Malt1 modulators and uses thereof

Abstract

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

Description

[0001] Cross-references to related applications

[0002] This application claims priority and benefit to U.S. Provisional Patent Application No. 63 / 092,768, filed October 16, 2020, the entire contents of which are incorporated herein by reference. Background of the Invention

[0004] Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is an intracellular signaling protein known from both innate immune cells (e.g., natural killer (NK) cells, dendritic cells (DCs), and mast cells) and adaptive immune cells (e.g., T cells and B cells). MALT1 plays a crucial role in influencing immune responses. For example, in T cell receptor signaling, MALT1 mediates nuclear factor κB (NFKB) signaling, leading to T cell activation and proliferation. Therefore, MALT1 is significant for understanding the mechanisms of autoimmunity and inflammatory pathology. Furthermore, constitutive (dysregulated) MALT1 activity is associated with cancers such as MALT lymphoma and activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL). Modulators of MALT1 activity could be used as potential therapeutic agents. Invention Overview

[0006] This document provides compounds designed to be used as MALT1 modulators. In some embodiments, these compounds are anticipated to be used as therapeutic agents for autoimmune and inflammatory diseases, disorders or conditions, or cancer.

[0007] On the one hand, this article provides compounds represented by formula (I) or pharmaceutically acceptable salts thereof:

[0008]

[0009] in:

[0010] R 1 Selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl and 5-10 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 3-6 The cycloalkyl group and the 5-10 membered heterocyclic group may optionally be independently selected from R on one or more available carbons, consisting of one, two, three or more groups. 1a The substituents are substituted, wherein if the 5-10 membered heterocyclic group contains a substituted cyclic nitrogen atom, the cyclic nitrogen atom may optionally be replaced by R. 1b Substitution, wherein if the 5-10 membered heterocyclic group contains a substituted cyclic sulfur atom, the cyclic sulfur atom may optionally be substituted by two O atoms;

[0011] R 2CH3or CF3;

[0012] R 3 is hydrogen; or

[0013] R 3 is selected from C 1-6 alkyl, C 1-6 alkenyl, C 3-7 alkynyl, C 1-3 cycloalkyl, 5-6 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl, wherein any one of the foregoing can be optionally substituted with one, two, or three substituents each independently selected from R 3a ;

[0014] R 4 is C 1-6 alkyl;

[0015] R 1a is, at each occurrence, independently selected from cyano, halogen, hydroxyl, oxo, C 1-6 alkyl, -C(O)OR A , -C(O)N(R A )2, -N(R A )2, C 1-6 alkoxy, 5-6 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the C 1-6 alkyl is optionally substituted with -N(R A )2, and wherein if the 5-6 membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom can be optionally substituted with R B ;

[0016] R 1b is selected from C 1-6 alkyl, -C(O)OR A , -C(O)C 1-6 alkyl, -C(O)C 3-6 cycloalkyl, -C(O)N(R A )2, and -S(O)2C 1-6 alkyl;

[0017] R 3a is, at each occurrence, independently selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, hydroxyl, C 1-4 alkenyl, cyano, azido, -NR C R D , C 3-6 cycloalkyl, C 1-4 alkoxy C 1-4alkyl, C 3-6 cycloalkyl, 5-6 membered heterocyclyl-O-, 5-6 membered heterocyclyl, and phenyl are optionally substituted with one, two, or three substituents each independently selected from R p ;

[0018] R p is independently selected for each occurrence from halogen, C 1-4 alkyl, C 1-4 haloalkyl, hydroxy, C 1-4 alkoxy, C 1-4 alkoxyC 1-4 alkyl, NR C R D and aminoC 1-3 alkyl;

[0019] R A is independently selected for each occurrence from hydrogen, C 1-6 alkyl, -C(O)C 1-6 alkyl, and -C(O)OC 1-6 alkyl;

[0020] R B is selected from C 1-6 alkyl, C 3-6 cycloalkyl, and -C(O)OC 1-6 alkyl;

[0021] R C and R D is independently selected for each occurrence from hydrogen, C 1-6 alkyl, haloC 1-6 alkyl, and C 3-4 cycloalkyl, or

[0022] R C and R D together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl or 4-6 membered heteroaryl, wherein the 4-6 membered heterocyclyl or 4-6 membered heteroaryl can contain an additional nitrogen or oxygen atom and is optionally substituted with one or two fluorines; and

[0023] t is 0 or 1.

[0024] In another aspect, provided herein is a compound represented by Formula (Ib):

[0025]

[0026] wherein:

[0027] R 1 is C 1-6 alkyl, C 3-6cycloalkyl or 5-10 membered heterocyclyl, wherein the C 3-6 cycloalkyl can optionally be substituted on one or more available carbons by one, two, three or more substituents each independently selected from R 1a , wherein if the 5-10 membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom can optionally be substituted by R 1b , and wherein if the 5-10 membered heterocyclyl contains a substitutable ring sulfur atom, the ring sulfur atom can optionally be substituted by two O atoms;

[0028] R 1a is independently selected at each occurrence from cyano, halogen, hydroxyl, C 1-6 alkyl, -C(O)OR A , -C(O)N(R A )2, -N(R A )2, C 1-6 alkoxy and 5-6 membered heteroaryl, wherein the C 1-6 alkyl is optionally substituted by -N(R A )2;

[0029] R 1b is selected from C 1-6 alkyl, -C(O)OR A , -C(O)C 1-6 alkyl, -C(O)C 3-6 cycloalkyl, -C(O)N(R A )2, and -S(O)2C 1-6 alkyl; and

[0030] R A is independently selected at each occurrence from hydrogen, C 1-6 alkyl, -C(O)C 1-6 alkyl, and -C(O)OC 1-6 alkyl.

[0031] In some embodiments, the compounds provided herein are selected from the compounds listed in Table 1, or a pharmaceutically acceptable salt thereof.

[0032] In another aspect, provided herein are pharmaceutical compositions comprising a compound disclosed herein and a pharmaceutically acceptable carrier.

[0033] In another aspect, provided herein are methods 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.

[0034] In another aspect, provided herein are methods of treating an autoimmune or inflammatory condition 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

[0036] As generally described herein, the present application provides compounds designed, for example, for use as MALT1 modulators. In certain embodiments, these compounds are expected to be useful as therapeutic agents for treating autoimmune and inflammatory diseases, disorders, or conditions or cancer.

[0037] DEFINITIONS

[0038] CHEMICAL DEFINITIONS

[0039] The definitions for specific functional groups and chemical terms are described in more detail below. Chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional group definitions can be found, for example, in R. C. Wa th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3 rd Edition, Cambridge University Press, Cambridge, 1987, describing general principles of organic chemistry, as well as specific functional groups and reactivity.

[0040] The compounds described herein can contain one or more asymmetric centers and thus can exist in various isomeric forms, e.g., enantiomeric and / or diastereomeric forms. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be separated 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 the preferred isomer can be prepared by asymmetric synthesis. See, e.g., Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present application additionally encompasses the compounds described herein in the form of an individual isomer substantially free of other isomers, and alternatively, in the form of a mixture of different isomers.

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

[0042] In the compositions provided herein, enantiomerically pure compounds can be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising an enantiomerically pure R-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure R-compound. In certain embodiments, the enantiomerically pure R-compound in such compositions can comprise, for example, at least about 95% by weight R-compound and at most about 5% by weight S-compound, based on the total weight of the compound. For example, a pharmaceutical composition comprising an enantiomerically pure S-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure S-compound. In certain embodiments, the enantiomerically pure S-compound in such compositions can comprise, for example, at least about 95% by weight S-compound and at most about 5% by weight R-compound, based on the total weight of the compound. In certain embodiments, the active ingredient can be formulated with little or no excipient or carrier.

[0043] The compounds described herein can also comprise one or more isotopic substitutions. For example, H can be any isotopic form, including 1 H, 2 H (deuterium or tritium), and 3 H (deuterium or tritium); C can be any isotopic form, including 12 C, 13 C, and 14 C; O can be any isotopic form, including 16 O, 18 O; F can be any isotopic form, including 18 F, 19 F; and the like.

[0044] The following terms are intended to have the meanings presented therewith below and to assist in understanding the description and intended scope of the application. When describing the application, which can include compounds, and pharmaceutically acceptable salts thereof, pharmaceutical compositions containing such compounds, and methods of using such compounds and compositions, the following terms have the following meanings unless otherwise indicated. It is also to be understood that any moiety defined below, when described herein, can be substituted by a variety of substituents, and each definition is intended to include such substituted moieties within its scope. Unless otherwise indicated, the term “substituted” is defined as follows. It is also to be understood that the terms “radical” and “group” are used interchangeably herein. The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an analogue” means one analogue or more than one analogue.

[0045] When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example, “C 1–6The term "alkyl" is intended to encompass C1, C2, C3, C4, C5, C6, and C6 alkyl groups. 1–6 C 1–5 C 1–4 C 1–3 C 1–2 C 2–6 C 2–5 C 2–4 C 2–3 C 3–6 C 3–5 C 3–4 C 4–6 C 4–5 and C 5–6 alkyl.

[0046] As used herein, "alkyl" refers to, for example, a straight-chain or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C"). 1–20 Alkyl group). In some embodiments, the alkyl group has 1 to 10 carbon atoms (“C10”). 1–10 Alkyl group). In some embodiments, the alkyl group has 1 to 9 carbon atoms (“C1”). 1–9 Alkyl group). In some embodiments, the alkyl group has 1 to 8 carbon atoms (“C1”). 1–8 Alkyl group). In some embodiments, the alkyl group has 1 to 7 carbon atoms (“C1”). 1–7 Alkyl group (“C”). In some embodiments, the alkyl group has 1 to 6 carbon atoms (“C”). 1–6 Alkyl group). In some embodiments, the alkyl group has 1 to 5 carbon atoms (“C1”). 1–5 Alkyl group). In some embodiments, the alkyl group has 1 to 4 carbon atoms (“C1”). 1–4 Alkyl group). In some embodiments, the alkyl group has 1 to 3 carbon atoms (“C1”). 1–3 Alkyl group (“alkyl”). In some embodiments, the alkyl group has 1 to 2 carbon atoms (“C”). 1-2 Alkyl group (“C1 alkyl”). In some embodiments, the alkyl group has one carbon atom (“C1 alkyl”). 1–6 Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, etc.

[0047] As used herein, “alkenyl” refers to a straight-chain or branched hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds), and optionally one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds). 2–20 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group does not contain any triple bonds. In some embodiments, the alkenyl group has 2 to 10 carbon atoms (“C”). 2–10Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 9 carbon atoms (“C”). 2–9 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 8 carbon atoms (“C”). 2–8 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 7 carbon atoms (“C”). 2–7 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 6 carbon atoms (“C”). 2–6 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 5 carbon atoms (“C”). 2–5 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 4 carbon atoms (“C”). 2–4 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 3 carbon atoms (“C”). 2–3 The alkenyl group (“C2-alkenyl”) has two carbon atoms in some embodiments. The one or more carbon-carbon double bonds can be internal (e.g., in 2-butenyl) or terminal (e.g., in 1-butenyl). 2–4 Examples of alkenyl groups include vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), etc. 2–6 Examples of alkenyl groups include the C group mentioned above. 2–4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), and hexenyl (C6). Other examples of alkenyl groups include heptenyl (C7), octenyl (C8), and octtrienyl (C8).

[0048] As used herein, “alkynyl” refers to a straight-chain or branched hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds), and optionally one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds). 2–20 The alkynyl group (“Alynyl”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 10 carbon atoms (“C”). 2–10 The alkynyl group (“C”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 9 carbon atoms (“C”). 2–9 The alkynyl group (“acetylenic”) has 2 to 8 carbon atoms in some embodiments. 2–8 The alkynyl group (“acetylation”) has 2 to 7 carbon atoms in some embodiments. 2–7 The alkynyl group (“C”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 6 carbon atoms (“C”). 2–6 The alkynyl group (“H”) has 2 to 5 carbon atoms in some embodiments. 2–5 The alkynyl group (“C”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 4 carbon atoms (“C”). 2–4alkynyl groups). In some embodiments, the alkynyl group has 2 to 3 carbon atoms ("C 2–3 alkynyl groups). In some embodiments, the alkynyl group has 2 carbon atoms ("C2alkynyl"). The one or more carbon-carbon triple bonds can be internal (as in 2-butyne) or terminal (as in 1-butyne). C 2–4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1–propynyl (C3), 2–propynyl (C3), 1–butynyl (C4), 2–butynyl (C4), and the like. C 2–6 Examples of alkenyl groups include the above-described C 2–4 alkynyl groups). In some embodiments, the alkynyl group has 2 to 3 carbon atoms ("C

[0049] As used herein, "alkylene," "alkenylene," "alkynylene," "cycloalkylene," "heterocyclylene," "heteroarylene," and "phenylene" refer to divalent groups of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl (e.g., saturated and partially saturated), heteroaryl, and phenyl groups, respectively.

[0050] 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 straight chain divalent chain. "Alkylene," "alkenylene," and "alkynylene" groups can be substituted or unsubstituted by one or more substituents as described herein.

[0051] As used herein, "aryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having from 6-14 ring carbon atoms and 0 heteroatoms in the aromatic ring system ("C 6–14 aryl"). In some embodiments, the aryl group has 6 ring carbon atoms ("C6aryl"; for example, phenyl). In some embodiments, the aryl group has 10 ring carbon atoms ("C 10 aryl"; for example, naphthyl groups such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms ("C 14 aryl"; for example, anthryl). "Aryl" also includes ring systems in which an aromatic ring as defined above is fused to one or more carbocyclyl or heterocyclyl groups, where the group or point of attachment is on the aromatic ring, and in such cases the number of carbon atoms continues to designate the number of carbon atoms in the aromatic ring system. Typical aryl groups include, but are not limited to, groups derived from acenaphthylene, acenaphthene, acephenanthrene, anthracene, azulene, benzene, (chrysene), coronene, fluoranthene, fluorene, hexacene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, periflanthene, picene, pyanthrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. In particular, aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl.

[0052] As used herein, "heteroaryl" refers to a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 electrons shared in the ring array), having ring carbon atoms and 1-4 ring heteroatoms in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valence permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring as defined above is fused to one or more carbocyclic or heterocyclic rings, wherein the point of attachment is on the heteroaryl ring, and 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, wherein the point of attachment is on the aryl or 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 contains no heteroatoms (e.g., indolyl, quinolyl, carbazolyl, and the like), the point of attachment can be on either ring, i.e., the ring that carries a heteroatom (e.g., 2-indolyl) or the ring that contains no heteroatoms (e.g., 5-indolyl).

[0053] In some embodiments, the heteroaryl is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, the heteroaryl is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, the heteroaryl is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0054] Exemplary 5-membered heteroaryls containing 1 heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryls containing 2 heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryls containing 3 heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryls containing 4 heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryls containing 1 heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryls containing 2 heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryls containing 3 or 4 heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryls containing 1 heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryls include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryls include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0055] Examples of representative heteroaryl groups include the following:

[0056]

[0057] wherein each Z is selected from carbonyl, N, NR 65 , O, and S; and R 65 is independently hydrogen, C 1-8alkyl, C 3-10 carbocyclyl, 4-10 membered heterocyclyl, C6-C 10 aryl and 5-10 membered heteroaryl.

[0058] As used herein, "carbocyclyl" or "carbocyclic" refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms ("C 3–10 carbocyclyl") and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has from 3 to 8 ring carbon atoms ("C 3–8 carbocyclyl"). In some embodiments, a carbocyclyl group has from 3 to 7 ring carbon atoms ("C 3-7 carbocyclyl"). In some embodiments, a carbocyclyl group has from 3 to 6 ring carbon atoms ("C 3–6 carbocyclyl"). In some embodiments, a carbocyclyl group has from 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. Exemplary C 3-8 carbocyclyl groups include, but are not limited to, the aforementioned C 3-6 carbocyclyl groups as well as 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. Exemplary C 3–10 carbocyclyl groups include, but are not limited to, the aforementioned C 3–8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-lH-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 monocyclic ("monocyclic carbocyclyl") or contains a fused, bridged, or spiro ring system, such as a bicyclic ring system ("bicyclic carbocyclyl"), and can be saturated or can be partially unsaturated. "Carbocyclyl" also includes ring systems in which a carbocyclyl ring as defined above is fused with 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 indicate the number of carbons in the carbocyclic ring system.

[0059] The term "cycloalkyl" refers to a radical derived from a cycloalkane, herein referred to as, for example, "C 4-8“Cycloalkyl” refers to a monovalent saturated cyclic, bicyclic, or bridged ring (e.g., adamantyl) hydrocarbon group of 3-12, 3-8, 4-8, or 4-6 carbons. Exemplary cycloalkyl groups include, but are not limited to, cyclohexane, cyclopentane, cyclobutane, and cyclopropane.

[0060] As used herein, “C 3-6 “Monocycloalkyl” or “monocyclo-C 3-6 “Cycloalkyl” refers to a monovalent saturated cyclic, bicyclic, or bridged ring (e.g., adamantyl) hydrocarbon group of 3-12, 3-8, 4-8, or 4-6 carbons. Exemplary cycloalkyl groups include, but are not limited to, cyclohexane, cyclopentane, cyclobutane, and cyclopropane.

[0061] As used herein, “Heterocyclyl” or “heterocycle” refers to a radical of a 3- to 10- membered nonaromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3-10 membered heterocyclyl”). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valence permits. Heterocyclyl groups can be monocyclic (“monocyclic heterocyclyl”) or fused, bridged or spiro ring systems, such as bicyclic ring systems (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems in which a heterocyclyl ring as defined above is fused to one or more carbocyclyl rings, wherein the point of attachment is on either the carbocyclyl or heterocyclyl ring, or ring systems in which a heterocyclyl ring as defined above is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such cases the number of ring members continues to indicate the number of ring members in the heterocyclyl ring system. The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical” can be used interchangeably.

[0062] In some embodiments, the heterocyclyl is a 4-7 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("4-7 membered heterocyclyl"). In some embodiments, the heterocyclyl is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("5-10 membered heterocyclyl"). In some embodiments, the heterocyclyl is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heterocyclyl"). In some embodiments, the heterocyclyl is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heterocyclyl"). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0063] Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, azirdinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing 1 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 2 heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, dithiolanyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing 2 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, hexahydrotriazinanyl. Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, azocinyl, oxocinyl, and thiocinyl. Exemplary 5-membered heterocyclyl groups fused to a C6aromatic ring (also referred to herein as 5,6-bicyclic heterocyclic rings) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aromatic ring (also referred to herein as 6,6-bicyclic heterocyclic rings) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0064] Examples of saturated or partially unsaturated heterocyclyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, pyrrolidinyl, pyridonyl, pyrrolidonyl, piperidinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, morpholinyl, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, oxetanyl, azetidinyl, and tetrahydropyrimidinyl. Where designated as optionally substituted or substituted, substituents on a heterocyclyl group (e.g., in the case of an optionally substituted heterocyclyl group) can be present at any substitutable position and include, for example, the position that attaches the heterocyclyl group.

[0065] “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 has been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero can apply to any of the above hydrocarbyl groups having from 1 to 5, and particularly 1 to 3, heteroatoms, e.g., alkyl such as heteroalkyl; carbocyclyl such as heterocyclyl; aryl such as heteroaryl; and the like.

[0066] As used herein, "cyano" refers to -CN.

[0067] The terms "halo" and "halogen" as used herein refer to an atom selected from fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), and iodine (iodo, -I). In certain embodiments, the halo group is fluorine or chlorine.

[0068] The term "alkoxy" as used herein refers to an alkyl group connected to another moiety through an oxygen atom (-O(alkyl)). Non-limiting examples include, for example, methoxy, ethoxy, propyloxy, and butyloxy.

[0069] "Haloalkoxy" is a haloalkyl group connected to another moiety through an oxygen atom, such as, but not limited to, -OCHCF2or -OCF3.

[0070] The term "haloalkyl" includes mono, poly, and perhaloalkyl groups substituted with one or more halogen atoms, wherein the halogen is independently selected from fluorine, chlorine, bromine, and iodine. For groups C 1-4 haloalkyl-O-C 1-4 alkyl, the point of attachment occurs on the alkyl moiety that is halogenated.

[0071] As used herein, "oxo" refers to -C=O.

[0072] In general, the term "substituted," whether preceded by the term "optionally" or not, refers to the replacement of at least one hydrogen present on a group, e.g., a carbon or nitrogen atom, by a permissible substituent, for example a substituent that results in a stable compound, e.g., a compound that is not capable of spontaneously undergoing further transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a "substituted" group has a substituent at one or more substitutable positions thereof, and when more than one position is substituted, the substituent is the same or different at each position.

[0073] A nitrogen atom can be substituted or unsubstituted as valence allows, and includes primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR bb )R aa , -C(=NR cc )OR aa , -C(=NRcc )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 3–10 carbocyclyl, 3-14 membered heterocyclyl, C 6–14 aryl and 5-14 membered heteroaryl, or two R cc groups attached to the same nitrogen atom are combined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups, and wherein R aa , R bb , R cc and R dd are as defined above.

[0074] These and other exemplary substituents are described in more detail in the , the Examples, and the claims. The application is not intended to be limited in any way to the above exemplary list of substituents.

[0075] Other Definitions

[0076] As used herein, the term "pharmaceutically acceptable carrier" means a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., phosphate, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0077] As used herein, "pharmaceutically acceptable salt" means those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66: 1-19. Pharmaceutically acceptable salts of the compounds of this application include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or by using other methods such as ion exchange resins. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, bicarbonate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pantothenate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (C 1–4 alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.

[0078] As used herein, a “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, such as 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, such as a mammal, e.g., a primate (e.g., a cynomolgus monkey, a rhesus monkey), a bovine, a porcine, a equine, an ovine, a caprine, a rodent, a feline, and / or a canine. 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.

[0079] Disease, disorder, and condition are used interchangeably herein.

[0080] As used herein, and unless otherwise specified, the terms “treat,” “treating” and “treatment” contemplate an action that occurs while a subject is suffering from the named disease, disorder, or condition that either reduces the severity of, or delays or slows the progression of, the disease, disorder, or condition (“therapeutic treatment”), and also contemplate an action that occurs before a subject begins to suffer from the named disease, disorder, or condition (“prophylactic treatment”).

[0081] As used herein, an “effective amount” of a compound refers to an amount sufficient to elicit the desired biological response. As will be appreciated by those of ordinary skill in the art, the effective amount of a compound of the application can vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and condition of the subject. An effective amount includes both therapeutic and prophylactic treatment.

[0082] As used herein, and 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 therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0083] Compounds

[0084] In one aspect, provided herein is a compound represented by Formula (I), or a pharmaceutically acceptable salt thereof:

[0085]

[0086] wherein:

[0087] R1 selected from C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl and 5-10 membered heterocyclyl, wherein the C 1-6 alkyl, C 3-6 cycloalkyl and 5-10 membered heterocyclyl can optionally be substituted on one or more available carbons by one, two, three or more substituents each independently selected from R 1a , wherein if the 5-10 membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom can optionally be substituted with R 1b , and wherein if the 5-10 membered heterocyclyl contains a substitutable ring sulfur atom, the ring sulfur atom can optionally be substituted with two O atoms;

[0088] R 2 is CH3or CF3;

[0089] R 3 is hydrogen; or

[0090] R 3 is selected from C 1-6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkyl, 5-6 membered heterocyclyl, 5-6 membered heterocyclyl-C 1-3 alkyl-, 5-6 membered heterocyclyl-O-, phenyl and 5-6 membered heteroaryl, any of which can optionally be substituted by one, two or three substituents each independently selected from R 3a ;

[0091] R 4 is C 1-6 alkyl;

[0092] R 1a is, at each occurrence, independently selected from cyano, halogen, hydroxyl, oxo, C 1-6 alkyl, -C(O)OR A , -C(O)N(R A )2, -N(R A )2, C 1-6 alkoxy, 5-6 membered heterocyclyl and 5-6 membered heteroaryl, wherein the C 1-6 alkyl is optionally substituted with -N(R A )2, and wherein if the 5-6 membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom can optionally be substituted with R B ;

[0093] R 1b is selected from C 1-6 alkyl, -C(O)OR A , -C(O)C 1-6alkyl, -C(O)C 3-6 cycloalkyl, -C(O)N(R A )2and -S(O)2C 1-6 alkyl;

[0094] R 3a is independently at each occurrence selected from 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 alkyl, 5-6 membered heterocyclyl-O-, 5-6 membered heterocyclyl and phenyl, wherein C 3-6 cycloalkyl, 5-6 membered heterocyclyl-O-, 5-6 membered heterocyclyl and phenyl are optionally substituted with one, two or three substituents each independently selected from R p ;

[0095] R p is independently at each occurrence selected from 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 alkyl;

[0096] R A is independently at each occurrence selected from hydrogen, C 1-6 alkyl, -C(O)C 1-6 alkyl and -C(O)OC 1-6 alkyl;

[0097] R B is selected from C 1-6 alkyl, C 3-6 cycloalkyl and -C(O)OC 1-6 alkyl;

[0098] R C and R D are independently at each occurrence selected from hydrogen, C 1-6 alkyl, halo C 1-6 alkyl and C 3-4 cycloalkyl, or

[0099] R C and R Dtogether with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl or a 4-6 membered heteroaryl, wherein the 4-6 membered heterocyclyl or 4-6 membered heteroaryl can contain an additional nitrogen atom or an oxygen atom and is optionally substituted with one or two fluorines; and

[0100] t is 0 or 1.

[0101] In another aspect, provided herein are compounds represented by Formula (I), or a pharmaceutically acceptable salt thereof:

[0102]

[0103] wherein:

[0104] R 1 is C 1-6 alkyl, C 3-6 cycloalkyl, or 5-10 membered heterocyclyl, wherein the C 3-6 cycloalkyl can be optionally substituted on one or more available carbons with one, two, three, or more substituents each independently selected from R 1a , wherein if the 5-10 membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom can be optionally substituted with R 1b , and wherein if the 5-10 membered heterocyclyl contains a substitutable ring sulfur atom, the ring sulfur atom can be optionally substituted with two O atoms;

[0105] R 2 is CH3or CF3;

[0106] R 3 is C 1-6 alkyl, wherein the C 1-6 alkyl can be optionally substituted with C 1-4 alkoxy;

[0107] R 4 is C 1-6 alkyl;

[0108] R 1a is independently selected at each occurrence from cyano, halogen, hydroxyl, C 1-6 alkyl, -C(O)OR A , -C(O)N(R A )2, -N(R A )2, C 1-6 alkoxy, and 5-6 membered heteroaryl, wherein the C 1-6 alkyl is optionally substituted with -N(R A )2;

[0109] R 1b is selected from C 1-6 alkyl, -C(O)OR A , -C(O)C1-6 alkyl, -C(O)C 3-6 cycloalkyl, -C(O)N(R A )2and -S(O)2C 1-6 alkyl;

[0110] R A is independently selected for each occurrence from hydrogen, C 1-6 alkyl, -C(O)C 1-6 alkyl and -C(O)OC 1-6 alkyl; and

[0111] t is 0 or 1.

[0112] In some embodiments, t = 0. In some embodiments, t = 1.

[0113] In some embodiments, R 4 is C 1-6 alkyl. In some embodiments, R 4 is CH3.

[0114] In another aspect, provided herein is a compound represented by Formula (Ia) or a pharmaceutically acceptable salt thereof:

[0115]

[0116] wherein:

[0117] R 1 is selected from C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl and 5-10 membered heterocyclyl, wherein the C 1-6 alkyl, C 3-6 cycloalkyl and 5-10 membered heterocyclyl can be optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from R 1a ; wherein if the 5-10 membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom can be optionally substituted with R 1b , and wherein if the 5-10 membered heterocyclyl contains a substitutable ring sulfur atom, the ring sulfur atom can be optionally substituted with two O atoms;

[0118] R 2 is CH3or CF3;

[0119] R 3 is hydrogen; or

[0120] R 3 is selected from C 1-6 alkyl, C 1-6 alkoxy, C 3-7 alkyl; andcycloalkyl, 5-6 membered heterocyclyl, 5-6 membered heterocyclyl-C 1-3 alkyl-, 5-6 membered heterocyclyl-O-, phenyl and 5-6 membered heteroaryl, any of which can be optionally substituted with one, two or three substituents each independently selected from R 3a ; and

[0121] R 1a is independently at each occurrence selected from cyano, halogen, hydroxyl, oxo, C 1-6 alkyl, -C(O)OR A , -C(O)N(R A )2, -N(R A )2, C 1-6 alkoxy, 5-6 membered heterocyclyl and 5-6 membered heteroaryl, wherein the C 1-6 alkyl is optionally substituted with -N(R A )2, and wherein if the 5-6 membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom can be optionally substituted with R B ;

[0122] R 1b is selected from C 1-6 alkyl, -C(O)OR A , -C(O)C 1-6 alkyl, -C(O)C 3-6 cycloalkyl, -C(O)N(R A )2and -S(O)2C 1-6 alkyl;

[0123] R 3a is independently at each occurrence selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, hydroxyl, C 1-4 alkenyl, cyano, azido, NR C R D , C 3-6 cycloalkyl, C 1-4 alkoxy C 1-4 alkoxy, 5-6 membered heterocyclyl-O-, 5-6 membered heterocyclyl and phenyl, wherein C 3-6 cycloalkyl, 5-6 membered heterocyclyl-O-, 5-6 membered heterocyclyl and phenyl are optionally substituted with one, two or three substituents each independently selected from R p ;

[0124] R p is selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, hydroxyl, C 1-4 alkoxy, C1-4 alkoxy C 1-4 alkyl, NR C R D and amino C 1-3 alkyl;

[0125] R A is, at each occurrence, independently selected from hydrogen, C 1-6 alkyl, -C(O)C 1-6 alkyl and -C(O)OC 1-6 alkyl;

[0126] R B is selected from C 1-6 alkyl, C 3-6 cycloalkyl and -C(O)OC 1-6 alkyl; and

[0127] R C and R D is, at each occurrence, independently selected from hydrogen, C 1-6 alkyl, halo C 1-6 alkyl and C 3-4 cycloalkyl, or

[0128] R C and R D together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl or 4-6 membered heteroaryl, wherein the 4-6 membered heterocyclyl or 4-6 membered heteroaryl can contain an additional nitrogen or oxygen atom and is optionally substituted with one or two fluorines.

