MALT1 Modulators and Uses Thereof

Abstract

Provided herein are compounds, compositions, and methods useful for modulating MALT1 and treating related diseases, disorders, and conditions.In some embodiments, the compounds of the compositions described herein can be administered simultaneously with, before, or after one or more other therapeutic agents.In some embodiments, the compounds of the compositions described herein can be administered separately by the same or different administration route, or together with other agents in the same pharmaceutical composition.

Description

[Technical Field]

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

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

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

[0004] In one aspect, the compound represented by formula (I) [ka] or a pharmaceutically acceptable salt thereof, R 1 is C 1~6 Alkyl, C 1~6 Alkoxy, C 3~6 cycloalkyl, and 5- to 10-membered heterocyclyl; 1~6 Alkyl, C 3~6 Cycloalkyl and 5- to 10-membered heterocyclyl are R 1a and optionally substituted on one or more available carbons with one, two, three, or more substituents each independently selected from R 1b and when the 5- to 10-membered heterocyclyl contains a substitutable ring sulfur atom, the ring sulfur atom is optionally substituted with two O atoms; R 2 is CH3 or CF3, R 3 is hydrogen, or R 3 is C 1~6 Alkyl, C 1~6 Alkoxy, C 3~7 Cycloalkyl, 5-6-membered heterocyclyl, 5-6-membered heterocyclyl-C 1~3 alkyl-, 5- to 6-membered heterocyclyl-O-, phenyl, and 5- to 6-membered heteroaryl, any of which is selected from the group consisting of R 3a and optionally substituted with 1, 2, or 3 substituents each independently selected from R 4 is C 1~6 is alkyl, R 1a Each occurrence represents cyano, halogen, hydroxyl, oxo, C 1~6 Alkyl, -C(O)OR A , -C(O)N(R A )2, -N(R A )2, C 1~6independently selected from the group consisting of alkoxy, 5- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl; C 1~6 Alkyl is -N(R A )2, wherein when the 5- to 6-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom is optionally substituted by R B and optionally substituted by R 1b is 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 is selected from the group consisting of alkyl, R 3a Each occurrence of represents a halogen, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, Hydroxy, C 1~4 Alkenyl, cyano, azido, -NR C R D , C 3~6 Cycloalkyl, C 1~4 Alkoxy C 1~4 independently selected from the group consisting of alkoxy, 5- to 6-membered heterocyclyl-O-, 5- to 6-membered heterocyclyl, and phenyl; C 3~6 Cycloalkyl, 5-6 membered heterocyclyl-O-, 5-6 membered heterocyclyl, and phenyl are R p and optionally substituted with 1, 2, or 3 substituents each independently selected from R p Each occurrence of represents a halogen, C 1~4 Alkyl, C 1~4 Haloalkyl, hydroxy, C 1~4 Alkoxy, C 1~4 Alkoxy C 1~4 Alkyl, NR C R D , and Amino C 1~3 independently selected from the group consisting of alkyl, R A Each occurrence of represents hydrogen, C 1~6 Alkyl, -C(O)C 1~6 Alkyl, and -C(O)OC 1~6 independently selected from the group consisting of alkyl, R B is C 1~6 Alkyl, C 3~6 Cycloalkyl, and -C(O)OC 1~6 is selected from the group consisting of alkyl, R C and R D Each occurrence of represents hydrogen, C 1~6 Alkyl, HaloC 1~6 Alkyl, and C 3~4 independently selected from the group consisting of cycloalkyl; R C and R D together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl or a 4- to 6-membered heteroaryl, which 4- to 6-membered heterocyclyl or 4- to 6-membered heteroaryl may contain an additional nitrogen atom or oxygen atom and is optionally substituted with 1 or 2 fluoro; t is either 0 or 1] is provided.

[0005] In another aspect, the compound represented by formula (Ib) [ka] or a pharmaceutically acceptable salt thereof, R 1 is C 1~6 Alkyl, C 3~6 cycloalkyl, or 5- to 10-membered heterocyclyl, C 3~6 Cycloalkyl is R 1aand optionally substituted on one or more available carbons with one, two, three, or more substituents each independently selected from R 1b and when the 5- to 10-membered heterocyclyl contains a substitutable ring sulfur atom, the ring sulfur atom is optionally substituted with two O atoms; R 1a Each occurrence represents cyano, halogen, hydroxyl, C 1~6 Alkyl, -C(O)OR A , -C(O)N(R A )2, -N(R A )2, C 1~6 independently selected from the group consisting of alkoxy, and 5-6 membered heteroaryl; 1~6 Alkyl is -N(R A )2, substituted as necessary, R 1b is 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 is selected from the group consisting of alkyl, R A Each occurrence of represents hydrogen, C 1~6 Alkyl, -C(O)C 1~6 Alkyl, and -C(O)OC 1~6 alkyl] is provided.

[0006] In some embodiments, the compounds provided herein are selected from the compounds set forth in Table 1, or a pharmaceutically acceptable salt thereof.

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

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

[0009] In another aspect, provided herein is a method of treating an autoimmune or inflammatory disorder or disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition disclosed herein. DETAILED DESCRIPTION OF THE INVENTION

[0010] Detailed Description As generally described herein, the present invention provides compounds that are designed to act as MALT1 modulators, for example. In certain embodiments, it is contemplated that such compounds are useful as therapeutic agents for treating autoimmune and inflammatory diseases, disorders or conditions, or cancer. definition chemical definition

[0011] Definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are listed in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th In addition, general principles of organic chemistry, as well as specific functional moieties and reactivities, are described in detail in: Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5 thEdition, John Wiley & Sons, Inc., New York, 2001, Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989, and Carruthers, Some Modern Methods of Organic Synthesis, 3 rd Edition, Cambridge University Press, Cambridge, 1987.

[0012] 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 a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts, or preferred isomers can be prepared by asymmetric 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 p. 268 (EL Eliel, Ed., University of Notre Dame Press, Notre Dame, IN 1972). The present invention additionally encompasses the compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

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

[0014] In the compositions provided herein, enantiomerically pure compounds may be present together with other active or inactive ingredients. For example, a pharmaceutical composition containing an enantiomerically pure R-compound can contain, for example, about 90% excipients and about 10% enantiomerically pure R-compound. In certain embodiments, the enantiomerically pure R-compound in such a composition can contain, for example, at least about 95% by weight of the R-compound and up to about 5% by weight of the S-compound, based on the total weight of the compound. For example, a pharmaceutical composition containing an enantiomerically pure S-compound can contain, for example, about 90% excipients and about 10% of the enantiomerically pure S-compound. In certain embodiments, the enantiomerically pure S-compound in such a composition can contain, for example, at least about 95% by weight of the S-compound and up to about 5% by weight of the R-compound, based on the total weight of the compound. In certain embodiments, the active ingredient can be formulated with little or no excipients or carriers.

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

[0016] The following terms are intended to have the meanings presented below and are useful in understanding the present description and the intended scope of the invention. In describing the present invention, which may include compounds and pharmaceutically acceptable salts thereof, pharmaceutical compositions containing such compounds, and methods of using such compounds and compositions, the following terms, when present, have the following meanings unless otherwise indicated. It is also understood that any of the moieties defined below, as described herein, may be substituted with various substituents, and that each definition is intended to include such substituted moieties within their scope as described below. Unless otherwise stated, the term "substituted" will be defined as described below. Furthermore, it should be understood that the terms "group" and "radical" can be considered interchangeable when used herein. The articles "a" and "an" can be used herein to refer to one or more than one (i.e., at least one) of the grammatical object of the article. For example, "an analog" means one analog or more than one analog.

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

[0018] As used herein, "alkyl" refers to the radical of a linear or branched saturated hydrocarbon group, e.g., having 1 to 20 carbon atoms ("C 1~20 In some embodiments, an alkyl group has 1 to 10 carbon atoms ("C 1~10 In some embodiments, the alkyl group has 1 to 9 carbon atoms ("C 1~9 In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C 1~8 In some embodiments, the alkyl group has 1 to 7 carbon atoms ("C 1~7 In some embodiments, the alkyl group has 1 to 6 carbon atoms ("C 1~6 In some embodiments, the alkyl group has 1 to 5 carbon atoms ("C 1~5 In some embodiments, the alkyl group has 1 to 4 carbon atoms ("C 1~4 In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C 1~3 In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C 1~2 In some embodiments, the alkyl group has one carbon atom ("C alkyl"). 1~6 Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, and the like.

[0019] As used herein, "alkenyl" refers to the radical of 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) ("C 2~20 In certain embodiments, alkenyl does not contain any triple bonds. In some embodiments, alkenyl groups have 2 to 10 carbon atoms ("C 2~10 In some embodiments, the alkenyl group has 2 to 9 carbon atoms ("C 2~9 In some embodiments, the alkenyl group has 2 to 8 carbon atoms ("C 2~8 In some embodiments, the alkenyl group has 2 to 7 carbon atoms ("C 2~7 In some embodiments, the alkenyl group has 2 to 6 carbon atoms ("C 2~6 In some embodiments, the alkenyl group has 2 to 5 carbon atoms ("C 2~5 In some embodiments, the alkenyl group has 2 to 4 carbon atoms ("C 2~4 In some embodiments, the alkenyl group has 2 to 3 carbon atoms ("C 2~3 In some embodiments, the alkenyl group has two carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (e.g., in 2-butenyl) or terminal (e.g., in 1-butenyl). C 2~4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. 2~6 Examples of alkenyl groups include the aforementioned C 2~4Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), etc. Further examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), etc.

[0020] As used herein, "alkynyl" refers to the radical of 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) ("C 2~20 In certain embodiments, alkynyl groups contain no double bonds. In some embodiments, alkynyl groups have 2 to 10 carbon atoms ("C 2~10 In some embodiments, an alkynyl group has 2 to 9 carbon atoms ("C 2~9 In some embodiments, the alkynyl group has 2 to 8 carbon atoms ("C 2~8 In some embodiments, an alkynyl group has 2 to 7 carbon atoms ("C 2~7 In some embodiments, an alkynyl group has 2 to 6 carbon atoms ("C 2~6 In some embodiments, the alkynyl group has 2 to 5 carbon atoms ("C 2~5 In some embodiments, the alkynyl group has 2 to 4 carbon atoms ("C 2~4 In some embodiments, the alkynyl group has 2 to 3 carbon atoms ("C 2~3 In some embodiments, the alkynyl group has two carbon atoms ("C2 alkynyl"). The carbon-carbon triple bond or bonds can be internal (e.g., in 2-butynyl) or terminal (e.g., in 1-butynyl). C 2~4Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. 2~6 Examples of alkenyl groups include the aforementioned C 2~4 Alkynyl groups include pentynyl (C5), hexynyl (C6), etc. Further examples of alkynyl include heptynyl (C7), octynyl (C8), etc.

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

[0022] When a range or number of carbons is provided for a particular "alkylene," "alkenylene," or "alkynylene" group, it is understood that the range or number refers to the range or number of carbons in a linear divalent chain of carbons. "Alkylene," "alkenylene," and "alkynylene" groups can be substituted or unsubstituted with one or more substituents described herein.

[0023] As used herein, "aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., 6, 10, or 14 pi electrons shared in a cyclic arrangement), provided that the aromatic ring system has 6 to 14 ring carbon atoms and 0 heteroatoms ("C 6~14 In some embodiments, an aryl group has 6 ring carbon atoms ("C aryl", e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10aryl," e.g., naphthyl, e.g., 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms ("C 14 "Aryl," e.g., anthracyl). "Aryl" also includes ring systems in which an aryl ring, as defined above, is fused to one or more carbocyclyl or heterocyclyl groups, where the radical or point of attachment is on the aryl ring, and in such cases the number of carbon atoms continues to designate the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Particularly, aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl.

[0024] As used herein, "heteroaryl" refers to a radical of a 5- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., 6 or 10 electrons are shared in the cyclic arrangement) provided with ring carbon atoms and 1 to 4 ring heteroatoms (each heteroatom independently selected from nitrogen, oxygen, and sulfur) in the aromatic ring system ("5- to 10-membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be to a carbon atom or a nitrogen atom, as allowed by valence. Heteroaryl bicyclic ring systems can 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 carbocyclyl or heterocyclyl groups, where the point of attachment is on the heteroaryl ring; in such cases, the number of ring members continues to designate 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 to one or more aryl groups, where the point of attachment can be on either the aryl ring or the heteroaryl ring, and in such cases the number of ring members designates the number of ring members in the fused (aryl / heteroaryl) ring system. In bicyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., on the ring bearing a heteroatom (e.g., 2-indolyl) or on the ring that does not contain a heteroatom (e.g., 5-indolyl).

[0025] In some embodiments, heteroaryl groups are 5-10 membered aromatic ring systems ("5-10 membered heteroaryl"), where the aromatic ring system has ring carbon atoms and 1-4 ring heteroatoms (each heteroatom independently selected from nitrogen, oxygen, and sulfur). In some embodiments, heteroaryl groups are 5-8 membered aromatic ring systems ("5-8 membered heteroaryl"), where the aromatic ring system has ring carbon atoms and 1-4 ring heteroatoms (each heteroatom independently selected from nitrogen, oxygen, and sulfur). In some embodiments, heteroaryl groups are 5-6 membered aromatic ring systems ("5-6 membered heteroaryl"), where the aromatic ring system has ring carbon atoms and 1-4 ring heteroatoms (each heteroatom independently selected from nitrogen, oxygen, and sulfur). In some embodiments, 5-6 membered heteroaryls have 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, 5-6 membered heteroaryls have 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0026] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, 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, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0027] Representative examples of heteroaryls include: [ka] wherein each Z is a carbonyl, N, NR 65 , O, and S; R 65 are independently hydrogen, C 1~8 Alkyl, C 3~10 Carbocyclyl, 4-10 membered heterocyclyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl].

[0028] As used herein, "carbocyclyl" or "carbocyclic" refers to a radical of a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms and 0 heteroatoms in a non-aromatic ring system ("C 3~10 In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3~8 In some embodiments, the carbocyclyl group has 3 to 7 ring carbon atoms ("C 3~7 In some embodiments, the carbocyclyl group has 3 to 6 ring carbon atoms ("C 3~6 In some embodiments, the carbocyclyl group has 5 to 10 ring carbon atoms ("C 5~10 carbocyclyl). Exemplary C 3~6 Carbocyclyl groups include, but are not limited to, cyclopropyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. 3~8 As a carbocyclyl group, the aforementioned C 3~6 Examples of carbocyclyl groups include, but are not limited to, cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. 3~10 As a carbocyclyl group, the aforementioned C3~8 Carbocyclyl groups, as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ), and the like. As the foregoing examples illustrate, in certain embodiments, a carbocyclyl group is either monocyclic (a "monocyclic carbocyclyl") or contains a fused, bridged, or spiro ring system, e.g., a bicyclic system (a "bicyclic carbocyclyl"), and may be saturated or partially unsaturated. "Carbocyclyl" also includes ring systems in which a carbocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, where the point of attachment is on the carbocyclyl ring, and in such cases the number of carbons continues to designate the number of carbons in the carbocyclic ring system.

[0029] The term "cycloalkyl" is used herein to refer to a group derived from, for example, a cycloalkane, such as "C 4~8 "Cycloalkyl" refers to a monovalent saturated cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) hydrocarbon group of 3 to 12, 3 to 8, 4 to 8, or 4 to 6 carbons, referred to as "cycloalkyl." Exemplary cycloalkyl groups include, but are not limited to, cyclohexane, cyclopentane, cyclobutane, and cyclopropane.

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

[0031] As used herein, "heterocyclyl" or "heterocyclic" refers to a radical of a 3- to 10-membered non-aromatic ring system ("3- to 10-membered heterocyclyl") having ring carbon atoms and 1 to 4 ring heteroatoms (each heteroatom independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment can be at a carbon atom or a nitrogen atom, as allowed by valence. Heterocyclyl groups can be either monocyclic ("monocyclic heterocyclyl") or fused, bridged, or spiro ring systems, e.g., bicyclic systems ("bicyclic heterocyclyl"), and can be saturated or partially unsaturated. Heterocyclyl bicyclic ring systems can contain one or more heteroatoms in either or both rings. "Heterocyclyl" also includes ring systems in which a heterocyclyl ring as defined above is fused to one or more carbocyclyl groups (where the point of attachment is on either the carbocyclyl or the heterocyclyl ring), or in which a heterocyclyl ring as defined above is fused to one or more aryl or heteroaryl groups (where the point of attachment is on the heterocyclyl ring), in which case the number of ring members continues to designate the number of ring members in the heterocyclyl ring system. The terms "heterocycle," "heterocyclyl," "heterocyclyl ring," "heterocyclic group," "heterocyclic moiety," and "heterocyclic radical" may be used interchangeably.

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

[0033] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclyl groups (also referred to herein as 5,6-bicyclic heterocyclic rings) fused to a C6 aryl ring include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like.Exemplary 6-membered heterocyclyl groups (also referred to herein as 6,6-bicyclic heterocyclic rings) fused to an aryl ring include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

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

[0035] "Hetero," when used to describe a compound or a group present on a compound, means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero can apply to any of the hydrocarbyl groups mentioned above having 1 to 5, especially 1 to 3, heteroatoms, such as applied to alkyl, e.g., heteroalkyl; carbocyclyl, e.g., heterocyclyl; aryl, e.g., heteroaryl; etc.

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

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

[0038] The term "alkoxy," as used herein, refers to an alkyl group that is attached to another moiety through an oxygen atom (-O(alkyl)). Non-limiting examples include, for example, methoxy, ethoxy, propoxy, and butoxy.

[0039] "Haloalkoxy" is a haloalkyl group that is attached to another moiety through an oxygen atom such as, but not limited to, -OCHCF2 or -OCF3.

[0040] The term "haloalkyl" includes monohaloalkyl, polyhaloalkyl, and perhaloalkyl groups substituted with one or more halogen atoms, where the halogens are independently selected from fluorine, chlorine, bromine, and iodine. 1~4 Haloalkyl-OC 1~4 For alkyl groups, the point of attachment occurs on the alkyl portion that is halogenated.

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

[0042] In general, the term "substituted," whether preceded by the term "optionally" or not, means that at least one hydrogen atom present on a group (e.g., a carbon or nitrogen atom) has been replaced with an acceptable substituent, e.g., a substituent that, upon substitution, results in a stable compound, e.g., a compound that does not spontaneously undergo transformation by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituents are either the same or different at each position.

[0043] Nitrogen atoms may be substituted or unsubstituted, as allowed by valence, including primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR bb )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 aryl, and 5-14 membered heteroaryl, or two R cc The groups taken together form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is selected from the group consisting of 0, 1, 2, 3, 4, or 5 R dd are independently substituted with R aa , R bb , R cc and R dd is as defined above.

[0044] These and other exemplary substituents are described in more detail in the detailed description, examples, and claims. The present invention is in no way intended to be limited by the preceding list of exemplary substituents. Other definitions

[0045] As used herein, " pharmaceutically acceptable carrier " refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound that is formulated with it.The pharmaceutically acceptable carrier, adjuvant, or vehicle that can be used in the compositions described herein includes, but is not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphate, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

[0046] As used herein, "pharmaceutically acceptable salt" refers to a salt that is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., within the scope of sound medical judgment, and that 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 the present invention include salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N-methyl-N ... + (C 1~4Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations, formed where appropriate using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkylsulfonate, and arylsulfonate.

[0047] As used herein, a "subject" to which administration is contemplated includes, but is not limited to, a human (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., an infant, a child, an adolescent) or an adult subject (e.g., a young adult, a middle-aged adult, or an elderly adult)), and / or a non-human animal, e.g., a mammal, e.g., a primate (e.g., a cynomolgus monkey, a rhesus monkey), a cow, a pig, a horse, a sheep, a goat, a rodent, a cat, and / or a dog. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0048] Disease, disorder, and condition are used interchangeably herein.

[0049] As used herein, unless otherwise specified, the terms "treat," "treating," and "treatment" contemplate actions that occur while a subject is suffering from the identified disease, disorder, or condition, or that reduce the severity of or delay or slow the progression of the disease, disorder, or condition ("therapeutic treatment"), as well as actions that occur before a subject begins to suffer from the identified disease, disorder, or condition ("prophylactic treatment").

[0050] As used herein, "effective amount" of a compound refers to the amount that is sufficient to induce desired biological response.As understood by those skilled in the art, the effective amount of the compound 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 method of administration, and the age, health and condition of the subject.The effective amount includes therapeutic treatment and prophylactic treatment.

[0051] As used herein, unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. A therapeutically effective amount of a compound means an amount of a therapeutic agent that, alone or in combination with other treatments, provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" can encompass an amount that improves overall treatment, reduces or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic effectiveness of another therapeutic agent. compound

[0052] In one aspect, the compound represented by formula (I) [ka] or a pharmaceutically acceptable salt thereof, R 1 is C 1~6 Alkyl, C 1~6 Alkoxy, C 3~6 cycloalkyl, and 5- to 10-membered heterocyclyl; 1~6 Alkyl, C 3~6 Cycloalkyl and 5- to 10-membered heterocyclyl are R 1a and wherein when a 5- to 10-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom is optionally substituted on one or more available carbons with one, two, three, or more substituents each independently selected from R 1band when the 5- to 10-membered heterocyclyl contains a substitutable ring sulfur atom, the ring sulfur atom is optionally substituted with two O atoms; R 2 is CH3 or CF3, R 3 is hydrogen, or R 3 is C 1~6 Alkyl, C 1~6 Alkoxy, C 3~7 Cycloalkyl, 5-6-membered heterocyclyl, 5-6-membered heterocyclyl-C 1~3 alkyl-, 5- to 6-membered heterocyclyl-O-, phenyl, and 5- to 6-membered heteroaryl, any of which is selected from the group consisting of R 3a and optionally substituted with 1, 2, or 3 substituents each independently selected from R 4 is C 1~6 is alkyl, R 1a Each occurrence represents cyano, halogen, hydroxyl, oxo, C 1~6 Alkyl, -C(O)OR A , -C(O)N(R A )2, -N(R A )2, C 1~6 independently selected from the group consisting of alkoxy, 5- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl; C 1~6 Alkyl is -N(R A )2, wherein when the 5- to 6-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom is optionally substituted by R B and optionally substituted by R 1b is 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 is selected from the group consisting of alkyl, R 3a Each occurrence of represents a halogen, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, Hydroxy, C 1~4 Alkenyl, cyano, azido, -NR C R D , C 3~6 Cycloalkyl, C 1~4 Alkoxy C 1~4 independently selected from the group consisting of alkoxy, 5- to 6-membered heterocyclyl-O-, 5- to 6-membered heterocyclyl, and phenyl; C 3~6 Cycloalkyl, 5-6 membered heterocyclyl-O-, 5-6 membered heterocyclyl, and phenyl are R p and optionally substituted with 1, 2, or 3 substituents each independently selected from R p Each occurrence of represents a halogen, C 1~4 Alkyl, C 1~4 Haloalkyl, hydroxy, C 1~4 Alkoxy, C 1~4 Alkoxy C 1~4 Alkyl, NR C R D , and Amino C 1~3 independently selected from the group consisting of alkyl, R A Each occurrence of represents hydrogen, C 1~6 Alkyl, -C(O)C 1~6 Alkyl, and -C(O)OC 1~6 independently selected from the group consisting of alkyl, R B is C 1~6 Alkyl, C 3~6 Cycloalkyl, and -C(O)OC 1~6 is selected from the group consisting of alkyl, R C and R D Each occurrence of represents hydrogen, C 1~6 Alkyl, HaloC 1~6 Alkyl, and C 3~4independently selected from the group consisting of cycloalkyl; R C and R D together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl or a 4- to 6-membered heteroaryl, which 4- to 6-membered heterocyclyl or 4- to 6-membered heteroaryl may contain an additional nitrogen atom or oxygen atom and is optionally substituted with 1 or 2 fluoro; t is 0 or 1] is provided.

