl.

18. The compound according to any one of claims 1-13, 16 and 17, wherein R 1 Selected from , , and .

19. The compound according to any one of claims 1-13 and 16, wherein R 1 C 3-6 cycloalkyl, wherein R 1 One, two, three or more carbon atoms are independently selected from R on one or more available carbons. 1a Substituents are substituted.

20. The compound according to any one of claims 1-13, 16 and 19, wherein R 1 for , or .

21. The compound according to any one of claims 1-13, 16, 19 and 20, wherein R 1a Selected from cyano, fluorine, hydroxyl, -O-CH3, -C(O)OH, -C(O)NH2, , , , , , , , , ,and .

22. The compound according to any one of claims 1-13, 16 and 19-21, wherein R 1 Selected from , , , , , , , , , , , , , , , and .

23. The compound according to any one of claims 1-12, wherein R 1 Selected from , , , , , , , , , , , , , , , , , , , and .

24. The compound according to any one of claims 1-13, wherein R 1 It is a 5-10 member heterocyclic group, where if R 1 If it contains a substituted cyclic nitrogen atom, then the cyclic nitrogen atom may optionally be replaced by R. 1b The 5-10 membered heterocyclic group may be substituted, wherein if the cyclic sulfur atom contains a substituted cyclic sulfur atom, the cyclic sulfur atom may optionally be substituted by two O atoms.

25. The compound according to any one of claims 1-13 and 24, wherein R 1 It is a 5-10 member heterocyclic group.

26. The compound according to any one of claims 1-13, 24 and 25, wherein R 1 Selected from , , , , , and .

27. The compound according to any one of claims 1-13 and 24, wherein R 1 for .

28. The compound according to any one of claims 1-13 and 24, wherein R 1 Selected from , , and .

29. The compound according to any one of claims 1-13, 24 and 28, wherein R 1b Selected from CH3 , , , , , and .

30. The compound according to any one of claims 1-13, 24, 28 and 29, wherein R 1 Selected from , , , , , , , , , , , , , , , , , , and .

31. The compound according to any one of claims 1-13, wherein R 1 Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , and .

32. The compound according to any one of claims 1-12, wherein R 1 Selected from CH3 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

33. The compound of claim 13, wherein R 1 Selected from CH3 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

34. A compound selected from any of the compounds listed in Table 1, or a pharmaceutically acceptable salt thereof.

35. A pharmaceutical composition comprising a compound of any one of claims 1-34 and a pharmaceutically acceptable carrier.

36. A method of treating cancer in a subject who requires such treatment, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-34 or a pharmaceutical composition of claim 35.

37. A method of treating an autoimmune or inflammatory disorder or disease in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-34 or a pharmaceutical composition of claim 35.

38. The method of claim 37, wherein the autoimmune or inflammatory disorder or disease is selected from acute graft-versus-host disease, chronic graft-versus-host disease, lupus, scleroderma, psoriatic arthritis, primary sclerosing cholangitis, rheumatoid arthritis, and inflammatory bowel disease.

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