[0129] In another aspect, provided herein is a compound represented by Formula (Ia) or a pharmaceutically acceptable salt thereof:

[0130]

[0131] wherein:

[0132] R 1 is C 1-6 alkyl, C 3-6 cycloalkyl and 5-10 membered heterocyclyl, wherein the C 3-6 cycloalkyl can be optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from R 1a ; wherein if the 5-10 membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom can be optionally substituted with R 1b , and wherein if the 5-10 membered heterocyclyl contains a substitutable ring sulfur atom, the ring sulfur atom can be optionally substituted with two O atoms;

[0133] R 2 is CH3or CF3;

[0134] R 3 is C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with C 1-4 alkoxy;

[0135] R 1a is independently selected at each occurrence from cyano, halogen, hydroxyl, C 1-6 alkyl, -C(O)OR A , -C(O)N(R A )2, -N(R A )2, C 1-6 alkoxy, and 5-6 membered heteroaryl, wherein the C 1-6 alkyl is optionally substituted with -N(R A )2;

[0136] R 1b is selected from C 1-6 alkyl, -C(O)OR A , -C(O)C 1-6 alkyl, -C(O)C 3-6 cycloalkyl, -C(O)N(R A )2, and -S(O)2C 1-6 alkyl; and

[0137] R A is independently selected at each occurrence from hydrogen, C 1-6 alkyl, -C(O)C 1-6 alkyl, and -C(O)OC 1-6 alkyl;

[0138] In some embodiments, R 2 is CH3. In some embodiments, R 2 is CF3.

[0139] In some embodiments, R 3 is C 1-6 alkyl, wherein R 3 is optionally substituted with C 1-4 alkoxy.

[0140] In some embodiments, R 3 is C 1-6 alkyl. In some embodiments, R 3 is

[0141] In some embodiments, R 3 is C 1-6 alkyl, wherein R 3 is substituted with C 1-4 alkoxy. In some embodiments, R3 for

[0142] On the other hand, this article provides compounds represented by formula (Ib) or pharmaceutically acceptable salts thereof:

[0143]

[0144] in:

[0145] R 1 C 1-6 Alkyl, C 3-6 Cycloalkyl or 5-10 membered heterocyclic group, wherein the C 3-6 The cycloalkyl group may optionally be formed on one or more available carbons by one, two, three or more atoms, each independently selected from R. 1a The substituents are substituted, wherein if the 5-10 membered heterocyclic group contains a substituted cyclic nitrogen atom, the cyclic nitrogen atom may optionally be replaced by R. 1b Substitution, wherein if the 5-10 membered heterocyclic group contains a substituted cyclic sulfur atom, the cyclic sulfur atom may optionally be substituted by two O atoms;

[0146] R 1a Each time it appears, it is independently selected from cyano, halogen, hydroxyl, C. 1-6 Alkyl, -C(O)OR A -C(O)N(R) A )2、-N(R A 2. C 1-6 alkoxy and 5-6 heteroaryl groups, wherein the C 1-6 Alkyl groups are optionally coated with -N(R) A )2 replaces;

[0147] R 1b Selected from C 1-6 Alkyl, -C(O)OR A -C(O)C 1-6 Alkyl, -C(O)C 1-6 Cycloalkyl, -C(O)N(R) A )2 and -S(O)2C 1-6 Alkyl groups; and

[0148] R A Each time it appears, it is independently selected from hydrogen and C. 1-6 Alkyl, -C(O)C 1-6 Alkyl groups and -C(O)OC 1-6 alkyl.

[0149] In some implementation schemes, R 1 C 1-6 Alkyl group. In some embodiments, R 1is CH3.

[0150] In some embodiments, R 1 is C 3-6 cycloalkyl, wherein R 1 may be optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from R 1a .

[0151] In some embodiments, R 1 is C 3-6 cycloalkyl. In some embodiments, R 1 is selected from

[0152] In some embodiments, R 1 is C 3-6 cycloalkyl, wherein R 1 may be optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from R 1a .

[0153] In some embodiments, R 1 is In some embodiments, R 1a is selected from cyano, fluoro, hydroxy, -O-CH3, -C(O)OH, -C(O)NH2,

[0154] In some embodiments, R 1 is selected from

[0155] In some embodiments, R 1 is selected from

[0156] In some embodiments, R 1 is 5-10 membered heterocyclyl, wherein if R 1 contains a substitutable ring nitrogen atom, that ring nitrogen atom can be optionally substituted with R 1b , and wherein if that 5-10 membered heterocyclyl contains a substitutable ring sulfur atom, that ring sulfur atom can be optionally substituted with two O atoms.

[0157] In some embodiments, R 1 is 5-10 membered heterocyclyl. In some embodiments, R 1 is selected from

[0158] In some embodiments, R1 In some embodiments, R In some embodiments, R 1 In some embodiments, R

[0159] In some embodiments, R 1 In some embodiments, R In some embodiments, R 1b In some embodiments, R

[0160] In some embodiments, R 1 In some embodiments, R In some embodiments, R 1 In some embodiments, R

[0161] In some embodiments, R 1 In some embodiments, R

[0162]

[0163]

[0164] In some embodiments, R 1 In some embodiments, R

[0165]

[0166]

[0167] In some embodiments, the compound provided herein is selected from the compounds listed in Table 1, or a pharmaceutically acceptable salt thereof.

[0168] In some embodiments, the compound is selected from:

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

[0170] 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;

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

[0172] (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 -carboxylic acid methyl ester;

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

[0174] N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6- yl}amino)phenyl]-2,2,2-trifluoroethyl]-N-methyloxolane-3-carboxamide;

[0175] 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;

[0176] 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;

[0177] (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;

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

[0179] 3-{[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6- yl}amino)phenyl]-2,2,2-trifluoroethyl}(methyl)carbamoyl]piperidine-1-carboxylic acid tert-butyl ester;

[0180] 3-{[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6- yl}amino)phenyl]-2,2,2-trifluoroethyl}(methyl)carbamoyl]pyrrolidine-1-carboxylic acid tert-butyl ester;

[0181] 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]carbamic acid tert-butyl ester;

[0182] (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;

[0183] 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;

[0184] 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)carbamic acid ester;

[0185] 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-acetylamino-N-methylcyclohexane-1-carboxamide;

[0186] N-[(1S)-1-(4-{[2-chloro-7-(propyl-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]amino}phenyl)-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ 6 -Thiazide-4-carboxamide;

[0187] 1-Acetyl-N-[(1S)-1-(4-{[2-chloro-7-(propyl-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]amino}phenyl)-2,2,2-trifluoroethyl]-N-methylpiperidine-4-carboxamide;

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

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

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

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

[0192] N-{1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]ethyl}-N-methylacetamide;

[0193] 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;

[0194] 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- thiazan-4-carboxamide;

[0195] N-[(1R)-1-[4-({2-chloro-7-[(1R)-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 - thiazan-4-carboxamide;

[0196] 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;

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

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

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

[0200] 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;

[0201] 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 - thiazan-4-carboxamide;

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

[0203] 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;

[0204] 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;

[0205] 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;

[0206] 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;

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

[0208] 4-{[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6- yl}amino)phenyl]-2,2,2-trifluoroethyl}(methyl)carbamoyl]piperidine-1-carboxylic acid methyl ester;

[0209] 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-methylsulfonyl-N-methylpiperidine-4- carboxamide;

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

[0211] N 3 -[(1 S)-1 -[4-({2-chloro-7-[(1 S)-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;

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

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

[0214] N 3 -[(1 S)-1 -[4-({2-chloro-7-[(1 S)-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;

[0215] N-[(1 S)-1 -[4-({2-chloro-7-[(1 S)-1 -methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6- yl}amino)phenyl]-2,2,2-trifluoroethyl]-1 -methylsulfonyl-N-methylpyrrolidine-3- carboxamide;

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

[0217] 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;

[0218] 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;

[0219] 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;

[0220] 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;

[0221] 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;

[0222] N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N,1-dimethylpiperidin-3-carboxamide

[0223] 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;

[0224] (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;

[0225] (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;

[0226] (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;

[0227] (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;

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

[0229] (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;

[0230] (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;

[0231] (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;

[0232] 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;

[0233] 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.

[0234] Pharmaceutical compositions and routes of administration

[0235] The compounds provided according to the present application are generally administered in the form of a pharmaceutical composition. Thus, the present application provides pharmaceutical compositions which contain, as an active ingredient, one or more of the compounds or a pharmaceutically acceptable salt or ester thereof, in combination with one or more pharmaceutically acceptable excipients, carriers including inert solid diluents and fillers, diluents including sterile aqueous solution, various organic solvents, osmo-regulators, 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 per se (see, e.g., Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G.S. Banker & C.T. Rhodes, Eds.)).

[0236] The pharmaceutical compositions can be administered in a single dose, or multiple doses, by any of the accepted modes of administration for agents having similar utilities, for example, by means described in those patents and patent applications incorporated herein by reference, including rectally, buccally, nasally, and transdermally, by intra-arterial injection, intravenous administration, intraperitoneal administration, parenterally, intramuscularly, subcutaneously, orally, topically, as an inhalant, or via an impregnated or coated device, such as a stent, e.g., a cylindrical polymer inserted into an artery.

[0237] One mode of administration is parenteral, particularly by injection. Forms in which the novel compositions of the present application can be incorporated for administration by injection include aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical vehicles. Saline solutions are also conventionally used for injection, but are less preferred in the context of the present application. Ethanol, glycerol, propylene glycol, liquid polyetheylene glycols, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils can also be employed. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

[0238] Sterile injectable solutions are prepared by incorporating the compound according to the present application in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient from the previously sterile-filtered solution thereof.

[0239] Oral administration is another route of administration of the compounds of the present application. Administration can be via a capsule or enteric tablet, or the like. In making the pharmaceutical compositions that include at least one of the compounds described herein, the active ingredient is typically diluted by an excipient and / or enclosed within such a carrier in the form of a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material (as noted above), which acts as a vehicle, a carrier, or a medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0240] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and propylhydroxy-benzoates; sweetening agents; and flavoring agents.

[0241] By employing methods known in the art, the compositions of the present application can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolution systems containing polymeric matrices, wafers, or reservoirs for the delivery of drugs. Examples of controlled release systems are given in U.S. Patent Nos. 3,845,770; 4,326,525; 4,902,514; and 5,616,345. Another formulation employed in the methods of the present application employs transdermal delivery devices ("patches"). Such transdermal patches can be used to provide continuous or discontinuous infusion of the compounds of the present application in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known and exemplified in, e.g., U.S. Patent Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches can be constructed to deliver drugs continuously or pulsed as desired.

[0242] The compositions are preferably formulated in unit dosage form. The term "unit dosage form" refers to physically discrete units suitable for single administration of a predetermined dosage unit of an active ingredient, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient (e.g., tablets, capsules, and ampoules). The compounds are generally administered in a pharmaceutically effective amount. Preferably, each dosage unit contains from 1 mg to 2 g of a compound described herein for oral administration, and from 0.1 to 700 mg of a compound described herein for parenteral administration. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen 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.

[0243] For preparing a solid composition such as a tablet, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present application. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed essentially evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

[0244] The tablets or pills of the application can be coated or otherwise compounded to provide a dosage form with prolonged action advantages or to protect the active ingredient from the acidic conditions of the stomach. For example, a tablet or pill can comprise an inner dosage component and an outer dosage component, the latter being in a form that is resistant to disintegration in the stomach so that the inner component is not released until the tablet or pill has passed through the stomach. Various materials can be used for such enteric layers or coatings, such materials including a number of polymers and mixtures of such materials with such materials as shellac, cetanol, and cellulose acetate.

[0245] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable volatile solvents, such as, for example, propylene glycol, polyethylene glycol, and inert gases, and dry powder compositions. Liquid or solid compositions can contain suitable pharmaceutically acceptable excipients as described above. Preferably, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably pharmaceutically acceptable solvents can be nebulized by use of inert gases or aerosols. Nebulized solutions can be inhaled 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 devices that deliver an appropriate portion of the compositions in the form of aerosols or nebulized particles.

[0246] In some embodiments, a pharmaceutical composition comprising a disclosed compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0247] Methods of use

[0248] The compounds and compositions described herein are generally useful for modulating MALT1 and can be used to treat diseases or disorders, particularly those that are sensitive to modulation of MALT1 proteolytic and / or autoproteolytic activity. In some embodiments, the compounds and compositions described herein can be used to inhibit MALT1. In some embodiments, it is contemplated that the compounds and compositions of the application can be used to treat diseases, disorders, or conditions characterized by dysregulated NF-kB activation, such as autoimmune or immune and inflammatory disorders, allergic disorders, respiratory disorders, and neoplastic disorders.

[0249] In typical embodiments, the present application 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 application includes a pharmaceutically acceptable addition salt, a pharmaceutically acceptable ester, a solvate of an addition salt (e.g., a hydrate), a tautomeric form, a polymorph, an enantiomer, a mixture of enantiomers, a stereoisomer, or a mixture of stereoisomers (pure or as racemic or non-racemic mixtures) of a compound described herein (e.g., a compound of Formula (I); e.g., a compound of a general formula named herein).

[0250] 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 bullous disorders (e.g., pemphigus vulgaris), antibody-mediated vasculitis syndromes including ANCA-associated vasculitis, Henoch-Schonlein purpura, and immune complex vasculitis (primary or secondary to infection or cancer).

[0251] In some embodiments, the tumor disorder is selected from the group consisting of carcinoma, sarcoma, lymphoma, leukemia and germ cell tumor, 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, hematological 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 Sezary syndrome, mycosis fungoides, cutaneous T-cell lymphoma, T-cell acute lymphoblastic leukemia, melanoma, mucosa-associated lymphoid tissue (MALT) lymphoma, multiple myeloma, plasma cell neoplasm, malignant lentigo melanoma, acral-lentiginous melanoma, squamous cell carcinoma, chronic myelogenous leukemia, myeloid leukemia, superficial spreading melanoma, acral-lentiginous melanoma, mucosal melanoma, nodular melanoma, polypoid melanoma, desmoplastic melanoma, amelanotic melanoma, soft tissue melanoma, melanoma with nevus-like cells, melanoma with features of Spitz nevus, uveal melanoma, precursor T-cell, leukemia / lymphoma, acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, follicular lymphoma, chronic lymphocytic leukemia / lymphoma, Burkitt's lymphoma, mycosis fungoides, peripheral T-cell lymphoma, nodular sclerosing type of Hodgkin's lymphoma, Hodgkin's lymphoma of mixed cellularity subtype, non-small cell lung cancer, large cell carcinoma, and small cell lung cancer.

[0252] In some embodiments, the tumor disorder is a 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 the group consisting of adenoma, adenocarcinoma, blastoma (e.g., hepatoblastoma, glioblastoma, neuroblastoma, and retinoblastoma), carcinoma (e.g., colorectal carcinoma or hepatocellular carcinoma, pancreatic cancer, prostate cancer, gastric cancer, esophageal cancer, cervical cancer, 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), nephroblastoma, lung tumor, colon tumor, lymphoid tumor, breast tumor, or melanoma.

[0253] In some embodiments, the allergic disorder is selected from the group consisting of contact dermatitis, celiac disease, asthma, hypersensitivity to house dust mites, pollen, and related allergens, and beryllium poisoning.

[0254] In some embodiments, the respiratory system 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.

[0255] In some embodiments, the compounds and compositions of the application are useful in the treatment of rheumatoid arthritis, systemic lupus erythematosus, vasculitic disorders, allergic diseases, asthma, chronic obstructive pulmonary disease (COPD), acute or chronic transplant rejection, graft-versus-host disease, hematopoietic cancers or solid tumors, chronic myelogenous leukemia, myeloid leukemia, non-Hodgkin's lymphoma or other B-cell lymphomas.

[0256] Combination therapy

[0257] The compounds or compositions described herein can be administered in combination with another agent or therapy. The subject to be administered the compounds disclosed herein can have a disease, disorder, or condition that will benefit from treatment with another agent or therapy, or a symptom thereof.

[0258] In some embodiments, the compounds of the compositions described herein can be administered simultaneously, or prior to 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 routes of administration, or together in the same pharmaceutical composition as the other agents.

[0259] In some embodiments, the compounds described herein can be administered as the sole active ingredient or in combination with other drugs, e.g., immunosuppressants or immunomodulators or other anti-inflammatory agents (e.g., for the treatment or prevention of acute or chronic rejection of allogeneic or xenogeneic transplants or inflammatory or autoimmune diseases), or chemotherapeutic agents (e.g., anti-proliferative agents for malignant cells). For example, the compounds of the application can be used in combination with a calcineurin inhibitor, e.g., cyclosporin A or FK506; an mTOR inhibitor, e.g., rapamycin, 40-0-(2-hydroxyethyl)-rapamycin, biolimus-7, or biolimus-9; an ascomycin having immunosuppressive properties, e.g., ABT-281, ASM981; a corticosteroid; cyclophosphamide; azathioprine; methotrexate; leflunomide; mizoribine; mycophenolic acid or salt; myriocin; or an IL-1 beta inhibitor.

[0260] In some embodiments, the compounds described herein are combined with an agent that is a PI3K inhibitor.

[0261] In some embodiments, the compounds described herein are combined with an agent that affects BTK (Bruton's tyrosine kinase).

[0262] For the treatment of oncological diseases, the compounds described herein can be used in combination with B-cell modulators (e.g. rituximab, ofatumumab, BTK or SYK inhibitors, inhibitors of PKC, PI3K, PDK, PIM, JAK and rmTOR and BH3 mimetics). Examples

[0263] The following representative examples are intended to aid in illustrating the present application and are not intended, nor should they be construed, as limiting the scope of the application.

[0264] The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions can vary depending on the particular reactants or solvent used, but such conditions can be determined by those skilled in the art by routine optimization.

[0265] In addition, it will be apparent to one skilled in the art that conventional protecting groups can need to be employed in order to prevent certain functional groups from undergoing undesirable reactions. Suitable protecting groups for particular functional groups, as well as suitable conditions for protection and deprotection, are well known in the art. For example, many protecting groups, and their introduction and removal, are described in T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, 2nded., Wiley, New York, 1991 and references cited therein.

[0266] 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). Note 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 generated using methods well known to those skilled in the art.

[0267] List of Abbreviations:

[0268] EtOAc ethyl acetate

[0269] THF tetrahydrofuran

[0270] PE petroleum ether

[0271] DMA dimethylacetamide

[0272] MeOH methanol

[0273] EtOH ethanol

[0274] DMF N,N-dimethylformamide

[0275] DMSO dimethyl sulfoxide

[0276] xphos 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

[0277] FA formic acid

[0278] DCM dichloromethane

[0279] MTBE methyl tert-butyl ether

[0280] TFA trifluoroacetic acid

[0281] MeCN, ACN acetonitrile

[0282] i-PrMgCl isopropylmagnesium chloride

[0283] xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

[0284] i-PrOH isopropyl alcohol

[0285] TMSCF3 trifluoromethyltrimethylsilane

[0286] MeI methyl iodide

[0287] LiHMDS lithium bis(trimethylsilyl)amide

[0288] h, hr, hrs hour(s)

[0289] Calcd calculated

[0290] UV ultraviolet

[0291] rt room temperature

[0292] DIEA, DIPEA N,N-diisopropylethylamine

[0293] HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0294] CDI 1,1'-carbonyldiimidazole

[0295] ee enantiomeric excess

[0296] TMS trimethylsilyl

[0297] Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0)

[0298] Et3N, TEA triethylamine

[0299] Cs2CO3 cesium carbonate

[0300] INT intermediate

[0301] EDCI l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride HOBT, HOBt 1-hydroxybenzotriazole

[0302] TLC thin layer chromatography

[0303] Conc. Boc tert-butyloxycarbonyl

[0304] AcCl acetyl chloride

[0305] NaBH3CN sodium cyanoborohydride

[0306] HO(CH2O)nH polyformaldehyde

[0307] LiOH.H2O lithium hydroxide monohydrate

[0308] NH4Cl ammonium chloride

[0309] MeNH2.HCl methylamine hydrochloride

[0310] Me2NH.HCl dimethylamine hydrochloride

[0311] TMSN3 trimethylsilyl azide

[0312] (C4H9)2SnO dibutyltin oxide

[0313] NH2NH2.H2O hydrazine hydrate

[0314] t-BuOH tert-butanol

[0315] t-BuOK potassium tert-butoxide

[0316] DPPA diphenylphosphoryl azide

[0317] NaOH sodium hydroxide

[0318] (n-Bu)4OAc tetrabutylammonium acetate

[0319] (COCl)2 oxalyl chloride

[0320] Na2CO3 sodium carbonate

[0321] POCl3 phosphorous oxychloride

[0322] TBSCl tert-butyldimethylsilyl chloride

[0323] TBS tert-butyldimethylsilyl

[0324] NaH sodium hydride

[0325] Ti(OEt)4 titanium ethoxide

[0326] TBAT tetrabutylammonium difluorotris(pentafluorophyl)silicate

[0327] o-n overnight

[0328] EDTA ethylenediaminetetraacetic acid

[0329] Example 1. Preparation of compounds

[0330] Methods of preparing the compounds described herein are illustrated in the following synthetic schemes. These schemes are presented to illustrate the application and should not be construed as limiting the scope or spirit of the application in any way. These schemes are presented to illustrate the application and should not be construed as limiting the scope or spirit of the application in any way. The starting materials shown in the schemes can be obtained from commercial sources or can be made from commercially available materials according to procedures described in the literature.

[0331] 1. Compounds prepared using Scheme 1

[0332] Scheme 1:

[0333]

[0334] containing R 3 triazolopyrimidine G-1a is reacted with carboxamide G-1b containing R 1 and R 2 to give compounds of Formula (I).

[0335] 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-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1- dioxide (Compound 1.1) [2-(4-amino)phenyl]-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ 6 - thioxan-4-carboxamide (also known as N- 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) 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)

[0336]

[0337] 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 6- A mixture of thiazane-4-carboxamide [INT 5.1] (779 mg, 1.82 mmol), Pd2(dba)3 (159 mg, 174 pmol), Xantphos (201 mg, 348 pmol) and Cs2CO3 (1.70 g, 5.22 mmol) in dioxane (6 mL) was stirred at 100 °C for 4 h. The mixture was concentrated under reduced pressure to give a 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 pm, Table: 29-58% B (A = water (0.05% ammonium hydroxide v / v), 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-1 lambda 6 - Thiazane-4-carboxamide [compound 1.1] (211 mg, 368 pmol) as a dry powder. m / z: [M+H] + C23H27CIF3N6O4S Calculated 575.2; found 575.3. 1 H NMR (400 MHz, DMSO-d6) d = 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%.

[0338] 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) 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)

[0339]

[0340] A mixture of 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5- a]pyrimidin-6-amine hydrochloride [INT 1.1] (100 mg, 378 pmol), N-[(1S)-1-(4- bromophenyl)-2,2,2-trifluoroethyl]-N-methylacetamide [INT 5.2] (117 mg, 378 pmol), Pd2(dba)3 (34.6 mg, 37.8 pmol), Xantphos (43.7 mg, 75.6 pmol) and Cs2CO3 (368 mg, 1.13 mmol) in dioxane (3 mL) was stirred at 100 °C under N2atmosphere for 3 h. The mixture was concentrated under reduced pressure to give a crude product which was purified by preparative HPLC (column: YMC Triart C18 250*50mm*7pm, stat: 31-71% B (A = water (0.05% ammonium hydroxide v / v), 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 pmol, 11.6% yield) as a yellow dry powder. m / z: [M+H]+C19H21ClF3N6O2 457.1 calculated; found 457.2. 1 H NMR (400 MHz, CD3OD) d = 8.90-8.85 (m, 1H), 7.40-7.27 (m, 2H), 7.11-7.01 (m, 2H), 6.50 (q, J = 9.2 Hz, 1H), 5.36 (q, J = 6.4 Hz, 1H), 3.37-3.35 (m, 3H), 2.95-2.72 (m, 3H), 2.36-2.19 (m, 3H), 1.64 (d, J = 6.8 Hz, 3H).

[0341] 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) 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)

[0342]

[0343] A mixture of 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5- a]pyrimidin-6-amine hydrochloride [INT 1.1] (80 mg, 302 pmol), N-[(1S)-1-(4- bromophenyl)-2,2,2-trifluoroethyl]-N-methyloxazane-2-carboxamide [INT 5.3] (114 mg, 302 pmol), Xantphos (34.9 mg, 60.4 pmol), Pd2(dba)3(27.6 mg, 30.2 pmol) and Cs2CO3(196 mg, 604 pmol) in dioxane (2 mL) was stirred at 100 °C under N2atmosphere for 3 h. The reaction mixture was concentrated under reduced pressure to give a crude product which was purified by silica gel flash chromatography (EtOAc / petroleum ether = 1 / 10 to 1 / 1) and preparative HPLC (column: YMC Triart C18 250*50 mm*7 pm, Method: 26-66% B (A = water (0.05% ammonium hydroxide v / v), 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- methyloxazane-2-carboxamide [compound 1.3] (30.1 mg, 57.1 pmol, 18.9% yield) as a yellow dry powder. m / z: [M+H]+C23H27ClF3N6O3calc 527.2; found 527.3. 1 H NMR (400 MHz, CD3OD) d = 8.91-8.83 (m, 1H), 7.47-7.26 (m, 2H), 7.06 (d, J = 8.4 Hz, 2H), 6.54-6.04 (m, 1H), 5.36 (q, J = 6.8 Hz, 1H), 4.41-4.25 (m, 1H), 4.08-3.95 (m, 1H), 3.71-3.51 (m, 1H), 3.36 (s, 3H), 2.98-2.69 (m, 3H), 1.98-1.90 (m, 1H), 1.85-1.66 (m, 3H), 1.64 (d, J = 6.8 Hz, 3H), 1.63-1.54 (m, 2H).

[0344] 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) ​ ​

[0345]

[0346] A mixture of 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5- a]pyrimidin-6-amine hydrochloride [INT 1.1] (50 mg, 189 pmol), (1r,4r)-4-{[(1S)-1- (4-bromophenyl)-2,2,2-trifluoroethyl](methyl)carbamoyl}cyclohexane-1 -carboxylic acid methyl ester [INT 5.4] (82.4 mg, 189 pmol), Xantphos (21.8 mg, 37.8 pmol), Pd2(dba)3(17.3 mg, 18.9 pmol) and Cs2CO3(123 mg, 378 pmol) in dioxane (2 mL) was stirred at 100 °C under N2atmosphere for 3 h. The reaction mixture was concentrated under reduced pressure to give a crude product which was purified by silica gel flash chromatography (EtOAc / petroleum ether = 1 / 10 to 1 / 1) and preparative HPLC (column: YMC Triart C18 250*50 mm*7 pm, St: 27-67% B (A = water (0.05% ammonium hydroxide v / v), B = acetonitrile), flow rate: 60 mL / min, UV detector 220 nm) to give (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-carboxylic acid methyl ester [compound 1.4] (14.2 mg, 24.3 pmol, 12.9% yield) as a yellow dry powder. m / z: [M+H]+C26H31ClF3N6O4calc. 583.2; found 583.3. 1 H NMR (400 MHz, CDC13) d = 8.90 (s, 1H), 7.32 (d, J = 8.4 Hz, 2H), 7.13-7.09 (m, 1H), 7.04 (d, J = 8.4 Hz, 2H), 6.63 (q, J = 8.2 Hz, 1H), 5.48 (q, J = 6.8 Hz, 1H), 3.69 (s, 3H), 3.49 (s, 3H), 2.92 (s, 3H), 2.63-2.54 (m, 1H), 2.44-2.35 (m, 1H), 2.17-2.06 (m, 2H), 2.00-1.92 (m, 1H), 1.91-1.83 (m, 1H), 1.72-1.63 (m, 2H), 1.61 (d, J = 6.8 Hz, 3H), 1.54-1.42 (m, 2H).

[0347] ​ ​

[0348]

[0349] A mixture of 2-chloro-7-[(1 S)-1 -methoxyethyl]-[1,2,4]triazolo[1,5- a]pyrimidin-6-amine hydrochloride [INT 1.1 ] (100 mg, 378 pmol), N-[(1 S)-1 -(4- bromophenyl)-2,2,2-trifluoroethyl]-N-methylthiazane-4-carboxamide [INT 5.5] (149 mg, 378 pmol), Xantphos (43.7 mg, 75.6 pmol), Pd2(dba)3(34.6 mg, 37.8 pmol) and Cs2CO3(246 mg, 756 pmol) in dioxane (5 mL) was stirred at 100 °C under N2atmosphere for 3 h. The reaction mixture was concentrated under reduced pressure to give a crude product which was purified by silica gel flash chromatography (EtOAc / petroleum ether = 1 / 10 to 1 / 1 ) and preparative HPLC (column: YMC Triart C18 250*50 mm*7 pm, St: 35-75% B (A = water (0.05% ammonium hydroxide v / v), B = acetonitrile), flow rate: 60 mL / min, UV detector 220 nm) to give N-[(1 S)-1 -[4-({2-chloro-7-[(1 S)-1 - methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2- trifluoroethyl]-N-methylthiazane-4-carboxamide [compound 1.5] (26.9 mg, 49.5 pmol, 13.1 % yield) as a yellow dry powder. m / z: [M+H]+C23H27ClF3N6O2S calculated 543.1 ; found 543.4. 1 H NMR (400 MHz, CDC13) d = 8.89 (s, 1 H), 7.31 (d, J = 8.4 Hz, 2H), 7.11 (s, 1 H), 7.04 (d, J = 8.4 Hz, 2H), 6.62 (q, J = 8.4 Hz, 1 H), 5.48 (q, J = 6.8 Hz, 1 H), 3.49 (s, 3H), 2.90 (s, 3H), 2.81 - 2.70 (m, 4H), 2.70 - 2.62 (m, 1 H), 2.17 - 2.11 (m, 1 H), 2.08 - 1.99 (m, 3H), 1.61 (d, J = 6.8 Hz, 3H).