[0053] In another aspect, the compounds represented by formula (I) are provided herein. [ka] or a pharmaceutically acceptable salt thereof, R 1 is C 1~6 Alkyl, C 3~6 cycloalkyl, or 5- to 10-membered heterocyclyl, C 3~6 Cycloalkyl is R 1a and wherein when a 5- to 10-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom is optionally substituted on one or more available carbons with one, two, three, or more substituents each independently selected from R 1b and when the 5- to 10-membered heterocyclyl contains a substitutable ring sulfur atom, the ring sulfur atom is optionally substituted with two O atoms; R 2 is CH3 or CF3, R 3 is C 1~6 alkyl, C 1~6 Alkyl is C 1~4 optionally substituted with alkoxy; R 4 is C 1~6 is alkyl, R 1aEach occurrence represents cyano, halogen, hydroxyl, C 1~6 Alkyl, -C(O)OR A , -C(O)N(R A )2, -N(R A )2, C 1~6 independently selected from the group consisting of alkoxy, and 5-6 membered heteroaryl; 1~6 Alkyl is -N(R A )2, substituted as necessary, R 1b is 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 is selected from the group consisting of alkyl, R A Each occurrence of represents hydrogen, C 1~6 Alkyl, -C(O)C 1~6 Alkyl, and -C(O)OC 1~6 independently selected from the group consisting of alkyl, t is 0 or 1] is provided.

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

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

[0056] In another aspect, the compound represented by formula (Ia) [ka] or a pharmaceutically acceptable salt thereof, R 1 is C 1~6 Alkyl, C 1~6 Alkoxy, C 3~6cycloalkyl, and 5- to 10-membered heterocyclyl; 1~6 Alkyl, C 3~6 Cycloalkyl and 5- to 10-membered heterocyclyl are R 1a and wherein when a 5- to 10-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom is optionally substituted on one or more available carbons with one, two, three, or more substituents each independently selected from R 1b and when the 5- to 10-membered heterocyclyl contains a substitutable ring sulfur atom, the ring sulfur atom is optionally substituted with two O atoms; R 2 is CH3 or CF3, R 3 is hydrogen, or R 3 is C 1~6 Alkyl, C 1~6 Alkoxy, C 3~7 Cycloalkyl, 5-6-membered heterocyclyl, 5-6-membered heterocyclyl-C 1~3 alkyl-, 5- to 6-membered heterocyclyl-O-, phenyl, and 5- to 6-membered heteroaryl, any of which is selected from the group consisting of R 3a and optionally substituted with 1, 2, or 3 substituents each independently selected from R 1a Each occurrence represents cyano, halogen, hydroxyl, oxo, C 1~6 Alkyl, -C(O)OR A , -C(O)N(R A )2, -N(R A )2, C 1~6 independently selected from the group consisting of alkoxy, 5- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl; C 1~6 Alkyl is -N(R A )2, wherein when the 5- to 6-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom is optionally substituted by R Band optionally substituted by R 1b is 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 is selected from the group consisting of alkyl, R 3a Each occurrence of represents a halogen, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, Hydroxy, C 1~4 Alkenyl, Cyano, Azido, NR C R D , C 3~6 Cycloalkyl, C 1~4 Alkoxy C 1~4 independently selected from the group consisting of alkoxy, 5- to 6-membered heterocyclyl-O-, 5- to 6-membered heterocyclyl, and phenyl; C 3~6 Cycloalkyl, 5-6 membered heterocyclyl-O-, 5-6 membered heterocyclyl, and phenyl are R p and optionally substituted with 1, 2, or 3 substituents each independently selected from R p is a halogen, C 1~4 Alkyl, C 1~4 Haloalkyl, hydroxy, C 1~4 Alkoxy, C 1~4 Alkoxy C 1~4 Alkyl, NR C R D , and Amino C 1~3 is selected from the group consisting of alkyl, R A Each occurrence of represents hydrogen, C 1~6 Alkyl, -C(O)C 1~6 Alkyl, and -C(O)OC 1~6 independently selected from the group consisting of alkyl, R B is C 1~6 Alkyl, C3~6 Cycloalkyl, and -C(O)OC 1~6 is selected from the group consisting of alkyl, R C and R D Each occurrence of represents hydrogen, C 1~6 Alkyl, HaloC 1~6 Alkyl, and C 3~4 independently selected from the group consisting of cycloalkyl; R C and R D together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl or a 4- to 6-membered heteroaryl, which may contain an additional nitrogen atom or oxygen atom and is optionally substituted with 1 or 2 fluoro. is provided.

[0057] In another aspect, the compound represented by formula (Ia) [ka] or a pharmaceutically acceptable salt thereof, R 1 is C 1~6 Alkyl, C 3~6 cycloalkyl, and 5- to 10-membered heterocyclyl, C 3~6 Cycloalkyl is R 1a and wherein when a 5- to 10-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom is optionally substituted on one or more available carbons with one, two, three, or more substituents each independently selected from R 1b and when the 5- to 10-membered heterocyclyl contains a substitutable ring sulfur atom, the ring sulfur atom is optionally substituted with two O atoms; R 2 is CH3 or CF3, R 3 is C 1~6alkyl, C 1~6 Alkyl is C 1~4 optionally substituted with alkoxy; R 1a Each occurrence represents cyano, halogen, hydroxyl, C 1~6 Alkyl, -C(O)OR A , -C(O)N(R A )2, -N(R A )2, C 1~6 independently selected from the group consisting of alkoxy, and 5-6 membered heteroaryl; 1~6 Alkyl is -N(R A )2, substituted as necessary, R 1b is 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 is selected from the group consisting of alkyl, R A Each occurrence of represents hydrogen, C 1~6 Alkyl, -C(O)C 1~6 Alkyl, and -C(O)OC 1~6 alkyl] is provided.

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

[0059] In some embodiments, R 3 is C 1~6 alkyl, and R 3 is C 1~4 Optionally substituted with alkoxy.

[0060] In some embodiments, R 3 is C 1~6 In some embodiments, R 3 teeth, [ka] is.

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

[0062] In another aspect, the compound represented by formula (Ib) [ka] or a pharmaceutically acceptable salt thereof, R 1 is C 1~6 Alkyl, C 3~6 cycloalkyl, or 5- to 10-membered heterocyclyl, C 3~6 Cycloalkyl is R 1a and wherein when a 5- to 10-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom is optionally substituted on one or more available carbons with one, two, three, or more substituents each independently selected from R 1b and when the 5- to 10-membered heterocyclyl contains a substitutable ring sulfur atom, the ring sulfur atom is optionally substituted with two O atoms; R 1a Each occurrence represents cyano, halogen, hydroxyl, C 1~6 Alkyl, -C(O)OR A , -C(O)N(R A )2, -N(R A )2, C 1~6 independently selected from the group consisting of alkoxy, and 5-6 membered heteroaryl; 1~6Alkyl is -N(R A )2, substituted as necessary, R 1b is 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 is selected from the group consisting of alkyl, R A Each occurrence of represents hydrogen, C 1~6 Alkyl, -C(O)C 1~6 Alkyl, and -C(O)OC 1~6 alkyl] is provided.

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

[0064] In some embodiments, R 1 is C 3~6 is cycloalkyl, and R 1 is R 1a It may be optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from:

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

[0066] In some embodiments, R 1 is C 3~6 is cycloalkyl, and R 1 is R 1aand is substituted on one or more available carbons with one, two, three, or more substituents each independently selected from:

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

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

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

[0070] In some embodiments, R 1 is a 5- to 10-membered heterocyclyl, where R 1 contains a substitutable ring nitrogen atom, the ring nitrogen atom is 1b and when the 5- to 10-membered heterocyclyl contains a substitutable ring sulfur atom, the ring sulfur atom may be optionally substituted with two O atoms.

[0071] In some embodiments, R 1 is a 5-10 membered heterocyclyl. 1 teeth, [ka] is selected from the group consisting of:

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

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

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

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

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

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

[0078] In some embodiments, the compounds provided herein are selected from the compounds set forth in Table 1, or a pharmaceutically acceptable salt thereof.

[0079] In some embodiments, the compound is N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ 6 -thiane-4-carboxamide; 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; 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; Methyl (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}cyclohexane-1-carboxylate; 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-methylthiane-4-carboxamide; 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-methyloxolane-3-carboxamide; 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; 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; (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; tert-Butyl 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-carboxylate; tert-Butyl 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-carboxylate; tert-Butyl 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-carboxylate; tert-Butyl 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; (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; 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-methylazetidine-3-carboxamide; N-(4-{[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin6-yl}amino)phenyl]-2,2,2-trifluoroethyl](methyl)carbamoyl}cyclohexyl)carbamate; N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-4-acetamido-N-methylcyclohexane-1-carboxamide; N-[(1S)-1-(4-{[2-chloro-7-(propan-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; 1-acetyl-N-[(1S)-1-(4-{[2-chloro-7-(propan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]amino}phenyl)-2,2,2-trifluoroethyl]-N-methylpiperidine-4-carboxamide; N-{1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]ethyl}-N-methylcyclobutanecarboxamide; N-{1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]ethyl}-N-methylcyclohexanecarboxamide; N-{1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]ethyl}-N-methylcyclopentanecarboxamide; N-{1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]ethyl}-N-methylcyclopropanecarboxamide; N-{1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]ethyl}-N-methylacetamide; 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; 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; 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; 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; 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-methylcyclopropanecarboxamide; 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 -thiane-4-carboxamide; 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-methylcyclobutanecarboxamide; 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-methylcyclopropanecarboxamide; 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 -thiane-4-carboxamide; 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; 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; 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; 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; 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; 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; Methyl 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-carboxylate; 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; 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; 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; 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; 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; 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; 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; 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; Methyl 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; 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; 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; 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; 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; 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-3-carboxamide 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; (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; (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; (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; (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; (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; (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; (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; (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; 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-thiopyran-4-carboxamide; 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. Pharmaceutical Compositions and Routes of Administration

[0080] The compounds provided by the present invention are usually administered in the form of pharmaceutical compositions.Accordingly, the present invention provides pharmaceutical compositions containing one or more of the compounds described above 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 can be administered alone or in combination with other therapeutic agents.Such compositions are prepared in a manner well known in the pharmaceutical arts (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.)).

[0081] The pharmaceutical compositions may be administered in either single or multiple doses by any of the accepted methods of administration of drugs having similar utilities described in the patents and patent applications incorporated by reference, including, for example, rectal, oral buccal, intranasal, and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, as an inhalant, or via impregnated or coated devices such as stents or cylindrical polymers inserted into an artery.

[0082] One method of administration is parenteral, particularly by injection. Forms in which the novel compositions of the present invention can be incorporated for administration by injection include aqueous or oily suspensions or emulsions (including sesame oil, corn oil, cottonseed oil, or peanut oil), as well as elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical vehicles. Aqueous solutions in saline are also commonly used for injections, but are less preferred in the context of the present invention. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils can also be used. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

[0083] Injectable sterile solution is prepared by incorporating the compound of the present invention in the required amount into suitable solvent with various other components as listed above as necessary, and then sterilizing by filtration.Generally, dispersion is prepared by incorporating various sterilized active ingredients into a sterile vehicle that contains basic dispersion medium and other components that are required from the list above.For the sterile powder that is used to prepare injectable sterile solution, the preferred preparation method is vacuum drying and freeze-drying technology, which can obtain the powder of active ingredient and any additional desired components obtained from the solution that has been previously sterilized and filtered.

[0084] Oral administration is another route of administration of the compounds according to the present invention. Administration may be via capsules or enteric-coated tablets, etc. In preparing pharmaceutical compositions containing at least one compound described herein, the active ingredient is usually diluted with an excipient and / or enclosed in a carrier, which may be in the form of a capsule, sachet, paper, or other container. When the excipient serves as a diluent, the excipient may be in the form of a solid, semi-solid, or liquid material (as described above) that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the composition may be in the form of a tablet, pill, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol (as a solid or in a liquid medium), ointment containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and packaged sterile powders.

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

[0086] The compositions of the present invention can be formulated to provide rapid, sustained, or delayed release of the active ingredient after administration to a patient by using procedures known in the art. Controlled-release drug delivery systems for oral administration include osmotic pump systems and dissolution systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled-release systems are shown in U.S. Patent Nos. 3,845,770, 4,326,525, 4,902,514, and 5,616,345. Another formulation for use in the methods of the present invention uses transdermal delivery devices ("patches"). Such transdermal patches can be used to deliver controlled amounts of the compounds of the present invention in continuous or discontinuous infusion. The construction and use of transdermal patches for the delivery of pharmaceuticals is well known in the art. See, for example, U.S. Patent Nos. 5,023,252, 4,992,445, and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

[0087] The compositions are preferably formulated in unit dosage form. The term "unit dosage form" refers to physically discrete units (e.g., tablets, capsules, ampoules) suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined amount of active substance calculated to produce a desired therapeutic effect in association with a suitable pharmaceutical excipient. The compounds are generally administered in a pharmaceutically effective amount. Preferably, each dosage unit contains 1 mg to 2 g of a compound described herein for oral administration, and preferably 0.1 to 700 mg of a compound described herein for parenteral administration. However, it will be understood that the amount of compound actually administered will typically be determined by a physician, taking into account relevant circumstances, including the condition to be treated, the selected route of administration, the actual compound administered and its relative activity, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

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

[0089] The tablets or pills of the present invention can be coated or otherwise compounded to provide a dosage form that offers the advantage of prolonged action or to protect against the acidic conditions of the stomach.For example, the tablets or pills can comprise an inner dosage and an outer dosage component, the latter being in the form of an outer coating on the former.These two components can be separated by an enteric layer, which serves to resist disintegration in the stomach and allow the inner component to pass intact into the duodenum or to delay release.A variety of materials can be used for such enteric layers or coatings, including materials including several polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0090] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. Preferably, the compositions are administered by oral or nasal respiratory route for local or systemic effect. Compositions, preferably in pharmaceutically acceptable solvents, can be nebulized by using inert gas. Nebulized solutions can be absorbed directly from the nebulizing device, or the nebulizing device can be attached to a face mask tent or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered, preferably orally or nasally, from a device that delivers the formulation in an appropriate manner.

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

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

[0093] In typical embodiments, the present invention is intended to encompass the compounds disclosed herein, as well as pharmaceutically acceptable salts, pharmaceutically acceptable esters, tautomeric 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, tautomeric 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, e.g., compounds of the formulae named herein.

[0094] In some embodiments, the autoimmune and inflammatory disorder is 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 allograft 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, Sjogren's syndrome, and antibody-mediated vasculitis syndromes, including bullous disorders (e.g., pemphigus vulgaris), ANCA-associated vasculitis, Henoch-Schönlein purpura, and immune complex vasculitis (either primary or secondary to infection or cancer).

[0095] In some embodiments, the oncological disorder is selected from the group consisting of 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 tumor, breast cancer, gastric cancer, germ cell tumor, glioblastoma, hepatic adenoma, Hodgkin's lymphoma, liver cancer, kidney cancer, lung cancer, pancreatic cancer, head / neck / throat cancer, ovarian cancer, skin tumor, prostate cancer, renal cell carcinoma, stomach cancer cancer, blood cancer, medulloblastoma, non-Hodgkin's lymphoma, diffuse large B-cell lymphoma (DLBCL), activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL), mantle cell lymphoma, marginal zone lymphoma, T-cell lymphoma, especially Sézary syndrome, mycosis fungoides, cutaneous T-cell lymphoma, T-cell acute lymphoblastic leukemia, melanoma, mucosa-associated lymphoid tissue (MALT) lymphoma, multiple myeloma, plasma cell neoplasms, lentigo maligna melanoma, acral lentiginous melanoma, squamous cell carcinoma, chronic myelogenous leukemia leukemia, myeloid leukemia, superficial spreading melanoma, acral lentiginous melanoma, mucosal melanoma, nodular melanoma, polypoid melanoma, desmoplastic melanoma, amelanotic malignant melanoma, soft tissue melanoma, melanoma with small nevus-like cells, melanoma with Spitz features, uveal melanoma, precursor T-cell, leukemia / lymphoma, acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, follicular lymphoma, chronic lymphocytic leukemia / lymphoma, Burkitt lymphoma, mycosis fungoides, peripheral T-cell lymphoma, nodular sclerosing type of Hodgkin lymphoma, mixed cellularity subtype of Hodgkin lymphoma, non-small cell lung cancer, large cell carcinoma, and small cell lung cancer.

[0096] In some embodiments, the oncological disorder is cancer in the form of a tumor or a blood-borne 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 adenoma, adenocarcinoma, blastoma (e.g., hepatoblastoma, glioblastoma, neuroblastoma, and retinoblastoma), carcinoma (e.g., colorectal or heptatocellular carcinoma, pancreatic, prostate, gastric, esophageal, cervical, and head and neck cancer, and adenocarcinoma), desmoid tumor, desmoplastic small round cell tumor, endocrine tumor, germ cell tumor, lymphoma, leukemia, sarcoma (e.g., Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, or any other soft tissue sarcoma), Wilms' tumor, lung tumor, colon tumor, lymphoid tumor, breast tumor, or melanoma.

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

[0098] In some embodiments, 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.

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

[0100] The compounds of the compositions described herein can be administered in combination with another drug or therapy. The subject to whom the compounds disclosed herein are administered can have a disease, disorder, or condition, or symptoms thereof, that can benefit from treatment with another drug or therapy.

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

[0102] In some embodiments, the compounds described herein can be administered as the sole active ingredient, or together with other drugs, such as immunosuppressants or immunomodulators, or other anti-inflammatory agents, or chemotherapeutic agents, such as malignant cell anti-proliferative agents, for example, to treat or prevent acute or chronic rejection of allografts or xenografts, or inflammatory or autoimmune disorders, for example, as adjuvants thereto.For example, the compounds of the present invention can be used in combination with calcineurin inhibitors, such as cyclosporin A or FK 506; rmTOR inhibitors, such as rapamycin, 40-0-(2-hydroxyethyl)-rapamycin, biolimus-7 or biolimus-9; ascomycins with immunosuppressive properties, such as ABT-281, ASM981; corticosteroids; cyclophosphamide; azathioprine; methotrexate; leflunomide; mizoribine; mycophenolic acid or salts; mycophenolate mofetil; or IL-1 beta inhibitors.

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

[0104] In some embodiments, the compounds described herein are combined with a co-agent that affects BTK (Bruton's tyrosine kinase).

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

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

[0107] The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. Where typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, it will be recognized that other process conditions may be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by one skilled in the art by routine optimization.

