WO2022081995A1 - Malt1 modulators and uses thereof - Google Patents

Abstract

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

Description

MALT1 MODULATORS AND USES THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority to and the benefit of U.S. Provisional Patent Application No.63/092,763, filed on October 16, 2020, the contents of which are incorporated herein by reference in their entirety. BACKGROUND [0002] Mucosa associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is an intracellular signaling protein, known from innate (e.g., natural killer cells NK, dendritic cells DC, and mast cells) and adaptive immune cells (e.g., T cells and B cells). MALT1 plays an essential role in influencing immune responses. For example, in T cell receptor signaling, MALT1 mediates nuclear factor ^Ǻ (NFKB) signaling, leading to T cell activation and proliferation. Accordingly, MALT1 is of interest in the mechanism of autoimmune and inflammatory pathologies. In addition, constitutive (dysregulated) MALT1 activity is associated with cancers such as MALT lymphoma and activated B cell-like diffuse large B Cell lymphoma (ABC-DLBCL). Modulators of MALT1 activity may be useful as potential therapeutics. SUMMARY [0003] Provided herein are compounds designed to act as MALT1 modulators. In some embodiments, such compounds are envisioned to be useful as therapeutic agents for treating autoimmune and inflammatory diseases, disorders, or conditions or cancers. [0004] In one aspect, provided herein is a compound represented by Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is selected from the group consisting of C1-6alkyl, C1-6alkoxy, C3-6cycloalkyl, and 5-10 membered heterocyclyl, wherein the C1-6alkyl, C3-6cycloalkyl, and 5-10 membered heterocyclyl may be optionally 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, that ring nitrogen atom may optionally be substituted by R^1b, and wherein if the 5-10 membered heterocyclyl contains a substitutable ring sulfur atom, that ring sulfur atom may be optionally substituted with two O atoms; R² is CH3 or CF3; R³ is hydrogen; or R³ is selected from the group consisting of C1-6alkyl, C1-6alkoxy, C3-7cycloalkyl, 5-6 membered heterocyclyl, 5-6 membered heterocyclyl-C1-3alkyl-, 5-6 membered heterocyclyl-O-, phenyl, and 5-6 membered heteroaryl, any of which may be optionally substituted with one, two or three substituents each independently selected from R^3a; R^4a, R^4b, and R^4c are independently selected from the group consisting of hydrogen, halogen, cyano, C_1-4alkyl, haloC_1-4alkyl, C_1-4alkoxy, haloC_1-4alkoxy, amino, hydroxy, hydroxymethyl, C_3-4cycloalkyl, C_1-4alkoxyC_1-4alkyl, -CONR^CR^D, and S(O)₂NH₂; wherein the C_{3- 4}cycloalkyl may be optionally substituted with one, two or three substituents each independently methyl or fluoro; R^1a is independently, for each occurrence, selected from the group consisting of cyano, halogen, hydroxyl, oxo, C1-6alkyl, -C(O)OR^A, -C(O)N(R^A)2, -N(R^A)2, C1-6alkoxy, 5-6 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the C1-6alkyl is optionally substituted with - N(R^A)2, wherein the 5-6 membered heterocyclyl or 5-6 membered heteroaryl may be optionally substituted with C1-6alkyl or oxo, and wherein if the 5-6 membered heterocyclyl or 5-6 membered heteroaryl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by R^B; R^1b is selected from the group consisting of C1-6alkyl, -C(O)OR^A, -C(O)C1-6alkyl, -C(O)C3- ₆cycloalkyl, -C(O)N(R^A)₂, -S(O)₂C_1-6alkyl, and 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl is optionally substituted with C_1-6alkyl; R^3a is independently, for each occurrence, selected from the group consisting of halogen, C_{1- 4}alkyl, C_1-4haloalkyl, C_1-4alkoxy, C_1-4haloalkoxy, hydroxy, C_1-4alkenyl, cyano, azido, -NR^CR^D, C_3-6cycloalkyl, C_1-4alkoxyC_1-4alkoxy, 5-6 membered heterocyclyl-O-, 5-6 membered heterocyclyl, and phenyl, wherein C_3-6cycloalkyl, 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; R^p is independently, for each occurrence, selected from the group consisting of halogen, C1- 4alkyl, C1-4haloalkyl, hydroxy, C1-4alkoxy, C1-4alkoxyC1-4alkyl, NR^CR^D, and aminoC1-3alkyl; R^A is independently, for each occurrence, selected from the group consisting of hydrogen, C1-6alkyl, -C(O)C1-6alkyl, and -C(O)OC1-6alkyl; R^B is selected from the group consisting of C1-6alkyl, C3-6cycloalkyl, and -C(O)OC1-6alkyl; and R^C and R^D are independently, for each occurrence, selected from the group consisting of hydrogen, C1-6alkyl, haloC1-6alkyl, and C3-4cycloalkyl, or R^C and R^D together with the nitrogen atom to which they are attached form 4-6 membered heterocyclyl or 4-6 membered heteroaryl, wherein the 4-6 membered heterocyclyl or 4-6 membered heteroaryl may contain a further nitrogen atom or an oxygen atom and is optionally substituted with one or two fluoro. [0005] In another aspect, provided herein is a compound represented by Formula (Ia):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is C1-6alkyl, C3-6cycloalkyl, or 5-10 membered heterocyclyl, wherein the C3-6cycloalkyl may be optionally 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, that ring nitrogen atom may optionally be substituted by R^1b, and wherein if the 5-10 membered heterocyclyl contains a substitutable ring sulfur atom, that ring sulfur atom may be optionally substituted with two O atoms; R^1a is independently, for each occurrence, selected from the group consisting of cyano, halogen, hydroxyl, C_1-6alkyl, -C(O)OR^A, -C(O)N(R^A)₂, -N(R^A)₂, C_1-6alkoxy, 5-6 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the C_1-6alkyl is optionally substituted with - N(R^A)₂, wherein the 5-6 membered heterocyclyl or 5-6 membered heteroaryl may be optionally substituted with C1-6alkyl or oxo, and wherein if the 5-6 membered heterocyclyl or 5-6 membered heteroaryl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by R^B; R^1b is selected from the group consisting of C1-6alkyl, -C(O)OR^A, -C(O)C1-6alkyl, -C(O)C3- 6cycloalkyl, -C(O)N(R^A)2, -S(O)2C1-6alkyl, and 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl is optionally substituted with C1-6alkyl; R^A is independently, for each occurrence, hydrogen, C1-6alkyl, -C(O)C1-6alkyl, and - C(O)OC1-6alkyl; and R^B is C1-6alkyl. [0006] In some embodiments, a compound provided herein is selected from a compound set forth in Table 1, or a pharmaceutically acceptable salt thereof. [0007] In another aspect, provided herein is a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable carrier. [0008] In another aspect, provided herein is a method of treating a cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition disclosed herein. [0009] In another aspect, provided herein is a method of treating an autoimmune or inflammatory disorder or disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition disclosed herein. DETAILED DESCRIPTION [0010] As generally described herein, the present invention provides compounds designed, for example, to act as MALT1 modulators. In certain embodiments, such compounds are envisioned to be useful as therapeutic agents for treating autoimmune and inflammatory diseases, disorders, or conditions or cancers. Definitions Chemical definitions [0011] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75^th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March’s Advanced Organic Chemistry, 5^th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3^rd Edition, Cambridge University Press, Cambridge, 1987. [0012] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and/or diastereomers. 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 isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw–Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p.268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The invention additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers. [0013] As used herein a pure enantiomeric compound is substantially free from other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, an “S” form of the compound is substantially free from the “R” form of the compound and is, thus, in enantiomeric excess of the “R” form. The term “enantiomerically pure” or “pure enantiomer” denotes that the compound comprises 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 the enantiomer. In certain embodiments, the weights are based upon total weight of all enantiomers or stereoisomers of the compound. [0014] In the compositions provided herein, an enantiomerically pure compound can be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising 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, for example, comprise, at least about 95% by weight R–compound and at most about 5% by weight S–compound, by total weight of the compound. For example, a pharmaceutical composition comprising 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, for example, comprise, at least about 95% by weight S– compound and at most about 5% by weight R–compound, by total weight of the compound. In certain embodiments, the active ingredient can be formulated with little or no excipient or carrier. [0015] Compound described herein may also comprise one or more isotopic substitutions. For example, H may be in any isotopic form, including ¹H, ²H (D or deuterium), and ³H (T or tritium); C may be in any isotopic form, including ¹²C, ¹³C, and ¹⁴C; O may be in any isotopic form, including ¹⁶O and ¹⁸O; F may be in any isotopic form, including ¹⁸F and ¹⁹F; and the like. [0016] The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present invention. When describing the invention, which may include compounds and pharmaceutically acceptable salts thereof, pharmaceutical compositions containing such compounds and methods of using such compounds and compositions, the following terms, if present, have the following meanings unless otherwise indicated. It should also be understood that when described herein any of the moieties defined forth below may be substituted with a variety of substituents, and that the respective definitions are intended to include such substituted moieties within their scope as set out below. Unless otherwise stated, the term “substituted” is to be defined as set out below. It should be further understood that the terms “groups” and “radicals” can be considered interchangeable when used herein. The articles “a” and “an” may be used herein to refer to one or to more than one (i.e. at least one) of the grammatical objects of the article. By way of example “an analogue” means one analogue or more than one analogue. [0017] When a range of values is listed, it is intended to encompass each value and sub–range within the range. For example, “C1–6 alkyl” is intended to encompass, C1, C2, C3, C4, C5, C6, C1– 6, C1–5, C1–4, C1–3, C1–2, C2–6, C2–5, C2–4, C2–3, C3–6, C3–5, C3–4, C4–6, C4–5, and C5–6 alkyl. [0018] As used herein, “alkyl” refers to a radical of a straight–chain or branched saturated hydrocarbon group, e.g., having 1 to 20 carbon atoms (“C_1–20 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C_1–10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C_1–9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C_1–8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C_1–7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1–6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1–5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1–4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1–3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C1 alkyl”). Examples of C1–6 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, and the like. [0019] As used herein, “alkenyl” refers to a radical of a straight–chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon–carbon double bonds (e.g., 1, 2, 3, or 4 carbon–carbon double bonds), and optionally one or more carbon–carbon triple bonds (e.g., 1, 2, 3, or 4 carbon–carbon triple bonds) (“C2–20 alkenyl”). In certain embodiments, alkenyl does not contain any triple bonds. In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C2–10 alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C_2–9 alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C_2–8 alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C_2–7 alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C_2–6 alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C_2–5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C_2–4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C_2–3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C2 alkenyl”). The one or more carbon–carbon double bonds can be internal (such as in 2–butenyl) or terminal (such as in 1–butenyl). Examples of C2–4 alkenyl groups include ethenyl (C2), 1–propenyl (C3), 2–propenyl (C3), 1–butenyl (C4), 2–butenyl (C4), butadienyl (C4), and the like. Examples of C2–6 alkenyl groups include the aforementioned C2–4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. [0020] As used herein, “alkynyl” refers to a radical of a straight–chain or branched hydrocarbon group having from 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) (“C2–20 alkynyl”). In certain embodiments, alkynyl does not contain any double bonds. In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C2–10 alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2–9 alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2–8 alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2–7 alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2–6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2–5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C_2–4 alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C_2–3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C₂ alkynyl”). The one or more carbon– carbon triple bonds can be internal (such as in 2–butynyl) or terminal (such as in 1–butynyl). Examples of C_2–4 alkynyl groups include, without limitation, ethynyl (C₂), 1–propynyl (C₃), 2– propynyl (C₃), 1–butynyl (C₄), 2–butynyl (C₄), and the like. Examples of C_2–6 alkenyl groups include the aforementioned C2–4 alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. [0021] As used herein, “alkylene,” “alkenylene,” “alkynylene,” “cycloalkylene,” “heterocyclylene,” “heteroarylene,” and “phenylene” refer to a divalent radical of an alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl (e.g., saturated and partially saturated), heteroaryl, and phenyl group respectively. [0022] When a range or number of carbons is provided for a particular “alkylene,” “alkenylene,” or “alkynylene,” group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain. “Alkylene,” “alkenylene,” and “alkynylene,” groups may be substituted or unsubstituted with one or more substituents as described herein. [0023] As used herein, “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6–14 aryl”). In some embodiments, an aryl group has six ring carbon atoms (“C6 aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“C10 aryl”; e.g., naphthyl such as 1–naphthyl and 2–naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C₁₄ aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Particularly aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. [0024] As used herein, “heteroaryl” refers to a radical of a 5–10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 electrons shared in a cyclic array) having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5–10 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl/heteroaryl) ring system. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2–indolyl) or the ring that does not contain a heteroatom (e.g., 5–indolyl). [0025] In some embodiments, a heteroaryl group is a 5–10 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5–8 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5–6 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, 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. [0026] Exemplary 5–membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5–membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5–membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5–membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6–membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6–membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6– membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7–membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6– bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6–bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. [0027] Examples of representative heteroaryls include the following:

wherein each Z is selected from carbonyl, N, NR^{65, O, and S; and R65 is independently hydrogen,} C₁-₈ alkyl, C₃-₁₀ carbocyclyl, 4-10 membered heterocyclyl, C₆-C₁₀ aryl, and 5-10 membered heteroaryl. [0028] 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 (“C3–10 carbocyclyl”) and zero heteroatoms in the non–aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C_3–8 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C_3-7 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C_3–6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C_5–10 carbocyclyl”). Exemplary C_3–6 carbocyclyl groups include, without limitation, cyclopropyl (C₃),cyclobutyl (C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅), cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), and the like. Exemplary C_3–8 carbocyclyl groups include, without limitation, the aforementioned C3–6 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 C3–10 carbocyclyl groups include, without limitation, the aforementioned C3–8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro–1H–indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) and can be saturated or can be partially unsaturated. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. [0029] The term “cycloalkyl” refers to a monovalent saturated cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) hydrocarbon group of 3-12, 3-8, 4-8, or 4-6 carbons, referred to herein, e.g., as "C_4-8cycloalkyl," derived from a cycloalkane. Exemplary cycloalkyl groups include, but are not limited to, cyclohexanes, cyclopentanes, cyclobutanes and cyclopropanes. [0030] As used herein, “C3-6 monocyclic cycloalkyl” or “monocyclic C3-6 cycloalkyl” refers to a 3- to 7-membered monocyclic hydrocarbon ring system that is saturated.3- to 7-membered monocyclic cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Where specified as being optionally substituted or substituted, substituents on a cycloalkyl (e.g., in the case of an optionally substituted cycloalkyl) may be present on any substitutable position and, include, e.g., the position at which the cycloalkyl group is attached. [0031] As used herein, “heterocyclyl” or “heterocyclic” refers to a radical of a 3– to 10– membered non–aromatic ring system 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 that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic system (“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 wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” may be used interchangeably. [0032] In some embodiments, a heterocyclyl group is a 4-7 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, a heterocyclyl group 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, a heterocyclyl group 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, a heterocyclyl group 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 one ring heteroatom selected from nitrogen, oxygen, and sulfur. [0033] Exemplary 3–membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary 4–membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5–membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl–2,5–dione. Exemplary 5–membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5–membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6–membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6– membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6–membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7–membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8–membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. [0034] Examples of saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, terahydropyranyl, pyrrolidinyl, pyridinonyl, pyrrolidonyl, piperidinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, morpholinyl, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, oxetanyl, azetidinyl and tetrahydropyrimidinyl. Where specified as being optionally substituted or substituted, substituents on a heterocyclyl (e.g., in the case of an optionally substituted heterocyclyl) may be present on any substitutable position and, include, e.g., the position at which the heterocyclyl group is attached. [0035] “Hetero” when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g., heteroalkyl; carbocyclyl, e.g., heterocyclyl; aryl, e.g., heteroaryl; and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms. [0036] As used herein, “cyano” refers to -CN. [0037] The terms “halo” and “halogen” as used herein refer to an atom selected from fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), and iodine (iodo, -I). In certain embodiments, the halo group is either fluoro or chloro. [0038] The term “alkoxy,” as used herein, refers to an alkyl group which is attached to another moiety via an oxygen atom (–O(alkyl)). Non-limiting examples include e.g., methoxy, ethoxy, propoxy, and butoxy. [0039] “Haloalkoxy” is a haloalkyl group which is attached to another moiety via an oxygen atom such as, e.g., but are not limited to –OCHCF2 or –OCF3. [0040] The term “haloalkyl” includes mono, poly, and perhaloalkyl groups substituted with one or more halogen atoms where the halogens are independently selected from fluorine, chlorine, bromine, and iodine. For the group C1-4haloalkyl-O-C1-4alkyl, the point of attachment occurs on the alkyl moiety which is halogenated. [0041] As used herein, “oxo” refers to -C=O. [0042] In general, the term “substituted”, whether preceded by the term “optionally” or not, means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo 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 of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. [0043] Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quarternary 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,

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 a nitrogen atom are joined 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. [0044] These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and Claims. The invention is not intended to be limited in any manner by the above exemplary listing of substituents. Other Definitions [0045] As used herein, “pharmaceutically acceptable carrier” refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, polyethylene glycol and wool fat. [0046] As used herein, “pharmaceutically acceptable salt” refers to 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., describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1–19. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3–phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p–toluenesulfonate, undecanoate, valerate salts, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N⁺(C1–4alkyl)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, lower alkyl sulfonate, and aryl sulfonate. [0047] 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, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle–aged adult or senior adult)) and/or a non-human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and/or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. The terms “human,” “patient,” and “subject” are used interchangeably herein. [0048] Disease, disorder, and condition are used interchangeably herein. [0049] As used herein, and unless otherwise specified, the terms “treat,” “treating” and “treatment” contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or retards or slows the progression of the disease, disorder or condition (“therapeutic treatment”), and also contemplates an action that occurs before a subject begins to suffer from the specified disease, disorder or condition (“prophylactic treatment”). [0050] As used herein, the “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 this art, the effective amount of a compound of the invention may 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 encompasses therapeutic and prophylactic treatment. [0051] 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, which provides a therapeutic benefit in the treatment of the 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. Compounds [0052] In one aspect, provided herein are compounds represented by Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is selected from the group consisting of C1-6alkyl, C1-6alkoxy, C3-6cycloalkyl, and 5-10 membered heterocyclyl, wherein the C1-6alkyl, C3-6cycloalkyl, and 5-10 membered heterocyclyl may be optionally 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, that ring nitrogen atom may optionally be substituted by R^1b, and wherein if the 5-10 membered heterocyclyl contains a substitutable ring sulfur atom, that ring sulfur atom may be optionally substituted with two O atoms; R² is CH₃ or CF₃; R³ is hydrogen; or R³ is selected from the group consisting of C_1-6alkyl, C_1-6alkoxy, C_3-7cycloalkyl, 5-6 membered heterocyclyl, 5-6 membered heterocyclyl-C_1-3alkyl-, 5-6 membered heterocyclyl-O-, phenyl, and 5-6 membered heteroaryl, any of which may be optionally substituted with one, two or three substituents each independently selected from R^3a

R^4a, R^4b, and R^4c are independently selected from the group consisting of hydrogen, halogen, cyano, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy, haloC1-4alkoxy, amino, hydroxy, hydroxymethyl, C3-4cycloalkyl, C1-4alkoxyC1-4alkyl, -CONR^CR^D, and S(O)2NH2; wherein the C3- 4cycloalkyl may be optionally substituted with one, two or three substituents each independently methyl or fluoro; R^1a is independently, for each occurrence, selected from the group consisting of cyano, halogen, hydroxyl, oxo, C1-6alkyl, -C(O)OR^A, -C(O)N(R^A)2, -N(R^A)2, C1-6alkoxy, 5-6 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the C_1-6alkyl is optionally substituted with - N(R^A)₂, wherein the 5-6 membered heterocyclyl or 5-6 membered heteroaryl may be optionally substituted with C_1-6alkyl or oxo, and wherein if the 5-6 membered heterocyclyl or 5-6 membered heteroaryl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by R^B; R^1b is selected from the group consisting of C_1-6alkyl, -C(O)OR^A, -C(O)C_1-6alkyl, -C(O)C_{3- 6}cycloalkyl, -C(O)N(R^A)₂, -S(O)₂C_1-6alkyl, and 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl is optionally substituted with C1-6alkyl; R^3a is independently, for each occurrence, selected from the group consisting of halogen, C1- 4alkyl, C1-4haloalkyl, C1-4alkoxy, C1-4haloalkoxy, hydroxy, C1-4alkenyl, cyano, azido, -NR^CR^D, C3-6cycloalkyl, C1-4alkoxyC1-4alkoxy, 5-6 membered heterocyclyl-O-, 5-6 membered heterocyclyl, and phenyl, wherein C3-6cycloalkyl, 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; 17 R^p is independently, for each occurrence, selected from the group consisting of halogen, C1- 4alkyl, C1-4haloalkyl, hydroxy, C1-4alkoxy, C1-4alkoxyC1-4alkyl, NR^CR^D, and aminoC1-3alkyl; R^A is independently, for each occurrence, selected from the group consisting of hydrogen, C1-6alkyl, -C(O)C1-6alkyl, and -C(O)OC1-6alkyl; R^B is selected from the group consisting of C1-6alkyl, C3-6cycloalkyl, and -C(O)OC1-6alkyl; and R^C and R^D are independently, for each occurrence, selected from the group consisting of hydrogen, C_1-6alkyl, haloC_1-6alkyl, and C_3-4cycloalkyl, or R^C and R^D together with the nitrogen atom to which they are attached form 4-6 membered heterocyclyl or 4-6 membered heteroaryl, wherein the 4-6 membered heterocyclyl or 4-6 membered heteroaryl may contain a further nitrogen atom or an oxygen atom and is optionally substituted with one or two fluoro. [0053] In another aspect, provided herein are compounds represented by Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is C1-6alkyl, C3-6cycloalkyl, or 5-10 membered heterocyclyl, wherein the C3-6cycloalkyl may be optionally 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, that ring nitrogen atom may optionally be substituted by R^1b, and wherein if the 5-10 membered heterocyclyl contains a substitutable ring sulfur atom, that ring sulfur atom may be optionally substituted with two O atoms; R² is CH3 or CF3; R³ is hydrogen; or R³ is C_1-6alkyl or C_3-7cycloalkyl, wherein the C_1-6alkyl may be optionally substituted with C_1-4alkoxy; R^4a, R^4b, and R^4c are independently selected from the group consisting of hydrogen, C_{1- 4}alkyl, haloC_1-4alkyl, and C_1-4alkoxy; R^1a is independently, for each occurrence, selected from the group consisting of cyano, halogen, hydroxyl, C_1-6alkyl, -C(O)OR^A, -C(O)N(R^A)₂, -N(R^A)₂, C_1-6alkoxy, 5-6 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the C_1-6alkyl is optionally substituted with - N(R^A)2, wherein the 5-6 membered heterocyclyl or 5-6 membered heteroaryl may be optionally substituted with C1-6alkyl or oxo, and wherein if the 5-6 membered heteroaryl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by R^B; R^1b is selected from the group consisting of C1-6alkyl, -C(O)OR^A, -C(O)C1-6alkyl, -C(O)C3- 6cycloalkyl, -C(O)N(R^A)2, -S(O)2C1-6alkyl, and 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl is optionally substituted with C1-6alkyl; R^A is independently, for each occurrence, selected from the group consisting of hydrogen, C_1-6alkyl, -C(O)C_1-6alkyl, and -C(O)OC_1-6alkyl; and R^B is C_1-6alkyl. [0054] In some embodiments, R² is CF3. In some embodiments, R² is CH3. [0055] In some embodiments, R³ is C_3-7cycloalkyl. In some embodiments, R³ is cyclopropyl. [0056] In some embodiments, R³ is C1-6alkyl. In some embodiments, R³ is propyl or isopropyl. In some embodiments, R³ is propyl. In some embodiments, R³ is isopropyl. [0057] In some embodiments, R³ is C1-6alkyl, wherein R³ is substituted with C1-4alkoxy. In some embodiments,

. [0058] In some embodiments, R³ is hydrogen. [0059] In some embodiments, R^4a, R^4b, and R^4c are hydrogen. [0060] In some embodiments, R^4b and R^4c are hydrogen and R^4a is C1-6alkyl, haloC1-4alkyl, or C1-4alkoxy. [0061] In some embodiments, R^4b and R^4c are hydrogen and R^4a is C_1-6alkyl. In some embodiments, R^4b and R^4c are hydrogen and R^4a is CH₃. [0062] In some embodiments, R^4b and R^4c are hydrogen and R^4a is haloC1-4alkyl. In some embodiments, R^4b and R^4c are hydrogen and R^4a is CF₃. [0063] In some embodiments, R^4b and R^4c are hydrogen and R^4a is C1-4alkoxy. In some embodiments, R^4b and R^4c are hydrogen and R^4a is -O-CH3. [0064] In some embodiments, R^4a and R^4c are hydrogen and R^4b is C_1-4alkyl or C_1-4alkoxy. [0065] In some embodiments, R^4a and R^4c are hydrogen and R^4b is C1-4alkoxy. In some embodiments, R^4a and R^4c are hydrogen and R^4b is -O-CH3. [0066] In some embodiments, R^4a and R^4c are hydrogen and R^4b is C1-4alkyl. In some embodiments, R^4a and R^4c are hydrogen and R^4b is CH3. [0067] In another aspect, provided herein are compounds represented by Formula (Ia):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is C1-6alkyl, C3-6cycloalkyl, or 5-10 membered heterocyclyl, wherein the C3-6cycloalkyl may be optionally 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, that ring nitrogen atom may optionally be substituted by R^1b, and wherein if the 5-10 membered heterocyclyl contains a substitutable ring sulfur atom, that ring sulfur atom may be optionally substituted with two O atoms; R^1a is independently, for each occurrence, selected from the group consisting of cyano, halogen, hydroxyl, C1-6alkyl, -C(O)OR^A, -C(O)N(R^A)2, -N(R^A)2, C1-6alkoxy, 5-6 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the C_1-6alkyl is optionally substituted with - N(R^A)₂, wherein the 5-6 membered heterocyclyl or 5-6 membered heteroaryl may be optionally substituted with C_1-6alkyl or oxo, and wherein if the 5-6 membered heterocyclyl or 5-6 membered heteroaryl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by R^B; R^1b is selected from the group consisting of C_1-6alkyl, -C(O)OR^A, -C(O)C_1-6alkyl, -C(O)C_3- 6cycloalkyl, -C(O)N(R^A)2, -S(O)2C1-6alkyl, and 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl is optionally substituted with C1-6alkyl; R^A is independently, for each occurrence, hydrogen, C1-6alkyl, -C(O)C1-6alkyl, and - C(O)OC1-6alkyl; and R^B is C1-6alkyl. [0068] In some embodiments, R¹ is C_1-6alkyl. In some embodiments, R¹ is CH₃. [0069] In some embodiments, R¹ is C3-6cycloalkyl, wherein R¹ may be optionally substituted on one or more available carbons by one, two, three, or more substituents each independently selected from R^1a. [0070] In some embodiments, R¹ is C3-6cycloalkyl, wherein R¹ is substituted on one or more available carbons by one, two, three, or more substituents each independently selected from R^1a.

[0072] In some embodiments, R¹ is 3-6 membered cycloalkyl, wherein R¹ may be optionally substituted with one or two substituents independently, for each occurrence, selected from cyano, fluoro, hydroxyl, -O-CH3, -C(O)CH3, -C(O)OCH3, -COOH, -C(O)NH2, -NH2, -CH2NH2, -C(O)N(H)CH3, -CH2N(H)C(O)CH3, -CH2N(H)C(O)OC(CH3)3, -N(H)C(O)CH3, -

[0073] In some embodiments, R¹ is 3-6 membered cycloalkyl, wherein R¹ may be optionally substituted with one or two substituents independently, for each occurrence, selected from cyano, fluoro, hydroxyl, -O-CH₃, -C(O)OCH₃, -COOH, -C(O)NH₂, -NH₂, -CH₂NH₂, -

[0074] In some embodiments,

wherein R¹ may be optionally substituted with one or two substituents independently, for each occurrence, selected from cyano, fluoro, hydroxyl, -O-CH₃, -C(O)CH₃, -C(O)OCH₃, -COOH, -C(O)NH₂, -NH₂, -CH₂NH₂, - C(O)N(H)CH3, -CH2N(H)C(O)CH3, -CH2N(H)C(O)OC(CH3)3, -N(H)C(O)CH3, -

[0075] In some embodiments,

wherein R¹ may be optionally substituted with one or two substituents independently, for each occurrence, selected from cyano, fluoro, hydroxyl, -O-CH3, -C(O)OCH3, -COOH, -C(O)NH2, -NH2, -CH2NH2, -C(O)N(H)CH3, -

[0076] In some embodiments, R¹ is C_3-6cycloalkyl. In some embodiments, R¹ is selected from

. [0077] In some embodiments, R¹ is selected from the group consisting of

[0079] In some embodiments, R¹ is 5-10 membered heterocyclyl, wherein if R¹ contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by R^1b, and wherein if the 5-10 membered heterocyclyl contains a substitutable ring sulfur atom, that ring sulfur atom may be optionally substituted with two O atoms. [0080] In some embodiments, R¹ is 5-10 membered heterocyclyl. In some embodiments, R¹ is

[0082] In some embodiments, R¹ is selected from the group consisting of

. In some embodiments, R^1b is selected from the group consisting of

[0083] In some embodiments, R¹ is selected from the group consisting of

,

, wherein R^1b is selected from the group consisting of C1-6alkyl, -C(O)OR^A, -C(O)C1-6alkyl, -C(O)C3-6cycloalkyl, -C(O)N(R^A)2, -S(O)2C1-6alkyl, and 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl is optionally substituted with C1-6alkyl. [0084] In some embodiments, R¹ is selected from the group consisting of

. [0088] In some embodiments, R¹ is selected from the group consisting of CH3,

. [0089] In some embodiments, a compound provided herein is selected from a compound set forth in Table 1, or a pharmaceutically acceptable salt thereof. [0090] In some embodiments, the compound is selected from the group consisting of (S)-N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N- methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; (R)-N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N- methylacetamide; tert-butyl 3-(((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)(methyl)carbamoyl)pyrrolidine-1-carboxylate; tert-butyl (S)-4-((1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)(methyl)carbamoyl)piperidine-1-carboxylate; tert-butyl 3-(((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)(methyl)carbamoyl)piperidine-1-carboxylate; 38 (S)-N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N- methyltetrahydro-2H-thiopyran-4-carboxamide; methyl (1S,4r)-4-(((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)(methyl)carbamoyl)cyclohexane-1-carboxylate; N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N- methyltetrahydro-2H-pyran-2-carboxamide; N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N- methyltetrahydrofuran-3-carboxamide; (S)-N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-4,4- difluoro-N-methylcyclohexane-1-carboxamide; (1r,4S)-N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)- 4-methoxy-N-methylcyclohexane-1-carboxamide; (S)-N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N- methyl-1-pivaloylpiperidine-4-carboxamide; (1r,4S)-4-cyano-N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)-N-methylcyclohexane-1-carboxamide; (1r,3S)-3-cyano-N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)-N-methylcyclobutane-1-carboxamide; (S)-N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N- methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)azetidine-3-carboxamide; (S)-2-acetyl-N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)- N-methyl-2-azaspiro[3.3]heptane-6-carboxamide; (S)-N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N- methyl-1-(3-methyl-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamide; (S)-N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N- methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)piperidine-4-carboxamide; N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)ethyl)-N-methyltetrahydro-2H- thiopyran-4-carboxamide 1,1-dioxide; (S)-N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)ethyl)-N-methyltetrahydro-2H- thiopyran-4-carboxamide 1,1-dioxide; (R)-N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)ethyl)-N-methyltetrahydro-2H- thiopyran-4-carboxamide 1,1-dioxide; (S)-N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N- methyl-1,4-dioxaspiro[4.5]decane-8-carboxamide; N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)ethyl)-N-methylacetamide; N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)ethyl)-N- methylcyclobutanecarboxamide; N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)ethyl)-N- methylcyclopentanecarboxamide; N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)ethyl)-N- methylcyclopropanecarboxamide; N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)ethyl)-N- methylcyclohexanecarboxamide; N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N- methylacetamide; (S)-N-(1-(4-((4-cyclopropyl-7-methoxy-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; (S)-N-(1-(4-((4-cyclopropyl-7-methyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)- N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; (S)-N-(1-(4-((4-cyclopropyl-6-(trifluoromethyl)-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; (S)-N-(1-(4-((4-cyclopropyl-6-methoxy-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; (S)-N-methyl-N-(2,2,2-trifluoro-1-(4-((4-isopropyl-1,5-naphthyridin-3- yl)amino)phenyl)ethyl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; (S)-N-methyl-N-(2,2,2-trifluoro-1-(4-((4-propyl-1,5-naphthyridin-3- yl)amino)phenyl)ethyl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; (S)-N-(1-(4-((4-cyclopropyl-6-methyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)- N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; N-((1S)-1-(4-((4-(1-ethoxyethyl)-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N- methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide; (1r,4S)-N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)- N-methyl-4-(2-methyl-2H-tetrazol-5-yl)cyclohexane-1-carboxamide; (1r,4S)-N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)- N-methyl-4-(1-methyl-1H-tetrazol-5-yl)cyclohexane-1-carboxamide; (S)-N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N- methyl-1-(3-methyl-1,2,4-oxadiazol-5-yl)azetidine-3-carboxamide; N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N- methylpyrrolidine-3-carboxamide; (S)-N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N- methylpiperidine-4-carboxamide; N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N- methylpiperidine-3-carboxamide; (S)-4-(aminomethyl)-N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)-N-methylcyclohexane-1-carboxamide; 1-acetyl-N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)- N-methylpyrrolidine-3-carboxamide; 1-(cyclopropanecarbonyl)-N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)- 2,2,2-trifluoroethyl)-N-methylpyrrolidine-3-carboxamide; (S)-1-(cyclopropanecarbonyl)-N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)- 2,2,2-trifluoroethyl)-N-methylpiperidine-4-carboxamide; 1-(cyclopropanecarbonyl)-N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)- 2,2,2-trifluoroethyl)-N-methylpiperidine-3-carboxamide; (S)-1-acetyl-N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)- N-methylpiperidine-4-carboxamide; N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N- methyl-1-(methylsulfonyl)pyrrolidine-3-carboxamide; (S)-N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-1- (isopropylsulfonyl)-N-methylpiperidine-4-carboxamide; methyl (S)-4-((1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)(methyl)carbamoyl)piperidine-1-carboxylate; N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N- methyl-1-(methylsulfonyl)piperidine-3-carboxamide; (S)-N³-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)- N¹,N³-dimethylpiperidine-1,3-dicarboxamide; (R)-N³-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)- N¹,N³-dimethylpiperidine-1,3-dicarboxamide; (S)-N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N- methyl-1-(methylsulfonyl)piperidine-4-carboxamide; 1-acetyl-N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)- N-methylpiperidine-3-carboxamide; N³-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N¹,N³- dimethylpyrrolidine-1,3-dicarboxamide; (S)-4-(acetamidomethyl)-N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)-N-methylcyclohexane-1-carboxamide; (S)-4-acetamido-N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)-N-methylcyclohexane-1-carboxamide; (S)-N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N,1- dimethylpiperidine-4-carboxamide; N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N,1- dimethylpyrrolidine-3-carboxamide; N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N,1- dimethylpiperidine-3-carboxamide; (1S,4r)-4-(((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)(methyl)carbamoyl)cyclohexane-1-carboxylic acid; (1S,3r)-3-(((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)(methyl)carbamoyl)cyclobutane-1-carboxylic acid; (1r,4S)-N¹-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)- N¹-methylcyclohexane-1,4-dicarboxamide; (1r,4S)-N¹-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)- N¹,N⁴-dimethylcyclohexane-1,4-dicarboxamide; (1r,4S)-N¹-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)- N¹,N⁴,N⁴-trimethylcyclohexane-1,4-dicarboxamide; (1r,4S)-N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)- N-methyl-4-(1H-tetrazol-5-yl)cyclohexane-1-carboxamide; (1r,3S)-N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)- N-methyl-3-(1H-tetrazol-5-yl)cyclobutane-1-carboxamide; (1r,4S)-N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)- 4-hydroxy-N-methylcyclohexane-1-carboxamide; (S)-4-amino-N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)- N-methylcyclohexane-1-carboxamide; (1s,4R)-4-amino-N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)-N-methylcyclohexane-1-carboxamide; (1r,4S)-4-amino-N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)-N-methylcyclohexane-1-carboxamide; (S)-N-(1-(4-((1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H- thiopyran-4-carboxamide 1,1-dioxide; (1r,4S)-N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)- N-methyl-4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)cyclohexane-1-carboxamide; (1r,4S)-N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)- N-methyl-4-(5-methyl-1,3,4-oxadiazol-2-yl)cyclohexane-1-carboxamide; (1r,4S)-N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)- N-methyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)cyclohexane-1-carboxamide; tert-butyl (S)-((4-((1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)(methyl)carbamoyl)cyclohexyl)methyl)carbamate; and a pharmaceutically acceptable salt thereof. Pharmaceutical Compositions and Routes of Administration [0091] Compounds provided in accordance with the present invention are usually administered in the form of pharmaceutical compositions. This invention therefore provides pharmaceutical compositions that contain, as the active ingredient, one or more of the compounds described, or a pharmaceutically acceptable salt or ester thereof, and one or more pharmaceutically acceptable excipients, carriers, including inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants. The pharmaceutical compositions may be administered alone or in combination with other therapeutic agents. Such compositions are prepared in a manner well known in the pharmaceutical art (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.) [0092] The pharmaceutical compositions may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, for example as described in those patents and patent applications incorporated by reference, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, as an inhalant, or via an impregnated or coated device such as a stent, for example, or an artery- inserted cylindrical polymer. [0093] One mode for administration is parenteral, particularly by injection. The forms in which the novel compositions of the present invention may 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 a sterile aqueous solution, and similar pharmaceutical vehicles. Aqueous solutions in saline are also conventionally used for injection, but less preferred in the context of the present invention. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. [0094] Sterile injectable solutions are prepared by incorporating a compound according to the present invention in the required amount in the appropriate solvent with various other ingredients as 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 a previously sterile- filtered solution thereof. [0095] Oral administration is another route for administration of compounds in accordance with the invention. Administration may be via capsule or enteric coated tablets, or the like. In making the pharmaceutical compositions that include at least one compound described herein, the active ingredient is usually diluted by an excipient and/or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material (as above), which acts as a vehicle, carrier or 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 a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders. [0096] 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. [0097] The compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Pat. Nos.3,845,770; 4,326,525; 4,902,514; and 5,616,345. Another formulation for use in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Pat. Nos.5,023,252, 4,992,445 and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents. [0098] The compositions are preferably formulated in a unit dosage form. The term "unit dosage forms" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, 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., a tablet, capsule, ampoule). The compounds are generally administered in a pharmaceutically effective amount. Preferably, for oral administration, each dosage unit contains from 1 mg to 2 g of a compound described herein, and for parenteral administration, preferably from 0.1 to 700 mg of a compound a compound described herein. It will be understood, however, that the amount of the compound actually administered usually will be determined by a physician, in the light of 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. [0099] For preparing solid compositions such as tablets, 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 invention. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. [00100] The tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate. [00101] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. Preferably, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner. [00102] In some embodiments, a pharmaceutical composition comprising a disclosed compound, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Methods of Use [00103] Compounds and compositions described herein are generally useful for modulating MALT1 and are useful for in treating diseases or disorders, in particular those susceptible to modulation of proteolytic and/or autoproteolytic activity of MALT1. In some embodiments, the compounds and compositions described herein are useful for inhibiting MALT1. In some embodiments, it is contemplated that the compounds and compositions of the present invention may be useful in the treatment of a disease, a disorder, or a condition characterized by dysregulated NF-kB activation, for example, autoimmune or immunological and inflammatory disorders, allergic disorders, respiratory disorders and oncological disorders. [00104] In typical embodiments, the present invention is intended to encompass the compounds disclosed herein, and the pharmaceutically acceptable salts, pharmaceutically acceptable esters, tautomeric forms, polymorphs, and prodrugs of such compounds. In some embodiments, the present invention includes a pharmaceutically acceptable addition salt, a pharmaceutically acceptable ester, a solvate (e.g., hydrate) of an addition salt, a tautomeric form, a polymorph, an enantiomer, a mixture of enantiomers, a stereoisomer or mixture of stereoisomers (pure or as a racemic or non-racemic mixture) of a compound described herein, e.g. a compound of Formula I); such as a compound of Formula named herein. [00105] In some embodiments, the autoimmune and inflammatory disorders are selected from arthritis, ankylosing spondylitis, inflammatory bowel disease, ulcerative colitis, gastritis, pancreatitis, Crohn's disease, celiac disease, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, rheumatoid arthritis, rheumatic fever, gout, organ or transplant rejection, acute or chronic graft-versus-host disease, chronic allograft rejection, Behcet's disease, uveitis, psoriasis, psoriatic arthritis, BENTA disease, polymyositis, dermatitis, atopic dermatitis, dermatomyositis, acne vulgaris, myasthenia gravis, hidradenitis suppurativa, Grave's disease, Hashimoto thyroiditis, Sjogren's syndrome, and blistering disorders (e.g., pemphigus vulgaris), antibody- mediated vasculitis syndromes, including ANCA-associated vasculitides, Henoch-Schonlein Purpura, and immune-complex vasculitides (either primary or secondary to infection or cancers). [00106] In some embodiments, the oncological disorders are selected from carcinoma, sarcoma, lymphoma, leukemia and germ cell tumors, adenocarcinoma, bladder cancer, clear cell carcinoma, skin cancer, brain cancer, cervical cancer, colon cancer, colorectal cancer, endometrial cancer, brain tumors, breast cancer, gastric cancer, germ cell tumors, glioblastoma, hepatic adenomas, Hodgkin's lymphoma, liver cancer, kidney cancer, lung cancer, pancreatic cancer, head/neck/throat cancer, ovarian cancer, dermal tumors, prostate cancer, renal cell carcinoma, stomach cancer, hematologic 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 lymphomas, in particular 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, lentigo maligna melanomas, 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 small nevus-like cells, melanoma with features of a Spitz nevus, uveal melanoma, precursor T-cell, leukemia/lymphoma, acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, follicular lymphoma, chronic lymphocytic leukemia/lymphoma, Burkitt's lymphoma, mycosis fungoides, peripheral T-cell lymphoma, nodular sclerosis form of Hodgkin lymphoma, mixed-cellularity subtype of Hodgkin lymphoma, non-small-cell lung cancer, large-cell carcinoma, and small-cell lung carcinoma. [00107] In some embodiments, the oncological disorder is a cancer in the form of a tumor or a blood born 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 an adenoma, an adenocarcinoma, a blastoma (e.g., hepatoblastoma, glioblastoma, neuroblastoma and retinoblastoma), a carcinoma (e.g., colorectal carcinoma or heptatocellular carcinoma, pancreatic, prostate, gastric, esophageal, cervical, and head and neck carcinomas, and adenocarcinoma), a desmoid tumor, a desmoplastic small round cell tumor, an endocrine tumor, a germ cell tumor, a lymphoma, a leukemia, a sarcoma (e.g., Ewing sarcoma, osteosarcoma, rhabdomyosarcoma, or any other soft tissue sarcoma), a Wilms tumor, a lung tumor, a colon tumor, a lymph tumor, a breast tumor or a melanoma. [00108] In some embodiments, the allergic disorder is selected from contact dermatitis, celiac disease, asthma, hypersensitivity to house dust mites, pollen and related allergens, and berylliosis. [00109] In some embodiments, the respiratory disorders 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. [00110] In some embodiments, the compounds and compositions of the present invention may be useful in the treatment of rheumatoid arthritis, systemic lupus erythematosus, vasculitic conditions, allergic diseases, asthma, chronic obstructive pulmonary disease (COPD), acute or chronic transplant rejection, graft versus host disease, cancers of hematopoietic origin or solid tumors, chronic myelogenous leukemia, myeloid leukemia, non-Hodgkin lymphoma or other B cell lymphomas. Combination Therapy [00111] A compound of composition described herein may be administered in combination with another agent or therapy. A subject to be administered a compound disclosed herein may have a disease, disorder, or condition, or a symptom thereof, that would benefit from treatment with another agent or therapy. [00112] In some embodiments, the compound of composition described herein may be administered either simultaneously with, or before or after, one or more other therapeutic agent. In some embodiments, the compound of composition described herein may be administered separately, by the same or different route of administration, or together in the same pharmaceutical composition as the other agents. [00113] In some embodiments, the compound described herein may be administered as the sole active ingredient or in conjunction with, e.g., as an adjuvant to, other drugs e.g., immunosuppressive or immunomodulating agents or other anti-inflammatory agents, e.g., for the treatment or prevention of alio- or xenograft acute or chronic rejection or inflammatory or autoimmune disorders, or a chemotherapeutic agent, e.g., a malignant cell anti-proliferative agent. For example, the compounds of the invention may be used in combination with a calcineurin inhibitor, e.g., cyclosporin A or FK 506; a rmTOR inhibitor, e.g., rapamycin, 40-0- (2-hydroxyethyl)-rapamycin, biolimus-7 or biolimus-9; an ascomycin having immunosuppressive properties, e.g., ABT-281, ASM981; corticosteroids; cyclophosphamide; azathioprene; methotrexate; leflunomide; mizoribine; mycophenolic acid or salt; mycophenolate mofetil; or IL-1 beta inhibitor. [00114] In some embodiments, the compound described herein is combined with a co-agent which is a PI3K inhibitor. [00115] In some embodiments, the compound described herein is combined with co-agent that influence BTK (Bruton's tyrosine kinase). [00116] For the treatment of oncological diseases, the compound described herein may be used in combination with B-cell modulating agents, e.g., Rituximab, Ofatumumab, BTK or SYK inhibitors, inhibitors of PKC, PI3K, PDK, PIM, JAK and rmTOR and BH3 mimetics. EXAMPLES [00117] The representative examples that follow are intended to help illustrate the invention, and are not intended to, nor should they be construed to, limit the scope of the invention. [00118] 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 of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimal reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization. [00119] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection are well known in the art. For example, numerous protecting groups, and their introduction and removal, are described in T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein. [00120] The compounds provided herein may 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 may either be performed manually or via an automated system. The compounds provided herein may 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 part per million (ppm) and are generated using methods well known to those of skill in the art.