[0350] ​ ​ Synthesis of N-[(1 S)-1 -[4-({2-chloro-7-[(1 S)-1 -methoxyethyl]- [1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N- methylthiazane-4-carboxamide (compound 1.5)

[0351] To a mixture of N-[(1 S)-1 -(4-bromophenyl)-2,2,2-trifluoroethyl]-N- methyloxazolidine-3-carboxamide [INT 5.6] (80 mg, 218 pmol) and 2-chloro-7-[(1 S)-1 - methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-amine hydrochloride [INT 1.1 ] (68.9 mg, 261 pmol) in dioxane (2 mL) was added Pd2(dba)3(19.9 mg, 21.8 pmol), Cs2CO3(213 mg, 654 pmol) and xantphos (12.6 mg, 21.8 pmol). The reaction mixture was stirred at 100 °C under N2for 3 h, then it was diluted with brine (20 mL) and extracted with EtOAc (10 mL x 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 preparative HPLC (column: Boston Prime C18 150*25mm*5pm pm, Method: 32-62% B (A = water (0.05% ammonium hydroxide), B = acetonitrile), flow rate: 25 mL / min, UV detector 220 nm) to give N-[(1 S)-1 -[4-({2-chloro-7-[(1 S)-1 - methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N- methyl oxazolidine-3-carboxamide [compound 1.6] (2.20 mg, 4.28 pmol, 2.0% yield) as off-white dry powder. m / z: [M+H]+C22H25C1F3N6O3calc 513.2; found 513.3. 1 H NMR (400 MHz, CDC13) d = 8.90 (s, 1 H), 7.37-7.31 (m, 2H), 7.12 (s, 1 H), 7.05 (d, J = 8.4 Hz, 2H), 6.62 (q, J = 8.8 Hz, 1 H), 5.49 (q, J = 6.8 Hz, 1 H), 4.18-4.01 (m, 1 H), 4.00-3.86 (m, 3H), 3.49 (s, 3H), 3.40-3.28 (m, 1 H), 2.97-2.82 (m, 3H), 2.32-2.09 (m, 2H), 1.62 (d, J = 6.8 Hz, 3H).

[0352] ​ ​ ​

[0353]

[0354] A mixture of 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5- a]pyrimidin-6-amine hydrochloride [INT 1.1] (60.4 mg, 229 pmol), N-[(1S)-1-(4- bromophenyl)-2,2,2-trifluoroethyl]-N-methyl-1,4-dioxaspiro[4.5]decane-8-carboxamide [INT 5.7] (100 mg, 229 pmol), Xantphos (26.5 mg, 45.8 pmol), Pd2(dba)3(20.9 mg, 22.9 pmol) and Cs2CO3(149 mg, 458 pmol) in dioxane (5 mL) was stirred at 100 °C under N2atmosphere for 3 h. The reaction mixture was concentrated under reduced pressure to give a crude product which was purified by silica gel flash chromatography (EtOAc / petroleum ether = 1 / 5 to 1 / 3) and preparative HPLC (column: YMC Triart C18 250*50 mm*7 pm, St: 33-73% B (A = water (0.05% ammonium hydroxide v / v), 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-1,4-dioxaspiro[4.5]decane-8- carboxamide [compound 1.7] (32.3 mg, 55.4 pmol, 24.2% yield) as a yellow dry powder. m / z: [M+H]+C26H31ClF3N6O4calc. 583.2; found 583.4. 1 H NMR (400 MHz, CDC13) d = 8.89 (s, 1H), 7.32 (d, J = 8.4 Hz, 2H), 7.10 (s, 1H), 7.03 (d, J = 8.4 Hz, 2H), 6.65 (q, J = 8.8 Hz, 1H), 5.48 (q, J = 6.8 Hz, 1H), 3.97 (s, 4H), 3.49 (s, 3H), 2.92 (s, 3H), 2.66-2.55 (m, 1H), 1.97-1.93 (m, 1H), 1.93-1.83 (m, 4H), 1.83-1.75 (m, 1H), 1.61 (d, J = 6.8 Hz, 3H), 1.57-1.52 (m, 2H).

[0355] ​ ​

[0356]

[0357] A mixture of 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5- a]pyrimidin-6-amine hydrochloride [INT 1.1] (100 mg, 378 pmol), N-[(1S)-1-(4- bromophenyl)-2,2,2-trifluoroethyl]-4,4-difluoro-N-methylcyclohexane-1-carboxamide [INT 5.8] (156 mg, 378 pmol), Xantphos (43.7 mg, 75.6 pmol), Pd2(dba)3(34.6 mg, 37.8 pmol) and Cs2CO3(368 mg, 1.13 mmol) in dioxane (5 mL) was stirred at 100 °C for 3 h under N2atmosphere. The reaction mixture was filtered through celite. The filter cake was washed with EtOAc (20 mL x 2). The filtrate was concentrated under reduced pressure to give a crude product which was purified by prep-HPLC (column: Welch Xtimate C18 150*25mm*5pm pm, Method: 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 pmol, 29.0% yield) as a yellow solid. m / z: [M+H]+C24H27ClF5N6O2calc 561.2; found 561.2. 1 H NMR (400 MHz, DMSO-d6) d = 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).

[0358] ​ ​ Synthesis of

[0359]

[0360] (1r,3S)-N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)- [1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-3- cyano-N-methylcyclobutane-1-carboxamide [Compound 1.9] (14.9 mg, 0.02857 mmol, 10.7% yield) as a yellow oil. m / z: [M+H]+C23H24ClF3N7O2 calculated 522.2; found 522.2. 1 H NMR (400 MHz, CD3OD) δ 8.87 (d, J = 1.7 Hz, 1H), 7.31 (d, J = 8.4 Hz, 2H), 7.07 (d, J = 8.4 Hz, 2H), 6.49 (q, J = 9.1 Hz, 1H), 5.37 (q, J = 6.7 Hz, 1H), 3.76 (h, J = 7.3, 6.7 Hz, 1H), 3.37 - 3.24 (m, 2H), 2.82 (s, 3H), 2.77 - 2.58 (m, 7H), 1.65 (d, J = 6.7 Hz, 3H).

[0361] HPLC conditions; System: Agilent 1260 Infinity II LC coupled with Agilent 6120B single quadrupole LC / MS system • Column description: Chromatorex SBM 100-5T 5 pm C18 (2) LC column 100 x 19 mm, Waters, Sun Fire; stationary phase: C18; solid support: totally porous silica; separation mode: reverse phase; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 30 ml / min; loading pump: 4 ml / min B; gradient conditions: 20-40-55-100% (B) 0-2-10-11.2 min.

[0362] 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) 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)

[0363]

[0364] A mixture of tert-butyl 4-{[(1 S)-1 -(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)carbamoyl}piperidine-1 - carboxylate [INT 7.1 ] (150 mg, 312 pmol), Pd2(dba)3 (28.5 mg, 31.2 pmol), Cs2CO3 (304 mg, 936 pmol), 2-chloro-7-[(1 S)-1 -methoxyethyl]-[1,2,4]triazolo[1,5- a]pyrimidin-6-amine hydrochloride [INT 1.1 ] (82.4 mg, 312 pmol) and xantphos (18.0 mg, 31.2 pmol) in dioxane was stirred at 100 °C under N2atmosphere for 4 h. Brine (20 mL) was added and the mixture was extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5pm, Method: 49-79% B (A = water (0.05% ammonium hydroxide v / v) - ACN), B = acetonitrile), flow rate: 30 mL / min, UV detector 220 nm) to give tert-butyl 4-{[(1 S)-1-[4-({2-chloro-7-[(1 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] (9.10 mg, 14.5 pmol, 4.7% yield) as a yellow dry powder. m / z: [M+H-100]+C28H36C1F3N7O4 requires 526.2; found 526.3. 1H NMR (400 MHz, CDC13) d = 8.90 (s, 1H), 7.32 (d, J = 8.8 Hz, 2H), 7.19-7.08 (m, 1H), 7.04 (d, J = 8.8 Hz, 2H), 6.63 (q, J = 8.8 Hz, 1H), 5.48 (q, J = 6.8 Hz, 1H), 4.19 (br d, J = 13.2 Hz, 2H), 3.49 (s, 3H), 3.00-2.91 (m, 3H), 2.85-2.69 (m, 3H), 1.82-1.68 (m, 4H), 1.62 (s, 3H), 1.47 (s, 9H).

[0365] 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) Synthesis of

[0366]

[0367] To a solution of tert-butyl 3-{[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)carbamoyl}piperidine-1-carboxylate [INT 7.2] (700 mg, 1.46 mmol), 2-chloro-7-[(1S)-1-methoxyethyl]- [1,2,4]triazolo[1,5-a]pyrimidin-6-amine hydrochloride [INT 1.1] (332 mg, 1.46 mmol), Cs2CO3(1.42 g, 4.38 mmol) and xantphos (168 mg, 292 μmol) in dioxane (5 mL) was added Pd2(dba)3(133 mg, 146 μmol) and the reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a crude product which was purified by flash chromatography on silica gel (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 250*50mm*7μm, Method: 47-87%B (A=water (0.225%FA), B=acetonitrile), Flow: 60 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}piperidine-1-carboxylate [compound 1.11] (10.6 mg, 16.9 μmol) as an off-white solid. m / z: [M+H]+C28H36ClF3N7O4 calculated 626.2; found 626.3. 1 H NMR (400 MHz, DMSO-d6) d = 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).

[0368] 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) 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) 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)

[0369]

[0370] To a mixture of tert-butyl 3-{[(1S)-1-(4-bromophenyl)-2,2,2- trifluoroethyl](methyl)carbamoyl}pyrrolidine-1-carboxylate [INT 7.3] (140 mg, 300 pmol), 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-amine hydrochloride [INT 1.1] (95.0 mg, 360 pmol), xantphos (17.3 mg, 30.0 pmol) and Cs2CO3(390 mg, 1.20 mmol) in dioxane (2 mL) was added Pd2(dba)3(27.4 mg, 30.0 pmol) and the mixture was stirred at 100 °C under N2for 3 h. The reaction mixture was diluted with brine (20 mL) and extracted with EtOAc (20 mL x 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 pm, method: 44-74% B (A = water (0.05% ammonium hydroxide v / v) - 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 pmol, 1.5% yield) as a yellow dry powder. m / z: [M+H]+C27H34ClF3N7O4calc. 612.2; found 612.4. 1H NMR (400 MHz, CDC13) d = 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).

[0371] 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) 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)carbamic acid methyl ester (also known as (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)amino)methyl dihydrogen phosphate) (Compound 1.16) 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](methyl)carbamate (Compound 1.17)

[0372]

[0373] To a suspension of tert-butyl N-[(4-{[(1 S)-1 -(4-bromophenyl)-2,2,2- trifluoroethyl](methyl)carbamoyl}cyclohexyl)methyl]carbamate [INT 7.4] (420 mg, 827 pmol), 2-chloro-7-[(1 S)-1 -methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-amine hydrochloride [INT 1.1 ] (282 mg, 1.07 mmol), Cs2CO3(537 mg, 1.65 mmol) and xantphos (95.4 mg, 165 pmol) in dioxane (3 mL) was added Pd2(dba)3(75.7 mg, 82.7 pmol). The resulting mixture was stirred at 100 °C under N2for 3 h. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by flash chromatography on silica gel (MeOH / dichloromethane = 0 / 1 to 1 / 99) to give tert-butyl N-[(4-{[(1 S)-1 -[4-({2-chloro-7-[(1 S)-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 pmol, 92.5% yield) as a yellow solid. 100 mg of the product was further purified by preparative HPLC (column: Phenomenex Gemini-NX 80*40 mm*3 pm, Table: 39-79% B (A = water (0.05% ammonium hydroxide v / v), B = MeOH), flow rate: 25 mL / min, UV detector 220 nm) to give tert-butyl N-[(4-{[(1 S)-1 -[4-({2-chloro-7-[(1 S)-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 pmol) as a yellow dry powder. m / z: [M+H]+C30H40ClF3N7O4calc. 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).

[0374] ​ ​ ​

[0375]

[0376] To a mixture of (lr,4S)-N-((S)-l-(4-bromophenyl)-2,2,2-trifluoroethyl)-4- methoxy-N-methylcyclohexane-l-carboxamide [INT 7.5] (90 mg, 220 pmol), 2- chloro-7-[(lS)-l-methoxyethyl]-[l,2,4]triazolo[l,5-a]pyrimidin-6-amine hydrochloride [INT 1.1] (50.0 mg, 220 pmol), Cs2CO3(143 mg, 440 pmol) and Xantphos (25.4 mg, 44.0 pmol) in dioxane (1 mL) was added Pd2(dba)3(20.1 mg, 22.0 pmol) under N2and the reaction mixture was stirred at 100 °C for 1 h. The reaction was quenched by the addition of water (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure to give the crude product which was purified by preparative HPLC (Column: YMC-Actus Triart C18 150*30 mm*5 pm, Method: 48-68% water (0.05% ammonium hydroxide v / v) - ACN, Flow rate: 35 mL / min, UV detector 220 nm) to give (lr,4S)-N-((S)-l-(4-((2-chloro-7-((S)-l-methoxyethyl)- [l,2,4]triazolo[l,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-4-methoxy-N- methylcyclohexane-l-carboxamide [Compound 1.14] (8.60 mg, 15.4 pmol, 7.0% yield) as a yellow dry powder. m / z: [M+H]+C25H31ClF3N6O3calc 555.2; found 555.3. 1 H NMR (400 MHz, DMSO-d6) d = 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).

[0377] ​ ​ ​

[0378]

[0379] To a solution of 1 -acetyl-N-[(1 S)-1 -(4-bromophenyl)-2,2,2-trifluoroethyl]-N- methylazetidine-3-carboxamide [INT 5.10] (100 mg, 254 pmol), 2-chloro-7-[(1 S)-1 - methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-amine hydrochloride [INT 1.1 ] (73.6 mg, 279 pmol), Cs2CO3(248 mg, 762 pmol) and xantphos (29.3 mg, 50.8 pmol) in dioxane (3 mL) was added Pd2(dba)3(23.2 mg, 25.4 pmol) and the reaction mixture was stirred at 100 °C for 16 h under N2. The reaction mixture was concentrated under reduced pressure to give a crude product which was purified by preparative HPLC (column: YMC Triart C18 250*50mm*7pm, St: 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-[(1 S)-1 -[4-({2-chloro-7-[(1 S)-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 pmol, 15.4% yield) as a yellow dry powder. m / z: [M+H]+C23H26ClF3N7O3calc 540.2; found 540.2. 1 H NMR (400 MHz, DMSO-d6) d = 8.85 (s, 1 H), 8.02 (s, 1 H), 7.33-7.15 (m, 2H), 6.97 (br d, J = 8.4 Hz, 2H), 6.42 (q, J = 9.2 Hz, 1 H), 5.16 (q, J = 6.8 Hz, 1 H), 4.38-4.17 (m, 2H), 4.10-3.99 (m, 1 H), 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).

[0380] ​ ​ ​ ​

[0381]

[0382] To a mixture of methyl N-(4-{[(1 S)-1 -(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)carbamoyl}cyclohexyl)carbamate [INT 9.1] (40 mg, 88.6 pmol), 2-chloro-7-[(1 S)-1 - methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-amine hydrochloride [INT 1.1] (20.1 mg, 88.6 pmol), Cs2CO3(57.6 mg, 177 pmol) and Xantphos (10.2 mg, 17.7 pmol) in dioxane (1 mL) was added Pd2(dba)3(8.11 mg, 8.86 pmol) at 20 °C and the mixture was stirred at 100 °C under N2for 1 h. The reaction mixture was cooled to 25 °C and combined with another batch of the same reaction (44.3 pmol scale of INT 9.1). Water (10 mL) was added and the mixture was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure to give the crude product which was purified by preparative HPLC (column: YMC-Actus Triart C18 150*30 mm*5 pm, Method: 46-66% water (0.05% ammonium hydroxide v / v)-ACN, flow rate: 35 mL / min, UV detector 220 nm) to give methyl N-(4-{[(1 S)-1 -[4-({2-chloro-7-[(1 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] (12.2 mg, 20.4 pmol, 15.3% yield) as a yellow dry powder. m / z: [M+H]+C26H32C1F3N7O4calc 598.2; found 598.3. 1 HNMR (400 MHz, DMSO-d6) d = 8.83 (s, 1 H), 7.98 (s, 1 H), 7.16 (br d, J = 8.4 Hz, 2H), 6.96 (d, J = 8.7 Hz, 3H), 6.55-6.07 (m, 1 H), 5.15 (q, J = 6.7 Hz, 1 H), 3.50 (s, 3H), 3.28-3.20 (m, 1 H), 3.16 (s, 3H), 2.87 (s, 3H), 2.61 (br s, 1 H), 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).

[0383] ​Synthesis of N-[(1 S)-1 -(4-{[2-chloro-7-(prop-2-yl)-[1,2,4]triazolo[1,5- a]pyrimidin-6-yl]amino}phenyl]-2,2,2-trifluoroethyl]-4-acetylamino-N- methylcyclohexane-1 -carboxamide (Compound 1.17) Synthesis of N-[(1 S)-1 -(4-{[2-chloro-7-(prop-2-yl)-[1,2,4]triazolo[1,5- a]pyrimidin-6-yl]amino}phenyl]-2,2,2-trifluoroethyl]-4-acetylamino-N- methylcyclohexane-1 -carboxamide (Compound 1.17)

[0384]

[0385] To a mixture of N-[(1 S)-1 -(4-bromophenyl)-2,2,2-trifluoroethyl]-4- acetylamino-N-methylcyclohexane-1 -carboxamide [INT 9.2] (20 mg, 45.9 pmol), 2-chloro-7-[(1 S)-1 -methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-amine hydrochloride [INT 1.1 ] (10.4 mg, 45.9 pmol), Cs2CO3(29.9 mg, 91.8 pmol) and Xantphos (5.31 mg, 9.18 pmol) in dioxane (2 mL) was added Pd2(dba)3(4.20 mg, 4.59 pmol) at 20 °C and the mixture was stirred at 100 °C under N2for 1 h. The reaction was combined with another batch of the same reaction (22.9 pmol scale) and concentrated under reduced pressure to give a crude product which was purified by preparative HPLC (column: YMC Actus Triart C18 150*30 mm*5 pm, Table: 42-62% water (0.05% ammonium hydroxide v / v) - ACN, flow rate: 35 mL / min, UV detector 220 nm) to give N-[(1 S)-1 -[4-({2-chloro-7-[(1 S)-1 - methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2- trifluoroethyl]-4-acetylamino-N-methylcyclohexane-1 -carboxamide [compound 1.17] (8.50 mg, 14.6 pmol, 21.2% yield) as a yellow dry powder. m / z: [M+H]+C26H32C1F3N7O3 calculated 582.2; found 582.2. 1 H NMR (400 MHz, DMSO-d6) d = 8.83 (s, 1 H), 7.98 (s, 1 H), 7.72 (d, J = 7.6 Hz, 1 H), 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, 1 H), 5.15 (q, J = 6.7 Hz, 1 H), 3.46 (br s, 1 H), 3.16 (s, 3H), 2.88 (s, 3H), 2.63 (br d, J = 7.2 Hz, 1 H), 1.91 -1.66 (m, 7H), 1.59 (d, J = 6.6 Hz, 3H), 1.51 -1.31 (m, 2H), 1.29-1.1 1 (m, 2H).

[0386] Synthesis of N-[(1 S)-1 -(4-{[2-chloro-7-(prop-2-yl)-[1,2,4]triazolo[1,5- a]pyrimidin-6-yl]amino}phenyl]-2,2,2-trifluoroethyl]-4-acetylamino-N- methylcyclohexane-1 -carboxamide (Compound 1.17) [2-(2,2,2-trifluoro-ethoxy)-2,2-difluoro-ethyl]-N-methyl-1,1-dioxo-1 lambda 6 - thiazane-4-carboxamide (also known as (S)-N-(1-(4- 1 -acetyl-N-[(1 S)-1 -(4-{[2-chloro-7-(prop-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-6- yl]amino}phenyl)-2,2,2-trifluoroethyl]-N-methylpiperidine-4-carboxamide (Compound 1.19) Synthesis of N-{1 -[4-({2-chloro-7-[(1 S)-1 -methoxyethyl]-[1,2,4]triazolo[1,5- a]pyrimidin-6-yl}amino)phenyl]ethyl}-N-methylcyclobutane carboxamide (Compound 1.20)

[0387]

[0388] To a solution of 2-chloro-7-(propan-2-yl)-[l,2,4]triazolo[l,5-a]pyrimidin-6-amine hydrochloride [INT 1.2] (30 mg, 120 pmol), N-[(lS)-l-(4-bromophenyl)-2,2,2- trifluoroethyl]-N-methyl-l,l-dioxo-l lambda 6 To a solution of 2-chloro-7-(propan-2-yl)-[l,2,4]triazolo[l,5-a]pyrimidin-6-amine hydrochloride [INT 1.2] (30 mg, 120 pmol), N-[(lS)-l-(4-bromophenyl)-2,2,2- trifluoroethyl]-N-methyl-l,l-dioxo-l lambda 6 - thiazane-4-carboxamide [compound 1.18] (22.1 mg, 39.5 pmol, 16.5% yield) as a white dry powder. m / z: [M+H]+calcd for C23H27ClF3N6O3S 559.1; found 559.1. 1 H NMR (400 MHz, DMSO-d6) d = 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).

[0389] Synthesis of N-{1 -[4-({2-chloro-7-[(1 S)-1 -methoxyethyl]-[1,2,4]triazolo[1,5- a]pyrimidin-6-yl}amino)phenyl]ethyl}-N-methylcyclobutane carboxamide (Compound 1.20) Synthesis of N-{1 -[4-({2-chloro-7-[(1 S)-1 -methoxyethyl]-[1,2,4]triazolo[1,5- a]pyrimidin-6-yl}amino)phenyl]ethyl}-N-methylcyclobutane carboxamide (Compound 1.20)

[0390]

[0391] A mixture of 2-chloro-7-(propan-2-yl)-[l,2,4]triazolo[l,5-a]pyrimidin-6-amine hydrochloride [INT 1.2] (50 mg, 201 pmol), l-acetyl-N-[(lS)-l-(4-bromophenyl)-2,2,2- trifluoroethyl]-N-methylpiperidine-4-carboxamide [INT 5.11] (93.0 mg, 221 pmol), xantphos (11.6 mg, 20.1 pmol), Pd2(dba)3(18.4 mg, 20.1 pmol) and Cs2CO3(196 mg, 602 pmol) in dioxane (1 mL) was stirred at 100 °C under N2atmosphere for 3 h. The mixture was concentrated under reduced pressure to give a crude product which was purified by preparative HPLC (column: Boston Prime C18 150*30 mm*5 pm, Method: 25-65% B (A = water (0.05% ammonium hydroxide v / v) - ACN), B = acetonitrile), flow rate: 25 mL / min, UV detector 220 nm) to give l-acetyl-N-[(lS)-l-(4-{[2-chloro-7-(propan-2-yl)-[l,2,4]triazolo[l,5-a]pyrimidin-6- yl]amino}phenyl)-2,2,2-trifluoroethyl]-N-methylpiperidine-4-carboxamide [compound 1.19] (19.1 mg, 34.6 pmol, 17.3% yield) as a white dry powder. m / z: [M+H]+C25H30ClF3N7O2calc 552.2; found 552.2. 1 H NMR (400 MHz, CDC13) d = 8.68 (s, 1H), 7.24 (br t, J = 7.6 Hz, 2H), 6.66 (d, J = 8.4 Hz, 2H), 6.57 (q, J = 9.2 Hz, 1H), 5.47 (br s, 1H), 4.61 (br d, J = 13.6 Hz, 1H), 3.97-3.86 (m, 2H), 3.22-3.08 (m, 1H), 2.92 (s, 3H), 2.85-2.62 (m, 2H), 2.11 (d, J = 2.4 Hz, 3H), 1.91-1.81 (m, 2H), 1.80-1.69 (m, 2H), 1.54 (s, 3H), 1.53 (s, 3H).

[0392] Synthesis of N-{1 -[4-({2-chloro-7-[(1 S)-1 -methoxyethyl]-[1,2,4]triazolo[1,5- a]pyrimidin-6-yl}amino)phenyl]ethyl}-N-methylcyclobutane carboxamide (Compound 1.20) Synthesis of N-{1 -[4-({2-chloro-7-[(1 S)-1 -methoxyethyl]-[1,2,4]triazolo[1,5- a]pyrimidin-6-yl}amino)phenyl]ethyl}-N-methylcyclobutane carboxamide (Compound 1.20)

[0393]

[0394] To a solution of N-[1-(4-bromophenyl)ethyl]-N-methylcyclobutanecarboxamide [INT 11.1] (60 mg, 202 pmol), 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5- a]pyrimidin-6-amine hydrochloride [INT 1.1] (45.9 mg, 202 pmol), Cs2CO3 (197 mg, 606 pmol) and xantphos (23.3 mg, 40.4 pmol) in dioxane (2 mL) was added Pd2(dba)3 (18.4 mg, 20.2 pmol) and the reaction mixture was stirred at 100 °C under N2for 2 h. The mixture was concentrated in vacuo to give a crude product which was purified by preparative HPLC (column: Phenomenex Gemini-NX 80*40 mm*3 pm, Method: 20-60% B (A = water (0.05% ammonium hydroxide v / v), B = acetonitrile), Flow: 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 pmol, 6.3% yield) as a yellow dry powder. m / z: [M+H]+C22H28ClN6O2calc 443.2; found 443.3. 1 H NMR (400 MHz, DMSO-d6) d = 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).

[0395] Synthesis of N-{1 -[4-({2-chloro-7-[(1 S)-1 -methoxyethyl]-[1,2,4]triazolo[1,5- a]pyrimidin-6-yl}amino)phenyl]ethyl}-N-methylcyclobutane carboxamide (Compound 1.20) Synthesis of N-{1 -[4-({2-chloro-7-[(1 S)-1 -methoxyethyl]-[1,2,4]triazolo[1,5- a]pyrimidin-6-yl}amino)phenyl]ethyl}-N-methylcyclobutane carboxamide (Compound 1.20)

[0396]

[0397] To a solution of N-[1-(4-bromophenyl)ethyl]-N-methylcyclohexanecarboxamide [INT 11.2] (50 mg, 154 pmol), 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5- a]pyrimidin-6-amine hydrochloride [INT 1.1] (35.0 mg, 154 pmol), Cs2CO3 (150 mg, 462 pmol) and xantphos (17.8 mg, 30.8 pmol) in dioxane (3 mL) was added Pd2(dba)3 (14.1 mg, 15.4 pmol) and the reaction mixture was stirred at 100 °C under N2for 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 pm, Statio: 35-75% B (A = water (0.05% ammonium hydroxide v / v), 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 pmol, 12.8% yield) as a yellow dry powder. m / z: [M+H]+C24H32CIN6O2calc 471.2; found 471.3. 1 H NMR (400 MHz, DMSO-d6) d = 8.79 (s, 1H), 7.79-7.70 (m, 1H), 7.11-7.03 (m, 2H), 6.96-6.88 (m, 2H), 5.83-5.12 (m, 2H), 3.17 (s, 3H), 2.75-2.53 (m, 3H), 1.74-1.60 (m, 5H), 1.58 (d, J = 6.8 Hz, 3H), 1.49 (br d, J = 6.8 Hz, 1H), 1.42 (br s, 1H), 1.34 (br d, J = 7.2 Hz, 3H), 1.27 (br d, J = 12.8 Hz, 2H), 1.24-1.09 (m, 2H).

[0398] Synthesis of N-{1 -[4-({2-chloro-7-[(1 S)-1 -methoxyethyl]-[1,2,4]triazolo[1,5- a]pyrimidin-6-yl}amino)phenyl]ethyl}-N-methylcyclobutane carboxamide (Compound 1.20) Synthesis of N-{1 -[4-({2-chloro-7-[(1 S)-1 -methoxyethyl]-[1,2,4]triazolo[1,5- a]pyrimidin-6-yl}amino)phenyl]ethyl}-N-methylcyclobutane carboxamide (Compound 1.20)

[0399]

[0400] To a solution of N-[1-(4-bromophenyl)ethyl]-N-methylcyclopentanecarboxamide [INT 11.3] (50 mg, 161 μmol) and 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5- a]pyrimidin-6-amine hydrochloride [INT 1.1] (36.6 mg, 161 μmol) in dioxane (3 mL) was added Cs2CO3(157 mg, 482 μmol), xantphos (18.5 mg, 32.1 μmol) and Pd2(dba)3(14.6 mg, 16.0 μmol). The reaction mixture was stirred at 100 °C under N2for 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, Method: 35-75% B (A = water (0.05% ammonium hydroxide v / v), B = acetonitrile), Flow: 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]+C23H30ClN6O2calc 457.2; found 457.3. 1 H NMR (400 MHz, DMSO-d6) d = 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).

[0401] Synthesis of N-{1 -[4-({2-chloro-7-[(1 S)-1 -methoxyethyl]-[1,2,4]triazolo[1,5- a]pyrimidin-6-yl}amino)phenyl]ethyl}-N-methylcyclobutane carboxamide (Compound 1.20) Synthesis of N-{1 -[4-({2-chloro-7-[(1 S)-1 -methoxyethyl]-[1,2,4]triazolo[1,5- a]pyrimidin-6-yl}amino)phenyl]ethyl}-N-methylcyclobutane carboxamide (Compound 1.20)

[0402]

[0403] To a mixture of N-[l-(4-bromophenyl)ethyl]-N-methylcyclopropanecarboxamide [INT 12.2] (50 mg, 177 pmol) and 2-chloro-7-[(lS)-l-methoxyethyl]- [l,2,4]triazolo[l,5-a]pyrimidin-6-amine hydrochloride [INT 1.1] (40.2 mg, 177 pmol) in dioxane (2 ml) was added Pd2(dba)3(16.2 mg, 17.7 pmol), Cs2CO3(173 mg, 531 pmol) and xantphos (20.4 mg, 35.4 pmol) at 25 °C. The mixture was stirred under N2at 100 °C 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 pm, St: 25-65% B (A = water (0.05% ammonium hydroxide v / v), B = acetonitrile), flow rate: 60 mL / min, UV detector 220 nm) to give N-{l-[4-({2-chloro-7-[(lS)-l-methoxyethyl]- [l,2,4]triazolo[l,5-a]pyrimidin-6-yl}amino)phenyl]ethyl}-N-methylcyclopropanecarboxamide [compound 1.23] (16.9 mg, 39.4 pmol, 22.2% yield) as a yellow dry powder. m / z: [M+H]+C21H26ClN6O2calc 429.2; found 429.3. 1 H NMR (400 MHz, DMSO-d6) d = 8.86 (s, 1H), 7.92 - 7.74 (m, 1H), 7.46 - 6.96 (m, 4H), 5.86 - 5.52 (m, 1H), 5.23 (q, J = 6.8 Hz, 1H), 3.24 (s, 3H), 2.87 - 2.58 (m, 3H), 2.19 - 1.89 (m, 1H), 1.64 (d, J = 6.8 Hz, 3H), 1.59 (br d, J = 6.4 Hz, 1H), 1.43 (br d, J = 7.2 Hz, 2H), 0.85 - 0.76 (m, 4H).