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

[0109] The compounds provided herein can be isolated and purified by known standard procedures.Such procedures include recrystallization, filtration, flash chromatography, trituration, high pressure liquid chromatography (HPLC) or supercritical fluid chromatography (SFC).It should be noted that flash chromatography can be performed manually or through an automated system.The compounds provided herein can be characterized by known standard procedures, such as nuclear magnetic resonance spectroscopy (NMR) or liquid chromatography mass spectrometry (LCMS).NMR chemical shifts are reported in parts per million (ppm) and are prepared using methods well known to those skilled in the art. List of abbreviations: EtOAc ethyl acetate THF tetrahydrofuran PE Petroleum Ether DMA Dimethylacetamide MeOH Methanol EtOH ethanol DMF N,N-dimethylformamide DMSO dimethyl sulfoxide xphos 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl FA formic acid DCM dichloromethane MTBE Methyl tert-butyl ether TFA trifluoroacetic acid MeCN, ACN Acetonitrile i-PrMgCl Isopropyl magnesium chloride xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene i-PrOH isopropyl alcohol TMSCF3 Trifluoromethyltrimethylsilane MeI iodomethane LiHMDS Lithium bis(trimethylsilyl)amide h, hr, hrs time Calcd Calculated value UV ultraviolet light rt room temperature DIEA, DIPEA N,N-Diisopropylethylamine HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate CDI 1,1'-carbonyldiimidazole ee enantiomeric excess TMS trimethylsilyl Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0) Et3N, TEA triethylamine Cs2CO3 Cesium Carbonate INT intermediate EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride HOBT, HOBt 1-hydroxybenzotriazole TLC thin layer chromatography Conc. Boc tert-butyloxycarbonyl AcCl Acetyl chloride NaBH3CN Sodium cyanoborohydride HO(CHO)nH Paraformaldehyde LiOH.H2O Lithium hydroxide monohydrate NH4Cl Ammonium chloride MeNH2.HCl methylamine hydrochloride Me2NH.HCl Dimethylamine Hydrochloride TMSN3 Trimethylsilyl Azide (C4H9)2SnO Dibutyltin Oxide NH2NH2.H2O Hydrazine hydrate t-BuOH tert-butyl alcohol t-BuOK Potassium tert-butoxide DPPA Diphenylphosphoryl azide NaOH Sodium hydroxide (n-Bu)4OAc Tetrabutylammonium acetate (COCl)2Oxalyl chloride Na2CO3 Sodium Carbonate POCl3 Phosphorus oxychloride TBSCl tert-butyldimethylsilyl chloride TBS tert-butyldimethylsilyl NaH sodium hydride Ti(OEt)4 Titanium Ethoxide TBAT Tetrabutylammonium difluorotriphenylsilicate on overnight EDTA Ethylenediaminetetraacetic acid Example 1 Preparation of compounds

[0110] Methods for preparing the compounds described herein are illustrated in the following synthetic schemes. These schemes are presented for the purpose of illustrating the present invention and should not be construed as limiting the scope or spirit of the present invention in any way. The starting materials shown in the schemes can be obtained from commercial sources or can be prepared from commercially available sources based on procedures described in the literature. 1. Compounds prepared using Scheme 1 Scheme 1: [ka]

[0111] R 3 Triazolopyrimidine G-1a containing R 1 and R 2 with a carboxamide G-1b containing the formula (I) to provide a compound of formula (I). 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 6Synthesis of N-thiane-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)phenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide) (Compound 1.1) [ka]

[0112] 2-Chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-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 in dioxane (6 mL). 6 A mixture of -thiane-4-carboxamide [INT5.1] (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) was stirred at 100 °C for 4 h. The mixture was concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (methanol / dichloromethane = 0 / 1 to 1 / 10) and preparative HPLC (column: YMC Triart C18 250 × 50 mm × 7 μm, column: 29 to 58% B (A = water (0.05 v / v % ammonia hydroxide)), B = acetonitrile), flow rate: 60 mL / min, UV detector 220 nm) 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-methyl-1,1-dioxo-1λ 6 -thiane-4-carboxamide [Compound 1.1] (211 mg, 368 μmol) was obtained as a dry powder. m / z: [M+H]+ calculated for C23H27ClF3N6O4S 575.2, found 575.3. 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 = 6.8 Hz, 1H), 3.25 - 3.14 (m, 3H), 3.12 (s, 3H), 3.10 - 3.05 (m, 2H), 2.86 (s, 3H), 2.08 - 1.94 (m, 4H), 1.55 (d, J = 6.8 Hz, 3H). Compound 1.1 was determined to have a chiral purity of at least 89%. Synthesis 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-methylacetamide (Compound 1.2) [ka]

[0113] A mixture of 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-amine hydrochloride [INT1.1] (100 mg, 378 μmol), N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methylacetamide [INT5.2] (117 mg, 378 μmol), Pd(dba) (34.6 mg, 37.8 μmol), Xantphos (43.7 mg, 75.6 μmol), and CsCO (368 mg, 1.13 mmol) in dioxane (3 mL) was stirred at 100 °C for 3 h under a N atmosphere. The mixture was concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC (column: YMC Triart C18 250 × 50 mm × 7 μm, column: 31–71% B (A = water (0.05 v / v % ammonia hydroxide)), B = acetonitrile), flow rate: 60 mL / min, UV detector 220 nm) 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-methylacetamide [Compound 1.2] (20.0 mg, 43.7 μmol, 11.6% yield) as a yellow dry powder. m / z: [M+H]+ calculated for C19H21ClF3N6O2 457.1, found 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). Synthesis 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-methyloxane-2-carboxamide (compound 1.3) [ka]

[0114] A mixture of 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-amine hydrochloride [INT1.1] (80 mg, 302 μmol), N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methyloxane-2-carboxamide [INT5.3] (114 mg, 302 μmol), Xantphos (34.9 mg, 60.4 μmol), Pd(dba) (27.6 mg, 30.2 μmol), and CsCO (196 mg, 604 μmol) in dioxane (2 mL) was stirred at 100 °C for 3 h under a N atmosphere. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (1:10 to 1:1 EtOAc / petroleum ether) and preparative HPLC (YMC Triart C18 250 × 50 mm × 7 μm column, column: 26 to 66% B (A = water (0.05% v / v ammonium hydroxide)), B = acetonitrile), flow rate: 60 mL / min, UV detector 220 nm) 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-methyloxane-2-carboxamide [Compound 1.3] (30.1 mg, 57.1 μmol, 18.9% yield) as a yellow dry powder. m / z: [M+H]+ calculated for C23H27ClF3N6O3 527.2, found 527.3. 1H 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). Synthesis of methyl (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}cyclohexane-1-carboxylate (compound 1.4) [ka]

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

[0116] A mixture of 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-amine hydrochloride [INT1.1] (100 mg, 378 μmol), N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methylthiane-4-carboxamide [INT5.5] (149 mg, 378 μmol), Xantphos (43.7 mg, 75.6 μmol), Pd(dba) (34.6 mg, 37.8 μmol), and CsCO (246 mg, 756 μmol) in dioxane (5 mL) was stirred at 100 °C for 3 h under a N atmosphere. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (1:10 to 1:1 EtOAc / petroleum ether) and preparative HPLC (YMC Triart C18 250 × 50 mm × 7 μm column, column: 35 to 75% B (A = water (0.05% v / v ammonium hydroxide)), B = acetonitrile), flow rate: 60 mL / min, UV detection at 220 nm) 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-methylthiane-4-carboxamide [Compound 1.5] (26.9 mg, 49.5 μmol, 13.1% yield) as a dry yellow powder. m / z: [M+H]+ calculated for C23H27ClF3N6O2S 543.1, found 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). Synthesis 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-methyloxolane-3-carboxamide (compound 1.6) [ka]

[0117] To a mixture of N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methyloxolane-3-carboxamide [INT5.6] (80 mg, 218 μmol) and 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-amine hydrochloride [INT1.1] (68.9 mg, 261 μmol) in dioxane (2 mL) was added Pd(dba) (19.9 mg, 21.8 μmol), CsCO (213 mg, 654 μmol), and Xantphos (12.6 mg, 21.8 μmol). The reaction mixture was stirred at 100 °C under N for 3 h, after which it was diluted with brine (20 mL) and extracted with EtOAc (10 mL × 3). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give the crude product, which was purified by preparative HPLC (column: Boston Prime C18 150 × 25 mm × 5 μm, column: 32-62% B (A = water (0.05% ammonium hydroxide), B = acetonitrile), flow rate: 25 mL / min, UV detector 220 nm) 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-methyloxolane-3-carboxamide [Compound 1.6] (2.20 mg, 4.28 μmol, yield 2.0%) as an off-white dry powder. m / z: [M+H]+ calculated for C22H25ClF3N6O3 513.2, found 513.3. 1H 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). Synthesis 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-methyl-1,4-dioxaspiro[4.5]decane-8-carboxamide (compound 1.7) [ka]

[0118] A mixture of 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-amine hydrochloride [INT1.1] (60.4 mg, 229 μmol), N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methyl-1,4-dioxaspiro[4.5]decane-8-carboxamide [INT5.7] (100 mg, 229 μmol), Xantphos (26.5 mg, 45.8 μmol), Pd(dba) (20.9 mg, 22.9 μmol), and CsCO (149 mg, 458 μmol) in dioxane (5 mL) was stirred at 100 °C for 3 h under a N atmosphere. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (Et0Ac / petroleum ether = 1 / 5 to 1 / 3) and preparative HPLC (column: YMC Triart C18 Purification by column chromatography (250 × 50 mm × 7 μm, column: 33–73% B (A = water (0.05 v / v% ammonia hydroxide)), B = acetonitrile), flow rate: 60 mL / min, UV detector 220 nm) afforded 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) as a yellow dry powder. m / z: [M+H] calculated for CHClFNO 583.2, found 583.4. 1H NMR (400 MHz, CDCl3) δ = 8.89 (s, 1H), 7.32 (d, J=8.4Hz, 2H), 7.10 (s, 1H), 7.03 (d, J=8.4 Hz, 2H), 6.65 (q, J=8.8 Hz, 1H), 5.48 (q,J=6.8 Hz, 1H), 3.97 (s, 4H), 3.49 (s, 3H), 2.92 (s, 3H), 2.66 - 2.55 (m, 1H),1.97 - 1.93 (m, 1H), 1.93 - 1.83 (m, 4H), 1.83 - 1.75 (m, 1H), 1.61 (d, J=6.8Hz, 3H), 1.57 - 1.52 (m, 2H). Synthesis of N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-4,4-difluoro-N-methylcyclohexane-1-carboxamide (compound 1.8) [ka]

[0119] A mixture of 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-amine hydrochloride [INT1.1] (100 mg, 378 μmol), N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-4,4-difluoro-N-methylcyclohexane-1-carboxamide [INT5.8] (156 mg, 378 μmol), Xantphos (43.7 mg, 75.6 μmol), Pd(dba) (34.6 mg, 37.8 μmol), and CsCO (368 mg, 1.13 mmol) in dioxane (5 mL) was stirred at 100 °C for 3 h under a N atmosphere. The reaction was filtered through Celite. The filter cake was washed with EtOAc (20 mL × 2). The filtrate was concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC (column: Welch Xtimate C18 150 × 25 mm × 5 μm, column: 49–79% B (A = water (10 mM NH4HCO3), B = acetonitrile), flow rate: 25 mL / min, UV detector 220 nm) 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]-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]+ calculated for C24H27ClF5N6O2 561.2, found 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). Synthesis of (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) [ka]

[0120] (1r,3S)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-3-cyano-N-methylcyclobutane-1-carboxamide [INT5.9] (0.1 g, 0.2665 mmol), 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-amine [the free base of INT1.1] (60.5 mg, 266 μmol), Xantphos (15.3 mg, 26.6 μmol), and CsCO (260 mg, 799 μmol) were mixed in dioxane (3 mL), and the reaction mixture was degassed with argon for 5 minutes. Pd2(dba)3 (12.1 mg, 13.3 μmol) was added, after which the reaction mixture was degassed with argon for 5 minutes and stirred at 100 °C for 10 hours. The reaction mixture was cooled to rt, and the solid was filtered off. The filtrate was purified by HPLC (see conditions below) to afford (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]+ calculated for C23H24ClF3N7O2 522.2, found 522.2. 1H 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=9.1 Hz, 1H), 5.37 (q, J=6.7Hz, 1H), 3.76 (h, J=7.3, 6.7 Hz, 1H), 3.37 - 3.24 (m, 2H), 2.82 (s, 3H), 2.77 -2.58 (m, 7H), 1.65 (d, J=6.7 Hz, 3H).

[0121] HPLC conditions: System: Agilent 1260 Infinity II LC connected to Agilent 6120B single quadrupole LC / MS system. Column description: Chromatorex SBM 100-5T 5 μm C18(2) 100 Å, LC column 100 × 19 mm, Waters, Sun Fire. Stationary phase: C18. Solid support: fully porous silica. Separation mode: reversed phase. Mobile phase A: water. Mobile phase B: acetonitrile. Flow rate: 30 ml / min. Loading pump: 4 ml / min B. Gradient conditions: 20% to 40% to 55% to 100% (B) in 0 min, 2 min, 10 min, and 11.2 min. Synthesis of tert-butyl 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-carboxylate (compound 1.10) [ka]

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

[0123] To a solution of tert-butyl 3-{[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)carbamoyl}piperidine-1-carboxylate [INT7.2] (700 mg, 1.46 mmol), 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-amine hydrochloride [INT1.1] (332 mg, 1.46 mmol), CsCO (1.42 g, 4.38 mmol), and Xantphos (168 mg, 292 μmol) in dioxane (5 mL), Pd(dba) (133 mg, 146 μmol) was added and the reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (EtOAc / PE = 0 / 1 to 1 / 1) to give tert-butyl 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-carboxylate [Compound 1.11] (480 mg, 766 μmol, 52.5% yield) as a yellow oil. 60.6 mg of this product was purified by preparative HPLC (column: YMC Triart C18 Purification by elution with a 250 × 50 mm × 7 μm column, column size: 47–87% B (A = water (0.225% FA), B = acetonitrile), flow rate: 60 mL / min, UV detector 220 nm) afforded tert-butyl 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-carboxylate [Compound 1.11] (10.6 mg, 16.9 μmol) as an off-white solid. m / z: [M+H] calculated for CHClFNO 626.2, found 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(br s, 2H), 2.68 (br s, 1H), 1.82 (br d, J=12.4 Hz, 1H), 1.69 - 1.54 (m, 5H),1.40 (s, 10H). Synthesis of tert-butyl 3-{[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl](methyl)carbamoyl}pyrrolidine-1-carboxylate (compound 1.12) [ka]

[0124] To a mixture of tert-butyl 3-{[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)carbamoyl}pyrrolidine-1-carboxylate [INT7.3] (140 mg, 300 μmol), 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-amine hydrochloride [INT1.1] (95.0 mg, 360 μmol), Xantphos (17.3 mg, 30.0 μmol), and CsCO (390 mg, 1.20 mmol) in dioxane (2 mL) was added Pd(dba) (27.4 mg, 30.0 μmol), and the mixture was stirred at 100 °C under N for 3 h. The reaction mixture was diluted with brine (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give the crude product, which was purified by silica gel flash chromatography (methanol / dichloromethane = 1 / 20). The product was then purified by preparative HPLC (column: Boston Prime C18 150 × 30 mm × 5 μm, column: 44–74% B (A = water (0.05 v / v % ammonia hydroxide)-ACN), B = acetonitrile), flow rate: 25 mL / min, UV detector 220 nm) to give tert-butyl 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-carboxylate [Compound 1.12] (2.70 mg, 4.41 μmol, 1.5% yield) as a dry yellow powder. m / z: [M+H]+ calculated for C27H34ClF3N7O4 612.2, found 612.4. 1H NMR (400 MHz, CDCl3) δ = 8.90 (d,J=3.2 Hz, 1H), 7.32 (br d, J=8.0 Hz, 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). Synthesis of tert-butyl 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 1.13) [ka]

[0125] To a suspension of tert-butyl N-[(4-{[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)carbamoyl}cyclohexyl)methyl]carbamate [INT7.4] (420 mg, 827 μmol), 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-amine hydrochloride [INT1.1] (282 mg, 1.07 mmol), CsCO (537 mg, 1.65 mmol), and Xantphos (95.4 mg, 165 μmol) in dioxane (3 mL) was added Pd(dba) (75.7 mg, 82.7 μmol). The resulting mixture was stirred at 100 °C under N for 3 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel flash chromatography (MeOH / dichloromethane=0 / 1 to 1 / 99) to give tert-butyl 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 1.13] (500 mg, 765 μmol, 92.5% yield) as a yellow solid. Further, 100 mg of the product was purified by preparative HPLC (column: Phenomenex Gemini-NX 80 × 40 mm × 3 μm, column: 39–79% B (A = water (0.05 v / v % ammonia hydroxide), B = MeOH), flow rate: 25 mL / min, UV detector 220 nm) to obtain tert-butyl N-[(4-{[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl](methyl)carbamoyl}cyclohexyl)methyl]carbamate [Compound 1.13] (500 mg, 39.1 μmol) as a yellow dry powder. m / z: [M+H]+ calculated for C30H40ClF3N7O4 654.3, found 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). Synthesis of (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) [ka]

[0126] To a mixture of (1r,4S)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-methoxy-N-methylcyclohexane-1-carboxamide [INT7.5] (90 mg, 220 μmol), 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-amine hydrochloride [INT1.1] (50.0 mg, 220 μmol), CsCO (143 mg, 440 μmol), and Xantphos (25.4 mg, 44.0 μmol) in dioxane (1 mL), Pd(dba) (20.1 mg, 22.0 μmol) was added under N and the reaction mixture was stirred at 100 °C for 1 h. The reaction was quenched by adding water (10 mL) and extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC (YMC-Actus Triart C18 150 × 30 mm × 5 μm column, column: 48–68% water (0.05% v / v ammonium hydroxide)-ACN, flow rate: 35 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-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]+ calculated for C25H31ClF3N6O3 555.2, found 555.3. 1H 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). Synthesis of 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-methylazetidine-3-carboxamide (compound 1.15) [ka]

[0127] To a solution of 1-acetyl-N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methylazetidine-3-carboxamide [INT5.10] (100 mg, 254 μmol), 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-amine hydrochloride [INT1.1] (73.6 mg, 279 μmol), CsCO (248 mg, 762 μmol), and Xantphos (29.3 mg, 50.8 μmol) in dioxane (3 mL) was added Pd(dba) (23.2 mg, 25.4 μmol), and the reaction mixture was stirred at 100 °C under N for 16 h. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC (column: YMC Triart C18 250 × 50 mm × 7 μm, column: 24-64% B (A = water (0.05% ammonium hydroxide)), B = acetonitrile), flow rate: 60 mL / min, UV detector 220 nm) to give 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-methylazetidine-3-carboxamide [Compound 1.15] (21.2 mg, 39.2 μmol, 15.4% yield) as a yellow dry powder. m / z: [M+H]+ calculated for C23H26ClF3N7O3 540.2, found 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, J=6.8 Hz, 1H), 4.38 - 4.17 (m, 2H), 4.10 - 3.99 (m, 1H), 3.92 - 3.81 (m,2H), 3.17 (s, 3H), 2.76 - 2.69 (m, 3H), 1.76 (d, J=2.8 Hz, 3H), 1.62 - 1.58 (m,3H). Synthesis of N-(4-{[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl](methyl)carbamoyl}cyclohexyl)carbamate (also known as methyl(4-(((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexyl)carbamate) (Compound 1.16) [ka]

[0128] To a mixture of methyl N-(4-{[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)carbamoyl}cyclohexyl)carbamate [INT9.1] (40 mg, 88.6 μmol), 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-amine hydrochloride [INT1.1] (20.1 mg, 88.6 μmol), CsCO (57.6 mg, 177 μmol), and Xantphos (10.2 mg, 17.7 μmol) in dioxane (1 mL) was added Pd(dba) (8.11 mg, 8.86 μmol) at 20 °C, and the mixture was stirred at 100 °C under N for 1 h. The reaction mixture was cooled to 25° C. and combined with another batch of the same reaction (44.3 μmol scale INT9.1). Water (10 mL) was added and the mixture was extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC (YMC-Actus Triart C18 150 × 30 mm × 5 μm column, column: 46–66% water (0.05% v / v ammonia hydroxide)-ACN, flow rate: 35 mL / min, UV detector 220 nm) to give methyl 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]+ calculated for C26H32ClF3N7O4 598.2, found 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). Synthesis 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]-4-acetamido-N-methylcyclohexane 1-carboxamide (compound 1.17) [ka]

[0129] To a mixture of N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-4-acetamido-N-methylcyclohexane-1-carboxamide [INT9.2] (20 mg, 45.9 μmol), 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-amine hydrochloride [INT1.1] (10.4 mg, 45.9 μmol), CsCO (29.9 mg, 91.8 μmol), and Xantphos (5.31 mg, 9.18 μmol) in dioxane (2 mL) was added Pd(dba) (4.20 mg, 4.59 μmol) at 20 °C, and the mixture was stirred at 100 °C under N for 1 h. The reaction was combined with another batch of the same reaction (22.9 μmol scale) and concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC (YMC Actus Triart C18 150 × 30 mm × 5 μm column, column: 42–62% water (0.05% v / v ammonium hydroxide)-ACN, flow rate: 35 mL / min, UV detector at 220 nm) 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]-4-acetamido-N-methylcyclohexane-1-carboxamide [Compound 1.17] (8.50 mg, 14.6 μmol, 21.2% yield) as a dry yellow powder. m / z: [M+H]+ calculated for C26H32ClF3N7O3 582.2, found 582.2. 1H 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=6.6Hz, 3H), 1.51 - 1.31 (m, 2H), 1.29 - 1.11 (m, 2H). N-[(1S)-1-(4-{[2-chloro-7-(propan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]amino}phenyl)-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ 6 Synthesis of -thiane-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-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide) (Compound 1.18) [ka]

[0130] 2-Chloro-7-(propan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-amine hydrochloride [INT1.2] (30 mg, 120 μmol), N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ in dioxane (5 mL). 6To a solution of -thiane-4-carboxamide [INT5.1] (51.3 mg, 120 μmol), Xantphos (13.8 mg, 24.0 μmol), and CsCO (117 mg, 360 μmol) was added Pd(dba) (10.9 mg, 12.0 μmol). The reaction was stirred at 100 °C under N for 2 h. The reaction was combined with another reaction (120 μmol scale) of the same type, quenched by the addition of water (30 mL), and extracted with EtOAc (30 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC (column: YMC-Actus Triart C18 150 × 30 mm × 5 μm, column: 40-60% B (A = water (0.05% ammonia hydroxide), B = ACN), flow rate: 35 mL / min, UV detector 220 nm) to give N-[(1S)-1-(4-{[2-chloro-7-(propan-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) was obtained as a dry white powder. m / z: [M+H]+ calculated for C23H27ClF3N6O3S 559.1, found 559.1. 1 H 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). Synthesis of 1-acetyl-N-[(1S)-1-(4-{[2-chloro-7-(propan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]amino}phenyl)-2,2,2-trifluoroethyl]-N-methylpiperidine-4-carboxamide (compound 1.19) [ka]

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

[0132] To a solution of N-[1-(4-bromophenyl)ethyl]-N-methylcyclobutanecarboxamide [INT11.1] (60 mg, 202 μmol), 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-amine hydrochloride [INT1.1] (45.9 mg, 202 μmol), CsCO (197 mg, 606 μmol), and Xantphos (23.3 mg, 40.4 μmol) in dioxane (2 mL) was added Pd(dba) (18.4 mg, 20.2 μmol), and the reaction mixture was stirred at 100 °C under N for 2 h. The mixture was concentrated in vacuo to give the crude product, which was purified by preparative HPLC (column: Phenomenex Gemini-NX 80 × 40 mm × 3 μm, column: 20–60% B (A = water (0.05 v / v % ammonia hydroxide), B = acetonitrile), flow rate: 25 mL / min, UV detector 220 nm) to give N-{1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]ethyl}-N-methylcyclobutanecarboxamide [Compound 1.20] (5.60 mg, 12.6 μmol, 6.3% yield) as a yellow dry powder. m / z: [M+H] calculated for CHClNO 443.2, found 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). Synthesis of N-{1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]ethyl}-N-methylcyclohexanecarboxamide (compound 1.21) [ka]

[0133] To a solution of N-[1-(4-bromophenyl)ethyl]-N-methylcyclohexanecarboxamide [INT11.2] (50 mg, 154 μmol), 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-amine hydrochloride [INT1.1] (35.0 mg, 154 μmol), CsCO (150 mg, 462 μmol), and Xantphos (17.8 mg, 30.8 μmol) in dioxane (3 mL) was added Pd(dba) (14.1 mg, 15.4 μmol), and the reaction mixture was stirred at 100 °C under N for 2 h. The mixture was concentrated in vacuo to give the crude product, which was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75 × 30 mm × 3 μm, column: 35–75% B (A = water (0.05 v / v% ammonia hydroxide), B = acetonitrile), flow rate: 25 mL / min, UV detector 220 nm) to give N-{1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]ethyl}-N-methylcyclohexanecarboxamide [Compound 1.21] (9.30 mg, 19.7 μmol, 12.8% yield) as a yellow dry powder. m / z: [M+H] calculated for CHClNO2 471.2, found 471.3. 1H 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 (brd, J=6.8 Hz, 1H), 1.42 (br s, 1H), 1.34 (br d, J=7.2 Hz, 3H), 1.27 (br d,J=12.8 Hz, 2H), 1.24 - 1.09 (m, 2H). Synthesis of N-{1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]ethyl}-N-methylcyclopentanecarboxamide (compound 1.22) [ka]