Calcd calculated UV ultraviolet rt room temperature DIEA, DIPEA N,N-Diisopropylethylamine HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate CDI 1,1’-carbonyldiimidazole ee enantiomeric excess TMS trimethylsilyl Pd₂(dba)₃ tris(dibenzylideneacetone)dipalladium(0) Et₃N, TEA triethylamine Cs₂CO₃ cesium carbonate INT intermediate P(t-Bu)3 Tri-tert-butylphosphine t-BuOH tert-butyl alcohol NaOtBu sodium tert-butoxide Boc tert-butyloxycarbonyl AcCl acetyl chloride NaBH₃CN sodium cyanoborohydride OH(CH2O)nH paraformaldehyde AcOH acetic acid LiOH.H₂O lithium hydroxide monohydrate NH4Cl ammonium chloride MeNH₂.HCl methylamine hydrochloride Me2NH.HCl dimethylamine hydrochloride TMSN₃ trimethylsilyl azide (C₄H₉)₂SnO dibutyltin oxide NH2NH2.H2O hydrazine hydrate Boc₂O di-tert-butyl dicarbonate PBr3 phosphorous tribromide BnOH benzyl alcohol DPPA diphenylphosphoryl azide Pd(OAc)2 palladium (II) acetate K₃PO₄ potassium phosphate NaOH sodium hydroxide Ph2O diphenyl ether KOtBu potassium tert-butoxide Pd(PPh3)2Cl2 Bis(triphenylphosphine)palladium(II) dichloride (n-Bu)₄OAc tetrabutylammonium acetate (COCl)2 oxalyl chloride Na₂CO₃ sodium carbonate BOP benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate TFAA trifluoroacetic anhydride NaN₃ sodium azide NH4OH ammonium hydroxide CH₃OTf methyl trifluoromethanesulfonate SOCl2 thionyl chloride Me2SO4 dimethyl sulfate POCl₃ phosphorous oxychloride Ac2O acetic anhydride BrCN cyanogen bromide ZnBr2 zinc bromide pTsOH.H₂O p-Toluenesulfonic acid monohydrate NaH sodium hydride TBSCl tert-Butyldimethylsilyl chloride TBS tert-Butyldimethylsilyl Ti(OEt)4 titanium ethoxide TBAT tetrabutylammonium difluorotriphenylsilicate Example 1. Preparation of the compounds [00121] Methods for preparing compounds described herein are illustrated in the following synthetic schemes. These schemes are given for the purpose of illustrating the invention and should not be regarded in any manner as limiting the scope or the spirit of the invention. Starting materials shown in the schemes may be obtained from commercial sources or can be prepared from commercially available sources based on procedures described in the literature. 1. Compounds Prepared using Scheme 1 Scheme 1:

[00122] Naphthyridin G-1a is reacted with R¹- and R²-containing carboxamide G-1b to provide a compound of Formula (I). Synthesis of N-[(1S)-1-{4-[(4-cyclopropyl-1,5-naphthyridin-3-yl)amino]phenyl}-2,2,2- trifluoroethyl]-N-methyl-1,1-dioxo-1^^-thiane-4-carboxamide (also known as (S)-N-(1-(4-((4- cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H- thiopyran-4-carboxamide 1,1-dioxide) (Compound 1.1)

[00123] To a mixture of 4-cyclopropyl-1,5-naphthyridin-3-amine [INT 1.1] (100 mg, 539 μmol) and N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo-1^^-thiane-4- carboxamide [INT 5.1] (276 mg, 646 μmol) in dioxane (2 mL) was added xantphos (31.1 mg, 53.9 μmol), dicaesium(1+) carbonate (524 mg, 1.61 mmol) and Pd2(dba)3 (49.3 mg, 53.9 μmol). The reaction mixture was stirred at 100 °C under nitrogen for 2 hours. The reaction mixture was diluted with CH2Cl2 (20 mL) and filtered. The filtrate was concentrated to give crude product which was purified by flash chromatography on silica gel (0-3% MeOH in CH2Cl2) and prep- HPLC (column: Boston Prime C18150*25mm*5um, table: 40-70% B (A = water(0.05% ammonia hydroxide), B = acetonitrile), flow rate: 30 mL/min, UV Detector 220nm) to give N- [(1S)-1-{4-[(4-cyclopropyl-1,5-naphthyridin-3-yl)amino]phenyl}-2,2,2-trifluoroethyl]-N- methyl-1,1-dioxo-1^^-thiane-4-carboxamide [Compound 1.1] (119.3 mg, 41.4% yield) as a dry powder. m/z: [M + H]+ Calcd for C26H28F3N4O3S 533.2; Found 533.3. ¹H NMR (400MHz, CHLOROFORM-d) į = 8.95 (dd, J=1.6, 4.4 Hz, 1H), 8.94 (s, 1H), 8.30 (dd, J=1.6, 8.4 Hz, 1H), 7.50 (dd, J=4.4, 8.4 Hz, 1H), 7.31 (d, J=8.4 Hz, 2H), 7.11 (d, J=8.8 Hz, 2H), 6.61 (q, J=8.8 Hz, 1H), 6.43 (s, 1H), 3.54-3.43 (m, 1H), 3.42-3.30 (m, 1H), 3.06-2.97 (m, 2H), 2.97-2.91 (m, 4H), 2.51-2.32 (m, 3H), 2.31-2.22 (m, 1H), 2.13-2.03 (m, 1H), 1.33-1.24 (m, 2H), 1.14-1.05 (m, 2H). Synthesis of (S)-N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)-N-methylacetamide (Compound 1.2)

[00124] A mixture of 4-cyclopropyl-1,5-naphthyridin-3-amine [INT 1.1] (100 mg, 539 μmol), (S)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methylacetamide [INT 5.2] (167 mg, 539 μmol), Pd₂(dba)₃ (49.3 mg, 53.9 μmol), Xantphos (61.9 mg, 107 μmol), and Cs₂CO₃ (524 mg, 1.61 mmol) in dioxane (3 mL) was stirred at 100 °C for 3 hr under N₂ atmosphere. The mixture was concentrated under reduced pressure to afford the crude product, which was purified by prep-HPLC (column: YMC Triart C18250*50mm*7μm, table: 27- 67% B (A = water (0.05% ammonia hydroxide )), B = acetonitrile), flow rate: 60 mL/min, UV Detector 220nm) to afford (S)-N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)-N-methylacetamide [Compound 1.2] (86.7 mg, 209 μmol, 38.8% yield) as a yellow dry powder. m/z: [M + H]+ Calcd for C22H22F3N4O 415.2; Found 415.2. ¹H NMR (400 MHz, MeOD) į = 8.89 (dd, J=1.6, 4.4 Hz, 1H), 8.80 - 8.78 (m, 1H), 8.30 (dd, J=1.6, 8.4 Hz, 1H), 7.61 (dd, J=4.4, 8.4 Hz, 1H), 7.38 - 7.28 (m, 2H), 7.08 - 7.02 (m, 2H), 6.50 (q, J=9.2 Hz, 1H), 2.95 - 2.74 (m, 3H), 2.36 - 2.20 (m, 3H), 2.19 - 2.11 (m, 1H), 1.13 (d, J=7.2 Hz, 4H). Synthesis of tert-butyl 3-(((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)(methyl)carbamoyl)pyrrolidine-1-carboxylate (Compound 1.3)

[00125] To a solution of tert-butyl 3-(((S)-1-(4-bromophenyl)-2,2,2- trifluoroethyl)(methyl)carbamoyl)pyrrolidine-1-carboxylate [INT 7.1] (200mg, 429 μmol), 4- cyclopropyl-1,5-naphthyridin-3-amine [INT 1.1] (87.2 mg, 471 μmol), Cs₂CO₃ (417 mg, 1.28 mmol), and xantphos (49.6 mg, 85.8 μmol) in dioxane (3 mL) was added Pd₂(dba)₃ (39.2 mg, 42.9 μmol). The reaction mixture was stirred at 100 ºC for 2 h under N₂. The reaction was quenched by adding water (30 mL) and was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to give the crude product, which was purified by flash chromatography on silica gel (PE/EtOAc = 1/0 to 1/2) to give tert-butyl 3-(((S)-1-(4-((4- cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)(methyl)carbamoyl)pyrrolidine-1-carboxylate [Compound 1.3] (160 mg). 80 mg were purified by prep-HPLC (column: YMC-Actus Triart C18150*30mm*5μm, condition:33%- 53% CH3CN in water (0.05% ammonia hydroxidev/v)-ACN,flowrate:35mL/min) to give tert- butyl 3-(((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)(methyl)carbamoyl)pyrrolidine-1-carboxylate [Compound 1.3] (11.7 mg, 20.5 μmol, 4.8% yield) as a white dry powder. m/z: [M + H]+ Calcd for C30H35F3N5O3570.3; Found 570.4. ¹H NMR (400MHz, DMSO-d6) δ = 8.89 (dd, J=2.0, 4.0 Hz, 1H), 8.76 (s, 1H), 8.50 - 8.39 (m, 1H), 8.31 (dd, J=1.6, 8.4 Hz, 1H), 7.63 (dd, J=4.0, 8.4 Hz, 1H), 7.32 - 7.16 (m, 2H), 7.00 - 6.88 (m, 2H), 6.52 - 6.09 (m, 1H), 3.56 - 3.50 (m, 1H), 3.50 - 3.35 (m, 2H), 3.32 - 3.16 (m, 2H), 2.93 - 2.87 (m, 2H), 2.68 (br s, 1H), 2.30 - 2.21 (m, 1H), 2.20 - 1.81 (m, 2H), 1.49 (qd, J=2.0, 5.6 Hz, 2H), 1.41 (s, 9H), 1.03 (qd, J=3.2, 8.8 Hz, 2H). 55 Synthesis of tert-butyl (S)-4-((1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)(methyl)carbamoyl)piperidine-1-carboxylate (Compound 1.4)

[00126] To a solution of tert-butyl (S)-4-((1-(4-bromophenyl)-2,2,2- trifluoroethyl)(methyl)carbamoyl)piperidine-1-carboxylate [INT 7.2] (200mg, 417 μmol), 4- cyclopropyl-1,5-naphthyridin-3-amine [INT 1.1] (77.2 mg, 417 μmol), Cs₂CO₃ (407 mg, 1.25 mmol), and xantphos (48.2 mg, 83.4 μmol) in dioxane (3 mL) was added Pd₂(dba)₃ (38.1 mg, 41.7 μmol). The reaction mixture was stirred at 100 ºC for 2 h, after which it was quenched by adding water (10 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product, which was purified by flash chromatography on silica gel (EtOAc/Petroleum ether = 1/2 to 1/0) and prep-HPLC (column: Phenomenex Gemini- NX C1875*30mm*3μm, table: 20-60% B (A = water(0.225%FA)-ACN), B = acetonitrile), flowrate: 30 mL/min, UV Detector 220nm) to afford tert-butyl (S)-4-((1-(4-((4-cyclopropyl-1,5- naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)piperidine-1- carboxylate [Compound 1.4] (104 mg, 179 μmol, 42.7% yield) as a brown dry product. m/z: [M + H]+ Calcd for C31H37F3N5O3584.3; Found 584.1. ¹H NMR (400MHz, DMSO-d6) δ = 8.87 (dd, J=1.6, 4.0 Hz, 1H), 8.74 (s, 1H), 8.41 (s, 1H), 8.29 (dd, J=1.6, 8.4 Hz, 1H), 7.62 (dd, J=4.0, 8.4 Hz, 1H), 7.18 (br d, J=8.4 Hz, 2H), 6.91 (d, J=8.8 Hz, 2H), 6.43 (br d, J=9.2 Hz, 1H), 3.95 (br s, 2H), 3.45 (br s, 2H), 2.93 (br d, J=10.4 Hz, 1H), 2.89 (s, 3H), 2.79 (br s, 2H), 2.62 (br s, 1H), 2.49 (td, J=1.6, 3.6 Hz, 1H), 2.23 (br t, J=5.6 Hz, 1H), 1.76 - 1.60 (m, 2H), 1.45 (td, J=2.8, 5.6 Hz, 2H), 1.39 (s, 9H), 1.05 - 0.98 (m, 2H). Synthesis of tert-butyl 3-(((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)(methyl)carbamoyl)piperidine-1-carboxylate (Compound 1.5)

[00127] To a solution of tert-butyl 3-(((S)-1-(4-bromophenyl)-2,2,2- trifluoroethyl)(methyl)carbamoyl)piperidine-1-carboxylate [INT 7.3] (500 mg, 1.04 mmol), 4- cyclopropyl-1,5-naphthyridin-3-amine [INT 1.1] (229 mg, 1.24 mmol), Cs₂CO₃ (1.01 g, 3.12 mmol), and xantphos (120 mg, 208 μmol) in dioxane (5 mL) was added Pd₂(dba)₃(95.2 mg, 104 μmol). The reaction mixture was stirred at 100 ºC for 2 h, after which it was concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc/PE = 0/1 to 1/1) to give tert-butyl 3-(((S)-1-(4-((4- cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)(methyl)carbamoyl)piperidine-1-carboxylate [Compound 1.5] (400 mg, 685 μmol, 65.8% yield) as yellow oil. An aliquot (74.8 mg) of this product was purified by prep- HPLC (column: YMC Triart C18250*50mm*7μm, condition: 44%-84% CH3CN in water (0.05% ammonia hydroxide v/v)-ACN,flowrate:60 mL/min) to give tert-butyl 3-(((S)-1-(4-((4- cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)(methyl)carbamoyl)piperidine-1-carboxylate [Compound 1.5] (14.8 mg, 25.3 μmol) as an off-white dry powder. m/z: [M + H]+ Calcd for C31H37F3N5O3584.2; Found 584.4. ¹H NMR (400MHz, DMSO-d6) į = 8.88 (dd, J=1.6, 4.0 Hz, 1H), 8.75 (s, 1H), 8.49 - 8.40 (m, 1H), 8.29 (dd, J=1.6, 8.4 Hz, 1H), 7.62 (dd, J=4.0, 8.4 Hz, 1H), 7.25 - 7.15 (m, 2H), 6.98 - 6.87 (m, 2H), 6.43 (q, J=9.6 Hz, 1H), 3.89 (br d, J=14.8 Hz, 2H), 3.30 (s, 3H), 2.92 - 2.88 (m, 2H), 2.77 (br s, 2H), 2.69 - 2.64 (m, 1H), 2.28 - 2.19 (m, 1H), 1.82 (br d, J=11.6 Hz, 1H), 1.63 (br d, J=12.4 Hz, 1H), 1.47 (br dd, J=2.8, 5.6 Hz, 2H), 1.41 - 1.33 (m, 9H), 1.10 - 0.95 (m, 2H). Synthesis of (S)-N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide (Compound 1.6)

[00128] A mixture of 4-cyclopropyl-1,5-naphthyridin-3-amine [INT 1.1] (100 mg, 539 μmol), (S)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4- carboxamide [INT 5.3] (234 mg, 592 μmol), Xantphos (61.9 mg, 107 μmol), Pd2(dba)3 (49.3 mg, 53.9 μmol), and Cs2CO3 (348 mg, 1.07 mmol) in dioxane (2 mL) was stirred at 100 °C for 6 hr under N2 atmosphere. The reaction was concentrated under reduced pressure to afford the crude product, which was purified by flash chromatography on silica gel (EtOAc/Petroleum ether = 1/10 to 1/1) and prep-HPLC (column: YMC Triart C18250*50mm*7μm, table: 38-78% B (A = water (0.05% ammonia hydroxide v/v)), B = acetonitrile), flow rate: 60 mL/min, UV Detector 220nm) to afford (S)-N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)- 2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide [Compound 1.6] (76.0 mg, 151 μmol, 28.2% yield) as a yellow dry powder. [M + H]+ Calcd for C26H28F3N4OS 501.2; Found 501.4. ¹H NMR (400 MHz, MeOD) į = 8.89 (dd, J=1.6, 4.0 Hz, 1H), 8.79 (s, 1H), 8.34 - 8.27 (m, 1H), 7.61 (dd, J=4.0, 8.4 Hz, 1H), 7.28 (d, J=8.4 Hz, 2H), 7.04 (d, J=8.4 Hz, 2H), 6.52 (q, J=8.8 Hz, 1H), 2.95 (s, 3H), 2.87 - 2.74 (m, 3H), 2.67 - 2.56 (m, 2H), 2.19 - 2.07 (m, 2H), 2.07 - 1.99 (m, 1H), 1.91 - 1.78 (m, 2H), 1.13 (d, J=7.2 Hz, 4H). Synthesis of methyl (1S,4r)-4-(((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)- 2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexane-1-carboxylate (Compound 1.7)

[00129] A mixture of 4-cyclopropyl-1,5-naphthyridin-3-amine [INT 1.1] (100 mg, 539 μmol), methyl (1S,4r)-4-(((S)-1-(4-bromophenyl)-2,2,2- trifluoroethyl)(methyl)carbamoyl)cyclohexane-1-carboxylate [INT 5.4] (258 mg, 592 μmol), Xantphos (61.9 mg, 107 μmol), Pd2(dba)3 (49.3 mg, 53.9 μmol), and Cs2CO3 (348 mg, 1.07 mmol) in dioxane (2 mL) was stirred at 100 °C for 6 hr under N2 atmosphere. The reaction was concentrated under reduced pressure to afford the crude product, which was purified by flash chromatography on silica gel (EtOAc/Petroleum ether = 1/10 to 1/1) and prep-HPLC (column: YMC Triart C18250*50mm*7μm, table: 38-78% B (A = water (0.05% ammonia hydroxide v/v)), B = acetonitrile), flow rate: 60 mL/min, UV Detector 220 nm) to afford methyl (1S,4r)-4- (((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)(methyl)carbamoyl)cyclohexane-1-carboxylate [Compound 1.7] (84.5 mg, 156 μmol, 29.0% yield) as a yellow dry powder. m/z: [M + H]+ Calcd for C29H32F3N4O3541.2; Found 541.4. ¹H NMR (400 MHz, CDCl₃) į = 8.94 (s, 2H), 8.29 (dd, J=1.6, 8.4 Hz, 1H), 7.48 (dd, J=4.4, 8.4 Hz, 1H), 7.31 (d, J=8.4 Hz, 2H), 7.11 (d, J=8.4 Hz, 2H), 6.64 (q, J=8.8 Hz, 1H), 6.42 (s, 1H), 3.69 (s, 3H), 2.96 - 2.79 (m, 3H), 2.64 - 2.54 (m, 1H), 2.44 - 2.34 (m, 1H), 2.17 - 2.04 (m, 3H), 2.01 - 1.92 (m, 1H), 1.92 - 1.83 (m, 1H), 1.73 - 1.64 (m, 2H), 1.56 - 1.42 (m, 2H), 1.33 - 1.25 (m, 2H), 1.11 - 1.05 (m, 2H). Synthesis of N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)-N-methyltetrahydro-2H-pyran-2-carboxamide (Compound 1.8)

[00130] A mixture of 4-cyclopropyl-1,5-naphthyridin-3-amine [INT 1.1] (50 mg, 269 μmol), N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-pyran-2-carboxamide [INT 7.4] (100 mg, 263 μmol), Xantphos (31.1 mg, 53.8 μmol), Pd2(dba)3 (24.6 mg, 26.9 μmol), and Cs2CO3 (175 mg, 538 μmol) in dioxane (5 mL) was stirred at 100 °C for 6 hr under N2 atmosphere. The reaction was concentrated under reduced pressure to afford the crude product, which was purified by flash chromatography on silica gel (EtOAc/Petroleum ether = 1/10 to 1/1) and prep-HPLC (column: YMC Triart C18250*50mm*7μm, table: 38-78% B (A = water (0.05% ammonia hydroxide v/v)), B = acetonitrile), flow rate: 60 mL/min, UV Detector 220nm). The isolated N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)-N-methyltetrahydro-2H-pyran-2-carboxamide [Compound 1.8] product was further purified by prep-HPLC (column: Phenomenex Gemini-NX 80*40mm*3μm, table: 35- 75% B (A = water (0.05% ammonia hydroxide v/v)), B = acetonitrile), flow rate: 25 mL/min, UV Detector 220nm) to afford N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3- yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-pyran-2-carboxamide [Compound 1.8] (3.10 mg, 6.39 μmol, 2.4% yield) as a yellow dry powder. m/z: [M + H]+ Calcd for C26H28F3N4O2485.2; Found 485.2. ¹H NMR (400 MHz, CDCl3) į = 8.95 (s, 2H), 8.29 (d, J=8.4 Hz, 1H), 7.48 (dd, J=4.0, 8.4 Hz, 1H), 7.42 - 7.32 (m, 2H), 7.11 (d, J=8.4 Hz, 2H), 6.61 (q, J=8.8 Hz, 1H), 6.42 (s, 1H), 4.24 - 4.17 (m, 1H), 4.12 - 4.03 (m, 1H), 3.58 - 3.47 (m, 1H), 2.97 - 2.84 (m, 3H), 2.12 - 2.05 (m, 1H), 2.04 - 1.90 (m, 2H), 1.89 - 1.78 (m, 2H), 1.76 - 1.66 (m, 2H), 1.31 - 1.27 (m, 2H), 1.11 - 1.02 (m, 2H). Synthesis of N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)-N-methyltetrahydrofuran-3-carboxamide (Compound 1.9)

[00131] A mixture of 4-cyclopropyl-1,5-naphthyridin-3-amine [INT 1.1] (83.3 mg, 450 μmol), N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydrofuran-3-carboxamide [INT 7.5] (110 mg, 300 μmol), Xantphos (34.7 mg, 60.0 μmol), Pd2(dba)3 (27.4 mg, 30.0 μmol), and Cs2CO3 (195 mg, 600 μmol) in dioxane (2 mL) was stirred at 100 °C for 2 hours under N2 atmosphere. The reaction was quenched by adding water (30 mL) and was extracted with EtOAc (2 x 80 mL). The combined organic layers were concentrated under reduced pressure to give the crude product, which was purified by prep-HPLC (column: Welch Xtimate C18 150*25mm*5μm, table: 35-65% B (A = water (10 mM NH₄HCO₃), B = acetonitrile), flow rate: 25 mL/min, UV Detector 220 nm) to give N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3- yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydrofuran-3-carboxamide [Compound 1.9] (67.9 mg, 144 μmol, 48.1% yield) as a yellow solid. m/z: [M + H]+ Calcd for C25H26F3N4O2471.2; Found 471.1. ¹H NMR (400MHz, DMSO-d6) į = 8.89 (dd, J = 1.6, 4.0 Hz, 1H), 8.76 (s, 1H), 8.52 - 8.38 (m, 1H), 8.30 (dd, J = 1.6, 8.4 Hz, 1H), 7.63 (dd, J = 4.0, 8.4 Hz, 1H), 7.32 - 7.14 (m, 2H), 6.99 - 6.88 (m, 2H), 6.50 - 6.09 (m, 1H), 3.81 - 3.60 (m, 4H), 3.55 - 3.43 (m, 1H), 2.88 -2.67 (m, 3H), 2.30 - 1.88 (m, 3H), 1.55 - 1.42 (m, 2H), 1.09 - 0.97 (m, 2H). Synthesis of (S)-N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)-4,4-difluoro-N-methylcyclohexane-1-carboxamide (Compound 1.10)

[00132] A mixture of 4-cyclopropyl-1,5-naphthyridin-3-amine [INT 1.1] (66.8 mg, 361 μmol), (S)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4,4-difluoro-N-methylcyclohexane-1- carboxamide [INT 7.6] (100 mg, 241 μmol), Xantphos (27.8 mg, 48.2 μmol), Pd2(dba)3 (22.0 mg, 24.1 μmol), and Cs2CO3 (157 mg, 482 μmol) in dioxane (2 mL) was stirred at 100 °C for 2 hours under N2 atmosphere. The reaction was quenched by adding water (30 mL) and was extracted with EtOAc (2 x 80 mL). The combined organic layers were concentrated under reduced pressure to give the crude product, which was purified by prep-HPLC (column: Welch Xtimate C18150*25mm*5μm, table: 45-75% B (A = water (10mM NH₄HCO₃), B = acetonitrile), flow rate: 25 mL/min, UV Detector 220 nm) to give (S)-N-(1-(4-((4-cyclopropyl- 1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-4,4-difluoro-N-methylcyclohexane-1- carboxamide [Compound 1.10] (19.4 mg, 37.4 μmol, 15.6% yield) as a yellow solid. m/z: [M + H]+ Calcd for C27H28F5N4O 519.2; Found 519.2. ¹H NMR (400MHz, DMSO-d6) į = 8.89 (d, J = 1.6, 4.0 Hz, 1H), 8.75 (s, 1H), 8.50 - 8.40 (m, 1H), 8.30 (dd, J=1.6, 8.4 Hz, 1H), 7.63 (dd, J = 4.4, 8.4 Hz, 1H), 7.49 - 7.15 (m, 2H), 7.00 - 6.88 (m, 2H), 6.52 - 6.12 (m, 1H), 2.97 - 2.64 (m, 4H), 2.29 - 2.19 (m, 1H), 2.05 (br s, 2H), 1.96 - 1.70 (m, 4H), 1.68 - 1.54 (m, 2H), 1.51 - 1.43 (m, 2H), 1.05 - 098 (m, 2H). Synthesis of (1r,4S)-N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)-4-methoxy-N-methylcyclohexane-1-carboxamide (Compound 1.11)

[00133] A mixture of (1r,4S)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-methoxy-N- methylcyclohexane-1-carboxamide [INT 7.7] (90 mg, 220 μmol), 4-cyclopropyl-1,5- naphthyridin-3-amine [INT 1.1] (40.7 mg, 220 μmol), Cs2CO3 (143 mg, 440 μmol), Xantphos (25.4 mg, 44.0 μmol), and Pd2(dba)3 (20.1 mg, 22.0 μmol) in dioxane (2 mL) was stirred at 100 ºC for 1 h. The reaction was quenched by adding water (10 mL) and was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to give the crude product, which was purified by prep-HPLC (column: YMC-Actus Triart C18150*30mm*5μm, table: 45-65% water (0.05% ammonia hydroxide v/v)-ACN, flow rate: 35 mL/min, UV Detector 220 nm) to afford (1r,4S)-N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)-4-methoxy-N-methylcyclohexane-1-carboxamide [Compound 1.11] (15.6 mg, 30.6 μmol, 13.9% yield) as a yellow dry powder. m/z: [M + H]+ Calcd for C28H32F3N4O2 513.2; Found 513.5. ¹H NMR (400 MHz, DMSO-d6) į = 8.88 (dd, J=1.6, 4.1 Hz, 1H), 8.75 (s, 1H), 8.42 (s, 1H), 8.29 (dd, J=1.8, 8.5 Hz, 1H), 7.62 (dd, J=4.1, 8.4 Hz, 1H), 7.18 (br d, J=8.3 Hz, 2H), 6.99 - 6.98 (m, 1H), 6.92 (br d, J=8.5 Hz, 1H), 6.45 (q, J=9.3 Hz, 1H), 3.22 (s, 3H), 3.13 - 3.06 (m, 1H), 2.87 (s, 3H), 2.62 (s, 1H), 2.29 - 2.18 (m, 1H), 2.02 (br s, 2H), 1.83 - 1.63 (m, 2H), 1.51 - 1.32 (m, 4H), 1.24 - 1.09 (m, 2H), 1.02 (qd, J=3.1, 8.8 Hz, 2H). Synthesis of (S)-N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)-N-methyl-1-pivaloylpiperidine-4-carboxamide (Compound 1.12)

[00134] A mixture of (S)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methyl-1- pivaloylpiperidine-4-carboxamide [INT 8.1] (0.05 g, 0.1079 mmol), 4-cyclopropyl-1,5- naphthyridin-3-amine [INT 1.1] (19.8 mg, 107 μmol), and Cs₂CO₃ (105 mg, 323 μmol) in dioxane (3 mL) was purged with Ar. Then bis(adamantan-1-yl)(butyl)phosphane (3.83 mg, 10.7 μmol) and Pd2(dba)3 (4.93 mg, 5.39 μmol) were added under Ar. The reaction mixture was stirred at 100 °C for 10 h. After cooling, the reaction mixture was purified by HPLC (see conditions below) to give (S)-N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)- 2,2,2-trifluoroethyl)-N-methyl-1-pivaloylpiperidine-4-carboxamide [Compound 1.12] (11.4 mg, 0.02024 mmol, 18.7% yield) as a yellow oil. m/z: [M + H]+ Calcd for C31H37F3N5O2568.3; Found 568.2. NMR: ¹H NMR (400 MHz, CD3OD) į = 8.91 - 8.81 (m, 1H), 8.79 (s, 1H), 8.30 (d, J=8 Hz, 1H), 7.65 - 7.58 (m, 1H), 7.38 - 7.26 (m, 2H), 7.09 - 7.02 (m, 2H), 6.54 (q, J=9.3 Hz, 1H), 4.51 - 4.41 (m, 2H), 3.15 – 2.92 (m, 6H), 2.23 - 2.10 (m, 1H), 1.93 - 1.77 (m, 2H), 1.73 - 1.60 (m, 2H), 1.30 (s, 9H), 1.18 - 1.11 (m, 4H). [00135] HPLC conditions: System - Agilent 1260 Infinity II LC coupled to an Agilent 6120B Single Quadrupole LC/MS System. Column - Description: Chromatorex SBM 100-5T 5 μm C18(2) 100 Å, LC Column 100 x 19 mm, Waters, Sun Fire. Stationary Phase: C18. Solid Support: Fully Porous Silica. Separation Mode: Reversed Phase. Mobile Phase Mobile phase A: water Mobile phase B: acetonitrile Flow rate: 30ml/min; loading pump 4ml/min B. Gradient conditions: 30-35-60-100% (B) 0-2-10-11.2 min. Synthesis of (1r,4S)-4-cyano-N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)- 2,2,2-trifluoroethyl)-N-methylcyclohexane-1-carboxamide (Compound 1.13)

[00136] (1r,4S)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-cyano-N- methylcyclohexane-1-carboxamide [INT 8.2] (110 mg, 0.2727 mmol), 4-cyclopropyl-1,5- naphthyridin-3-amine [INT 1.1] (50.3 mg, 272 μmol), and Cs2CO3 (266 mg, 818 μmol) were mixed in dioxane (5 mL). Argon was bubbled through the reaction mixture for 0.5 h. Then xantphos (15.6 mg, 27.2 μmol) and Pd2(dba)3 (12.4 mg, 13.6 μmol) were added and the reaction mixture was stirred under an argon atmosphere at 100 °C for 16 h. The reaction mixture was cooled, filtered, and concentrated under reduced pressure. The resulting residue was purified by HPLC (see conditions below) to give (1r,4S)-4-cyano-N-((S)-1-(4-((4-cyclopropyl- 1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylcyclohexane-1-carboxamide [Compound 1.13] (21.0 mg, 0.04137 mmol, 15.2% yield) as a brown solid. m/z: [M + H]+ Calcd for C28H29F3N5O 508.2; Found 508.0. ¹H NMR (400 MHz, DMSO-d₆) į = 8.92 - 8.85 (m, 1H), 8.75 (s, 1H), 8.41 (s, 1H), 8.33 - 8.26 (m, 1H), 7.67 - 7.58 (m, 1H), 7.28 - 7.14 (m, 2H), 6.92 (d, J=8.4 Hz, 2H), 6.43 (t, J=9.5 Hz, 1H), 2.87 (s, 3H), 2.82 - 2.57 (m, 3H), 2.31 - 2.19 (m, 1H), 2.10 – 1.90 (m, 2H), 1.83 - 1.68 (m, 2H), 1.67 - 1.36 (m, 5H), 1.07 - 0.98 (m, 2H). [00137] HPLC conditions: System - Agilent 1260 Infinity II LC coupled to an Agilent 6120B Single Quadrupole LC/MS System. Column - Description: XBridge BEH 5 ^m C18(2) 130 Å, LC Column 100 x 20 mm, YMC-Actus Triart. Stationary Phase: C18 with ethylene endcapping. Solid Support: Fully Porous Silica. Separation Mode: Reversed Phase. Mobile Phase - Mobile phase A: water. Mobile phase B: acetonitrile+0.1% NH3 (20% water solution NH3). Flow rate: 30ml/min; loading pump 4ml/min B. Gradient conditions: 10-40-65-100% (B) 0-2-10-11.2 min. Synthesis of (1r,3S)-3-cyano-N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)- 2,2,2-trifluoroethyl)-N-methylcyclobutane-1-carboxamide (Compound 1.14)

[00138] (1r,3S)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-3-cyano-N- methylcyclobutane-1-carboxamide [INT 8.3] (0.1 g, 0.2665 mmol), 4-cyclopropyl-1,5- naphthyridin-3-amine [INT 1.1] (49.2 mg, 266 μmol), xantphos (15.3 mg, 26.6 μmol), and Cs2CO3 (260 mg, 799 μmol) were mixed in dioxane (3 mL) and the reaction mixture was degassed with Argon for 5 min. Pd2(dba)3 (12.1 mg, 13.3 μmol) was added. Then the reaction mixture was degassed with Argon for 5 min and stirred at 100 °C for 10 h. The reaction mixture was cooled to rt and the solid was filtered off. The filtrate was purified by HPLC (see conditions below) to obtain (1r,3S)-3-cyano-N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3- yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylcyclobutane-1-carboxamide [Compound 1.14] (11.2 mg, 0.02337 mmol, 8.8% yield) as a yellow oil. m/z: [M + H]+ Calcd for C26H25F3N5O 480.2; Found 480.2. ¹H NMR (400 MHz, DMSO-d₆) į = 8.89 (dd, J=4.1, 1.8 Hz, 1H), 8.75 (s, 1H), 8.42 (s, 1H), 8.30 (dd, J=8.4, 1.7 Hz, 1H), 7.63 (dd, J=8.4, 4.2 Hz, 1H), 7.28 - 7.17 (m, 2H), 6.92 (d, J=8.2 Hz, 2H), 6.43 - 6.34 (m, 1H), 3.74 (q, J=8.6 Hz, 1H), 3.20 - 3.13 (m, 1H), 2.75 - 2.65 (m, 4H), 2.63 - 2.51 (m, 3H), 2.27 - 2.21 (m, 1H), 1.53 - 1.44 (m, 2H), 1.07 - 0.98 (m, 2H). [00139] HPLC conditions: System - Agilent 1260 Infinity II LC coupled to an Agilent 6120B Single Quadrupole LC/MS System. Column - Description: XBridge BEH 5 ^m C18(2) 130 Å, LC Column 100 x 20 mm, YMC-Actus Triart. Stationary Phase: C18 with ethylene endcapping. Solid Support: Fully Porous Silica. Separation Mode: Reversed Phase. Mobile Phase - Mobile phase A: water. Mobile phase B: acetonitrile+0.1% NH3 (20% water solution NH3). Flow rate: 30ml/min; loading pump 4ml/min B. Gradient conditions: 10-30-55-100% (B) 0-2-10-11.2 min. Synthesis of (S)-N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)-N-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)azetidine-3-carboxamide (Compound 1.15)