[0404] Synthesis of N-{1 -[4-({2-chloro-7-[(1 S)-1 -methoxyethyl]-[1,2,4]triazolo[1,5- a]pyrimidin-6-yl}amino)phenyl]ethyl}-N-methylcyclobutane carboxamide (Compound 1.20) Synthesis of N-{1 -[4-({2-chloro-7-[(1 S)-1 -methoxyethyl]-[1,2,4]triazolo[1,5- a]pyrimidin-6-yl}amino)phenyl]ethyl}-N-methylcyclobutane carboxamide (Compound 1.20)

[0405]

[0406] To a solution of N-[1-(4-bromophenyl)ethyl]-N-methylacetamide [INT 12.1] (30 mg, 117 pmol) and 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5- a]pyrimidin-6-amine hydrochloride [INT 1.1] (26.6 mg, 117 pmol) in dioxane (2 mL) was added Pd2(dba)3 (10.7 mg, 11.7 pmol), Cs2CO3 (114 mg, 351 pmol) and xantphos (13.5 mg, 23.4 pmol). The reaction mixture was stirred at 100 °C under N2for 2 h. The reaction mixture was concentrated under reduced pressure to give a crude product which was purified by preparative HPLC (column: YMC-Actus Triart C18 150*30 mm*5 pm, Table: 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 pmol, 5.3% yield) as a yellow dry powder. m / z: [M+H]+C19H24CIN6O2calc 403.2; found 403.2. 1 H NMR (400 MHz, DMSO-d6) d = 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).

[0407] Synthesis of N-{1 -[4-({2-chloro-7-[(1 S)-1 -methoxyethyl]-[1,2,4]triazolo[1,5- a]pyrimidin-6-yl}amino)phenyl]ethyl}-N-methylcyclobutane carboxamide (Compound 1.20) Synthesis of N-{1 -[4-({2-chloro-7-[(1 S)-1 -methoxyethyl]-[1,2,4]triazolo[1,5- a]pyrimidin-6-yl}amino)phenyl]ethyl}-N-methylcyclobutane carboxamide (Compound 1.20)

[0408]

[0409] To a mixture of 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5- a]pyrimidin-6-amine hydrochloride [INT 1.1] (120 mg, 0.5271 mmol), N-[1-(4- bromophenyl)-2,2,2-trifluoroethyl]-N-methylacetamide [INT 13.1] (150 mg, 0.4836 mmol), xantphos (80 mg, 0.1382 mmol) and Cs2CO3(500 mg, 1.53 mmol) in dioxane (2 mL) was added Pd2(dba)3(80 mg, 0.08736 mmol) and the mixture was stirred at 100 °C under N2for 12 h. The reaction was diluted with EtOAc (30 mL), filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: Boston Prime C18 150*30 mm*5 μm, conditions: 40% - 60% CH3CN in water (0.05% ammonium hydroxide v / v), 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 yellow dry powder. m / z: [M+H]+C19H21ClF3N6O2calc 457.1; found 457.1. 1 H NMR (400 MHz, DMSO-d6) d = 8.84 (s, 1H), 8.07 - 7.90 (m, 1H), 7.34 - 7.13 (m, 2H), 6.97 (br d, J = 8.6 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).

[0410] Synthesis of N-{1 -[4-({2-chloro-7-[(1 S)-1 -methoxyethyl]-[1,2,4]triazolo[1,5- a]pyrimidin-6-yl}amino)phenyl]ethyl}-N-methylcyclobutane carboxamide (Compound 1.20) [2-(4-amino)phenyl]-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ 6 - thioxan-4-carboxamide (also known as N- Synthesis of N-{1 -[4-({2-chloro-7-[(1 S)-1 -methoxyethyl]-[1,2,4]triazolo[1,5- a]pyrimidin-6-yl}amino)phenyl]ethyl}-N-methylcyclobutane carboxamide (Compound 1.20) Synthesis of N-{1 -[4-({2-chloro-7-[(1 S)-1 -methoxyethyl]-[1,2,4]triazolo[1,5- a]pyrimidin-6-yl}amino)phenyl]ethyl}-N-methylcyclobutane carboxamide (Compound 1.20) Synthesis of N-{1 -[4-({2-chloro-7-[(1 S)-1 -methoxyethyl]-[1,2,4]triazolo[1,5- a]pyrimidin-6-yl}amino)phenyl]ethyl}-N-methylcyclobutane carboxamide (Compound 1.20) Synthesis of N-{1 -[4-({2-chloro-7-[(1 S)-1 -methoxyethyl]-[1,2,4]triazolo[1,5- a]pyrimidin-6-yl}amino)phenyl]ethyl}-N-methylcyclobutane carboxamide (Compound 1.20) Synthesis of N-{1 -[4-({2-chloro-7-[(1 S)-1 -methoxyethyl]-[1,2,4]triazolo[1,5- a]pyrimidin-6-yl}amino)phenyl]ethyl}-N-methylcyclobutane car Synthesis of N-[(1R)-1-[4-({2-chloro-7-[(1R)-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) Synthesis of N-[(1R)-1-[4-({2-chloro-7-[(1R)-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)

[0411]

[0412] To N-[(1R)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ 6- To a solution of thiazane-4-carboxamide [INT 14.1] (50 mg, 116 pmol) and 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-amine hydrochloride [INT 1.1] (31.6 mg, 139 pmol) in dioxane (2 mL) was added Pd2(dba)3 (10.6 mg, 11.6 pmol), Cs2CO3 (113 mg, 348 pmol) and xantphos (13.4 mg, 23.2 pmol). The reaction mixture was stirred at 100 °C under N2for 2 h. The reaction mixture was concentrated under reduced pressure to give a crude product which was purified by preparative HPLC (column: Boston Green ODS 150*30 mm*5 pm, Method: 24-64% B (A = water (0.05% ammonium 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-1lambda 6 - Thiazane-4-carboxamide [compound 1.26] (16.4 mg, 28.5 pmol, 24.6% yield) as a yellow dry powder. m / z: [M+H]+calcd for C23H27ClF3N6O4S 575.1; found 575.3. 1 H NMR (400 MHz, DMSO-d6) d = 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).

[0413] Synthesis of N-[(1R)-1-[4-({2-chloro-7-[(1R)-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) [2-(2,3-dihydro-7-methyl-2-oxo-4- quinazolinyl)-ethyl]-n-methyl-1,1-dioxo-1 lambda 6 - thioxan-4-carboxamide (also known as N- Synthesis of N-[(1R)-1-[4-({2-chloro-7-[(1R)-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) Synthesis of N-[(1R)-1-[4-({2-chloro-7-[(1R)-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) Synthesis of N-[(1R)-1-[4-({2-chloro-7-[(1R)-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)

[0414]

[0415] A mixture of 2-chloro-7-[(1 R)-1-methoxyethyl]-[1,2,4]triazolo[1,5- a]pyrimidin-6-amine hydrochloride [INT 1.3] (60 mg, 227 pmol), N-[(1 R)-1-(4- bromophenyl)-2,2,2-trifluoroethyl]-N-methyl-1,1 -dioxo-1 lambda 6 A mixture of 2-chloro-7-[(1 R)-1-methoxyethyl]-[1,2,4]triazolo[1,5- a]pyrimidin-6-amine hydrochloride [INT 1.3] (60 mg, 227 pmol), N-[(1 R)-1-(4- bromophenyl)-2,2,2-trifluoroethyl]-N-methyl-1,1 -dioxo-1 lambda 6 - thiazane-4-carboxamide [compound 1.27] (5.20 mg, 9.04 pmol, 4.0% yield) as a white dry powder. m / z: [M+H]+calcd for C23H27ClF3N6O4S 575.1 ; found 575.3. 1 H NMR (400 MHz, CD3OD) d = 8.86 (s, 1 H), 7.30 (d, J = 8.4 Hz, 2H), 7.06 (d, J = 8.4 Hz, 2H), 6.52 (q, J = 9.2 Hz, 1 H), 5.36 (q, J = 6.8 Hz, 1 H), 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).

[0416] Synthesis of N-[(1R)-1-[4-({2-chloro-7-[(1R)-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) Synthesis of N-[(1R)-1-[4-({2-chloro-7-[(1R)-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)

[0417]

[0418] N-[(1S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethyl]-N- methylcyclobutanecarboxamide [INT 16.1] (0.1 g, 0.2745 mmol), 2-chloro-7-[(1S)-1- methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-amine [free base of INT 1.1] (62.3 mg, 274 µmol), Cs2CO3 (268 mg, 823 µmol) and xantphos (15.8 mg, 27.4 µmol) were mixed in dioxane (2 mL) and the reaction mixture was degassed with argon for 5 minutes. Pd2(dba)3 (12.5 mg, 13.7 µmol) was added, followed by degassing the reaction mixture with argon for 5 minutes and stirring at 100 °C for 10 hours. The reaction mixture was cooled to room temperature. The solids were filtered off. The filtrate was purified by HPLC (see below conditions) to give N-[(1S)-1-[4-({2-chloro-7-[(1S)-1- methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)-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]+calcd for C23H27ClF3N6O2 511.2; found 511.2. 1 H NMR (400 MHz, DMSO-d6) d = 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).

[0419] HPLC conditions; system: Agilent 1260 Infinity II LC coupled with Agilent 6120B single quadrupole LC / MS system; column description: Chromatorex SBM 100-5T 5 pm C18 (2) LC column 100 x 19 mm, Waters, Sun Fire; stationary phase: C18; solid support: totally porous silica; mode of separation: reverse phase; mobile phase A: water.

[0420] Synthesis of N-[(1R)-1-[4-({2-chloro-7-[(1R)-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) Synthesis of N-[(1R)-1-[4-({2-chloro-7-[(1R)-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)

[0421]

[0422] N-[(1S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethyl]-N-methylcyclopropanecarboxamide [INT 16.2] (0.1 g, 0.2855 mmol), 2-chloro-7-[(1S)-1-methoxyethyl]- [1,2,4]triazolo[1,5-a]pyrimidin-6-amine [free base of INT 1.1] (64.8 mg, 0.2846 mmol), Cs2CO3(277 mg, 853 μmol) and xantphos (16.4 mg, 28.4 μmol) were mixed in dioxane (2 mL). Pd2(dba)3(13.0 mg, 14.2 μmol) was added under inert atmosphere. The mixture was stirred at 100 °C for 10 h, then the reaction mixture was cooled to rt. The solids were filtered off and the filtrate was purified by HPLC (see below conditions) to give N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]- [1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)-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]+C22H25ClF3N6O2calc. 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).

[0423] HPLC conditions; system: Agilent 1260 Infinity II LC coupled to Agilent 6120B single quadrupole LC / MS system; column description: Chromatorex SBM 100-5T 5 μm C18 (2) LC column 100x 19mm, Waters, Sun Fire; stationary phase: C18; solid support: fully porous silica; separation mode: reversed phase; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 30 ml / min; loading pump: 4 ml / min B; gradient conditions: 20-40-50-100% (B) 0-2-10-11.2 min.

[0424] Synthesis of N-[(1R)-1-[4-({2-chloro-7-[(1R)-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) [2-(2,6-dimethyl-4-pyridinyl)-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1 lambda 6 - thiazan-4-carboxamide (also known as Synthesis of N-[(1R)-1-[4-({2-chloro-7-[(1R)-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) Synthesis of N-[(1R)-1-[4-({2-chloro-7-[(1R)-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) Synthesis of N-[(1R)-1-[4-({2-chloro-7-[(1R)-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)

[0425]

[0426] N-[(1S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ 6 A mixture of thiazide-4-carboxamide [INT 16.3] (100 mg, 0.2260 mmol), 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidine-6-amine [INT 1.1 free base] (51.4 mg, 226 μmol), Cs₂CO₃ (220 mg, 678 μmol), and dioxane (3 mL) was purged with argon. Then xantphos (26.1 mg, 45.2 μmol) and Pd₂(dba)₃ (20.6 mg, 22.6 μmol) were added, and the reaction mixture was stirred at 100 °C for 10 hours. After cooling, the reaction mixture was diluted with EtOAc (30 mL) and concentrated under reduced pressure. The resulting residue was purified by HPLC (see below conditions) to give N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)-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), is a yellow solid. m / z: [M+H]+C24H29ClF3N6O4S Calculated value 589.2; Found value 589.0. 1H NMR (500 MHz, DMSO-d6) d = 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).

[0427] HPLC conditions; system: Agilent 1260 Infinity II LC coupled with Agilent 6120B single quadrupole LC / MS system; column description: Chromatorex SBM 100-5T 5 pm C18 (2) LC column 100 x 19 mm, Waters, Sun Fire; stationary phase: C18; solid support: totally 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) 0-2-10-11.2 min.

[0428] Synthesis of N-[(1R)-1-[4-({2-chloro-7-[(1R)-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) Synthesis of N-[(1R)-1-[4-({2-chloro-7-[(1R)-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)

[0429]

[0430] N-[(1S)-1-(4-bromo-3-methylphenyl)-2,2,2-trifluoroethyl]-N- methylcyclobutanecarboxamide [INT 17.1] (0.12 g, 0.3294 mmol), 2-chloro-7-[(1S)-1- methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-amine [free base of INT 1.1] (74.8 mg, 329 µmol), Cs2CO3 (321 mg, 988 µmol) and xantphos (19.0 mg, 32.9 µmol) were mixed in dioxane (2 mL) and the reaction mixture was degassed with argon for 5 minutes. Pd2(dba)3 (15.0 mg, 16.4 µmol) was added and then the reaction mixture was degassed with argon for 5 minutes and stirred at 100 °C for 10 hours. The reaction mixture was cooled to room temperature and the solids were filtered off. The filtrate was purified by HPLC (see below for conditions) to give N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]- [1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)-3-methylphenyl]-2,2,2-trifluoroethyl]-N- methylcyclobutanecarboxamide [compound 1.31] (7.31 mg, 0.01431 mmol, 4.4% yield) as a yellow solid. m / z: [M+H]+C23H27ClF3N6O2calc. 511.2; found 511.2. 1 H NMR (500 MHz, DMSO-d6) d = 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 = 9.5 Hz, 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).

[0431] HPLC conditions; system: Agilent 1260 Infinity II LC coupled with Agilent 6120B single quadrupole LC / MS system; column description: Chromatorex SBM 100-5T 5 pm C18 (2) LC column 100 x 19 mm, Waters, Sun Fire; stationary phase: C18; solid support: totally porous silica; separation mode: reverse phase; mobile phase A: water mobile phase B: acetonitrile; flow rate: 30 ml / min; loading pump: 4 ml / min B; gradient conditions: 30-45-60-100% (B) 0-2-10-11.2 min.

[0432] Synthesis of N-[(1R)-1-[4-({2-chloro-7-[(1R)-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) Synthesis of N-[(1R)-1-[4-({2-chloro-7-[(1R)-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)

[0433]

[0434] N-[(1S)-1-(4-bromo-3-methylphenyl)-2,2,2-trifluoroethyl]-N-methylcyclopropanecarboxamide [INT 17.2] (50 mg, 0.1427 mmol), 2-chloro-7-[(1S)-1-methoxyethyl]- [1,2,4]triazolo[1,5-a]pyrimidin-6-amine [free base of INT 1.1] (32.3 mg, 142 μmol) and Cs2CO3(139 mg, 428 μmol) were mixed in dioxane (5 mL). Argon was bubbled through the reaction mixture for 15 minutes. Xantphos (16.4 mg, 28.5 μmol) and Pd2(dba)3(13.0 mg, 14.2 μmol) were then added and the reaction mixture was stirred at 100 °C for 14 hours. The reaction mixture was cooled, filtered and concentrated in vacuo. The resulting residue was purified by HPLC (see 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]+C22H25ClF3N6O2calc 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 = 9.5 Hz, 1H), 5.17 (q, J = 6.6 Hz, 1H), 3.25 (s, 3H), 3.01 (s, 3H), 2.32 (s, 3H), 2.06-1.97 (m, 1H), 1.56 (d, J = 6.7 Hz, 3H), 0.90-0.81 (m, 4H).

[0435] HPLC conditions; system: Agilent 1260 Infinity II LC coupled to Agilent 6120B single quadrupole LC / MS system; column description: Chromatorex SBM 100-5T 5 pm C18 (2) LC column 100 x 19 mm, Waters, Sun Fire; stationary phase: C18; solid support: totally porous silica; separation mode: reversed phase; mobile phase A: water mobile phase B: acetonitrile; flow rate: 30 ml / min; loading pump: 4 ml / min B; gradient conditions: 20-40-65-100% (B) 0-2-10-11.2 min.

[0436] Synthesis of N-[(1R)-1-[4-({2-chloro-7-[(1R)-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 [[[[amino]-3-methylphenyl]-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1λ] 6 -Thiazide-4-carboxamide (also known as ​ 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 trifluoroacetic acid salt (Compound 2.1) 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 trifluoroacetic acid salt (Compound 2.1)

[0437]

[0438] N-[(1S)-1-(4-bromo-3-methylphenyl)-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1 lambda 6 - thiazine-4-carboxamide [INT 17.3] (0.1 g, 0.2260 mmol), 2-chloro-7-[(1S)-1- methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-amine [free base of INT 1.1] (51.4 mg, 226 µmol), Cs2CO3 (220 mg, 678 µmol) and xantphos (13.0 mg, 22.6 µmol) were mixed in dioxane (2 mL) and 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 solids were 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-1 lambda 6 - thiazine-4-carboxamide [compound 1.33] (20.7 mg, 0.03515 mmol, 15.5% yield) as a yellow solid. m / z: [M+H]+calcd for C24H29ClF3N6O4S 589.2; found 589.0. 1H NMR (600 MHz, DMSO-d6) d = 8.74 (s, 1H), 7.24 (s, 1H), 7.15 (s, 1H), 7.03 (d, J = 8.6 Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H), 6.41 (q, J = 9.4 Hz, 1H), 5.16 (q, J = 6.7 Hz, 1H), 3.21 (d, J = 13.9 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).

[0439] HPLC conditions; system: Agilent 1260 Infinity II LC coupled with Agilent 6120B single quadrupole LC / MS system; column description: Chromatorex SBM 100-5T 5 pm C18 (2) LC column 100 x 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: 10-30-55-100% (B) 0-2-10-11.2 min.

[0440] 2. Compounds prepared using Scheme 2

[0441] Scheme 2:

[0442]

[0443] treating the starting material G-2a with an acid to give a compound of Formula (I). R G2a Boc (for cyclic carbamates) or HBoc (for acyclic carbamates). R G2b H (for secondary amines) or H2(for primary amines).

[0444] 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 trifluoroacetic acid salt (Compound 2.1) 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 trifluoroacetic acid salt (Compound 2.1)

[0445]

[0446] 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 pmol) in 4 M HC1 / dioxane (10 mL, 40.0 mmol) was stirred at 25 °C for 4 h. 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, HC1 salt] (250 mg, 444 pmol, 92.9 % yield) as a yellow solid. 50 mg (95.0 mmol) of crude product was purified by preparative HPLC (column: Boston Green ODS 150*30 mm*5 um, method: 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 trifluoroacetic acid salt [Compound 2.1] (17.6 mg, 27.5 pmol) as a yellow dry powder. m / z: [M+H]+C23H28ClF3N7O2calc 526.2; found 526.3. 1 H NMR (400 MHz, CDC13) d = 9.66 (br s, 1H), 9.16 (br s, 1H), 8.89 (s, 1H), 7.31 (d, J = 8.4 Hz, 2H), 7.14 (s, 1H), 7.05 (d, J = 8.8 Hz, 2H), 6.57 (q, J = 8.8 Hz, 1H), 5.48 (q, J = 6.8 Hz, 1H), 3.57 (br s, 5H), 3.14 (br d, J = 5.2 Hz, 2H), 2.99 (br s, 1H), 2.93 (s, 3H), 2.23 - 1.94 (m, 4H), 1.61 (d, J = 6.8 Hz, 3H).

[0447] 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 trifluoroacetic acid salt (Compound 2.1) 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 trifluoroacetic acid salt (Compound 2.1)

[0448]

[0449] 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 pmol) in 4 M HCI / dioxane (6 mL) was stirred at 20 °C for 16 h. 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, HCI salt] (140 mg, 266 pmol, 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 pm, Method: 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 pmol, 11.7% yield) as a yellow solid. m / z: [M+H]+C23H28ClF3N7O2calc 526.2; found 526.3. 1 H NMR (400 MHz, CDC13) d = 8.89 (s, 1H), 7.31 (d, J = 8.4 Hz, 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).

[0450] 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 trifluoroacetic acid salt (Compound 2.1) 3. Compounds prepared using Scheme 3

[0451]

[0452] 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 pmol) in 4 M HC1 / dioxane (10 mL, 40.0 mmol) was stirred at 25 °C for 2 h. The mixture was concentrated under reduced pressure to give a crude product, which was purified by preparative HPLC (column: Boston Green ODS 150*30 mm*5 pm, table: 16-56% B (A = water (0.05% HC1) - 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 pmol, 17.5% yield) as a yellow powder. m / z: [M+H]+C22H26ClF3N7O2calc 512.1, 514.1; found 512.3, 514.2. 1 H NMR (400 MHz, CDC13) d = 10.16 (br s, 1H), 9.42 (br s, 1H), 8.90 (br s, 1H), 7.47-7.27 (m, 2H), 7.14-7.00 (m, 2H), 6.62-6.43 (m, 1H), 5.48 (br d, J = 6.0 Hz, 1H), 3.68 (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).

[0453] 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 trifluoroacetic acid salt (Compound 2.1) 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 trifluoroacetic acid salt (Compound 2.1) 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 trifluoroacetic acid salt (Compound 2.1)

[0454]

[0455] 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 pmol) in 4 N HC1 / dioxane (5 mL) was stirred at 20 °C for 12 h. 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, HC1 salt] (370 mg, 616 pmol, 98.6% yield) as a yellow solid. 100 mg of the product was further purified by preparative HPLC (column: YMC Triart C18 250*50 mm*7 pm, column: 12-52% B (A=water (0.225% FA), B=acetonitrile), flow rate: 60 mL / min, UV detector 220 nm) 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; formic acid [Compound 2.4] (21.7 mg, 36.1 pmol, 21.7% yield) as a yellow dry powder. m / z: [M+H]+C25H32C1F3N7O2calc 554.2; found 554.4. 1 H NMR (400 MHz, DMSO-d6) d = 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).

[0456] 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 trifluoroacetic acid salt (Compound 2.1)

[0457] Scheme 3:

[0458]

[0459] The starting material G-3a is treated with G-3b containing R G3b to give a compound of formula (I). R G3a is NH (for cyclic amines) or NH2(for primary amines); X is CO or SO2; R G3b is CH3, iPr, OMe or NHMe; and R G3c is N (for cyclic amides, ureas or carbamates) or NH (for acyclic amides, ureas or carbamates).

[0460] 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 trifluoroacetic acid salt (Compound 2.1) ​

[0461] 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 pmol) and triethylamine (53.6 mg, 530 pmol) in DCM (2 mL) was added acetyl chloride (29.1 mg, 371 pmol) at 25 °C and the mixture was stirred at 25 °C for 12 h. The mixture was concentrated under reduced pressure to give a crude product. The crude product was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5pm, Method: 35-65% B (A=water (0.05% ammonium hydroxide v / v), 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 pmol, 29.4% yield) as a yellow dry powder. m / z: [M+H]+C25H30ClF3N7O3calc 568.2; found 568.4. 1H NMR (400 MHz, CDC13) 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).

[0462] ​ ​ ​

[0463]

[0464] 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 pmol) and triethylamine (57.4 mg, 568 pmol) in DCM (5 mL) was added propan-2-sulfonyl chloride (40.4 mg, 284 pmol) 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. The crude product was purified by preparative HPLC (column: Boston Prime C18 150*30 mm*5 pm, method: 40-70% B (A = water (0.05% ammonium hydroxide v / v) - 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-methyl-1-(propan-2- sulfonyl)piperidine-4-carboxamide [compound 3.2] (9.10 mg, 14.3 pmol, 10.1% yield) as a yellow dry powder. m / z: [M+H]+calcd for C26H34ClF3N7O4S 632.2; found 632.3. 1H NMR (400 MHz, CDC13) d = 8.89 (s, 1H), 7.32 (br d, J = 8.4 Hz, 2H), 7.18-7.01 (m, 3H), 6.62 (q, J = 9.2 Hz, 1H), 5.48 (q, J = 6.8 Hz, 1H), 3.85 (dt, J = 4.4, 8.8 Hz, 2H), 3.49 (s, 3H), 3.19 (td, J = 6.8, 13.6 Hz, 1H), 3.08-2.99 (m, 2H), 2.93 (s, 3H), 2.85-2.67 (m, 1H), 1.98-1.87 (m, 3H), 1.87-1.79 (m, 1H), 1.62 (s, 3H), 1.37 (d, J = 6.8 Hz, 6H).

[0465] ​ ​ ​

[0466]

[0467] 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 pmol) and triethylamine (71.6 mg, 708 pmol) 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 (column: YMC Triart C18 250*50 mm*7 pm, method: 33-73% B (A = water (0.05% ammonium hydroxide v / v) - 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 pmol, 44.6% yield) as a yellow dry powder. m / z: [M+H]+C25H30ClF3N7O4calc 584.2; found 584.5. 1H NMR (400 MHz, CDC13) d = 8.89 (s, 1H), 7.32 (d, J = 8.4 Hz, 2H), 7.12 (s, 1H), 7.04 (d, J = 8.8 Hz, 2H), 6.62 (q, J = 9.2 Hz, 1H), 5.48 (q, J = 6.8 Hz, 1H), 4.22 (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).

[0468] ​ ​

[0469]

[0470] 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 pmol), DIPEA (91.5 mg, 708 pmol), and triethylamine (71.6 mg, 708 pmol) 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*50mm*7pm, Method: 30-70% B (A = water (0.05% ammonium hydroxide v / v) - 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 pmol, 19.8% yield) as a yellow dry powder. m / z: [M+H]+calcd for C24H30ClF3N7O4S 604.2; found 604.3. 1H NMR (400 MHz, CDC13) d = 8.89 (s, 1H), 7.35-7.29 (m, 2H), 7.12 (s, 1H), 7.05 (d, J = 8.8 Hz, 2H), 6.62 (q, J = 8.8 Hz, 1H), 5.49 (q, J = 6.8 Hz, 1H), 3.91-3.75 (m, 2H), 3.54-3.47 (m, 3H), 3.16-2.86 (m, 5H), 2.83 (s, 3H), 2.78-2.71 (m, 1H), 2.05-1.91 (m, 3H), 1.91-1.84 (m, 1H), 1.62 (d, J = 6.8 Hz, 3H).

[0471] 1 -acetyl- N- [( 1 S)- 1 -[4-({2-chloro-7-[( 1 S)- 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)

[0472]

[0473] 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 pmol) and acetyl chloride (20.8 mg, 266 pmol) in DCM (2 mL) was added triethylamine (38.4 mg, 380 pmol) at 25 °C and the mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a crude product which was purified by preparative HPLC (column: YMC Triart C18 250*50mm*7pm, St: 31-71% B (A = water (0.05% ammonium hydroxide v / v), 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 pmol, 20.6% yield) as a yellow dry powder. m / z: [M+H]+C25H30ClF3N7O3calc 568.2; found 568.3. 1H NMR (400 MHz, CDC13) 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).

[0474] 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)

[0475]

[0476] To a mixture of N-[(1 S)-1 -[4-({2-chloro-7-[(1 S)-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 pmol) in CH2CI2(3 mL) at 0 °C was added triethylamine (38.4 mg, 380 pmol) followed by N-methylcarbamoyl chloride (10.5 mg, 113 pmol). The mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give a crude product which was purified by preparative HPLC (column: Phenomenex Gemini-NX 80*40 mm*3 pm, Method: 22-62% B (A = water (0.05% ammonium hydroxide), B = acetonitrile), Flow rate: 25 mL / min, UV detector 220 nm) to give N3-[(1 S)-1 -[4-({2-chloro-7-[(1 S)-1 -methoxyethyl]- [1,2,4]triazolo[1,5-a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-N1,N3- dimethylpiperidine 1,3-dicarboxamide [compound 3.6] (8.00 mg, 13.7 pmol, 14.4% yield) as a yellow solid. m / z: [M+H]+C25H31CI F3N803 calculated 583.2; found 583.4. 1H NMR (400 MHz, DMSO-d6) d = 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).

[0477] 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)

[0478]

[0479] 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 pmol) in CH2Cl2(2 mL) at 0 °C was added triethylamine (38.4 mg, 380 pmol) followed by methanesulfonyl chloride (90 mg, 785 pmol). The mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give a crude product which was purified by preparative HPLC (column: Boston Prime C18 150*30 mm*5 pm, method: 34-64% B (water (0.05% ammonium hydroxide v / v), 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 pmol, 7.5% yield) as a white dry powder. m / z: [M+H]+calcd for C24H30ClF3N7O4S 604.2; found 604.3. 1H NMR (400 MHz, DMSO-d6) d = 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), 2.88-2.65 (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).