[0134] To a solution of N-[1-(4-bromophenyl)ethyl]-N-methylcyclopentanecarboxamide [INT11.3] (50 mg, 161 μmol) and 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-amine hydrochloride [INT1.1] (36.6 mg, 161 μmol) in dioxane (3 mL) was added CsCO (157 mg, 482 μmol), Xantphos (18.5 mg, 32.1 μmol), and Pd(dba) (14.6 mg, 16.0 μmol). The reaction mixture was stirred at 100 °C under N for 2 h. The mixture was concentrated in vacuo to give the crude product, which was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75 × 30 mm × 3 μm, column: 35–75% B (A = water (0.05 v / v% ammonia hydroxide), B = acetonitrile), flow rate: 25 mL / min, UV detector 220 nm) to give 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] calculated for CHClNO2 457.2, found 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). Synthesis of N-{1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]ethyl}-N-methylcyclopropanecarboxamide (compound 1.23) [ka]

[0135] To a mixture of N-[1-(4-bromophenyl)ethyl]-N-methylcyclopropanecarboxamide [INT12.2] (50 mg, 177 μmol) and 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-amine hydrochloride [INT1.1] (40.2 mg, 177 μmol) in dioxane (2 ml) was added Pd(dba) (16.2 mg, 17.7 μmol), CsCO (173 mg, 531 μmol), and Xantphos (20.4 mg, 35.4 μmol) at 25° C. The mixture was stirred at 100° C. under N for 12 h. The mixture was concentrated in vacuo to give the crude product, which was purified by preparative HPLC (column: YMC Triart C18 250 × 50 mm × 7 μm, column: 25–65% B (A = water (0.05 v / v% ammonia hydroxide), B = acetonitrile), flow rate: 60 mL / min, UV detector 220 nm) to give N-{1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]ethyl}-N-methylcyclopropanecarboxamide [compound 1.23] (16.9 mg, 39.4 μmol, 22.2% yield) as a yellow dry powder. m / z: [M+H] calculated for CHClNO2 429.2, found 429.3. 1H 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 (brd, J=6.4 Hz, 1H), 1.43 (br d, J=7.2 Hz, 2H), 0.85 - 0.76 (m, 4H). Synthesis of N-{1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]ethyl}-N-methylacetamide (Compound 1.24) [ka]

[0136] To a solution of N-[1-(4-bromophenyl)ethyl]-N-methylacetamide [INT12.1] (30 mg, 117 μmol) and 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-amine hydrochloride [INT1.1] (26.6 mg, 117 μmol) in dioxane (2 mL) was added Pd(dba) (10.7 mg, 11.7 μmol), CsCO (114 mg, 351 μmol), and Xantphos (13.5 mg, 23.4 μmol). The reaction mixture was stirred at 100 °C under N for 2 h. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC (column: YMC-Actus Triart C18 150 × 30 mm × 5 μm, column: 37–57% B (A = water (0.05% ammonium hydroxide)), B = acetonitrile), flow rate: 35 mL / min, UV detector 220 nm) to give 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] calculated for CHClNO2 403.2, found 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). Synthesis of 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) [ka]

[0137] To a mixture of 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-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 CsCO (500 mg, 1.53 mmol) in dioxane (2 mL) was added Pd(dba) (80 mg, 0.08736 mmol), and the mixture was stirred at 100 °C under N for 12 h. The reaction was diluted with EtOAc (30 mL), filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (Boston Prime C18 150 × 30 mm × 5 μm column, conditions: 40%–60% CH3CN in water (0.05% v / v ammonia hydroxide), flow rate: 25 mL / min) to give 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 dry yellow powder. m / z: [M+H]+ calculated for CHCIFNO2 457.1, found 457.1. 1 H NMR (400MHz, DMSO-d6) δ = 8.84 (s, 1H), 8.07 -7.90 (m, 1H), 7.34 - 7.13 (m, 2H), 6.97 (br d, J=8.6 Hz, 2H), 6.50 - 5.82 (m,1H), 5.16 (q, J=6.7 Hz, 1H), 3.17 (s, 3H), 2.90 - 2.59 (m, 3H), 2.31 - 2.10 (m,3H), 1.60 (d, J=6.7 Hz, 3H). N-[(1R)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ 6 Synthesis of N-thiane-4-carboxamide (also known as N-((R)-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-thiopyran-4-carboxamide 1,1-dioxide) (Compound 1.26) [ka]

[0138] N-[(1R)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ in dioxane (2 mL) 6 To a solution of 50 mg (116 μmol) of 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-amine hydrochloride [INT1.1] (31.6 mg (139 μmol)) was added Pd(dba) (10.6 mg (11.6 μmol), CsCO (113 mg (348 μmol), and Xantphos (13.4 mg (23.2 μmol)). The reaction mixture was stirred at 100° C. under N for 2 h. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC (column: Boston Green ODS 150 × 30 mm × 5 μm, column: 24-64% B (A = water (0.05% ammonia hydroxide)), B = acetonitrile), flow rate: 30 mL / min, UV detector 220 nm) to give 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) was obtained as a dry yellow powder. m / z: [M+H]+ calculated for C23H27ClF3N6O4S 575.1, found 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). 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 Synthesis of N-thiane-4-carboxamide (also known as N-((R)-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-thiopyran-4-carboxamide 1,1-dioxide) (Compound 1.27) [ka]

[0139] 2-Chloro-7-[(1R)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-amine hydrochloride [INT1.3] (60 mg, 227 μmol), N-[(1R)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ in dioxane (2 mL). 6A mixture of 1-thiane-4-carboxamide [INT14.1] (97.2 mg, 227 μmol), Pd(dba) (20.7 mg, 22.7 μmol), Xantphos (26.2 mg, 45.4 μmol), and CsCO (221 mg, 681 μmol) was stirred at 100 °C under a N atmosphere for 3 h. The mixture was concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (methanol / dichloromethane = 0 / 1 to 1 / 20). The resulting product was purified by preparative HPLC (column: YMC Triart C18 250 × 50 mm × 7 μm, column: 26–66% B (A = water (0.05 v / v % ammonia hydroxide)), B = acetonitrile), flow rate: 60 mL / min, UV detector 220 nm) and preparative TLC (SiO2, dichloromethane:methanol = 20:1) to give 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) was obtained as a dry white powder. m / z: [M+H]+ calculated for C23H27ClF3N6O4S 575.1, found 575.3. 1 H NMR (400 MHz, CD3OD) δ = 8.86 (s, 1H), 7.30 (d, J=8.4Hz, 2H), 7.06 (d, J=8.4 Hz, 2H), 6.52 (q, J=9.2 Hz, 1H), 5.36 (q, J=6.8 Hz,1H), 3.36 (s, 3H), 3.25 - 3.10 (m, 5H), 3.02 - 2.75 (m, 3H), 2.35 - 2.12 (m,4H), 1.64 (d, J=6.8 Hz, 3H). Synthesis of 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) [ka]

[0140] N-[(1S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethyl]-N-methylcyclobutanecarboxamide [INT16.1] (0.1 g, 0.2745 mmol), 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-amine [the free base of INT1.1] (62.3 mg, 274 μmol), CsCO (268 mg, 823 μmol), and Xantphos (15.8 mg, 27.4 μmol) were mixed in dioxane (2 mL). The reaction mixture was degassed with argon for 5 min. Pd(dba) (12.5 mg, 13.7 μmol) was added, and the reaction mixture was degassed with argon for 5 min and stirred at 100 °C for 10 h. The reaction mixture was cooled to rt. 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] calculated for CHClFNO 511.2, found 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).

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

[0142] N-[(1S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethyl]-N-methylcyclopropanecarboxamide [INT16.2] (0.1 g, 0.2855 mmol), 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-amine [the free base of INT1.1] (64.8 mg, 0.2846 mmol), CsCO (277 mg, 853 μmol), and Xantphos (16.4 mg, 28.4 μmol) were mixed in dioxane (2 mL). Pd(dba) (13.0 mg, 14.2 μmol) was added under an inert atmosphere. The mixture was stirred at 100 °C for 10 h, after which the reaction mixture was cooled to rt. 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-methylcyclopropanecarboxamide [Compound 1.29] (15.7 mg, 0.03173 mmol, 11.1% yield) as a yellow solid. m / z: [M+H] calculated for C22H25ClF3N6O2 497.2, found 497.2. 1 H NMR (400 MHz, CD3OD) δ = 8.89 (d, J=2.4 Hz, 1H), 7.48 (d, J=8.4 Hz, 1H), 6.94 (dt,J=8.7, 4.3 Hz, 2H), 6.51 (q, J=8.9 Hz, 1H), 5.38 (q, J=6.7 Hz, 1H), 3.38 (s,3H), 3.01 (s, 3H), 2.71 - 2.58 (m, 1H), 2.33 - 2.11 (m, 3H), 2.07 - 1.95 (m,1H), 1.65 (d, J=6.7 Hz, 3H), 1.03 - 0.86 (m, 4H).

[0143] HPLC conditions: System: Agilent 1260 Infinity II LC connected to Agilent 6120B single quadrupole LC / MS system; Column description: Chromatorex SBM 100-5T 5 μm C18(2) 100 Å, LC column 100 × 19 mm, Waters, Sun Fire; Stationary phase: C18; Solid support: fully porous silica; Separation mode: reversed phase; Mobile phase A: water; Mobile phase B: acetonitrile; Flow rate: 30 ml / min; Loading pump: 4 ml / min B; Gradient conditions: 20% to 40% to 50% to 100% (B) in 0 min to 2 min to 10 min to 11.2 min. 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 Synthesis of N-thiane-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-thiopyran-4-carboxamide 1,1-dioxide) (Compound 1.30) [ka]

[0144] N-[(1S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ 6A mixture of 1-thiane-4-carboxamide [INT16.3] (100 mg, 0.2260 mmol), 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-amine [the free base of INT1.1] (51.4 mg, 226 μmol), CsCO (220 mg, 678 μmol), and dioxane (3 mL) was purged with argon. Xantphos (26.1 mg, 45.2 μmol) and Pd(dba) (20.6 mg, 22.6 μmol) were then added, and the reaction mixture was stirred at 100 °C for 10 h. 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 -thiane-4-carboxamide [Compound 1.30] (12.5 mg, 0.02128 mmol, 9.4% yield) was obtained as a yellow solid. m / z: [M+H]+ calculated for C24H29ClF3N6O4S 589.2, found 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).

[0145] HPLC conditions: System: Agilent 1260 Infinity II LC connected to Agilent 6120B single quadrupole LC / MS system; Column description: Chromatorex SBM 100-5T 5 μm C18(2) 100 Å, LC column 100 × 19 mm, Waters, Sun Fire; Stationary phase: C18; Solid support: fully porous silica; Separation mode: reversed phase; Mobile phase A: water; Mobile phase B: acetonitrile; Flow rate: 30 ml / min; Loading pump: 4 ml / min B; Gradient conditions: 20%–35%–50%–100% (B) from 0 min to 2 min, 10 min to 11.2 min. Synthesis of 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-methylcyclobutanecarboxamide (compound 1.31) [ka]

[0146] N-[(1S)-1-(4-bromo-3-methylphenyl)-2,2,2-trifluoroethyl]-N-methylcyclobutanecarboxamide [INT17.1] (0.12 g, 0.3294 mmol), 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-amine [the free base of INT1.1] (74.8 mg, 329 μmol), CsCO (321 mg, 988 μmol), and Xantphos (19.0 mg, 32.9 μmol) were mixed in dioxane (2 mL). The reaction mixture was degassed with argon for 5 minutes. Pd(dba) (15.0 mg, 16.4 μmol) was added, and the reaction mixture was degassed with argon for 5 minutes and stirred at 100 °C for 10 hours. The reaction mixture was cooled to rt, and the solid was filtered off. The filtrate was purified by HPLC (see conditions below) to 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-methylcyclobutanecarboxamide [Compound 1.31] (7.31 mg, 0.01431 mmol, 4.4% yield) as a yellow solid. m / z: [M+H]+ calculated for C23H27ClF3N6O2 511.2, found 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).

[0147] HPLC conditions: System: Agilent 1260 Infinity II LC connected to Agilent 6120B single quadrupole LC / MS system; Column description: Chromatorex SBM 100-5T 5 μm C18(2) 100 Å, LC column 100 × 19 mm, Waters, Sun Fire; Stationary phase: C18; Solid support: fully porous silica; Separation mode: reversed phase; Mobile phase A: water; Mobile phase B: acetonitrile; Flow rate: 30 ml / min; Loading pump: 4 ml / min B; Gradient conditions: 30%–45%–60%–100% (B) from 0 min to 2 min, 10 min to 11.2 min. Synthesis of 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-methylcyclopropanecarboxamide (compound 1.32) [ka]

[0148] N-[(1S)-1-(4-bromo-3-methylphenyl)-2,2,2-trifluoroethyl]-N-methylcyclopropanecarboxamide [INT17.2] (50 mg, 0.1427 mmol), 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-amine [the free base of INT1.1] (32.3 mg, 142 μmol), and CsCO (139 mg, 428 μmol) were mixed in dioxane (5 mL). Argon was bubbled through the reaction mixture for 15 min. Xantphos (16.4 mg, 28.5 μmol) and Pd(dba) (13.0 mg, 14.2 μmol) were then added, and the reaction mixture was stirred at 100 °C for 14 h. The reaction mixture was cooled, filtered, and concentrated in vacuo. 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-methylcyclopropanecarboxamide [Compound 1.32] (21.6 mg, 0.04358 mmol, 30.6% yield) as a yellow solid. m / z: [M+H]+ calculated for C22H25ClF3N6O2 497.2, found 497.0. 1 H 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=9.5Hz, 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).

[0149] HPLC conditions: System: Agilent 1260 Infinity II LC connected to Agilent 6120B single quadrupole LC / MS system; Column description: Chromatorex SBM 100-5T 5 μm C18(2) 100 Å, LC column 100 × 19 mm, Waters, Sun Fire; Stationary phase: C18; Solid support: fully porous silica; Separation mode: reversed phase; Mobile phase A: water; Mobile phase B: acetonitrile; Flow rate: 30 ml / min; Loading pump: 4 ml / min B; Gradient conditions: 20% to 40% to 65% to 100% (B) in 0 min to 2 min to 10 min to 11.2 min. 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 Synthesis of N-thiane-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-thiopyran-4-carboxamide 1,1-dioxide) (Compound 1.33) [ka]

[0150] N-[(1S)-1-(4-bromo-3-methylphenyl)-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ 6-thiane-4-carboxamide [INT17.3] (0.1 g, 0.2260 mmol), 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-amine [the free base of INT1.1] (51.4 mg, 226 μmol), Cs2CO3 (220 mg, 678 μmol), and Xantphos (13.0 mg, 22.6 μmol) were mixed in dioxane (2 mL). The reaction mixture was degassed with argon for 5 minutes. Pd2(dba)3 (10.3 mg, 11.3 μmol) was added. The reaction mixture was then degassed with argon for 5 minutes and stirred at 100 °C for 10 hours. The reaction mixture was cooled to 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-methyl-1,1-dioxo-1λ 6 -thiane-4-carboxamide [Compound 1.33] (20.7 mg, 0.03515 mmol, 15.5% yield) was obtained as a yellow solid. m / z: [M+H]+ calculated for C24H29ClF3N6O4S 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=9.4Hz, 1H), 5.16 (q, J=6.7 Hz, 1H), 3.21 (d, J=13.9 Hz, 3H), 3.18 - 3.05 (m, 5H),2.89 (s, 3H), 2.34 - 2.28 (m, 3H), 2.11 - 1.95 (m, 4H), 1.54 (d, J=6.7 Hz, 3H).

[0151] HPLC conditions: System: Agilent 1260 Infinity II LC connected to Agilent 6120B single quadrupole LC / MS system; Column description: Chromatorex SBM 100-5T 5 μm C18(2) 100 Å, LC column 100 × 19 mm, Waters, Sun Fire; Stationary phase: C18; Solid support: fully porous silica; Separation mode: reversed phase; Mobile phase A: water; Mobile phase B: acetonitrile; Flow rate: 30 ml / min; Loading pump: 4 ml / min B; Gradient conditions: 10% to 30% to 55% to 100% (B) in 0 min to 2 min to 10 min to 11.2 min. 2. Compounds prepared using Scheme 2 Scheme 2: [ka]

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

[0153] A mixture of tert-butyl 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-carboxylate [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 μmol) of the crude product was purified by preparative HPLC (column: Boston Green ODS 150 × 30 mm × 5 μm, column: 10–50% B (A = water (0.1% TFA)-ACN), B = acetonitrile), flow rate: 30 mL / min, UV detector 220 nm) 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 trifluoroacetate [Compound 2.1] (17.6 mg, 27.5 μmol) as a yellow dry powder. m / z: [M+H]+ calculated for C23H28ClF3N7O2 526.2, found 526.3. 1H 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 (brd, J=5.2 Hz, 2H), 2.99 (br s, 1H), 2.93 (s, 3H), 2.23 - 1.94 (m, 4H), 1.61 (d,J=6.8 Hz, 3H). Synthesis of N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methylpiperidine-3-carboxamide (compound 2.2) [ka]

[0154] A solution of tert-butyl 3-{[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl](methyl)carbamoyl}piperidine-1-carboxylate [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 this crude product was purified by preparative HPLC (column: Phenomenex Gemini-NX 80 × 40 mm × 3 μm, column: 22–62% B (A = water (0.05% ammonium hydroxide)), B = acetonitrile), flow rate: 25 mL / min, UV detector 220 nm) 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 [Compound 2.2] (5.30 mg, 10.0 μmol, 11.7% yield) as a yellow solid. m / z: [M+H]+ calculated for C23H28ClF3N7O2 526.2, found 526.3. 1H NMR (400 MHz, CDCl3) δ = 8.89 (s, 1H), 7.31 (d, J=8.4Hz, 2H), 7.11 (s, 1H), 7.04 (d, J=8.8 Hz, 2H), 6.61 (q, J=9.2 Hz, 1H), 5.48 (q,J=6.8 Hz, 1H), 3.51 - 3.45 (m, 3H), 3.15 - 2.98 (m, 2H), 2.93 (s, 3H), 2.85 -2.67 (m, 2H), 2.62 (s, 2H), 2.05 - 1.96 (m, 1H), 1.82 - 1.70 (m, 2H), 1.61 (d,J=6.8 Hz, 3H), 1.59 - 1.50 (m, 1H). Synthesis of N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylpyrrolidine-3-carboxamide hydrochloride (compound 2.3) [ka]

[0155] A mixture of tert-butyl 3-{[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl](methyl)carbamoyl}pyrrolidine-1-carboxylate [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 give the crude product, which was purified by preparative HPLC (column: Boston Green ODS 150 × 30 mm × 5 μm, column: 16–56% B (A = water (0.05% HCl)-ACN), B = acetonitrile), flow rate: 30 mL / min, UV detector 220 nm) 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-methylpyrrolidine-3-carboxamide hydrochloride [Compound 2.3] (31.3 mg, 57.1 μmol, 17.5% yield) as a yellow powder. m / z: [M+H]+ calculated for C22H26ClF3N7O2 512.1, 514.1, found 512.3, 514.2. 1 H NMR (400 MHz, CDCl3) δ = 10.16 (brs, 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 (br d, J=14.8 Hz,4H), 3.49 (s, 3H), 3.04 - 2.79 (m, 3H), 2.47 (br s, 1H), 2.22 - 2.09 (m, 2H),1.61 (br d, J=6.0 Hz, 3H). Synthesis 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; formic acid (compound 2.4) [ka]

[0156] A solution of tert-butyl 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 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. Further, 100 mg of the product was purified by preparative HPLC (column: YMC Triart C18 250 × 50 mm × 7 μm, column: 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; formate [Compound 2.4] (21.7 mg, 36.1 μmol, 21.7% yield) as a yellow dry powder. m / z: [M+H]+ calculated for C25H32ClF3N7O2 554.2, found 554.4. 1H 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). 3. Compounds prepared using Scheme 3 Scheme 3: [ka]

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

[0158] 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-methylpiperidine-4-carboxamide hydrochloride [Compound 2.1, HCl salt] (60 mg, 106 μmol) and triethylamine (53.6 mg, 530 μmol) in DCM (2 mL) was added acetyl chloride (29.1 mg, 371 μmol) at 25° C., and the mixture was stirred at 25° C. for 12 hours. The mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC (column: Boston Prime C18 150 × 30 mm × 5 μm, column: 35–65% B (A = water (0.05% v / v ammonium hydroxide), B = acetonitrile), flow rate: 30 mL / min, UV detector 220 nm) to give 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 [Compound 3.1] (17.7 mg, 31.1 μmol, 29.4% yield) as a yellow dry powder. m / z: [M+H]+ calculated for C25H30ClF3N7O3 568.2, found 568.4. 1 H 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). Synthesis 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-methyl-1-(propane-2-sulfonyl)piperidine-4-carboxamide (compound 3.2) [ka]

[0159] 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] (80 mg, 142 μmol) and triethylamine (57.4 mg, 568 μmol) in DCM (5 mL) was added propane-2-sulfonyl chloride (40.4 mg, 284 μmol) at 25° C., 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 × 30 mm × 5 μm, column: 40–70% B (A = water (0.05% v / v ammonium hydroxide)-ACN), B = acetonitrile), flow rate: 30 mL / min, UV detection at 220 nm) 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-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]+ calculated for C26H34ClF3N7O4S 632.2, found 632.3. 1H NMR (400 MHz, CDCl3) δ = 8.89 (s,1H), 7.32 (br d, J=8.4 Hz, 2H), 7.18 - 7.01 (m, 3H), 6.62 (q, J=9.2 Hz, 1H),5.48 (q, J=6.8 Hz, 1H), 3.85 (dt, J=4.4, 8.8 Hz, 2H), 3.49 (s, 3H), 3.19 (td,J=6.8, 13.6 Hz, 1H), 3.08 - 2.99 (m, 2H), 2.93 (s, 3H), 2.85 - 2.67 (m, 1H),1.98 - 1.87 (m, 3H), 1.87 - 1.79 (m, 1H), 1.62 (s, 3H), 1.37 (d, J=6.8 Hz, 6H). Synthesis of methyl 4-{[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl](methyl)carbamoyl}piperidine-1-carboxylate (compound 3.3) [ka]