[00140] (S)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methyl-1-(5-methyl-1,3,4- oxadiazol-2-yl)azetidine-3-carboxamide [INT 8.4] (0.036 g, 0.08309 mmol), 4-cyclopropyl-1,5- naphthyridin-3-amine [INT 1.1] (15.3 mg, 83.0 μmol), Cs2CO3 (81.1 mg, 249 μmol), and xantphos (4.80 mg, 8.30 μmol) were mixed in dioxane (3 mL) and the reaction mixture was degassed with Argon for 5 min. Pd₂(dba)₃ (3.80 mg, 4.15 μmol) was added, after which the reaction mixture was degassed with argon for 5 min and stirred at 100 °C for 10 h. The reaction mixture was cooled to rt and the solid was filtered off. The filtrate was purified by HPLC (see conditions below) to obtain (S)-N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)- 2,2,2-trifluoroethyl)-N-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)azetidine-3-carboxamide [Compound 1.15] (13.3 mg, 0.02474 mmol, 29.8% yield) as a yellow solid. m/z: [M + H]+ Calcd for C27H27F3N7O2538.2; Found 538.2. ¹H NMR (400 MHz, CD3OD) į = 8.90 (dd, J=4.3, 1.7 Hz, 1H), 8.79 (s, 1H), 8.30 (dd, J=8.4, 1.7 Hz, 1H), 7.61 (dd, J=8.5, 4.2 Hz, 1H), 7.38 - 7.29 (m, 2H), 7.10 - 7.01 (m, 2H), 6.52 (q, J=9.1 Hz, 1H), 4.46 - 4.28 (m, 4H), 4.11 (tt, J=8.7, 6.2 Hz, 1H), 2.84 (s, 3H), 2.67 (s, 1H), 2.39 (s, 3H), 2.22 - 2.10 (m, 1H), 1.20 - 1.08 (m, 4H). [00141] HPLC conditions: System - Agilent 1260 Infinity II LC coupled to an Agilent 6120B Single Quadrupole LC/MS System. Column - Description: XBridge BEH 5 ^m C18(2) 130 Å, LC Column 100 x 20 mm, YMC-Actus Triart. Stationary Phase: C18 with ethylene endcapping. Solid Support: Fully Porous Silica. Separation Mode: Reversed Phase. Mobile Phase - Mobile phase A: water. Mobile phase B: acetonitrile+0.1% NH3 (20% water solution NH3). Flow rate: 30ml/min; loading pump 4ml/min B. Gradient conditions: 10-30-45-100% (B) 0-2-10-11.2 min. Synthesis of (S)-2-acetyl-N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)-N-methyl-2-azaspiro[3.3]heptane-6-carboxamide (Compound 1.16) [00142] (S)-2-acetyl-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methyl-2- azaspiro[3.3]heptane-6-carboxamide [INT 8.5] (0.1 g, 0.2308 mmol), 4-cyclopropyl-1,5- naphthyridin-3-amine [INT 1.1] (42.6 mg, 230 μmol), xantphos (13.3 mg, 23.0 μmol), and Cs2CO3 (225 mg, 692 μmol) were mixed in dioxane (3 mL) and the reaction mixture was degassed with argon for 5 min. Pd₂(dba)₃ (10.5 mg, 11.5 μmol) was added, after which the reaction mixture was degassed with argon for 5 min and stirred at 100 °C for 10 h. The reaction mixture was cooled to rt and the solid was filtered off. The filtrate was purified by HPLC (see conditions below) to obtain (S)-2-acetyl-N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3- yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyl-2-azaspiro[3.3]heptane-6-carboxamide [Compound 1.16]. m/z: [M + H]+ Calcd for C29H31F3N5O2538.2; Found 538.4. ¹H NMR (400 MHz, DMSO-d₆) į = 8.89 (s, 1H), 8.75 (s, 1H), 8.42 (s, 1H), 8.33 - 8.26 (m, 1H), 7.62 (dd, J=8.3, 4.1 Hz, 1H), 7.19 (d, J=8.1 Hz, 2H), 6.92 (d, J=8.5 Hz, 2H), 6.44 - 6.37 (m, 1H), 4.07 (d, J=57.0 Hz, 4H), 3.90 - 3.68 (m, 4H), 2.73 (s, 3H), 2.70 - 2.61 (m, 1H), 2.26 - 2.21 (m, 1H), 1.71 (d, J=6.3 Hz, 3H), 1.51 - 1.44 (m, 2H), 1.06 - 1.01 (m, 2H). [00143] HPLC conditions: System - Agilent 1260 Infinity II LC coupled to an Agilent 6120B Single Quadrupole LC/MS System. Column - Description: XBridge BEH 5 ^m C18(2) 130 Å, LC Column 100 x 20 mm, YMC-Actus Triart. Stationary Phase: C18 with ethylene endcapping. Solid Support: Fully Porous Silica. Separation Mode: Reversed Phase. Mobile Phase - Mobile phase A: water. Mobile phase B: acetonitrile+0.1% NH3 (20% water solution NH3). Flow rate: 30ml/min; loading pump 4ml/min B. Gradient conditions: 10-30-45-100% (B) 0-2-10-11.2 min. Synthesis of (S)-N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)-N-methyl-1-(3-methyl-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamide (Compound 1.17)

[00144] A mixture of (S)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methyl-1-(3-methyl- 1,2,4-oxadiazol-5-yl)piperidine-4-carboxamide [INT 8.6] (0.2 g, 0.4335 mmol), 4-cyclopropyl- 1,5-naphthyridin-3-amine [INT 1.1] (80.2 mg, 433 μmol), and Cs2CO3 (423 mg, 1.30 mmol) in dioxane (5 mL) was purged with Ar. Then xantphos (50.1 mg, 86.7 μmol) and Pd2(dba)3 (39.6 mg, 43.3 μmol) were added under Ar and the reaction mixture was stirred at 100 °C for 10 h. After cooling the reaction mixture was purified by HPLC (see conditions below) to give (S)-N- (1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyl-1-(3- methyl-1,2,4-oxadiazol-5-yl)piperidine-4-carboxamide [Compound 1.17] (7.22 mg, 0.01276 mmol, 3.0% yield) as a yellow oil. m/z: [M + H]+ Calcd for C29H31F3N7O2566.2; Found 567.0. ¹H NMR (400 MHz, CD₃OD) į = 8.92 - 8.89 (m, 1H), 8.80 (s, 1H), 8.33 - 8.29 (m, 1H), 7.64 - 7.59 (m, 1H), 7.30 (d, J=8.3 Hz, 2H), 7.05 (d, J=8.6 Hz, 2H), 6.54 (q, J=8 Hz, 1H), 4.18 - 4.07 (m, 2H), 3.30 - 3.19 (m, 2H), 3.14 - 3.05 (m, 1H), 3.02 (s, 3H), 2.20 - 2.12 (m, 4H), 1.98 - 1.71 (m, 4H), 1.18 - 1.11 (m, 4H). [00145] HPLC conditions: System - Agilent 1260 Infinity II LC coupled to an Agilent 6120B Single Quadrupole LC/MS System. Column - Description: XBridge BEH 5 ^m C18(2) 130 Å, LC Column 100 x 20 mm, YMC-Actus Triart. Stationary Phase: C18 with ethylene endcapping. Solid Support: Fully Porous Silica. Separation Mode: Reversed Phase. Mobile Phase - Mobile phase A: water. Mobile phase B: acetonitrile+0.1% NH₃ (20% water solution NH₃). Flow rate: 30ml/min; loading pump 4ml/min B. Gradient conditions: 10-35-60-100% (B) 0-2-10-11.2 min. Synthesis of (S)-N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)-N-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)piperidine-4-carboxamide (Compound 1.18)

[00146] (S)-N-(1-(4-(l2-azaneyl)phenyl)-2,2,2-trifluoroethyl)-N-methyl-1-(5-methyl-1,3,4- oxadiazol-2-yl)piperidine-4-carboxamide [INT 8.7] (100 mg, 0.2167 mmol), 4-cyclopropyl-1,5- naphthyridin-3-amine [INT 1.1] (40.0 mg, 216 μmol), and Cs2CO3 (211 mg, 650 μmol) were mixed in dioxane (4 mL). Argon was then bubbled through the reaction mixture for 0.5 h. Then xantphos (12.4 mg, 21.6 μmol) and Pd2(dba)3 (9.88 mg, 10.8 μmol) were added and the reaction mixture was stirred under an argon atmosphere at 100 °C for 16 h. The reaction mixture was cooled, filtered, and concentrated under reduced pressure. The residue was purified by HPLC (see conditions below) to give (S)-N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3- yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)piperidine-4- carboxamide [Compound 1.18] (12.2 mg, 0.02166 mmol, 10.0% yield) as a yellow gum. m/z: [M + H]+ Calcd for C29H31F3N7O2566.2; Found 566.4. ¹H NMR (400 MHz, CD₃OD) į = 8.93 - 8.87 (m, 1H), 8.80 (s, 1H), 8.30 (d, J=8.4, 1H), 7.61 (dd, J=8.4, 4.2 Hz, 1H), 7.39 - 7.26 (m, 2H), 7.11 - 7.01 (m, 2H), 6.54 (q, J=9.1 Hz, 1H), 4.03 - 3.93 (m, 2H), 3.25 - 3.04 (m, 2H), 3.02 (s, 3H), 2.67 (s, 2H), 2.40 (s, 3H), 2.25 - 2.10 (m, 1H), 1.99 - 1.74 (m, 4H), 1.18 - 1.08 (m, 4H). [00147] HPLC conditions: System - Agilent 1260 Infinity II LC coupled to an Agilent 6120B Single Quadrupole LC/MS System. Column - Description: XBridge BEH 5 ^m C18(2) 130 Å, LC Column 100 x 20 mm, YMC-Actus Triart. Stationary Phase: C18 with ethylene endcapping. Solid Support: Fully Porous Silica. Separation Mode: Reversed Phase. Mobile Phase - Mobile phase A: water. Mobile phase B: acetonitrile+0.1% NH3 (20% water solution NH3). Flow rate: 30ml/min; loading pump 4ml/min B. Gradient conditions: 10-20-45-100% (B) 0-2-10-11.2 min. Synthesis of N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)ethyl)-N- methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide (Compound 1.19)

[00148] N-(1-(4-bromophenyl)ethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1- dioxide [INT 13.1] (88.4 mg, 0.2361 mmol), 4-cyclopropyl-1,5-naphthyridin-3-amine [INT 1.1] (39.6 mg, 214 μmol), and Cs₂CO₃ (209 mg, 643 μmol) were mixed in dioxane (5 mL). Then argon was bubbled through the reaction mixture for 0.5 h. Then xantphos (24.8 mg, 42.9 μmol) and Pd₂(dba)₃ (19.5 mg, 21.4 μmol) were added and the reaction mixture was stirred under argon atmosphere at 100 °C for 12 h. The reaction mixture was cooled, filtered and concentrated under reduced pressure. The residue was purified by HPLC (see conditions below) to give N-(1-(4-((4- cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)ethyl)-N-methyltetrahydro-2H-thiopyran-4- carboxamide 1,1-dioxide [Compound 1.19] (9.10 mg, 0.01901 mmol, 8.9% yield) as a yellow solid. m/z: [M + H]+ Calcd for C26H31N4O3S 479.2; Found 479.2. ¹H NMR (400 MHz, CD3OD) į = 8.88 (dd, J=4.2, 1.8 Hz, 1H), 8.78 (s, 1H), 8.32 - 8.24 (m, 1H), 7.61 - 7.53 (m, 1H), 7.28 - 7.18 (m, 2H), 7.11 - 7.00 (m, 2H), 5.92 (q, J=7.0 Hz, 1H), 3.34 - 3.15 (m, 5H), 2.82 (s, 2H), 2.69 (s, 1H), 2.41 - 2.18 (m, 1H), 2.19 (s, 3H), 2.15 - 2.01 (m, 2H), 1.66 (d, J=6.8 Hz, 1H), 1.50 (d, J=7.1 Hz, 2H), 1.21 - 1.00 (m, 3H). [00149] Device (Mobile Phase, Column): System - Agilent 1260 Infinity II LC coupled to an Agilent 6120B Single Quadrupole LC/MS System. Column - Description: Chromatorex SBM 100-5T 5 ^m C18(2) 100 Å, LC Column 100 x 19 mm, Waters, Sun Fire. Stationary Phase: C18. Solid Support: Fully Porous Silica. Separation Mode: Reversed Phase. Mobile Phase - Mobile phase A: water. Mobile phase B: acetonitrile. Synthesis of (S)-N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)ethyl)-N- methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide (Compound 1.20)

[00150] (S)-N-(1-(4-bromophenyl)ethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide [INT 15.1] (150 mg, 0.4007 mmol), 4-cyclopropyl-1,5-naphthyridin-3-amine [INT 1.1] (81.5 mg, 440 μmol), Cs₂CO₃ (390 mg, 1.20 mmol), and xantphos (46.3 mg, 80.1 μmol) were mixed in dioxane (5 mL). The reaction mixture was degassed with argon, after which Pd₂(dba)₃ (36.6 mg, 40.0 μmol) was added and the reaction mixture was stirred at 100 °C under an inert atmosphere for 10 hours. The reaction was diluted with EtOAc (50 mL), filtered, and concentrated under reduced pressure. The residue was purified by HPLC (see conditions below) to give (S)-N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)ethyl)-N- methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide [Compound 1.20] (94.4 mg, 0.1973 mmol, 49.4% yield) as a yellow solid. m/z: [M + H]+ Calcd for C26H31N4O3S 479.2; Found 479.2. ¹H NMR (400 MHz, DMSO-d6) į = 8.86 (dd, J=4.1, 1.8 Hz, 1H), 8.74 (s, 1H), 8.26 (dd, J=8.4, 1.8 Hz, 1H), 8.16 (d, J=19.1 Hz, 1H), 7.58 (dd, J=8.3, 4.0 Hz, 1H), 7.19 - 7.06 (m, 2H), 6.96 - 6.86 (m, 2H), 5.87 - 5.17 (m, 1H), 3.26 - 2.92 (m, 5H), 2.70 (s, 2H), 2.27 - 2.18 (m, 1H), 2.10 - 1.94 (m, 5H), 1.59 - 1.31 (m, 5H), 1.09 - 0.98 (m, 2H). [00151] HPLC conditions: System - Agilent 1260 Infinity II LC coupled to an Agilent 6120B Single Quadrupole LC/MS System. Column - Description: Chromatorex SBM 100-5T 5 ^m C18(2) 100 Å, LC Column 100 x 19 mm, Waters, Sun Fire. Stationary Phase: C18. Solid Support: Fully Porous Silica. Separation Mode: Reversed Phase. Mobile Phase - Mobile phase A: water. Mobile phase B: acetonitrile. Flow rate: 30ml/min; loading pump 4ml/min B. Gradient conditions: 10-15-40-100% (B) 0-2-10-11.2 min. Synthesis of (R)-N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)ethyl)-N- methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide (Compound 1.21)

[00152] A mixture of (R)-N-(1-(4-bromophenyl)ethyl)-N-methyltetrahydro-2H-thiopyran-4- carboxamide 1,1-dioxide [INT 17.1] (0.17 g, 0.4541 mmol), 4-cyclopropyl-1,5-naphthyridin-3- amine [INT 1.1] (92.4 mg, 499 μmol), cesium carbonate (443 mg, 1.36 mmol), and dioxane (15 mL) was purged with Ar. Then xantphos (52.5 mg, 90.8 μmol) and tris(dibenzylideneacetone) dipalladium (41.5 mg, 45.4 μmol) were added and the reaction mixture was stirred at 100 °C for 10 h. The reaction was cooled, diluted with EtOAc (50 mL), and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by HPLC (see conditions below) to obtain (R)-N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)ethyl)-N- methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide [Compound 1.21] (66.0 mg, 0.1378 mmol, 30.4% yield) as a yellow solid. m/z: [M+H]+ Calcd for C26H31N4O3S 479.2; Found 479.2. ¹H NMR (400 MHz, DMSO) į = 8.88-8.85 (m, 1H), 8.74 (s, 1H), 8.29 - 8.18 (m, 2H), 7.62 - 7.56 (m, 1H), 7.18 - 7.06 (m, 2H), 6.95 - 6.86 (m, 2H), 5.81 - 5.20 (m, 1H), 3.29 - 2.90 (m, 5H), 2.69 (s, 3H), 2.24 - 1.96 (m, 5H), 1.56 - 1.33 (m, 5H), 1.05 - 0.99 (m, 2H). [00153] HPLC conditions: System - Agilent 1260 Infinity II LC coupled to an Agilent 6120B Single Quadrupole LC/MS System. Column - Description: Chromatorex SBM 100-5T 5 ^m C18(2) 100 Å, LC Column 100 x 19 mm, Waters, Sun Fire. Stationary Phase: C18. Solid Support: Fully Porous Silica. Separation Mode: Reversed Phase. Mobile Phase - Mobile phase A: water. Mobile phase B: acetonitrile. Flow rate: 30ml/min; loading pump 4ml/min B. Gradient conditions: 10-20-45-100% (B) 0-2-10-11.2 min. Synthesis of tert-butyl (S)-((4-((1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)- 2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexyl)methyl)carbamate (Compound 1.22)

Compound 1.22 [00154] To a suspension of tert-butyl (S)-((4-((1-(4-bromophenyl)-2,2,2- trifluoroethyl)(methyl)carbamoyl)cyclohexyl)methyl)carbamate [INT 19.1] (380 mg, 748 μmol), 4-cyclopropyl-1,5-naphthyridin-3-amine [INT 1.1] (180 mg, 972 μmol), Cs2CO3 (485 mg, 1.49 mmol), and xantphos (86.2 mg, 149 μmol) in dioxane (3 mL) was added Pd2(dba)3 (68.4 mg, 74.8 μmol). The resulting mixture was stirred at 100 °C for 4 h under N2. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel (MeOH/Dichloromethane = 0/1 to 1/99) to give tert-butyl (S)-((4- ((1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)(methyl)carbamoyl)cyclohexyl)methyl)carbamate [Compound 1.22] (400 mg, 653 μmol, 87.5% yield) as a yellow solid. 100 mg of the product was further purified by prep-HPLC (column: Phenomenex Gemini-NX 80*40mm*3μm, table:41-81% B (A=water (0.05% ammonia hydroxide v/v), B = acetonitrile), flow rate: 25 mL/min,UV Detector 220nm) to afford tert-butyl (S)-((4-((1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)(methyl)carbamoyl)cyclohexyl)methyl)carbamate [Compound 1.22] (52.2 mg, 85μmol) as a yellow dry powder. m/z: [M + H]+ Calcd for C33H41F3N5O3612.3; Found 612.7. ¹H NMR (400MHz, CDCl₃) į = 8.86 (br s, 2H), 8.20 (d, J=8.4 Hz, 1H), 7.39 (dd, J=4.0, 8.0 Hz, 1H), 7.22 (d, J=7.6 Hz, 2H), 7.01 (d, J=8.0 Hz, 2H), 6.56 (q, J=8.4 Hz, 1H), 6.42 (br s, 1H), 4.56 (br s, 1H), 2.98 - 2.88 (m, 2H), 2.83 (s, 3H), 2.45 (t, J=11.6 Hz, 1H), 2.06 - 1.89 (m, 2H), 1.86 - 1.71 (m, 4H), 1.58 - 1.47 (m, 2H), 1.36 (br s, 9H), 1.19 (d, J=7.6 Hz, 2H), 1.01 (d, J=4.4 Hz, 2H), 0.98 - 0.86 (m, 2H). Synthesis of (S)-N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)-N-methyl-1,4-dioxaspiro[4.5]decane-8-carboxamide (Compound 1.23)

[00155] A mixture of (S)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methyl-1,4- dioxaspiro[4.5]decane-8-carboxamide [INT 5.5] (100 mg, 229 μmol), 4-cyclopropyl-1,5- naphthyridin-3-amine [INT 1.1] (42.4 mg, 229 μmol), Xantphos (26.5 mg, 45.8 μmol), Pd₂(dba)₃ (20.9 mg, 22.9 μmol), and Cs₂CO₃ (149 mg, 458 μmol) in dioxane (5 mL) was stirred at 100 °C for 3 hr under N₂ atmosphere. The reaction was concentrated under reduced pressure to afford the crude product, which was purified by flash chromatography on silica gel (EtOAc/Petroleum ether = 1/5 to 1/3) and prep-HPLC (column: YMC Triart C18 250*50mm*7μm, table: 33-73% B (A = water (0.05% ammonia hydroxide v/v)), B = acetonitrile), flow rate: 60 mL/min, UV Detector 220nm) to afford (S)-N-(1-(4-((4-cyclopropyl- 1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyl-1,4-dioxaspiro[4.5]decane- 8-carboxamide [Compound 1.23] (47.5 mg, 87.8 μmol, 38.6% yield) as a yellow dry powder. m/z: [M+H]+ Calcd for C29H32F3N4O3541.2; Found 541.5. ¹H NMR (400MHz, CDCl₃) į = 8.95 (s, 2H), 8.33 - 8.26 (m, 1H), 7.48 (dd, J=4.0, 8.4 Hz, 1H), 7.32 (d, J=8.0 Hz, 2H), 7.11 (d, J=8.4 Hz, 2H), 6.66 (q, J=8.4 Hz, 1H), 6.43 (s, 1H), 3.97 (s, 4H), 2.93 (s, 3H), 2.66 - 2.55 (m, 1H), 2.11 - 2.03 (m, 1H), 2.03 - 1.91 (m, 2H), 1.91 - 1.84 (m, 3H), 1.83 - 1.75 (m, 1H), 1.65 - 1.59 (m, 1H), 1.57 - 1.51 (m, 1H), 1.32 - 1.25 (m, 2H), 1.11 - 1.03 (m, 2H). Synthesis of N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)ethyl)-N- methylacetamide (Compound 1.24)

[00156] To a solution of N-[1-(4-bromophenyl)ethyl]-N-methylacetamide [INT 13.2] (50 mg, 195 μmol) and 4-cyclopropyl-1,5-naphthyridin-3-amine [INT 1.1] (36.1 mg, 195 μmol) in dioxane (2 mL) was added cesium carbonate (190 mg, 585 μmol), xantphos (22.5 mg, 39.0 μmol), and Pd2(dba)3 (17.8 mg, 19.5 μmol) and the reaction mixture was stirred at 100 ºC for 2 h under N2. The mixture was concentrated in vacuo to give the crude product, which was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875*30mm*3μm, table: 24-64% B (A =water (0.05% ammonium hydroxide v/v), B = acetonitrile), flow rate: 25 mL/min, UV Detector 220nm) to afford N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)ethyl)-N- methylacetamide [Compound 1.24] (7.00 mg, 19.4 μmol, 10.0% yield) as off-white dry power. m/z: [M + H]+ Calcd for C22H25N4O 361.2; Found 361.2. ¹H NMR (400MHz, DMSO-d₆) į = 8.88 - 8.84 (m, 1H), 8.73 (s, 1H), 8.26 (dd, J=1.6, 8.4 Hz, 1H), 8.22 - 8.14 (m, 1H), 7.63 - 7.52 (m, 1H), 7.12 (dd, J=4.4, 8.0 Hz, 2H), 6.90 (dd, J=4.4, 8.4 Hz, 2H), 5.77 - 5.04 (m, 1H), 2.71 - 2.52 (m, 3H), 2.22 - 2.15 (m, 1H), 2.15 - 2.00 (m, 3H), 1.48 (d, J=7.2 Hz, 1H), 1.43 - 1.37 (m, 2H), 1.36 (d, J=7.2 Hz, 2H), 1.07 - 0.97 (m, 2H). Synthesis of N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)ethyl)-N- methylcyclobutanecarboxamide (Compound 1.25)

[00157] To a solution of N-[1-(4-bromophenyl)ethyl]-N-methylcyclobutanecarboxamide [INT 21.1] (50 mg, 168 μmol) and 4-cyclopropyl-1,5-naphthyridin-3-amine [INT 1.1] (31.1 mg, 168 μmol) in dioxane (5 mL) was added Pd₂(dba)₃ (15.3 mg, 16.8 μmol), cesium carbonate (164 mg, 504 μmol), and xantphos (19.4 mg, 33.6 μmol) and the reaction mixture was stirred at 100 ºC for 2 h under N₂. The mixture was concentrated in vacuo to give the crude product, which was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875*30mm*3μm, table: 13- 53% B (A =water(0.225%FA, B =acetonitrile), flow rate: 25 mL/min, UV Detector 220nm) to afford N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)ethyl)-N- methylcyclobutanecarboxamide [Compound 1.25] (5.90 mg, 14.7 μmol, 8.8% yield) as an orange solid. m/z: [M + H]+ Calcd for C25H29N4O 401.2; Found 401.3. ¹H NMR (400MHz, DMSO-d6) į = 8.87 (d, J=3.2 Hz, 1H), 8.74 (s, 1H), 8.34 - 8.17 (m, 2H), 7.65 - 7.53 (m, 1H), 7.13 - 7.07 (m, 2H), 6.95 - 6.89 (m, 2H), 5.80 - 4.89 (m, 1H), 2.52 (s, 3H), 2.34 - 2.20 (m, 2H), 2.13 (td, J=8.4, 17.6 Hz, 4H), 1.94 - 1.85 (m, 1H), 1.75 (br s, 1H), 1.45 (d, J=6.8 Hz, 1H), 1.36 (d, J=6.8 Hz, 4H), 1.03 (d, J=8.8 Hz, 2H). Synthesis of N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)ethyl)-N- methylcyclopentanecarboxamide (Compound 1.26) [00158] To a solution of N-[1-(4-bromophenyl)ethyl]-N-methylcyclopentanecarboxamide [INT 21.2] (40 mg, 128 μmol) and 4-cyclopropyl-1,5-naphthyridin-3-amine [INT 21.1] (23.7 mg, 128 μmol) in dioxane (1 mL) was added cesium carbonate (125 mg, 384 μmol), xantphos (14.8 mg, 25.6 μmol), and Pd2(dba)3 (11.7 mg, 12.8 μmol) and the reaction mixture was stirred at 100 ºC for 2 h under N2. The mixture was concentrated in vacuo to give the crude product, which was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875*30mm*3μm, table: 17-57% B (A = water (0.225%FA)), B = acetonitrile), flow rate: 25 mL/min, UV Detector 220 nm) to afford N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)ethyl)-N- methylcyclopentanecarboxamide [Compound 1.26] (13.8 mg, 33.2 μmol, 26.0% yield) as a yellow dry power. m/z: [M + H]+ Calcd for C26H31N4O 415.2; Found 415.4. ¹H NMR (400MHz, DMSO-d6) į = 8.89 - 8.84 (m, 1H), 8.74 (s, 1H), 8.26 (d, J=8.4 Hz, 1H), 8.24 - 8.16 (m, 1H), 7.58 (dd, J=4.0, 8.4 Hz, 1H), 7.15 - 7.05 (m, 2H), 6.95 - 6.86 (m, 2H), 5.84 - 5.19 (m, 1H), 3.18 - 2.91 (m, 1H), 2.66 (s, 3H), 2.23 - 2.13 (m, 1H), 1.87 - 1.59 (m, 6H), 1.57 - 1.46 (m, 3H), 1.43 - 1.33 (m, 4H), 1.06 - 0.98 (m, 2H). Synthesis of N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)ethyl)-N- methylcyclopropanecarboxamide (Compound 1.27)

[00159] To a mixture of N-[1-(4-bromophenyl)ethyl]-N-methylcyclopropanecarboxamide [INT 13.3] (50 mg, 177 μmol) and 4-cyclopropyl-1,5-naphthyridin-3-amine [INT 1.1] (39.2 mg, 212 μmol) in dioxane (1mL ) was added Pd2(dba)3 (16.2 mg, 17.7 μmol), cesium carbonate (173 mg, 531 μmol), and xantphos (20.4 mg, 35.4 μmol) at 25°C and the mixture was stirred at 100 °C for 12 hr under N2. The mixture was concentrated in vacuo to give the crude product, which was purified by prep-HPLC (column: YMC Triart C18250*50mm*7μm, table: 25-65% B (A =water (0.05% ammonia hydroxide v/v), B = acetonitrile), flow rate: 60 mL/min, UV Detector 220nm) to afford N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)ethyl)-N- methylcyclopropanecarboxamide [Compound 1.27] (24.7 mg, 63.9 μmol, 36.1% yield) as a yellow dry power. m/z: [M + H]+ Calcd for C24H27N4O 387.2; Found 387.3. ¹H NMR (400MHz, DMSO-d₆) į = 8.88 - 8.83 (m, 1H), 8.75 (s, 1H), 8.29 - 8.23 (m, 1H), 8.22 - 8.15 (m, 1H), 7.57 (dd, J=4.0, 8.4 Hz, 1H), 7.18 - 7.07 (m, 2H), 6.95 - 6.88 (m, 2H), 5.81 - 5.46 (m, 1H), 2.81 - 2.52 (m, 3H), 2.23 - 2.13 (m, 1H), 2.12 - 1.81 (m, 1H), 1.53 (br d, J=6.4 Hz, 1H), 1.43 - 1.33 (m, 4H), 1.05 - 0.98 (m, 2H), 0.80 - 0.70 (m, 4H). Synthesis of N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)ethyl)-N- methylcyclohexanecarboxamide (Compound 1.28)

[00160] To a solution of N-[1-(4-bromophenyl)ethyl]-N-methylcyclohexanecarboxamide [INT 21.3] (80 mg, 246 μmol), 4-cyclopropyl-1,5-naphthyridin-3-amine [INT 1.1] (45.3 mg, 245 μmol), cesium carbonate (240 mg, 738 μmol), and xantphos (28.4 mg, 49.1 μmol) in dioxane (1 mL) was added Pd2(dba)3 (22.4 mg, 24.5 μmol) and the reaction mixture was stirred at 100 ºC for 2 h under N2. The mixture was concentrated in vacuo to give the crude product, which was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875*30mm*3μm, table: 19-59% B (A = water (0.225% FA), B = acetonitrile), flow rate: 25 mL/min, UV Detector 220 nm) to afford N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)ethyl)-N- methylcyclohexanecarboxamide [Compound 1.28] (38.0 mg, 88.6 μmol, 36.1% yield) as a yellow dry power. m/z: [M + H]+ Calcd for C27H33N4O 429.3; Found 429.4. ¹H NMR (400MHz, DMSO-d6) į = 8.90 - 8.82 (m, 1H), 8.74 (s, 1H), 8.30 - 8.15 (m, 2H), 7.57 (dd, J=4.0, 8.4 Hz, 1H), 7.16 - 7.01 (m, 2H), 6.96 - 6.85 (m, 2H), 5.84 - 5.16 (m, 1H), 2.76 - 2.53 (m, 3H), 2.23 - 2.13 (m, 1H), 1.66 (d, J=13.6 Hz, 6H), 1.54 - 1.41 (m, 2H), 1.39 (td, J=2.8, 5.6 Hz, 2H), 1.37 - 1.32 (m, 3H), 1.27 (d, J=13.2 Hz, 2H), 1.16 (d, J=10.4 Hz, 1H), 1.02 (dd, J=2.4, 8.8 Hz, 2H). Synthesis of N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)- N-methylacetamide (Compound 1.29)

[00161] To a mixture of 4-cyclopropyl-1,5-naphthyridin-3-amine [INT 1.1] (100 mg, 0.5398 mmol), N-[1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methylacetamide [INT 22.1] (150 mg, 0.4836 mmol), xantphos (80 mg, 0.1382 mmol), and cesium carbonate (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 for 12 hr under N2. The reaction was diluted with EtOAc (30 mL), filtered and concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (column: Boston Prime C18150*30mm*5μm, condition: 23%-45% CH₃CN in water (0.225% FA), flow rate: 25 mL/min) to give N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)-N-methylacetamide [Compound 1.29] (39.9 mg, 0.09627 mmol, 19.9% yield) as a yellow dry powder. m/z: [M + H]+ Calcd for C22H22F3N4O 415.2; Found 415.2. ¹H NMR (400MHz, DMSO-d6) į= 8.89 (dd, J=1.6, 4.0 Hz, 1H), 8.76 (s, 1H), 8.50 - 8.39 (m, 1H), 8.30 (d, J=8.4 Hz, 1H), 7.63 (dd, J=4.0, 8.4 Hz, 1H), 7.35 - 7.17 (m, 2H), 7.00 - 6.86 (m, 2H), 6.51 - 5.85 (m, 1H), 2.90 - 2.59 (m, 3H), 2.31 - 2.09 (m, 4H), 1.51 - 1.43 (m, 2H), 1.08 - 0.97 (m, 2H). Synthesis of (S)-N-(1-(4-((4-cyclopropyl-7-methoxy-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide (Compound 1.30)

[00162] To a solution of 4-cyclopropyl-7-methoxy-1,5-naphthyridin-3-amine hydrochloride [INT 1.2] (20 mg, 79.4 μmol), (S)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N- methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide [INT 5.1] (34.0 mg, 79.4 μmol), xantphos (9.14 mg, 15.8 μmol), and cesium carbonate (77.5 mg, 238 μmol) in dioxane (5 mL) was added Pd2(dba)3 (7.27 mg, 7.94 μmol). The reaction was stirred at 100 °C for 2 h under N2. The reaction was quenched by adding water (20 mL) and was extracted with EtOAc (20 mL). The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to give the crude product, which was purified by prep-HPLC (column: Boston Prime C18150*30mm*5μm, table:40-63% B (A=water(0.05% ammonia hydroxide), B = ACN), flow rate: 25 mL/min,UV Detector 220 nm) to afford (S)-N-(1-(4-((4-cyclopropyl-7-methoxy- 1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4- carboxamide 1,1-dioxide [Compound 1.30] (2.90 mg, 5.15 μmol, 6.5% yield) as an off-white dry powder. m/z: [M + H]+ Calcd for C27H30F3N4O4S 563.2; Found 563.1. ¹H NMR (400MHz, DMSO-d₆) į = 8.71 - 8.61 (m, 2H), 8.31 - 8.20 (m, 1H), 7.70 (d, J=2.8 Hz, 1H), 7.29 - 7.12 (m, 2H), 6.88 - 6.74 (m, 2H), 6.47 - 6.03 (m, 1H), 3.95 (s, 3H), 3.21 - 3.03 (m, 5H), 2.90 (s, 3H), 2.34 - 2.26 (m, 1H), 2.09 - 1.90 (m, 4H), 1.57-1.49 (m, 2H), 1.06 - 0.96 (m, 2H). Synthesis of (S)-N-(1-(4-((4-cyclopropyl-7-methyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide (Compound 1.31)

[00163] To a solution of 4-cyclopropyl-7-methyl-1,5-naphthyridin-3-amine hydrochloride [INT 1.3] (70 mg), (S)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H- thiopyran-4-carboxamide 1,1-dioxide [INT 5.1] (126 mg, 296 μmol), xantphos (34.2 mg, 59.2 μmol), and cesium carbonate (289 mg, 887 μmol) in dioxane (5 mL) was added Pd2(dba)3 (27.1 mg, 29.6 μmol). The reaction was stirred at 100 °C for 2 h under N2, after which it was quenched by adding water (30 mL) and extracted with EtOAc (30 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product, which was purified by prep-HPLC (column: Boston Prime C18150*30mm*5μm, table: 40-63% B (A=water(0.05% ammonia hydroxide), B = ACN), flow rate: 25 mL/min, UV Detector 220 nm) to afford (S)-N-(1-(4-((4-cyclopropyl-7-methyl-1,5-naphthyridin-3- yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1- dioxide [Compound 1.31] (18.0 mg, 32.9 μmol, 11.1% yield) as an off-white dry powder. m/z: [M + H]+ Calcd for C27H30F3N4O3S 547.2; Found 547.1. ¹H NMR (400MHz, DMSO-d6) į = 8.75 (d, J=2.0 Hz, 1H), 8.68 (s, 1H), 8.41 - 8.30 (m, 1H), 8.09 (s, 1H), 7.30 - 7.13 (m, 2H), 6.94 - 6.82 (m, 2H), 6.48 - 6.07 (m, 1H), 3.23 - 3.04 (m, 5H), 2.90 (s, 3H), 2.53 (s, 3H), 2.31 - 2.21 (m, 1H), 2.08 - 1.92 (m, 4H), 1.57-1.47 (m, 2H), 1.06-0.96 (m, 2H). Synthesis of (S)-N-(1-(4-((4-cyclopropyl-6-(trifluoromethyl)-1,5-naphthyridin-3- yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1- dioxide (Compound 1.32)

[00164] A mixture of 4-cyclopropyl-6-(trifluoromethyl)-1,5-naphthyridin-3-amine hydrochloride [INT 1.4] (150 mg, 517 μmol), (S)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)- N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide [INT 5.1] (221 mg, 517 μmol), Pd₂(dba)₃ (47.3 mg, 51.7 μmol), cesium carbonate (505 mg, 1.55 mmol), and xantphos (29.9 mg, 51.7 μmol) in dioxane (2 ml) was stirred at 100 °C for 3 hr under N₂ atmosphere. 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, which was purified by prep- HPLC (column: YMC Triart C18250*50mm*7μm, table: 39-79% B (A = water (0.05% ammonia hydroxide v/v)-ACN), B = acetonitrile), flowrate: 60 mL/min, UV Detector 220 nm) to afford (S)-N-(1-(4-((4-cyclopropyl-6-(trifluoromethyl)-1,5-naphthyridin-3-yl)amino)phenyl)- 2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide [Compound 1.32] (85.8 mg, 142 μmol, 27.6% yield) as a yellow dry powder. m/z: [M+H]+ Calcd for C27H27F6N4O3S 601.2; Found 601.1. ¹H NMR (400MHz, CDCl3) į = 9.01 - 8.98 (m, 1H), 8.54 (br s, 1H), 7.88 - 7.78 (m, 1H), 7.36 (d, J=8.4 Hz, 2H), 7.14 (d, J=8.4 Hz, 2H), 6.68 - 6.57 (m, 1H), 6.50 (s, 1H), 3.55 - 3.45 (m, 1H), 3.40 - 3.31 (m, 1H), 3.05 - 2.94 (m, 6H), 2.51 - 2.35 (m, 3H), 2.33 - 2.20 (m, 1H), 2.13 - 2.03 (m, 1H), 1.40 - 1.29 (m, 4H). 79 Synthesis of (S)-N-(1-(4-((4-cyclopropyl-6-methoxy-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide (Compound 1.33)

[00165] A mixture of 4-cyclopropyl-6-methoxy-1,5-naphthyridin-3-amine hydrochloride [INT 1.5] (109 mg, 433 μmol), (S)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N- methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide [INT 5.1] (185 mg, 433 μmol), cesium carbonate (420 mg, 1.29 mmol), Pd₂(dba)₃ (39.6 mg, 43.3 μmol), and xantphos (25.0 mg, 43.3 μmol) in dioxane (2 ml) was stirred at 100 °C for 3 hr under N₂ atmosphere. Brine (30 mL) was added and the mixture was extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by prep- HPLC (column: YMC Triart C18250*50mm*7μm, table: 35-75% B (A = water (0.05% ammonia hydroxide v/v)-ACN), B = acetonitrile), flowrate: 60 mL/min, UV Detector 220 nm) to afford (S)-N-(1-(4-((4-cyclopropyl-6-methoxy-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide [Compound 1.33] (21.4 mg, 38.0 μmol, 8.8% yield) as a yellow powder. m/z: [M+H]+ Calcd for C27H30F3N4O4S 563.2; Found 563.2. ¹H NMR (400MHz, CDCl3) į = 8.69 (s, 1H), 8.24 (br s, 1H), 7.31 (d, J=8.0 Hz, 2H), 7.09 (d, J=8.4 Hz, 2H), 7.02 (d, J=9.2 Hz, 1H), 6.67 - 6.54 (m, 1H), 6.34 (br s, 1H), 4.13 - 4.08 (m, 3H), 3.55 - 3.45 (m, 1H), 3.40 - 3.30 (m, 1H), 3.07 - 2.93 (m, 6H), 2.51 - 2.23 (m, 4H), 2.05 - 1.96 (m, 1H), 1.37 (br s, 2H), 1.23 (br s, 2H). Synthesis of (S)-N-methyl-N-(2,2,2-trifluoro-1-(4-((4-isopropyl-1,5-naphthyridin-3- yl)amino)phenyl)ethyl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide (Compound 1.34)

[00166] To a solution of 4-isopropyl-1,5-naphthyridin-3-amine hydrochloride [INT 1.6] (70 mg), (S)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4- carboxamide 1,1-dioxide [INT 5.1] (53.5 mg, 125 μmol), xantphos (14.4 mg, 25.0 μmol), and cesium carbonate (122 mg, 375 μmol) in dioxane (5 mL) was added Pd2(dba)3 (11.4 mg, 12.5 μmol). The reaction was stirred at 100 °C for 2 h under N2, after which it was quenched by adding water (30 mL) and extracted with EtOAc (30 mL). The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to give the crude product, which was purified by prep-HPLC (column: Boston Prime C18150*30mm*5μm, table:45-65% B (A = water (0.05% ammonia hydroxide), B = ACN), flow rate: 25 mL/min,UV Detector 220 nm) to afford (S)-N-methyl-N-(2,2,2-trifluoro-1-(4-((4-isopropyl-1,5-naphthyridin- 3-yl)amino)phenyl)ethyl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide [Compound 1.34] (9.10 mg, 17.0 μmol, 13.6% yield) as an off-white dry powder. m/z: [M + H]+ Calcd for C26H30F3N4O3S 535.2; Found 535.3. ¹H NMR (400MHz, DMSO-d₆) į = 8.96 (d, J=2.4 Hz, 1H), 8.75 (s, 1H), 8.34 (d, J=8.4 Hz, 1H), 8.20 (s, 1H), 7.67 (dd, J=4.0, 8.4 Hz, 1H), 7.18 (d, J=8.0 Hz, 2H), 6.86 (d, J=8.4 Hz, 2H), 6.51 - 5.98 (m, 1H), 4.04 - 3.87 (m, 1H), 3.27 - 3.06 (m, 5H), 2.91 (s, 3H), 2.12 - 1.95 (m, 4H), 1.51 (d, J=7.2 Hz, 6H). Synthesis of (S)-N-methyl-N-(2,2,2-trifluoro-1-(4-((4-propyl-1,5-naphthyridin-3- yl)amino)phenyl)ethyl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide hydrochloride (Compound 1.35)

[00167] To a solution of 4-propyl-1,5-naphthyridin-3-amine hydrochloride [INT 1.7] (40 mg, 178 μmol) in dioxane (2 mL) was added (S)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N- methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide [INT 5.1] (83.5 mg, 195 μmol), xantphos (30.8 mg, 53.4 μmol), cesium carbonate (173 mg, 534 μmol), and tris(dibenzylideneacetone) dipalladium (16.2 mg, 17.8 μmol). The reaction was stirred at 100 °C for 2 h under N₂. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by prep-HPLC (column: YMC Triart C18250*50mm*7μm, table: 30- 70% B (A = water (0.05% ammonia hydroxide v/v), B = acetonitrile), flow rate: 60 81 mL/min, UV Detector 220 nm followed by column: Boston Green ODS 150*30mm*5um, table: 23-63% B (A = water (0.05% HCl), B = acetonitrile), flow rate: 30 mL/min, UV Detector 220 nm) to afford (S)-N-methyl-N-(2,2,2-trifluoro-1-(4-((4-propyl-1,5-naphthyridin-3- yl)amino)phenyl)ethyl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide hydrochloride [Compound 1.35] (31.3 mg, 54.9 μmol) as a brown solid. m/z: [M + H]+ Calcd for C26H30F3N4O3S 535.2; Found 535.1. ¹H NMR (400MHz, DMSO-d6) į = 9.13 - 8.94 (m, 2H), 8.89 - 8.52 (m, 2H), 7.91 - 7.74 (m, 1H), 7.41 - 7.25 (m, 2H), 7.25 - 7.12 (m, 2H), 6.58 - 6.13 (m, 1H), 3.41 - 3.04 (m, 7H), 3.00 - 2.65 (m, 3H), 2.19 - 1.92 (m, 4H), 1.69 - 1.52 (m, 2H), 0.97 (t, J=7.2 Hz, 3H). Synthesis of (S)-N-(1-(4-((4-cyclopropyl-6-methyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide (Compound 1.36)

[00168] To a solution of 4-cyclopropyl-6-methyl-1,5-naphthyridin-3-amine hydrochloride [INT 1.7] (70 mg, 296 μmol), (S)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N- methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide [INT 5.1] (189 mg, 443 μmol), cesium carbonate (289 mg, 887 μmol), and xantphos (34.2 mg, 59.2 μmol) in dioxane (2 mL) was added Pd₂(dba)₃ (27.1 mg, 29.6 μmol). The reaction mixture was stirred at 100 ºC for 1 h under N2. The reaction was combined with another of the same (67.8 μmol scale of INT 1.7) and was quenched by adding water (20 mL). The mixture was then extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to give the crude product, which was purified by flash chromatography on silica gel (PE/EtOAc = 1/0 to 1/2) to give the product, which was further purified by prep-HPLC (column: Diamonsil C18150*30mm*5μm, condition: 36%-76% CH₃CN in water (0.05% ammonia hydroxidev/v)-ACN,flowrate:50 mL/min) to give (S)-N-(1-(4-((4-cyclopropyl-6-methyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide [Compound 1.36] (15.4 mg, 28.1 μmol, 7.7% yield) as a yellow dry powder. m/z: [M + H]+ Calcd for C27H30F3N4O3S 547.2; Found 547.2. ¹H NMR (400MHz, DMSO-d6) į = 8.65 (s, 1H), 8.43 - 8.32 (m, 1H), 8.16 (d, J=8.4 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.30 - 7.15 (m, 2H), 6.95 - 6.78 (m, 2H), 6.53 - 6.01 (m, 1H), 3.26 - 3.07 (m, 5H), 2.90 (s, 2H), 2.65 (s, 4H), 2.32 - 2.20 (m, 1H), 2.13 - 1.94 (m, 4H), 1.62 - 1.56 (m, 2H), 1.03 - 0.96 (m, 2H). Synthesis of N-((1S)-1-(4-((4-(1-ethoxyethyl)-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide (Compound 1.37)

[00169] To a mixture of 4-(1-ethoxyethyl)-1,5-naphthyridin-3-amine hydrochloride [INT 1.7] (15 mg, 59.1 μmol) and (S)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H- thiopyran-4-carboxamide 1,1-dioxide [INT 5.1] (30.3 mg, 70.9 μmol) in dioxane (1 mL) was added cesium carbonate (76.8 mg, 236 μmol), xantphos (3.41 mg, 5.91 μmol), and Pd2(dba)3 (5.41 mg, 5.91 μmol). The reaction mixture was stirred at 100 °C for 3 hours, after which it was concentrated to give crude product, which was purified by prep-HPLC (column: Phenomenex Gemini-NX 150*30mm*5μm, table: 38-78% B (A = water (0.225% FA), B = acetonitrile), flowrate: 25 mL/min, UV Detector 220 nm) to give N-((1S)-1-(4-((4-(1-ethoxyethyl)-1,5- naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4- carboxamide 1,1-dioxide [Compound 1.37] (2.10 mg, 3.71 μmol, 6.3% yield) as a yellow dry powder. m/z: [M + H]+ Calcd for C27H32F3N4O4S 565.2; Found 565.3. ¹H NMR (400MHz, CDCl₃) į = 9.07 (d, J=4.0 Hz, 1H), 8.88 (dd, J=1.6, 4.0 Hz, 1H), 8.40 - 8.26 (m, 2H), 7.48 (dd, J=4.0, 8.4 Hz, 1H), 7.32 (d, J=8.0 Hz, 2H), 7.17 (d, J=8.4 Hz, 2H), 6.66 - 6.56 (m, 1H), 6.19 (q, J=6.8 Hz, 1H), 3.70 - 3.59 (m, 1H), 3.57 - 3.47 (m, 2H), 3.42 - 3.31 (m, 1H), 3.06 - 2.91 (m, 6H), 2.47 - 2.24 (m, 4H), 1.60 - 1.58 (m, 3H), 1.32 - 1.27 (m, 3H).