[0480] Synthesis of 1 -acetyl- N- [( 1 S)- 1 -[4-({2-chloro-7-[( 1 S)- 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)

[0481]

[0482] 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 pmol) and triethylamine (137 mg, 1.36 mmol) in DCM (2 mL) was added acetyl chloride (74.9 mg, 955 pmol) at 25 °C and the mixture was stirred at 25 °C for 12 h. The mixture was concentrated under reduced pressure to give a crude product which was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5pm, method: 22-52% B (A = water (0.05% ammonium hydroxide v / v) - 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 pmol, 5.6% yield) as a yellow dry powder. m / z: [M+H]+C24H28ClF3N7O3calc 554.2; found 554.4. 1H NMR (400 MHz, CDC13) d = 8.94 - 8.88 (m, 1H), 7.35 - 7.29 (m, 2H), 7.14 (s, 1H), 7.05 (dd, J = 4.0, 8.4 Hz, 2H), 6.65 - 6.53 (m, 1H), 5.48 (q, J = 6.8 Hz, 1H), 4.01 - 3.51 (m, 4H), 3.49 (s, 3H), 3.44 - 3.25 (m, 1H), 3.00 - 2.91 (m, 3H), 2.53 - 2.11 (m, 2H), 2.11 - 2.06 (m, 3H), 1.62 (br s, 3H).

[0483] 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) Synthesis of N-[(1S)-1-[4-({2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-

[0484]

[0485] 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 pmol) in CH2Cl2(3 mL) at 0 °C was added triethylamine (110 mg, 1.09 mmol) followed by N-methylcarbamoyl chloride (30.5 mg, 327 pmol). The mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give a crude product which was purified by preparative HPLC (column: Boston Prime C18 150*30 mm*5 pm, method: 22-52% B (A = water (0.05% ammonium hydroxide v / v) - 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 pmol, 7.4% yield) as a yellow dry powder. m / z: [M+H]+calcd for C24H29ClF3N8O3 569.1; found 569.4. 1H NMR (400 MHz, CDC13) d = 8.91 (d, J = 5.6 Hz, 1H), 7.35 - 7.29 (m, 2H), 7.13 (s, 1H), 7.05 (d, J = 8.4 Hz, 2H), 6.64 - 6.54 (m, 1H), 5.48 (q, J = 6.8 Hz, 1H), 4.21 (br d, J = 4.0 Hz, 1H), 3.81 - 3.68 (m, 1H), 3.63 - 3.54 (m, 2H), 3.49 (d, J = 1.2 Hz, 3H), 3.44 - 3.28 (m, 2H), 2.94 (d, J = 4.4 Hz, 3H), 2.84 (dd, J = 2.4, 4.8 Hz, 3H), 2.42 - 2.11 (m, 2H), 1.63 (br s, 3H).

[0486] a]pyrimidin-6-yl}amino)phenyl]-2,2,2-trifluoroethyl]-1-methanesulfonyl-N-methylpyrrolidine-3-carboxamide (Compound 3.10) 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)

[0487]

[0488] 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 pmol), 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 h. The crude product was purified by preparative HPLC (column: Boston Green ODS 150*30 mm*5 pm, method: 28-68% B (A = water (0.05% HC1)-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 pmol, 12.2% yield) as a yellow dry powder. m / z: [M+H]+calcd for C23H28ClF3N7O4S 590.1; found 590.4. 1H NMR (400 MHz, CDC13) 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).

[0489] 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) 4. Compounds prepared using Scheme 4

[0490]

[0491] 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 [free base of Compound 2.4] (90 mg, 162 pmol) in CH2Cl2(1.5 mL) was added Et3N (49.0 mg, 485 pmol) and acetyl chloride (63.5 mg, 810 pmol). The resulting mixture was stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: YMC Triart C18 250*50 mm*7 pm, Method: 26-66% B (A = water (0.05% ammonium hydroxide v / v), 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- (acetylamino methyl)-N-methylcyclohexane-1-carboxamide [Compound 3.11] (23.8 mg, 39.9 pmol, 24.6% yield) as a yellow dry powder. m / z: [M+H]+C27H34ClF3N7O3calc 596.2; found 596.2. 1H NMR (400 MHz, CDC13) δ = 8.81 (s, 1H), 7.23 (br d, J = 8.4 Hz, 2H), 7.04 (s, 1H), 6.96 (d, J = 8.4 Hz, 2H), 6.55 (q, J = 9.2 Hz, 1H), 5.64-5.52 (m, 1H), 5.40 (q, J = 6.8 Hz, 1H), 3.41 (s, 3H), 3.13-3.00 (m, 2H), 2.83 (s, 3H), 2.52-2.41 (m, 1H), 1.96-1.90 (m, 3H), 1.80-1.66 (m, 3H), 1.60-1.41 (m, 6H), 1.06-0.85 (m, 2H).

[0492] N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6- ​ ​

[0493]

[0494] 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 [free base of Compound 2.4] (90 mg, 162 pmol) in CH2Cl2(1.5 mL) was added Et3N (49.0 mg, 485 pmol) and methyl chloroformate (75.7 mg, 810 pmol). The resulting mixture was stirred at 20 °C for 2 h. The reaction was poured into water (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (15 mL x 2) and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: YMC Triart C18 250*50 mm*7 pm, Method: 31-71% B (A = water (0.05% ammonium hydroxide v / v), 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) aminocarbonyl]cyclohexyl)methyl]carbamate [Compound 3.12] (19.3 mg, 31.5 pmol, 19.4% yield) as a yellow dry powder. m / z: [M+H]+C27H34ClF3N7O4calc 612.2; found 612.2. 1H NMR (400 MHz, CDC13) δ = 8.81 (s, 1H), 7.23 (br d, J = 8.0 Hz, 2H), 7.04 (s, 1H), 6.96 (br d, J = 8.4 Hz, 2H), 6.55 (q, J = 8.8 Hz, 1H), 5.40 (q, J = 6.8 Hz, 1H), 4.72 (br s, 1H), 3.59 (s, 3H), 3.41 (s, 3H), 3.08-2.92 (m, 2H), 2.83 (s, 3H), 2.46 (br t, J = 11.6 Hz, 1H), 1.83-1.67 (m, 4H), 1.65-1.38 (m, 6H), 0.95 (br t, J = 11.2 Hz, 2H).

[0495] ​

[0496] Scheme 4:

[0497]

[0498] The starting material G-4a is treated with G-4b to give the compound of formula (I).

[0499] ​ 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-4-carboxamide (Compound 4.1) Synthesis

[0500]

[0501] Cyclopropanecarboxylic acid (36.5 mg, 425 μmol) was added to a mixture of N-((S)-1-(4-(((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylpiperidin-4-carboxamide hydrochloride [compound 2.1, HCl salt] (80 mg, 142 μmol), EDCI (54.4 mg, 284 μmol), hydroxybenzotriazole (19.1 mg, 142 μmol), and triethylamine (43.0 mg, 425 μmol) in DCM (3 mL). The mixture was stirred at 25 °C for 12 hours. The crude product was purified by preparative HPLC (column: Phenomenex Gemini-NX 80*40mm*3μm, table: 21-61% B (A = water (0.05% ammonium hydroxide v / v), B = acetonitrile), flow rate: 25mL / min, UV detector 220nm) to obtain N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-1-(cyclopropanecarbonyl)-N-methylpiperidin-4-carboxamide [compound 4.1] (20.5mg, 34.5μmol, 24.3% yield), as a yellow dry powder. m / z: [M+H]+C27H32ClF3N7O3 Calculated value 594.2; Measured value 594.5. 1 H NMR (400MHz, CDCl3) δ = 8.89 (s, 1H), 7.32 (br d, J = 8.0Hz, 2H), 7.17-7.02 (m, 3H), 6.63 (q, J = 9.2Hz, 1H), 5.48 (q, J = 6.8Hz, 1H), 4.62 (br s,1H),4.32(brs,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=6.8Hz,3H),0.99(br s,2H),0.78(br d,J=7.8Hz,2H).

[0502] 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] 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] 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]

[0503]

[0504] To a mixture of cyclopropanecarboxylic acid (12.2 mg, 142 pmol), EDCI (27.2 mg, 142 pmol) and HOBt (19.1 mg, 142 pmol) in CH2CI2(3 mL) was added N-[(1 S)-1 -[4-({2-chloro-7-[(1 S)-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 pmol) and the mixture was stirred at 25 °C under N2for 16 h. The reaction mixture was concentrated under reduced pressure to give a crude product which was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30 mm*3 pm, Method: 34-74% B (A = water (0.225% FA), B = acetonitrile), flow rate: 25 mL / min, UV detector 220 nm) to give N-[(1 S)-1 -[4-({2-chloro-7-[(1 S)-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 pmol, 5.0% yield) as a yellow solid. m / z: [M+H]+C27H32CI F3N7O3calc 594.2; found 594.4. 1 H NMR (400 MHz, DMSO-d6) d = 8.85 (s, 1 H), 8.02 (br s, 1 H), 7.30-7.16 (m, 2H), 6.97 (br d, J = 8.0 Hz, 2H), 6.44 (br d, J = 8.8 Hz, 1 H), 5.16 (br d, J = 6.4 Hz, 1 H), 4.47-4.19 (m, 2H), 3.16 (s, 3H), 2.89 (br s, 3H), 2.70 (br d, J = 18.8 Hz, 1 H), 2.62 (br s, 2H), 2.00 (br s, 1 H), 1.91 -1.72 (m, 2H), 1.71 -1.63 (m, 1 H), 1.59 (br d, J = 6.4 Hz, 3H), 1.24 (br s, 1 H), 0.72 (br s, 4H).

[0505] 5. Compounds prepared using Scheme 5 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) 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)

[0506]

[0507] 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 pmol), EDCI (104 mg, 546 pmol), hydroxybenzotriazole (36.8 mg, 273 pmol) and triethylamine (82.7 mg, 818 pmol) in DCM (3 mL) was added cyclopropanecarboxylic acid (70.4 mg, 818 pmol). The mixture was stirred at 25 °C for 12 h. The crude product was purified by preparative HPLC (column: Boston Prime C18 150*30 mm*5 pm, method: 39-69% B (A = water (0.05% ammonium hydroxide v / v) - 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 pmol, 9.3% yield) as a yellow dry powder. m / z: [M+H]+C26H30ClF3N7O3 calculated 580.2; found 580.5. 1 H NMR (400 MHz, CDC13) d = 8.92-8.90 (m, 1H), 7.37-7.30 (m, 2H), 7.13 (s, 1H), 7.08-7.02 (m, 2H), 6.67-6.55 (m, 1H), 5.48 (q, J = 6.8 Hz, 1H), 4.09-3.53 (m, 4H), 3.49 (s, 3H), 3.45-3.26 (m, 1H), 3.00-2.92 (m, 3H), 2.55-2.02 (m, 2H), 1.64 (br d, J = 5.4 Hz, 1H), 1.63 (s, 3H), 1.09-0.96 (m, 2H), 0.79 (br d, J = 7.6 Hz, 2H).

[0508] 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)

[0509] Scheme 5:

[0510]

[0511] The starting material G-5a is treated with HO(CH20)nH (paraformaldehyde) and NaBH3CN to give the compound of formula (I).

[0512] 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-dimethylpiperidine-3- carboxamide hydrochloride (Compound 5.3) 6. Compounds prepared using Scheme 6

[0513]

[0514] 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, HCI salt] (80 mg, 152 pmol), sodium cyanoborohydride (14.2 mg, 227 pmol), and triethylamine (30.7 mg, 304 pmol) in MeOH (3 mL) was stirred at 25 °C for 0.5 h. Paraformaldehyde (22.8 mg, 760 pmol) 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 pm, Method: 39-79% B (A = water (0.05% ammonium hydroxide v / v), 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 pmol, 26.8% yield) as a yellow dry powder. m / z: [M+H]+C24H30ClF3N7O2calc 540.2; found 540.5. 1 H NMR (400 MHz, CDC13) 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).

[0515] 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) 7. Compounds prepared using Scheme 7

[0516] 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 pmol) and paraformaldehyde (14.2 mg, 474 pmol) in MeOH (1 mL) was added triethylamine (19.2 mg, 190 pmol) and sodium cyanoborohydride (8.92 mg, 142 pmol). The mixture was stirred at 25 °C under N2for 16 h. The reaction mixture was concentrated under reduced pressure to give a crude product, which was purified by preparative HPLC (column: YMC Triart C18 250*50mm*7pm, 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 pmol, 9.2% yield) as a yellow dry powder. m / z: [M+H]+C24H30ClF3N7O2calc 540.2; found 540.3. 1 H NMR (400 MHz, DMSO-d6) d = 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).

[0517] 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) 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) ​

[0518]

[0519] 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 pmol), sodium cyanoborohydride (25.7 mg, 409 pmol) and triethylamine (55.2 mg, 546 pmol) in MeOH (3 mL) was stirred at 25 °C for 0.5 h. Then paraformaldehyde (40.8 mg, 1.36 mmol) was added and the reaction was stirred at 25 °C for 12 h. The crude product was purified by preparative HPLC (column: Boston Green ODS 150*30 mm*5 pm, Method: 16-56% B (A = water (0.05% HC1) - 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 pmol, 9.3% yield) as a yellow dry powder. m / z: [M+H]+C23H28ClF3N7O2calc 526.2; found 526.3. 1 H NMR (400 MHz, CDC13) d = 12.84 (br s, 1H), 8.91 (s, 1H), 7.33-7.28 (m, 2H), 7.15 (br d, J = 3.6 Hz, 1H), 7.05 (br d, J = 8.4 Hz, 2H), 6.58-6.43 (m, 1H), 5.48 (q, J = 6.8 Hz, 1H), 4.04-3.87 (m, 1H), 3.80 (br s, 2H), 3.49 (s, 3H), 3.48-3.36 (m, 1H), 3.04 (br s, 1H), 3.00-2.96 (m, 3H), 2.94 (s, 3H), 2.71 (br d, J = 17.2 Hz, 1H), 2.11 (br s, 1H), 1.60 (s, 3H).

[0520] ​

[0521] Scheme 6:

[0522]

[0523] ​ ​ ​

[0524] A solution of (1r,4S)-4-((tert-butyldimethylsilyl)oxy)-N-((S)-1-(4-((2-chloro-7- ((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2- trifluoroethyl)-N-methylcyclohexane-1-carboxamide [INT 18.1] (100 mg, 152 pmol) in TFA (0.5 mL) and CH2Cl2(0.5 mL) was stirred at 20 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Boston Green ODS 150*30 mm*5 pm, method: 23-63% B (A = water (0.05% HC1), 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 pmol, 7.9% yield) as a yellow dry powder. m / z: [M+H]+C24H29ClF3N6O3calc 541.2; found 541.3. 1 H NMR (400 MHz, CDC13) 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).

[0525] ​

[0526] Scheme 7:

[0527]

[0528] treating the starting material G-7a with a hydrolysis reagent to give a compound of formula (I).

[0529] ​ ​ ​

[0530]

[0531] To a mixture of (1S,4r)-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)cyclohexane-1-carboxylate [Compound 1.4] (100 mg, 171 pmol) in THF (2 mL) and H2O (1 mL) was added 1 N HC1 (1 mL, 1 mmol) 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 x 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 prep-HPLC (column: Boston Green ODS 150*30 mm*5 pm, wave: 28-68% B (A = water (0.05% HC1 v / v), 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 pmol, 43.7% yield) as a yellow dry powder. m / z: [M+H]+C25H29ClF3N6O4calc 569.2; found 569.2. 1 H NMR (400 MHz, DMSO-d6) d = 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).

[0532] ​ ​

[0533]

[0534] A mixture of (1S,4r)-4-(((S)-1-(4-((2-chloro-7-isopropyl-[1,2,4]triazolo[1,5- a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexane-1- carboxylic acid methyl ester [INT18.2] (50 mg, 88.1 μmol) and lithium hydroxide monohydrate (7.38 mg, 176 μmol) in H2O (2 mL) and THF (2 mL) was stirred at 20 °C for 12 h. The mixture was concentrated under reduced pressure to give a residue, which was diluted with water (5 mL). The resulting mixture was adjusted to pH = 4 with 1 N HC1 and extracted with EtOAc (5 mL x 2). The combined organic layers were washed with brine (10 mL) and concentrated to give a yellow solid. The solid was purified by prep-HPLC (column: Boston Prime C18 150*30 mm*5 μm, Method: 15-45% B (A = water (0.05% ammonium hydroxide v / v), 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]+C25H29ClF3N6O3calc 553.2; found 553.1. 1 H NMR (400 MHz, DMSO-d6) d = 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).

[0535] (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)carbamate (Compound 7.1 ) 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 ) 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 )

[0536]

[0537] Methyl (1S,3r)-3-(((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)- [1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl) carbamoyl)cyclobutane-1-carboxylate [INT18.3] (0.136 g, 0.2450 mmol) was dissolved in a mixture of tetrahydrofuran (0.9 mL) and water (0.1 mL). Lithium hydroxide monohydrate (10.2 mg, 245 μmol) was added to the reaction mixture and it was stirred for 10 hours. The pH of the reaction mixture was adjusted to 7 with dilute aqueous HC1. The solvent was distilled off and the residue was purified by HPLC (see conditions below) to give (1S,3r)-3-(((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)- [1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl) carbamoyl)cyclobutane-1-carboxylic acid [Compound 7.3] (5.70 mg, 0.01053 mmol, 4.3% yield) as a yellow solid. m / z: [M+H]+C23H25C1F3N6O4 requires 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).

[0538] HPLC conditions; system: Agilent 1260 Infinity II LC coupled to Agilent 6120B single quadrupole LC / MS system; column description: Chromatorex SBM 100-5T C18 LC column 100 x 19 mm, Waters, SunFire; stationary phase: C18; solid support: totally porous silica; mode of separation: reverse phase; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 30 ml / min; loading pump: 4 ml / min B; gradient conditions: 0-0-25-100% (B) 0-2-10-11.2 min.

[0539] 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 )

[0540] Scheme 8:

[0541]

[0542] treating the starting material G-8a with an amine containing compound to give a compound of Formula (I). R G8 and R G8’ are H or Me.

[0543] 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 ) 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 ) 9. Compounds prepared using Scheme 9

[0544]

[0545] 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. NH4Cl (9.36 mg, 175 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*50mm*7µm, Table: 25-65% B (A = Water (0.05% Ammonium Hydroxide v / v), B = Acetonitrile), Flow rate: 60 mL / min, UV detector 220 nm) to give (1r,4S)-N1-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)- [1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N1-methylcyclohexane-1,4-dicarboxamide [Compound 8.1] (4.00 mg, 7.04 µmol, 8.0% yield) as a yellow dry powder. m / z: [M+H]+ C25H30ClF3N7O3 calculated 568.2; found 568.1. 1H NMR (400 MHz, MeOD) d = 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).

[0546] 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-(1 H-tetrazol-5-yl)cyclobutane-1 -carboxamide (Compound 9.1 ) 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-(1 H-tetrazol-5-yl)cyclobutane-1 -carboxamide (Compound 9.1 ) 10. Isolation and purification 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 )

[0547]

[0548] 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 pmol) in DMF (1 mL) was added HATU (49.8 mg, 131 pmol) and DIPEA (51.1 mg, 396 pmol) and the mixture was stirred at 25 °C for 0.5 h. Then methylamine hydrochloride (8.84 mg, 131 pmol) 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*50mm*7pm, Method: 26-66% B (A = water (0.05% ammonium hydroxide v / v), B = acetonitrile), Flow rate: 60 mL / min, UV detector 220 nm) to give (1r,4S)-N1-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)- [1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N1,N4-dimethylcyclohexane-1,4-dicarboxamide [Compound 8.2] (19.8 mg, 34.0 pmol, 38.7% yield) as a yellow dry powder. m / z: [M+H]+C26H32ClF3N7O3calc 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).

[0549] 11. Isolation and purification 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 ) 12. Synthesis of intermediates Synthesis of 2-chloro-7-[(1 S)-1 -methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6- amine hydrochloride (Intermediate 1.1 )

[0550]

[0551] 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. Then dimethylamine hydrochloride (10.6 mg, 131 μmol) was added and the mixture was stirred at 25 °C for 12 h. The mixture was purified by preparative HPLC (column: YMC Triart C18 250*50mm*7μm, Method: 30-70%B (A=water (0.05% ammonium hydroxide v / v), B=acetonitrile), Flow rate: 60 mL / min, UV detector 220 nm) to give (1r,4S)-N1-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)- [1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N1,N4,N4- trimethylcyclohexane-1,4-dicarboxamide [Compound 8.3] (12.4 mg, 20.8 μmol, 23.7% yield) as a yellow dry powder. m / z: [M+H]+calcd for C27H34ClF3N7O3 596.2; found 596.2. 1H 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).

[0552] Synthesis of (S)-4-methoxy-3-oxopentanoic acid tert-butyl ester (INT1-b)

[0553] Scheme 9:

[0554]

[0555] ​ ​ ​

[0556] (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 h. EtOAc (10 mL) and H2O (5 mL) were added and the organic phase was evaporated in vacuo at 45 °C. The residue was purified by HPLC (see 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]+calcd for C23H25ClF3N10O2 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).

[0557] HPLC conditions; system: Agilent 1260 Infinity II LC coupled with Agilent 6120B single quadrupole LC / MS system; column: Chromatorex SBM 100-5T 5 pm C18 (2) LC column 100 x 19 mm, Waters, SunFire; stationary phase: C18; solid support: fully porous silica; separation mode: reversed phase; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 30 ml / min; loading pump: 4 ml / min B; gradient conditions: 20-30-70-100% (B) 0-2-10-11.2 min.

[0558] ​ ​ ​

[0559] Scheme 10:

[0560]

[0561] 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] can be further purified by chiral SFC (column: DAICEL CHIRALPAK AD 250 mm*50 mm, 10 μm, mode: 30-30% 0.1% NH3H2O ETOH), flow rate: 200 mL / min, UV detector 220 nm) resulting in the separation and isolation of [Compound 1.1] (>98% chiral purity) and N-((S)-1-(4-((2-chloro-7-((R)-1- methoxyethyl)-[1,2,4]triazolo[1,5-a]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]+C23H27ClF3N6O4S calculated 575.1; found 575.0. 1 H NMR (400 MHz, DMSO) d = 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).

[0562] ​ ​ ​

[0563] Scheme 11:

[0564]

[0565] 1 -acetyl-N-((1 S)-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] can be further purified by chiral SFC (column: DAICEL CHIRALPAK IG (250mm*50mm, 10um), mode: 50-50% B (A = water (0.1 % ammonium hydroxide), B = MeOH), flow rate: 200 mL / min) resulting in the isolation and separation 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]+C25H30C1F3N7O3calc 568.2; found 568.1. 1 H NMR (400 MHz, CDC13) 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).

[0566] ​

[0567] The following intermediates were synthesized and used for the synthesis of the example compounds.

[0568] ​ ​

[0569]

[0570] ​

[0571] A solution of (S)-2-methoxypropanoic acid [INT 1-a] (20 g, 192 mmol) in anhydrous tetrahydrofuran (342 mL) was cooled to 0 °C. At 0 °C, carbonyldiimidazole (30.6 g, 189 mmol) was added in portions and the mixture was stirred at this temperature for 1.25 h. At 0 °C, to a separate flask, a solution of 3-(tert-butoxy)-3-oxopropanoic acid (46.1 g, 288 mmol) in anhydrous tetrahydrofuran (342 mL) was added with 1-methylethylmagnesium chloride (1+) (249 mL, 499 mmol, 2 M in THF) and the mixture was stirred at room temperature for 1.25 h. Then, this solution was added to the acylimidazole solution at 0 °C through a cannula and the resulting mixture was stirred at room temperature overnight. The reaction mixture was cooled to 0 °C and quenched by the addition of 10% aqueous citric acid solution, extracted with EtOAc, washed with saturated aqueous NaHC03, dried over anhydrous Na2S04and concentrated under reduced pressure to give the crude product which was purified by silica gel flash chromatography (acetone / hexanes = 0 / 1 to 1 / 9) to give (S)-tert-butyl 4-methoxy-3-oxopentanoate [INT 1-b] (30.0 g, 148 mmol, 55.6%) as an oil.

[0572] (S)-2-amino-7-(1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid tert-butyl ester Synthesis of (S)-2-amino-7-(1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid tert-butyl ester

[0573] A solution of (S)-tert-butyl 4-methoxy-3-oxopentanoate [INT 1-b] (25 g, 123 mmol) and dimethylaminomethyl dimethylamine (11.1 mL, 83.6 mmol) was heated at 120 °C for 1.5 h. The mixture was cooled to room temperature and 4H-1,2,4-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 h. Upon completion, the mixture was concentrated under reduced pressure and recrystallized from EtOH / water (1:1, 600 mL), filtered and the filter cake was washed with 30% EtOH / water followed by MTBE to give 2-amino-7-(1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid tert-butyl ester (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 hexanes to give more (S)-2-amino-7-(1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid tert-butyl ester [INT 1-c] (5.3 g, 18.0 mmol, 23%) as a solid. Total 18.0 g, 75% yield. Chiral HPLC showed 96.9% ee. 1H NMR (400 MHz, CDC13) δ = 8.75 (s, 1H), 5.40 (q, J = 6.8 Hz, 1H), 4.95 (br s, 2H), 3.30 (s, 3H), 1.75 (d, J = 6.8 Hz, 3H), 1.62 (s, 9H).

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

[0575] To a mixture of tert-butyl 2-amino-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5- a]pyrimidine-6-carboxylate [INT 1-c] (1.2 g, 4.09 mmol) and copper(II) chloride dihydrate (173 mg, 1.02 mmol) in cone. HC1 (20 mL) was added a solution of sodium nitrite (338 mg, 4.90 mmol) in H20 (5 mL) at 5 °C under ice-bath and the mixture was stirred at 5 °C for 30 min. Then the mixture was warmed to 25 °C and stirred for 16 h. Water (100 mL) was added and 1 N aqueous NaOH solution was added to adjust the pH to 3-4. The mixture was extracted with CHCl3:i-PrOH = 3:1 (100 mL x 3) and the combined organic layer was dried over anhydrous Na2S04and concentrated under reduced pressure to give 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5- a]pyrimidine-6-carboxylic acid [INT 1-d] as a solid (962 mg, 92.4% yield). m / z: [M+H]+calcd for C9H10ClN403257.0; 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).

[0576] Synthesis of (S)-2-amino-7-(1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid tert-butyl ester Synthesis of (S)-2-amino-7-(1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid tert-butyl ester

[0577] To a solution of 2-chloro-7-[(1 S)-1 -methoxyethyl]-[1,2,4]triazolo[1,5- a]pyrimidine-6-carboxylic acid [INT 1 -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 N2atmosphere for 2 hours. The mixture was concentrated under reduced pressure to give a crude product which was purified by silica gel flash chromatography (EtOAc / petroleum ether = 1 / 10 to 1 / 5) to give N-{2-chloro-7-[(1 S)-1 -methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6- yl}carbamic acid tert-butyl ester [INT 1 -e] as a solid (420 mg, 25.4% yield). m / z: [M+H]+ calculated for C13H19CIN5O3 328.1 ; found 328.0. 1 H NMR (400 MHz, CDC13) δ = 9.62 (br s, 1 H), 8.05 (s, 1 H), 5.45 (q, J = 6.8 Hz, 1 H), 3.48 (s, 3H), 1.63 (d, J = 6.8 Hz, 3H), 1.56 (s, 9H).

[0578] Synthesis of (S)-2-amino-7-(1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid tert-butyl ester Synthesis of (S)-2-amino-7-(1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid tert-butyl ester

[0579] A mixture of N-{2-chloro-7-[(1 S)-1 -methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6- yl}carbamic acid tert-butyl ester [INT 1 -e] (420 mg, 1.28 mmol) in 4N HCI / dioxane (5 mL) was stirred at 25 °C for 2 hours. LCMS showed the reaction was complete and a new peak with desired MS was detected (Rt = 0.611 min, m / z: 227.8 [M+H]+). The mixture was concentrated under reduced pressure to give 2-chloro-7-[(1 S)-1 -methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-amine hydrochloride [INT 1.1 ] as a solid (400 mg, crude).

[0580] Synthesis of 2-chloro-7-isopropyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-amine hydrochloride (Intermediate 1.2)

[0581] Synthesis of (S)-2-amino-7-(1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid tert-butyl ester

[0582] A mixture of 4-methyl-3-oxopentanoic acid methyl ester [INT 1-f] (23.2 g, 160 mmol) and DMF-DMA (19.0 g, 160 mmol) was stirred at 120 °C for 2 h under N2atmosphere. Then 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 a crude product which was purified by silica gel flash chromatography (EtOAc / petroleum ether = 1 / 10 to 3 / 2) to give 2-amino-7-isopropyl-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid methyl ester [INT 1-g] (20.6 g, 87.7 mmol, 54.7% yield) as off-white solid. m / z: [M+H]+calcd for C10H14N5O2 236.1; found 236.2. 1 H NMR (400 MHz, CDC13) 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).

[0583] Synthesis of (S)-2-amino-7-(1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid tert-butyl ester

[0584] To a mixture of 2-amino-7-isopropyl-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid methyl ester [INT 1-g] (10.17 g, 34.5 mmol) and copper(II) chloride dihydrate (1.46 g, 8.62 mmol) in concentrated HC1 (30 mL) was added a solution of sodium nitrite (2.85 g, 41.4 mmol) in H20 (5 mL) at 5 °C. The mixture was stirred at 5 °C (ice bath cooling) for 30 min. Then the mixture was warmed to 25 °C and stirred for 12 h. 2N aqueous NaOH solution was added to adjust the pH to 7, and the mixture was extracted with EtOAc (200 mL x 2). The combined organic layers were washed with brine (200 mL x 3), dried over anhydrous Na2S04, and concentrated under reduced pressure to give a crude product which was purified by silica gel flash chromatography (EtOAc / petroleum ether = 0 / 1 to 1 / 1) to give 2-chloro-7-isopropyl-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid methyl ester [INT 1-h] (3.00 g, 11.7 mmol, 34.1% yield) as a yellow solid. m / z: [M+H]+calcd for C10H12CIN4O2 255.1; found 255.0. 1H NMR (400 MHz, CDC13) 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).