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

[0161] 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) was added methanesulfonyl chloride (120 mg, 1.04 mmol) at 0° C., and the mixture was stirred at 25° C. for 12 h. The crude product was purified by preparative HPLC (column: YMC Triart C18 250 × 50 mm × 7 μm, column: 30–70% B (A = water (0.05 v / v % ammonium hydroxide)-ACN, B = acetonitrile), flow rate: 60 mL / min, UV detector 220 nm) 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]-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]+ calculated for C24H30ClF3N7O4S 604.2, found 604.3. 1H NMR (400 MHz, CDCl3) δ = 8.89 (s,1H), 7.35 - 7.29 (m, 2H), 7.12 (s, 1H), 7.05 (d, J=8.8 Hz, 2H), 6.62 (q, J=8.8Hz, 1H), 5.49 (q, J=6.8 Hz, 1H), 3.91 - 3.75 (m, 2H), 3.54 - 3.47 (m, 3H), 3.16- 2.86 (m, 5H), 2.83 (s, 3H), 2.78 - 2.71 (m, 1H), 2.05 - 1.91 (m, 3H), 1.91 -1.84 (m, 1H), 1.62 (d, J=6.8 Hz, 3H). Synthesis of 1-acetyl-N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methylpiperidine-3-carboxamide (compound 3.5) [ka]

[0162] 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-3-carboxamide [Compound 2.2] (40 mg, 76.0 μmol) and acetyl chloride (20.8 mg, 266 μmol) in DCM (2 mL) was added triethylamine (38.4 mg, 380 μmol) at 25° C., and the mixture was stirred at 25° C. for 12 hours. The reaction was concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC (column: YMC Triart C18 250 × 50 mm × 7 μm, column: 31–71% B (A = water (0.05 v / v % ammonia hydroxide)), B = acetonitrile), flow rate: 60 mL / min, UV detector 220 nm) to give 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 [compound 3.5] (8.90 mg, 15.6 μmol, 20.6% yield) as a dry yellow powder. m / z: [M+H]+ calculated for C25H30ClF3N7O3 568.2, found 568.3. 1 H 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=6.8 Hz, 1H), 4.73 - 4.55 (m, 1H), 3.90 - 3.78 (m, 1H), 3.49 (s, 3H),3.22 - 3.03 (m, 1H), 2.94 (s, 3H), 2.82 - 2.64 (m, 2H), 2.11 (s, 3H), 2.07 -1.99 (m, 1H), 1.96 - 1.82 (m, 2H), 1.81 - 1.66 (m, 1H), 1.63 - 1.60 (m, 2H), 1.58- 1.45 (m, 1H). Synthesis of 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) [ka]

[0163] 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-3-carboxamide [Compound 2.2] (50 mg, 95.0 μmol) in CHCl (3 mL) was added triethylamine (38.4 mg, 380 μmol) followed by N-methylcarbamoyl chloride (10.5 mg, 113 μmol) at 0° C. The mixture was stirred at 25° C. for 16 hours. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC (column: Phenomenex Gemini-NX 80 × 40 mm × 3 μm, column: 22–62% B (A = water (0.05% ammonia hydroxide)), B = acetonitrile), flow rate: 25 mL / min, UV detector 220 nm) 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,N-dimethylpiperidine 1,3-dicarboxamide [Compound 3.6] (8.00 mg, 13.7 μmol, 14.4% yield) as a yellow solid. m / z: [M+H]+ calculated for C25H31ClF3N8O3 583.2, found 583.4. 1H 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). Synthesis 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]-1-methanesulfonyl-N-methylpiperidine-3-carboxamide (compound 3.7) [ka]

[0164] 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-3-carboxamide [Compound 2.2] (50 mg, 95.0 μmol) in CHCl (2 mL) was added triethylamine (38.4 mg, 380 μmol) followed by methanesulfonyl chloride (90 mg, 785 μmol) at 0° C. The mixture was stirred at 25° C. for 16 hours. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC (column: Boston Prime C18 150 × 30 mm × 5 μm, column: 34-64% B (water (0.05 v / v % ammonia hydroxide), B = acetonitrile), flow rate: 25 mL / min, UV detector 220 nm) 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]-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]+ calculated for C24H30ClF3N7O4S 604.2, found 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). Synthesis of 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) [ka]

[0165] 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) was added acetyl chloride (74.9 mg, 955 μmol) at 25° C., and the mixture was stirred at 25° C. for 12 h. The mixture was concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC (column: Boston Prime C18 150 × 30 mm × 5 μm, column: 22–52% B (A = water (0.05 v / v % ammonia hydroxide)-ACN), B = acetonitrile), flow rate: 30 mL / min, UV detector 220 nm) to give 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]+ calculated for C24H28ClF3N7O3 554.2, found 554.4. 1H NMR (400 MHz, CDCl3) δ = 8.94 -8.88 (m, 1H), 7.35 - 7.29 (m, 2H), 7.14 (s, 1H), 7.05 (dd, J=4.0, 8.4 Hz, 2H),6.65 - 6.53 (m, 1H), 5.48 (q, J=6.8 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). Synthesis of 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) [ka]

[0166] 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 CHCl (3 mL) was added triethylamine (110 mg, 1.09 mmol) followed by N-methylcarbamoyl chloride (30.5 mg, 327 μmol) at 0° C. The mixture was stirred at 25° C. for 16 h. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC (column: Boston Prime C18 150 × 30 mm × 5 μm, column: 22–52% B (A = water (0.05 v / v % ammonia hydroxide)-ACN)), B = acetonitrile), flow rate: 25 mL / min, UV detector 220 nm) to give 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]+ calculated for C24H29ClF3N8O3 569.1, found 569.4. 1 H NMR (400MHz, CDCl3) δ = 8.91 (d,J=5.6 Hz, 1H), 7.35 - 7.29 (m, 2H), 7.13 (s, 1H), 7.05 (d, J=8.4 Hz, 2H), 6.64- 6.54 (m, 1H), 5.48 (q, J=6.8 Hz, 1H), 4.21 (br d, J=4.0 Hz, 1H), 3.81 - 3.68(m, 1H), 3.63 - 3.54 (m, 2H), 3.49 (d, J=1.2 Hz, 3H), 3.44 - 3.28 (m, 2H), 2.94(d, J=4.4Hz, 3H), 2.84 (dd, J=2.4, 4.8 Hz, 3H), 2.42 - 2.11 (m, 2H), 1.63 (brs, 3H). Synthesis of N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-1-methanesulfonyl-N-methylpyrrolidine-3-carboxamide (compound 3.10) [ka]

[0167] 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) was added methanesulfonyl chloride (310 mg, 2.70 mmol) at 0° C. The mixture was stirred at 15° C. for 12 hours. The crude product was purified by preparative HPLC (column: Boston Green ODS 150 × 30 mm × 5 μm, column: 28–68% B (A = water (0.05% HCl)-ACN, B = acetonitrile), flow rate: 30 mL / min, UV detector 220 nm) 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]-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]+ calculated for C23H28ClF3N7O4S 590.1, found 590.4. 1H 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). Synthesis 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]-4-(acetamidomethyl)-N-methylcyclohexane-1-carboxamide (compound 3.11) [ka]

[0168] To a 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) in CHCl (1.5 mL) was added EtN (49.0 mg, 485 μmol) and acetyl chloride (63.5 mg, 810 μmol). The resulting mixture was stirred at 20° C. for 2 hours. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: YMC Triart C18 250 × 50 mm × 7 μm, column: 26–66% B (A = water (0.05 v / v% ammonia hydroxide), B = acetonitrile), flow rate: 60 mL / min, UV detector 220 nm) 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]-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]+ calculated for C27H34ClF3N7O3 596.2, found 596.2. 1 H NMR (400 MHz, CDCl3) δ = 8.81 (s, 1H), 7.23 (brd, J=8.4 Hz, 2H), 7.04 (s, 1H), 6.96 (d, J=8.4 Hz, 2H),6.55 (q, J=9.2 Hz, 1H), 5.64 - 5.52 (m, 1H), 5.40 (q, J=6.8Hz, 1H), 3.41 (s, 3H), 3.13 - 3.00 (m, 2H), 2.83 (s, 3H), 2.52 - 2.41 (m, 1H),1.96 - 1.90 (m, 3H), 1.80 - 1.66 (m, 3H), 1.60 - 1.41 (m, 6H), 1.06 - 0.85 (m,2H). Synthesis of methyl N-[(4-{[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl](methyl)carbamoyl}cyclohexyl)methyl]carbamate (compound 3.12) [ka]

[0169] To a 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) in CHCl (1.5 mL) was added EtN (49.0 mg, 485 μmol) and methyl chloroformate (75.7 mg, 810 μmol). The resulting mixture was stirred at 20° C. for 2 hours. The reaction was poured into water (10 mL) and extracted with EtOAc (10 mL × 2). The combined organic layers were washed with brine (15 mL × 2) and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: YMC Triart C18 250 × 50 mm × 7 μm, column: 31–71% B (A = water (0.05 v / v% ammonia hydroxide), B = acetonitrile), flow rate: 60 mL / min, UV detector 220 nm) to give methyl 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]+ calculated for C27H34ClF3N7O4 612.2, found 612.2. 1H NMR (400 MHz, CDCl3) δ =8.81 (s, 1H), 7.23 (br d, J=8.0Hz, 2H), 7.04 (s, 1H), 6.96 (br d, J=8.4 Hz, 2H), 6.55 (q, J=8.8 Hz, 1H), 5.40(q, J=6.8 Hz, 1H), 4.72 (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). 4. Compounds prepared using Scheme 4 Scheme 4: [ka]

[0170] Starting material G-4a is treated with G-4b to provide compounds of formula (I). Synthesis 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)-1-(cyclopropanecarbonyl)-N-methylpiperidine-4-carboxamide (compound 4.1) [ka]

[0171] 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-methylpiperidine-4-carboxamide hydrochloride [Compound 2.1, HCl salt] (80 mg, 142 μmol), EDCI (54.4 mg, 284 μmol), hydroxybenzotriazole (19.1 mg, 142 μmol), and triethylamine (43.0 mg, 425 μmol) in DCM (3 mL) was added cyclopropanecarboxylic acid (36.5 mg, 425 μmol). The mixture was stirred at 25° C. for 12 hours. The crude product was purified by preparative HPLC (column: Phenomenex Gemini-NX 80 × 40 mm × 3 μm, column: 21–61% B (A = water (0.05 v / v % ammonia hydroxide), B = acetonitrile), flow rate: 25 mL / min, UV detector 220 nm) 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)-1-(cyclopropanecarbonyl)-N-methylpiperidine-4-carboxamide [Compound 4.1] (20.5 mg, 34.5 μmol, 24.3% yield) as a yellow dry powder. m / z: [M+H]+ calculated for C27H32ClF3N7O3 594.2, found 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). Synthesis 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]-1-cyclopropanecarbonyl-N-methylpiperidine-3-carboxamide [Compound 4.2] [ka]

[0172] To a mixture of cyclopropanecarboxylic acid (12.2 mg, 142 μmol), EDCI (27.2 mg, 142 μmol), and HOBt (19.1 mg, 142 μmol) in CHCl (3 mL) was added 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 [Compound 2.2] (50 mg, 95.0 μmol), and the mixture was stirred at 25° C. under N for 16 h. The reaction was concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75 × 30 mm × 3 μm, column: 34–74% B (A = water (0.225% FA), B = acetonitrile), flow rate: 25 mL / min, UV detector 220 nm) 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]-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]+ calculated for C27H32ClF3N7O3 594.2, found 594.4. 1H 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=6.4 Hz, 3H), 1.24 (br s, 1H), 0.72 (br s,4H). Synthesis of N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-1-cyclopropanecarbonyl-N-methylpyrrolidine-3-carboxamide (compound 4.3) [ka]

[0173] 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) was added cyclopropanecarboxylic acid (70.4 mg, 818 μmol). The mixture was stirred at 25° C. for 12 hours. The crude product was purified by preparative HPLC (column: Boston Prime C18 150 × 30 mm × 5 μm, column: 39–69% B (A = water (0.05 v / v % ammonium hydroxide)-ACN), B = acetonitrile), flow rate: 30 mL / min, UV detector 220 nm) 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]-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]+ calculated for C26H30ClF3N7O3 580.2, found 580.5. 1 H NMR (400 MHz, CDCl3) δ = 8.92 -8.90 (m, 1H), 7.37 - 7.30 (m, 2H), 7.13 (s, 1H), 7.08 - 7.02 (m, 2H), 6.67 -6.55 (m, 1H), 5.48 (q, J=6.8 Hz, 1H), 4.09 - 3.53 (m, 4H), 3.49 (s, 3H), 3.45 -3.26 (m, 1H), 3.00 - 2.92 (m, 3H), 2.55 - 2.02 (m, 2H), 1.64 (br d, J=5.4 Hz,1H), 1.63 (s, 3H), 1.09 - 0.96 (m, 2H), 0.79 (br d, J=7.6 Hz, 2H). 5. Compounds prepared using Scheme 5 Scheme 5: [ka]

[0174] Starting material G-5a is treated with HO(CHO)H (paraformaldehyde) and NaBHCN to provide compounds of formula (I). Synthesis 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,1-dimethylpiperidine-4-carboxamide (compound 5.1) [ka]

[0175] 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-methylpiperidine-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 × 40 mm × 3 μm, column: 39–79% B (A = water (0.05 v / v % ammonia hydroxide), B = acetonitrile), flow rate: 25 mL / min, UV detector 220 nm) 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,1-dimethylpiperidine-4-carboxamide [Compound 5.1] (22.0 mg, 40.7 μmol, 26.8% yield) as a yellow dry powder. m / z: [M+H]+ calculated for C24H30ClF3N7O2 540.2, found 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). Synthesis 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,1-dimethylpiperidine-3-carboxamide (compound 5.2) [ka]

[0176] 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-3-carboxamide [Compound 2.2] (50 mg, 95.0 μmol) and paraformaldehyde (14.2 mg, 474 μmol) in MeOH (1 mL) was added triethylamine (19.2 mg, 190 μmol) and sodium cyanoborohydride (8.92 mg, 142 μmol). The mixture was stirred at 25 °C under N for 16 hours. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC (column: YMC Triart C18 250 × 50 mm × 7 μm, column: 11–51% B (A = water (0.225% FA), B = acetonitrile), flow rate: 60 mL / min, UV detector 220 nm) 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,1-dimethylpiperidine-3-carboxamide [Compound 5.2] (4.70 mg, 8.70 μmol, 9.2% yield) as a yellow dry powder. m / z: [M+H]+ calculated for C24H30ClF3N7O2 540.2, found 540.3. 1H 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). Synthesis 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,1-dimethylpyrrolidine-3-carboxamide hydrochloride (compound 5.3) [ka]

[0177] 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 for 0.5 h at 25° C. Paraformaldehyde (40.8 mg, 1.36 mmol) was then 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 × 30 mm × 5 μm, column: 16–56% B (A = water (0.05% HCl)-ACN), B = acetonitrile), flow rate: 30 mL / min, UV detector 220 nm) 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,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]+ calculated for C23H28ClF3N7O2 526.2, found 526.3. 1 H NMR (400MHz, CDCl3) δ = 12.84 (brs, 1H), 8.91 (s, 1H), 7.33 - 7.28 (m, 2H), 7.15 (br d, J=3.6 Hz, 1H), 7.05 (brd, J=8.4 Hz, 2H), 6.58 - 6.43 (m, 1H), 5.48 (q, J=6.8 Hz, 1H), 4.04 - 3.87 (m,1H), 3.80 (br s, 2H), 3.49 (s, 3H), 3.48 - 3.36 (m, 1H), 3.04 (br s, 1H), 3.00- 2.96 (m, 3H), 2.94 (s, 3H), 2.71 (br d, J=17.2 Hz, 1H), 2.11 (br s, 1H), 1.60(s, 3H). 6. Compounds prepared using Scheme 6 Scheme 6: [ka] Synthesis of (1r,4S)-N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-4-hydroxy-N-methylcyclohexane-1-carboxamide (Compound 6.1)

[0178] A solution of (1r,4S)-4-((tert-butyldimethylsilyl)oxy)-N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylcyclohexane-1-carboxamide [INT18.1] (100 mg, 152 μmol) in TFA (0.5 mL) and CHCl (0.5 mL) was stirred at 20° C. for 0.5 h. The reaction mixture was concentrated under reduced pressure to provide a residue. The residue was purified by preparative HPLC (column: Boston Green ODS 150 × 30 mm × 5 μm, column: 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]+ calculated for C24H29ClF3N6O3 541.2, found 541.3. 1H NMR (400 MHz, CDCl3) δ = 9.05 (s, 1H), 7.47 (br d,J=8.0 Hz, 2H), 7.43 (s, 1H), 7.20 (br d, J=8.4 Hz, 2H), 6.78 (q, J=8.8 Hz, 1H),5.64 (q, J=6.4 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). 7. Compounds prepared using Scheme 7 Scheme 7: [ka]

[0179] Starting material G-7a is treated with a hydrolyzing agent to provide compounds of formula (I). Synthesis 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) [ka]

[0180] To a mixture of methyl (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 HO (1 mL), 1 N HCl (1 mL, 1 mmol) was added, and the mixture was stirred at 70° C. for 6 h. Water (10 mL) was added, and the mixture was extracted with EtOAc (10 mL × 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC (column: Boston Green ODS 150 × 30 mm × 5 μm, column: 28–68% B (A = water (0.05 v / v % HCl)), B = acetonitrile), flow rate: 30 mL / min, UV detector 220 nm) and lyophilized to give (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]+ calculated for C25H29ClF3N6O4 569.2, found 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). 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 ammonium salt (compound 7.2) [ka]

[0181] A mixture of methyl (1S,4r)-4-(((S)-1-(4-((2-chloro-7-isopropyl-[1,2,4]triazolo[1,5-a]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 HO (2 mL) and THF (2 mL) was stirred at 20° C. for 12 hours. The mixture was concentrated under reduced pressure to give a residue that was diluted with water (5 mL). The resulting mixture was adjusted to pH=4 with 1N HCl and extracted with EtOAc (5 mL×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 × 30 mm × 5 μm, column: 15–45% B (A = water (0.05 v / v % ammonia hydroxide), B = acetonitrile), flow rate: 30 mL / min, UV detector 220 nm) 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-carboxylic acid ammonium salt [Compound 7.2] (2.80 mg, 4.91 μmol, 5.6% yield) as a white dry powder. m / z: [M+H] calculated for CHClFNO 553.2, found 553.1. 1H 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). 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 (compound 7.3) [ka]

[0182] Methyl (1S,3r)-3-(((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]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, which was stirred for 10 hours. The pH of the reaction mixture was adjusted to 7 with dilute aqueous HCl. The solvent was evaporated 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] calculated for CHClFNO 541.2, found 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).

[0183] HPLC conditions: System: Agilent 1260 Infinity II LC connected to Agilent 6120B single quadrupole LC / MS system; Column description: Chromatorex SBM 100-5T C18 100Å, LC column 100 × 19 mm, Waters, Sun Fire; Stationary phase: C18; Solid support: fully porous silica; Separation mode: reversed phase; Mobile phase A: water; Mobile phase B: acetonitrile; Flow rate: 30 ml / min; Loading pump: 4 ml / min B; Gradient conditions: 0% B, 0% B, 25% B, 100% B, 11.2 min. 8. Compounds prepared using Scheme 8 Scheme 8: [ka]

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

[0185] 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) was added HATU (49.8 mg, 131 μmol) and DIEA (33.9 mg, 263 μmol), and the mixture was stirred at 25° C. for 0.5 h. Next, NHCl (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 C18 250 × 50 mm × 7 μm, column: 25–65% B (A = water (0.05 v / v % ammonia hydroxide)), 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]+ calculated for C25H30ClF3N7O3 568.2, found 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). Synthesis of (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) [ka]

[0186] 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) was added HATU (49.8 mg, 131 μmol) and DIPEA (51.1 mg, 396 μmol), and the mixture was stirred at 25° C. for 0.5 h. Next, methanamine 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 Triart C18 250 × 50 mm × 7 μm, column: 26–66% B (A = water (0.05 v / v % ammonia hydroxide)), 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-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]+ calculated for C26H32ClF3N7O3 582.2, found 582.2. 1H 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=8.8 Hz, 1H), 5.36 (q, J=6.8 Hz, 1H),3.36 (s, 3H), 2.96 (s, 3H), 2.82 - 2.72 (m, 1H), 2.70 (s, 3H), 2.29 - 2.17 (m,1H), 1.96 - 1.78 (m, 4H), 1.64 (d, J=6.8 Hz, 3H), 1.62 - 1.51 (m, 4H). Synthesis of (1r,4S)-N1-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N1,N4,N4-trimethylcyclohexane-1,4-dicarboxamide (Compound 8.3) [ka]

[0187] 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) was added HATU (49.8 mg, 131 μmol) and DIPEA (51.1 mg, 396 μmol), and the mixture was stirred at 25° C. for 0.5 h. Dimethylamine hydrochloride (10.6 mg, 131 μmol) was then added, and the mixture was stirred at 25° C. for 12 h. The mixture was purified by preparative HPLC (column: YMC Triart C18 250 × 50 mm × 7 μm, column: 30–70% B (A = water (0.05 v / v % ammonia hydroxide)), 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]+ calculated for C27H34ClF3N7O3 596.2, found 596.2. 1 H NMR (400 MHz, CD3OD) δ = 8.87 (s, 1H), 7.40 - 7.25 (m,2H), 7.13 - 7.01 (m, 2H), 6.53 (q, J=8.8 Hz, 1H), 5.36 (q, J=6.8 Hz, 1H), 3.36(s, 3H), 3.12 (s, 3H), 2.98 - 2.95 (m, 3H), 2.93 (s, 3H), 2.82 - 2.73 (m, 2H),1.97 - 1.80 (m, 4H), 1.64 (d, J=6.8 Hz, 3H), 1.63 - 1.51 (m, 4H). 9. Compounds prepared using Scheme 9 Scheme 9: [ka] Synthesis of (1r,3S)-N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyl-3-(1H-tetrazol-5-yl)cyclobutane-1-carboxamide (Compound 9.1)

[0188] (1r,3S)—N—((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]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 HO (5 mL) were added, and the organic phase was evaporated in vacuo 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] calculated for CHClFNO 565.2, found 565.0. 1H 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).