Synthesis of ( -N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-

trifluoroethyl)-N-methyl-4-(2-methyl-2H-tetrazol-5-yl)cyclohexane-1-carboxamide (Compound 1.38)

[00170] To a solution of (1r,4S)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methyl-4- (2-methyl-2H-tetrazol-5-yl)cyclohexane-1-carboxamide [INT 5.9] (218 mg, 474 μmol) in dioxane (5 mL) was added 4-cyclopropyl-1,5-naphthyridin-3-amine [INT 1.1] (80 mg, 431 μmol), xantphos (74.6 mg, 129 μmol), tris(dibenzylideneacetone) dipalladium (39.4 mg, 43.1 μmol), and cesium carbonate (420 mg, 1.29 mmol). The reaction was stirred at 100 °C for 2 h under N₂. The mixture was concentrated under reduced pressure to give the crude product, which was purified by flash chromatography on silica gel (EtOAc/PE = 0/1 to 1/1) followed by prep-HPLC (column : YMC-Actus Triart C18150*30mm*5μm, table: 56 - 76% B (A = water (ammonia hydroxide v/v), B = acetonitrile), flow rate: 35 mL/min, UV Detector 220 nm) to afford (1r,4S)-N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)-N-methyl-4-(2-methyl-2H-tetrazol-5-yl)cyclohexane-1-carboxamide [Compound 1.38] (102 mg, 181 μmol, 41.9% yield) as a yellow solid. m/z: [M + H]+ Calcd for C29H32F3N8O 565.3; Found 565.4. ¹H NMR (400MHz, DMSO-d6) į = 8.91 - 8.85 (m, 1H), 8.76 (s, 1H), 8.46 - 8.40 (m, 1H), 8.32 - 8.27 (m, 1H), 7.65 - 7.59 (m, 1H), 7.29 - 7.16 (m, 2H), 6.99 - 6.89 (m, 2H), 6.54 - 6.16 (m, 1H), 4.30 (s, 3H), 2.91 (s, 4H), 2.85 - 2.72 (m, 1H), 2.30 - 2.19 (m, 1H), 2.14 - 1.96 (m, 2H), 1.93 - 1.77 (m, 2H), 1.70 - 1.52 (m, 4H), 1.50 - 1.43 (m, 2H), 1.07 - 0.98 (m, 2H).

Synthesis of (1r,4S)-N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)-N-methyl-4-(1-methyl-1H-tetrazol-5-yl)cyclohexane-1-carboxamide (Compound 1.39)

[00171] To a solution of (1r,4S)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methyl-4- (1-methyl-1H-tetrazol-5-yl)cyclohexane-1-carboxamide [INT 5.10] (170 mg, 221 μmol) in dioxane (5 mL) was added 4-cyclopropyl-1,5-naphthyridin-3-amine [INT 1.1] (45.0 mg, 243 μmol), xantphos (38.3 mg, 66.2 μmol), tris(dibenzylideneacetone) dipalladium (20.1 mg, 22.0 μmol), and cesium carbonate (216 mg, 663 μmol). The reaction was stirred at 100 °C for 2 h under N₂. The mixture was concentrated under reduced pressure to give the crude product, which was purified by flash chromatography on silica gel (MeOH/DCM = 0/1 to 1/20) and prep- HPLC (column : YMC-Actus Triart C18150*30mm*5μm, table: 45 - 65% B (A = water (ammonia hydroxide v/v), B = acetonitrile), flow rate: 35 mL/min, UV Detector 220 nm) to afford (1r,4S)-N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)-N-methyl-4-(1-methyl-1H-tetrazol-5-yl)cyclohexane-1-carboxamide [Compound 1.39] (8.80 mg, 15.5 μmol, 7.1% yield) as a yellow solid. m/z: [M + H]+ Calcd for C29H32F3N8O 565.3; Found 565.4. ¹H NMR (400MHz, DMSO-d6) į = 8.92 - 8.85 (m, 1H), 8.76 (s, 1H), 8.47 - 8.39 (m, 1H), 8.30 (dd, J=1.6, 8.4 Hz, 1H), 7.66 - 7.58 (m, 1H), 7.31 - 7.16 (m, 2H), 7.01 - 6.87 (m, 2H), 6.53 - 6.17 (m, 1H), 4.03 (s, 3H), 3.13 - 3.00 (m, 1H), 2.95 - 2.63 (m, 4H), 2.30 - 2.20 (m, 1H), 2.03 - 1.78 (m, 4H), 1.73 - 1.52 (m, 4H), 1.50 - 1.40 (m, 2H), 1.09 - 0.97 (m, 2H).

Synthesis of (S)-N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)-N-methyl-1-(3-methyl-1,2,4-oxadiazol-5-yl)azetidine-3-carboxamide (Compound 1.40)

[00172] (S)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methyl-1-(3-methyl-1,2,4- oxadiazol-5-yl)azetidine-3-carboxamide [INT 27.1] (0.027 g, 0.06232 mmol), 4-cyclopropyl- 1,5-naphthyridin-3-amine [INT 1.1] (11.5 mg, 62.3 μmol), sodium tert-butoxide (17.8 mg, 186 μmol) and tri-tert-butylphosphane (2.52 mg, 6.23 μmol) were mixed in toluene (3 mL) and the reaction mixture was degassed with argon for 5 min. Tris(dibenzylideneacetone) dipalladium (2.84 mg, 3.11 μmol) was added. Then the reaction mixture was degassed with argon for 5 min and stirred at 80 °C for 10 h. The reaction mixture was then cooled to rt and the solid was filtered off. The filtrate was purified by HPLC (see conditions below) to obtain (S)-N-(1-(4-((4- cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyl-1-(3-methyl- 1,2,4-oxadiazol-5-yl)azetidine-3-carboxamide [Compound 1.40] (5.70 mg, 0.01060 mmol, 17.0% yield) as a yellow solid. m/z: [M + H]+ Calcd for C27H27F3N7O2538.2; Found 538.2 ¹H NMR (400 MHz, CD₃OD) į = 8.94 - 8.87 (m, 1H), 8.80 (s, 1H), 8.31 (dd, J=8.5, 1.7 Hz, 1H), 7.62 (dd, J=8.4, 4.2 Hz, 1H), 7.33 (d, J=8.2 Hz, 2H), 7.10 - 7.01 (m, 2H), 6.53 (q, J=9.0 Hz, 1H), 4.54 - 4.44 (m, 1H), 4.47 - 4.34 (m, 3H), 4.11 (tt, J=8.5, 6.0 Hz, 1H), 3.36 (s, 1H), 2.88 - 2.64 (m, 3H), 2.19 (s, 3H), 2.25 - 2.10 (m, 1H), 1.19 - 1.10 (m, 4H). [00173] HPLC conditions: System - Agilent 1260 Infinity II LC coupled to an Agilent 6120B Single Quadrupole LC/MS System. Column - Description: XBridge BEH 5 ^m C18(2) 130 Å, LC Column 100 x 20 mm, YMC-Actus Triart. Stationary Phase: C18 with ethylene endcapping. Solid Support: Fully Porous Silica. Separation Mode: Reversed Phase. Mobile Phase - Mobile phase A: water. Mobile phase B: acetonitrile+0.1% NH₃ (20% water solution NH₃). Flow rate: 30 ml/min; loading pump 4ml/min B. Gradient conditions: 10-30-45-100% (B) 0-2-10-11.2 min. 86 2. Compounds Prepared using Scheme 2 Scheme 2:

[00174] Starting material G-2a is treated with an acid (e.g., HCl) to provide a compound of formula (I), where R^G2a is either Boc or HBoc, R^G2b is H, and n = 1 or 2. Synthesis of N-[(1S)-1-{4-[(4-cyclopropyl-1,5-naphthyridin-3-yl)amino]phenyl}-2,2,2- trifluoroethyl]-N-methylpyrrolidine-3-carboxamide (also known as N-((S)-1-(4-((4-cyclopropyl- 1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylpyrrolidine-3-carboxamide) (Co

[00175] A solution of tert-butyl 3-(((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3- yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)pyrrolidine-1-carboxylate [Compound 1.3] (80mg, 140 μmol) in 4M HCl·dioxane (10 mL) was stirred at 25 °C for 5 hours. The reaction was concentrated under reduced pressure to give the crude product, which was purified by prep-HPLC (column: Phenomenex Gemini-NX 150*30mm*5μm, condition: 40%-60% CH₃CN in water (0.05% ammonia hydroxide v/v)-ACN, flowrate: 35mL/min) to give N-[(1S)-1-{4-[(4-cyclopropyl-1,5-naphthyridin-3-yl)amino]phenyl}-2,2,2-trifluoroethyl]-N- methylpyrrolidine-3-carboxamide [Compound 2.1] (8.10 mg, 17.2 μmol) as a dry powder. m/z: [M + H]+ Calcd for C25H27F3N5O 470.2; Found 470.3. ¹H NMR (400MHz, DMSO-d₆) į = 8.88 (dd, J=1.6, 4.0 Hz, 1H), 8.75 (s, 1H), 8.43 (s, 1H), 8.29 (dd, J=1.6, 8.4 Hz, 1H), 7.62 (dd, J=4.0, 8.4 Hz, 1H), 7.32-7.14 (m, 2H), 7.00-6.87 (m, 2H), 6.54-5.94 (m, 1H), 3.24 (br d, J=8.0 Hz, 2H), 3.11-2.97 (m, 1H), 2.87 (s, 3H), 2.81 (br d, J=6.8 Hz, 2H), 2.66 (br s, 1H), 2.24 (tt, J=5.6, 8.8 Hz, 1H), 2.05-1.84 (m, 1H), 1.83-1.68 (m, 1H), 1.52-1.39 (m, 2H), 1.10-0.95 (m, 2H). Synthesis of (S)-N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)-N-methylpiperidine-4-carboxamide hydrochloride (Compound 2.2)

[00176] A solution of tert-butyl (S)-4-((1-(4-((4-cyclopropyl-1,5-naphthyridin-3- yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)piperidine-1-carboxylate [Compound 1.4] (50 mg, 85.6 μmol) in 4 M HCl in dioxane (5 mL) was stirred at 25 °C for 5 h. The reaction was concentrated under reduced pressure to give the crude product, which was purified by prep- HPLC (column: YMC Triart 30*150mm*7μm, table: 7-47% B (A = water (0.05% HCl)-ACN), B = acetonitrile), flowrate: 30 mL/min, UV Detector 220 nm) to give (S)-N-(1-(4-((4- cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylpiperidine-4- carboxamide hydrochloride [Compound 2.2] (34.0 mg, 65.3 μmol, 76.4% yield) as a brown dry powder. m/z: [M + H]+ Calcd for C26H29F3N5O 484.2; Found 484.3. ¹H NMR (400MHz, DMSO-d6) į = 8.99 - 8.81 (m, 3H), 8.66 - 8.44 (m, 2H), 7.74 (br s, 1H), 7.34 - 7.20 (m, 2H), 7.04 (br s, 2H), 6.61 - 6.09 (m, 1H), 3.29 (br d, J=12.0 Hz, 1H), 3.13 - 2.93 (m, 3H), 2.91 (s, 3H), 2.67 - 2.64 (m, 1H), 2.17 (br s, 1H), 1.93 - 1.70 (m, 4H), 1.28 (br s, 2H), 1.07 (br d, J=7.6 Hz, 2H). Synthesis of N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)-N-methylpiperidine-3-carboxamide (Compound 2.3)

[00177] Tert-butyl 3-(((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)(methyl)carbamoyl)piperidine-1-carboxylate [Compound 1.5] (300mg, 514 μmol) in 4M HCI/dioxane (8 mL) was stirred at 20 °C for 16 hr. The reaction mixture was concentrated under pressure to give N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3- yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylpiperidine-3-carboxamide [Compound 2.3] (200 mg, 413 μmol, 80.4% yield) as a brown solid. 80 mg of this crude product was purified by prep-HPLC (column: Boston Prime C18150*30mm*5μm, table: 33-63% B (A = water (0.05% ammonia hydroxide )), B = acetonitrile), flow rate: 25 mL/min UV Detector 220 nm) to afford N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N- methylpiperidine-3-carboxamide (9.70 mg, 20.0 μmol) as a yellow dry powder. m/z: [M + H]+ Calcd for C26H29F3N5O 484.2; Found 484.3.

(400MHz, DMSO-d6) į = 8.87 (dd, J=1.6, 4.0 Hz, 1H), 8.74 (s, 1H), 8.45-8.38 (m, 1H), 8.28 (dd, J=1.6, 8.4 Hz, 1H), 7.61 (dd, J=4.0, 8.4 Hz, 1H), 7.27-7.13 (m, 2H), 7.00-6.86 (m, 2H), 6.50-6.01 (m, 1H), 2.94 (br d, J=12.4 Hz, 1H), 2.87 (s, 3H), 2.73 (br t, J=10.8 Hz, 1H), 2.68-2.58 (m, 1H), 2.47-2.30 (m, 2H), 2.24 (tt, J=5.6, 8.8 Hz, 1H), 1.75 (br d, J=13.6 Hz, 1H), 1.53 (br t, J=10.8 Hz, 2H), 1.46 (qd, J=3.2, 5.6 Hz, 2H), 1.37 (br t, J=12.0 Hz, 1H), 1.06-0.95 (m, 2H). 3. Compounds Prepared using Scheme 3 Scheme 3:

[00178] Starting material G-3a is treated with R^G3-containing carboxylic acid G-3b to provide a compound of Formula (I), where R^G3 is either cyclopropyl or methyl. Synthesis of 1-acetyl-N-[(1S)-1-{4-[(4-cyclopropyl-1,5-naphthyridin-3- yl)amino]phenyl}-2,2,2- trifluoroethyl]-N-methylpyrrolidine-3-carboxamide (also known as 1-acetyl-N-((S)-1-(4-((4- cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylpyrrolidine-3- carboxamide) (Compound 3.1)

[00179] To a mixture of acetic acid (9.12 mg, 152 μmol), EDCI (36.4 mg, 190 μmol), HOBT (25.6 mg, 190 μmol) in CH₂Cl₂ (3 mL ) was added N-((S)-1-(4-((4-cyclopropyl-1,5- naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylpyrrolidine-3-carboxamide [Compound 2.1] (60mg, 127 μmol) and the mixture was stirred at 25 °C for 2 hours. LCMS showed the reaction was complete and desired MS was observed. The reaction was concentrated under reduced pressure to give the crude product, which was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875*30mm*3μm, condition: 22%-72% CH3CN in water (0.04%NH3H2O+10mM NH4HCO3)-ACN, flowrate: 25mL/min) to give 1-acetyl-N-[(1S)-1-{4- [(4-cyclopropyl-1,5-naphthyridin-3- yl)amino]phenyl}-2,2,2-trifluoroethyl]-N- methylpyrrolidine-3-carboxamide [Compound 3.1] (14.7 mg, 28.7 μmol) as a dry powder. m/z: [M + H]+ Calcd for C27H29F3N5O2512.2; Found 512.1. ¹H NMR (400MHz, DMSO-d6) į = 8.89 (dd, J=1.6, 4.0 Hz, 1H), 8.76 (s, 1H), 8.50-8.41 (m, 1H), 8.31 (dd, J=1.6, 8.4 Hz, 1H), 7.63 (dd, J=4.0, 8.4 Hz, 1H), 7.33-7.16 (m, 2H), 7.00-6.86 (m, 2H), 6.54-6.10 (m, 1H), 3.71-3.36 (m, 5H), 2.94-2.68 (m, 3H), 2.30-2.24 (m, 1H), 2.22-1.80 (m, 5H), 1.53-1.44 (m, 2H), 1.03 (qd, J=3.2, 8.8 Hz, 2H). Synthesis of 1-(cyclopropanecarbonyl)-N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3- yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylpyrrolidine-3-carboxamide hydrochloride (Compound 3.2)

[00180] To a mixture of cyclopropanecarboxylic acid (16.3 mg, 190 μmol), EDCI (36.4 mg, 190 μmol), and HOBT (25.6 mg, 190 μmol) in CH2Cl2 (3 mL) was added N-((S)-1-(4-((4- cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylpyrrolidine-3- carboxamide [Compound 2.1] (60mg, 127 μmol) and the mixture was stirred at 25 °C for 2 hr. The reaction was concentrated under reduced pressure to give the crude product, which was purified by prep-HPLC (column: Phenomenex Gemini-NX C1880*30mm*5μm, condition: 20%-50% CH3CN in water (0.05% HCl)- ACN,flowrate:25 mL/min) to give 1- (cyclopropanecarbonyl)-N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)- 2,2,2-trifluoroethyl)-N-methylpyrrolidine-3-carboxamide hydrochloride [Compound 3.2] (10.6 mg, 18.4 μmol, 14.5% yield) as an orange dry powder. m/z: [M + H]+ Calcd for C29H31F3N5O2538.2; Found 538.1. ¹H NMR (400MHz, DMSO-d6) į = 8.96 (br s, 1H), 8.87 (br s, 1H), 8.75 (br s, 1H), 8.52 (br s, 1H), 7.75 (br s, 1H), 7.38 - 7.21 (m, 2H), 7.06 (br s, 2H), 6.56 - 6.18 (m, 1H), 3.63 - 3.22 (m, 5H), 2.99 - 2.69 (m, 3H), 2.18 - 2.08 (m, 2H), 1.97 - 1.66 (m, 2H), 1.23 (br s, 2H), 1.07 (br s, 2H), 0.72 (br d, J=5.4 Hz, 4H). Synthesis of (S)-1-(cyclopropanecarbonyl)-N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3- yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylpiperidine-4-carboxamide hydrochloride (Compound 3.3)

[00181] To a mixture of (S)-N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)- 2,2,2-trifluoroethyl)-N-methylpiperidine-4-carboxamide hydrochloride [Compound 2.2] (150 mg, 310 μmol), (3-{[(ethylimino)methylidene]amino}propyl)dimethylamine hydrochloride (118 mg, 620 μmol), and hydroxybenzotriazole (41.8 mg, 310 μmol) in DCM (5 mL) was added cyclopropanecarboxylic acid (80.0 mg, 930 μmol) and the mixture was stirred at 25 °C for 12 hr. The crude product was purified by prep-HPLC (column: YMC Triart 30*150mm*7μm, table: 22-62% B (A = water (0.05% HCl)-ACN), B = acetonitrile), flowrate: 30 mL/min, UV Detector 220 nm) to afford (S)-1-(cyclopropanecarbonyl)-N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3- yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylpiperidine-4-carboxamide hydrochloride [Compound 3.3] (33.2 mg, 56.4 μmol, 18.2% yield). m/z: [M + H]+ Calcd for C30H33F3N5O2 552.2; Found 552.0. ¹H NMR (400MHz, DMSO-d6) į = 9.06 - 8.85 (m, 3H), 8.62 (br s, 1H), 7.91 - 7.72 (m, 1H), 7.39 - 7.22 (m, 2H), 7.17 - 7.05 (m, 2H), 6.50 (q, J=9.6 Hz, 1H), 4.40 - 4.23 (m, 2H), 3.23 - 3.12 (m, 2H), 3.08 - 3.00 (m, 1H), 2.93 (s, 3H), 2.65 (br s, 1H), 2.15 - 2.04 (m, 1H), 2.02 - 1.92 (m, 1H), 1.88 - 1.65 (m, 2H), 1.63 - 1.31 (m, 2H), 1.22 - 1.02 (m, 4H), 0.76 - 0.63 (m, 4H). Synthesis of 1-(cyclopropanecarbonyl)-N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3- yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylpiperidine-3-carboxamide (Compound 3.4)

[00182] To a mixture of cyclopropanecarboxylic acid (16.0 mg, 186 μmol), EDCI (35.6 mg, 186 μmol), and HOBT (25.1 mg, 186 μmol) in CH2Cl2 (3 mL) was added N-((S)-1-(4-((4- cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylpiperidine-3- carboxamide [Compound 2.3] (60mg, 124 μmol) and the mixture was stirred at 25 °C for 16 hr. The reaction was concentrated under reduced pressure to give the crude product, which was purified by prep-HPLC (column: YMC Triart C18250*50mm*7μm, table: 33-73% B (A = water (0.05% ammonia hydroxide v/v)), B = acetonitrile), flow rate: 60 mL/min, UV Detector 220 nm) to afford 1-(cyclopropanecarbonyl)-N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3- yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylpiperidine-3-carboxamide [Compound 3.4] (5.90 mg, 10.6 μmol, 8.6% yield) as a yellow solid. m/z: [M + H]+ Calcd for C30H33F3N5O2S 552.2; Found 552.4. ¹H NMR (400MHz, DMSO-d6) į = 8.88 (dd, J=1.6, 4.0 Hz, 1H), 8.75 (s, 1H), 8.44 (s, 1H), 8.30 (dd, J=1.6, 8.4 Hz, 1H), 7.63 (dd, J=4.0, 8.4 Hz, 1H), 7.29 - 7.15 (m, 2H), 6.92 (br d, J=8.4 Hz, 2H), 6.43 (br d, J=9.6 Hz, 1H), 4.40 - 4.20 (m, 2H), 3.08 (br s, 1H), 2.90 (br d, J=10.8 Hz, 3H), 2.74 - 2.57 (m, 1H), 2.36 - 2.19 (m, 2H), 1.99 (br s, 1H), 1.89 - 1.69 (m, 2H), 1.63 (br s, 1H), 1.47 (qd, J=3.2, 5.6 Hz, 2H), 1.23 (br s, 1H), 1.07 - 0.98 (m, 2H), 0.77 - 0.60 (m, 4H). 4. Compounds Prepared using Scheme 4 Scheme 4:

[00183] Starting material G-4a is treated with R^G4b-containing G-4b to provide a compound of Formula (I). R^G4a is either NH or NH₂, X is CO or SO₂, R^G4b is CH₃, iPr, OMe, or NHMe, and R^G4c is either N or NH. Synthesis of 1-acetyl-N-[(1S)-1-{4-[(4-cyclopropyl-1,5-naphthyridin-3-yl)amino]phenyl}-2,2,2- trifluoroethyl]-N- methylpiperidine-4-carboxamide hydrochloride (also known as (S)-1-acetyl- N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N- methylpiperidine-4-carboxamide hydrochloride) (Compound 4.1)

[00184] To a mixture of (S)-N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)- 2,2,2-trifluoroethyl)-N-methylpiperidine-4-carboxamide [Compound 2.2] (80 mg, 165 μmol) and acetyl chloride (45.2 mg, 577 μmol) in DCM (2 mL) was added triethylamine (83.4 mg, 825 μmol) at 25 °C and the mixture was stirred at 25 °C for 12 hours. The crude product was purified by prep-HPLC (column: YMC Triart 30*150mm*7μm, table: 17-57% B (A = water (0.05% HCl)-ACN), B = acetonitrile), flow rate: 30 mL/min, UV Detector 220 nm) to afford 1- acetyl-N-[(1S)-1-{4-[(4-cyclopropyl-1,5-naphthyridin-3-yl)amino]phenyl}-2,2,2-trifluoroethyl]- N- methylpiperidine-4-carboxamide hydrochloride [Compound 4.1] (10.4 mg, 18.5 μmol) as a dry product. m/z: [M + H]+ Calcd for C28H31F3N5O2526.2; 527.2; Found 526.4. ¹H NMR (400MHz, DMSO-d6) į = 9.14 - 9.00 (m, 2H), 8.96 (s, 1H), 8.71 (br d, J=8.0 Hz, 1H), 7.85 (dd, J=4.8, 8.0 Hz, 1H), 7.38 - 7.25 (m, 2H), 7.21 - 7.12 (m, 2H), 6.51 (q, J=9.6*3 Hz, 1H), 4.37 (br d, J=12.8 Hz, 1H), 3.83 (br d, J=10.8 Hz, 1H), 3.13 - 3.00 (m, 2H), 2.93 (s, 3H), 2.68 - 2.62 (m, 1H), 2.06 (br d, J=6.4 Hz, 1H), 2.00 (s, 3H), 1.81 - 1.62 (m, 2H), 1.59 - 1.47 (m, 1H), 1.45 - 1.28 (m, 1H), 1.18 - 0.97 (m, 4H). Synthesis of N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)-N-methyl-1-(methylsulfonyl)pyrrolidine-3-carboxamide (Compound 4.2)

[00185] To a solution of N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)- 2,2,2-trifluoroethyl)-N-methylpyrrolidine-3-carboxamide [Compound 2.1] (50 mg, 106 μmol) and DIPEA (41.1 mg, 318 μmol) in DCM (2 mL) was added methanesulfonyl chloride (120 mg, 1.04 mmol) at 0 °C and the reaction mixture was stirred at 20 ºC for 1h. The reaction was concentrated under reduced pressure to give the crude product, which was purified by prep- HPLC (column: Phenomenex Gemini-NX C1875*30mm*3μm, condition: 23%-63% CH3CN in water (0.04%NH₃H₂O + 10 mM NH₄HCO₃)-ACN,flowrate:25 mL/min) to give N-((S)-1-(4-((4- cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyl-1- (methylsulfonyl)pyrrolidine-3-carboxamide [Compound 4.2] (19.7 mg, 35.9 μmol, 33.9% yield) as a yellow dry powder. m/z: [M + H]+ Calcd for C26H29F3N5O3S 548.2; Found 548.2. ¹H NMR (400MHz, DMSO-d6) į = 8.89 (dd, J=1.6, 4.0 Hz, 1H), 8.76 (s, 1H), 8.48 - 8.41 (m, 1H), 8.30 (dd, J=1.6, 8.4 Hz, 1H), 7.63 (dd, J=4.0, 8.4 Hz, 1H), 7.30 - 7.17 (m, 2H), 6.99 - 6.89 (m, 2H), 6.53 - 6.10 (m, 1H), 3.62 - 3.53 (m, 1H), 3.51 - 3.34 (m, 2H), 3.31 - 3.21 (m, 2H), 2.94 - 2.68 (m, 6H), 2.29 - 1.87 (m, 3H), 1.48 (td, J=2.4, 5.6 Hz, 2H), 1.03 (qd, J=3.2, 8.8 Hz, 2H). Synthesis of (S)-N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)-1-(isopropylsulfonyl)-N-methylpiperidine-4-carboxamide hydrochloride (Compound 4.3)

[00186] To a mixture of (S)-N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)- 2,2,2-trifluoroethyl)-N-methylpiperidine-4-carboxamide [Compound 2.2] (150 mg, 310 μmol) and triethylamine (125 mg, 1.24 mmol) in DCM (5 mL) was added propane-2-sulfonyl chloride (88.4 mg, 620 μmol) at 25 °C and the mixture was stirred at 25 °C for 12 hr. The crude product was purified by prep-HPLC (column: YMC Triart 30*150mm*7μm, table: 25-65% B (A = water(0.05% HCl)-ACN), B = acetonitrile), flowrate: 30 mL/min, UV Detector 220 nm) to afford (S)-N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-1- (isopropylsulfonyl)-N-methylpiperidine-4-carboxamide hydrochloride [Compound 4.3] (8.90 mg, 14.2 μmol, 4.6% yield) as a brown dry product. m/z: [M + H]+ Calcd for C29H35F3N5O3S 590.2; Found 590.5. ¹H NMR (400MHz, DMSO-d6) į = 8.97 (dd, J=1.6, 4.4 Hz, 1H), 8.94 - 8.69 (m, 2H), 8.55 (br s, 1H), 7.86 - 7.67 (m, 1H), 7.34 - 7.22 (m, 2H), 7.07 (br d, J=8.0 Hz, 2H), 6.49 (q, J=9.6 Hz, 1H), 3.66 (br d, J=9.6 Hz, 1H), 3.36 - 3.34 (m, 2H), 3.06 - 2.93 (m, 3H), 2.91 (s, 3H), 2.65 (s, 1H), 2.12 (br s, 1H), 1.85 - 1.69 (m, 2H), 1.62 - 1.48 (m, 2H), 1.21 (d, J=6.8 Hz, 8H), 1.11 - 1.03 (m, 2H). Synthesis of methyl (S)-4-((1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)(methyl)carbamoyl)piperidine-1-carboxylate (Compound 4.4)

[00187] To a mixture of (S)-N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)- 2,2,2-trifluoroethyl)-N-methylpiperidine-4-carboxamide [Compound 2.2] (80 mg, 165 μmol) and triethylamine (66.7 mg, 660 μmol) in DMF (1.5 mL ) was added methyl carbonochloridate (50 mg, 529 μmol) and the mixture was stirred at 25 °C for 12 hr. The crude product was purified by Prep-HPLC (column: Boston Prime C18150*30mm*5μm, table: 44-67% B (A = water (0.05% ammonia hydroxide v/v)-ACN), B = acetonitrile), flowrate: 25 mL/min, UV Detector 220 nm) to afford methyl (S)-4-((1-(4-((4-cyclopropyl-1,5-naphthyridin-3- yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)piperidine-1-carboxylate [Compound 4.4] (15.6 mg, 28.8 μmol, 17.4% yield) as a yellow dry powder. m/z: [M + H]+ Calcd for C28H31F3N5O3542.2; Found 542.4. ¹H NMR (400MHz, DMSO-d6) į = 8.88 (dd, J=1.6, 4.0 Hz, 1H), 8.75 (s, 1H), 8.52 - 8.38 (m, 1H), 8.29 (dd, J=1.6, 8.4 Hz, 1H), 7.62 (dd, J=4.0, 8.4 Hz, 1H), 7.29 - 7.14 (m, 2H), 7.03 - 6.78 (m, 2H), 6.44 (q, J=9.2 Hz, 1H), 3.98 (br s, 2H), 3.58 (s, 3H), 3.06 - 2.63 (m, 6H), 2.29 - 2.19 (m, 1H), 1.77 - 1.57 (m, 2H), 1.55 - 1.35 (m, 4H), 1.08 - 0.96 (m, 2H). Synthesis of N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)-N-methyl-1-(methylsulfonyl)piperidine-3-carboxamide (Compound 4.5)

[00188] To a mixture of N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)- 2,2,2-trifluoroethyl)-N-methylpiperidine-3-carboxamide [Compound 2.3] (100 mg, 206 μmol) in CH₂Cl₂ (3 mL) was added triethylamine (83.3 mg, 824 μmol), after which methanesulfonyl chloride (10 mg, 87.3 μmol) was added at 0 °C. The mixture was stirred at 25 °C for 16 hr. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by prep-HPLC (column: YMC Triart C18250*50mm*7μm, table: 17-57% B (A = water (0.05% ammonia hydroxide )), B = acetonitrile), flow rate: 60 mL/min, UV Detector 220 nm) to give N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)-N-methyl-1-(methylsulfonyl)piperidine-3-carboxamide [Compound 4.5] (28.2 mg, 50.2 μmol, 24.5% yield) as a yellow solid. m/z: [M + H]+ Calcd for C27H31F3N5O3S 562.2; Found 562.2. ¹H NMR (400MHz, DMSO-d6) į = 8.89 (dd, J=1.6, 4.4 Hz, 1H), 8.76 (s, 1H), 8.44 (s, 1H), 8.30 (dd, J=1.6, 8.4 Hz, 1H), 7.63 (dd, J=4.0, 8.4 Hz, 1H), 7.30 - 7.16 (m, 2H), 6.93 (d, J=8.8 Hz, 2H), 6.50 - 6.38 (m, 1H), 3.65 - 3.52 (m, 2H), 2.94 - 2.88 (m, 6H), 2.87 - 2.80 (m, 1H), 2.76 - 2.57 (m, 2H), 2.29 - 2.22 (m, 1H), 1.97 - 1.71 (m, 2H), 1.64 - 1.54 (m, 1H), 1.51 - 1.46 (m, 2H), 1.45 - 1.35 (m, 1H), 1.09 - 0.97 (m, 2H). Synthesis of (S)-N3-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)-N1,N3-dimethylpiperidine-1,3-dicarboxamide (Compound 4.6) and (R)-N3-((S)- 1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N1,N3- dimethylpiperidine-1,3-dicarboxamide (Compound 4.7)

[00189] To a mixture of N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)- 2,2,2-trifluoroethyl)-N-methylpiperidine-3-carboxamide [Compound 2.3] (100mg, 206 μmol) in CH2Cl2 (3 mL) was added triethylamine (83.3 mg, 824 μmol), followed by the addition of N- methylcarbamoyl chloride (19.2 mg, 206 μmol) at 0 °C. The mixture was stirred at 25 °C for 16 hr. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by prep-HPLC (column: Phenomenex Gemini-NX 80*40mm*3μm, table: 22-62% B (A = water (0.05% ammonia hydroxide )), B = acetonitrile), flow rate: 25 mL/min, UV Detector 220 nm) to give (S)-N3-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3- yl)amino)phenyl)-2,2,2-trifluoroethyl)-N1,N3-dimethylpiperidine-1,3-dicarboxamide [Compound 4.6] (6.10 mg, 11.2 μmol, 5.5% yield) and (R)-N3-((S)-1-(4-((4-cyclopropyl-1,5- naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N1,N3-dimethylpiperidine-1,3- dicarboxamide [Compound 4.7] (7.40 mg, 13.6 μmol, 6.7% yield) as yellow solids. [00190] (S)-N3-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)-N1,N3-dimethylpiperidine-1,3-dicarboxamide [Compound 4.6]: m/z: [M + H]+ Calcd for C28H32F3N6O2541.2; Found 541.4. ¹H NMR (400MHz, DMSO-d6) į = 8.88 (br d, J=2.8 Hz, 1H), 8.76 (s, 1H), 8.43 (s, 1H), 8.30 (d, J=8.2 Hz, 1H), 7.62 (dd, J=4.0, 8.4 Hz, 1H), 7.30 - 7.15 (m, 2H), 6.94 (br d, J=8.4 Hz, 2H), 6.54 - 6.08 (m, 2H), 4.06 - 3.62 (m, 2H), 2.92 - 2.87 (m, 3H), 2.71 - 2.63 (m, 2H), 2.63 - 2.57 (m, 1H), 2.54 (br d, J=4.0 Hz, 3H), 2.35 - 2.19 (m, 1H), 2.11 - 1.77 (m, 1H), 1.60 (br d, J=12.4 Hz, 1H), 1.53 (br d, J=10.4 Hz, 1H), 1.49 - 1.44 (m, 2H), 1.38 (br d, J=12.8 Hz, 1H), 1.03 (td, J=2.8, 5.6 Hz, 2H). [00191] (R)-N3-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)-N1,N3-dimethylpiperidine-1,3-dicarboxamide [Compound 4.7]: m/z: [M + H]+ 96 Calcd for C28H32F3N6O2541.2; Found 541.4. ¹H NMR (400MHz, DMSO-d6) į = 8.88 (br d, J=2.4 Hz, 1H), 8.75 (s, 1H), 8.49 - 8.38 (m, 1H), 8.30 (br d, J=8.4 Hz, 1H), 7.62 (br dd, J=4.0, 8.4 Hz, 1H), 7.18 (br d, J=7.6 Hz, 2H), 6.99 - 6.88 (m, 2H), 6.60 - 6.07 (m, 2H), 4.04 (br d, J=9.6 Hz, 1H), 3.96 - 3.69 (m, 1H), 2.90 (s, 3H), 2.71 - 2.65 (m, 2H), 2.62 (br s, 1H), 2.56 (br d, J=4.0 Hz, 3H), 2.34 - 2.05 (m, 1H), 1.80 (br d, J=12.8 Hz, 1H), 1.62 - 1.50 (m, 2H), 1.47 (br d, J=3.2 Hz, 2H), 1.42 - 1.26 (m, 1H), 1.03 (br dd, J=2.4, 5.6 Hz, 2H). Synthesis of (S)-N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)-N-methyl-1-(methylsulfonyl)piperidine-4-carboxamide (Compound 4.8)