[0585] Synthesis of (S)-2-amino-7-(1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid tert-butyl ester

[0586] To a mixture of methyl 2-chloro-7-isopropyl-[l,2,4]triazolo[l,5-a]pyrimidine-6-carboxylate [INT 1-h] (1 g, 3.92 mmol) in THF (10 mL) was added lithium hydroxide (1+) hydrate (2 M in H20, 2.94 mL, 5.88 mmol) and the mixture was stirred at 25 °C for 3 hours. The THF was removed under reduced pressure and water (10 mL) was added. IN HC1 was added to adjust the pH to 3-4 and the mixture was filtered. The filter cake was washed with water (20 mL x 2), collected and concentrated under reduced pressure to give a solid. The solid was purified by preparative HPLC (column: Boston Green ODS 150*30 mm*5 pm, table: 8-48% B (A = water (0.05% HC1), B = acetonitrile), flow rate: 30 mL / min, UV detector 220 nm) to give 2-chloro-7-isopropyl-[l,2,4]triazolo[l,5-a]pyrimidine-6-carboxylic acid [INT 1-i] (300 mg, 1.24 mmol, 31.8% yield) as a white dry powder. m / z: [M+H]+calcd for C9H10ClN402241.1; 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).

[0587] Synthesis of (S)-2-amino-7-(1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid tert-butyl ester Synthesis of (S)-2-amino-7-(1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid tert-butyl ester

[0588] To a solution of 2-chloro-7-isopropyl-[l,2,4]triazolo[l,5-a]pyrimidine-6-carboxylic acid [INT 1-i] (150 mg, 623 pmol) in toluene (5 mL) was added diphenylphosphoryl azide (257 mg, 934 pmol), t-BuOH (2 mL) and potassium tert-butoxide (208 mg, 1.86 mmol). The reaction mixture was stirred at 100 °C under N2for 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-[l,2,4]triazolo[l,5-a]pyrimidin-6- yl)carbamate [INT 1-j] (80.0 mg, 256 pmol, 41.2% yield) as a yellow solid. m / z: [M+H]+C13H19ClN5O2calc 312.1; found 312.1.

[0589] Synthesis of (S)-2-amino-7-(1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid tert-butyl ester

[0590] A solution of tert-butyl (2-chloro-7-isopropyl-[l,2,4]triazolo[l,5-a]pyrimidin-6- yl)carbamate [INT 1-j] (80 mg, 256 pmol) in 4 M HCI / dioxane (10 mL) was stirred at 15 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give 2-chloro-7-isopropyl-[l,2,4]triazolo[l,5-a]pyrimidin-6-amine hydrochloride [INT 1.2] (63.0 mg, 253 pmol, 99.2% yield) as a white solid. m / z: [M+H]+C8H11ClN5calc 212.1; found 211.7.

[0591] Synthesis of (R)-2-chloro-7-(l-methoxyethyl)-[l,2,4]triazolo[l,5-a]pyrimidin-6-amine hydrochloride (Intermediate 1.3):

[0592]

[0593] (R)-2-chloro-7-(l-methoxyethyl)-[l,2,4]triazolo[l,5-a]pyrimidin-6-amine [INT 1.3] can be prepared using (2R)-2-methoxypropanoic acid as starting material, by the same synthetic route as outlined for INT 1.1. m / z: [M+H]+C8H11ClN5O calc 228.1; found 228.1.

[0594] Synthesis of (R)-N-((S)-l-(4-bromophenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2- sulfmamide (Intermediate 2.1):

[0595]

[0596] Synthesis of (S)-2-amino-7-(1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid tert-butyl ester

[0597] To a solution of 4-bromobenzaldehyde [INT 2-a] (100 g, 541 mmol, 1.0 eq) in toluene (500 mL) was added (R)-2-methylpropane-2-sulfinamide (72.1 g, 595 mmol, 1.1 eq) at 25 °C. The mixture was stirred at 25 °C for 15 min. To the above reaction was then added NaOH (21.6 g, 541 mmol, 1.0 eq) and the mixture was stirred at 25 °C for 12 h. Na2SO4(50 g) was added to the mixture and stirred for 20 min. The four reaction mixtures were combined and filtered through celite to give a filtrate which was concentrated in vacuo to give a crude product as an oil. The crude product was dissolved in petroleum ether (1.0 L) and stirred at -50 °C for 1.0 h, filtered to give (R,E)-N-(4-bromobenzylidene)-2-methylpropane-2-sulfinamide [INT 2-b] as a solid (620 g, 2.15 mol, 99.5% yield).

[0598] Synthesis of (S)-2-amino-7-(1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid tert-butyl ester Synthesis of (S)-2-amino-7-(1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid tert-butyl ester

[0599] To a solution of (R,E)-N-(4-bromobenzylidene)-2-methylpropane-2-sulfinamide [INT 2-b] (206 g, 715 mmol, 1.0 eq) and tetrabutylammonium acetate (216 g, 715 mmol, 218 mL, 1.0 eq) in DMF (1.4 L) was added TMSCF3(259 g, 1.82 mol, 2.5 eq) at 0 °C. The mixture was stirred at 5 °C for 1.5 h. The procedure was repeated twice and the three reaction mixtures were combined for work-up. The mixture was poured into saturated NH4Cl solution (13.0 L) and stirred for 10 min to give a suspension. The suspension was filtered to give a filter cake which was washed 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 a crude product as an oil which was purified by silica gel column chromatography using petroleum ether / ethyl acetate (10 / 1 ~ 1 / 1) to give (R)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide [INT 2.1] as a solid (389 g, 1.09 mol, 50.6% yield). 1H NMR (400 MHz, CDC13) 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 = 6.40 Hz, 2H).

[0600] Synthesis of (S)-1-(4-bromophenyl)-2,2,2-trifluoro-N-methylethan-1-amine hydrochloride (INT 3.1):

[0601]

[0602] Synthesis of (S)-2-amino-7-(1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid tert-butyl ester Synthesis of (S)-2-amino-7-(1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid tert-butyl ester

[0603] To a solution of LiHMDS (1.0 M, 838 mL, 3.0 eq) was added (R)-N-((S)-1-(4- bromophenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfmide [INT 2.1] (100 g, 279 mmol, 1.0 eq) at 0-10 °C and stirred for 0.5 h at 0-10 °C. To the above mixture was added Mel (119 g, 838 mmol, 52.1 mL, 3.0 eq) at 0-10 °C and stirred for 1 h at 25 °C. The procedure was repeated twice, the three combined reaction mixtures were poured into saturated NH4Cl (3.0 L) and diluted with EtOAc (1.0 L). The mixture was separated to get 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) and dried over Na2S04, filtered and concentrated in vacuo to get 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 get (R)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N,2-dimethylpropane-2- sulfmide [INT 3-b] as an oil (161 g, 432.5 mmol, 51.6 % yield).

[0604] Synthesis of (S)-2-amino-7-(1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid tert-butyl ester

[0605] To a mixture of (R)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N,2- dimethylpropane-2-sulfmamide [INT 3-b] (202 g, 543 mmol, 1.0 eq) in EtOAc (600 mL) was added HCl / EtOAc (4.0 M, 2.02 L, 14.9 eq) slowly. The above mixture was stirred at 20 °C for 1 h. The reaction mixture was filtered to get a solid and washed with EtOAc (200 mL) and the mother liquor was concentrated under vacuum to get a solid. The solid was purified by silica gel column chromatography using petroleum ether / ethyl acetate (10 / 1 to 1 / 0), combined the fractions and concentrated by oil pump at 45 °C for 1 h to remove the solvent residue to get (S)-1-(4-bromophenyl)-2,2,2-trifluoro-N-methylethan-1-amine hydrochloride [INT 3.1] (115 g, 378 mmol, 69.6% yield, 100% purity, HC1) 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).

[0606] SFC: Rt = 0.776 min, 99.98% ee; Column: Chiralpak AD-3, 100 x 4.6 mm, I.D., 3 um; Mobile phase: A: CO2, B: MeOH (0.05% IPA); Gradient: A: B = 97:3; Flow rate: 3 mL / min; Column temperature: 35 °C.

[0607] LCMS: Rt = 1.755 min, 100.0% purity, m / z = 268.0, 270.0 (M+1)+. Gradient was 5% B over 0.40 min, 5-95% B from 0.4-3.0 min, hold at 95% B for 1.00 min, then 95-5% B over 0.01 min at a flow rate of 1.0 mL / min. Mobile phase A was 0.037% trifluoroacetic acid in water and mobile phase B was 0.018% trifluoroacetic acid in acetonitrile. The column used for the chromatography was a Kinetex C18 50*2.1 mm column (5 um particles). The detection method was diode array (DAD) as well as positive electrospray ionization. The MS range was 100-1000.

[0608] Synthesis of tetrahydro-2H-thiopyran-4-carbonyl chloride 1,1-dioxide (Intermediate 4.1):

[0609]

[0610] To a solution of tetrahydro-2H-thiopyran-4-carboxylic acid 1,1-dioxide [INT 4-a] (41.0 g, 230 mmol, 1.0 eq) in DCM (410 mL) was added (COCl)2(58.4 g, 460 mmol, 40.3 mL, 2.0 eq) and DMF (168 mg, 2.30 mmol, 177 μL, 0.01 eq) at 0 °C under N2. The mixture was allowed to warm to 20 °C and stirred at 20 °C for 2 h. The suspension became clear, which indicated that most of the starting material was consumed. The reaction mixture was concentrated in vacuo to give the crude product as a solid, which was concentrated by an oil pump to remove the solvent residue to give tetrahydro-2H-thiopyran-4-carbonyl chloride 1,1-dioxide [INT 4.1] (46.5 g, crude) as a solid.

[0611] Synthesis of tetrahydro-2H-pyran-2-carbonyl chloride (Intermediate 4.2):

[0612]

[0613] To a mixture of tetrahydro-2H-pyran-2-carboxylic acid [INT 4-b] (330 mg, 2.53 mmol) in dichloromethane (4 mL) was added oxalyl chloride (478 mg, 3.79 mmol) and DMF (18.4 mg, 252 μmol) slowly and the mixture was stirred at 40 °C for 2 h. The mixture was concentrated under reduced pressure to give tetrahydro-2H-pyran-2-carbonyl chloride [INT 4.2] (370 mg, 2.49 mmol, 98.6% yield) as a yellow gum.

[0614] Synthesis of (1r,4r)-4-(chlorocarbonyl)cyclohexane-1-carboxylic acid methyl ester (Intermediate 4.3):

[0615]

[0616] To a mixture of (1r,4r)-4-(methoxycarbonyl)cyclohexane-1-carboxylic acid [INT 4-c] (1.45 g, 7.78 mmol) in dichloromethane (10 mL) was added oxalyl chloride (2.93 g, 23.3 mmol) and DMF (56.8 mg, 778 μmol) slowly and the mixture was stirred at 40 °C for 2 h. The mixture was concentrated under reduced pressure to give (1r,4r)-4-(chlorocarbonyl)cyclohexane-1-carboxylic acid methyl ester [INT 4.3] (1.59 g, 7.76 mmol) as a yellow gum crude.

[0617] Synthesis of thiane-4-carbonyl chloride (Intermediate 4.4):

[0618]

[0619] To a mixture of thiane-4-carboxylic acid [INT 4-d] (370 mg, 2.53 mmol) in dichloromethane (2 mL) was added oxalyl chloride (478 mg, 3.79 mmol) and DMF (18.4 mg, 252 pmol) slowly. The mixture was stirred at 40 °C for 2 h. The mixture was concentrated under reduced pressure to give the crude thiane-4-carbonyl chloride [INT 4.4] (415 mg, 2.52 mmol) as a yellow gum.

[0620] Synthesis of oxolan-3-carbonyl chloride (Intermediate 4.5):

[0621]

[0622] To a mixture of oxolan-3-carboxylic acid [INT 4-e] (1 g, 8.61 mmol) in CH2Cl2(10 mL) was added oxalyl chloride (2.18 g, 17.2 mmol) and N,N-dimethylformamide (62.9 mg, 861 pmol). The reaction mixture was stirred at 25 °C for 1.5 h. The reaction mixture was concentrated to give oxolan-3-carbonyl chloride [INT 4.5] (1.10 g, 8.17 mmol) as a yellow oil.

[0623] Synthesis of 1,4-dioxaspiro[4.5]decane-8-carbonyl chloride (Intermediate 4.6):

[0624]

[0625] To a mixture of 1,4-dioxaspiro[4.5]decane-8-carboxylic acid [INT 4-f] (560 mg, 3.00 mmol) in dichloromethane (2 mL) was added oxalyl chloride (567 mg, 4.50 mmol) and DMF (21.9 mg, 300 pmol) slowly and the mixture was stirred at 40 °C for 2 h. The mixture was concentrated under reduced pressure to give the crude 1,4-dioxaspiro[4.5]decane-8-carbonyl chloride [INT 4.6] (610 mg, 2.98 mmol) as a yellow gum.

[0626] Synthesis of 4,4-difluorocyclohexane-1-carbonyl chloride (Intermediate 4.7):

[0627]

[0628] To a mixture of 4,4-difluorocyclohexane-1 -carboxylic acid [INT 4-g] (1 g, 6.09 mmol) in dichloromethane (15 mL) was added slowly oxalyl chloride (2.29 g, 18.2 mmol) and DMF (44.5 mg, 609 pmol) and the mixture was stirred at 40 °C for 2 hours. The mixture was concentrated under reduced pressure to give crude 4,4-difluorocyclohexane-1 -carbonyl chloride [INT 4.7] (1.1 1 g, 6.07 mmol) as a yellow gum.

[0629] Synthesis of 1 -acetylazetidine-3-carbonyl chloride (Intermediate 4.8):

[0630]

[0631] To a solution of 1 -acetylazetidine-3-carboxylic acid [INT 4-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 mixture was concentrated under reduced pressure to give 1 -acetylazetidine-3-carbonyl chloride [INT 4.8] (337 mg, 2.08 mmol).

[0632] Synthesis of 1 -acetylpiperidine-4-carbonyl chloride (Intermediate 4.9):

[0633]

[0634] To a mixture of 1 -acetylpiperidine-4-carboxylic acid [INT 4-i] (1 g, 5.84 mmol) in dichloromethane (10 mL) was added slowly oxalyl chloride (2.20 g, 17.5 mmol) and DMF (42.6 mg, 584 pmol) and the mixture was stirred at 40 °C for 2 hours. The mixture was concentrated under reduced pressure to give crude 1 -acetylpiperidine-4-carbonyl chloride [INT 4.9] (1.10 g, 5.80 mmol) as a green oil.

[0635] Synthesis of (1 r,3r)-3-(chloroformyl)cyclobutane-1 -carboxylic acid methyl ester (Intermediate 4.10):

[0636]

[0637] To a mixture of (lr,3r)-3-(methoxycarbonyl)cyclobutane-l -carboxylic acid [INT 4-j] (100 mg, 632 pmol) in CH2CI2(2 mL) was added DMF (one drop) and oxalyl chloride (239 mg, 1.89 mmol) at 20 °C. The mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give crude (lr,3r)-methyl 3-(chloroformyl)cyclobutane-l -carboxylate [INT 4.10] as a light yellow oil (111 mg, 628 pmol).

[0638] Synthesis of (S)-N-(l-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H- thiopyran-4-carboxamide 1,1-dioxide (Intermediate 5.1):

[0639]

[0640] To a solution of (S)-l-(4-bromophenyl)-2,2,2-trifluoro-N-methylethan-l -amine hydrochloride [INT 3.1] (39.0 g, 128 mmol, 1.0 eq, HC1) and TEA (45.7 g, 451 mmol, 62.8 mL, 3.5 eq) in DCM (200 mL) was added tetrahydro-2H-thiopyran-4-carbonyl chloride 1,1-dioxide [INT 4.1] (45.3 g, 231 mmol, 1.8 eq) at 0-10 °C. The mixture was stirred at 20 °C for 12 h. The mixture was separated to give the organic layer and the aqueous layer was extracted with DCM (100 mL). The combined organic layers were concentrated under vacuum to give crude product as an oil. The crude product was purified by silica gel column chromatography using petroleum ether / ethyl acetate (15 / 1 ~ 3 / 1) to give (S)-N-(l-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide [INT 5.1] as a solid (26.0 g, 60.7 mmol, 47.4% yield, 100% purity). 1 H NMR (400 MHz, CDC13) 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).

[0641] SFC: Rt = 1.21 min, 100.0% ee; Column: Chiralpak AD-3, 50 x 4.6 mm I.D., 3 um; Mobile phase: A: CO2, B: MeOH (0.05% IPAm, v / v); Flow rate: 3.4 mL / min; Column temperature: 35 °C.

[0642] LCMS: Rt = 2.431 min, 100% purity, m / z = 428.0, 430.0 (M+1)+. Gradient was 5% B in 0.40 min, 5-95% B in 0.4-3.0 min, hold 95% B for 1.00 min, then 95-5% B in 0.01 min at a flow rate of 1.0 mL / min. Mobile phase A was 0.037% trifluoroacetic acid in water and mobile phase B was 0.018% trifluoroacetic acid in acetonitrile. The column used for the chromatography was a Kinetex C18 50*2.1 mm column (5 um particles). The detection method was diode array (DAD) as well as positive electrospray ionization. The MS range was 100-1000.

[0643] Synthesis of N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methylacetamide (Intermediate 5.2):

[0644]

[0645] To a mixture of [(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)amine [free base of INT 3.1] (1 g, 3.73 mmol) and Et3N (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 a 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 [INT 5.2] as a colorless oil (750 mg, 2.41 mmol, 64.6% yield). m / z: [M+H]+C11H12BrF3NO calc 310.0, 312.0; found 309.8, 311.8. 1 H NMR (400 MHz, CDC13) 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).

[0646] Synthesis of N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro- 2H-pyran-2-carboxamide [INT 5.3]:

[0647]

[0648] To a mixture of (S)-1-(4-bromophenyl)-2,2,2-trifluoro-N-methylethan-1-amine hydrochloride [INT 3.1] (400 mg, 1.31 mmol) and Et3N (662 mg, 6.55 mmol) in dichloromethane (2 mL) was added a solution of tetrahydro-2H-pyran-2-carbonyl chloride [INT 4.2] (370 mg, 2.49 mmol) in dichloromethane (2 mL). The mixture was stirred at 25 °C for 16 h. Water (10 mL) was added and the mixture was extracted with dichloromethane (10 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a 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 [INT 5.3] (400 mg, 1.05 mmol, 80.3% yield) as a yellow oil. m / z: [M+H]+C15H18BrF3NO2calc 380.0, 382.0; found 380.0.

[0649] Synthesis of (1S,4r)-methyl 4-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexane-1-carboxylate [INT 5.4]:

[0650]

[0651] To a mixture of (1r,4r)-methyl 4-(chloroformyl)cyclohexane-1 -carboxylate [INT 4.3] (1.59 g, 7.76 mmol) and Et3N (2.65 g, 26.2 mmol) in dichloromethane (6 mL) was added a solution of [(1 S)-1 -(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)amine hydrochloride [INT 3.1 ] (1.6 g, 5.25 mmol) in dichloromethane (6 mL) and the mixture was stirred at 25 °C for 16 h. Water (30 mL) was added and the mixture was extracted with dichloromethane (30 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anh. Na2S04, filtered and concentrated under reduced pressure to give a crude product which was purified by silica gel flash chromatography (EtOAc / petroleum ether = 1 / 10 to 1 / 5) to give (1 S,4r)-methyl 4-(((S)-1 -(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexane-1 - carboxylate [INT 5.4] (1.10 g, 2.52 mmol, 32.5% yield) as a yellow oil. m / z: [M+H]+C18H22BrF3N03calcd 436.1, 438.1 ; found 438.0.

[0652] Synthesis of N-[(1 S)-1 -(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methylthiane-4- carboxamide (Intermediate 5.5):

[0653]

[0654] To a mixture of [(1 S)-1 -(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)amine hydrochloride [INT 3.1 ] (400 mg, 1.31 mmol) and Et3N (662 mg, 6.55 mmol) in dichloromethane (2 mL) was added a solution of thiane-4-carbonyl chloride [INT 4.4] (415 mg, 2.52 mmol) in dichloromethane (2 mL) and the mixture was stirred at 25 °C for 3 h. The mixture was purified by silica gel flash chromatography (EtOAc / petroleum ether = 1 / 10 to 1 / 5) to give N-[(1 S)-1 -(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methylthiane-4-carboxamide [INT 5.5] (132 mg, 333 pmol, 25.4% yield) as a colourless oil. m / z: [M+H]+C15H18BrF3NOS calcd 396.0, 398.0; found 397.9.

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

[0656]

[0657] To a mixture of [(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)amine hydrochloride [INT 3.1] (1 g, 3.28 mmol) and triethylamine (1.65 g, 16.4 mmol) in CH2Cl2(10 mL) was added oxetan-3-carbonyl chloride [INT 4.5] (662 mg, 4.92 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated, diluted with water (30 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous Na2SO4and 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-methyloxetan-3-carboxamide [INT 5.6] (360 mg, 983 pmol, 30.0% yield) as a yellow oil. m / z: [M+H]+C14H16BrF3NO2calc 366.0; found 365.7. 1 H NMR (400 MHz, CDC13) 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).

[0658] Synthesis of N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methyl-1,4- dioxaspiro[4.5]decan-8-carboxamide (Intermediate 5.7):

[0659]

[0660] To a mixture of [(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)amine hydrochloride [INT 3.1] (500 mg, 1.64 mmol) and Et3N (829 mg, 8.20 mmol) in dichloromethane (10 mL) was added a solution of 4,4-difluorocyclohexane-1-carbonyl chloride [INT 4.7] (598 mg, 3.28 mmol) in dichloromethane (10 mL) and the mixture was stirred at 25 °C for 16 h. Water (10 mL) was added and the mixture was extracted with dichloromethane (30 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a 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 [INT 5.8] (539 mg, 1.30 mmol, 79.3% yield) as a colorless gum. m / z: [M+H]+C16H18BrF5NO calculated 414.0; found 414.0.

[0661] Synthesis of N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-4,4-difluoro-N- methylcyclohexane-1-carboxamide (INT 5.8):

[0662]

[0663] To a mixture of [(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)amine hydrochloride [INT 3.1] (500 mg, 1.64 mmol) and Et3N (829 mg, 8.20 mmol) in dichloromethane (10 mL) was added a solution of 4,4-difluorocyclohexane-1-carbonyl chloride [INT 4.7] (598 mg, 3.28 mmol) in dichloromethane (10 mL) and the mixture was stirred at 25 °C for 16 h. Water (10 mL) was added and the mixture was extracted with dichloromethane (30 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a 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 [INT 5.8] (539 mg, 1.30 mmol, 79.3% yield) as a colorless gum. m / z: [M+H]+C16H18BrF5NO calculated 414.0; found 414.0.

[0664] Synthesis of (1r,3S)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-3- cyano-N-methylcyclobutane-1-carboxamide [INT 5.9]:

[0665]

[0666] (1r,3r)-3-cyanocyclobutane-1-carboxylic acid [INT 5-a] (1 g, 7.99 mmol) and (S)-1-(4-bromophenyl)-2,2,2-trifluoro-N-methylethan-1-amine hydrochloride [INT 3.1] (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 h. The reaction was quenched by the addition of saturated sodium bicarbonate solution (20 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4and concentrated under reduced pressure to give (1r,3S)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-3-cyano-N- methylcyclobutane-1-carboxamide [INT 5.9] as a brown gum (2.06 g, 5.49 mmol, 68.7% yield). m / z: [M+H]+C15H15BrF3N2O calculated 375.0; found 375.0.

[0667] Synthesis of 1-acetyl-N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N- methylazetidine-3-carboxamide [INT 5.10]:

[0668]

[0669] To a solution of 1 -acetylazetidine-3-carbonyl chloride [INT 4.8] (300 mg, 1.85 mmol) and [(1 S)-1 -(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)amine hydrochloride [INT 3.1 ] (563 mg, 1.85 mmol) in CH2CI2(3 mL) was added triethylamine (561 mg, 5.55 mmol). The mixture was stirred at 20 °C for 4 h. The reaction mixture was concentrated under reduced pressure to give a crude product which was purified by flash chromatography on silica gel (EtOAc / PE = 0 / 1 to 1 / 5) to give 1 -acetyl-N-[(1 S)-1 -(4-bromophenyl)-2,2,2-trifluoroethyl]-N- methylazetidine-3-carboxamide [INT 5.10] (250 mg, 635 pmol, 34.3% yield) as a yellow oil. m / z: [M+H]+C15H17BrF3N2O2calc 393.0, 395.0; found 394.8.

[0670] 1 -acetyl-N-[(1 S)-1 -(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methylpiperidine-4- carboxamide (Intermediate 5.11 ) was synthesised according to the procedure described in Example 5.1, substituting [(1 S)-1 -(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)amine hydrochloride [INT 3.1 ] (500 mg, 1.64 mmol) and Et3N (829 mg, 8.20 mmol) in dichloromethane (10 mL) with 1 -acetyl piperidine-4-carbonyl chloride [INT 4.9] (550 mg, 2.90 mmol).

[0671]

[0672] To a solution of 1 -acetylazetidine-3-carbonyl chloride [INT 4.8] (300 mg, 1.85 mmol) and [(1 S)-1 -(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)amine hydrochloride [INT 3.1 ] (563 mg, 1.85 mmol) in CH2CI2(3 mL) was added triethylamine (561 mg, 5.55 mmol). The mixture was stirred at 20 °C for 4 h. The reaction mixture was concentrated under reduced pressure to give a crude product which was purified by flash chromatography on silica gel (EtOAc / PE = 0 / 1 to 1 / 5) to give 1 -acetyl-N-[(1 S)-1 -(4-bromophenyl)-2,2,2-trifluoroethyl]-N- methylazetidine-3-carboxamide [INT 5.10] (250 mg, 635 pmol, 34.3% yield) as a yellow oil. m / z: [M+H]+C15H17BrF3N2O2calc 393.0, 395.0; found 394.8. 1H NMR (400 MHz, CDC13) 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).

[0673] Synthesis of 1-acetyl-N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N- methylpiperidine-4-carboxamide (Intermediate 5.12):

[0674]

[0675] To a mixture of (1r,3r)-3-(chloroformyl)cyclobutane-1 -carboxylate [INT 4.10] (111 mg, 628 pmol) and [(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl](methyl)amine hydrochloride [INT 3.1] (120 mg, 394 pmol) in CH2CI2(2 mL) was added N,N-diisopropylethylamine (254 mg, 1.97 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 h and then at 20 °C for 12 h. The reaction was diluted with CH2CI2(50 mL) and 1 N HCI (20 mL). The organic phase was separated and washed with brine (20 mL), dried over anhydrous Na2S04and 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 (1S,3r)-3-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclobutane-1 - carboxylate [INT 5.12] (84.8 mg, 207 pmol, 53.0% yield (53% purity)) as a yellow oil. m / z: [M+H]+calcd for Ci6Hi8BrF3N03, 408.0; found, 408.0.

[0676] Synthesis of (S)-1-(4-bromophenyl)-2,2,2-trifluoroethan-1-amine (Intermediate 6.1):

[0677]

[0678] To a mixture of (S)-N-[(lS)-l-(4-bromophenyl)-2,2,2-trifluoroethyl]-2- methylpropane-2-sulfmamide [INT 2.1] (30 g, 83.7 mmol) in MeOH (100 mL) was added 4 M HC1 / dioxane (30 mL). The mixture was stirred at 15 °C for 1 h. The mixture was concentrated under reduced pressure to give a crude product. The mixture was diluted with water (50 mL) and extracted with EtOAc (100 mL*2). The combined organic layers were washed with 1 M HC1 (100 ml x 2). The aqueous phase was basified with 2 N NaOH to pH = 9-10 and extracted with CH2Cl2(100 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure to give (S)-l-(4-bromophenyl)-2,2,2- trifluoroethan-l-amine [INT 6.1] (11.0 g, 43.2 mmol, 51.6% yield) as an oil. m / z: [M+H]+C8H8BrF3N calcd 254.0 256.0; found 255.8.

[0679] Synthesis of (S)-tert-butyl 4-((l-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)piperidine-l-carboxylate (Intermediate 7.1):

[0680]

[0681] Synthesis of (S)-2-amino-7-(1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid tert-butyl ester Synthesis of (S)-2-amino-7-(1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid tert-butyl ester

[0682] To a mixture of l-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (5.41 g, 23.6 mmol), EDCI (6.78 g, 35.4 mmol) and HOBT (4.78 g, 35.4 mmol) in CH2Cl2(10 mL) was added (S)-l-(4-bromophenyl)-2,2,2-trifluoroethan-l-amine [INT 6.1] (6 g, 23.6 mmol) and the mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give a crude product. The mixture was diluted with water (50 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with NaHC03(100 mL x 2). The combined organic layers were dried over anhydrous Na2S04, 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 (S)-tert-butyl 4-((l-(4-bromophenyl)-2,2,2-trifluoroethyl)carbamoyl)piperidine-l-carboxylate [INT 7-a] (5.16 g, 11.0 mmol, 47.3% yield) as a yellow solid. 1H NMR (400 MHz, CDC13) δ = 7.59 - 7.55 (m, 2H), 7.29 (d, J = 2.8 Hz, 2H), 6.18 (br d, J = 9.2 Hz, 1H), 5.72 (quintet, J = 8.4 Hz, 1H), 4.16 (br d, J = 7.2 Hz, 2H), 2.87 - 2.72 (m, 2H), 2.37 (tt, J = 3.6, 12.0 Hz, 1H), 2.01 - 1.71 (m, 4H), 1.49 (s, 9H).

[0683] Synthesis of (S)-2-amino-7-(1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid tert-butyl ester Synthesis of (S)-2-amino-7-(1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid tert-butyl ester

[0684] To a solution of (S)-tert-butyl 4-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)carbamoyl)piperidine-1- carboxylate [INT 7-a] (2 g, 4.29 mmol) in DMF (30 mL) was added Cs2C03(2.79 g, 8.58 mmol) and the reaction mixture was stirred at 25 °C for 1 h. Then iodomethane (1.81 g, 12.8 mmol) was added at 0 °C and stirred at 25 °C for 4 h. Brine (50 mL) was added and the mixture was extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (50 mL x 2), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to give the crude product which was purified by silica gel flash chromatography (EtOAc / pet. ether = 1 / 5 to 1 / 0) to give (S)-tert-butyl 4-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)piperidine-1- carboxylate [INT 7.1] (1.20 g, 2.50 mmol, 58.5% yield) as a white solid. 1 H NMR (400 MHz, Chloroform-d) δ = 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).