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

[0190] N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide [compound 1.1] was purified by chiral SFC (column: DAICEL CHIRALPAK AD 250 mm x 50 mm, 10 μm, column: 30% NH₃H₂O in 0.1% NH₃H₂O) Further purification by HPLC using HPLC with HCl (ETOH), flow rate: 200 mL / min, UV detector 220 nm) allowed separation and isolation of [Compound 1.1] (>98% chiral purity) and N-((S)-1-(4-((2-chloro-7-((R)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide [Compound 10.1] (>98% chiral purity). For Compound 10.1, m / z: [M+H] calculated for CHClFNOS 575.1, found 575.0. 1 H 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). 11. Separation and isolation of compound 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 11.1) Scheme 11: [ka]

[0191] 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-methylpiperidine-4-carboxamide [compound 3.1] was purified by chiral SFC (column: DAICEL CHIRALPAK Further purification by IG (250 mm x 50 mm, 10 μm), column: 50-50% B (A = water (0.1% ammonium hydroxide), B = MeOH), flow rate: 200 mL / min) allowed separation and isolation of compound 3.1 (100% chiral purity) and 1-acetyl-N-((S)-1-(4-((2-chloro-7-((R)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylpiperidine-4-carboxamide [compound 11.1] (97% chiral purity). For compound 11.1, m / z: [M+H] calculated for CHClFNO: 568.2, found: 568.1. 1 H 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). 12. Synthesis of intermediates

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

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

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

[0195] To a mixture of tert-butyl 2-amino-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylate [INT1-c] (1.2 g, 4.09 mmol) and copper(II) chloride dihydrate (173 mg, 1.02 mmol) in concentrated HCl (20 mL), a solution of sodium nitrite (338 mg, 4.90 mmol) in HO (5 mL) was added at 5 °C using an ice bath, and the mixture was stirred at 5 °C for 30 min. The mixture was then warmed to 25 °C and stirred for 16 h. Water (100 mL) was added, and the pH was adjusted to 3-4 by adding 1 N aqueous NaOH. 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 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid [INT1-d] (962 mg, 92.4% yield) as a solid. m / z: [M+H]+ calculated for C9H10ClNO3 257.0, found 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). Synthesis of tert-butyl N-{2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}carbamate (INT1-e):

[0196] To a solution of 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid [INT1-d] (1.3 g, 5.06 mmol) in t-BuOH (10 mL) was added {[azido(phenoxy)phosphoryl]oxy}benzene (2.08 g, 7.58 mmol) and triethylamine (1.02 g, 10.1 mmol), and the mixture was stirred at 100° C. under a N atmosphere for 2 h. The mixture was concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (EtOAc / petroleum ether = 1 / 10 to 1 / 5) to give tert-butyl N-{2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}carbamate [INT1-e] (420 mg, 25.4% yield) as a solid. m / z: [M+H]+ calculated for C13H19ClNO3 328.1, found 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). Synthesis of 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-amine hydrochloride (INT1.1):

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

[0198] A mixture of methyl 4-methyl-3-oxopentanoate [INT1-f] (23.2 g, 160 mmol) and DMF-DMA (19.0 g, 160 mmol) was stirred at 120 °C for 2 h under a N atmosphere. Next, a mixture of 1H-1,2,4-triazole-3,5-diamine (15.8 g, 160 mmol) in EtOH (30 mL) was added, and the mixture was stirred at 85 °C for 2 h. The mixture was concentrated under reduced pressure to give the crude product, which was purified by silica gel flash 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 [INT1-g] (20.6 g, 87.7 mmol, 54.7% yield) as an off-white solid. m / z: [M+H]+ calculated for C10H14N5O2 236.1, found 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). Synthesis of methyl 2-chloro-7-isopropyl-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylate (INT1-h):

[0199] To a mixture of methyl 2-amino-7-isopropyl-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylate [INT1-g] (10.17 g, 34.5 mmol) and copper(II) chloride dihydrate (1.46 g, 8.62 mmol) in concentrated HCl (30 mL) was added a solution of sodium nitrite (2.85 g, 41.4 mmol) in HO (5 mL) at 5 °C. The mixture was stirred at 5 °C (cooled in an ice bath) for 30 minutes. The mixture was then warmed to 25 °C and stirred for 12 hours. 2N aqueous NaOH was added to adjust the pH to 7, and the mixture was extracted with EtOAc (200 mL × 2). The combined organic layers were washed with brine (200 mL × 3), dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product, which was purified by silica gel flash 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 [INT1-h] (3.00 g, 11.7 mmol, 34.1% yield) as a yellow solid. m / z: [M+H]+ calculated for C10H12ClNO2 255.1, found 255.0. 1 H NMR (400 MHz, CDCl3) δ = 9.16 (d, J=1.2 Hz, 1H), 4.60 -4.44 (m, 1H), 4.03 (d, J = 0.4 Hz, 3H), 1.61 (dd, J = 1.2, 7.2 Hz, 6H). Synthesis of 2-chloro-7-isopropyl-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid (INT1-i):

[0200] To a mixture of methyl 2-chloro-7-isopropyl-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylate [INT1-h] (1 g, 3.92 mmol) in THF (10 mL), lithium hydroxide(1+) hydrate (2 M in HO, 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. 1N HCl was added to adjust the pH to 3-4, and the mixture was filtered. The filter cake was washed with water (20 mL × 2), collected, and concentrated under reduced pressure to give a solid. The solid was purified by preparative HPLC (column: Boston Green ODS 150 × 30 mm × 5 μm, column: 8–48% B (A = water (0.05% HCl), B = acetonitrile), flow rate: 30 mL / min, UV detector 220 nm) to give 2-chloro-7-isopropyl-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid [INT1-i] (300 mg, 1.24 mmol, 31.8% yield) as a white dry powder. m / z: [M+H]+ calculated for C9H10ClNO2 241.1, found 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). Synthesis of tert-butyl (2-chloro-7-isopropyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)carbamate (INT1-j):

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

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

[0203] (R)-2-Chloro-7-(1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-amine [INT1.3] can be prepared by the same synthetic route outlined for INT1.1 using (2R)-2-methoxypropanoic acid as the starting material. m / z: [M+H] calculated for C8H11ClNO 228.1, found 228.1. Synthesis of (R)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide (Intermediate 2.1): [ka] Synthesis of (R,E)-N-(4-bromobenzylidene)-2-methylpropane-2-sulfinamide (INT2-b):

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

[0205] To a solution of (R,E)-N-(4-bromobenzylidene)-2-methylpropane-2-sulfinamide [INT2-b] (206 g, 715 mmol, 1.0 equiv.) and tetrabutylammonium acetate (216 g, 715 mmol, 218 mL, 1.0 equiv.) in DMF (1.4 L) was added TMSCF (259 g, 1.82 mol, 2.5 equiv.) at 0 °C. The mixture was stirred at 5 °C for 1.5 h. This process was repeated twice, and the three reaction mixtures were combined for workup. The mixture was poured into saturated NH Cl solution (13.0 L) and stirred for 10 min to give a suspension. The suspension was filtered to give a filter cake, which was eluted with water (5.0 L). The filter cake was triturated with MTBE / petroleum ether (v / v=1:4, 2.0 L) to give the product as a solid, and the mother liquor was concentrated in vacuo to give the crude product as an oil, which was purified by silica gel column chromatography using petroleum ether / ethyl acetate (10 / 1 to 1 / 1) to give (R)—N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide [INT2.1] (389 g, 1.09 mol, 50.6% yield) as a solid. 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). Synthesis of (S)-1-(4-bromophenyl)-2,2,2-trifluoro-N-methylethan-1-amine hydrochloride (Intermediate 3.1): [ka] Synthesis of (R)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N,2-dimethylpropane-2-sulfinamide [INT3-b]:

[0206] To a solution of LiHMDS (1.0 M, 838 mL, 3.0 equiv.), (R)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide [INT2.1] (100 g, 279 mmol, 1.0 equiv.) was added at 0–10 °C and stirred at 0–10 °C for 0.5 h. To the mixture, MeI (119 g, 838 mmol, 52.1 mL, 3.0 equiv.) was added at 0–10 °C and stirred at 25 °C for 1 h. This process was repeated twice, and the combined reaction mixture was 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 NaSO, filtered, and concentrated in vacuo to give the crude product as an oil. The crude product was purified by silica gel column chromatography using petroleum ether / ethyl acetate (15 / 1 to 1 / 1) to give (R)—N—((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N,2-dimethylpropane-2-sulfinamide [INT3-b] (161 g, 432.5 mmol, 51.6% yield) as an oil. Synthesis of (S)-1-(4-bromophenyl)-2,2,2-trifluoro-N-methylethan-1-amine hydrochloride [INT3.1]:

[0207] To a mixture of (R)—N—((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N,2-dimethylpropane-2-sulfinamide [INT3-b] (202 g, 543 mmol, 1.0 equiv.) in EtOAc (600 mL) was slowly added HCl / EtOAc (4.0 M, 2.02 L, 14.9 equiv.). The mixture was stirred at 20° C. for 1 hour. The reaction mixture was filtered to give a solid, which was eluted with EtOAc (200 mL), and the mother liquor was concentrated in vacuo to give a solid. The solid was purified by silica gel column chromatography using petroleum ether / ethyl acetate (10 / 1 to 1 / 0), combined with the filter cake, and concentrated by oil pump at 45°C for 1 hour to remove solvent residues to give (S)-1-(4-bromophenyl)-2,2,2-trifluoro-N-methylethan-1-amine hydrochloride [INT3.1] (115 g, 378 mmol, 69.6% yield, 100% purity, HCl) as a solid. 1 H 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).

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

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

[0210] To a solution of tetrahydro-2H-thiopyran-4-carboxylic acid 1,1-dioxide [INT4-a] (41.0 g, 230 mmol, 1.0 equiv.) in DCM (410 mL) was added (COCl) (58.4 g, 460 mmol, 40.3 mL, 2.0 equiv.) and DMF (168 mg, 2.30 mmol, 177 μL, 0.01 equiv.) at 0 °C under N. The mixture was warmed to 20 °C and stirred at 20 °C for 2 h. The suspension turned clear, indicating that most of the starting material had been consumed. The reaction mixture was concentrated in vacuo to give the crude product as a solid, which was concentrated by oil pump to remove solvent residues to give tetrahydro-2H-thiopyran-4-carbonyl chloride 1,1-dioxide [INT4.1] (46.5 g, crude) as a solid. Synthesis of tetrahydro-2H-pyran-2-carbonyl chloride (intermediate 4.2): [ka]

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

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

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

[0214] To a mixture of oxolane-3-carboxylic acid [INT4-e] (1 g, 8.61 mmol) in CHCl (10 mL) was added oxalic acid dichloride (2.18 g, 17.2 mmol) and N,N-dimethylformamide (62.9 mg, 861 μmol). The reaction mixture was stirred at 25° C. for 1.5 hours. The reaction mixture was concentrated to give oxolane-3-carbonyl chloride [INT4.5] (1.10 g, 8.17 mmol) as a yellow oil. Synthesis of 1,4-dioxaspiro[4.5]decane-8-carbonyl chloride (intermediate 4.6): [ka]

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

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

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

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

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

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

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

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

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

[0224] To a mixture of (S)-1-(4-bromophenyl)-2,2,2-trifluoro-N-methylethan-1-amine hydrochloride [INT3.1] (400 mg, 1.31 mmol) and EtN (662 mg, 6.55 mmol) in dichloromethane (2 mL) was added a solution of tetrahydro-2H-pyran-2-carbonyl chloride [INT4.2] (370 mg, 2.49 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 × 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product, which was purified by silica gel flash 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 [INT5.3] (400 mg, 1.05 mmol, 80.3% yield) as a yellow oil. m / z: [M+H]+ calculated for CHBrF3NO2 380.0, 382.0, found 380.0. Synthesis of methyl (1S,4r)-4-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexane-1-carboxylate (Intermediate 5.4): [ka]

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

[0226] To a mixture of [(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)amine hydrochloride [INT3.1] (400 mg, 1.31 mmol) and EtN (662 mg, 6.55 mmol) in dichloromethane (2 mL) was added a solution of thiane-4-carbonyl chloride [INT4.4] (415 mg, 2.52 mmol) in dichloromethane (2 mL), and the mixture was stirred for 3 h at 25 °C. The mixture was purified by silica gel flash chromatography (EtOAc / petroleum ether = 1 / 10 to 1 / 5) to afford N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methylthiane-4-carboxamide [INT5.5] (132 mg, 333 μmol, 25.4% yield) as a colorless oil. m / z: [M+H]+ calculated for C15H18BrF3NOS 396.0, 398.0, found 397.9. Synthesis of N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methyloxolane-3-carboxamide (Intermediate 5.6): [ka]

[0227] To a mixture of [(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)amine hydrochloride [INT3.1] (1 g, 3.28 mmol) and triethylamine (1.65 g, 16.4 mmol) in CHCl (10 mL) was added oxolane-3-carbonyl chloride [INT4.5] (662 mg, 4.92 mmol) at 0° C. The reaction mixture was stirred at 25° C. for 12 hours. The reaction mixture was concentrated, diluted with water (30 mL), and extracted with EtOAc (20 mL×3). The combined organic layer was washed with brine (30 mL×2), dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (0–15% EtOAc in petroleum ether) to give N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methyloxolane-3-carboxamide [INT5.6] (360 mg, 983 μmol, 30.0% yield) as a yellow oil. m / z: [M+H] calculated for C14H16BrF3NO2 366.0, found 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). Synthesis of N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methyl-1,4-dioxaspiro[4.5]decane-8-carboxamide (Intermediate 5.7): [ka]

[0228] To a mixture of [(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)amine hydrochloride [INT3.1] (450 mg, 1.47 mmol) and EtN (743 mg, 7.35 mmol) in dichloromethane (2 mL) was added a solution of 1,4-dioxaspiro[4.5]decane-8-carbonyl chloride [INT4.6] (430 mg, 2.10 mmol) in dichloromethane (2 mL), and the mixture was stirred for 3 hours at 25° C. Water (10 mL) was added, and the mixture was extracted with dichloromethane (10 mL × 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product, which was purified by silica gel flash 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 [INT5.7] (210 mg, 481 μmol, 32.7% yield) as a yellow oil. m / z: [M+H]+ calculated for CHBrFNO3 436.1, 438.1, found 437.9. Synthesis of N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-4,4-difluoro-N-methylcyclohexane-1-carboxamide (Intermediate 5.8): [ka]

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

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

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

[0232] To a mixture of [(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)amine hydrochloride [INT3.1] (500 mg, 1.64 mmol) and EtN (829 mg, 8.20 mmol) in dichloromethane (10 mL) was added 1-acetylpiperidine-4-carbonyl chloride [INT4.9] (550 mg, 2.90 mmol), and the mixture was stirred at 25 °C for 3 h. The mixture was concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (methanol / dichloromethane = 0 / 1 to 1 / 20) to give 1-acetyl-N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methylpiperidine-4-carboxamide [INT5.11] (680 mg, 1.61 mmol, 98.5% yield) as a yellow solid. m / z: [M+H]+ calculated for CHBrFNO 421.1, 423.1, found 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). Synthesis of 1-acetyl-N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methylpiperidine-4-carboxamide (Intermediate 5.12): [ka]

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

[0234] 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) was added 4 M HCl / dioxane (30 mL). The mixture was stirred at 15 °C for 1 h. The mixture was concentrated under reduced pressure to give the crude product. The mixture was diluted with water (50 mL) and extracted with EtOAc (100 mL × 2). The combined organic layers were washed with 1 M HCl (100 mL × 2). The aqueous phase was basified with 2 N NaOH to pH = 9-10 and extracted with CHCl (100 mL × 2). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to afford (S)-1-(4-bromophenyl)-2,2,2-trifluoroethan-1-amine [INT6.1] (11.0 g, 43.2 mmol, 51.6% yield) as an oil. m / z: [M+H] calculated for CHBrFN 254.0, 256.0, found 255.8. Synthesis of tert-butyl (S)-4-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)piperidine-1-carboxylate (Intermediate 7.1): [ka] Synthesis of tert-butyl (S)-4-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)carbamoyl)piperidine-1-carboxylate (INT7-a):

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

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

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

[0238] To a solution of tert-butyl 3-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)carbamoyl)piperidine-1-carboxylate [INT7-b] (1.4 g, 3.00 mmol) in DMF (10 mL) was added CsCO (1.95 g, 6.00 mmol) and the reaction mixture was stirred at 25 °C for 1 h. Then, methyl iodide (1.27 g, 9.00 mmol) was 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 × 3). The combined organic layers were washed with brine (50 mL × 2), dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (PE / EtOAc = 1 / 0 to 5 / 1) to give tert-butyl 3-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)piperidine-1-carboxylate [INT7.2] (800 mg, 1.66 mmol, 55.9% yield) as a colorless oil. m / z: [M-56 + H] calculated for CHBrFNO 425.1, found 424.7. Synthesis of tert-butyl 3-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)pyrrolidine-1-carboxylate (Intermediate 7.3): [ka] Synthesis of tert-butyl 3-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)carbamoyl)pyrrolidine-1-carboxylate (INT7-c):

[0239] 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 CHCl (30 mL) was added (S)-1-(4-bromophenyl)-2,2,2-trifluoroethan-1-amine [INT6.1] (2 g, 7.87 mmol), and the mixture was stirred at 15 °C for 16 h. The reaction was concentrated under reduced pressure to give the crude product. This crude product was combined with material from a separate identical reaction on the same scale. The mixture was diluted with water (50 mL) and extracted with EtOAc (100 mL × 2). The combined organic layers were washed with NaHCO (100 mL × 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude material, which was purified by silica gel flash chromatography (EA / PE = 0 / 1 to 1 / 5) to give tert-butyl 3-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)carbamoyl)pyrrolidine-1-carboxylate [INT7-c] (4.26 g, 9.43 mmol, 59.9% yield) as a yellow oil. m / z: [M-56+H]+ calculated for CHBrFNO3 395.0, 397.0, found 396.6. 1 H NMR (400MHz, CDCl3) δ = 7.55 (br d,J=8.0 Hz, 2H), 7.25 (br s, 2H), 6.22 (br s, 1H), 5.69 (quin, J=8.0 Hz, 1H),3.72 - 3.42 (m, 3H), 3.40 - 3.29 (m, 1H), 3.03 - 2.88 (m, 1H), 2.06 - 2.03 (m,2H), 1.46 (d, J=6.8 Hz, 9H). Synthesis of tert-butyl 3-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)pyrrolidine-1-carboxylate (INT7.3):

[0240] To a solution of tert-butyl 3-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)carbamoyl)pyrrolidine-1-carboxylate [INT7-c] (4.26 g, 9.43 mmol) in DMF (50 mL), CsCO (6.12 g, 18.8 mmol) was added and the reaction mixture was stirred at 25 °C for 1 h. Then, methyl iodide (4.00 g, 28.2 mmol) was 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 × 3). The combined organic layers were washed with brine (100 mL × 2), dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (EtOAc / petroleum ether = 1 / 5 to 1 / 0) to give tert-butyl 3-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)pyrrolidine-1-carboxylate [INT7.3] (2.20 g, 4.73 mmol, 50.2% yield) as a yellow oil. [M-56 + H] calculated for CHBrFNO 409.1, found 409.1. 1 H NMR (400MHz, CDCl3) δ = 7.61 - 7.51(m, 2H), 7.24 (br d, J=6.4 Hz, 2H), 6.61 (q, J=8.8 Hz, 1H), 3.77 - 3.49 (m,3H), 3.46 - 3.36 (m, 1H), 3.33 - 3.21 (m, 1H), 3.14 (s, 1H), 2.89 (s, 2H), 2.25- 2.07 (m, 2H), 1.48 - 1.41 (m, 9H). tert-Butyl (S)-((4-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexyl)methyl)carbamate (Intermediate 7.4): [ka] Synthesis of tert-butyl (S)-((4-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)carbamoyl)cyclohexyl)methyl)carbamate (INT7-d):

[0241] 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 CHCl (20 mL), (S)-1-(4-bromophenyl)-2,2,2-trifluoroethan-1-amine [INT6.1] (1.9 g, 7.47 mmol) was added, and the mixture was stirred at 25° C. for 16 h. The reaction was quenched by adding saturated NaCO (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (200 mL × 2), dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (EtOAc / dichloromethane = 0 / 1 to 1 / 9) to give tert-butyl (S)-((4-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)carbamoyl)cyclohexyl)methyl)carbamate [INT7-d] (2.53 g, 5.12 mmol, 68.7% yield) as a white solid. m / z: [M+H-56] calculated for CHBrFNO 437.1, found 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 (br d,J=6.4 Hz, 2H), 2.31 (br t, J=12.0 Hz, 1H), 1.97 - 1.66 (m, 5H), 1.47 - 1.40 (m,3H), 1.43 (s, 9H), 1.07 - 0.90 (m, 2H). Synthesis of tert-butyl (S)-((4-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexyl)methyl)carbamate (INT7.4):

[0242] A suspension of tert-butyl (S)-((4-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)carbamoyl)cyclohexyl)methyl)carbamate [INT7-d] (1 g, 2.02 mmol) and Cs2CO3 (1.97 g, 6.06 mmol) in DMF (15 mL) was stirred for 1 h. Then, MeI (860 mg, 6.06 mmol) was added, and the resulting mixture was stirred for 3 h. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (100 mL × 2). The combined organic layers were washed with water (200 mL × 2) and brine (200 mL), dried over Na2SO4, and filtered. The filtrate was concentrated to give a residue, which was purified by preparative HPLC (column: Boston Prime C18 150 × 30 mm × 5 μm, column: 54–84% B (A = water (0.05% v / v ammonium hydroxide), B = acetonitrile), flow rate: 30 mL / min, UV detector 220 nm) to give tert-butyl (S)-((4-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexyl)methyl)carbamate [INT7.4] (400 mg, 788 μmol, 39.2% yield) as a white solid. m / z: [M −56 + H] calculated for CHBrFNO 451.1, 453.1, found 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). (1r,4S)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-methoxy-N-methylcyclohexane-1-carboxamide (Intermediate 7.5): [ka] Synthesis of (1r,4S)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-methoxycyclohexane-1-carboxamide (INT7-e):

[0243] 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 CHCl (20 mL) was added (S)-1-(4-bromophenyl)-2,2,2-trifluoroethan-1-amine [INT6.1] (700 mg, 2.75 mmol), and the mixture was stirred at 25° C. for 16 h. The reaction mixture was quenched by adding water (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with saturated NaHCO3 (20 mL) and brine (10 mL × 2), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was purified by silica gel flash 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 [INT7-e] (456 mg, 1.15 mmol, 42.2% yield) as a white solid. m / z: [M+H]+ calculated for CHBrFNO2 394.1, 396.1, found 395.9. 1H 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). Synthesis of (1r,4S)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-methoxy-N-methylcyclohexane-1-carboxamide (INT7.5):

[0244] A mixture of (1r,4S)—N—((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-methoxycyclohexane-1-carboxamide [INT7-e] (455 mg, 1.15 mmol) and CsCO (749 mg, 2.30 mmol) in DMF (1 mL) was stirred at 25° C. for 1 h. CHCl (816 mg, 5.75 mmol) was added, and the mixture was stirred for 2 h. The reaction was quenched by adding water (10 mL) and extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (EtOAc / PE = 0 / 1 to 1 / 3) to give (1r,4S)—N—((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-methoxy-N-methylcyclohexane-1-carboxamide [INT7.5] (130 mg, 318 μmol, 27.7% yield) as a colorless oil. m / z: [M+H] calculated for CHBrFNO 408.1, found 407.8. (1r,4S)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-((tert-butyldimethylsilyl)oxy)-N-methylcyclohexane-1-carboxamide (Intermediate 8.1): [ka] Synthesis of (1r,4S)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-hydroxycyclohexane-1-carboxamide (INT8-a):

[0245] 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 CHCl (20 mL) was added (S)-1-(4-bromophenyl)-2,2,2-trifluoroethan-1-amine [INT6.1] (2 g, 7.87 mmol), and the mixture was stirred at 25° C. for 16 h. The reaction was quenched by adding water (100 mL) and extracted with CHCl (100 mL × 3). The combined organic layers were washed with saturated aqueous NaHCO3 (200 mL × 2) and brine (200 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was purified by silica gel flash 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 [INT8-a] (1.80 g, 4.73 mmol, 60.1% yield) as a white solid. m / z: [M+H]+ calculated for CHBrF3NO2 380.0, 382.0, found 381.7. Synthesis of (1r,4S)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-((tert-butyldimethylsilyl)oxy)-N-methylcyclohexane-1-carboxamide (INT8.1):

[0246] A suspension of (1r,4S)—N—((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-hydroxycyclohexane-1-carboxamide [INT8-a] (500 mg, 1.31 mmol), imidazole (178 mg, 2.62 mmol), and tert-butyl(chloro)dimethylsilane (295 mg, 1.96 mmol) in CHCl (5 mL) was stirred for 12 h at 25° C. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (30 mL × 2). The combined organic layers were washed with saturated Na2CO3 (100 mL × 2) and brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (EtOAc / petroleum ether = 0 / 1 to 5 / 95) to give (1r,4r)-N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-4-[(tertbutyldimethylsilyl)oxy]cyclohexane-1-carboxamide (440 mg, 889 μmol, 68.0% yield) as a white solid. m / z: [M+H]+ calculated for CHBrFNOSi 496.1, found 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).