[0685] Synthesis of tert-butyl 3-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)piperidine-1- carboxylate (INT 7.2):

[0686]

[0687] Synthesis of (S)-2-amino-7-(1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid tert-butyl ester Synthesis of (S)-2-amino-7-(1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid tert-butyl ester

[0688] 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 CH2Cl2(20 mL) was added (S)-1-(4-bromophenyl)-2,2,2-trifluoroethan-1-amine [INT 6.1] (1.8 g, 7.08 mmol) and the mixture was stirred at 25 °C for 16 h. The reaction was quenched by the addition of water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over anhydrous Na2SO4and 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 [INT 7-b] (1.40 g, 3.00 mmol, 42.5% yield) as a yellow solid. m / z: [M+H-56]+C19H25BrF3N2O3calc 408.9; found 408.8.

[0689] Synthesis of (S)-2-amino-7-(1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid tert-butyl ester Synthesis of (S)-2-amino-7-(1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid tert-butyl ester

[0690] To a solution of tert-butyl 3-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)carbamoyl)piperidine-1-carboxylate [INT 7-b] (1.4 g, 3.00 mmol) in DMF (10 mL) was added Cs2CO3(1.95 g, 6.00 mmol) and the reaction mixture was stirred at 25 °C for 1 h. Then iodomethane (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 the addition of water (50 mL) and then it was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over anhydrous Na2SO4and 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 [INT 7.2] (800 mg, 1.66 mmol, 55.9% yield) as a colorless oil. m / z: [M–56+H]+C20H27BrF3N2O3calc 425.1; found 424.7.

[0691] Synthesis of tert-butyl 3-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)pyrrolidine-1-carboxylate (INT 7.3):

[0692]

[0693] Synthesis of (S)-2-amino-7-(1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid tert-butyl ester Synthesis of (S)-2-amino-7-(1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid tert-butyl ester Synthesis of (S)-2-amino-7-(1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid tert-butyl ester Synthesis of (S)-2-amino-7-(1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid tert-butyl ester Synthesis of (S)-2-amino-7-(1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid tert-butyl ester Synthesis of (S)-2-amino-7-(1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid tert-butyl ester Synthesis of (S)-2-amino-7-(1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid tert-butyl ester Synthesis of (S)-2-amino-7-(1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid tert-butyl ester Synthesis of (S)-2-amino-7-(1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid tert-butyl ester Synthesis of (S)-2-amino-7-(1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid tert-butyl ester Synthesis of (S)-2-amino-7-(1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid tert-butyl ester Synthesis of (S)-2-amino-7-(1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid tert-butyl ester Synthesis of (S)-2-amino-7-(1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylic acid tert-butyl ester Synthesis

[0694] To a mixture of 1-[(tert-butoxy)carbonyl]pyrrolidine-3-carboxylic acid (1.69 g, 7.87 mmol), EDCI (2.26 g, 11.8 mmol) and HOBT (1.59 g, 11.8 mmol) in CH2Cl2(30 mL) was added (S)-1-(4-bromophenyl)-2,2,2-trifluoroethan-1-amine [INT 6.1] (2 g, 7.87 mmol) and the mixture was stirred at 15 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give crude product. This was combined with material from a separate identical reaction of the same scale. The mixture was diluted with water (50 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with NaHC03(100 mL x 2). The combined organic layers were dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to give 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 [INT 7-c] (4.26 g, 9.43 mmol, 59.9% yield) as a yellow oil. m / z: [M-56+H]+calcd for C18H23BrF3N2O3 395.0, 397.0; found 396.6. 1 H NMR (400 MHz, CDC13) d = 7.55 (br d, J = 8.0 Hz, 2H), 7.25 (br s, 2H), 6.22 (br s, 1H), 5.69 (quintet, J = 8.0 Hz, 1H), 3.72 - 3.42 (m, 3H), 3.40 - 3.29 (m, 1H), 3.03 - 2.88 (m, 1H), 2.06 - 2.03 (m, 2H), 1.46 (d, J = 6.8 Hz, 9H).

[0695] 3-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)pyrrolidine-1-carboxylic acid tert- Synthesis of butyl ester (INT 7.3):

[0696] Cs₂CO₃ (6.12 g, 18.8 mmol) was added to a DMF (50 mL) solution of 3-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)carbamoyl)pyrrolidine-1-carboxylic acid tert-butyl ester [INT 7-c] (4.26 g, 9.43 mmol), and the reaction mixture was stirred at 25 °C for 1 h. Iodomethane (4.00 g, 28.2 mmol) was then added at 0 °C, and the reaction was stirred at 25 °C for 4 h. The reaction was quenched by adding water (50 mL) and then extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to give a crude product. This crude product was purified by silica gel rapid chromatography (EtOAc / petroleum ether = 1 / 5 to 1 / 0) to give 3-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)pyrrolidine-1-carboxylic acid tert-butyl ester [INT 7.3] (2.20 g, 4.73 mmol, 50.2% yield), a yellow oil. [M-56+H]+C19H₂₅BrF₃N₂O₃ Calculated value 409.1 Found value 409.1 1 H NMR (400MHz, CDCl3)d=7.61-7.51(m,2H),7.24(br d,J=6.4Hz,2H),6.61(q,J=8.8Hz,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).

[0697] (S)-((4-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexyl)methyl)tert-butyl carbamate (intermediate 7.4):

[0698]

[0699] (S)-((4-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)carbamoyl)cyclohexyl)methyl)carbamoic acid Synthesis of tert-butyl ester (INT 7-d):

[0700] To a mixture of 4-({[(tert-butoxy)carbonyl]amino}methyl)cyclohexane-1 - carboxylic acid (1.92 g, 7.47 mmol), EDCI (2.16 g, 1 1.2 mmol) and HOBT (1.51 g, 1 1.2 mmol) in CH2CI2(20 mL) was added (S)-1 -(4-bromophenyl)-2,2,2- trifluoroethan-1 -amine [INT 6.1 ] (1.9 g, 7.47 mmol) and the mixture was stirred at 25 °C for 16 h. The reaction was quenched by the addition of saturated Na2CO3(100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (200 mL x 2), dried over anhydrous Na2SO4and 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 (S)-((4-((1 -(4-bromophenyl)-2,2,2-trifluoroethyl)carbamoyl)cyclohexyl)methyl)carbamic acid tert-butyl ester [INT 7-d] (2.53 g, 5.12 mmol, 68.7% yield) as a white solid. m / z: [M+H-56]+C21H29BrF3N2O3calc 437.1 ; found 436.9. 1 H NMR (400 MHz, CD3OD) d = 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, 1 H), 4.61 (br s, 1 H), 2.89 (br d, J = 6.4 Hz, 2H), 2.31 (br t, J = 12.0 Hz, 1 H), 1.97 - 1.66 (m, 5H), 1.47 - 1.40 (m, 3H), 1.43 (s, 9H), 1.07 - 0.90 (m, 2H).

[0701] (S)-((4-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexyl)methyl)amino Synthesis of tert-butyl carbamate (INT7.4):

[0702] A suspension of (S)-((4-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)carbamoyl)cyclohexyl)methyl)tert-butyl carbamate [INT 7-d] (1 g, 2.02 mmol) and Cs₂CO₃ (1.97 g, 6.06 mmol) in DMF (15 mL) was stirred for 1 hour. Then, MeI (860 mg, 6.06 mmol) was added, and the resulting mixture was stirred for 3 hours. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with water (200 mL x 2) and brine (200 mL), dried over Na₂SO₄, and filtered. The filtrate was concentrated to obtain the residue, which was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5μm, table: 54-84% B (A = water (0.05% ammonium hydroxide v / v), B = acetonitrile), flow rate: 30mL / min, UV detector 220nm) to obtain (S)-((4-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexyl)methyl)tert-butyl carbamate [INT 7.4] (400mg, 788μmol, 39.2% yield), a white solid. m / z: [M-56+H]+C22H31BrF3N2O3 Calculated values ​​451.1, 453.1; Measured value 452.9. 1 HNMR (400MHz, CDCl3) δ = 7.58-7.50 (m, 2H), 7.25 (d, J = 8.4Hz, 2H), 6.65 (q, J = 8.8Hz, 1H), 4.60 (br s, 1H), 3.02 (br t,J=6.4Hz,2H),2.87(s,3H),2.53(tt,J=3.2,11.6Hz,1H),1.96-1.77(m,4H),1.71-1.54(m,3H),1.46(s,9H),1.08-0.95(m,2H).

[0703] (1r,4S)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-methoxy-N-methylcyclohexane-1-carboxamide (intermediate 7.5):

[0704]

[0705] (1r,4S)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-methoxycyclohexane-1-carboxamide Synthesis of (INT7-e):

[0706] To a mixture of (lr,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 CH2CI2(20 mL) was added (S)-1 -(4-bromophenyl)-2,2,2-trifluoroethan-1 -amine [INT 6.1] (700 mg, 2.75 mmol) and the mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched by the addition of water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with saturated NaHC03(20 mL) and brine (10 mL x 2), dried over anhydrous Na2S04and 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 (lr,4S)-N-((S)-1 -(4-bromophenyl)-2,2,2-trifluoroethyl)-4- methoxycyclohexane-1 -carboxamide [INT 7-e] (456 mg, 1.15 mmol, 42.2% yield) as a white solid. m / z: [M+H]+C16H20BrF3NO2calculated 394.1, 396.1 ; found 395.9. 1 H NMR (400 MHz, CD3OD) d = 7.58 (d, J = 8.6 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H), 5.68 (q, J = 8.3 Hz, 1 H), 3.34 (s, 3H), 3.24-3.09 (m, 1 H), 2.41 -2.24 (m, 1 H), 2.20-2.05 (m, 2H), 1.95-1.84 (m, 1 H), 1.83-1.71 (m, 1 H), 1.64-1.39 (m, 2H), 1.30-1.09 (m, 2H).

[0707] (1r,4S)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-methoxy-N-methylcyclohexane-1- Synthesis of formamide (INT7.5):

[0708] A mixture of (1r,4S)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-methoxycyclohexane-1-carboxamide [INT 7-e] (455 mg, 1.15 mmol) and Cs₂CO₃ (749 mg, 2.30 mmol) in DMF (1 mL) was stirred at 25 °C for 1 hour. CH₃I (816 mg, 5.75 mmol) was added, and the mixture was stirred for 2 hours. The reaction was quenched by adding water (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to obtain a crude product. This crude product was purified by silica gel rapid chromatography (EtOAc / PE = 0 / 1 to 1 / 3) to give a colorless oily (1r,4S)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-methoxy-N-methylcyclohexane-1-carboxamide [INT 7.5] (130 mg, 318 μmol, 27.7% yield). m / z: [M+H]+C₁₇H₂₂BrF₃NO₂ Calculated value 408.1; Found value 407.8.

[0709] (1r,4S)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-((tert-butyldimethylsilyl)oxy)-N-methylcyclohexane-1-carboxamide (intermediate 8.1):

[0710]

[0711] (1r,4S)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-hydroxycyclohexane-1-carboxamide (INT) Synthesis of 8-a):

[0712] To a mixture of (lr,4r)-4-hydroxycyclohexane-l -carboxylic acid (1.13 g, 7.87 mmol), EDCI (2.28 g, 11.8 mmol) and HOBt (1.59 g, 11.8 mmol) in CH2Cl2(20 mL) was added (S)-l-(4-bromophenyl)-2,2,2-trifluoroethan-l -amine [INT 6.1] (2 g, 7.87 mmol) and the mixture was stirred at 25 °C for 16 h. The reaction was quenched by the addition of water (100 mL) and extracted with CH2Cl2(100 mL x 3). The combined organic layers were washed with saturated aqueous NaHC03solution (200 mL x 2) and brine (200 mL), dried over anhydrous Na2S04and 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 (lr,4S)-N-((S)-l-(4-bromophenyl)-2,2,2-trifluoroethyl)-4- hydroxycyclohexane-l -carboxamide [INT 8-a] (1.80 g, 4.73 mmol, 60.1 % yield) as a white solid. m / z: [M+H]+C15H18BrF3NO2calc 380.0, 382.0; found 381.7.

[0713] (1r,4S)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-((tert-butyldimethylsilyl) Synthesis of (-O-)-N-methylcyclohexane-1-carboxamide (INT 8.1):

[0714] A suspension of (lr,4S)-N-((S)-l-(4-bromophenyl)-2,2,2-trifluoroethyl)-4- hydroxycyclohexane-l -carboxamide [INT 8-a] (500 mg, 1.31 mmol), imidazole (178 mg, 2.62 mmol) and tert-butyldimethylsilyl chloride (295 mg, 1.96 mmol) in CH2Cl2(5 mL) was stirred at 25 °C for 12 h. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with saturated Na2C03(100 mL x 2) and brine (100 mL), dried over Na2S04, 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 (lr,4r)-N-[(lS)-l-(4-bromophenyl)-2,2,2-trifluoroethyl]-4-[(tert- butyldimethylsilyl)oxy]cyclohexane-l -carboxamide (440 mg, 889 pmol, 68.0 % yield) as a white solid. m / z: [M+H]+C21H32BrF3NO2Si calc 496.1; found 496.0. 1H NMR (400 MHz, CDC13) 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).

[0715] 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 Cs2C03(2.26 g, 6.96 mmol) in DMF (3 mL) was stirred at 20 °C for 1 h. Then Mel (987 mg, 6.96 mmol) was added and the reaction mixture was stirred at 20 °C for 3 h. The reaction mixture was combined with the mixture from another identical reaction, poured into water (30 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with water (50 mL x 2) and brine (50 mL), dried over Na2S04, filtered and concentrated under reduced pressure to give a 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 [INT 8.1] (495 mg, 973 pmol, 42.3% yield) as a white solid. m / z: [M+H]+calcd for C22H34BrF3NO2Si 508.1, 510.1; found 510.1. 1 H NMR (400 MHz, CDC13) 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).

[0716] (S)-(4-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexyl)carbamic acid methyl ester (Intermediate 9.1):

[0717]

[0718] (S)-(4-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)carbamoyl)cyclohexyl)tert-butyl carbamate Synthesis of (INT9-a):

[0719] 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 CH2CI2(2 mL) was added (S)-1 -(4-bromophenyl)-2,2,2-trifluoroethan-1 -amine [INT 6.1 ] (2.5 g, 5.90 mmol) and the mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched by the addition of water (30 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2S04and 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 [INT 9-a] (2.70 g, 5.63 mmol, 95.7% yield) as a white solid. m / z: [M-Boc]+C20H26BrF3N2O3calc 378.1 ; found 378.9.

[0720] (S)-4-amino-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)cyclohexane-1-carboxamide hydrochloride (INT) Synthesis of 9-b):

[0721] A solution of tert-butyl (S)-(4-((1 -(4-bromophenyl)-2,2,2-trifluoroethyl)carbamoyl)cyclohexyl)carbamate [INT 9-a] (3.1 g, 6.46 mmol) in 4 M HCI 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 [INT 9-b] (2.60 g, 6.25 mmol, 97.0% yield) as a white solid. m / z: [M+H]+C15H19BrF3N2O calc 379.1 ; found 379.1.

[0722] (S)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-(1,3-dioxoisoindolin-2-yl)cyclohexane Synthesis of alkyl-1-carboxamide (INT 9-c)

[0723] A mixture of (S)-4-amino-N-(l-(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- lH-isoindole-2-carboxylate (1.16 g, 5.32 mmol), and Na2CO3(1.12 g, 10.6 mmol) in THF (20 mL) was stirred at 25 °C for 1 h. The reaction was combined with a crude batch of the same reaction of the same scale and concentrated under reduced pressure to give a crude product. The crude product was triturated with EtOAc / PE (1 / 1, 50 mL) to give (S)-N-(l-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-(l,3-dioxoisoindolin-2-yl)cyclohexane-l- carboxamide [INT 9-c] (3.60 g, 7.06 mmol, 99.4% yield) as a white solid. m / z: [M+Na]+C23H20BrF3N2O3calc 531.1, 533.1; found 532.8.

[0724] (S)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-(1,3-dioxoisoindolin-2-yl)-N-methyl Synthesis of cyclohexane-1-carboxamide (INT9-d):

[0725] A mixture of (S)-N-(l-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-(l,3-dioxoisoindolin-2- yl)cyclohexane-l-carboxamide [INT 9-c] (3.7 g, 7.26 mmol) and Cs2CO3(4.72 g, 14.5 mmol) in DMF (40 mL) was stirred at 25 °C for 1 h. CH3I (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 the addition of water (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a crude product which was purified by silica gel flash chromatography (EtOAc / PE = 0 / 1 to 1 / 3) to give (S)-N-(l-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-(l,3-dioxoisoindolin-2-yl)-N- methylcyclohexane-l-carboxamide [INT 9-d] (996 mg, 1.90 mmol, 26.2% yield) as a white solid. m / z: [M+H]+C24H23BrF3N2O3calc 523.1; found 523.2.

[0726] (S)-4-amino-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methylcyclohexane-1-carboxamide Synthesis of (INT9-e)

[0727] To a mixture of (S)-N-(l-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-(l,3- dioxoisoindolin-2-yl)-N-methylcyclohexane-l-carboxamide [INT 9-d] (300 mg, 573 pmol) in EtOH (1 mL) was added NH2NH2.H2O (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-(l-(4-bromophenyl)-2,2,2- trifluoroethyl)-N-methylcyclohexane-l-carboxamide [INT 9-e] (220 mg, 559 pmol, 97.7% yield) as a yellow solid. m / z: [M-NH2]+C16H20BrF3N2O calc 376.1; found 376.1.

[0728] (S)-(4-((1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexyl)carbamoic acid Synthesis of methyl ester (INT9.1):

[0729] To a solution of (S)-4-amino-N-(l-(4-bromophenyl)-2,2,2-trifluoroethyl)-N- methylcyclohexane-l-carboxamide [INT 9-e] (90 mg, 228 pmol) and Et3N (115 mg, 1.14 mmol) in CH2Cl2(1 mL) was added methyl chloroformate (64.6 mg, 684 pmol) and the mixture was stirred for 1 h. The reaction was quenched by the addition of water (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure to give the crude product which was purified by preparative TLC (EtOAc / PE = 1 / 2) to give (S)-(4-((l-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexyl)carbamic acid methyl ester [INT 9.1] (60.0 mg, 132 pmol, 58.8% yield) as a colorless oil. m / z: [M+H]+C18H23BrF3N2O3calc 451.1, 453.1; found 452.9.

[0730] Synthesis of (S)-4-acetylamino-N-(l-(4-bromophenyl)-2,2,2-trifluoroethyl)-N- methylcyclohexane-l-carboxamide (Intermediate 9.2):

[0731]

[0732] To a mixture of (S)-4-amino-N-(l-(4-bromophenyl)-2,2,2-trifluoroethyl)-N- methylcyclohexane-1-carboxamide [INT 9-e] (110 mg, 279 pmol) and triethylamine (140 mg, 1.39 mmol) in DCM (1 mL) was added acetyl chloride (76.6 mg, 976 pmol) at 25 °C and the mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give crude (S)-4-acetylamino-N-(l-(4-bromophenyl)-2,2,2- trifluoroethyl)-N-methylcyclohexane-1-carboxamide [INT 9.2] (120 mg, 275 pmol, 99.1% yield) as a white solid. m / z: [M+H]+calcd for C18H23BrF3N2O2, 435.1; found, 435.2.

[0733] Synthesis of 1-(4-bromophenyl)-N-methylethan-1-amine (INT 10.1):

[0734]

[0735] To a solution of 1-(4-bromophenyl)ethan-1-one [INT 10-a] (10 g, 50.3 mmol) in MeOH (100 mL) was added sodium cyanoborohydride (8.79 g, 140 mmol) and methylamine hydrochloride (31.5 g, 468 mmol). The mixture was stirred at 20 °C for 12 h. The reaction was quenched by the addition of water (100 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2S04and concentrated under reduced pressure to give 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 [INT 10.1] (7.50 g, 32.8 mmol, 65.2% yield) as a colorless oil. m / z: [M+H]+calcd for C9H13BrN, 214.0; found, 213.9.

[0736] Synthesis of N-(l-(4-bromophenyl)ethyl)-N-methylcyclobutanecarboxamide (INT 11.1):

[0737]

[0738] To a mixture of cyclopentanecarboxylic acid [INT 11-a] (389 mg, 3.89 mmol) and HATU (2.21 g, 5.83 mmol) in CH2Cl2(15 mL) was added DIPEA (1.49 g, 11.6 mmol) and 1-(4-bromophenyl)-N-methylethan-1-amine [INT 10.1] (1 g, 4.67 mmol). The reaction mixture was stirred at 20 °C for 16 hours under nitrogen. The reaction mixture was concentrated under reduced pressure to give a crude product which was purified by preparative HPLC (column: Phenomenex Gemini-NX 80*40 mm*3 um, Method: 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-methylcyclopentanecarboxamide [INT 11.1] (150 mg, 506 µmol, 13.0% yield) as an off-white dry powder. m / z: [M+H]+C14H19BrNO calculated 296.1, 298.1; found 298.1.

[0739] Synthesis of N-[1-(4-bromophenyl)ethyl]-N-methylcyclohexanecarboxamide (Intermediate 11.2):

[0740]

[0741] To a mixture of [1-(4-bromophenyl)ethyl](methyl)amine [INT 10.1] (500 mg, 2.33 mmol) and HATU (1.32 g, 3.49 mmol) in CH2Cl2(10 mL) was added DIPEA (902 mg, 6.98 mmol) and cyclohexanecarboxylic acid [INT 11-b] (447 mg, 3.49 mmol). The reaction mixture was stirred at 20 °C for 16 hours under nitrogen. The mixture was diluted with water (50 mL) and extracted with EtOAC (50 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over Na2SO4, 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 [INT 11.2] (700 mg, 2.15 mmol, 92.7% yield) as a colourless oil. m / z: [M+H]+C16H23BrNO calculated 324.1, 326.1; found 326.1.

[0742] Synthesis of N-[1-(4-bromophenyl)ethyl]-N-methylcyclopentanecarboxamide (Intermediate 11.3):

[0743]

[0744] To a mixture of cyclopentanecarboxylic acid [INT 11-c] (63.9 mg, 560 μmol) and HATU (266 mg, 700 μmol) in CH2Cl2(3 mL) was added DIPEA (180 mg, 1.40 mmol) and [l-(4-bromophenyl)ethyl](methyl)amine [INT 10.1] (100 mg, 467 μmol). The reaction mixture was stirred at 20 °C under nitrogen 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 x 2). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SO4and concentrated under reduced pressure to give N-[l-(4-bromophenyl)ethyl]-N-methylcyclopentanecarboxamide [INT 11.3] (110 mg, 354 μmol, 76.3% yield) as a colorless oil. m / z: [M+H]+C15H21BrNO calculated 310.1, 312.1; found 312.1.

[0745] Synthesis of N-(l-(4-bromophenyl)ethyl)-N-methylacetamide (Intermediate 12.1):

[0746]

[0747] To a mixture of l-(4-bromophenyl)-N-methylethan-l -amine [INT 10.1] (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 a crude product which was purified by silica gel flash chromatography (EtOAc / PE = 0 / 1 to 1 / 3) to give N-(l-(4-bromophenyl)ethyl)-N-methylacetamide [INT 12.1] (100 mg, 390 μmol, 84.0% yield) as a yellow oil. m / z: [M+H]+C11H15BrNO calculated 256.0, 258.0; found 257.9.

[0748] Synthesis of N-[l-(4-bromophenyl)ethyl]-N-methylcyclopropanecarboxamide (Intermediate 12.2):

[0749]

[0750] To a mixture of [l-(4-bromophenyl)ethyl](methyl)amine [INT 10.1] (740 mg, 3.45 mmol) and triethylamine (349 mg, 3.45 mmol) in CH2Cl2(10 mL) was added cyclopropanecarbonyl chloride [INT 12-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-[l-(4-bromophenyl)ethyl]-N-methylcyclopropanecarboxamide [INT 12.2] (556 mg, 1.97 mmol) as a brown oil. m / z: [M+H]+calcd for C13H17BrNO 282.0; found 282.1.

[0751] Synthesis of N-(l-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methylacetamide (Intermediate 13.1):

[0752]

[0753] Synthesis of (E)-N-(4-bromophenylmethylene)-2-methylpropane-2-sulfinamide (INT 13-a):

[0754] To a solution of 4-bromobenzaldehyde [INT 2-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 [INT 13-a] (7.35 g, 25.5 mmol, 94.4% yield) as a colorless gum. 1 H NMR (400 MHz, DMSO-d6) d = 8.55 (s, 1H), 7.89 (d, J = 8.4 Hz, 2H), 7.80-7.72 (m, 2H), 1.18 (s, 9H).

[0755] Synthesis of N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide (INT13-b):

[0756] Pure 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-sulfmamide [INT 13-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-sulfmamide [INT 13-b] (3.50 g, 9.77 mmol, 80.8% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) d = 7.68-7.62 (m, 2H), 7.61-7.57 (m, 2H), 6.48 (d, J = 9.5 Hz, 1H), 5.27 (quint, J = 8.6 Hz, 1H), 1.14 (s, 9H).

[0757] Synthesis of 1-(4-bromophenyl)-2,2,2-trifluoroethyl-1-amine (INT13-c):

[0758] A 4 M solution of HCI 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-sulfmamide [INT 13-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 a 1 N NaOH solution. The mixture was extracted with ethyl acetate (2 x 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 [INT 13-c] (2.16 g, 8.50 mmol, 87.0% yield) as a brown oil. m / z: [M-NH2]+C8H7BrF3N calcd 237.0; found 237.0. 1 H NMR (400 MHz, DMSO-d6) d = 7.68-7.62 (m, 2H), 7.61-7.57 (m, 2H), 6.48 (d, J = 9.5 Hz, 1H), 5.27 (quint, J = 8.6 Hz, 1H), 1.14 (s, 9H).

[0759] Synthesis of N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)acetamide [INT13-d]:

[0760] To a solution of 1-(4-bromophenyl)-2,2,2-trifluoroethan-1-amine [INT 13-c] (2.7 g, 8.50 mmol) and triethylamine (1.72 g, 17.0 mmol) in CH2Cl2(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 CH2Cl2(50 mL), washed with water (50 mL), dried over anhydrous Na2SO4and 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 [INT 13-d] (2.50 g, 8.44 mmol, 99.6% yield) as an off-white solid. m / z: [M+H]+C10H10BrF3NO calculated 296.0, 298.0; found 295.8. 1 H NMR (400 MHz, 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).

[0761] Synthesis of N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methylacetamide (INT13.1):

[0762] 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 [INT 13-d] (2.5 g, 8.44 mmol) was added and the reaction mixture was stirred at 0 °C for 30 min. Then iodomethane (3.59 g, 25.3 mmol) was added and the reaction mixture was warmed to 20 °C over 12 h under N2. The reaction was quenched by the addition of saturated NH4Cl (150 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4and 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 [INT 13.1] (1.83 g, 5.90 mmol, 70.1% yield) as a brown oil. m / z: [M+H]+C11H12BrF3NO calculated 310.0, 312.0; found 311.7. 1H NMR (400 MHz, 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).

[0763] Synthesis of (R)-N-(l-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H- thiopyran-4-carboxamide 1,1-dioxide (INT 14.1):

[0764]

[0765] (S)-N-((R)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide (INT14- Synthesis of a):

[0766] (S)-N-((R)-l-(4-bromophenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfmamide [INT 14-a] was prepared using (S)-(-)-2-methyl-2-propane sulfmamide following the same synthetic route as (R)-N-((S)-l-(4-bromophenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2- sulfmamide [INT 2.1].

[0767] Synthesis of (R)-1-(4-bromophenyl)-2,2,2-trifluoroethyl-1-amine (INT 14-b):

[0768] To a mixture of (S)-N-((R)-l-(4-bromophenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2- sulfmamide [INT 14-a] (8 g, 22.3 mmol) in MeOH (60 mL) was added 4 M HCI 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 x 2). The combined organic layers were washed with 1 M HCI (50 mL x 2). The aqueous phase was basified with 2 N NaOH to pH = 9-10 and extracted with CH2CI2(50 mL x 2). The combined organic layers were dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure to give the crude product (R)-l-(4-bromophenyl)-2,2,2-trifluoroethan-l-amine [INT 14-b] (3.50 g, 13.7 mmol, 61.8% yield) as a yellow solid. m / z: [M+H]+calcd for C8H8BrF3N 254.0, 256.0; found 254.1.

[0769] (R)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)tetrahydro-2H-thiaran-4-carboxamide 1,1-dioxide Synthesis of (INT 14-c):

[0770] To a mixture of tetrahydro-2H-thiopyran-4-carboxylic acid 1,1-dioxide [INT 4-a] (1.68 g, 9.44 mmol), EDCI (2.26 g, 11.8 mmol) and HOBt (1.59 g, 11.8 mmol) in CH2Cl2(20 mL) was added (R)-1-(4-bromophenyl)-2,2,2-trifluoroethan-1-amine [INT 14-b] (2 g, 7.87 mmol). The mixture was stirred at 25 °C for 16 h. The reaction was quenched by the addition of water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over anhydrous Na2SO4and 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 [INT 14-c] (2.20 g, 5.31 mmol, 67.4% yield) as a white solid. m / z: [M+H]+calcd for Ci4Hi6BrF3NO3S 414.0, 416.0; found 416.2.

[0771] (R)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiaran-4-carboxamide 1,1-di Synthesis of oxides (INT 14.1):

[0772] To a solution of (R)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)tetrahydro-2H- thiopyran-4-carboxamide 1,1-dioxide [INT 14-c] (1 g, 2.41 mmol) in DMF (10 mL) was added Cs2CO3(1.57 g, 4.82 mmol) and the reaction mixture was stirred at 25 °C for 1 h. Then iodomethane (1.02 g, 7.23 mmol) was added at 0 °C and the reaction was stirred at 25 °C for 2 h. The reaction was quenched by the addition of water (50 mL) and then it was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over anhydrous Na2SO4and 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 [INT 14.1] (700 mg, 1.63 mmol, 67.9% yield) as a colorless oil. m / z: [M+H]+calcd for Ci5Hi8BrF3NO3S 428.0, 430.0; found 430.1.

[0773] Synthesis of (S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoro-N- methylethan-1 -amine hydrochloride (INT 15.1):

[0774]

[0775] Synthesis of (R,E)-N-(4-bromo-2-methylbenzylmethyl)-2-methylpropane-2-sulfinamide (INT15-b):

[0776] (R)-2-methylpropane-2-sulfmamide (12.1 g, 100 mmol) and 4-bromo-2- methylbenzaldehyde [INT 15-a] (10 g, 50.2 mmol) were dissolved in tetrahydrofuran (50 mL) and tetraethyl orthotitanate (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 x 300 mL). The organic extracts were combined, dried over Na2S04and 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-sulfmamide [INT 15-b] (10.4 g, 34.5 mmol, 68.8% yield) as a yellow solid. 1 H NMR (400 MHz, CDC13) δ 8.76 (s, 1H), 7.75 (d, J = 8.7 Hz, 1H), 7.46-7.37 (m, 2H), 2.56 (s, 3H), 1.24 (s, 9H).

[0777] (R)-N-((S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide Synthesis of (INT15-c):

[0778] (R,E)-N-(4-bromo-2-methylbenzylidene)-2-methylpropane-2-sulfmamide [INT 15-b] (18.8 g, 62.2 mmol) and tetrabutylammonium triphenyl difluorosilicate (50.3 g, 93.3 mmol) were dissolved in THF (300 mL). At -80 °C trifluoromethyltrimethylsilane (44.2 g, 311 mmol) was added dropwise. The mixture was stirred for 30 min at -30 °C before aqueous NH4CI solution (200 mL) was added. The mixture was extracted with EtOAc (2 x 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-sulfmamide [INT 15-c] (19.0 g, 51.0 mmol, 82.2% yield) as a yellowish oil. m / z: [M+H]+calcd for Ci3Hi8BrF3NOS 372.0; found 372.2. 1 H NMR (500 MHz, CDC13) 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).

[0779] (R)-N-((S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethyl)-N,2-dimethylpropane-2-sulfin Synthesis of amide (INT15-d):

[0780] (R)-N-((S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2- sulfmamide [INT 15-c] (10 g, 26.8 mmol) was dissolved in THF (300 mL). At 0 °C lithium bis(trimethylsilyl)amide (74.3 mL, 80.3 mmol) was added. The mixture was stirred for 20 min at 0 °C. Iodomethane (22.7 g, 160 mmol) was added. The mixture was stirred for 10 h at 20 °C before aqueous NH4CI solution (50 mL) was added. The mixture was extracted with EtOAc (2 x 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- sulfmamide [INT 15-d] (8.50 g, 22.0 mmol, 82.5% yield) as a brown oil. m / z: [M+H]+calcd for Ci4H20BrF3NOS 386.0, 388.0; found 388.0. 1H NMR (400 MHz, CDC13) 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).

[0781] (S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoro-N-methylethyl-1-amine hydrochloride (INT 15.1) become:

[0782] (R)-N-((S)-l-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethyl)-N,2-dimethylpropane-2- sulfinamide [INT 15-d] (10 g, 25.8 mmol) was dissolved in methanol (20 mL). Hydrogen chloride (4 M in 1,4-dioxane, 100 mL, 2.36 mol) was added. The mixture was stirred at 20 °C for 10 h. 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)-l-(4-bromo-2-methylphenyl)-2,2,2-trifluoro-N-methylethan-l-amine hydrochloride [INT 15.1] (6.27 g, 19.6 mmol, 76.3 % yield) as a white solid. m / z: [M+H]+Ci0Hi2BrF3N calc 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).

[0783] Synthesis of (S)-l-(4-bromo-3-methylphenyl)-2,2,2-trifluoro-N-methylethan-l-amine hydrochloride (Intermediate 15.2):

[0784]

[0785] Synthesis of (R,E)-N-(4-bromo-3-methylbenzylmethyl)-2-methylpropane-2-sulfinamide (INT 15-f):

[0786] (R)-2-methylpropane-2-sulfmamide (18.1 g, 150 mmol) and 4-bromo-3- methylbenzaldehyde [INT 15-e] (15 g, 75.3 mmol) were dissolved in tetrahydrofuran (100 mL) and tetraethyl orthotitanate (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 x 300 mL). The organic extracts were re-extracted with water (3 x 200 mL), dried over Na2S04and evaporated in vacuo to give (R,E)-N-(4-bromo-3-methylbenzylidene)-2- methylpropane-2-sulfmamide [INT 15-f] (15.2 g, 50.2 mmol, 66.9% yield) as a yellow solid. 1 H NMR (400 MHz, CDC13) δ 8.49 (s, 1H), 7.67 (d, J = 2.2 Hz, 1H), 7.65-7.52 (m, 1H), 7.51-7.43 (m, 1H), 2.43 (s, 3H), 1.23 (s, 9H).

[0787] (R)-N-((S)-1-(4-bromo-3-methylphenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide Synthesis of (INT15-g):

[0788] (R,E)-N-(4-bromo-3-methylbenzylidene)-2-methylpropane-2-sulfmamide [INT 15-f] (21 g, 69.4 mmol) and tetrabutylammonium triphenyl difluorosilicate (56.1 g, 104 mmol) were dissolved in THF (500 mL). Trifluoromethyltrimethylsilane (49.3 g, 347 mmol) was added dropwise at -80 °C. The mixture was stirred at -30 °C for 30 min, followed by the addition of aqueous NH4C1 (300 mL). The mixture was extracted with EtOAc (2 x 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-sulfmamide [INT 15-g] (18.5 g, 49.7 mmol, 71.7% yield) as a white solid. m / z: [M+H]+calcd for Ci3Hi8BrF3NOS 372.0; found 372.0. 1 H NMR (500 MHz, CDC13) 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).

[0789] (R)-N-((S)-1-(4-bromo-3-methylphenyl)-2,2,2-trifluoroethyl)-N,2-dimethylpropane-2-sulfin Synthesis of amide (INT15-h):

[0790] (R)-N-((S)-1-(4-bromo-3-methylphenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2- sulfinamide [INT 15-g] (10 g, 26.8 mmol) was dissolved in THF (200 mL). Lithium bis(trimethylsilyl)amide (1+) (74.3 mL, 80.3 mmol) was added at 0 °C. The mixture was stirred at 0 °C for 20 min. Iodomethane (22.7 g, 160 mmol) was added. The mixture was stirred at 20 °C for 10 h, followed by the addition of aqueous NH4Cl solution (200 mL). The mixture was extracted with EtOAc (2 x 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 [INT 15-h] (9.09 g, 23.5 mmol, 88.2% yield) as a brown oil. m / z: [M+H]+calcd for Ci4H20BrF3NS 386.0; found 386.0. 1 H NMR (400 MHz, CDC13) 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).

[0791] (S)-1-(4-bromo-3-methylphenyl)-2,2,2-trifluoro-N-methylethyl-1-amine hydrochloride (INT15.2) become:

[0792] (R)-N-((S)-1-(4-bromo-3-methylphenyl)-2,2,2-trifluoroethyl)-N,2-dimethylpropane-2- sulfinamide [INT 15-h] (10.7 g, 27.7 mmol) was dissolved in methanol (20 mL), followed by the addition of hydrogen chloride (4 M in 1,4-dioxane, 100 mL, 2.54 mol). The mixture was stirred at 20 °C for 10 h, followed by evaporation 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 [INT 15.2] (5.41 g, 16.9 mmol, 61.3% yield) as a beige solid. m / z: [M+H]+calcd for Ci0Hi2BrF3N 282.0, 284.0; found 284.0. 1H NMR (500 MHz, DMSO-d6) δ 10.51 (s, 2H), 7.76 (d, J = 8.3 Hz, 1H), 7.63 (d, J = 2.2 Hz, 1H), 7.41 (dd, J = 8.3, 2.2 Hz, 1H), 5.42 (s, 1H), 2.43 (s, 3H), 2.37 (s, 3H).

[0793] Synthesis of (S)-N-(l-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethyl)-N- methylcyclobutanecarboxamide (Intermediate 16.1):

[0794]

[0795] (S)-l-(4-bromo-2-methylphenyl)-2,2,2-trifluoro-N-methylethan-l-amine hydrochloride [INT 15.1] (0.2 g, 0.6278 mmol) and cyclobanecarboxylic acid (125 mg, 1.25 mmol) were mixed in pyridine (2 mL) followed by the addition of phosphorous 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 NaHSO4(3 x 5 mL). The organic phase was dried over sodium sulfate and evaporated in vacuo at 45 °C to give (S)-N-(l-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethyl)-N- methylcyclobutanecarboxamide [INT 16.1] (190 mg, 0.5216 mmol, 83.3% yield) as a yellow oil. m / z: [M+H]+calcd for C15H18BrF3NO 364.1, 366.1; found 366.0. 1 H NMR (400 MHz, CDC13) 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).

[0796] Synthesis of N-[(lS)-l-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethyl]-N- methylcyclopropanecarboxamide (Intermediate 16.2):

[0797]

[0798] [(1S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethyl](methyl)amine hydrochloride [INT 15.1] (0.2 g, 0.6278 mmol) and cyclopropanecarboxylic acid (107 mg, 1.25 mmol) were mixed in pyridine (2 mL). Then phosphorous 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 NaHSO4solution (3 x 5 mL). The organic phase was dried over sodium sulfate and evaporated under vacuum at 45 °C to give N-[(1S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethyl]-N-methylcyclopropanecarboxamide [INT 16.2] (190 mg, 0.5425 mmol, 86.7% yield) as a light yellow solid. m / z: [M+H]+calcd for Ci4Hi6BrF3NO 350.0; found 350.0. 1 H NMR (400 MHz, CDC13) δ = 7.38 (s, 3H), 6.53 (q, J = 8.9 Hz, 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).

[0799] N-[(1S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1 6 Synthesis of N-[(1S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethyl]-N-methyl-1,1- dioxo-1

[0800]

[0801] To a solution of N-[(1S)-1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethyl]-N- methyl-1,1-dioxo-1 6 thiane-4-carboxylic acid [INT 4-a] (833 mg, 4.68 mmol) in pyridine (3 mL). The reaction mixture was stirred overnight. Aqueous NaHC03solution (3 mL) was added and the mixture was extracted with EtOAc (3 x 10 mL) and washed with NaHS04(3 x 10 mL). The combined organic layers were dried over anhydrous Na2S04and 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-1 6- thiane-4-carboxamide [INT 16.3] (132 mg, 0.2985 mmol, 19.1% yield) as a pink solid. m / z: [M+H]+C16H20BrF3NO3S calculated 442.0, 444.0; found 444.0.

[0802] HPLC conditions: System Agilent 1260 Infinity II LC coupled with Agilent 6120B single quadrupole LC / MS system; Column description: Chromatorex SBM 100-5T 5 pm C18 (2) LC column 100 x 19 mm, Waters, Sun Fire stationary phase: C18 solid support: totally porous silica; mode of separation: reverse phase; mobile 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) 0-2-10-11.2 min.

[0803] Synthesis of (S)-N-(1-(4-bromo-3-methylphenyl)-2,2,2-trifluoroethyl)-N- methylcyclobutanecarboxamide [INT 17.1]:

[0804]

[0805] (S)-1-(4-bromo-3-methylphenyl)-2,2,2-trifluoro-N-methylethan-1-amine hydrochloride [INT 15.2] (0.2 g, 0.6278 mmol) and cyclobutanecarboxylic acid (125 mg, 1.25 mmol) were mixed in pyridine (2 mL) followed by the addition of phosphorus oxychloride (211 mg, 1.38 mmol) at 20 °C. The mixture was stirred at 90 °C for 10 h. EtOAc (20 mL) was added and the mixture was washed with aqueous NaHSO4(3 x 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 [INT 17.1] (228 mg, 0.6260 mmol, 100% yield) as a yellow oil. m / z: [M+H]+C15H18BrF3NO calculated 364.0, 366.0; found 366.0. 1H NMR (400 MHz, CDC13) 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).

[0806] Synthesis of N-[(1S)-1-(4-bromo-3-methylphenyl)-2,2,2-trifluoroethyl]-N- methylcyclopropanecarboxamide (INT 17.2):

[0807]

[0808] [(1S)-1-(4-bromo-3-methylphenyl)-2,2,2-trifluoroethyl](methyl)amine hydrochloride [INT 15.2] (1.25 g, 3.92 mmol) and cyclopropanecarboxylic acid (674 mg, 7.84 mmol) were mixed in pyridine (20 mL). Phosphorus oxychloride (1.32 g, 8.62 mmol) was added. The mixture was stirred at 90 °C for 10 h. MTBE (300 mL) was added. The mixture was washed with aqueous NaHSO4(3 x 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 [INT 17.2] (480 mg, 1.37 mmol, 35.0% yield) as a yellow solid. m / z: [M+H]+calcd for Ci4Hi6BrF3NO 350.0; found 350.0.

[0809] Synthesis of N-[(1S)-1-(4-bromo-3-methylphenyl)-2,2,2-trifluoroethyl]-N- methylcyclopropanecarboxamide (INT 17.3):

[0810]

[0811] [(1S)-1-(4-bromo-3-methylphenyl)-2,2,2-trifluoroethyl](methyl)amine hydrochloride [INT 15.2] (0.5 g, 1.56 mmol) and 1,1-dioxo-1 lambda 6- Thiane-4-carboxylic acid [INT 4-a] (833 mg, 4.68 mmol) was mixed in pyridine (2 mL). Phosphorous oxychloride (788 mg, 5.14 mmol) was added. The mixture was stirred at 90 °C for 10 hours. EtOAc (20 mL) was added and the mixture was washed with aqueous NaHSO4(3 x 5 mL). The organic phase was dried over sodium sulfate and evaporated in vacuo at 45 °C to give the crude N-[(1 S)-1 -(4-bromo-3-methylphenyl)-2,2,2-trifluoroethyl]-N-methyl-1,1 -dioxo-1 λ 6 - Thiane-4-carboxylic acid [INT 4-a] (833 mg, 4.68 mmol) was mixed in pyridine (2 mL). Phosphorous oxychloride (788 mg, 5.14 mmol) was added. The mixture was stirred at 90 °C for 10 hours. EtOAc (20 mL) was added and the mixture was washed with aqueous NaHSO4(3 x 5 mL). The organic phase was dried over sodium sulfate and evaporated in vacuo at 45 °C to give the crude N-[(1 S)-1 -(4-bromo-3-methylphenyl)-2,2,2-trifluoroethyl]-N-methyl-1,1 -dioxo-1 λ

[0812] (1 r,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 )

[0813]

[0814] To a suspension of (1r,4S)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4- ((tert-butyldimethylsilyl)oxy)-N-methylcyclohexane-1-carboxamide [INT 8.1] (100 mg, 196 pmol), 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-amine hydrochloride [INT 1.1] (67.0 mg, 254 pmol), Cs2CO3(127 mg, 392 pmol) and xantphos (22.6 mg, 39.2 pmol) in dioxane (3 mL) was added Pd2(dba)3(17.9 mg, 19.6 pmol). The resulting mixture was stirred at 100 °C under N2for 4 h. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over Na2SO4and filtered. The filtrate was concentrated under reduced pressure to give (1r,4S)-4-((tert-butyldimethylsilyl)oxy)-N-((S)-1-(4-((2-chloro-7-((S)-1- methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N- methylcyclohexane-1-carboxamide [INT 18.1] (100 mg, 152 pmol, 78.1 % yield) as a yellow oil. m / z: [M+H]+C30H43ClF3N6O3Si calculated 655.3; found 655.2.

[0815] Synthesis of (1S,4r)-4-(((S)-1-(4-((2-chloro-7-isopropyl-[1,2,4]triazolo[1,5-a]pyrimidin- 6-yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexane-1-carboxylic acid methyl ester (Intermediate 18.2):

[0816]

[0817] A suspension of 2-chloro-7-(prop-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-amine hydrochloride [INT 1.2] (35 mg, 141 μmol), (1S,4r)-4-(((S)-1-(4-bromophenyl)-2,2,2- trifluoroethyl)(methyl)aminocarbonyl)cyclohexane-1 -carboxylate [INT 5.4] (61.5 mg, 141 μmol), cesium carbonate (137 mg, 423 μmol), tris(dibenzylideneacetone)dipalladium (6.45 mg, 7.05 μmol) and xantphos (8.15 mg, 14.1 μmol) in dioxane (2 mL) was stirred at 100 °C under N2for 1.5 h. The mixture was concentrated under reduced pressure to give a 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)aminocarbonyl)cyclohexane-1- carboxylate [INT 18.2] (38.5 mg, 67.9 μmol, 48.1 % yield) as a yellow solid. m / z: [M+Na]+C26H30ClF3N6O3Na requires 589.2; found 589.3.

[0818] 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) aminocarbonyl)cyclobutane-1 -carboxylate (Intermediate 18.3):

[0819]

[0820] A mixture of (1S,3r)-3-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclobutane-1-carboxylate [INT 5.12] (0.1 g, 0.2449 mmol), 2-chloro-7-[(1S)-1-methoxyethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-6-amine [INT 1.1 free base] (55.5 mg, 244 μmol), and cesium carbonate (239 mg, 734 μmol) in dioxane (3 mL) was purged with Ar. Then, tris(dibenzylideneacetone)dipalladium (11.1 mg, 12.2 μmol) and xantphos (14.1 mg, 24.4 μmol) were added under Ar, and the reaction mixture was stirred at 100 °C for 10 hours. After cooling, the reaction mixture was diluted with MTBE (50 mL), filtered, and the filtrate was concentrated under reduced pressure to give (1S,3r)-3-(((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclobutane-1-carboxylic acid methyl ester [INT 18.3] (68.0 mg, 0.1225 mmol, 50.3% yield), as a yellow oil. m / z: [M+H]+C24H27ClF3N6O4 Calculated value 555.2; Found value 555.0.

[0821] Exemplary compound of formula (I)

[0822] The following compounds in Table 1 were synthesized using identified intermediates according to schemes 1-11 as described above.

[0823] Table 1.

[0824]

[0825]

[0826]

[0827]

[0828]

[0829]

[0830]

[0831]

[0832]

[0833]

[0834]

[0835]

[0836]

[0837]

[0838]

[0839]

[0840]

[0841]

[0842]

[0843]

[0844]

[0845]

[0846]

[0847]

[0848]

[0849]

[0850]

[0851]

[0852]

[0853]

[0854]

[0855]

[0856]

[0857]

[0858]

[0859]

[0860]

[0861]

[0862]

[0863]

[0864]

[0865]

[0866]

[0867] Example 2. MALT1 Biochemical Assay

[0868] Inhibitor potency was assessed by measuring the enzyme activity of full-length MALT1 (SEQ ID NO: 1) at varying concentrations of compound. The enzymatic assay consisted of a single substrate reaction that monitored the release of a fluorescent dye upon cleavage of a peptide substrate. The peptide substrate had the following sequence: Ac-Leu-Arg-Ser-Arg-Rh110-dPro (custom synthesized by WuXi AppTec, Shanghai, China). The assay buffer consisted of 50 mM Hepes, pH 7.5, 0.8 M sodium citrate, 1 mM DTT, 0.004% Tween-20, and 0.005% bovine serum albumin (BSA). Steady-state kinetic analysis of peptide substrate binding resulted in a Michaelis-menten constant (K M ) of 150 μΜ. The assay was performed in 384-well F-bottom polypropylene black microplates (Greiner Bio One, Cat# 781209) at 15 nM enzyme and 30 μΜ peptide substrate. After 60 minutes, iodoacetate was added to a final concentration of 10 mM to quench the reaction. Total fluorescence was measured using an Envision (PerkinElmer) at a fluorescence excitation of 485 nm and emission of 520 nm.

[0869] To determine potency, 1 μΐ, of serially diluted compound (in 100% DMSO) was pre-incubated with 40 μΐ, of enzyme for 30 minutes. The reaction was initiated by the addition of 10 μΐ, of peptide substrate. Relative fluorescence units were converted to percent inhibition by using 0% and 100% inhibitory controls as references. The 100% inhibitory control consisted of (S)-1 -(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-3-(2-chloro-7-(1 - methoxyethyl)pyrazolo[1,5-a]pyrimidin-6-yl)urea (IC 50 = 15 nM) at a final concentration of 1 μΜ, while the 0% inhibitory control consisted of 2% DMSO. IC 50 values were calculated by fitting the concentration-response curves to a four-parameter logistic equation in GraphPad Prism.

[0870] The results of this assay are summarized in Table 2 below. In this table, "A" indicates IC 50 less than 0.1 μΜ; "B" indicates IC 50 from 0.1 μΜ to 1 μΜ; and "C" indicates IC 50 greater than 1 μΜ. "N / A" indicates not tested. For compounds tested in multiple experiments, the results shown represent the mean value.

[0871] Table 2.

[0872]

[0873]

[0874]

[0875] Example 3. Jurkat IL-2 assay

[0876] In a cell-based assay, Jurkat (ATCC, clone E6.1) (immortalized T cell line) was used, exposed to dose response of compounds and assessed for viability and inhibition of IL-2 by ELISA to determine the inhibitory effect. Cells were cultured in RPMI / 10% FBS (Invitrogen 11875093, Atlanta Biologicals S12450H), maintained below 3E6 / mL, and only used in assays below passage 25. Compounds were labeled onto 384w plates (PerkinElmer Culturplate, 6007680) by ECHO. Cells were seeded in fresh media on top of compounds and incubated for 30 minutes, then stimulated with soluble anti-CD3 / 28 / 2 (Stemcell, 10970) for 24 hours. Supernatant was collected and assessed for IL-2 (MSD, 384w, L21SA-1). To assess viability of cells treated with compounds, cells were lysed with CTG reagent (Promega, G7570) and measured by luminometer. IL-2 curves were calculated as percent of DMSO (100%) and signal inhibition (0%, (S)-1-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-3-(2-chloro-7-(1-methoxyethyl)pyrazolo[1,5-a]pyrimidin-6-yl)urea) control. IC50s were calculated using four parameter fit in GraphPad Prism. 50 .

[0877] Results of this assay are summarized in Table 3 below. In this table, “A” indicates an IC 50 less than 0.1 µM; “B” indicates an IC 50 from 0.1 µM to 1 µM; and “C” indicates an IC 50 greater than 1 µM. “N / A” indicates not tested. For compounds tested in multiple experiments, the results shown represent the average.

[0878] Table 3.

[0879]

[0880]

[0881]

[0882] Example 4. High throughput dialysis (HTD) human plasma protein binding assay

[0883] Various compounds of Formula (I) were evaluated for binding to human plasma proteins using the equilibrium dialysis method described herein.

[0884] Dialysis membrane and matrix preparation

[0885] Dialysis membrane strips (HTD 96a / b, Cat. No. 1101, HTDialysis LLC, Gales Ferry, CT, USA) were soaked in ultrapure water at room temperature for about 1 hour. Each membrane strip containing 2 membranes was separated and soaked in 20:80 ethanol / water (v / v) for about 20 minutes after which they could be used or stored in solution at 2-8 °C for up to one month. Prior to the experiment, the membranes were rinsed 3 times and soaked in ultrapure water for 20 minutes. [0...

Claims

1. A compound represented by Formula (I) or a pharmaceutically acceptable salt thereof: (I) wherein: R 1 selected from C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl and 5-10 membered heterocyclyl, wherein said C 1-6 alkyl, C 3-6 cycloalkyl and 5-10 membered heterocyclyl can optionally be substituted on one or more available carbons by one, two, three or more substituents each independently selected from R 1a , wherein if said 5-10 membered heterocyclyl contains a substitutable ring nitrogen atom, said ring nitrogen atom can optionally be substituted by R 1b , and wherein if said 5-10 membered heterocyclyl contains a substitutable ring sulfur atom, said ring sulfur atom can optionally be substituted by two O atoms; R 2 R is CF3; R 3 is C 1-6 alkyl, wherein R 3 is optionally substituted with C 1-4 alkoxy; R 4 is C 1-6 alkyl; R 1a independently at each occurrence selected from cyano, halogen, hydroxyl, oxo, C 1-6 alkyl, -C(O)OR A , -C(O)N(R A )2, -N(R A )2, C 1-6 alkoxy, 5-6 membered heterocyclyl, and 5-6 membered heteroaryl, wherein said C 1-6 alkyl is optionally substituted with -N(R A )2, and wherein if said 5-6 membered heterocyclyl contains a substitutable ring nitrogen atom, said ring nitrogen atom can be optionally substituted with R B ; R 1b selected from C 1-6 alkyl, -C(O)OR A , -C(O)C 1-6 alkyl, -C(O)C 3-6 cycloalkyl, -C(O)N(R A )2and -S(O)2C 1-6 alkyl; R A independently at each occurrence selected from hydrogen, C 1-6 alkyl, -C(O)C 1-6 alkyl and -C(O)OC 1-6 alkyl; R B selected from C 1-6 alkyl, C 3-6 cycloalkyl and -C(O)OC 1-6 alkyl; and t is 0 or 1.

2. The compound according to claim 1, wherein R 3 is C 1-6 alkyl.

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

4. A compound according to claim 1 or 2, wherein R 3 is C 1-6 alkyl, wherein R 3 is substituted by C 1-4 alkoxy.

5. The compound according to claim 1 or 2, wherein R 3 is .

6. The compound according to claim 1 or 2, wherein t = 0.

7. The compound according to claim 1 or 2, wherein t = 1.

8. The compound according to claim 7, wherein R 4 is C 1-6 alkyl.

9. The compound according to claim 7, wherein R 4 is CH3.

10. A compound represented by Formula (lb) or a pharmaceutically acceptable salt thereof: (Ib) wherein: R 1 is C 1-6 alkyl, C 3-6 cycloalkyl or 5-10 membered heterocyclyl, wherein said C 3-6 cycloalkyl can optionally be substituted on one or more available carbons by one, two, three or more substituents each independently selected from R 1a , wherein if said 5-10 membered heterocyclyl contains a substitutable ring nitrogen atom, said ring nitrogen atom can optionally be substituted by R 1b , and wherein if said 5-10 membered heterocyclyl contains a substitutable ring sulfur atom, said ring sulfur atom can optionally be substituted by two O atoms; R 1a independently at each occurrence selected from cyano, halogen, hydroxyl, C 1-6 alkyl, -C(O)OR A , -C(O)N(R A )2, -N(R A )2, C 1-6 alkoxy and 5-6 membered heteroaryl, wherein said C 1-6 alkyl is optionally substituted with -N(R A )2; R 1b selected from C 1-6 alkyl, -C(O)OR A , -C(O)C 1-6 alkyl, -C(O)C 3-6 cycloalkyl, -C(O)N(R A )2and -S(O)2C 1-6 alkyl; and R A independently at each occurrence selected from hydrogen, C 1-6 alkyl, -C(O)C 1-6 alkyl and -C(O)OC 1-6 alkyl.

11. A compound according to claim 10, wherein R 1 is C 1-6 alkyl.

12. The compound according to claim 10, wherein R 1 is CH3.

13. The compound according to claim 10, wherein R 1 is C 3-6 cycloalkyl, wherein R 1 may optionally be substituted on one or more available carbons by one, two, three or more substituents each independently selected from R 1a .

14. The compound according to claim 10, wherein R 1 is C 3-6 cycloalkyl.

15. The compound according to claim 10, wherein R 1 is selected from , , and .

16. The compound according to claim 10, wherein R 1 is C 3-6 cycloalkyl, wherein R 1 is substituted on one, two, three or more available carbons with one, two, three or more substituents each independently selected from R 1a .

17. The compound according to claim 10, wherein R 1 is , or .

18. The compound according to claim 10, wherein R 1a is selected from the group consisting of cyano, fluoro, hydroxy, -O-CH3, -C(O)OH, -C(O)NH2, , , , , , , , , , and .

19. The compound according to claim 10, wherein R 1 is selected from , , , , , , , , , , , , , , , and .

20. The compound according to claim 10, wherein R 1 selected from 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 and .

21. The compound according to claim 10, wherein R 1 is 5-10 membered heterocyclyl, wherein if R 1 contains a substitutable ring nitrogen atom, said ring nitrogen atom is optionally substituted with R 1b and wherein if said 5-10 membered heterocyclyl contains a substitutable ring sulfur atom, said ring sulfur atom is optionally substituted with two O atoms.

22. The compound according to claim 10, wherein R 1 is 5-10 membered heterocyclyl.

23. The compound according to claim 10, wherein R 1 is selected from , , , , , and .

24. The compound according to claim 10, wherein R 1 is .

25. The compound according to claim 10, wherein R 1 is selected from 、 、 and .

26. The compound according to claim 10, wherein R 1b is selected from CH3, , , , , , and .

27. The compound according to claim 10, wherein R 1 is selected from , , , , , , , , , , , , , , , , , , and .

28. The compound according to claim 10, wherein R 1 is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , and .

29. The compound according to claim 10, wherein R 1 is selected from CH3, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

30. The compound according to claim 10, wherein R 1 is selected from CH3, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

31. A compound selected from any of the compounds listed below, or a pharmaceutically acceptable salt thereof: 。 32. A pharmaceutical composition comprising a compound of any one of claims 1-31 and a pharmaceutically acceptable carrier.

33. Use of a compound of any one of claims 1-31 or a pharmaceutical composition of claim 32 in the manufacture of a medicament for treating a MALTl -associated cancer in a subject in need thereof.

34. Use of a compound of any one of claims 1-31 or a pharmaceutical composition of claim 32 in the manufacture of a medicament for treating a MALTl -associated autoimmune or inflammatory disorder in a subject in need thereof.

35. The use according to claim 34, wherein the MALTl -associated autoimmune or inflammatory disorder is selected from acute graft-versus-host disease, chronic graft-versus-host disease, lupus, psoriasis, psoriatic arthritis, polymyositis, dermatomyositis, Behcet’s disease, vasculitis disorders, dermatitis, rheumatoid arthritis, and inflammatory bowel disease.

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