[0247] 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 CsCO (2.26 g, 6.96 mmol) in DMF (3 mL) was stirred at 20 °C for 1 h. MeI (987 mg, 6.96 mmol) was then added, and the reaction mixture was stirred at 20 °C for 3 h. The reaction mixture was combined with a mixture from an additional identical reaction, poured into water (30 mL), and extracted with EtOAc (30 mL × 2). The combined organic layers were washed with water (50 mL × 2) and brine (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give the crude material. This material was purified by silica gel flash 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 [INT8.1] (495 mg, 973 μmol, 42.3% yield) as a white solid. m / z: [M+H]+ calculated for CHBrFNOSi 508.1, 510.1, found 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). Methyl (S)-(4-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexyl)carbamate (Intermediate 9.1): [ka] Synthesis of tert-butyl (S)-(4-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)carbamoyl)cyclohexyl)carbamate (INT9-a):

[0248] 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 CHCl (2 mL) was added (S)-1-(4-bromophenyl)-2,2,2-trifluoroethan-1-amine [INT6.1] (2.5 g, 5.90 mmol), and the mixture was stirred at 25° C. for 16 h. The reaction mixture was quenched by adding water (30 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine (2 × 50 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (EtOAc / PE = 0 / 1 to 1 / 3) to give tert-butyl (S)-(4-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)carbamoyl)cyclohexyl)carbamate [INT9-a] (2.70 g, 5.63 mmol, 95.7% yield) as a white solid. m / z: [M-Boc] calculated for CHBrFNO 378.1, found 378.9. Synthesis of (S)-4-amino-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)cyclohexane-1-carboxamide hydrochloride (INT9-b):

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

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

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

[0252] To a mixture of (S)—N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-(1,3-dioxoisoindolin-2-yl)-N-methylcyclohexane-1-carboxamide [INT9-d] (300 mg, 573 μmol) in EtOH (1 mL) was added NH NH .HO (143 mg, 2.86 mmol), 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 [INT9-e] (220 mg, 559 μmol, 97.7% yield) as a yellow solid. m / z: [M-NH2]+ calculated for C16H20BrF3N2O 376.1, found 376.1. Synthesis of methyl (S)-(4-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexyl)carbamate (INT9.1):

[0253] To a solution of (S)-4-amino-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methylcyclohexane-1-carboxamide [INT9-e] (90 mg, 228 μmol) and EtN (115 mg, 1.14 mmol) in CHCl (1 mL) was added methyl chloroformate (64.6 mg, 684 μmol) and the mixture was stirred for 1 h. The reaction was quenched by adding water (10 mL) and extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product, which was purified by preparative TLC (EtOAc / PE = 1 / 2) to give methyl (S)-(4-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexyl)carbamate [INT9.1] (60.0 mg, 132 μmol, 58.8% yield) as a colorless oil. m / z: [M+H] calculated for CHBrFNO 451.1, 453.1, found 452.9. Synthesis of (S)-4-acetamido-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methylcyclohexane-1-carboxamide (Intermediate 9.2): [ka]

[0254] To a mixture of (S)-4-amino-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methylcyclohexane-1-carboxamide [INT9-e] (110 mg, 279 μmol) and triethylamine (140 mg, 1.39 mmol) in DCM (1 mL) was added acetyl chloride (76.6 mg, 976 μmol) at 25° C., and the mixture was stirred at 25° C. for 1 h. The reaction mixture was concentrated under reduced pressure to give the crude product (S)-4-acetamido-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methylcyclohexane-1-carboxamide [INT9.2] (120 mg, 275 μmol, 99.1% yield) as a white solid. m / z: [M+H]+ calculated for C18H23BrF3N2O2 435.1, found 435.2. Synthesis of 1-(4-bromophenyl)-N-methylethan-1-amine (Intermediate 10.1): [ka]

[0255] To a solution of 1-(4-bromophenyl)ethan-1-one [INT10-a] (10 g, 50.3 mmol) in MeOH (100 mL) was added sodium cyanoborohydride (8.79 g, 140 mmol) and methanamine hydrochloride (31.5 g, 468 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 × 2). The combined organic layers were washed with brine (2 × 50 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (EtOAc / PE = 0 / 1 to 1 / 0) to give 1-(4-bromophenyl)-N-methylethan-1-amine [INT10.1] (7.50 g, 32.8 mmol, 65.2% yield) as a colorless oil. m / z: [M+H]+ calculated for C9H13BrN 214.0, found 213.9. Synthesis of N-(1-(4-bromophenyl)ethyl)-N-methylcyclobutanecarboxamide (Intermediate 11.1): [ka]

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

[0257] To a mixture of [1-(4-bromophenyl)ethyl](methyl)amine [INT10.1] (500 mg, 2.33 mmol) and HATU (1.32 g, 3.49 mmol) in CHCl (10 mL) was added DIPEA (902 mg, 6.98 mmol) and cyclohexanecarboxylic acid [INT11-b] (447 mg, 3.49 mmol). The reaction mixture was stirred under nitrogen at 20 °C for 16 h. 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 NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel flash chromatography (petroleum ether:ethyl acetate=5:1) to give N-[1-(4-bromophenyl)ethyl]-N-methylcyclohexanecarboxamide [INT11.2] (700 mg, 2.15 mmol, 92.7% yield) as a colorless oil. m / z: [M+H]+ calculated for CHBrNO 324.1, 326.1, found 326.1. Synthesis of N-[1-(4-bromophenyl)ethyl]-N-methylcyclopentanecarboxamide (Intermediate 11.3): [ka]

[0258] To a mixture of cyclopentanecarboxylic acid [INT11-c] (63.9 mg, 560 μmol) and HATU (266 mg, 700 μmol) in CHCl (3 mL) was added DIPEA (180 mg, 1.40 mmol) and [1-(4-bromophenyl)ethyl](methyl)amine [INT10.1] (100 mg, 467 μmol). The reaction mixture was stirred under nitrogen at 20 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give 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 NaSO, and concentrated under reduced pressure to give N-[1-(4-bromophenyl)ethyl]-N-methylcyclopentanecarboxamide [INT11.3] (110 mg, 354 μmol, 76.3% yield) as a colorless oil. m / z: [M+H]+ calculated for C15H21BrNO 310.1, 312.1, found 312.1. Synthesis of N-(1-(4-bromophenyl)ethyl)-N-methylacetamide (Intermediate 12.1): [ka]

[0259] To a mixture of 1-(4-bromophenyl)-N-methylethan-1-amine [INT10.1] (100 mg, 467 μmol) in DCM (2 mL) was added triethylamine (235 mg, 2.33 mmol) and acetyl chloride (127 mg, 1.63 mmol). The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (EtOAc / PE = 0 / 1 to 1 / 3) to give N-(1-(4-bromophenyl)ethyl)-N-methylacetamide [INT12.1] (100 mg, 390 μmol, 84.0% yield) as a yellow oil. m / z: [M+H]+ calculated for CHBrNO 256.0, 258.0, found 257.9. Synthesis of N-[1-(4-bromophenyl)ethyl]-N-methylcyclopropanecarboxamide (Intermediate 12.2): [ka]

[0260] To a mixture of [1-(4-bromophenyl)ethyl](methyl)amine [INT10.1] (740 mg, 3.45 mmol) and triethylamine (349 mg, 3.45 mmol) in CHCl (10 mL) was added cyclopropanecarbonyl chloride [INT12-a] (1.25 g, 12.0 mmol) at 25° C., and the mixture was stirred at 25° C. for 12 h. The reaction mixture was concentrated under reduced pressure to give N-[1-(4-bromophenyl)ethyl]-N-methylcyclopropanecarboxamide [INT12.2] (556 mg, 1.97 mmol) as a brown oil. m / z: [M+H] calculated for CHBrNO 282.0, found 282.1. Synthesis of N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methylacetamide (Intermediate 13.1): [ka] Synthesis of (E)-N-(4-bromobenzylidene)-2-methylpropane-2-sulfinamide (INT13-a):

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

[0262] Neat trimethyl(trifluoromethyl)silane (4.29 g, 30.2 mmol) was added to a stirred solution of tetrabutylazanium acetate (3.64 g, 12.1 mmol) and (E)-N-(4-bromobenzylidene)-2-methylpropane-2-sulfinamide [INT13-a] (3.5 g, 12.1 mmol) in DMF (30 mL) at 0 °C. The mixture was stirred at 0–5 °C for 3 h. The mixture was 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 [INT13-b] (3.50 g, 9.77 mmol, 80.8% yield) as an off-white solid. 1 H 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 (quin, J=8.6 Hz, 1H), 1.14 (s, 9H). Synthesis of 1-(4-bromophenyl)-2,2,2-trifluoroethan-1-amine (INT13-c):

[0263] 4 M HCl in dioxane (9.75 mL, 39.0 mmol) was added to a suspension of N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide [INT13-b] (3.5 g, 9.77 mmol) in methanol (20 mL), and the reaction mixture was stirred at 20 °C for 1 h. 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-trifluoroethan-1-amine [INT13-c] (2.16 g, 8.50 mmol, 87.0% yield) as a brown oil. m / z: [M-NH2]+ calculated for C8H7BrF3N 237.0, found 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). Synthesis of N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)acetamide [INT13-d]:

[0264] To a solution of 1-(4-bromophenyl)-2,2,2-trifluoroethan-1-amine [INT13-c] (2.7 g, 8.50 mmol) and triethylamine (1.72 g, 17.0 mmol) in CHCl (30 mL) was added acetyl chloride (996 mg, 12.7 mmol), and the reaction mixture was stirred at 20° C. for 12 h. The reaction was diluted with CHCl (50 mL), washed with water (50 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (50% ethyl acetate in PE) to give N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)acetamide [INT13-d] (2.50 g, 8.44 mmol, 99.6% yield) as an off-white solid. m / z: [M+H]+ calculated for C10H10BrF3NO 296.0, 298.0, found 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). Synthesis of N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methylacetamide (INT13.1):

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

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

[0267] To 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 4 M HCl in dioxane (20 mL). The mixture was stirred at 20 °C for 1.5 h. The mixture was concentrated under reduced pressure to give the 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 × 2). The aqueous phase was basified to pH = 9-10 with 2 N NaOH and extracted with CHCl (50 mL × 2). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product (R)-1-(4-bromophenyl)-2,2,2-trifluoroethan-1-amine [INT14-b] (3.50 g, 13.7 mmol, 61.8% yield) as a yellow solid. m / z: [M+H] calculated for CHBrFN 254.0, 256.0, found 254.1. Synthesis of (R)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide (INT14-c):

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

[0269] To a solution of (R)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide [INT14-c] (1 g, 2.41 mmol) in DMF (10 mL) was added CsCO (1.57 g, 4.82 mmol), and the reaction mixture was stirred at 25 °C for 1 h. Methyl iodide (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), which was then extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL × 2), dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (PE / EtOAc = 1 / 0 to 1 / 1) to give (R)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide [INT14.1] (700 mg, 1.63 mmol, 67.9% yield) as a colorless oil. m / z: [M+H]+ calculated for CHBrFNOS 428.0, 430.0, found 430.1. Synthesis of (S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoro-N-methylethan-1-amine hydrochloride (Intermediate 15.1): [ka] Synthesis of (R,E)-N-(4-bromo-2-methylbenzylidene)-2-methylpropane-2-sulfinamide (INT15-b):

[0270] (R)-2-Methylpropane-2-sulfinamide (12.1 g, 100 mmol) and 4-bromo-2-methylbenzaldehyde [INT15-a] (10 g, 50.2 mmol) were dissolved in tetrahydrofuran (50 mL), and titanium ethoxide (34.2 g, 150 mmol) was added. The mixture was stirred at 25 °C for 10 h. The reaction mixture was then poured into water (500 mL) and extracted with EtOAc (3 × 300 mL). The organic extracts were combined, dried over Na2SO4, and evaporated in vacuo. The residue was purified by flash chromatography (hexane / MTBE = 1 / 0 to 0 / 1) to give (R,E)-N-(4-bromo-2-methylbenzylidene)-2-methylpropane-2-sulfinamide [INT15-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=8.7Hz, 1H), 7.46 - 7.37 (m, 2H), 2.56 (s, 3H), 1.24 (s, 9H). Synthesis of (R)-N-((S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide (INT15-c):

[0271] (R,E)-N-(4-Bromo-2-methylbenzylidene)-2-methylpropane-2-sulfinamide [INT15-b] (18.8 g, 62.2 mmol) and tetrabutylammonium triphenyldifluorosilicate (50.3 g, 93.3 mmol) were dissolved in THF (300 mL). Trifluoromethyltrimethylsilane (44.2 g, 311 mmol) was added dropwise at -80 °C. The mixture was stirred at -30 °C for 30 minutes, after which aqueous NH4Cl (200 mL) was added. The mixture was extracted with EtOAc (2 × 200 mL). The organic phase was dried over sodium sulfate and evaporated in vacuo at 45 °C. The residue was purified by flash chromatography to give (R)—N—((S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide [INT15-c] (19.0 g, 51.0 mmol, 82.2% yield) as a pale yellow oil. m / z: [M+H] calculated for CHBrFNOS 372.0, found 372.2. 1 H 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). Synthesis of (R)-N-((S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethyl)-N,2-dimethylpropane-2-sulfinamide (INT15-d):

[0272] (R)-N-((S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide [INT15-c] (10 g, 26.8 mmol) was dissolved in THF (300 mL). Lithium bis(trimethylsilyl)amide (74.3 mL, 80.3 mmol) was added at 0° C. The mixture was stirred at 0° C. for 20 minutes. Methyl iodide (22.7 g, 160 mmol) was added. The mixture was stirred at 20° C. for 10 hours, after which aqueous NH4Cl (50 mL) was added. The mixture was extracted with EtOAc (2×30 mL). The organic phase was dried over sodium sulfate and evaporated in vacuo at 45° C. to give crude (R)—N—((S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethyl)-N,2-dimethylpropane-2-sulfinamide [INT15-d] (8.50 g, 22.0 mmol, 82.5% yield) as a brown oil. m / z: [M+H] calculated for CHBrFNOS 386.0, 388.0, found 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). Synthesis of (S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoro-N-methylethan-1-amine hydrochloride (INT15.1):

[0273] (R)-N-((S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethyl)-N,2-dimethylpropane-2-sulfinamide [INT15-d] (10 g, 25.8 mmol) was dissolved in methanol (20 mL). Hydrogen chloride (4 M in 1,4-dioxane, 100 mL, 2.36 mol) was added. The mixture was stirred at 20° C. for 10 hours. The mixture was evaporated in vacuo at 50° C. MTBE (100 mL) was added. The formed solid was filtered and washed with MTBE (100 mL) to give (S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoro-N-methylethan-1-amine hydrochloride [INT15.1] (6.27 g, 19.6 mmol, 76.3% yield) as a white solid. m / z: [M+H]+ calculated for C10H12BrF3N 282.0, 284.0, found 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). Synthesis of (S)-1-(4-bromo-3-methylphenyl)-2,2,2-trifluoro-N-methylethan-1-amine hydrochloride (Intermediate 15.2): [ka] Synthesis of (R,E)-N-(4-bromo-3-methylbenzylidene)-2-methylpropane-2-sulfinamide (INT15-f):

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

[0275] (R,E)-N-(4-Bromo-3-methylbenzylidene)-2-methylpropane-2-sulfinamide [INT15-f] (21 g, 69.4 mmol) and tetrabutylammonium triphenyldifluorosilicate (56.1 g, 104 mmol) were dissolved in THF (500 mL). Trifluoromethyltrimethylsilane (49.3 g, 347 mmol) was added dropwise at −80° C. The mixture was stirred at −30° C. for 30 minutes, after which aqueous NH4Cl (300 mL) was added. The mixture was extracted with EtOAc (2×300 mL). The organic phase was dried over sodium sulfate and evaporated in vacuo at 45° C. The residue was purified by flash chromatography to give (R)—N—((S)-1-(4-bromo-3-methylphenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide [INT15-g] (18.5 g, 49.7 mmol, 71.7% yield) as a white solid. m / z: [M+H] calculated for CHBrFNOS 372.0, found 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). Synthesis of (R)-N-((S)-1-(4-bromo-3-methylphenyl)-2,2,2-trifluoroethyl)-N,2-dimethylpropane-2-sulfinamide (INT15-h):

[0276] (R)—N—((S)-1-(4-bromo-3-methylphenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide [INT15-g] (10 g, 26.8 mmol) was dissolved in THF (200 mL). Lithium(1+) bis(trimethylsilyl)azanide (74.3 mL, 80.3 mmol) was added at 0° C. The mixture was stirred at 0° C. for 20 minutes. Methyl iodide (22.7 g, 160 mmol) was added. The mixture was stirred at 20° C. for 10 hours, after which aqueous NH4Cl (200 mL) was added. The mixture was extracted with EtOAc (2×200 mL). The organic phase was dried over sodium sulfate and evaporated in vacuo at 45° C. to give crude (R)—N—((S)-1-(4-bromo-3-methylphenyl)-2,2,2-trifluoroethyl)-N,2-dimethylpropane-2-sulfinamide [INT15-h] (9.09 g, 23.5 mmol, 88.2% yield) as a brown oil. m / z: [M+H] calculated for CHBrFNOS 386.0, found 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). Synthesis of (S)-1-(4-bromo-3-methylphenyl)-2,2,2-trifluoro-N-methylethan-1-amine hydrochloride (INT15.2):

[0277] (R)-N-((S)-1-(4-bromo-3-methylphenyl)-2,2,2-trifluoroethyl)-N,2-dimethylpropane-2-sulfinamide [INT15-h] (10.7 g, 27.7 mmol) was dissolved in methanol (20 mL), and then hydrogen chloride (4 M in 1,4-dioxane, 100 mL, 2.54 mol) was added. The mixture was stirred at 20 °C for 10 hours, after which it was evaporated in vacuo at 50 °C. MTBE (100 mL) was added. The formed solid was filtered and washed with MTBE (50 mL) to give (S)-1-(4-bromo-3-methylphenyl)-2,2,2-trifluoro-N-methylethan-1-amine hydrochloride [INT15.2] (5.41 g, 16.9 mmol, 61.3% yield) as a beige solid. m / z: [M+H]+ calculated for C10H12BrF3N 282.0, 284.0, found 284.0. 1 H NMR (500 MHz, DMSO-d6 ) δ 10.51 (s, 2H), 7.76 (d, J=8.3Hz, 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). Synthesis of (S)-N-(1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethyl)-N-methylcyclobutanecarboxamide (Intermediate 16.1): [ka]

[0278] (S)-1-(4-Bromo-2-methylphenyl)-2,2,2-trifluoro-N-methylethan-1-amine hydrochloride [INT15.1] (0.2 g, 0.6278 mmol) and cyclobutanecarboxylic acid (125 mg, 1.25 mmol) were mixed in pyridine (2 mL), followed by the addition of phosphorus oxychloride (211 mg, 1.38 mmol). The mixture was stirred at 90 °C for 10 h. EtOAc (20 mL) was added, and the mixture was washed with aqueous NaHSO (3 × 5 mL). The organic phase was dried over sodium sulfate and evaporated in vacuo at 45° C. to give (S)—N-(1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethyl)-N-methylcyclobutanecarboxamide [INT16.1] (190 mg, 0.5216 mmol, 83.3% yield) as a yellow oil. m / z: [M+H] calculated for CHBrFNO 364.1, 366.1, found 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). Synthesis of N-[(1S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethyl]-N-methylcyclopropanecarboxamide (Intermediate 16.2): [ka]

[0279] [(1S)-1-(4-Bromo-2-methylphenyl)-2,2,2-trifluoroethyl](methyl)amine hydrochloride [INT15.1] (0.2 g, 0.6278 mmol) and cyclopropanecarboxylic acid (107 mg, 1.25 mmol) were mixed in pyridine (2 mL). Then, phosphorus oxychloride (211 mg, 1.38 mmol) was added. The mixture was stirred at 90 °C for 10 h. EtOAc (20 mL) was added. The mixture was washed with aqueous NaHSO (3 × 5 mL). The organic phase was dried over sodium sulfate and evaporated in vacuo at 45° C. to give N-[(1S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethyl]-N-methylcyclopropanecarboxamide [INT16.2] (190 mg, 0.5425 mmol, 86.7% yield) as a pale yellow solid. m / z: [M+H] calculated for CHBrFNO 350.0, found 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). N-[(1S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ 6 Synthesis of -thiane-4-carboxamide (Intermediate 16.3): [ka]

[0280] Phosphorus oxychloride (788 mg, 5.14 mmol) was dissolved in pyridine (3 mL) with [(1S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethyl](methyl)amine hydrochloride [INT15.1] (500 mg, 1.56 mmol) and 1,1-dioxo-1λ 6To a solution of N-thiane-4-carboxylic acid [INT4-a] (833 mg, 4.68 mmol) was added at 0°C. The reaction mixture was stirred overnight. Aqueous sodium bicarbonate (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 conditions below) to give N-[(1S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ 6 -thiane-4-carboxamide [INT16.3] (132 mg, 0.2985 mmol, 19.1% yield) was obtained as a pink solid. m / z: [M+H]+ calculated for C16H20BrF3NO3S 442.0, 444.0, found 444.0.

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

[0282] (S)-1-(4-Bromo-3-methylphenyl)-2,2,2-trifluoro-N-methylethan-1-amine hydrochloride [INT15.2] (0.2 g, 0.6278 mmol) and cyclobutanecarboxylic acid (125 mg, 1.25 mmol) were mixed in pyridine (2 mL), 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 NaHSO (3×5 mL). The organic extract was dried over sodium sulfate and evaporated in vacuo at 35° C. to give (S)—N-(1-(4-bromo-3-methylphenyl)-2,2,2-trifluoroethyl)-N-methylcyclobutanecarboxamide [INT17.1] (228 mg, 0.6260 mmol, 100% yield) as a yellow oil. m / z: [M+H] calculated for CHBrFNO 364.0, 366.0, found 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). Synthesis of N-[(1S)-1-(4-bromo-3-methylphenyl)-2,2,2-trifluoroethyl]-N-methylcyclopropanecarboxamide (Intermediate 17.2): [ka]

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

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

[0285] To a suspension of (1r,4S)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-((tert-butyldimethylsilyl)oxy)-N-methylcyclohexane-1-carboxamide [INT8.1] (100 mg, 196 μmol), 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-amine hydrochloride [INT1.1] (67.0 mg, 254 μmol), CsCO (127 mg, 392 μmol), and Xantphos (22.6 mg, 39.2 μmol) in dioxane (3 mL) was added Pd(dba) (17.9 mg, 19.6 μmol). The resulting mixture was stirred at 100 °C under N for 4 h. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (15 mL × 3). The combined organic layers were washed with brine (50 mL × 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 [INT18.1] (100 mg, 152 μmol, 78.1% yield) as a yellow oil. m / z: [M+H]+ calculated for CH3ClF3NO3Si 655.3, found 655.2. Synthesis of methyl (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 (Intermediate 18.2): [ka]

[0286] A suspension of 2-chloro-7-(propan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-amine hydrochloride [INT1.2] (35 mg, 141 μmol), methyl (1S,4r)-4-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexane-1-carboxylate [INT5.4] (61.5 mg, 141 μmol), cesium carbonate (137 mg, 423 μmol), tris(dibenzylideneacetone)dipalladium (6.45 mg, 7.05 μmol), and Xantphos (8.15 mg, 14.1 μmol) in dioxane (2 mL) was stirred at 100 °C for 1.5 h under N. The mixture was concentrated under reduced pressure to give the crude product, which was purified by silica gel flash chromatography (MeOH / dichloromethane = 0 / 1 to 1 / 99) to give methyl (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] (38.5 mg, 67.9 μmol, 48.1% yield) as a yellow solid. m / z: [M+Na]+ calculated for CHClFNONa 589.2, found 589.3. Synthesis of 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 (Intermediate 18.3) [ka]

[0287] To a mixture of methyl (1S,3r)-3-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclobutane-1-carboxylate [INT5.12] (0.1 g, 0.2449 mmol), 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-amine [the free base of INT1.1] (55.5 mg, 244 μmol), and cesium carbonate (239 mg, 734 μmol) in dioxane (3 mL) was purged with argon. Next, tris(dibenzylideneacetone)dipalladium (11.1 mg, 12.2 μmol) and Xantphos (14.1 mg, 24.4 μmol) were added under argon, and the reaction mixture was stirred at 100 °C for 10 h. The reaction mixture was cooled, then diluted with MTBE (50 mL), filtered, and the filtrate was concentrated under reduced pressure to give 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] (68.0 mg, 0.1225 mmol, 50.3% yield) as a yellow oil. m / z: [M+H] calculated for CHClFNO 555.2, found 555.0. Exemplary Compounds of Formula (I)

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

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

[0290] To determine potency, 1 μL of serially diluted compound (in 100% DMSO) was pre-incubated with 40 μL of enzyme for 30 minutes. The reaction was initiated by adding 10 μL of peptide substrate. Relative fluorescence units were converted to percent inhibition by using 0% and 100% inhibition controls as references. The 100% inhibition control was (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 (IC) at a final concentration of 1 μM. 50 = 15 nM), while the 0% inhibition control consisted of 2% DMSO. 50 Values ​​were calculated by fitting the concentration-response curves to a four-parameter logistic equation in GraphPad Prism.

[0291] The results from this assay are summarized in Table 2 below. In this table, "A" indicates an IC<0.1 μM 50 "B" indicates IC from 0.1 μM to 1 μM 50 "C" indicates IC greater than 1 μM 50 "N / A" indicates not tested. For compounds tested in more than one experiment, the results shown represent the mean. [Table 2-1] [Table 2-2] [Table 2-3] Example 3 Jurkat IL-2 assay

[0292] Inhibition was determined using a Jurkat (ATCC, clone E6.1) immortalized T cell line exposed to compound dose-response in a cell-based assay and assessed for viability, and Il-2 inhibition was determined by ELISA. Cells were cultured in RPMI / 10% FBS (Invitrogen 11875093, Atlanta Biologicals S12450H), maintained at <3E6 / mL, and used in the assay for no more than 25 passages. Compounds were stamped onto 384-well plates (PerkinElmer Culturplate, 6007680) by ECHO. Cells were plated on top of the compound in fresh medium, incubated for 30 minutes, and then stimulated with soluble anti-CD3 / 28 / 2 (Stemcell, 10970) for 24 hours. Supernatants were collected and assayed for Il-2 (MSD, 384-well, L21SA-1). To assess the viability of compound-treated cells, cells were lysed with CTG reagent (Promega, G7570) and measured by luminometer. IL-2 curves were calculated as a percentage of the DMSO (100%) control 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) control. IC 50 was calculated using a four-parameter fit in GraphPad Prism.

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

[0294] Human plasma protein binding of various compounds of formula (I) was assessed using the equilibrium dialysis method described herein. Preparation of dialysis membrane and matrix

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

[0296] On the day of the experiment, human plasma (BioIVT, catalog number HUMANPLNHPNN, sodium heparin or EDTA-K2 anticoagulant, pooled from multiple individuals) 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 between 7.0 and 8.0. Dialysis Procedure

[0297] Test compounds and warfarin control (Stru Chem, Catalog No. SC-16139) were dissolved in dimethyl sulfoxide (DMSO) to obtain a 10 mM stock solution. A working solution in DMSO was prepared at 400 μM. To prepare the loading matrix, 5 μL of the compound working solution was added to 995 μL of blank human plasma at a 1:200 ratio and mixed thoroughly.

[0298] Time 0 (T0) samples to be used for recovery determination were prepared as follows: 50 μL aliquots of loading matrix were transferred in triplicate to a sample collection plate. Samples were immediately matched with the reverse blank buffer (basic solution (14.2 g / L Na2HPO4 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 at 2–8 °C for further processing along with the other post-dialysis samples.

[0299] To load the dialysis device (96-well equilibrium dialysis plate, model 96b, catalog number 1006, HTDialysis LLC, Gales Ferry, CT, USA), 150 μL aliquots of loading matrix were transferred in triplicate to the donor side of each dialysis well, and 150 μL of dialysis buffer was loaded into the receiver side of the well. The dialysis plate was placed in a humidified incubator at 37°C with 5% CO on a shaking platform and rotated slowly (approximately 100 rpm) for 4 hours.

[0300] At the end of dialysis, 50 μL aliquots of samples were taken from both the buffer and matrix sides of the dialysis device. These samples were transferred to a new 96-well plate (polypropylene, 2.2 mL / well, catalog number DWP-22-96-SQ-UCL, Apricot). Each sample was mixed with an equal volume of the inverse blank matrix (buffer or matrix) to reach a final volume of 100 μL of 1:1 matrix / dialysis buffer (v / v) in each well. All samples were further processed by adding 500 μL of stop solution containing an internal standard. The mixture was vortexed and centrifuged at 4000 rpm for approximately 20 minutes. A 100 μL aliquot of the supernatant from all samples was then removed for LC-MS / MS analysis. The concentrations of the test compounds in the matrix and buffer samples were expressed as the analyte / internal standard peak area ratio (PAR) (no standard curve).

[0301] Single blank samples were prepared by transferring 50 μL of blank matrix to a 96-well plate (polypropylene, 2.2 mL / well, catalog number DWP-22-96-SQ-UCL, Apricot) and adding 50 μL of blank PBS buffer to each well. The blank plasma must match the plasma species used on the plasma side of the well. The matrix-matched samples were then further processed by adding 500 μL of stop solution containing the internal standard, following the same sample processing method as the dialyzed samples. Data Calculation

[0302] The % unbound value was calculated using the following equation: % unbound = 100 × F / T, where [F] is the analyte concentration or analyte / internal standard peak area ratio on the buffer (receiver) side of the membrane, and [T] is the analyte concentration or analyte / internal standard peak area ratio on the matrix (donor) side of the membrane.

[0303] The results from this assay are summarized below in Table 4. In this table, "A" indicates that the % unbound compound was less than 8%, "B" indicates that the % unbound compound was between 8% and 20%, and "C" indicates that the % unbound compound was greater than 20%. [Table 4-1] [Table 4-2] Example 5 Thermodynamic solubility (Ts) assay in fasted-state simulated intestinal fluid (FaSSIF)

[0304] The solubility of various compounds of formula (I) was determined using a thermodynamic solubility assay. The thermodynamic solubility assay used a shake flask method followed by HPLC-UV analysis. The following stepwise procedure was followed:

[0305] At least 2.0 mg of sample was weighed into the lower chamber of a Whatman mini-uniprep vial (catalog number UN203NPUORG), and 450 μL of FaSSIF medium (0.056% (w / v) lecithin, 0.161% (w / v) sodium taurocholate, 0.39% (w / v) monobasic potassium phosphate, 0.77% (w / v) potassium chloride, deionized HO, pH 6.5) was added to each vial.

[0306] After adding the buffer, the filter piston of the mini-uniprep vial was lowered to the liquid level to ensure full contact of the filter with the buffer and compound during incubation.

[0307] The samples were then vortexed for 2 minutes and then incubated at 25°C with shaking (880 rpm) for 24 hours.

[0308] The samples were then centrifuged at 4000 rpm (20°C) for 10 minutes.

[0309] The miniuniprep was then compressed to prepare a filtrate, and the test concentration of the compound in the filtrate was determined using HPLC-UV (Waters XBridge C18, 4.6 × 100 mm column, mobile phase A: 0.1% TFA in HO, mobile phase B: 0.1% TFA in acetonitrile). At least five UV standard solutions (e.g., amiodarone hydrochloride, carbamazepine, dexamethasone) were injected into the HPLC in order from lowest to highest concentration, followed by testing the supernatant for thermodynamic solubility in duplicate. The solubility of the tested compounds is expressed in μg / mL.

[0310] The results from this assay are summarized below in Table 5, where "A" indicates a solubility of less than 250 μg / mL, "B" indicates a solubility between 250 μg / mL and 1750 μg / mL, and "C" indicates a solubility of greater than 1750 μg / mL. [Table 5] Equivalents and Scope

[0311] In the claims, articles such as "a," "an," and "the" can mean one or more than one, unless otherwise indicated or otherwise clear from the context. A claim or description containing "or" between one or more members of a group is considered to be satisfied when one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process, unless otherwise indicated or otherwise clear from the context. The invention includes embodiments in which only one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one or all of the group members are present in, employed in, or otherwise relevant to a given product or process.

[0312] Furthermore, the present invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the enumerated claims are introduced into another claim. For example, any claim that is dependent on another claim can be amended to include one or more limitations found in any other claim that is dependent on the same base claim. Where multiple elements are presented as a list, e.g., in Markush group format, each subgroup of those elements is also disclosed, and any element(s) can be removed from the group. In general, when the invention or aspects of the invention are referred to as including particular elements and / or features, it is understood that a particular embodiment of the invention or aspect of the invention consists of or consists essentially of such elements and / or features. For purposes of simplicity, those embodiments are not specifically described herein in these terms. Also, note that the terms "comprising" and "comprising" are intended to be open and allow for the inclusion of additional elements or steps. Where ranges are given, both ends are included. Furthermore, unless otherwise indicated or otherwise apparent from the context and the understanding of one of ordinary skill in the art, values ​​expressed as ranges can assume any particular value or subrange within the ranges described in various embodiments of the invention to the tenth of the unit of the lower limit of that range, unless otherwise clearly indicated by context.

[0313] This application refers to various issued patents, published patent applications, papers, and other publications, all of which are incorporated herein by reference. In the event of a conflict between any of the incorporated references and this specification, this specification shall control. In addition, any particular embodiment of the present invention that falls within the prior art may be expressly excluded from any one or more of the claims. Such embodiments may be excluded even if the exclusion is not expressly set forth herein because they are deemed to be known to those skilled in the art. Any particular embodiment of the present invention may be excluded from any claim for any reason, regardless of whether it relates to the existence of prior art.

[0314] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments described herein. The scope of the embodiments of the invention described herein is not intended to be limited to the foregoing description, but rather is as set forth in the appended claims. Those skilled in the art will recognize that various changes and modifications to this description can be made without departing from the spirit or scope of the invention as defined in the following claims. The present invention provides, for example, the following items. (Item 1) Compounds represented by formula (I) [ka] ...

Claims

1. Compounds represented by formula (I) [Chemical 160] or a pharmaceutically acceptable salt thereof, R １ is C １～６ Alkyl, C １～６ Alkoxy, C ３～６ cycloalkyl, and 5- to 10-membered heterocyclyl, １～６ Alkyl, C ３～６ Cycloalkyl and 5- to 10-membered heterocyclyl are R １ａ and wherein, when said 5- to 10-membered heterocyclyl contains a substitutable ring nitrogen atom, said ring nitrogen atom is optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from R １ｂ and when said 5- to 10-membered heterocyclyl contains a substitutable ring sulfur atom, said ring sulfur atom is optionally substituted with two O atoms; R ２ is CH ３ or CF ３ and R ３ is C １～６ alkyl, and R 3 is optionally substituted with C 1-4 alkoxy; R ４ is C １～６ is alkyl, R １ａ Each occurrence represents cyano, halogen, hydroxyl, oxo, C １～６ Alkyl, —C(O)OR Ａ , -C(O)N(R Ａ ) ２ , -N(R Ａ ) ２ , C １～６ independently selected from the group consisting of alkoxy, 5- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl; １～６ Alkyl is —N(R Ａ ) ２ wherein if said 5- to 6-membered heterocyclyl contains a substitutable ring nitrogen atom, said ring nitrogen atom may be optionally substituted by R Ｂ and optionally substituted by R １ｂ is 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) ２ C １～６ is selected from the group consisting of alkyl, R Ａ Each occurrence of represents hydrogen, C １～６ Alkyl, —C(O)C １～６ Alkyl, and —C(O)OC １～６ independently selected from the group consisting of alkyl, R Ｂ is C １～６ Alkyl, C ３～６ cycloalkyl, and —C(O)OC １～６ is selected from the group consisting of alkyl, t is 0 or 1].

2. R ２ But CH ３ 2. The compound of claim 1, wherein:

3. R ２ But CF ３ 2. The compound of claim 1, wherein:

4. R ３ But C １～６ The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R is alkyl.

5. R ３ but, 【Chemistry 161】 5. The compound according to any one of claims 1 to 4, wherein:

6. R ３ But C １～６ alkyl, and R ３ But C １～４ The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, which is substituted with alkoxy.

7. R ３ but, 【Chemistry 162】 7. The compound according to any one of claims 1 to 3 and 6, or a pharmaceutically acceptable salt thereof, wherein:

8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein t=0.

9. 8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein t=1.

10. R ４ But C １～６ 10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein: R is alkyl;

11. R ４ But CH ３ 11. The compound of claim 9 or 10, wherein:

12. Compounds represented by formula (Ib) 【Chemical 163】 or a pharmaceutically acceptable salt thereof, R １ is C １～６ Alkyl, C ３～６ cycloalkyl, or 5- to 10-membered heterocyclyl, ３～６ Cycloalkyl is R １ａ and wherein, when said 5- to 10-membered heterocyclyl contains a substitutable ring nitrogen atom, said ring nitrogen atom is optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from R １ｂ and when said 5- to 10-membered heterocyclyl contains a substitutable ring sulfur atom, said ring sulfur atom is optionally substituted with two O atoms; R １ａ Each occurrence represents cyano, halogen, hydroxyl, C １～６ Alkyl, —C(O)OR Ａ , -C(O)N(R Ａ ) ２ , -N(R Ａ ) ２ , C １～６ alkoxy, and 5- to 6-membered heteroaryl; １～６ Alkyl is —N(R Ａ ) ２ , where necessary, R １ｂ is 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) ２ C １～６ is selected from the group consisting of alkyl, R Ａ Each occurrence of represents hydrogen, C １～６ Alkyl, —C(O)C １～６ Alkyl, and —C(O)OC １～６ alkyl].

13. R １ But C １～６ 13. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein:

14. R １ But CH ３ 14. The compound according to any one of claims 1 to 13, wherein:

15. R １ But C ３～６ is cycloalkyl, and R １ But, R １ａ 13. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, optionally substituted on one or more available carbons with one, two, three, or more substituents each independently selected from:

16. R １ But C ３～６ 16. The compound of any one of claims 1 to 12 and 15, or a pharmaceutically acceptable salt thereof, which is cycloalkyl.

17. R １ but, 【Chemistry 164】 17. The compound of any one of claims 1 to 12, 15, and 16, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

18. R １ But C ３～６ is cycloalkyl, and R １ But, R １ａ 16. The compound of any one of claims 1 to 12 and 15, or a pharmaceutically acceptable salt thereof, substituted on one or more available carbons with one, two, three or more substituents each independently selected from:

19. R １ but, 【Chemistry 165】 19. The compound of any one of claims 1 to 12, 15, and 18, or a pharmaceutically acceptable salt thereof, wherein:

20. R １ａ is cyano, fluoro, hydroxyl, —O—CH ３ , -C(O)OH, -C(O)NH ２ , 【Chemistry 166】 【Chemistry 167】 20. The compound of any one of claims 1 to 12, 15, 18, and 19, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

21. R １ but, 【Chemical 168】 【Chemistry 169】 21. The compound of any one of claims 1 to 12, 15, and 18 to 20, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

22. R １ but, 【Chemistry 170】 【Chemistry 171】 12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

23. R １ is a 5- to 10-membered heterocyclyl, where R １ contains a substitutable ring nitrogen atom, said ring nitrogen atom is １ｂ and when the 5- to 10-membered heterocyclyl contains a substitutable ring sulfur atom, the ring sulfur atom is optionally substituted with two O atoms, or a pharmaceutically acceptable salt thereof.

24. R １ 24. The compound of any one of claims 1 to 12 and 23, or a pharmaceutically acceptable salt thereof, wherein is 5-10 membered heterocyclyl.

25. R １ but, 【Chemistry 172】 25. The compound of any one of claims 1 to 12, 23, and 24, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

26. R １ but, 【Chemistry 173】 24. The compound of any one of claims 1 to 12 and 23, wherein:

27. R １ but, 【Chemistry 174】 24. The compound of any one of claims 1 to 12 and 23, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

28. R １ｂ But CH ３ , 【Chemistry 175】 28. The compound of any one of claims 1 to 12, 23, and 27, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

29. R １ but, 【Chemistry 176】 【Chemistry 177】 29. The compound of any one of claims 1 to 12, 23, 27, and 28, selected from the group consisting of:

30. R １ but, 【Chemistry 178】 【Chemistry 179】 【Chemistry 180】 13. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

31. R １ But CH ３ , 【Chemistry 181】 【Chemistry 182】 【Chemistry 183】 12. The compound of claim 1, wherein the compound is selected from the group consisting of:

32. R １ But CH ３ , 【Chemistry 184】 【Chemistry 185】 【Chemical 186】 13. The compound of claim 12, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

33. The following 【Chemistry 187】 【Chemical 188】 【Chemical 189】 【Chemistry 190】 【Chemistry 191】 【Chemistry 192】 【Chemistry 193】 【Chemistry 194】 【Chemistry 195】 【Chemistry 196】 1. A compound selected from any of the compounds set forth in 1. above, or a pharmaceutically acceptable salt thereof.

34. 34. A pharmaceutical composition comprising a compound according to any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

35. A composition comprising a compound of any one of claims 1 to 33 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 34, for treating cancer in a subject in need thereof.

36. 35. A composition comprising a compound according to any one of claims 1 to 33 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 34, for treating an autoimmune or inflammatory disorder or disease in a subject in need thereof.

37. 37. The composition of claim 36, wherein the autoimmune or inflammatory disorder or disease is selected from the group consisting of acute graft-versus-host disease, chronic graft-versus-host disease, lupus, psoriasis, psoriatic arthritis, polymyositis and dermatomyositis, Behcet's disease, vasculitic conditions, dermatitis, rheumatoid arthritis, and inflammatory bowel disease.

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