[00192] To a mixture of (S)-N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)- 2,2,2-trifluoroethyl)-N-methylpiperidine-4-carboxamide [Compound 2.2] (80 mg, 165 μmol), ethylbis(propan-2-yl)amine (85.3 mg, 660 μmol), and triethylamine (66.7 mg, 660 μmol) in DMF (1.5 mL) was added methanesulfonyl chloride (10 mg, 87.3 μmol) at 0 °C. The mixture was stirred at 25 °C for 12 hr, after which the crude product was purified by prep-HPLC (column: Boston Prime C18150*25mm*5μm, table: 14-54% B (A = water (0.05% ammonia hydroxide), B = acetonitrile), flowrate: 30 mL/min, UV Detector 220 nm) to afford (S)-N-(1-(4- ((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyl-1- (methylsulfonyl)piperidine-4-carboxamide [Compound 4.8] (7.30 mg, 12.9 μmol, 7.9% yield) as a yellow dry powder. m/z: [M + H]+ Calcd for C27H31F3N5O3S 562.2; Found 562.3. ¹H NMR (400MHz, DMSO-d6) į = 8.86 (dd, J=1.6, 4.0 Hz, 1H), 8.73 (s, 1H), 8.46 - 8.37 (m, 1H), 8.27 (dd, J=1.6, 8.4 Hz, 1H), 7.60 (dd, J=4.0, 8.4 Hz, 1H), 7.26 - 7.13 (m, 2H), 6.96 - 6.84 (m, 2H), 6.50 - 6.09 (m, 1H), 3.56 (br d, J=8.4 Hz, 2H), 2.88 (s, 3H), 2.83 - 2.62 (s, 6H), 2.26 - 2.18 (m, 1H), 1.88 - 1.68 (m, 2H), 1.64 - 1.52 (m, 2H), 1.45 (dd, J=2.4, 5.6 Hz, 2H), 1.05 - 0.95 (m, 2H). Synthesis of 1-acetyl-N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)-N-methylpiperidine-3-carboxamide (Compound 4.9)

[00193] To a mixture of N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)- 2,2,2-trifluoroethyl)-N-methylpiperidine-3-carboxamide [Compound 2.3] (100mg, 206 μmol) and acetyl chloride (56.5 mg, 721 μmol) in DCM (2 mL) was added triethylamine (103 mg, 1.02 mmol) at 25 °C and the mixture was stirred at 25 °C for 12 hr. The reaction was concentrated under reduced pressure to give the crude product, which was purified by prep-HPLC (column: YMC Triart C18250*50mm*7μm, table: 31-71% B (A = water (0.05% ammonia hydroxide v/v)), B = acetonitrile), flow rate: 60 mL/min, UV Detector 220 nm) to afford 1-acetyl-N-((S)-1- (4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N- methylpiperidine-3-carboxamide [Compound 4.9] (18.0 mg, 34.2 μmol, 16.6% yield) as a yellow solid. m/z: [M + H]+ Calcd for C28H31F3N5O2526.4; Found 526.3. ¹H NMR (400MHz, DMSO-d6) į = 8.89 (dd, J=1.6, 4.0 Hz, 1H), 8.79 - 8.74 (m, 1H), 8.44 (s, 1H), 8.30 (dd, J=1.6, 8.4 Hz, 1H), 7.63 (dd, J=4.0, 8.4 Hz, 1H), 7.39 - 7.12 (m, 2H), 7.01 - 6.89 (m, 2H), 6.45 (br d, J=8.8 Hz, 1H), 4.47 - 4.26 (m, 1H), 3.80 (br d, J=12.0 Hz, 2H), 3.09 - 2.81 (m, 3H), 2.75 - 2.58 (m, 2H), 2.35 - 2.22 (m, 1H), 2.04 (s, 1H), 2.00 (d, J=4.4 Hz, 2H), 1.95 - 1.79 (m, 1H), 1.65 (br d, J=17.2 Hz, 1H), 1.54 - 1.32 (m, 3H), 1.29 - 1.11 (m, 1H), 1.03 (td, J=2.8, 5.6 Hz, 2H). Synthesis of N3-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)-N1,N3-dimethylpyrrolidine-1,3-dicarboxamide (Compound 4.10)

[00194] To a solution of N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)- 2,2,2-trifluoroethyl)-N-methylpyrrolidine-3-carboxamide [Compound 2.1] (80mg, 170 μmol) and ethylbis(propan-2-yl)amine (21.9 mg, 170 μmol) in DCM (1 mL) was added N- methylcarbamoyl chloride (47.5 mg, 509 μmol) at 0 °C. The reaction mixture was stirred at 20 ºC for 1 h. The reaction was combined with another of the same and was concentrated under reduced pressure to give the crude product, which was purified by SFC (column: REGIS (R,R)WHELK-O1(250mm*25mm, 10 μm), condition: 45%-60% 0.1%NH₃H₂O ETOH,flowrate:80 mL/min) to give N3-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3- yl)amino)phenyl)-2,2,2-trifluoroethyl)-N1,N3-dimethylpyrrolidine-1,3-dicarboxamide [Compound 4.10] (14.1 mg, 26.7 μmol, 15.7% yield) as a yellow dry powder. m/z: [M + H]+ Calcd for C27H30F3N6O2527.2; Found 527.2. ¹H NMR (400MHz, DMSO-d6) į = 8.88 (dd, J=1.6, 4.4 Hz, 1H), 8.76 (s, 1H), 8.49 - 8.41 (m, 1H), 8.30 (dd, J=1.6, 6.8 Hz, 1H), 7.62 (dd, J=4.4, 8.4 Hz, 1H), 7.33 - 7.16 (m, 2H), 7.02 - 6.88 (m, 2H), 6.51 - 6.13 (m, 1H), 6.10 - 6.00 (m, 1H), 3.76 - 3.39 (m, 3H), 3.31 - 3.15 (m, 2H), 2.90 (s, 3H), 2.55 (t, J=4.0 Hz, 3H), 2.30 - 2.20 (m, 1H), 2.18 - 1.83 (m, 2H), 1.51 - 1.45 (m, 2H), 1.11 - 0.98 (m, 2H). Synthesis of (S)-4-(acetamidomethyl)-N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3- yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylcyclohexane-1-carboxamide (Compound 4.11)

[00195] To a solution of (S)-4-(aminomethyl)-N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3- yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylcyclohexane-1-carboxamide [Compound 10.4, free base] (125 mg, 244 μmol) in CH₂Cl₂ (1.5 mL) was added Et₃N (74.0 mg, 732 μmol) and acetyl chloride (19.1 mg, 244 μmol). The resulting mixture was stirred at 20 °C for 2 h. The reaction was concentrated under reduced pressure to give a residue, which was purified by prep- HPLC (column: YMC Triart C18250*50mm*7μm, table: 25-65% B (A=water (0.05% ammonia hydroxide v/v), B = acetonitrile), flow rate: 60 mL/min,UV Detector 220 nm) to afford (S)-4- (acetamidomethyl)-N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)-N-methylcyclohexane-1-carboxamide [Compound 4.11] (58.9 mg, 106 μmol, 43.6% yield) as a yellow dry powder. m/z: [M + H]+ Calcd for C30H35F3N5O2554.3; Found 554.4. ¹H NMR (400MHz, CDCl₃) į = 8.92 (s, 2H), 8.27 (d, J=8.4 Hz, 1H), 7.53 - 7.42 (m, 1H), 7.29 (d, J=8.0 Hz, 2H), 7.08 (d, J=8.0 Hz, 2H), 6.62 (q, J=8.8 Hz, 1H), 6.54 - 6.43 (m, 1H), 5.80 - 5.51 (m, 1H), 3.21 - 3.04 (m, 2H), 2.90 (s, 3H), 2.61 - 2.45 (m, 1H), 2.12 - 2.01 (m, 2H), 1.99 (s, 3H), 1.89 - 1.71 (m, 3H), 1.67 - 1.43 (m, 3H), 1.26 (d, J=8.0 Hz, 2H), 1.13 - 0.95 (m, 4H). Synthesis of (S)-4-acetamido-N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)- 2,2,2-trifluoroethyl)-N-methylcyclohexane-1-carboxamide (Compound 4.12)

[00196] To a mixture of (S)-4-amino-N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3- yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylcyclohexane-1-carboxamide [Compound 10.1, free base] (60 mg, 120 μmol) and triethylamine (60.7 mg, 600 μmol) in DCM (1 mL) was added acetyl chloride (32.9 mg, 420 μmol) at 25 °C and the mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by prep-HPLC (column: YMC Triart C18250*50mm*7μm, table: 26-66% water (0.05% ammonia hydroxide v/v)-ACN, flow rate: 60 mL/min, UV Detector 220 nm) to afford (S)-4-acetamido-N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)-N-methylcyclohexane-1-carboxamide [Compound 4.12] (30.5 mg, 56.5 μmol, 47.1% yield) as a yellow dry powder. m/z: [M + H]+ Calcd for C29H33F3N5O2540.3; Found 540.4. ¹H NMR (400MHz, DMSO-d6) į = 8.88 (dd, J=1.2, 4.0 Hz, 1H), 8.75 (s, 1H), 8.42 (s, 1H), 8.29 (dd, J=2.0, 8.4 Hz, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.62 (dd, J=4.2, 8.4 Hz, 1H), 7.18 (d, J=8.4 Hz, 2H), 6.92 (d, J=8.6 Hz, 2H), 6.45 (q, J=9.2 Hz, 1H), 3.50 - 3.42 (m, 1H), 2.88 (s, 3H), 2.68 - 2.59 (m, 1H), 2.26 - 2.22 (m, 1H), 1.89 - 1.67 (m, 7H), 1.52 - 1.33 (m, 4H), 1.31 - 1.11 (m, 2H), 1.04 -1.01 (m, 2H). 5. Compounds Prepared using Scheme 5 Scheme 5:

[00197] Starting material G-5a is treated with Et3N, paraformaldehyde, and NaBH3CN to provide a compound of Formula (I). Synthesis of N-[(1S)-1-{4-[(4-cyclopropyl-1,5-naphthyridin-3-yl)amino]phenyl}-2,2,2- trifluoroethyl]-N,1- dimethylpiperidine-4-carboxamide (also known as (S)-N-(1-(4-((4- cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N,1-dimethylpiperidine- 4-carboxamide) (Compound 5.1)

[00198] To a mixture of (S)-N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)- 2,2,2-trifluoroethyl)-N-methylpiperidine-4-carboxamide [Compound 2.2] (80 mg, 165 μmol), paraformaldehyde (49.5 mg, 1.65 mmol) and triethylamine (33.3 mg, 330 μmol) in MeOH (5 mL) was stirred at 25 °C for 0.5 hour. Then the mixture was added sodium cyanoborohydride (15.5 mg, 247 μmol) and stirred at 25 °C for 12 hours. The crude product was purified by prep- HPLC (column: YMC Triart 30*150mm*7μm, table: 14-54% B (A = water (0.05% HCl)-ACN), B = acetonitrile), flowrate: 30 mL/min, UV Detector 220 nm) to afford N-[(1S)-1-{4-[(4- cyclopropyl-1,5-naphthyridin-3-yl)amino]phenyl}-2,2,2-trifluoroethyl]-N,1- dimethylpiperidine- 4-carboxamide [Compound 5.1] (7.70 mg, 15.4 μmol) as a dry product. m/z: [M + H]+ Calcd for C27H31F3N5O 498.2; 499.2; Found 498.1. ¹H NMR (400MHz, DMSO-d6) į = 10.38 (br s, 1H), 9.09-8.98 (m, 2H), 8.94 (s, 1H), 8.65 (br d, J=8.0 Hz, 1H), 7.83 (dd, J=4.4, 8.0 Hz, 1H), 7.37-7.24 (m, 2H), 7.12 (br d, J=8.0 Hz, 2H), 6.56-6.16 (m, 1H), 3.67-3.65 (m, 1H), 3.06-2.87 (m, 6H), 2.78-2.62 (m, 4H), 2.15-2.05 (m, 1H), 2.01-1.81 (m, 4H), 1.11 (br d, J=8.0 Hz, 4H). Synthesis of N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)-N,1-dimethylpyrrolidine-3-carboxamide (Compound 5.2)

[00199] To a solution of N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)- 2,2,2-trifluoroethyl)-N-methylpyrrolidine-3-carboxamide [Compound 2.1] (50 mg, 106 μmol) and paraformaldehyde (31.5 mg, 1.05 mmol) in MeOH (2 mL) was added acetic acid (19.0 mg, 318 μmol) and the reaction mixture was stirred at 20 ºC for 30 min. NaBH3CN (13.3 mg, 212 μmol) was then added and the reaction mixture was allowed to warm to 25 ºC for 3 h. The reaction was concentrated under reduced pressure to give the crude product, which was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875*30mm*3μm, condition: 40%-66% CH3CN in water (0.04%NH3H2O+10mM NH4HCO3)-ACN,flowrate:25 mL/min) to give N-((S)- 1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N,1- dimethylpyrrolidine-3-carboxamide [Compound 5.2] (9.90 mg, 20.4 μmol, 19.3% yield) as a yellow dry powder. m/z: [M + H]+ Calcd for C26H29F3N5O 484.2; Found 484.2. ¹H NMR (400MHz, DMSO-d6) į = 8.88 (dd, J=1.6, 4.0 Hz, 1H), 8.75 (s, 1H), 8.42 (s, 1H), 8.30 (dd, J=2.0, 8.4 Hz, 1H), 7.62 (dd, J=4.0, 8.4 Hz, 1H), 7.29 - 7.16 (m, 2H), 6.92 (d, J=8.4 Hz, 2H), 6.45 (q, J=9.2 Hz, 1H), 2.84 (s, 3H), 2.77 - 2.52 (m, 2H), 2.45 - 2.24 (m, 3H), 2.23 (d, J=4.0 Hz, 3H), 2.14 - 1.76 (m, 3H), 1.52 - 1.42 (m, 2H), 1.07-0.96 (m, 2H). Synthesis of N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)-N,1-dimethylpiperidine-3-carboxamide (Compound 5.3)

[00200] To a mixture of N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)- 2,2,2-trifluoroethyl)-N-methylpiperidine-3-carboxamide [Compound 2.1] (80 mg, 165 μmol) and paraformaldehyde (24.7 mg, 825 μmol) in MeOH (1 mL) was added triethylamine (33.3 mg, 330 μmol) and sodium cyanoborohydride (15.5 mg, 247 μmol). The mixture was stirred at 25 °C for 16 hr. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by prep-HPLC (column: YMC Triart C18250*50mm*7μm, table: 44-84% B (A = water (0.05% ammonia hydroxide )), B = acetonitrile), flow rate: 60 mL/min, UV Detector 220 nm) to give N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)- 2,2,2-trifluoroethyl)-N,1-dimethylpiperidine-3-carboxamide [Compound 5.3] (11.3 mg, 22.7 μmol, 13.7% yield) as a yellow dry powder. m/z: [M + H]+ Calcd for C27H31F3N5O 498.2; Found 498.3. ¹H NMR (400MHz, DMSO-d6) į = 8.88 (br d, J=2.8 Hz, 1H), 8.75 (s, 1H), 8.41 (s, 1H), 8.29 (d, J=8.0 Hz, 1H), 7.62 (dd, J=4.0, 8.4 Hz, 1H), 7.28 - 7.10 (m, 2H), 6.92 (br d, J=8.4 Hz, 2H), 6.43 (q, J=9.2 Hz, 1H), 2.88 (s, 3H), 2.82 - 2.71 (m, 2H), 2.66 (br s, 1H), 2.29 - 2.20 (m, 1H), 2.16 (s, 3H), 1.90 (br t, J=10.8 Hz, 1H), 1.82 - 1.74 (m, 1H), 1.73 - 1.60 (m, 2H), 1.50 (br d, J=12.0 Hz, 1H), 1.45 (br d, J=3.2 Hz, 2H), 1.35 - 1.23 (m, 1H), 1.07 - 0.97 (m, 2H). 6. Compounds Prepared using Scheme 6 Scheme 6:

[00201] Starting material G-6a is treated with LiOH.H2O to provide a compound of Formula (I). Synthesis of (1r,4r)-4-{[(1S)-1-{4-[(4-cyclopropyl-1,5-naphthyridin-3-yl)amino]phenyl}-2,2,2- trifluoroethyl](methyl)carbamoyl}cyclohexane-1-carboxylic acid (also known as (1S,4r)-4-(((S)- 1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)(methyl)carbamoyl)cyclohexane-1-carboxylic acid) (Compound 6.1)

[00202] To a mixture of methyl (1S,4r)-4-(((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3- yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexane-1-carboxylate [Compound 1.7] (100 mg, 184 μmol) in MeOH (1.5 mL) and H2O (0.5 mL) was added LiOH^H2O (15.4 mg, 368 μmol) and the mixture was stirred at 25 °C for 2 hours. 1 N HCl was added to adjust the pH to 3-4 and the mixture was concentrated under reduced pressure to afford the crude product, which was purified by prep-HPLC (column: YMC Triart 30*150mm*7μm, table: 20-60% B (A = water (0.05% HCl v/v)), B = acetonitrile), flowrate: 30 mL/min, UV Detector 220nm) to afford (1r,4r)-4-{[(1S)-1-{4-[(4-cyclopropyl-1,5-naphthyridin-3- yl)amino]phenyl}-2,2,2-trifluoroethyl](methyl)carbamoyl}cyclohexane-1-carboxylic acid [Compound 6.1] (11.0 mg, 20.8 μmol) as a dry powder. m/z: [M+H]+ Calcd for C28H30F3N4O3527.2; Found 527.4. ¹H NMR (400 MHz, MeOD) į = 9.07 (s, 1H), 9.02-8.96 (m, 2H), 7.97 (dd, J=5.6, 8.4 Hz, 1H), 7.48-7.43 (m, 2H), 7.41-7.36 (m, 2H), 6.63 (q, J=9.2 Hz, 1H), 3.00 (s, 3H), 2.82-2.76 (m, 1H), 2.39-2.29 (m, 1H), 2.13-2.04 (m, 2H), 1.98-1.86 (m, 3H), 1.64-1.51 (m, 4H), 1.36-1.30 (m, 2H), 0.80-0.74 (m, 2H). Synthesis of (1S,3r)-3-(((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)(methyl)carbamoyl)cyclobutane-1-carboxylic acid (ammonium salt) (Compound 6.2)

[00203] To a mixture of methyl (1S,3r)-3-(((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3- yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclobutane-1-carboxylate [INT 28.5] (160 mg, 195 μmol) in MeOH (1 mL) was added a solution of lithium hydroxide monohydrate (16.3 mg, 390 μmol) in water (1 mL). The mixture was stirred at 20 °C for 1 h. The reaction was concentrated under reduced pressure to give the crude residue, which was diluted with water (3 mL) and adjusted with 1 N HCl to pH = 4. The mixture was concentrated under reduced pressure to give the crude product, which was purified by prep-HPLC (column: Boston Green ODS 150*30mm*5um, table: 12-52% B (A = water (0.05% HCl), B = acetonitrile), flow rate: 30 mL/min, UV Detector 220 nm), and further purified by prep-HPLC (column: YMC-Triart Prep C18150*40mm*7μm, table: 3-43% B (A = water (0.05% ammonia hydroxide), B = acetonitrile), flow rate: 30 mL/min, UV Detector 220 nm)to give (1S,3r)-3-(((S)-1-(4-((4- cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)(methyl)carbamoyl)cyclobutane-1-carboxylic acid (ammonium salt) [Compound 6.2] (21.8 mg, 42.2 μmol, 21.8% yield) as a yellow solid. m/z: [M + H]+ Calcd for C26H26F3N4O3499.2; Found 499.1. ¹H NMR (400MHz, DMSO-d₆) į = 8.88 (d, J=2.8 Hz, 1H), 8.75 (s, 1H), 8.42 (s, 1H), 8.29 (d, J=8.4 Hz, 1H), 7.62(dd, J=4.4, 8.4 Hz, 1H), 7.29 - 7.13 (m, 2H), 6.92 (d, J=8.0 Hz, 2H), 6.52 - 5.49 (m, 1H), 3.05 - 2.89 (m, 1H), 2.77 - 2.60 (m, 3H), 2.45 - 2.18 (m, 6H), 1.54 - 1.40 (m, 2H), 1.10 - 0.95 (m, 2H). 7. Compounds Prepared using Scheme 7 Scheme 7:

[00204] Starting material G-7a is treated with an amine-containing compound (e.g., NH4Cl, MeNH2, or Me2NH) to provide a compound of Formula (I), where R^G8 and R^G8’ are either H or Me. Synthesis of (1r,4r)-N1-[(1S)-1-{4-[(4- cyclopropyl-1,5-naphthyridin-3-yl)amino]phenyl}-2,2,2- trifluoroethyl]-N1-methylcyclohexane-1,4-dicarboxamide (also known as (1r,4S)-N1-((S)-1-(4- ((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N1- methylcyclohexane-1,4-dicarboxamide) (Compound 7.1)

[00205] To a mixture of (1S,4r)-4-(((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3- yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexane-1-carboxylic acid [Compound 6.1] (70 mg, 132 μmol) in DMF (1 mL) was added HATU (75.2 mg, 198 μmol) and DIEA (51.1 mg, 396 μmol) and the mixture was stirred at 25 °C for 0.5 hour. Then NH4Cl (14.1 mg, 264 μmol) was added and the mixture was stirred at 25 °C for 12 hours. The mixture was purified by prep-HPLC (column: Diamonsil C18150*30mm*5μm, table: 14-54% B (A = water (0.05% ammonia hydroxide v/v)), B = acetonitrile), flowrate: 50 mL/min, UV Detector 220 nm) to afford (1r,4r)-N1-[(1S)-1-{4-[(4- cyclopropyl-1,5-naphthyridin-3-yl)amino]phenyl}- 2,2,2-trifluoroethyl]-N1-methylcyclohexane-1,4-dicarboxamide [Compound 7.1] (21.9 mg, 41.6 μmol) as a dry powder. m/z: [M+H]+ Calcd for C28H31F3N5O2526.2; Found 526.4. ¹H NMR (400 MHz, CDCl₃) į = 8.95 (s, 2H), 8.29 (dd, J=1.6, 8.4 Hz, 1H), 7.49 (dd, J=4.0, 8.4 Hz, 1H), 7.32 (br d, J=8.4 Hz, 2H), 7.11 (d, J=8.4 Hz, 2H), 6.64 (q, J=8.8 Hz, 1H), 6.42 (s, 1H), 5.52-5.18 (m, 2H), 2.95 - 2.80 (m, 3H), 2.67 - 2.57 (m, 1H), 2.30 - 2.20 (m, 1H), 2.10 - 1.96 (m, 4H), 1.94 - 1.85 (m, 1H), 1.75 - 1.59 (m, 4H), 1.32 - 1.26 (m, 2H), 1.12 - 1.04 (m, 2H). Synthesis of (1r,4S)-N1-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)-N1,N4-dimethylcyclohexane-1,4-dicarboxamide (Compound 7.2)

[00206] To a mixture of (1S,4r)-4-(((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3- yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexane-1-carboxylic acid [Compound 6.1] (70 mg, 132 μmol) in DMF (1 mL) was added HATU (75.2 mg, 198 μmol) and DIPEA (51.1 mg, 396 μmol) and the mixture was stirred at 25 °C for 0.5 hr. Then methanamine hydrochloride (13.3 mg, 198 μmol) was added and the mixture was stirred at 25 °C for 12 hr. The mixture was purified by prep-HPLC (column: YMC Triart C18 250*50mm*7μm, table: 29-69% B (A = water (0.05% ammonia hydroxide v/v)), B = acetonitrile), flow rate: 60 mL/min, UV Detector 220 nm) to afford (1r,4S)-N1-((S)-1-(4-((4- cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N1,N4- dimethylcyclohexane-1,4-dicarboxamide [Compound 7.2] (22.6 mg, 41.8 μmol, 31.7% yield) as a yellow dry powder. m/z: [M+H]+ Calcd for C29H33F3N5O2540.3; Found 540.4. ¹H NMR (400 MHz, CDCl₃) į = 8.95 (s, 2H), 8.29 (dd, J=1.6, 8.4 Hz, 1H), 7.49 (dd, J=4.0, 8.4 Hz, 1H), 7.31 (d, J=8.4 Hz, 2H), 7.11 (d, J=8.4 Hz, 2H), 6.64 (q, J=9.2 Hz, 1H), 6.42 (s, 1H), 5.53 - 5.42 (m, 1H), 2.93 (s, 3H), 2.82 (d, J=4.8 Hz, 3H), 2.68 - 2.57 (m, 1H), 2.20 - 2.04 (m, 2H), 2.03 - 1.93 (m, 3H), 1.92 - 1.84 (m, 1H), 1.72 - 1.61 (m, 4H), 1.31 - 1.27 (m, 2H), 1.13 - 1.04 (m, 2H). Synthesis of (1r,4S)-N1-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)-N1,N4,N4-trimethylcyclohexane-1,4-dicarboxamide (Compound 7.3)

[00207] To a mixture of (1S,4r)-4-(((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3- yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexane-1-carboxylic acid [Compound 6.1] (70 mg, 132 μmol) in DMF (1 mL) was added HATU (75.2 mg, 198 μmol) and DIPEA (51.1 mg, 396 μmol) and the mixture was stirred at 25 °C for 0.5 hr. Then dimethylamine hydrochloride (16.1 mg, 198 μmol) was added, and the mixture was stirred at 25 °C for 12 hr. The mixture was purified by prep-HPLC (column: YMC Triart C18 250*50mm*7μm, table: 31-71% B (A = water (0.05% ammonia hydroxide v/v)), B = acetonitrile), flow rate: 60 mL/min, UV Detector 220 nm) to afford (1r,4S)-N1-((S)-1-(4-((4- cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N1,N4,N4- trimethylcyclohexane-1,4-dicarboxamide [Compound 7.3] (27.2 mg, 49.1 μmol, 37.2% yield) as a yellow dry powder. m/z: [M+H]+ Calcd for C30H35F3N5O2554.3; Found 554.6. ¹H NMR (400 MHz, CDCl3) į = 8.98 - 8.93 (m, 2H), 8.29 (dd, J=1.6, 8.4 Hz, 1H), 7.48 (dd, J=4.0, 8.4 Hz, 1H), 7.32 (d, J=8.4 Hz, 2H), 7.11 (d, J=8.4 Hz, 2H), 6.64 (q, J=8.8 Hz, 1H), 6.43 (s, 1H), 3.08 (s, 3H), 2.94 (d, J=9.6 Hz, 6H), 2.71 - 2.57 (m, 2H), 2.12 - 2.04 (m, 1H), 2.02 - 1.94 (m, 1H), 1.93 - 1.85 (m, 3H), 1.75 - 1.63 (m, 4H), 1.32 - 1.27 (m, 2H), 1.11 - 1.04 (m, 2H). 8. Compounds Prepared using Scheme 8 Scheme 8:

[00208] Starting material G-8a is treated with TMSN3 to provide a compound of Formula (I). Synthesis of (1r,4S)-N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)-N-methyl-4-(1H-tetrazol-5-yl)cyclohexane-1-carboxamide (Compound 8.1)

[00209] (1r,4S)-4-cyano-N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)- 2,2,2-trifluoroethyl)-N-methylcyclohexane-1-carboxamide [Compound 1.13] (50 mg, 0.09851 mmol), trimethylsilyl azide (90.7 mg, 788 μmol) and dibutyltin oxide (98.0 mg, 394 μmol) were mixed in benzene (2 mL). The reaction mixture was stirred at 35 °C for 60 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by HPLC (see conditions below) to give (1r,4S)-N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3- yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyl-4-(1H-tetrazol-5-yl)cyclohexane-1- carboxamide [Compound 8.1] (9.21 mg, 0.01673 mmol, 16.9% yield) as a yellow gum. m/z: [M + H]+ Calcd for C28H30F3N8O 551.2; Found 551.2. ¹H NMR (400 MHz, CD3OD) į = 8.90 (dd, J=4.3, 1.8 Hz, 1H), 8.80 (s, 1H), 8.31 (dd, J=8.4, 1.8 Hz, 1H), 7.61 (dd, J=8.4, 4.2 Hz, 1H), 7.30 (d, J = 8.3 Hz, 2H), 7.06 (d, J=8.4 Hz, 2H), 6.57 (q, J=9.2 Hz, 1H), 3.06 (s, 1H), 3.01 (s, 3H), 2.88 (s, 1H), 2.26 - 2.10 (m, 4H), 2.07 - 2.00 (m, 1H), 1.98 - 1.92 (m, 1H), 1.82 - 1.69 (m, 4H), 1.18 - 1.10 (m, 4H). [00210] HPLC conditions: System - Agilent 1260 Infinity II LC coupled to an Agilent 6120B Single Quadrupole LC/MS System. Column - Description: XBridge BEH 5 ^m C18(2) 130 Å, LC Column 100 x 20 mm, YMC-Actus Triart. Stationary Phase - C18 with ethylene endcapping. Solid Support - fully porous silica. Separation Mode - Reversed Phase. Mobile Phase - Mobile phase A: water. Mobile phase B:acetonitrile+0.1% NH3 (20% water solution NH3). Flow rate: 30ml/min; loading pump 4ml/min B. Gradient conditions: 0-0-50- 100% (B) 0-2-10-11.2 min.

[00211] (1r,3S)-3-cyano-N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)- 2,2,2-trifluoroethyl)-N-methylcyclobutane-1-carboxamide [Compound 1.14] (0.05 g, 0.1042 mmol) was dissolved in benzene (2 mL), after which trimethylsilyl azide (47.9 mg, 416 μmol) and dibutyltin oxide (51.7 mg, 208 μmol) were added. The mixture was stirred for 10 hr at 50 °C. EtOAc (10 mL) was added, and the mixture was extracted with water (5 mL). The organic phase was evaporated in vacuo at 45 °C, and the resulting residue was purified by HPLC (see conditions below) to obtain (1r,3S)-N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3- yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyl-3-(1H-tetrazol-5-yl)cyclobutane-1- carboxamide [Compound 8.2] (17.8 mg, 0.03417 mmol, 32.7% yield) as a yellow oil. m/z: [M + H]+ Calcd for C26H26F3N8O 523.2; Found 523.2. ¹H NMR (400 MHz, DMSO-d6) į = 8.88 (dd, J=4.1, 1.8 Hz, 1H), 8.76 (s, 1H), 8.43 (s, 1H), 8.29 (dd, J=8.4, 1.8 Hz, 1H), 7.62 (dd, J=8.4, 4.1 Hz, 1H), 7.23 (d, J=8.3 Hz, 2H), 6.97 - 6.90 (m, 2H), 6.47 (q, J=9.5 Hz, 1H), 3.83 - 3.61 (m, 2H), 2.77 - 2.65 (m, 8H), 2.25 (tt, J=8.7, 5.5 Hz, 1H), 1.47 (dp, J=5.9, 3.0, 2.6 Hz, 2H), 1.02 (dq, J=9.4, 3.5 Hz, 2H). [00212] HPLC conditions: System - Agilent 1260 Infinity II LC coupled to an Agilent 6120B Single Quadrupole LC/MS System. Column - Description: Chromatorex SBM 100-5T 5 ^m C18(2) 100 Å, LC Column 100 x 19 mm, Waters, Sun Fire. Stationary Phase: C18. Solid Support: Fully Porous Silica. Separation Mode: Reversed Phase. Mobile Phase - Mobile phase A: water. Mobile phase B: acetonitrile. Flow rate: 30ml/min; loading pump 4ml/min B. Gradient conditions: 20-25-50-100% (B) 0-2-10-11.2 min. 9. Compounds Prepared using Scheme 9 Scheme 9:

Synthesis of (1r,4S)-N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)-4-hydroxy-N-methylcyclohexane-1-carboxamide (Compound 9.1) [00213] A solution of (1r,4S)-4-((tert-butyldimethylsilyl)oxy)-N-((S)-1-(4-((4-cyclopropyl- 1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylcyclohexanecarboxamide [INT 28.1] (88 mg, 143 μmol) in TFA (1 mL) and CH₂Cl₂ (1 mL) was stirred at 20 °C for 0.5 hour. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC (column: Boston Green ODS 150 * 30 mm * 5 μm, table: 7- 47% B (A = water (0.05% HCl), B = acetonitrile), flow rate: 30 mL/min, UV Detector 220 nm) to give (1r,4S)-N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)-4-hydroxy-N-methylcyclohexane-1-carboxamide [Compound 9.1] (20.3 mg, 0.041 mmol, 28.5% yield) as an orange dry powder. m/z: [M + H]+ Calcd for C27H30F3N4O2 499.2; Found 499.3. ¹H NMR (400 MHz, CHLOROFORM-d) į = 9.29 (d, J=4.8 Hz, 1H), 9.08 (s, 1H), 8.89 (d, J=8.0 Hz, 1H), 7.78 (dd, J=5.2, 8.0 Hz, 2H), 7.47 - 7.40 (m, 2H), 7.34 (d, J=8.4 Hz, 2H), 6.69 (q, J=8.4 Hz, 1H), 3.79 - 3.60 (m, 1H), 2.95 (s, 3H), 2.64 - 2.50 (m, 1H), 2.28 (br s, 1H), 2.18 - 2.05 (m, 2H), 1.99 - 1.81 (m, 2H), 1.78 - 1.62 (m, 4H), 1.43 - 1.28 (m, 2H), 0.93 (br s, 2H). 10. Compounds Prepared using Scheme 10 Scheme 10:

[00214] Starting material G-10a is treated with NH2NH2·H2O to provide a compound of Formula (I), where n = 0 or 1. Synthesis of 4-amino-N-[(1S)-1-{4-[(4-cyclopropyl1,5-naphthyridin-3-yl)amino]phenyl}-2,2,2- trifluoroethyl]-N-methylcyclohexane-1-carboxamide hydrochloride (Compound 10.1)

[00215] To a solution of N-[(1S)-1-{4-[(4-cyclopropyl-1,5-naphthyridin-3-yl)amino]phenyl}- 2,2,2-trifluoroethyl]-4-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-N-methylcyclohexane-1- carboxamide [INT 28.2] (70.0 mg, 111 μmol) in EtOH (1 mL) was added NH2NH2^.H2O (1 mL) and the mixture was stirred at 25 ºC for 1 hour. The reaction mixture was concentrated under reduced pressure to give the crude product which was purified by prep-HPLC (column: Boston Green ODS 150 * 30 mm * 5 μm, table: 0 - 39% water (0.05% HCl)-ACN, flow rate: 30 mL/min, UV Detector 220 nm) to give 4-amino-N-[(1S)-1-{4-[(4-cyclopropyl1,5-naphthyridin- 3-yl)amino]phenyl}-2,2,2-trifluoroethyl]-N-methylcyclohexane-1-carboxamide hydrochloride [Compound 10.1] (26.6 mg, 44.9% yield) as a tan dry powder. m/z: [M + H]+ Calcd for C27H31F3N5O 498.2; Found 498.2. ¹H NMR (400 MHz, DMSO-d6) į = 9.50 (s, 1H), 9.10 (d, J=4.0 Hz, 1H), 9.06 (s, 1H), 8.87 (d, J=8.4 Hz, 1H), 8.26 (br s, 3H), 7.94 (dd, J=5.2, 8.4 Hz, 1H), 7.45 - 7.15 (m, 4H), 6.61 - 6.26 (m, 1H), 2.90 (s, 4H), 2.73 - 2.59 (m, 1H), 2.12 - 1.92 (m, 3H), 1.90 - 1.66 (m, 2H), 1.63 - 1.29 (m, 4H), 1.24 - 1.04 (m, 2H), 0.88 (br s, 2H). Synthesis of (1s,4R)-4-amino-N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)- 2,2,2-trifluoroethyl)-N-methylcyclohexane-1-carboxamide hydrochloride (Compound 10.2)

[00216] To a mixture of (1s,4R)-N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3- yl)amino)phenyl)-2,2,2-trifluoroethyl)-4-(1,3-dioxoisoindolin-2-yl)-N-methylcyclohexane-1- carboxamide [INT 28.3] (380 mg, 605 μmol) in EtOH (4 mL) was added NH2NH2.H2O (90.6 mg, 1.81 mmol) and the mixture was stirred at 20 ºC for 16 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by prep-HPLC (column: YMC-Triart Prep C18150*40mm*7μm, table: 0-30% water (0.05% HCl)-ACN, flow rate: 30 mL/min, UV Detector 220 nm) to afford (1s,4R)-4-amino-N- ((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N- methylcyclohexane-1-carboxamide hydrochloride [Compound 10.2] (230 mg, 431 μmol, 71.2% yield) as a tan dry powder. m/z: [M + H]+ Calcd for C27H31F3N5O 498.2; Found 498.2. ¹H NMR (400MHz, DMSO-d₆) į = 9.47 (br s, 1H), 9.09 (dd, J=1.2, 5.2 Hz, 1H), 9.04 (s, 1H), 8.85 (d, J=8.0 Hz, 1H), 8.31 - 8.07 (m, 3H), 7.92 (dd, J=5.2, 8.4 Hz, 1H), 7.36 - 7.14 (m, 4H), 6.64 - 6.14 (m, 1H), 3.25 - 3.15 (m, 1H), 2.62 - 2.90 (m, 4H), 2.10 - 1.95 (m, 1H), 1.94 - 1.85 (m, 1H), 1.84 - 1.70 (m, 5H), 1.68 - 1.49 (m, 2H), 1.19 - 1.05 (m, 2H), 1.01 - 0.78 (m, 2H). Synthesis of (1r,4S)-4-amino-N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)- 2,2,2-trifluoroethyl)-N-methylcyclohexane-1-carboxamide hydrochloride (Compound 10.3)

[00217] To a mixture of (1r,4S)-N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3- yl)amino)phenyl)-2,2,2-trifluoroethyl)-4-(1,3-dioxoisoindolin-2-yl)-N-methylcyclohexane-1- carboxamide [INT 28.4] (1.1 g, 1.75 mmol) in EtOH (10mL) was added NH₂NH₂.H₂O (526 mg, 10.5 mmol) and the mixture was stirred at 20 ºC for 16 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by prep-HPLC (column: YMC-Triart Prep C18150*40mm*7μm, table: 4-44% water (0.05% HCl)-ACN, flow rate: 30 mL/min, UV Detector 220 nm) to afford (1r,4S)-4-amino-N-((S)-1-(4- ((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N- methylcyclohexane-1-carboxamide hydrochloride [Compound 10.3] (362 mg, 678 μmol, 38.7% yield) as a tan dry powder. m/z: [M + H]+ Calcd for C27H31F3N5O 498.2; Found 498.2. ¹H NMR (400MHz, DMSO-d₆) į = 9.61 (br s, 1H), 9.14 - 9.10 (m, 1H), 9.08 (s, 1H), 8.92 (d, J=8.4 Hz, 1H), 8.28 (s, 3H), 7.96 (dd, J=5.2, 8.0 Hz, 1H), 7.64 - 7.17 (m, 4H), 6.55 - 6.48 (m, 1H), 3.10 - 2.85 (m, 4H), 2.72 - 2.62 (m, 1H), 2.10 - 1.90 (m, 3H), 1.88 - 1.72 (m, 2H), 1.59 - 1.34 (m, 4H), 1.23 - 1.05 (m, 2H), 1.03 - 0.65 (m, 2H). Synthesis of (S)-4-(aminomethyl)-N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3- yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylcyclohexane-1-carboxamide formic acid (Compound 10.4)

[00218] A suspension (S)-N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)- 2,2,2-trifluoroethyl)-4-((1,3-dioxoisoindolin-2-yl)methyl)-N-methylcyclohexane-1-carboxamide [INT 28.6] (75 mg, 116 μmol) and hydrazine hydrate (59.1 mg, 1.16 mmol) in EtOH (5 mL) was stirred at 40 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a crude residue, which was purified by prep-HPLC (column: YMC Triart 30*150mm*7μm, table: 15-35% B (A = water (0.225% FA), B = acetonitrile), flow rate: 35 mL/min,UV Detector 220 nm) to afford (S)-4-(aminomethyl)-N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3- yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylcyclohexane-1-carboxamide formic acid [Compound 10.4] (4.30 mg, 7.71 μmol, 6.7% yield) as a yellow dry powder. m/z: [M + H]+ Calcd for C28H33F3N5O 512.3; Found 512.2. ¹H NMR (400 MHz, CDCl3) į = 8.93 (br d, J=2.8 Hz, 2H), 8.51 (br d, J=16.0 Hz, 1H), 8.28 (br d, J=8.0 Hz, 1H), 7.47 (br dd, J=4.0, 8.0 Hz, 1H), 7.34-7.27 (m, 2H), 7.14-7.02 (m, 2H), 6.67-6.56 (m, 1H), 6.49 (br s, 1H), 2.90 (br s, 3H), 2.76 (br s, 2H), 2.06 (br s, 2H), 1.91-1.53 (m, 9H), 1.27 (br d, J=7.6 Hz, 2H), 1.07 (br d, J=4.0 Hz, 2H). 11. Compounds Prepared using Scheme 11 Scheme 11:

Synthesis of tert-butyl N-(4-{[(1S)-1-{4-[(4-cyclopropyl-1,5-naphthyridin-3-yl)amino]phenyl}- 2,2,2-trifluoroethyl](methyl)carbamoyl}cyclohexyl)carbamate hydrochloride (Compound 11.1) [00219] To a solution of 4-amino-N-[(1S)-1-{4-[(4-cyclopropyl-1,5-naphthyridin-3- yl)amino]phenyl}-2,2,2-trifluoroethyl]-N-methylcyclohexane-1-carboxamide [Compound 10.1 free base] (65.0 mg, 130 μmol) and Et3N (65.7 mg, 650 μmol) in CH2Cl2 (2 mL) was added Boc2O (42.3 mg, 194 μmol) and the mixture was stirred at 20 ºC for 1 hour. The reaction mixture was concentrated under reduced pressure to give the crude product which was purified by prep-HPLC (column: Boston Green ODS 150 * 30 mm * 5 μm, table: 24 - 64% water (0.05% HCl)-ACN, B = acetonitrile), flow rate: 30 mL/min, UV Detector 220 nm) to give tert-butyl N- (4-{[(1S)-1-{4-[(4-cyclopropyl-1,5-naphthyridin-3-yl)amino]phenyl}-2,2,2- trifluoroethyl](methyl)carbamoyl}cyclohexyl)carbamate hydrochloride [Compound 11.1] (30.9 mg, 37.5% yield) as an orange dry powder. m/z: [M + H]+ Calcd for C32H39F3N5O3598.3; Found 598.5.¹H NMR (400MHz, DMSO-d₆) į = 9.20 - 9.05 (m, 1H), 9.04 - 8.99 (m, 1H), 8.96 (s, 1H), 8.71 (d, J=8.0 Hz, 1H), 8.05 (br s, 1H), 7.85 (dd, J=4.8, 8.4 Hz, 1H), 7.42 - 7.22 (m, 2H), 7.15 (br d, J=8.4 Hz, 2H), 6.79 (br d, J=7.2 Hz, 1H), 6.50 (q, J=9.2 Hz, 1H), 3.20 (br s, 1H), 2.94 - 2.81 (m, 3H), 2.69 - 2.56 (m, 1H), 2.10 - 1.98 (m, 1H), 1.89 - 1.63 (m, 4H), 1.60 - 1.33 (m, 11H), 1.29 - 1.14 (m, 2H), 1.14 - 0.97 (m, 4H). 12. Compounds Prepared using Scheme 12 Scheme 12:

Synthesis of (S)-N-(1-(4-((1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N- methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide (Compound 12.1) [00220] To a mixture of 3-bromo-1,5-naphthyridine [INT 24.1] (120 mg, 574 μmol), (S)-N- (1-(4-aminophenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1- dioxide hydrochloride [INT 23.1] (230 mg, 574 μmol), Cs2CO3 (371 mg, 1.14 mmol), and xantphos (65.9 mg, 114 μmol) in dioxane (1 mL) was added Pd2(dba)3 (52.5 mg, 57.4 μmol) under N2 atmosphere. The mixture was stirred at 100 °C for 1 hour. The reaction was concentrated under reduced pressure to give the crude product, which was purified by prep- HPLC (column: Phenomenex Gemini-NX C1875 * 30 mm * 3 μm, table: 21 - 61% water (0.05% ammonia hydroxide v/v)-ACN, flow rate: 25 mL/min, UV Detector 220 nm) to give (S)- N-(1-(4-((1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H- thiopyran-4-carboxamide 1,1-dioxide [Compound 12.1] (59.1 mg, 20.9% yield) as a yellow dry powder. m/z: [M + H]+ Calcd for C23H24F3N4O3S 493.1; Found 493.2. ¹H NMR (400MHz, DMSO-d₆) į = 9.21 (s, 1H), 8.81 (d, J=2.8 Hz, 2H), 8.26 (d, J=8.0 Hz, 1H), 7.85 (d, J=2.4 Hz, 1H), 7.51 (dd, J=4.4, 8.4 Hz, 1H), 7.45 - 7.32 (m, 4H), 6.56 - 6.12 (m, 1H), 3.32 - 3.09 (m, 5H), 2.97 - 2.64 (m, 3H), 2.12 - 1.96 (m, 4H). 13. Compounds Prepared using Scheme 13 Scheme 13:

Synthesis of (1r,4S)-N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)-N-methyl-4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)cyclohexane-1-carboxamide (Example 13, Compound 13.1) [00221] A solution of (1r,4S)-N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3- yl)amino)phenyl)-2,2,2-trifluoroethyl)-4-(hydrazinecarbonyl)-N-methylcyclohexane-1- carboxamide [INT 25.1] (50.0 mg, 92.4 μmol) and 1,1’-carbonyldiimidazole (29.8 mg, 184 μmol) in THF (5 mL) was stirred at 20 ºC for 12 hours. The reaction was concentrated under reduced pressure to give the crude product, which was purified by prep-HPLC (Column: YMC- Actus Triart C18150 * 30 mm * 5μm, table: 32 - 52% B (A = water (0.05% ammonia hydroxide v/v)-ACN, B = acetonitrile), flow rate: 35 mL/min, UV Detector 220 nm) to give (1r,4S)-N-((S)- 1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyl-4-(5- oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)cyclohexane-1-carboxamide [Compound 13.1] (9.00 mg, 15.9 μmol 17.2% yield) as a yellow dry powder. m/z: [M + H]+ Calcd for C29H30F3N6O3 567.2; Found 567.2. ¹H NMR (400MHz, CDCl3) į = 9.01 - 8.93 (m, 2H), 8.58 (br s, 1H), 8.33 (d, J=7.6 Hz, 1H), 7.51 (dd, J=4.4, 8.4 Hz, 1H), 7.33 (d, J=8.4 Hz, 2H), 7.12 (d, J=8.4 Hz, 2H), 6.65 (q, J=9.2 Hz, 1H), 6.46 (br s, 1H), 2.94 (s, 3H), 2.74 - 2.59 (m, 2H), 2.19 (d, J=8.4 Hz, 2H), 2.12 - 1.71 (m, 7H), 1.32 (d, J=8.0 Hz, 2H), 1.07 (br d, J=4.4 Hz, 2H). 14. Compounds Prepared using Scheme 14 Scheme 14:

Synthesis of (1r,4S)-N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)-N-methyl-4-(5-methyl-1,3,4-oxadiazol-2-yl)cyclohexane-1-carboxamide (Compound 14.1) [00222] A mixture of (1r,4S)-N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3- yl)amino)phenyl)-2,2,2-trifluoroethyl)-4-(hydrazinecarbonyl)-N-methylcyclohexane-1- carboxamide [INT 25.1] (50.0 mg, 92.4 μmol) and 1,1,1-triethoxyethane (74.9 mg, 462 μmol) in AcOH (2 mL) was stirred at 120 °C for 3 hours. The reaction was concentrated under reduced pressure to give the crude product, which was purified by prep-HPLC (Column: YMC-Actus Triart C18150 * 30 mm * 5 μm, table: 48 - 68% B (A = water (0.05% ammonia hydroxide v/v)- ACN), B = acetonitrile), flow rate: 35 mL/min, UV Detector 220 nm) to give (1r,4S)-N-((S)-1- (4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyl-4-(5- methyl-1,3,4-oxadiazol-2-yl)cyclohexane-1-carboxamide [Compound 14.1] (15.7 mg, 29.9% yield) as a yellow dry powder. m/z: [M + H]+ Calcd for C30H32F3N6O2565.2; Found 565.2. ¹H NMR (400MHz, CDCl3) į= 9.00 - 8.92 (m, 2H), 8.32 (d, J=8.4 Hz, 1H), 7.54 - 7.47 (m, 1H), 7.33 (d, J=8.4 Hz, 2H), 7.12 (d, J=8.4 Hz, 2H), 6.66 (q, J=9.2 Hz, 1H), 6.46 (br s, 1H), 2.99 - 2.89 (m, 4H), 2.72 - 2.62 (m, 1H), 2.51 (s, 3H), 2.28 (d, J=4.0 Hz, 2H), 2.13 - 2.01 (m, 2H), 1.96 (d, J=12.8 Hz, 1H), 1.85 - 1.67 (m, 4H), 1.31 (d, J=6.8 Hz, 2H), 1.12 - 1.03 (m, 2H). 15. Compounds Prepared using Scheme 15 Scheme 15:

Synthesis of (1r,4S)-N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl) phenyl)-2,2,2-

trifluoroethyl)-N-methyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)cyclohexane-1-carboxamide (Compound 15.1): [00223] A mixture of (1r,4S)-4-(((((Z)-1-aminoethylidene)amino)oxy)carbonyl)-N-((S)-1-(4- ((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N- methylcyclohexane-1-carboxamide [INT 26.1] (170 mg, 291 μmol) in toluene (1 mL) was stirred at 120 °C for 2.5 hours. The reaction mixture was concentrated to give a crude product, which was purified by prep-HPLC (column: Boston Prime C18150 * 25 mm * 5 μm, table: 16 - 56% B (A = water (0.05% FA), B = acetonitrile), flowrate: 25 mL/min, UV Detector 220 nm) to give (1r,4S)-N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)-N-methyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)cyclohexane-1-carboxamide [Compound 15.1] (52.6 mg, 93.1 μmol, 32.0% yield) as a yellow dry powder. m/z: [M + H]+ Calcd for C30H32F3N6O2565.2; Found 565.2. ¹H NMR (400MHz, CDCl₃) į = 9.01 - 8.91 (m, 2H), 8.32 (d, J=8.0 Hz, 1H), 7.50 (dd, J=4.4, 8.4 Hz, 1H), 7.33 (d, J=8.4 Hz, 2H), 7.12 (d, J=8.4 Hz, 2H), 6.65 (q, J=9.2 Hz, 1H), 6.45 (s, 1H), 3.05 - 2.97 (m, 1H), 2.97 - 2.80 (m, 3H), 2.74 - 2.62 (m, 1H), 2.39 (s, 3H), 2.34 - 2.24 (m, 2H), 2.13 - 2.01 (m, 2H), 2.01 - 1.91 (m, 1H), 1.85 - 1.76 (m, 2H), 1.75 - 1.67 (m, 2H), 1.36 - 1.26 (m, 2H), 1.14 - 1.03 (m, 2H). 12. Synthesis of Exemplary Intermediates [00224] The following exemplary intermediates were synthesized and used for the synthesis of one or more exemplified compounds of formula (I). Synthesis of 4-cyclopropyl-1,5-naphthyridin-3-amine [Intermediate 1.1]:

Synthesis of 1,3-diethyl 2-{[(pyridin-3-yl)amino]methylidene}propanedioate [INT 1-b]: [00225] A mixture of pyridin-3-amine (46 g, 488 mmol) and 1,3-diethyl 2- (ethoxymethylidene)propanedioate [INT 1-a] (126 g, 585 mmol) in EtOH (400 mL) was stirred at 85 °C for 16 hours. The reaction mixture was concentrated, triturated with petroleum ether (1500 mL) and filtered. The precipitate was dried to give 1,3-diethyl 2-{[(pyridin-3- yl)amino]methylidene}propanedioate [INT 1-b] (103 g, 80.4% yield) as a solid. ¹H NMR (400MHz, CHLOROFORM-d) į = 11.01 (br d, J = 13.2 Hz, 1H), 8.52-8.44 (m, 2H), 8.41 (d, J = 4.4 Hz, 1H), 7.51-7.45 (m, 1H), 7.32 (dd, J = 4.8, 8.4 Hz, 1H), 4.32 (q, J = 7.2 Hz, 2H), 4.25 (q, J = 7.2 Hz, 2H), 1.38 (t, J = 7.2 Hz, 3H), 1.33 (t, J = 7.2 Hz, 3H). Synthesis of ethyl 4-hydroxy-1,5-naphthyridine-3-carboxylate [INT 1-c]: [00226] 1,3-diethyl 2-{[(pyridin-3-yl)amino]methylidene}propanedioate [INT 1-b] (52 g, 196 mmol) was added to Ph₂O (500 mL) at 250 °C. The reaction mixture was stirred at 250 °C for 5 min. and the reaction mixture was cooled to room temperature. Another batch of the same reaction conditions was performed and combined with the first batch. Petroleum ether (2000 mL) was added. The mixture was stirred for 10 min and filtered. The precipitate was triturated with petroleum ether (500 mL) and dried to give ethyl 4-hydroxy-1,5-naphthyridine-3- carboxylate [INT 1-c] (37.0 g, 50% purity, 21.6% average yield) as a solid. ¹H NMR (400MHz, DMSO-d6) į = 12.96-12.40 (br s, 1H) 8.70 (d, J = 2.4 Hz, 1H), 8.68 (s, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.71 (d, J = 8.4 Hz), 4.26-4.20 (m, 2H), 1.30-1.26 (m, 3H). Synthesis of ethyl 4-bromo-1,5-naphthyridine-3-carboxylate [INT 1-d]: [00227] To a mixture of ethyl 4-hydroxy-1,5-naphthyridine-3-carboxylate [INT 1-c] (20 g, 91.6 mmol) in DMF (200 mL) was added tribromophosphane (49.5 g, 183 mmol) at 0 °C. Then the reaction mixture was stirred at 15 °C under nitrogen for 12 hours. The reaction mixture was basified with saturated NaHCO₃ to pH = 8 and EtOAc (1000 mL) was added. The mixture was filtered and the filtrate was extracted with EtOAc (500 mL × 2). The combined organic layers were washed with brine (1500 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give crude product which was purified by flash chromatography on silica gel (0-45% EtOAc in petroleum ether) to give ethyl 4-bromo-1,5-naphthyridine-3- carboxylate [INT 1-d] (8.20 g, 31.9% yield) as a solid. m/z: [M + H]+ Calcd for C11H10BrN2O2281.1; Found 280.9. ¹H NMR (400MHz, CHLOROFORM-d) į = 9.17 (d, J = 4.0 Hz, 1H), 9.14 (s, 1H), 8.47 (d, J = 8.8 Hz, 1H), 7.79 (dd, J = 4.0, 8.4 Hz, 1H), 4.55 (q, J = 7.2 Hz, 2H), 1.50 (t, J = 7.2 Hz, 3H). Synthesis of ethyl 4-cyclopropyl-1,5-naphthyridine-3-carboxylate [INT 1-e]: [00228] To a mixture of ethyl 4-bromo-1,5-naphthyridine-3-carboxylate [INT 1-d] (10.5 g, 37.3 mmol) and cyclopropylboronic acid (6.40 g, 74.6 mmol) in toluene (200 mL) was added tripotassium phosphate (23.5 g, 111 mmol) and palladium(2+) diacetate (1.67 g, 7.46 mmol). The reaction mixture was stirred at 100 °C under nitrogen for 16 hours. The reaction mixture was diluted with EtOAc (500 mL) and filtered. The filtrate was concentrated to give crude product which was purified by flash chromatography on silica gel (0-20% EtOAc in petroleum ether) to give ethyl 4-cyclopropyl-1,5-naphthyridine-3-carboxylate [INT 1-e] (4.40 g, 48.7% yield) as an oil. m/z: [M + H]+ Calcd for C14H15N2O2243.1; Found 243.0. ¹H NMR (400MHz, CHLOROFORM-d) į = 9.05 (s, 1H), 8.99 (dd, J = 2.0, 4.4 Hz, 1H), 8.38 (dd, J = 2.0, 8.4 Hz, 1H), 7.66 (dd, J = 4.0, 8.4 Hz, 1H), 4.50 (q, J = 7.2 Hz, 2H), 2.82-2.72 (m, 1H), 1.47 (t, J = 7.2 Hz, 3H), 1.45-1.40 (m, 2H), 1.29-1.23 (m, 2H). Synthesis of 4-cyclopropyl-1,5-naphthyridine-3-carboxylic acid [INT 1-f]: [00229] To a mixture of ethyl 4-cyclopropyl-1,5-naphthyridine-3-carboxylate [INT 1-e] (4.4 g, 18.1 mmol) in THF (15 mL), MeOH (15 mL) and H2O (15 mL) was added lithium(1+) hydrate hydroxide (2.27 g, 54.0 mmol). The reaction mixture was stirred at 15 °C for 3 hours. The reaction mixture was concentrated to give a residue. The residue was dissolved in water (30 mL), acidified with 1 M HCl to pH = 4 and filtered. The precipitate was dried to give 4- cyclopropyl-1,5-naphthyridine-3-carboxylic acid [INT 1-f] (3.30 g, 85.2% yield) as a solid. m/z: [M + H]+ Calcd for C12H11N2O2215.1; Found 214.8. ¹H NMR (400MHz, METHANOL-d4) į = 9.00 (s, 1H), 8.98 (dd, J = 1.6, 4.0 Hz, 1H), 8.37 (dd, J = 1.6, 8.4 Hz, 1H), 7.78 (dd, J = 4.4, 8.4 Hz, 1H), 2.89-2.79 (m, 1H), 1.60-1.55 (m, 2H), 1.28-1.22 (m, 2H). Synthesis of benzyl N-(4-cyclopropyl-1,5-naphthyridin-3-yl)carbamate [INT 1-g]: [00230] This reaction was done in two batches. Batch #1: To a mixture of 4-cyclopropyl-1,5- naphthyridine-3-carboxylic acid [INT 1-f] (200 mg, 933 μmol) and phenylmethanol (120 mg, 1.11 mmol) in toluene (2 mL) was added {[azido(phenoxy)phosphoryl]oxy}benzene (382 mg, 1.39 mmol) and triethylamine (188 mg, 1.86 mmol). The reaction mixture was stirred at 100 °C under nitrogen for 3 hours. Batch #2: To a mixture of 4-cyclopropyl-1,5-naphthyridine-3- carboxylic acid (50 mg, 233 μmol) and phenylmethanol (30.1 mg, 279 μmol) in toluene (1 mL ) was added {[azido(phenoxy)phosphoryl]oxy}benzene (96.0 mg, 349 μmol) and triethylamine (47.1 mg, 466 μmol). The reaction mixture was stirred at 100 °C under nitrogen for 3 hours. The two reaction batches were combined and concentrated to give crude product which was purified by flash chromatography on silica gel (0-4% MeOH in CH2Cl2) to give benzyl N-(4- cyclopropyl-1,5-naphthyridin-3-yl)carbamate [INT 1-g] (230 mg, 61.9% average yield) as an oil. m/z: [M + H]+ Calcd for C19H18N3O2320.1; Found 319.9. ¹H NMR (400MHz, CHLOROFORM-d) į = 9.68 (br s, 1H), 8.98 (dd, J = 1.6, 4.0 Hz, 1H), 8.36 (d, J = 8.8 Hz, 1H), 7.55 (dd, J = 4.4, 8.4 Hz, 1H), 7.50-7.37 (m, 6H), 5.30 (s, 2H), 2.08-1.97 (m, 1H), 1.39-1.33 (m, 2H), 1.05-0.96 (m, 2H). Synthesis of 4-cyclopropyl-1,5-naphthyridin-3-amine [INT 1.1]: [00231] To a mixture of benzyl N-(4-cyclopropyl-1,5-naphthyridin-3-yl)carbamate [INT 1-g] (230 mg, 720 μmol) in THF (4 mL) and H₂O (2 mL) was added sodium hydroxide (287 mg, 7.19 mmol). The reaction mixture was stirred at 70 °C for 12 hours. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (5 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give crude product which was purified by flash chromatography on silica gel (0-3% MeOH in CH2Cl2) to give 4-cyclopropyl-1,5-naphthyridin-3-amine [INT 1.1] (100 mg, 75.1% yield) as a solid. NMR (400MHz, CHLOROFORM-d) į = 8.90 (dd, J = 1.6, 4.0 Hz, 1H), 8.51 (s, 1H), 8.21 (dd, J = 2.0, 8.4 Hz, 1H), 7.36 (dd, J = 4.4, 8.4 Hz, 1H), 4.47 (br s, 2H), 1.96-1.86 (m, 1H), 1.31-1.24 (m, 2H), 0.91-0.84 (m, 2H). Synthesis of 4-cyclopropyl-7-methoxy-1,5-naphthyridin-3-amine hydrochloride [Intermediate 1.2]:

Synthesis of diethyl 2-(((5-methoxypyridin-3-yl)amino)methylene)malonate [INT 1-i]: [00232] A solution of pyridin-3-amine [INT 1-h] (5 g, 40.2 mmol) and 1,3-diethyl 2- (ethoxymethylidene)propanedioate (9.71 mL, 48.2 mmol) in EtOH (32.9 mL) was stirred at 85 °C for 16 h. The mixture was concentrated under reduced pressure to give the crude product which was treated with pentene (300 mL). The mixture was sonicated and stirred for 30min, after which it was filtered to give diethyl 2-(((5-methoxypyridin-3-yl)amino)methylene)malonate [INT 1-i] (11.0 g, 37.6 mmol, 93.2% yield) as a pale yellow solid. m/z: [M + H]+ Calcd for C14H19N2O5295.1; Found 295.1. ¹H NMR (400 MHz, CDCl₃) į = 10.98 (d, J=13.4 Hz, 1H), 8.45 (d, J=13.4 Hz, 1H), 8.11 (d, J=2.3 Hz, 2H), 6.95 (t, J=2.3 Hz, 1H), 4.32 (q, J=7.1 Hz, 2H), 4.26 (q, J=7.1 Hz, 2H), 3.89 (s, 3H), 1.38 (t, J=7.1 Hz, 3H), 1.33 (t, J=7.1 Hz, 3H). Synthesis of ethyl 4-hydroxy-7-methoxy-1,5-naphthyridine-3-carboxylate [INT 1-j]: [00233] A solution of diethyl 2-(((5-methoxypyridin-3-yl)amino)methylene)malonate [INT 1- i] (450 mg, 1.52 mmol) in diphenyl ether (2.53 mL) in a sealed tube was heated to 250 °C in a microwave reactor for 20 mins. After completion, the mixture was poured into hexane. The mixture was stirred at 0 °C for 15 mins, and the precipitation was filtered. The filter cake was washed with hexane followed by EtOAc to give ethyl 4-hydroxy-7-methoxy-1,5-naphthyridine- 3-carboxylate [INT 1-j] (318 mg, 1.28 mmol, 84.3% yield) as a brown solid. m/z: [M + H]+ Calcd for C12H13N2O4249.1; Found 249.1. Synthesis of ethyl 4-bromo-7-methoxy-1,5-naphthyridine-3-carboxylate [INT 1-k]: [00234] To a solution of ethyl 4-hydroxy-7-methoxy-1,5-naphthyridine-3-carboxylate [INT 1-j] (2.8 g, 11.2 mmol) in dimethylformamide (9.33 mL) was added phosphorus tribromide (1.25 mL, 13.4 mmol) at room temperature and the mixture was stirred until completion. After completion, the mixture was poured onto ice water and the pH was adjusted to 8 with saturated aqueous NaHCO3. The mixture was stirred at 0 °C for 15 mins, then the precipitation was filtered to give ethyl 4-bromo-7-methoxy-1,5-naphthyridine-3-carboxylate [INT 1-k] (2.80 g, 8.99 mmol, 80.4% yield) as a brown solid. m/z: [M + H]+ Calcd for C12H12BrN2O3311.0; Found 311.0. ¹H NMR (400 MHz, CDCl3) į = 9.09 (s, 1H), 8.86 (d, J=2.8 Hz, 1H), 7.64 (d, J=2.8 Hz, 1H), 4.51 (q, J=7.1 Hz, 2H), 4.02 (s, 3H), 1.47 (t, J=7.2 Hz, 3H). Synthesis of ethyl 4-cyclopropyl-7-methoxy-1,5-naphthyridine-3-carboxylate [INT 1-l]: [00235] A mixture of ethyl 4-bromo-7-methoxy-1,5-naphthyridine-3-carboxylate [INT 1-k] (800 mg, 2.57 mmol), cyclopropylboronic acid (441 mg, 5.14 mmol), potassium phosphate (1.04 g, 7.71 mmol), and palladium(II) acetate (576 mg, 2.57 mmol) in toluene (25.6 mL) in a sealed tube was degassed. The mixture was heated at 95 ºC for 2 h. The mixture was cooled to rt and filtered through a pad of Celite. The filtrate was concentrated. EtOAc was added to the residue. The resulting solution was washed with sat. aq. NaHCO₃, water, and brine, dried over anhydrous MgSO₄ and concentrated under reduced pressure to give the crude product, which was purified by flash chromatography on silica gel (EtOAc/hexane = 0/1 to 1/1) to give ethyl 4-cyclopropyl- 7-methoxy-1,5-naphthyridine-3-carboxylate [INT 1-l] (143 mg, 0.5251 mmol, 20.4% yield) as a yellow solid. m/z: [M + H]+ Calcd for C15H17N2O3273.1; Found 273.1. ¹H NMR (400 MHz, CDCl3) į = 9.00 (s, 1H), 8.70 (d, J=2.9 Hz, 1H), 7.58 (d, J=2.9 Hz, 1H), 4.47 (q, J=7.1 Hz, 2H), 3.98 (s, 3H), 2.76 (tt, J=8.8, 5.7 Hz, 1H), 1.45 (t, J=7.2 Hz, 3H), 1.42 – 1.39 (m, 2H), 1.25 – 1.20 (m, 2H). Synthesis of 4-cyclopropyl-7-methoxy-1,5-naphthyridine-3-carboxylic acid [INT 1-m]: [00236] To a solution of ethyl 4-cyclopropyl-7-methoxy-1,5-naphthyridine-3-carboxylate [INT 1-l] (145 mg, 532 μmol) in THF (5 mL) and H2O (5 mL) was added lithium (1+) hydrate hydroxide (156 mg, 3.72 mmol). The mixture was stirred at 20 °C for 16 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was dissolved with water (3 mL) and adjusted with 1 M HCl to pH = 4 - 5. A precipitate was collected by filtration and washed with water (10 mL). The filter cake was dried under reduced pressure to give 4-cyclopropyl-7-methoxy-1,5-naphthyridine-3-carboxylic acid [INT 1-m] (90.0 mg, 0.368 mmol, 69.7% yield) as a yellow solid. m/z: [M + H]+ Calcd for C13H13N2O3245.1; Found 244.9. Synthesis of tert-butyl (4-cyclopropyl-7-methoxy-1,5-naphthyridin-3-yl)carbamate [INT 1-n]: [00237] To a solution of 4-cyclopropyl-7-methoxy-1,5-naphthyridine-3-carboxylic acid [INT 1-m] (70.0 mg, 286 μmol) in toluene (5 mL) was added diphenyl phosphoryl azide (157 mg, 572 μmol), t-BuOH (2 mL) and potassium tert-butoxide (208 mg, 1.86 mmol). The reaction mixture was stirred at 100 °C for 16 hours under N₂ atmosphere. The mixture was concentrated under reduced pressure to give the crude product, which was purified by flash chromatography on silica gel (0 - 50 % EtOAc in petroleum ether) to give tert-butyl (4-cyclopropyl-7-methoxy-1,5- naphthyridin-3-yl)carbamate [INT 1-n] (22.5 mg, 0.071 mmol, 24.9% yield) as a white solid. m/z: [M + H]+ Calcd for C17H22N3O3316.2; Found 316.0. Synthesis of 4-cyclopropyl-7-methoxy-1,5-naphthyridin-3-amine hydrochloride [INT 1.2]: [00238] A solution of tert-butyl (4-cyclopropyl-7-methoxy-1,5-naphthyridin-3-yl)carbamate [INT 1-n] (22.3 mg, 70.7 μmol) in 4 M HCl/dioxane (5 mL) was stirred at 20 °C for 16 hours. The reaction was concentrated under reduced pressure to give 4-cyclopropyl-7-methoxy-1,5- naphthyridin-3-amine hydrochloride [INT 1.2] (17.7 mg, 70.3 μmol, 100% yield) as a white solid. m/z: [M + H]+ Calcd for C12H14N3O 216.1; Found 216.0. Synthesis of 4-cyclopropyl-7-methyl-1,5-naphthyridin-3-amine hydrochloride [Intermediate 1.3]:

Synthesis of diethyl 2-(((5-methylpyridin-3-yl)amino)methylene)malonate [INT 1-p]: [00239] A solution of 5-methylpyridin-3-am [INT 1-o] (7 g, 64.7 mmol) and 1,3-diethyl 2- (ethoxymethylidene)propanedioate (15.6 mL, 77.6 mmol) in EtOH (53.0 mL) was stirred at 85 °C for 16h. The mixture was concentrated under reduced pressure to give the crude product which was treated with pentane. The mixture was sonicated and stirred for 30min, filtered to give diethyl 2-(((5-methylpyridin-3-yl)amino)methylene)malonate [INT 1-p] (15.0 g, 53.8 mmol) as a pale white solid. m/z: [M + H]+ Calcd for C14H19N2O4279.1; Found 279.2. Synthesis of ethyl 4-hydroxy-7-methyl-1,5-naphthyridine-3-carboxylate [INT 1-q]: [00240] A solution of diethyl 2-(((5-methylpyridin-3-yl)amino)methylene)malonate [INT 1- p] (4 g, 14.3 mmol) in diphenyl ether (23.8 mL) in a sealed tube was heated to 250 °C in a microwave reactor for 20 mins. After completion, the mixture was diluted with EtOAc, stirred for 15 mins, and the precipitation was filtered. The filter cake was washed with EtOAc to give crude ethyl 4-hydroxy-7-methyl-1,5-naphthyridine-3-carboxylate [INT 1-q] (2.10 g, 9.04 mmol, 63.2% yield) as a brown solid, which was used as is in the next step. Synthesis of ethyl 4-bromo-7-methyl-1,5-naphthyridine-3-carboxylate [INT 1-r]: [00241] To a solution of ethyl 4-hydroxy-7-methyl-1,5-naphthyridine-3-carboxylate [INT 1- q] (2.05 g, 8.82 mmol) in dimethylformamide (7.35 mL) was added phosphorus tribromide (986 μL, 10.5 mmol) at room temperature and the mixture was stirred until completion. After completion, the mixture was poured onto ice water and the pH was adjusted to 8 with saturated aqueous NaHCO3. The mixture was stirred at 0 °C for 15 mins, then the precipitation was filtered and washed with water. The filtrate was then extracted with EtOAc (x 3), dried over anhydrous NaHCO3, and concentrated under reduced pressure. This mixture was combined with the filtered solid and purified by flash chromatography on silica gel (EtOAc/hexane = 1/9 to 1/1) to give ethyl 4-bromo-7-methyl-1,5-naphthyridine-3-carboxylate [INT 1-r] (480 mg, 1.62 mmol, 18.4% yield) as a yellow solid. m/z: [M + H]+ Calcd for C12H12BrN2O2295.0; Found 294.9. Synthesis of ethyl 4-cyclopropyl-7-methoxy-1,5-naphthyridine-3-carboxylate [INT 1-s]: [00242] A mixture of ethyl 4-bromo-7-methyl-1,5-naphthyridine-3-carboxylate [INT 1-r] (400 mg, 1.35 mmol), cyclopropylboronic acid (231 mg, 2.70 mmol), potassium phosphate (551 mg, 4.05 mmol), and palladium(II) acetate (60.6 mg, 270 μmol) in toluene (13.5 mL) was stirred at 100 °C until LCMS indicated completion. After completion, the mixture was diluted with EtOAc and filtered over short path silica. The filtrate was concentrated under reduced pressure to give the crude product, which was purified by flash chromatography on silica gel (EtOAc/hexane = 0/1 to 1/1) to give ethyl 4-cyclopropyl-7-methyl-1,5-naphthyridine-3- carboxylate [INT 1-s] (159 mg, 0.6236 mmol, 45.9% yield) as a yellow solid. m/z: [M + H]+ Calcd for C15H17N2O2257.1; Found 257.0. ¹H NMR (400 MHz, CDCl3) į = 9.00 (s, 1H), 122 8.82 (d, J=2.2 Hz, 1H), 8.10 (s, 1H), 4.48 (q, J=7.1 Hz, 2H), 2.76 (tt, J=8.8, 5.7 Hz, 1H), 2.57 (s, 3H), 1.45 (t, J=7.1 Hz, 3H), 1.43 -1.39 (m, 2H), 1.25 - 1.20 (m, 2H). Synthesis of 4-cyclopropyl-7-methyl-1,5-naphthyridine-3-carboxylic acid [INT 1-t]: [00243] To a solution of ethyl 4-cyclopropyl-7-methyl-1,5-naphthyridine-3-carboxylate [INT 1-s] (147 mg, 573 μmol) in THF (2 mL) and H2O (2 mL) was added lithium (1+) hydrate hydroxide (168 mg, 4.01 mmol). The mixture was stirred at 20 °C for 16 hours. The reaction mixture was concentrated under reduced pressure to give the residue. The residue was dissolved with water (3 mL), adjusted with 1 M HCl solution to pH = 4 - 5. A precipitate was collected by filtration, washed with water (10 mL). The filter cake was dried under reduced pressure to give 4-cyclopropyl-7-methyl-1,5-naphthyridine-3-carboxylic acid [INT 1-t] (110 mg, 482 μmol, 84.6% yield) as a yellow solid. m/z: [M + H]+ Calcd for C13H13N2O2229.1; Found 229.0. Synthesis of tert-butyl (4-cyclopropyl-7-methyl-1,5-naphthyridin-3-yl)carbamate [INT 1-u]: [00244] To a solution of 4-cyclopropyl-7-methyl-1,5-naphthyridine-3-carboxylic acid [INT 1- t] (90 mg, 394 μmol) in toluene (5 mL) was added diphenyl phosphoryl azide (216 mg, 788 μmol), t-BuOH (2 mL), and potassium tert-butoxide (132 mg, 1.18 mmol). The reaction mixture was stirred at 100 °C for 16 hours under N2 atmosphere. The mixture was concentrated under reduced pressure to give the crude product, which was purified by flash chromatography on silica gel (0 - 50 % EtOAc in petroleum ether) to give tert-butyl (4-cyclopropyl-7-methyl-1,5- naphthyridin-3-yl)carbamate [INT 1-u] (80.0 mg, 68.3% yield) as a white solid. m/z: [M + H]+ Calcd for C17H22N3O2300.2; Found 300.0. Synthesis of 4-cyclopropyl-7-methyl-1,5-naphthyridin-3-amine hydrochloride [INT 1.3]: [00245] A solution of tert-butyl (4-cyclopropyl-7-methyl-1,5-naphthyridin-3-yl)carbamate [INT 1-u] (70.0 mg, 233 μmol) in 4 M HCl/dioxane (20 mL) was stirred at 20 °C for 3 hours. The reaction was concentrated under reduced pressure to give 4-cyclopropyl-7-methyl-1,5- naphthyridin-3-amine hydrochloride [INT 1.3] (70.0 mg, crude) as a yellow solid. m/z: [M + H]+ Calcd for C12H14N3200.1; Found 199.8. Synthesis of 4-cyclopropyl-6-(trifluoromethyl)-1,5-naphthyridin-3-amine hydrochloride [Intermediate 1.4]:

Synthesis of diethyl 2-(((6-(trifluoromethyl)pyridin-3-yl)amino)methylene)malonate [INT 1-w]: [00246] A solution of 6-(trifluoromethyl)pyridin-3-amine [INT 1-v] (10 g, 61.6 mmol) in ethyl alcohol (10 mL) was added dropwise into neat 1,3-diethyl 2- (ethoxymethylidene)propanedioate (13.9 g, 64.6 mmol). The Solution was stirred for 1 h at rt, after which it was heated to 80 °C. After 3.5 hours, the mixture was cooled to 0 °C. Cold EtOH (5 mL) was added and the solids were broken up and filtered (orange color filters out washing with cold EtOH), yielding diethyl 2-(((6-(trifluoromethyl)pyridin-3- yl)amino)methylene)malonate [INT 1-w] (19.2 g, 57.7 mmol, 94% yield) as an off-white fluffy solid. m/z: [M + H]+ Calcd for C14H16F3N2O4333.1; Found 333.0. ¹H NMR (400 MHz, CDCl₃): į = 11.13 (d, J=13.1 Hz, 1H), 8.54 (s, 1H), 8.47 (d, J=13.1 Hz, 1H), 7.70 (d, J=8.6 Hz, 1H), 7.59 (d, J=8.7 Hz, 1H), 4.33 (q, J=7.1 Hz, 2H), 4.27 (q, J=7.2 Hz, 2H), 1.39 (t, J=7.2 Hz, 3H), 1.34 (t, J=7.1 Hz, 3H). Synthesis of ethyl 4-hydroxy-6-(trifluoromethyl)-1,5-naphthyridine-3-carboxylate [INT 1-x]: [00247] A preheated (100 °C) solution of diethyl 2-(((6-(trifluoromethyl)pyridin-3- yl)amino)methylene)malonate [INT 1-w] (19.4 g, 58.3 mmol) in Dowtherm A (11.6 mL) was added to a refluxing 260 °C solution of Dowtherm A (97.1 mL) heated by a manual heating mantle with probes in the reaction mixture and mantle. After 4h, the mixture was poured onto cold (-30 °C) octane and the mixture was stirred at -30 °C for 15 min. The mixture was then filtered and the residue was triturated in EtOAc and H2O (together) overnight. The mixture was filtered to yield a mixture of ethyl 4-hydroxy-6-(trifluoromethyl)-1,5-naphthyridine-3- carboxylate [INT 1-x] (5.50 g, 19.2 mmol, 33% yield), ethyl 4-hydroxy-6-(trifluoromethyl)-1,7- naphthyridine-3-carboxylate (4.50 g, 15.7 mmol, 27% yield) and ethyl 4-ethoxy-6- (trifluoromethyl)-1,5-naphthyridine-3-carboxylate (1.11 g, 3.53 mmol, 6% yield) as a grayish beige powder.1H-NMR shows 55:45 ratio of regioisomers (desired 1,5-naphtyridine is major). plus ~ 10 mol% of the ethyl ether products). m/z: [M + H]+ Calcd for C12H10N2O3287.1; Found 286.9. ¹H NMR (400 MHz, D2O): į = 8.71 (s, 1H), 8.08 (d, J=8.7 Hz, 1H), 7.80 (d, J=8.7 Hz, 1H), 4.21 (q, J=7.0 Hz, 2H), 1.24 (t, J=7.1 Hz, 3H). Synthesis of ethyl 4-bromo-6-(trifluoromethyl)-1,5-naphthyridine-3-carboxylate [INT 1-y]: [00248] Ethyl 4-hydroxy-6-(trifluoromethyl)-1,5-naphthyridine-3-carboxylate [INT 1-x] (3.5 g, 12.2 mmol) was suspended/dissolved in dimethylformamide (12.2 mL) at 0 °C. Phosphorus tribromide (2.50 mL, 26.4 mmol) was added dropwise. The mixture was warmed to rt. After 2 h, the reaction was poured into ice cold sat. aqueous NaHCO₃, stirred for 10 min, and filtered to yield 7.2 g of gray solid. This solid was purified by flash chromatography (5-15% EtOAc/hexane) to yield ethyl 4-bromo-6-(trifluoromethyl)-1,5-naphthyridine-3-carboxylate [INT 1-y] (4.18 g, 11.9 mmol, 98% yield from the corresponding OH isomer). m/z: [M + H]+ Calcd for C12H9BrF3N2O2349.0; Found 349.0. ¹H NMR (400 MHz, CDCl3): į = 9.21 (s, 1H), 8.64 (d, J=8.7 Hz, 1H), 8.07 (d, J=8.7 Hz, 1H), 4.55 (q, J=7.1 Hz, 2H), 1.49 (t, J=7.1 Hz, 3H). Synthesis of ethyl 4-cyclopropyl-6-(trifluoromethyl)-1,5-naphthyridine-3-carboxylate [INT 1-z]: [00249] A mixture of ethyl 4-bromo-6-(trifluoromethyl)-1,5-naphthyridine-3-carboxylate [INT 1-y] (800 mg, 2.29 mmol), cyclopropylboronic acid (393 mg, 4.58 mmol), potassium phosphate (933 mg, 6.86 mmol), and palladium(II) acetate (102 mg, 458 μmol) in toluene (22.8 mL) was stirred at 100 °C until LCMS indicated completion. After completion, the mixture was diluted with EtOAc and filtered over short path silica. The filtrate was concentrated under reduced pressure to give the crude product, which was purified by flash chromatography on silica gel (EtOAc/hexane = 0/1 to 1/1) to give ethyl 4-cyclopropyl-6-(trifluoromethyl)-1,5- naphthyridine-3-carboxylate [INT 1-z] (517 mg, 1.66 mmol, 72.8% yield) as a yellow solid. m/z: [M + H]+ Calcd for C15H14F3N2O2311.1; Found 310.9. ¹H NMR (400 MHz, CDCl₃) į = 9.13 (s, 1H), 8.53 (d, J=8.7 Hz, 1H), 7.94 (d, J=8.7 Hz, 1H), 4.50 (q, J = 7.1 Hz, 2H), 2.90 - 2.83 (m, 1H), 1.91 - 1.87 (m, 2H), 1.47 (t, J=7.1 Hz, 3H), 1.26-1.31 (m, 2H). Synthesis of 4-cyclopropyl-6-(trifluoromethyl)-1,5-naphthyridine-3-carboxylic acid [INT 1-aa]: [00250] To a mixture of ethyl 4-cyclopropyl-6-(trifluoromethyl)-1,5-naphthyridine-3- carboxylate [INT 1-z] (445 mg, 1.43 mmol) in THF (3 mL) and H2O (1 mL) was added lithium(1+) hydrate hydroxide (120 mg, 2.86 mmol). The mixture was stirred at 15 °C for 4 hours, after which it was concentrated under reduced pressure to give a residue. The residue was dissolved with water (10 mL) and adjusted with 1 M HCl to pH = 3-4. The mixture was extracted with EtOAc (50 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 4-cyclopropyl-6- (trifluoromethyl)-1,5-naphthyridine-3-carboxylic acid [INT 1-aa] (400 mg, 99.2% yield) as an off-white solid. m/z: [M + H]+ Calcd for C13H10F3N2O2283.1; Found 282.9. ¹H NMR (400MHz, CDCl3) į = 9.37 (s, 1H), 8.64 (d, J=8.4 Hz, 1H), 7.99 (d, J=8.8 Hz, 1H), 3.19 - 3.10 (m, 1H), 2.15 - 2.09 (m, 2H), 1.43 - 1.34 (m, 2H). Synthesis of tert-butyl (4-cyclopropyl-6-(trifluoromethyl)-1,5-naphthyridin-3-yl)carbamate [INT 1-bb]: [00251] A mixture of 4-cyclopropyl-6-(trifluoromethyl)-1,5-naphthyridine-3-carboxylic acid [INT 1-aa] (400 mg, 1.41 mmol), 2-methylpropan-2-ol (1.56 g, 21.1 mmol), diphenylphosphoryl azide (513 mg, 2.11 mmol), and triethylamine (428 mg, 4.23 mmol) in toluene (4 mL) was stirred at 100 °C for 2 hours. The reaction mixture was quenched with saturated NaHCO3 (50 mL) and extracted with EtOAc (50 mL × 2). The combined organic layers were washed with brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product, which was purified by flash chromatography on silica gel (0 - 10% EtOAc in petroleum ether) to give tert-butyl (4-cyclopropyl-6-(trifluoromethyl)-1,5- naphthyridin-3-yl)carbamate [INT 1-bb] (257 mg, 0.727 mmol, 51.6% yield) as a yellow solid. m/z: [M + H]+ Calcd for C17H19F3N3O2354.1; Found 354.1. ¹H NMR (400MHz, CDCl3) į = 9.73 (s, 1H), 8.51 (d, J=8.4 Hz, 1H), 7.83 (d, J=8.8 Hz, 1H), 2.10 - 1.95 (m, 1H), 1.59 (s, 9H), 1.39 - 1.33 (m, 2H), 1.21 - 1.15 (m, 2H). Synthesis of 4-cyclopropyl-6-(trifluoromethyl)-1,5-naphthyridin-3-amine hydrochloride [INT 1.4]: [00252] A mixture of tert-butyl (4-cyclopropyl-6-(trifluoromethyl)-1,5-naphthyridin-3- yl)carbamate [INT 1-bb] (207 mg, 585 μmol) in 4 M HCl/dioxane (10 mL, 40.0 mmol) was stirred at 25 °C for 4 hours. The mixture was concentrated under reduced pressure to afford the crude product 4-cyclopropyl-6-(trifluoromethyl)-1,5-naphthyridin-3-amine hydrochloride [INT 1.4] (150 mg, 88.7% yield) as a yellow solid. m/z: [M+H]+ Calcd for C12H11F3N3254.1; Found 253.9. Synthesis of 4-cyclopropyl-6-(trifluoromethyl)-1,5-naphthyridin-3-amine hydrochloride [Intermediate 1.5]:

Synthesis of ethyl 4-cyclopropyl-6-methoxy-1,5-naphthyridine-3-carboxylate [INT 1-dd]: [00253] A mixture of ethyl 4-bromo-6-methoxy-1,5-naphthyridine-3-carboxylate [INT 1-cc] (1000 mg, 3.21 mmol), cyclopropylboronic acid (551 mg, 6.42 mmol), potassium phosphate (1.30 g, 9.62 mmol), and palladium(II) acetate (144 mg, 642 μmol) in toluene (32.0 mL) was degassed in a sealed tube. The mixture was heated at 95 ºC for 2 h. The mixture was cooled to rt and filtered through a pad of celite. The filtrate was concentrated and EtOAc was added to the residue. The resulting solution was washed with sat. aq. NaHCO₃, water, and brine, dried over anhydrous MgSO₄, and concentrated under reduced pressure to give the crude product, which was purified by flash chromatography on silica gel (EtOAc/hexane = 0/1 to 3/7) to give ethyl 4- cyclopropyl-6-methoxy-1,5-naphthyridine-3-carboxylate [INT 1-dd] (743 mg, 2.73 mmol, 85.0% yield) as a yellow solid. m/z: [M + H]+ Calcd for C15H17N2O3273.1; Found 273.1. ¹H NMR (400 MHz, CDCl3) į = 8.87 (s, 1H), 8.15 (d, J=9.0 Hz, 1H), 7.12 (d, J = 9.0 Hz, 1H), 4.47 (q, J=7.1 Hz, 2H), 4.06 (s, 3H), 2.67 (tt, J=8.8, 5.7 Hz, 1H), 1.69 – 1.65 (m, 2H), 1.45 (t, J=7.1 Hz, 3H), 1.18 – 1.13 (m, 2H). Synthesis of 4-cyclopropyl-6-methoxy-1,5-naphthyridine-3-carboxylic acid [INT 1-ee]: [00254] To a mixture of ethyl 4-cyclopropyl-6-methoxy-1,5-naphthyridine-3-carboxylate [INT 1-dd] (646 mg, 2.37 mmol) in THF (6 mL) and H2O (2 mL) was added LiOH·H2O (793 mg, 18.9 mmol) and the mixture was stirred at 50 °C for 16 hours. The mixture was concentrated under reduced pressure to afford the crude product. 1N HCl was added to adjust the pH to 3-4 and the mixture was extracted with EtOAc (50 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 4-cyclopropyl-6-methoxy-1,5-naphthyridine-3-carboxylic acid [INT 1-ee] (400 mg, 1.64 mmol, 69.2% yield) as an off-white solid. m/z: [M + H]⁺ Calcd for C₁₃H₁₃N₂O₃245.1; Found 244.9. ¹H NMR (400MHz, DMSO-d₆) į = 8.81 (s, 1H), 8.24 (d, J=9.2 Hz, 1H), 7.29 (d, J=9.2 Hz, 1H), 4.01 (s, 3H), 2.74 - 2.66 (m, 1H), 1.87 - 1.79 (m, 2H), 1.16 - 1.10 (m, 2H). Synthesis of tert-butyl (4-cyclopropyl-6-methoxy-1,5-naphthyridin-3-yl)carbamate [INT 1-ff]: [00255] A mixture of 4-cyclopropyl-6-methoxy-1,5-naphthyridine-3-carboxylic acid [INT 1- ee] (400 mg, 1.63 mmol), 2-methylpropan-2-ol (1.80 g, 24.4 mmol), diphenylphosphoryl azide (593 mg, 2.44 mmol) and triethylamine (494 mg, 4.89 mmol) in toluene (4 mL) was stirred at 100 °C for 2 hours. The reaction mixture was quenched with saturated NaHCO₃ (30 mL) and extracted with EtOAc (30 mL × 2). The combined organic layers were washed with brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product, which was purified by flash chromatography on silica gel (0 - 10% EtOAc in petroleum ether) to give tert-butyl (4-cyclopropyl-6-methoxy-1,5-naphthyridin-3- yl)carbamate [INT 1-ff] (231 mg, 0.732 mmol, 44.9% yield) as a white solid. m/z: [M+H]+ Calcd for C17H22N3O3316.2; Found 316.0. ¹H NMR (400MHz, DMSO-d6) į = 9.11 (s, 1H), 8.58 (s, 1H), 8.16 (d, J=9.2 Hz, 1H), 7.13 (d, J=9.2 Hz, 1H), 3.97 (s, 3H), 2.25 - 2.20 (m, 1H), 1.59 - 1.53 (m, 2H), 1.47 (s, 9H), 1.08 - 1.02 (m, 2H). Synthesis of 4-cyclopropyl-6-methoxy-1,5-naphthyridin-3-amine hydrochloride [INT 1.5]: [00256] A mixture of tert-butyl (4-cyclopropyl-6-methoxy-1,5-naphthyridin-3-yl)carbamate [INT 1-ff] (181 mg, 573 μmol) in 4 M HCl/dioxane (5 mL) was stirred at 25 °C for 4 hours. The mixture was concentrated under reduced pressure to afford the crude product 4-cyclopropyl- 6-methoxy-1,5-naphthyridin-3-amine hydrochloride [INT 1.5] (110 mg, 437 μmol 76.4% yield) as a yellow solid. m/z: [M+H]+ Calcd for C12H14N3O 216.1; Found 215.9. Synthesis of 4-(propan-2-yl)-1,5-naphthyridin-3-amine hydrochloride [Intermediate 1.6]:

Synthesis of diethyl 2-((pyridin-3-ylamino)methylene)malonate [INT 1-hh]: [00257] A solution of pyridin-3-amine [INT 1-gg] (35 g, 371 mmol) and 1,3-diethyl 2- (ethoxymethylidene)propanedioate (89.9 mL, 445 mmol) in EtOH (304 mL) was stirred at 85 °C for 16h. The mixture was concentrated under reduced pressure to give the crude product which was treated with pentene (1.5L). The mixture was sonicated and stirred for 30min, filtered to give diethyl 2-((pyridin-3-ylamino)methylene)malonate [INT 1-hh] (93.7 g, 354 mmol, 95.6% yield) as a pale white solid. m/z: [M + H]+ Calcd for C13H17N2O4265.1; Found 265.1. ¹H NMR (400 MHz, CDCl3) į = 11.01 (d, J=13.3 Hz, 1H), 8.48 – 8.46 (m, 2H), 8.41 (d, J=4.7 Hz, 1H), 7.48 (m, 1H), 7.32 (dd, J=8.3, 4.7 Hz, 1H), 4.32 (q, J=7.1 Hz, 2H), 4.26 (q, J=7.1 Hz, 2H), 1.39 (t, J=7.1 Hz, 3H), 1.33 (t, J=7.1 Hz, 3H). Synthesis of 4-hydroxy-1,5-naphthyridine-3-carboxylate [INT 1-ii]: [00258] Diethyl 2-((pyridin-3-ylamino)methylene)malonate [INT 1-hh] (44.2 g, 167 mmol) was added in portions in diphenyl ether (240 mL) at 250 ºC. The reaction mixture was stirred for 30 min. The reaction mixture was cooled to rt and hexane (800 mL) was added. The resulting mixture was sonicated and stirred for 30 min, then filtered. The filter cake was washed with hexanes:EtOAc (1:1, 400 mL) and EtOH (50 mL x 2), after which it was dried under high vacuum to give ethyl 4-hydroxy-1,5-naphthyridine-3-carboxylate [INT 1-ii] (10.9 g, 50.3 mmol, 29.9% yield) as a brown solid. m/z: [M + H]+ Calcd for C11H11N2O3219.1; Found 219.0. ¹H NMR (400 MHz, DMSO-d6): į = 8.72 (d, J=4.2 Hz, 1H), 8.58 (s, 1H), 8.06 (d, J=8.5 Hz, 1H) 7.70 (dd, J=8.5, 4.3 Hz, 1H), 4.23 (q, J=7.1 Hz, 2H), 1.29 (t, J=7.1 Hz, 3H). Synthesis of ethyl 4-bromo-1,5-naphthyridine-3-carboxylate [INT 1-d]: [00259] To a solution of ethyl 4-hydroxy-1,5-naphthyridine-3-carboxylate [INT 1-ii] (6.4g, 29.3 mmol) in dimethylformamide (24.4 mL) was added phosphorus tribromide (3.29 mL, 35.1 mmol) at room temperature and the mixture was stirred until completion. After completion, the mixture was poured onto ice water and the pH was adjusted to 8 with saturated aqueous NaHCO3. The mixture was stirred at 0 °C for 15 mins, then the precipitation was filtered and washed with water. The filtrate was then extracted with EtOAc (x 3), dried over anhydrous MgSO4, and concentrated under reduced pressure. This material was combined with the filtered solid and purified by flash chromatography on silica gel (EtOAc/hexane = 1/9 to 1/1) to give ethyl 4-bromo-1,5-naphthyridine-3-carboxylate [INT 1-d] (790 mg, 2.81 mmol, 9.6% yield) as a yellow solid. m/z: [M + H]+ Calcd for C11H10BrN2O2281.0; Found 281.0. ¹H NMR (400 MHz, CDCl₃) į = 9.16 (dd, J=4.1, 1.6 Hz, 1H), 9.13 (s, 1H), 8.46 (dd, J=8.5, 1.6 Hz, 1H), 7.78 (dd, J=8.5, 4.1 Hz, 1H), 4.54 (q, J=7.1 Hz, 2H), 1.49 (t, J=7.2 Hz, 3H). Synthesis of ethyl 4-(propan-2-yl)-1,5-naphthyridine-3-carboxylate [INT 1-jj] and ethyl 4- propyl-1,5-naphthyridine-3-carboxylate [INT 1-kk]: [00260] To a flame dried microware tube was added ethyl 4-bromo-1,5-naphthyridine-3- carboxylate [INT 1-d] (600 mg, 2.13 mmol), palladium(II) acetate (4.78 mg, 21.3 μmol), xphos (20.3 mg, 42.6 μmol) and THF (8.52 mL). The vessel was evacuated and backfilled with argon (repeated 3 times). The mixture was cooled to 0 °C in an ice bath and a 0.5 M THF solution of 2-propylzinc bromide (5.10 mL, 2.55 mmol) was added slowly via syringe. The reaction was stirred at room temperature for 0.5h, after which additional palladium(II) acetate (4.78 mg, 21.3 μmol) and xphos (20.3 mg, 42.6 μmol) were added under argon. The mixture was cooled to 0 °C in an ice bath and a 0.5 M THF solution of 2-propylzinc bromide (3.4 mL) was added slowly via syringe. The reaction was stirred at room temperature for 0.5 h, after which it was quenched by the addition of sat. aq. NH4Cl and extracted with ethyl acetate (x 3). The combined organic layer was dried over Mg2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (EtOAc/hexane = 0/1 to 1/4) to give ethyl 4- (propan-2-yl)-1,5-naphthyridine-3-carboxylate [INT 1-jj] (127 mg, 0.5227 mmol, 24.4% yield) as a yellow oil and ethyl 4-propyl-1,5-naphthyridine-3-carboxylate [INT 1-kk] (190 mg, 0.7778 mmol, 36.5% yield) as a yellow solid. [00261] Ethyl 4-(propan-2-yl)-1,5-naphthyridine-3-carboxylate [INT 1-jj]: m/z: [M + H]+ Calcd for C14H17N2O2245.1; Found 245.1. ¹H NMR (400 MHz, CDCl3) į = 9.00 (dd, J=4.2, 1.8 Hz, 1H), 8.99 (s, 1H), 8.37 (dd, J=8.5, 1.8 Hz, 1H), 7.65 (dd, J=8.5, 4.0 Hz, 1H), 4.48 (q, J=7.1 Hz, 2H), 4.29 – 4.20 (m, 1H), 1.61 (q, J=7.2 Hz, 6H), 1.45 (q, J=7.1 Hz, 3H). [00262] Ethyl 4-propyl-1,5-naphthyridine-3-carboxylate [INT 1-kk]: [M + H]+ Calcd for C14H17N2O2245.1; Found 245.1. ¹H NMR (400 MHz, CDCl3) į = 9.29 (s, 1H), 9.04 (dd, J=4.1, 1.7 Hz, 1H), 8.38 (dd, J=8.5, 1.7 Hz, 1H), 7.68 (dd, J=8.5, 4.1 Hz, 1H), 4.49 (q, J=7.1 Hz, 2H), 3.66 (t, J = 7.8 Hz, 2H), 1.79 – 1.70 (m, 2H), 1.47 (t, J=7.1 Hz, 3H), 1.08 (t, J=7.3 Hz, 3H). Synthesis of 4-(propan-2-yl)-1,5-naphthyridine-3-carboxylic acid [INT 1-ll]: [00263] To a solution of ethyl 4-(propan-2-yl)-1,5-naphthyridine-3-carboxylate [INT 1-kk] (157 mg, 642 μmol) in THF (1mL) and H2O (1 mL) was added lithium (1+) hydrate hydroxide (134 mg, 3.21 mmol). The mixture was stirred at 20 °C for 16 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was dissolved with water (5 mL). The resulting mixture was adjusted with 1 M HCl solution to pH = 4 - 5. A precipitate was collected by filtration and washed with water (10 mL). The filter cake was dried under reduced pressure to give 4-(propan-2-yl)-1,5-naphthyridine-3-carboxylic acid [INT 1-ll] (90.0 mg, 416 μmol, 65.2% yield) as a white solid. m/z: [M + H]+ Calcd for C12H13N2O2217.1; Found 217.0. Synthesis of tert-butyl (4-isopropyl-1,5-naphthyridin-3-yl)carbamate [INT 1-mm]: [00264] To a solution of 4-(propan-2-yl)-1,5-naphthyridine-3-carboxylic acid [INT 1-ll] (70.0 mg, 323 μmol) in toluene (5 mL) was added diphenyl phosphoryl azide (177 mg, 646 μmol), t- BuOH (2 mL) and potassium tert-butoxide (108 mg, 969 μmol). The reaction mixture was stirred at 100 °C for 1 hour under N2 atmosphere. The mixture was concentrated under reduced pressure to give the crude product, which was purified by flash chromatography on silica gel (0 - 50 % EtOAc in petroleum ether) to give tert-butyl (4-isopropyl-1,5-naphthyridin-3-yl)carbamate [INT 1-mm] (36.0 mg, 125 μmol 38.7% yield) as a white solid. m/z: [M + H]+ Calcd for C16H22N3O2288.2; Found 288.0. Synthesis of 4-(propan-2-yl)-1,5-naphthyridin-3-amine hydrochloride [INT 1.6]: [00265] A solution of tert-butyl (4-isopropyl-1,5-naphthyridin-3-yl)carbamate [INT 1-mm] (36.0 mg, 125 μmol) in 4 M HCl/dioxane (2 mL) was stirred at 18 °C for 16 hours. The mixture was concentrated under reduced pressure to give 4-(propan-2-yl)-1,5-naphthyridin-3-amine hydrochloride [INT 1.6] (70.0 mg, 374 μmol, 40% purity, 100% yield) as a brown solid. m/z: [M + H]+ Calcd for C11H14N3188.1; Found 187.9. Synthesis of 4-(propan-2-yl)-1,5-naphthyridin-3-amine hydrochloride [Intermediate 1.7]:

Synthesis of 4-propyl-1,5-naphthyridine-3-carboxylic acid [INT 1-nn]: [00266] To a solution of ethyl 4-propyl-1,5-naphthyridine-3-carboxylate [INT 1-kk] (190 mg, 0.777 mmol) in THF (1 mL) and MeOH (1 mL) was added lithium(1⁺) hydrate hydroxide (65.0 mg, 1.55 mmol) in H2O (1 mL). The reaction was stirred at 20 °C for 2 hours. The reaction mixture was poured into water (5 mL), acidified with 1 N HCl to pH = 3 - 4 and extracted with EtOAc (10 mL × 2). The combined organic layers were washed with brine (10 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 4-propyl-1,5- naphthyridine-3-carboxylic acid [INT 1-nn] (165 mg, 0.763 mmol, 98.2% yield) as a yellow solid. m/z: [M + H]+ Calcd for C12H13N2O2217.1; Found 217.0. ¹H NMR (400MHz, DMSO-d6) į = 13.65 (s, 1H), 9.21 (s, 1H), 9.14 - 9.08 (m, 1H), 8.47 - 8.41 (m, 1H), 7.90 - 7.84 (m, 1H), 3.60 (t, J=7.6 Hz, 2H), 1.72 - 1.60 (m, 2H), 0.98 (t, J=7.2 Hz, 3H). Synthesis of tert-butyl (4-propyl-1,5-naphthyridin-3-yl)carbamate [INT 1-oo]: [00267] A solution of 4-propyl-1,5-naphthyridine-3-carboxylic acid [INT 1-nn] (145 mg, 0.670 mmol), diphenylphosphoryl azide (368 mg, 1.34 mmol), and triethylamine (338 mg, 3.35 mmol) in t-BuOH (2 mL) was stirred at 100 °C for 2 hours under N₂ atmosphere. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by flash chromatography on silica gel (0-25% EtOAc in petroleum ether) to give tert-butyl (4- propyl-1,5-naphthyridin-3-yl)carbamate [INT 1-oo] (65.0 mg, 0.226 mmol, 33.8% yield) as a yellow solid. m/z: [M + H]+ Calcd for C16H22N3O2288.2; Found 288.0. ¹H NMR (400MHz, CDCl3) į = 9.39 (s, 1H), 9.02 - 8.89 (m, 1H), 8.43 - 8.34 (m, 1H), 7.61 - 7.52 (m, 1H), 6.52 (s, 1H), 3.26 (t, J=7.6 Hz, 2H), 1.78 - 1.67 (m, 2H), 1.57 (s, 9H), 1.07 (t, J=7.2 Hz, 3H). Synthesis of 4-propyl-1,5-naphthyridin-3-amine hydrochloride [INT 1.7]: [00268] A solution of tert-butyl (4-propyl-1,5-naphthyridin-3-yl)carbamate [INT 1-oo] (65.0 mg, 0.226 mmol) in 4 M HCl/dioxane (2 mL) was stirred at 20 °C for 12 hours. The reaction was concentrated under reduced pressure to give the crude 4-propyl-1,5-naphthyridin-3-amine hydrochloride (50.0 mg, 0.224 mmol, 99% yield) as a yellow solid. m/z: [M + H]+ Calcd for C11H14N3188.1; Found 188.0.

Synthesis of 4-cyclopropyl-6-methyl-1,5-naphthyridin-3-amine hydrochloride [Intermediate 1.8]:

Synthesis of diethyl 2-(((6-methylpyridin-3-yl)amino)methylene)malonate [INT 1-qq]: [00269] A solution of 6-methylpyridin-3-amine [INT 1-pp] (10 g, 92.5 mmol) in ethyl alcohol (11 mL) was added dropwise into neat 1,3-diethyl 2-(ethoxymethylidene)propanedioate (20.9 g, 97.1 mmol). The solution was stirred for 1 h at rt, after which it was warmed to 60 °C for 1 h. The reaction was cooled to 0 °C (fills with small crystals after ~ 30min in ice bath). Cold EtOH (5 mL) was then added and the solids were broken up and filtered (dark brown color filters out). The solids were washed with cold EtOH, yielding 14g of diethyl 2-(((6- methylpyridin-3-yl)amino)methylene)malonate [INT 1-qq] as a pale beige fluffy solid. The filtrate was concentrated under vacuum until viscous, diluted in heptanes, and recrystallized (60 °C to 0 °C). Filtration (washing with heptanes) of this solid yielded an extra 7.4 g of product as a beige solid, providing a total of 21.4 g (80.0 mmol, 87% yield) of diethyl 2-(((6-methylpyridin- 3-yl)amino)methylene)malonate [INT 1-qq]. m/z: [M + H]+ Calcd for C14H19N2O4279.13; Found 279.00. ¹H NMR (400 MHz, CDCl3) į = 10.97 (d, J=13.5 Hz, 1H), 8.44 (d, J=13.5 Hz, 1H), 8.37 (s, 1H), 7.38 (d, J=8.4 Hz, 1H), 7.17 (d, J=8.4 Hz, 1H), 4.31 (q, J=7.1 Hz, 2H), 4.25 (q, J=7.1 Hz, 2H), 2.55 (s, 3H), 1.38 (t, J=7.1 Hz, 3H), 1.32 (t, J=7.1 Hz, 3H). Synthesis of ethyl 4-hydroxy-6-methyl-1,5-naphthyridine-3-carboxylate [INT 1-rr]: [00270] A preheated (100 °C) solution of diethyl 2-(((6-methylpyridin-3- yl)amino)methylene)malonate [INT 1-qq] (10 g, 35.9 mmol) in Dowtherm A (7.18 mL) was added to a refluxing 260 °C solution of Dowtherm A (59.8 mL ) heated by a manual heating mantle with probes in the reaction mixture and in the mantle. After 20 min, the mixture was poured onto cold (-30 °C) octane and the mixture was stirred at -30 °C for 15 min. The mixture was then filtered, and the resulting residue was triturated in EtOAc and 3% NH3/H2O. The product that did not dissolve was recovered by filtration to provide ethyl 4-hydroxy-6-methyl- 1,5-naphthyridine-3-carboxylate [INT 1-rr] (1.20 g, 4.65 mmol.12.9% yield) as a beige solid. The filtrate phases were separated, and the EtOAc phase was extracted with 3% NH3/H2O. The aqueous phases were combined, washed with MTBE (x 2) and partially concentrated under vacuum until a beige solid appeared. This was recovered by filtration to yield additional ethyl 4- hydroxy-6-methyl-1,5-naphthyridine-3-carboxylate [INT 1-rr] (1.55 g, 6.00 mmol, 16.6% yield) as a beige solid (9:1 "1,5" to "1,7" isomer ratio). m/z: [M + H]+ Calcd for C12H13N2O3233.1; Found 233.0. ¹H NMR (400 MHz, CDCl₃) į = 8.60 (s, 1H), 7.83 (d, J=8.6 Hz, 1H), 7.36 (d, J=8.6 Hz, 1H), 4.26 (q, J=7.2 Hz, 3H), 2.57 (s, 2H), 1.26 (t, J=7.2 Hz, 3H). Synthesis of ethyl 4-bromo-6-methyl-1,5-naphthyridine-3-carboxylate [INT 1-ss]: [00271] Ethyl 4-hydroxy-6-methyl-1,5-naphthyridine-3-carboxylate [INT 1-rr] (2.75 g, 10.6 mmol) was suspended/dissolved in dimethylformamide (11.7 mL) at 0 °C. Phosphorus tribromide (1.32 mL, 14 mmol) was added dropwise, after which the mixture was warmed to rt and stirred for 1 h. The mixture was poured into aqueous NaHCO3, extracted with DCM (x 3), partially concentrated (so DMF remains) and poured into cold H2O. The resulting solid was recovered by filtration to yield 1.95 g of a crude 9:1 isomer mixture, which was purified by flash chromatography on silica (5-35% EtOAc/Hex) to yield ethyl 4-bromo-6- methyl-1,5- naphthyridine-3-carboxylate [INT 1-ss] (1.60 g, 5.42 mmol, 51% yield from corresponding OH isomer) and ethyl 4-bromo-6-methyl-1,7-naphthyridine-3- carboxylate (77.0 mg, 0.2608 mmol, 25% yield from corresponding OH isomer). For ethyl 4-bromo-6-methyl-1,5-naphthyridine-3- carboxylate [INT 1-ss]; m/z: [M + H]+ Calcd for C12H12BrN2O2295.0; Found 295.0. ¹H NMR (400 MHz, CDCl₃) į = 9.04 (s, 1H), 8.28 (d, J=8.6 Hz, 1H), 7.61 (d, J=8.6 Hz, 1H), 4.52 (q, J=7.1 Hz, 2H), 2.87 (s, 3H), 1.48 (t, J=7.1 Hz, 3H). Synthesis of ethyl 4-cyclopropyl-6-methyl-1,5-naphthyridine-3-carboxylate [INT 1-tt]: [00272] A mixture of ethyl 4-bromo-6-methyl-1,5-naphthyridine-3-carboxylate [INT 1-ss] (800 mg, 2.71 mmol), cyclopropylboronic acid (465 mg, 5.42 mmol), and potassium phosphate (1.10 g, 8.13 mmol), palladium(II) acetate (121 mg, 542 μmol) in toluene (27.0 mL) was stirred at 100 °C for 1 hour. After completion, the mixture was diluted with EtOAc and filtered over short path silica. The filtrate was concentrated under reduced pressure to give the crude product, which was purified by flash chromatography on silica gel (EtOAc/hexane = 0/1 to 1/1) to give ethyl 4-cyclopropyl-6-methyl-1,5-naphthyridine-3-carboxylate [INT 1-tt] (306 mg, 1.19 mmol, 44.0% yield) as a brown solid. m/z: [M + H]+ Calcd for C15H17N2O2257.1; Found 257.0. ¹H NMR (400 MHz, CDCl3) į = 8.96 (s, 1H), 8.20 (d, J=8.6 Hz, 1H), 7.48 (d, J=8.6 Hz, 1H), 4.47 (q, J=7.1 Hz, 2H), 2.78 (ddd, J=8.9, 5.7, 3.1 Hz, 1H), 2.73 (s, 3H), 1.67 - 1.63 (m, 2H), 1.45 (t, J=7.1 Hz, 3H), 1.22 - 1.17 (m, 2H). Synthesis of 4-cyclopropyl-6-methyl-1,5-naphthyridine-3-carboxylic acid [INT 1-uu]: [00273] To a mixture of ethyl 4-cyclopropyl-6-methyl-1,5-naphthyridine-3-carboxylate [INT 1-tt] (150 mg, 585 μmol) in THF (3 mL) and H₂O (1 mL) was added lithium(1+) hydrate hydroxide (49.0 mg, 1.17 mmol) and the mixture was stirred at 50 °C for 6 hours. 1N HCl was added dropwise into the mixture until a precipitate was formed, which was collected by filtration to give 4-cyclopropyl-6-methyl-1,5-naphthyridine-3-carboxylic acid [INT 1-uu] (120 mg, 526 μmol, 90.2 % yield) as a white solid. m/z: [M + H]+ Calcd for C13H13N2O2229.1; Found 228.9. Synthesis of tert-butyl (4-cyclopropyl-6-methyl-1,5-naphthyridin-3-yl)carbamate [INT 1-vv]: [00274] To a solution of 4-cyclopropyl-6-methyl-1,5-naphthyridine-3-carboxylic acid [INT 1- uu] (100 mg, 438 μmol) in toluene (1 mL) was added diphenylphosphoryl azide (180 mg, 657 μmol), triethylamine (132 mg, 1.31 mmol), and 2-methyl-2-propanol (486 mg, 6.56 mmol). The reaction mixture was stirred at 100 °C for 2 hours under N2 atmosphere. The reaction was diluted with water (50 mL) and extracted with EtOAc (30 mL × 2). The combined organic layers were washed with brine (30 mL × 2), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product, which was purified by flash chromatography on silica gel (0 - 18% EtOAc in petroleum ether) to give tert-butyl (4- cyclopropyl-6-methyl-1,5-naphthyridin-3-yl)carbamate [INT 1-vv] (100 mg, 334 μmol, 76.3% yield) as a yellow solid. m/z: [M + H]+ Calcd for C17H22N3O2300.2; Found 300.0. ¹H NMR (400MHz, DMSO-d6) į = 9.12 (br s, 1H), 8.66 (s, 1H), 8.19 (d, J=8.4 Hz, 1H), 7.55 (d, J=8.4 Hz, 1H), 2.65 (s, 3H), 2.34 (tt, J=5.6, 8.8 Hz, 1H), 1.53 - 1.43 (m, 11H), 1.11 - 1.03 (m, 2H). Synthesis of 4-cyclopropyl-6-methyl-1,5-naphthyridin-3-amine hydrochloride [INT 1.8]: [00275] A solution of tert-butyl (4-cyclopropyl-6-methyl-1,5-naphthyridin-3-yl)carbamate [INT 1-vv] (100 mg, 334 μmol) in 4 M HCl/dioxane (5 mL) was stirred at 15 ºC for 2 hours. The reaction was concentrated under reduced pressure to give crude 4-cyclopropyl-6-methyl-1,5- naphthyridin-3-amine hydrochloride [INT 1.8] (80.0 mg, 100% yield) as a yellow solid. m/z: [M + H]+ Calcd for C12H14N3200.1; Found 200.2. Synthesis of 4-(1-ethoxyethyl)-1,5-naphthyridin-3-amine hydrochloride [Intermediate 1.9]:

Synthesis of 4-bromo-1,5-naphthyridine-3-carboxylic acid [INT 1-ww]: [00276] To a mixture of ethyl 4-bromo-1,5-naphthyridine-3-carboxylate [INT 1-d] (500 mg, 1.77 mmol) in THF (6 mL) and H2O (2 mL) was added lithium(1+) hydrate hydroxide (222 mg, 5.31 mmol). The reaction mixture was stirred at 20 °C for 12 hours. The reaction mixture was concentrated, diluted with water (5 mL), and acidified with 1 M HCl to pH = 3. The resulting mixture was filtered and the precipitate was dried to give 4-bromo-1,5-naphthyridine-3- carboxylic acid [INT 1-ww] (370 mg, 1.46 mmol, 82.7% yield) as a white solid. ¹H NMR (400MHz, CD3OD) į = 9.13 - 9.10 (m, 2H), 8.51 (dd, J=1.6, 8.4 Hz, 1H), 7.92 (dd, J=4.4, 8.4 Hz, 1H). Synthesis of tert-butyl (4-bromo-1,5-naphthyridin-3-yl)carbamate [INT 1-xx]: [00277] To a mixture of 4-bromo-1,5-naphthyridine-3-carboxylic acid [INT 1-ww] (340 mg, 1.34 mmol) and 2-methylpropan-2-ol (1.48 g, 20.0 mmol) in toluene (4 mL) were added diphenylphosphoryl azide (553 mg, 2.01 mmol) and triethylamine (406 mg, 4.02 mmol). The reaction mixture was stirred at 100 °C for 3 hours under N₂ atmosphere. The reaction mixture was concentrated to give the crude product, which was purified by flash chromatography on silica gel (0-15% EtOAc in petroleum ether) to give tert-butyl (4-bromo-1,5-naphthyridin-3- yl)carbamate [INT 1-xx] (240 mg, 0.740 mmol 55.2% yield) as a white solid. m/z: [M + H]+ Calcd for C13H15BrN3O2324.0, 326.0; Found 324.0.¹H NMR (400MHz, CDCl3) į = 9.78 (s, 1H), 9.02 (dd, J=1.6, 4.4 Hz, 1H), 8.40 (dd, J=1.6, 8.4 Hz, 1H), 7.61 (dd, J=4.4, 8.4 Hz, 1H), 7.31 (br s, 1H), 1.59 (s, 9H). Synthesis of tert-butyl (4-(1-ethoxyvinyl)-1,5-naphthyridin-3-yl)carbamate [INT 1-yy]: [00278] To a mixture of tert-butyl N-(4-bromo-1,5-naphthyridin-3-yl)carbamate [INT 1-xx] (240 mg, 740 μmol) and tributyl(1-ethoxyethenyl)stannane (293 mg, 814 μmol) in dioxane (3 mL) was added palladium(2+) bis(triphenylphosphane) dichloride (51.9 mg, 74.0 μmol). The reaction mixture was stirred at 100 °C for 12 hours under N2 atmosphere. The reaction mixture was quenched with saturated KF solution (20 mL) and stirred at 15 °C for 12 hours. The resulting mixture was extracted with EtOAc (10 mL × 2). 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 flash chromatography on silica gel (0-30% EtOAc in petroleum ether) to give tert-butyl (4-(1-ethoxyvinyl)-1,5-naphthyridin-3-yl)carbamate [INT 1-yy] (140 mg, 60% yield) as a gray solid. m/z: [M + H]+ Calcd for C17H22N3O3316.2; Found 316.2.

NMR (400MHz, CDCl₃) į = 9.82 (br s, 1H), 8.98 (dd, J=1.6, 4.0 Hz, 1H), 8.37 (dd, J=1.6, 8.4 Hz, 1H), 7.54 (dd, J=4.0, 8.4 Hz, 1H), 7.49 (br s, 1H), 4.96 (d, J=2.8 Hz, 1H), 4.57 (d, J=2.8 Hz, 1H), 4.14 (q, J=6.8 Hz, 2H), 1.57 (s, 9H), 1.44 (t, J=6.8 Hz, 3H). Synthesis of tert-butyl (4-(1-ethoxyethyl)-1,5-naphthyridin-3-yl)carbamate [INT 1-zz]: [00279] To a mixture of tert-butyl (4-(1-ethoxyvinyl)-1,5-naphthyridin-3-yl)carbamate [INT 1-yy] (120 mg, 380 μmol) in THF (2 mL) was added dry Pd/C (10.0 mg, 10% purity). The reaction mixture was stirred at 20 °C under a H2 balloon (15 psi) for 1.5 hours. The reaction mixture was filtered and the filtrate was concentrated to give the crude product, which was purified by flash chromatography on silica gel (0-15% EtOAc in petroleum ether) to give tert- butyl (4-(1-ethoxyethyl)-1,5-naphthyridin-3-yl)carbamate [INT 1-zz] (15.0 mg, 12.5% yield) as a yellow oil.¹H NMR (400MHz, CDCl3) į = 9.84 (s, 1H), 9.20 (s, 1H), 8.88 (dd, J=2.0, 4.0 Hz, 1H), 8.36 (dd, J=1.6, 8.4 Hz, 1H), 7.53 (dd, J=4.0, 8.4 Hz, 1H), 6.19 (q, J=6.8 Hz, 1H), 3.67 - 3.56 (m, 1H), 3.52 - 3.40 (m, 1H), 1.59 - 1.56 (m, 12H), 1.28 (t, J=7.2 Hz, 3H). Synthesis of tert-butyl (4-(1-ethoxyethyl)-1,5-naphthyridin-3-yl)carbamate [INT 1.9]: [00280] A mixture of tert-butyl (4-(1-ethoxyethyl)-1,5-naphthyridin-3-yl)carbamate [INT 1- zz] (15.0 mg, 47.2 μmol) in 4 M HCl/dioxane (1 mL) was stirred at 20 °C for 12 hours. The reaction mixture was concentrated to give 4-(1-ethoxyethyl)-1,5-naphthyridin-3-amine hydrochloride [INT 1.9] (12.0 mg, 100% yield) as a brown solid. m/z: [M + H]+ Calcd for C12H16N3O 218.1; Found 218.1. Synthesis of (R)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2- sulfinamide [Intermediate 2.1]:

Synthesis of (R,E)-N-(4-bromobenzylidene)-2-methylpropane-2-sulfinamide [INT 2-b]: [00281] 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 mins. Then to above reaction was added NaOH (21.6 g, 541 mmol, 1.0 eq) and the mixture was stirred at 25 °C for 12 hours. Na₂SO₄ (50 g) was added to the mixture and stirred for 20 mins. Four reaction mixtures were combined and filtered through celite to give the filtrate, which was concentrated in vacuum to give the crude product as an oil. The crude product was dissolved in Petroleum ether (1.0 L) and stirred at -50 °C for 1.0 hour, filtered to give (R,E)-N-(4-bromobenzylidene)-2-methylpropane-2-sulfinamide [INT 2-b] (620 g, 2.15 mol, 99.5% yield) as a solid. Synthesis of (R)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide [INT 2.1]: [00282] 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 hours. This process was repeated 2 times and the three reaction mixture was combined for work-up. The mixture was poured to saturated NH₄Cl solution (13.0 L) and stirred for 10 mins to give the suspension. The suspension was filtered to give the filter cake and eluted with water (5.0 L). The filter cake was triturated with MTBE/ Petroleum ether (v/v = 1:4, 2.0 L) and to give the product as a solid and the mother liquid was concentrated in vacuum to give the crude product as an oil which was purified by column chromatography on silica gel with 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] (389 g, 1.09 mol, 50.6% yield) as a solid. ¹H NMR (400 MHz, CDCl3) į = 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). Synthesis of (S)-1-(4-bromophenyl)-2,2,2-trifluoro-N-methylethan-1-amine [Intermediate 3.1]:

Synthesis of (R)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N,2-dimethylpropane-2- sulfinamide [INT 3-b]: [00283] 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-sulfinamide [INT 2.1] (100 g, 279 mmol, 1.0 eq) at 0-10 °C and stirred at 0-10 °C for 0.5 hour. To the above mixture was added MeI (119 g, 838 mmol, 52.1 mL, 3.0 eq) at 0-10 °C and stirred at 25 °C for 1 hour. The process was repeated 2 times and the three combined reaction mixtures were poured to saturated NH4Cl (3.0 L) and diluted with EtOAc (1.0 L). The mixture was separated to give the organic layer and the aqueous layer was extracted with EtOAc (500 mL). The combined organic layer was washed with saturated NaCl (1.0 L) and dried with Na2SO4, filtered and concentrated in vacuum to give the crude product as an oil. The crude product was purified by column chromatography on silica gel with petroleum ether/ethyl acetate (15/1~ 1/1) to give (R)-N-((S)-1-(4-bromophenyl)-2,2,2- trifluoroethyl)-N,2-dimethylpropane-2-sulfinamide [INT 3-b] (161 g, 432.5 mmol, 51.6% yield) as an oil. Synthesis of (S)-1-(4-bromophenyl)-2,2,2-trifluoro-N-methylethan-1-amine hydrochloride [INT 3.1]: [00284] To the mixture of (R)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N,2- dimethylpropane-2-sulfinamide [INT 3-b] (202 g, 543 mmol, 1.0 eq) in EtOAc (600 mL) was added HCl/EtOAc (4.0 M, 2.02 L, 14.9 eq) slowly. The above mixture was stirred at 20 °C for 1 hour. The reaction mixture was filtered to give a solid and eluted with EtOAc (200 mL) and the mother liquid was concentrated in vacuum to give a solid. The solid was purified by column chromatography on silica gel with petroleum ether/ethyl acetate (10/1~1/0) and combined with the filter cake and concentrated by oil pump at 45 °C for 1 hour to remove the solvent residue to give (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, HCl) as a solid. ¹H NMR (400 MHz, DMSO-d6) į = 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). [00285] SFC: Rt = 0.776 min, 99.98% ee; Column: Chiralpak AD-3, 100×4.6 mm,I.D., 3 um; Mobile phase: A: CO2, B: MeOH (0.05%IPAm); Gradient: A: B=97:3; Flow rate: 3 mL/min; Column temp.: 35 °C. [00286] LCMS: Rt = 1.755 min, 100.0% purity, m/z = 268.0, 270.0 (M+1)+. The gradient was 5%B in 0.40min and 5-95% B at 0.4-3.0min, hold on 95% B for 1.00min, and then 95-5% B in 0.01min, the flow rate was 1.0 ml/min. Mobile phase A was 0.037% Trifluoroacetic Acid in water, mobile phase B was 0.018% Trifluoroacetic Acid in acetonitrile. The column used for chromatography was a Kinetex C1850*2.1mm column (5um particles). Detection methods are diode array (DAD) as well as positive electrospray ionization.MS range was 100-1000. Synthesis of Tetrahydro-2H-thiopyran-4-carbonyl chloride 1,1-dioxide [Intermediate 4.1]:

[00287] 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 warmed to 20 °C and stirred at 20 °C for 2 hours. The suspension turned to clear, which showed the most of starting material was consumed. The reaction mixture was concentrated in vacuum to give the crude product as a solid, which was concentrated by 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. Synthesis of (1s,4s)-4-(1,3-dioxoisoindolin-2-yl)cyclohexane-1-carbonyl chloride [Intermediate 4.5]:

Synthesis of (1s,4s)-4-(1,3-dioxoisoindolin-2-yl)cyclohexane-1-carboxylic acid [INT 4-c]: [00288] A mixture of (1s,4s)-4-aminocyclohexane-1-carboxylic acid [INT 4-b] (5 g, 34.9 mmol), ethyl 1,3-dioxo-2,3-dihydro-1H-isoindole-2-carboxylate (11.4 g, 52.3 mmol), and Na₂CO₃ (11.0 g, 104 mmol) in THF (50 mL) was stirred at 25 ϨC for 1 hour. Water (20 mL) was added to the reaction mixture and the resulting aqueous solution was washed with EtOAc (20 mL × 2). The aqueous solution was acidified with concentrated HCl to pH = 6 and the resulting solution was extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (1s,4s)-4-(1,3-dioxoisoindolin-2-yl)cyclohexane-1-carboxylic acid [INT 4-c] (2.20 g, 8.05 mmol, 23% yield) as a white solid. ¹H NMR (400MHz, CDCl₃) į = 12.55 - 8.96 (m, 1H), 7.81 (dd, J=3.2, 5.6 Hz, 2H), 7.69 (dd, J=3.2, 5.6 Hz, 2H), 4.17 - 4.13 (m, 1H), 2.79 (s, 1H), 2.57 - 2.32 (m, 4H), 1.77 - 1.53 (m, 4H). Synthesis of (1s,4s)-4-(1,3-dioxoisoindolin-2-yl)cyclohexane-1-carbonyl chloride [INT 4.5]: [00289] To a solution of (1s,4s)-4-(1,3-dioxoisoindolin-2-yl)cyclohexane-1-carboxylic acid [INT 4-c] (2.2 g, 8.05 mmol) and DMF (58.8 mg, 805 μmol) in CH2Cl2 (20 mL) was added oxalyl dichloride (3.03 g, 24.1 mmol) and the mixture was stirred at 40 ºC for 2 hours. The reaction mixture was concentrated under reduced pressure to give the crude product (1s,4s)-4- (1,3-dioxoisoindolin-2-yl)cyclohexane-1-carbonyl chloride [INT 4.5] (1.88 g, 6.44 mmol, 80.3% yield) as a white solid. Synthesis of (1r,4r)-4-(1,3-dioxoisoindolin-2-yl)cyclohexane-1-carbonyl chloride [Intermediate 4.6]:

Synthesis of (1r,4r)-4-(1,3-dioxoisoindolin-2-yl)cyclohexane-1-carboxylic acid [INT 4-e]: [00290] A mixture of (1r,4r)-4-aminocyclohexane-1-carboxylic acid [INT 4-d] (1.13 g, 7.89 mmol), ethyl 1,3-dioxo-2,3-dihydro-1H-isoindole-2-carboxylate (2.58 g, 11.8 mmol), and Na2CO3 (2.50 g, 23.6 mmol) in THF (10 mL) was stirred at 25 ºC for 1 hour. Water (20 mL) was added to the reaction mixture and the resulting aqueous solution was washed with EtOAc (20 mL × 2). The aqueous solution was acidified with concentrated HCl to pH = 6 and the resulting solution was extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (1r,4r)-4-(1,3-dioxoisoindolin-2-yl)cyclohexane-1-carboxylic acid [INT 4-e] (1.13 g, 4.13 mmol, 52.5% yield) as a white solid. m/z: [M + H]+ Calcd for C15H16NO4274.1; Found 274.1.¹H NMR (400MHz, CDCl3) į = 13.29 - 9.77 (br s, 1H), 7.83 (dd, J=3.2, 5.2 Hz, 2H), 7.71 (dd, J=3.2, 5.6 Hz, 2H), 4.33 - 3.99 (m, 1H), 2.55 - 2.40 (m, 1H), 2.39 - 2.25 (m, 2H), 2.15 - 2.10 (m, 2H), 1.92 - 1.78 (m, 2H), 1.48 - 1.73 (m, 2H). Synthesis of (1r,4r)-4-(1,3-dioxoisoindolin-2-yl)cyclohexane-1-carbonyl chloride [INT 4.6]: [00291] To a solution of (1r,4r)-4-(1,3-dioxoisoindolin-2-yl)cyclohexane-1-carboxylic acid [INT 4-e] (1.13 g, 4.13 mmol) and DMF (30.1 mg, 413 μmol) in CH₂Cl₂ (10 mL) was added oxalyl dichloride (1.55 g, 12.3 mmol) and the mixture was stirred at 40 ºC for 2 hours. The reaction mixture was concentrated under reduced pressure to give (1r,4r)-4-(1,3-dioxoisoindolin- 2-yl)cyclohexane-1-carbonyl chloride [INT 4.6] (1.19 g, 4.08 mmol 99.1% yield) as a white solid. Synthesis of (1r,4r)-4-(2-methyl-2H-tetrazol-5-yl)cyclohexane-1-carbonyl chloride [Intermediate 4.8]:

Synthesis of (1r,4r)-4-carbamoylcyclohexane-1-carboxylate [INT 4-g]: [00292] A mixture of (1r,4r)-4-(methoxycarbonyl)cyclohexane-1-carboxylic acid [INT 4-f] (10.0 g, 53.7 mmol), BOP (23.7 g, 53.7 mmol) and NH4OH (26.7 g, 214 mmol) in DMF (50 mL) was stirred at 20 °C for 2 hours. The reaction was diluted with EtOAc (100 mL), washed with water (40 mL) and brine (40 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude methyl (1r,4r)-4-carbamoylcyclohexane-1- carboxylate [INT 4-g] (7.53 g, 40.7 mmol, 75.7% yield) as a white solid. m/z: [M + H]+ Calcd for C9H16NO3186.1; Found 186.1. ¹H NMR (400MHz, CDCl₃) į = 5.85 - 5.50 (m, 2H), 3.66 (s, 3H), 2.35 - 2.25 (m, 1H), 2.16 - 2.10 (m, 1H), 2.09 - 1.95 (m, 4H), 1.56 - 1.38 (m, 4H). Synthesis of (1r,4r)-4-cyanocyclohexane-1-carboxylate [INT 4-h]: [00293] To a solution of methyl (1r,4r)-4-carbamoylcyclohexane-1-carboxylate [INT 4-g] (7.1 g, 38.3 mmol) in pyridine (30 mL) was added trifluoroacetic anhydride (48.0 g, 229 mmol) at 0 °C. The reaction was stirred at 0 °C for 2 hours under N₂ atmosphere. The mixture was diluted with DCM (200 mL) and water (80 mL). The organic phase was washed with 1 M HCl (50 mL), H2O (50 mL), and brine (80 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude product, which was purified by flash chromatography on silica gel (0 - 25% EtOAc in petroleum ether) to give methyl (1r,4r)-4- cyanocyclohexane-1-carboxylate [INT 4-h] (4.10 g, 24.5 mmol, 64% yield) as an oil. ¹H NMR (400MHz, CDCl3) į = 3.66 (s, 3H), 2.53 - 2.42 (m, 1H), 2.41 - 2.30 (m, 1H), 2.16 - 2.01 (m, 4H), 1.68 - 1.44 (m, 4H). Synthesis of methyl (1r,4r)-4-(1H-tetrazol-5-yl)cyclohexane-1-carboxylate [INT 4-i]: [00294] To a solution of methyl (1r,4r)-4-cyanocyclohexane-1-carboxylate [INT 4-h] (4.10 g, 24.5 mmol) and ammonium chloride (1.96 g, 36.7 mmol) in DMF (30 mL) was added azidosodium (3.14 g, 48.2 mmol). The reaction mixture was stirred at 110 ºC for 12 hours under N₂ atmosphere to afford crude methyl (1r,4r)-4-(1H-tetrazol-5-yl)cyclohexane-1-carboxylate [INT 4-i] (5.20 g, 100% yield, in DMF solution). The reaction mixture was used for the next step directly without purification. m/z: [M + H]+ Calcd for C9H15N4O2211.1; Found 211.0. Synthesis of methyl (1r,4r)-4-(2-methyl-2H-tetrazol-5-yl)cyclohexane-1-carboxylate [INT 4-j] and methyl (1r,4r)-4-(1-methyl-1H-tetrazol-5-yl)cyclohexane-1-carboxylate [INT 4-k]: [00295] To a mixture of methyl (1r,4r)-4-(1H-tetrazol-5-yl)cyclohexane-1-carboxylate [INT 4-i] (5.20 g, 24.7 mmol, in 30 mL of DMF) in DMF (20 mL) was added potassium carbonate (6.82 g, 49.4 mmol) and the mixture was stirred at 20 °C for 20 mins. Methyl trifluoromethanesulfonate (20.1 g, 123 mmol) was added and the mixture was stirred at 20 °C for 12 hours. The reaction was quenched by addition of saturated NaHCO3 (30 mL) and H2O (20 mL). The mixture was extracted with EtOAc (50 mL × 2). The combined organic layers were washed with brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product, which was purified by flash chromatography on silica gel (0 - 50% EtOAc in petroleum ether) to afford methyl (1r,4r)-4-(2-methyl-2H- tetrazol-5-yl)cyclohexane-1-carboxylate [INT 4-j] (1.95 g, 8.70 mmol, 35.2% yield) as a white solid and methyl (1r,4r)-4-(1-methyl-1H-tetrazol-5-yl)cyclohexane-1-carboxylate [INT 4-k] (1 g, 4.46 mmol, 18.0% yield) as an off-white solid. [INT 4-j]; ¹H NMR (400MHz, CDCl₃) į = 4.29 (s, 3H), 3.68 (s, 3H), 2.98 - 2.87 (m, 1H), 2.44 - 2.31 (m, 1H), 2.24 - 2.08 (m, 4H), 1.69 - 1.53 (m, 4H). [INT 4-k]; ¹H NMR (400MHz, CDCl₃) į = 4.00 (s, 3H), 3.67 (s, 3H), 2.84 - 2.74 (m, 1H), 2.48 - 2.36 (m, 1H), 2.21 - 2.11 (m, 2H), 2.07 - 1.97 (m, 2H), 1.84 - 1.71 (m, 2H), 1.63 - 1.49 (m, 2H). Synthesis of (1r,4r)-4-(2-methyl-2H-tetrazol-5-yl)cyclohexane-1-carboxylic acid [INT 4-l]: [00296] To a solution of methyl (1r,4r)-4-(2-methyl-2H-tetrazol-5-yl)cyclohexane-1- carboxylate [INT 4-j] (1.85 g, 8.24 mmol) in THF (12 mL) was added lithium(1⁺) hydrate hydroxide (688 mg, 16.4 mmol) in H2O (4 mL). The reaction mixture was stirred at 20 °C for 3 hours, after which it was poured into water (10 mL), acidified with 1 M HCl to pH = 5-6 and extracted with EtOAc (30 mL × 2). The combined organic layers were washed with brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford (1r,4r)-4-(2-methyl-2H-tetrazol-5-yl)cyclohexane-1-carboxylic acid [INT 4-l] (1.45 g, 6.90 mmol 83.8% yield) as a white solid. ¹H NMR (400MHz, DMSO-d6) į = 12.09 (br s, 1H), 4.29 (s, 3H), 2.92 - 2.82 (m, 1H), 2.32 - 2.21 (m, 1H), 2.10 - 1.93 (m, 4H), 1.59 - 1.40 (m, 4H). Synthesis of (1r,4r)-4-(2-methyl-2H-tetrazol-5-yl)cyclohexane-1-carbonyl chloride [INT 4.8]: [00297] To a solution of (1r,4r)-4-(2-methyl-2H-1,2,3,4-tetrazol-5-yl)cyclohexane-1- carboxylic acid [INT 4-l] (450 mg, 2.14 mmol) in CH₂Cl₂ (5 mL) was added oxalic dichloride (407 mg, 3.21 mmol) and DMF (0.1 mL). The reaction was stirred at 20 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to give crude (1r,4r)-4-(2-methyl-2H- tetrazol-5-yl)cyclohexane-1-carbonyl chloride [INT 4.8] (490 mg, 100% yield, crude). Synthesis of (1r,4r)-4-(1-methyl-1H-tetrazol-5-yl)cyclohexane-1-carbonyl chloride [Intermediate 4.9]:

Synthesis of (1r,4r)-4-(2-methyl-2H-tetrazol-5-yl)cyclohexane-1-carbonyl chloride [INT 4.8]: [00298] To a solution of methyl (1r,4r)-4-(1-methyl-1H-tetrazol-5-yl)cyclohexane-1- carboxylate [INT 4-k] (1.00 g, 4.45 mmol) in THF (12 mL) was added lithium(1⁺) hydrate hydroxide (373 mg, 8.90 mmol) in H2O (4 mL) and the mixture was stirred at 20 °C for 3 hours. The reaction mixture was poured into water (10 mL), acidified with 1 M HCl to pH = 5 - 6 and extracted with EtOAc (30 mL × 2). The combined organic layers were washed with brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford (1r,4r)-4-(1-methyl-1H-tetrazol-5-yl)cyclohexane-1-carboxylic acid [INT 4-m] (720 mg, 3.42 mmol, 77.0% yield) as a white solid. ¹H NMR (400MHz, DMSO-d₆) į = 12.10 (br s, 1H), 4.01 (s, 3H), 3.04 - 2.95 (m, 1H), 2.36 - 2.25 (m, 1H), 2.05 - 1.91 (m, 4H), 1.62 - 1.42 (m, 4H). Synthesis of (1r,4r)-4-(1-methyl-1H-tetrazol-5-yl)cyclohexane-1-carbonyl chloride [INT 4.9]: [00299] To a solution of (1r,4r)-4-(1-methyl-1H-tetrazol-5-yl)cyclohexane-1-carboxylic acid [INT 4-m] (720 mg, 3.42 mmol) in CH₂Cl₂ (10 mL) was added oxalic dichloride (651 mg, 5.13 mmol) and DMF (0.1 mL). The reaction was stirred at 20 °C for 2 hours under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give crude (1r,4r)-4-(1-methyl- 1H-tetrazol-5-yl)cyclohexane-1-carbonyl chloride [INT 4.9] (800 mg, 100% yield, crude). Synthesis of (S)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H- thiopyran-4-carboxamide 1,1-dioxide [Intermediate 5.1]:

[00300] To a solution of (S)-1-(4-bromophenyl)-2,2,2-trifluoro-N-methylethan-1-amine hydrochloride [INT 3.1] (39.0 g, 128 mmol, 1.0 eq, HCl) and TEA (45.7 g, 451 mmol, 62.8 mL, 3.5 eq) in DCM (200 mL) 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 hours. The mixture was separated to give the organic layer, and the aqueous layer was extracted with DCM (100 mL). The combined organic layer was concentrated in vacuum to give the crude product as an oil. The crude product was purified by column chromatography on silica gel with petroleum ether/ethyl acetate (15/1~3/1) to give (S)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)- N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide [INT 5.1] (26.0 g, 60.7 mmol, 47.4% yield, 100% purity) as a solid. ¹H NMR (400 MHz, CDCl3) į = 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). [00301] SFC: Rt = 1.21 min, 100.0% ee; Column: Chiralpak AD-3, 50×4.6 mm I.D., 3um; Mobile phase: A: CO2, B: MeOH (0.05%IPAm, v/v); Flow rate: 3.4 mL/min; Column temp.: 35 °C. [00302] LCMS: Rt = 2.431 min, 100% purity, m/z = 428.0, 430.0(M+1)+. The gradient was 5%B in 0.40min and 5-95% B at 0.4-3.0min, hold on 95% B for 1.00min, and then 95-5%B in 0.01min, the flow rate was 1.0 ml/min. Mobile phase A was 0.037% Trifluoroacetic Acid in water, mobile phase B was 0.018% Trifluoroacetic Acid in acetonitrile. The column used for chromatography was a Kinetex C1850*2.1mm column (5um particles). Detection methods are diode array (DAD) as well as positive electrospray ionization.MS range was 100-1000. Synthesis of (1S)-1-(4-bromophenyl)-2,2,2-trifluoroethan-1-amine [Intermediate 6.1]:

[00303] To a mixture of (S)-N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-2- methylpropane-2-sulfinamide [INT 2.1] (30 g, 83.7 mmol) in MeOH (100 mL) was added 4 M HCl/dioxane (30 mL). The mixture was stirred at 15 ºC for 1 hour. The mixture was concentrated under reduced pressure to afford the crude product. The mixture was diluted with water (50 mL) and extracted with EtOAc (100 mL*2). The combined organic layers were washed with 1 M HCl (100ml x 2). The aqueous phase was basified with 2N NaOH to pH=9-10 and extracted with CH2Cl2 (100mL x 2). The combined organic layers dried over anhydrous Na₂SO₄, filtered, concentrated under reduced pressure to give the (1S)-1-(4-bromophenyl)-2,2,2- trifluoroethan-1-amine [INT 6.1] (11.0 g, 43.2 mmol) as an oil. m/z: [M + H]+ Calcd for C8H8BrF3N 254.0256.0; Found 255.8. Synthesis of Tert-butyl 3-{[(1S)-1-(4-bromophenyl)-2,2,2- trifluoroethyl](methyl)carbamoyl}pyrrolidine-1-carboxylate [Intermediate 7.1]:

Synthesis of tert-butyl 3-{[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]carbamoyl}pyrrolidine- 1-carboxylate [INT 7-a]: [00304] To a mixture of 1-[(tert-butoxy)carbonyl]pyrrolidine-3-carboxylic acid (2.53 g, 11.8 mmol), EDCI (3.39 g, 17.7 mmol), HOBT (2.39 g, 17.7 mmol) in CH2Cl2 (30 mL) was added (1S)-1-(4-bromophenyl)-2,2,2-trifluoroethan-1-amine [INT 6.1] (3g, 11.8 mmol) and the mixture was stirred at 25 °C for 16 hours. LCMS showed the reaction was complete. The reaction was concentrated under reduced pressure to give the crude product which was purified by flash chromatography on silica gel (EtOAc/PE = 0/1 to 1/20) to give tert-butyl 3-{[(1S)-1-(4- bromophenyl)-2,2,2-trifluoroethyl]carbamoyl}pyrrolidine-1-carboxylate [INT 7-a] (1.4 g, 3.10 mmol) as a solid. m/z: [M - 56]+ Calcd for C14H15BrF3N2O3395.0, 397.0; Found 395.0. ¹H NMR (400MHz, DMSO-d6) į = 9.26 (br dd, J=3.2, 9.2 Hz, 1H), 7.66 (br d, J=8.4 Hz, 2H), 7.54 (br d, J=8.4 Hz, 2H), 5.83 (quin, J=8.8 Hz, 1H), 3.50 (br dd, J=8.0, 10.0 Hz, 1H), 3.33-3.05 (m, 4H), 2.13-1.80 (m, 2H), 1.43-1.34 (m, 9H). Synthesis of tert-butyl 3-{[(1S)-1-(4-bromophenyl)-2,2,2- trifluoroethyl](methyl)carbamoyl}pyrrolidine-1-carboxylate [INT 7.1]: [00305] To a solution of tert-butyl 3-{[(1S)-1-(4-bromophenyl)-2,2,2- trifluoroethyl]carbamoyl}pyrrolidine-1-carboxylate [INT 7-a] (500mg, 1.10 mmol) in DMF (7 mL) was added dicaesium(1+) carbonate (1.07 g, 3.30 mmol) and the reaction mixture was stirred at 25 ºC for 0.5 hour. Dimethyl sulfate (554 mg, 4.40 mmol) was then added at 0 °C and was stirred at 25 °C for 4 hours. LCMS showed the reaction was complete and desired MS was observed. The reaction was quenched by adding 1M NaOH(aq) (5 mL) and water (20mL), then it was extracted with EtOAc (3x20mL). The combined organic layers were washed with brine (2x20 mL), dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to give the crude product which was purified by flash chromatography on silica gel (PE/EtOAc = 1/0 to 1/2) to give tert-butyl 3-{[(1S)-1-(4-bromophenyl)-2,2,2- trifluoroethyl](methyl)carbamoyl}pyrrolidine-1-carboxylate [INT 7.1] (200 mg, 429 μmol) as an oil. m/z: [M - 56]+ Calcd for C15H17BrF3N2O3409.0,411.0; Found 409.0. ¹H NMR (400MHz, DMSO-d6) į = 7.69 (br d, J=8.4 Hz, 2H), 7.43-7.23 (m, 2H), 6.64-6.27 (m, 1H), 3.55- 3.43 (m, 2H), 3.30-3.09 (m, 3H), 2.88 (br s, 3H), 2.64 (br s, 1H), 2.08 (br s, 1H), 1.91 (br s, 1H), 1.42-1.39 (m, 9H). Synthesis of (S)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N-methyl-1-pivaloylpiperidine- 4-carboxamide [Intermediate 8.1]:

[00306] (S)-1-(4-bromophenyl)-2,2,2-trifluoro-N-methylethan-1-amine hydrochloride [INT 3.1] (1 g, 3.28 mmol) and 1-(2,2-dimethylpropanoyl)piperidine-4-carboxylic acid (1.39 g, 6.56 mmol) were mixed in pyridine (10 mL). Phosphoroyl trichloride (1.50 g, 9.84 mmol) was added and the reaction mixture was stirred at 90 °C for 72 h. The solvent was distilled off under reduced pressure. Water (10 mL) was added to the residue and it was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with water (3 x 10 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane/MtBE 100-0%, CV=8-12) to obtain (S)-N-(1-(4-bromophenyl)-2,2,2- trifluoroethyl)-N-methyl-1-pivaloylpiperidine-4-carboxamide [INT 8.1] (550 mg, 1.18 mmol, 36.4% yield) as a white solid. m/z: [M + H]+ Calcd for C20H27BrF3N2O2463.1; Found 463.0. Synthesis of 1-(5-methyl-1,3,4-oxadiazol-2-yl)azetidine-3-carboxylic acid [Intermediate 9.1]:

[00307] DIPEA (3.76 g, 29.1 mmol) was added to a solution of 2-bromo-5-methyl-1,3,4- oxadiazole (1 g, 6.13 mmol) and azetidine-3-carboxylic acid (589 mg, 5.83 mmol) in dimethylformamide (5 mL) and the reaction mixture was stirred at 100 °C for 10 h. The mixture was purified by HPLC to obtain 1-(5-methyl-1,3,4-oxadiazol-2-yl)azetidine-3- carboxylic acid [INT 9.1] (262 mg, 1.43 mmol, 24.7% yield) as a white solid. m/z: [M + H]+ Calcd for C7H10N3O3184.1; Found 184.2. [00308] HPLC conditions: System - Agilent 1260 Infinity II LC coupled to an Agilent 6120B Single Quadrupole LC/MS System. Column - Description: Chromatorex SBM 100-5T 5 ^m C18(2) 100 Å, LC Column 100 x 19 mm, Waters, Sun Fire. Stationary Phase: C18. Solid Support: Fully Porous Silica. Separation Mode: Reversed Phase. Mobile Phase - Mobile phase A: water + formic acid (0.1%). Mobile phase B: acetonitrile + formic acid (0.1%). Flow rate: 30ml/min; loading pump 4ml/min B. Eluation conditions: gradient mode – 0-0-2-100% (B) 0-2- 10-11.2min. Synthesis of 2-acetyl-2-azaspiro[3.3]heptane-6-carboxylic acid [Intermediate 10.1]:

[00309] 2-azaspiro[3.3]heptane-6-carboxylic acid hydrochloride (1 g, 5.62 mmol), DIPEA (2.24 g, 17.4 mmol) and acetyl acetate (630 mg, 6.18 mmol) were dissolved in tetrahydrofuran (5 mL). The reaction mixture was stirred for 10 h. The solvent was distilled off under reduced pressure. The residue was purified by HPLC to obtain 2-acetyl-2- azaspiro[3.3]heptane-6-carboxylic acid [INT 10.1] (815 mg, 4.45 mmol, 79.9% yield) as a white solid. m/z: [M + H]⁺ Calcd for C9H14NO3184.1; Found 184.2. 148 [00310] HPLC conditions: System - Agilent 1260 Infinity II LC coupled to an Agilent 6120B Single Quadrupole LC/MS System. Column - Description: Chromatorex SBM 100-5T 5 ^m C18(2) 100 Å, LC Column 100 x 19 mm, Waters, Sun Fire. Stationary Phase: C18. Solid Support: Fully Porous Silica. Separation Mode: Reversed Phase. Mobile Phase - Mobile phase A: water + formic acid (0.1%). Mobile phase B: acetonitrile + formic acid (0.1%). Flow rate: 30ml/min; loading pump 4ml/min B. Eluation conditions: gradient mode – 0-0-2-100% (B) 0-2- 10-11.2min. Synthesis of 1-(3-methyl-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylic acid [Intermediate 11.1]:

Synthesis of tert-butyl 1-cyanopiperidine-4-carboxylate [INT 11-a]: [00311] Tert-butyl piperidine-4-carboxylate hydrochloride (11.9 g, 53.6 mmol) and sodium bicarbonate (17.9 g, 214 mmol) were dissolved in a mixture of methylene chloride (125 mL) and water (125 mL). The reaction mixture was cooled to 0 °C. A solution of carbononitridic bromide (6.81 g, 64.3 mmol) in methylene chloride (100 mL) was added dropwise at 0 °C. The reaction mixture was warmed to 25 °C for 2 h. The reaction was extracted with methylene chloride (2 x 100 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give tert-butyl 1- cyanopiperidine-4-carboxylate [INT 11-a] (10.2 g, 48.7 mmol, 91.0% yield) as a yellow solid. m/z: [M + H]+ Calcd for C11H19N2O2211.1; Found 210.0. Synthesis of tert-butyl 1-(3-methyl-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylate [INT 11-b]: [00312] Tert-butyl 1-cyanopiperidine-4-carboxylate [INT 11-a] (11.5 g, 54.6 mmol), N'- hydroxyethanimidamide (4.85 g, 65.5 mmol) and zinc bromide (41.7 mL, 65.5 mmol) were mixed in tetrahydrofuran (250 mL). The reaction mixture was stirred under an argon atmosphere at 82 °C for 12 h. Then para-toluene sulfonate hydrate (10.3 g, 54.6 mmol) was added and the reaction mixture was stirred at 82 °C for 12 h. The reaction mixture was cooled, quenched by adding a saturated NaHCO3 (200 mL) solution and extracted with EtOAc (2 x 300 mL). The combined organic layers were washed with brine (1 x 300 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product which was purified by flash chromatography on silica gel (MeCN/CHCl3 = 4.2/95.8 to 4.2/95.8) to give tert-butyl 1- (3-methyl-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylate [INT 11-b] (6.00 g, 22.4 mmol, 41.3% yield) as a yellow oil. m/z: [M + H]+ Calcd for C13H22N3O3268.2; Found 268.2. Synthesis of 1-(3-methyl-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylic acid [INT 11.1]: [00313] A mixture of tert-butyl 1-(3-methyl-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylate [INT 11-b] (5.7 g, 21.3 mmol) and hydrogen chloride (4 M in dioxane, 60 mL, 240 mmol) was stirred at 40 °C for 10 h. Then the solvent was distilled off and the residue was triturated with MtBE (200 mL). It was filtrated and the solid was washed with MtBE (2 x 100 mL) to obtain 1- (3-methyl-1,2,4-oxadiazol-5-yl)piperidine-4-carboxylic acid [INT 11.1] (3.61 g, 17.0 mmol, 80.4% yield) as a white solid. ¹H NMR (400 MHz, DMSO) į = 9.17 (s, 1H), 3.81 - 3.89 (m, 2H), 2.49 - 2.54 (m, 1H), 2.07 (s, 3H), 1.83 - 1.90 (m, 2H), 1.45 - 1.58 (m, 4H). Synthesis of 1-(4-bromophenyl)-N-methylethan-1-amine [Intermediate 12.1]:

[00314] To a solution of 1-(4-bromophenyl)ethan-1-one (10 g, 50.3 mmol) in MeOH (100 mL) was added sodium cyanoborohydride (8.79 g, 140 mmol) and methanamine hydrochloride (31.5 g, 468 mmol). The mixture was stirred at 20 °C for 12 h. The reaction was quenched by adding water (100 mL) and was extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product which was purified by flash chromatography on silica gel (EtOAc/PE = 0/1 to 1/0) to give 1-(4-bromophenyl)-N-methylethan-1-amine [INT 12.1] (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. Synthesis of N-(1-(4-bromophenyl)ethyl)-N-methyltetrahydro-2H-thiopyran-4- carboxamide 1,1-dioxide [Intermediate 13.1]:

[00315] Tetrahydro-2H-thiopyran-4-carbonyl chloride 1,1-dioxide [INT 4.1] (102 mg, 0.5186 mmol) was added to a mixture of 1-(4-bromophenyl)-N-methylethan-1-amine [INT 12.1] (110 mg, 518 μmol) in methylene chloride (50 mL) at 0 °C. The reaction mixture was stirred at r.t for 60 h. The reaction mixture was evaporated under reduced pressure. The crude product was purified by HPLC to give N-(1-(4-bromophenyl)ethyl)-N-methyltetrahydro-2H-thiopyran-4- carboxamide 1,1-dioxide [INT 13.1] (124 mg, 0.3337 mmol, 64.2% yield) as a white solid. m/z: [M + H]+ Calcd for C15H21BrNO3S 374.0; Found 374.0. [00316] HPLC conditions: System - Agilent 1260 Infinity II LC coupled to an Agilent 6120B Single Quadrupole LC/MS System. Column - Description: Chromatorex SBM 100-5T 5 ^m C18(2) 100 Å, LC Column 100 x 19 mm, Waters, Sun Fire. Stationary Phase: C18. Solid Support: Fully Porous Silica. Separation Mode: Reversed Phase. Mobile Phase - Mobile phase A: water. Mobile phase B: methanol. Flow rate: 30ml/min; loading pump 4ml/min B. Eluation conditions: isocratic mode - 43% (B) 0.5-6.5min. Synthesis of N-[1-(4-bromophenyl)ethyl]-N-methylacetamide [Intermediate 13.2]:

[00317] To a mixture of [1-(4-bromophenyl)ethyl](methyl)amine [INT 12.1] (740 mg, 3.45 mmol) and triethylamine (1.74 g, 17.2 mmol) in CH2Cl2 (10 mL) was added acetyl chloride (942 mg, 12.0 mmol) at 25 °C and the mixture was stirred at 25 °C for 12 hours. The mixture solution was concentrated under reduced pressure to give crude product which was purified by flash chromatography on silica gel (0 - 60% EtOAc in petroleum ether) to afford N-[1-(4- bromophenyl)ethyl]-N-methylacetamide [INT 13.2] (265 mg, 30.0% yield) as a yellow oil. m/z: [M + H]+ Calcd for C11H15BrNO 256.0; Found 256.1. ¹H NMR (400MHz, CDCl₃) į = 7.54 - 7.42 (m, 2H), 7.21 - 7.06 (m, 2H), 6.02 (q, J=7.2 Hz, 1H), 2.69 - 2.61 (m, 3H), 2.24 - 2.12 (m, 3H), 1.52 - 1.37 (m, 3H). Synthesis of [(1S)-1-(4-bromophenyl)ethyl](methyl)amine hydrochloride [Intermediate 14.1]:

Synthesis of [ -1-(4-bromophenyl)ethyl](methyl) hydrochloride [INT 14-b]:

[00318] Di-tert-butyl dicarbonate (3.55 g, 16.3 mmol) was added dropwise to the solution of (1S)-1-(4-bromophenyl)ethan-1-amine [INT 14-a] (3 g, 14.9 mmol) and triethylamine (1.80 g, 17.8 mmol) in methylene chloride (50 mL) at 0 °C while stirring. The reaction mixture was stirred for 2h at rt. Then the mixture was extracted with aq. NaHSO4 (3 x 10 mL). The organic phase was separated, dried with Na2SO4 and evaporated in vacuo to give tert-butyl N-[(1S)-1-(4- bromophenyl)ethyl]carbamate [INT 14-b] (3.80 g, 12.6 mmol, 85.0% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d6) į 7.49 (d, J=7.7 Hz, 2H), 7.41 (d, J=8.5 Hz, 1H), 7.24 (d, J=7.9 Hz, 2H), 4.56 (t, J=7.7 Hz, 1H), 1.35 (s, 9H), 1.26 (d, J=7.0 Hz, 3H). Synthesis of [(1S)-1-(4-bromophenyl)ethyl](methyl)amine hydrochloride [INT 14-c]: [00319] Tert-butyl N-[(1S)-1-(4-bromophenyl)ethyl]carbamate [INT 14-b] (0.1 g, 0.3331 mmol) was dissolved in tetrahydrofuran (10 mL) and cooled to 0 °C. Sodium hydride (60 % dispersion in mineral oil) (14.6 mg, 366 μmol) was added in portions. The mixture was stirred for 30 min at 0 °C. Methyl iodide (56.6 mg, 399 μmol) was added dropwise at 0 °C. The reaction mixture was stirred for 10h at rt. Then the mixture was poured into aq. NH₄Cl and extracted with EtOAc (3 x 50 mL). The combined organic extracts were dried with Na₂SO₄ and evaporated in vacuo to give tert-butyl N-[(1S)-1-(4-bromophenyl)ethyl]-N-methylcarbamate [INT 14-c] (99.0 mg, 0.3150 mmol, 95.1% yield) as a colorless oil. m/z: [M + H - tert- Bu]⁺ Calcd for C10H12BrNO2258.0, 260.0; Found 260.2. Synthesis of [(1S)-1-(4-bromophenyl)ethyl](methyl)amine hydrochloride [INT 14.1]: [00320] Tert-butyl N-[(1S)-1-(4-bromophenyl)ethyl]-N-methylcarbamate [INT 14-c] (0.8 g, 2.54 mmol) was dissolved in dioxane (2 mL) and Hydrogen chloride solution 4.0 M in dioxane (2 mL, 8.00 mmol) was added. The reaction mixture was stirred for 3 h at rt. The solvent was evaporated under reduced pressure to give [(1S)-1-(4- bromophenyl)ethyl](methyl)amine hydrochloride [INT 14.1] (570 mg, 2.27 mmol, 89.6% yield) as a white solid. ¹H NMR (500 MHz, DMSO-d6) į 9.90 (s, 1H), 9.41 (s, 1H), 7.63 (dd, J=8.4, 2.9 Hz, 2H), 7.53 (dd, J=8.5, 2.9 Hz, 2H), 4.28 (s, 1H), 2.32 (s, 3H), 1.53 (dd, J = 6.8, 2.9 Hz, 3H). Synthesis of N-[(1S)-1-(4- bromophenyl)ethyl]-N-methyl-1,1-dioxo-1^^-thiane-4- carboxamide [Intermediate 15.1]:

[00321] [(1S)-1-(4-bromophenyl)ethyl](methyl)amine hydrochloride [INT 14.1] (425 mg, 1.69 mmol) and 1,1-dioxo-1^^-thiane-4-carboxylic acid (450 mg, 2.53 mmol) were dissolved in pyridine (20 mL). The reaction mixture was cooled to 0 °C. Phosphorus oxychloride (387 mg, 2.53 mmol) was added dropwise. The reaction mixture was slowly warmed to rt and stirred for 2 h. The reaction mixture was quenched with a saturated aqueous solution of NaHCO3 (100 mL). The mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (50 mL). The organic layer was dried over Na₂SO₄ and concentrated under reduced pressure. The residue was dissolved in MTBE (150 mL). The organic layer was washed with an aqueous saturated solution of NaHSO₄. The organic layer was dried over Na₂SO₄ and concentrated under reduced pressure to give N-[(1S)-1-(4-bromophenyl)ethyl]-N- methyl-1,1-dioxo-1^^-thiane-4-carboxamide [INT 15.1] (446 mg, 1.19 mmol, 70.5% yield) as a white solid. m/z: [M + H]+ Calcd for C15H21BrNO3S 374.0; Found 374.2.

Synthesis of [(1R)-1-(4-bromophenyl)ethyl](methyl)amine hydrochloride [Intermediate 16.1]:

Synthesis of tert-butyl N-[(1R)-1-(4-bromophenyl)ethyl]carbamate [INT 16-b]: [00322] To a solution of (1R)-1-(4-bromophenyl)ethan-1-amine [INT 16-a] (2.8 g, 13.9 mmol) and triethylamine (1.75 g, 17.3 mmol) in methylene chloride (150 mL) was added di-tert- butyl dicarbonate (3.31 g, 15.2 mmol) at 0 °C and the reaction mixture was stirred for 10 h. Then the mixture was washed with water (50 mL). The organic layer was dried over Na₂SO₄ and concentrated under reduced pressure. The residue was triturated with n-hexane and filtered to obtain tert-butyl N-[(1R)-1-(4-bromophenyl)ethyl]carbamate [INT 16-b] (2.70 g, 8.99 mmol, 64.7% yield) as a white solid. ¹H NMR (400 MHz, DMSO) į = 7.49 (d, J=8 Hz, 2H), 7.43 - 7.37 (m, 1H), 7.24 (d, J=8 Hz, 2H), 4.61 - 4.52 (m, 1H), 1.35 (s, 9H), 1.27 (d, J=8 Hz, 3H). Synthesis of tert-butyl N-[(1R)-1-(4- bromophenyl)ethyl]-N-methylcarbamate [INT 16-c]: [00323] To a solution of tert-butyl N-[(1R)-1-(4-bromophenyl)ethyl]carbamate [INT 16-b] (2.2 g, 7.32 mmol) in tetrahydrofuran (15 mL) was added sodium hydride (210 mg, 8.78 mmol) under Ar at 0 °C and the mixture was stirred for 30 min. Then methyl iodide (1.54 g, 10.9 mmol) was added and the reaction mixture was stirred for 10 h. Aqueous NH4Cl (20 mL) was added and it was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with water (50 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was dissolved in MeCN (30 mL), washed with n-hexane (30 mL) and concentrated under reduced pressure to obtain tert-butyl N-[(1R)-1-(4- bromophenyl)ethyl]-N-methylcarbamate [INT 16-c] (1.74 g, 5.55 mmol, 75.6% yield) as a yellow oil. ¹H NMR (400 MHz, DMSO) į = 7.46 - 7.40 (m, 2H), 7.17 - 7.10 (m, 2H), 5.54 - 5.28 (m, 1H), 2.55 (s, 3H), 1.46 (s, 12H). Synthesis of [(1R)-1-(4-bromophenyl)ethyl](methyl)amine hydrochloride [INT 16.1]: [00324] To tert-butyl N-[(1R)-1-(4-bromophenyl)ethyl]-N-methylcarbamate [INT 16-c] (1.8 g, 5.72 mmol) hydrogen chloride (4 M in dioxane, 40 mL, 160 mmol) was added and the mixture was stirred at rt for 10 h. Then it was filtrated and the precipitate was washed with Et2O (30 mL) to obtain [(1R)-1-(4-bromophenyl)ethyl](methyl)amine hydrochloride [INT 16.1] (600 mg, 2.39 mmol, 41.9% yield) as a white solid. m/z: [M+H]+ Calcd for C9H13BrN 214.0, 216.0; Found 216.0.¹H NMR (400 MHz, DMSO) į = 9.74 (s, 1H), 9.29 (d, J = 8 Hz, 1H), 7.64 (d, J = 8 Hz, 2H), 7.51 (d, 2H), 4.25-4.32 (m, 1H), 2.34 (s, 3H), 1.52 (d, J = 4 Hz, 3H). Synthesis of N-[(1R)-1-(4-bromophenyl)ethyl]-N-methyl-1,1-dioxo-1^^-thiane-4- carboxamide [Intermediate 17.1]:

[00325] To a solution of [(1R)-1-(4-bromophenyl)ethyl](methyl)amine hydrochloride [INT 16.1] (0.84 g, 3.35 mmol) and 1,1-dioxo-1^^-thiane-4-carboxylic acid (655 mg, 3.68 mmol) in pyridine (50 m) was added phosphoroyl trichloride (769 mg, 5.02 mmol) at 0 °C and the mixture was stirred for 1 h. Then it was concentrated under reduced pressure, water (20 mL) was added to the residue and it was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with water (3 x 50 mL), dried over Na2SO4 and concentrated under reduced pressure to obtain N-[(1R)-1-(4-bromophenyl)ethyl]-N-methyl-1,1-dioxo-1^^-thiane-4-carboxamide [INT 17.1] (800 mg, 2.13 mmol, 64.0% yield) as a white solid. m/z: [M+H]+ Calcd for C15H21BrNO3S 374.0; Found 374.0.

Synthesis of (1r,4S)-4-((tert-butyldimethylsilyl)oxy)-N-((S)-1-(4-((4-cyclopropyl-1,5- naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylcyclohexanecarboxamide [Intermediate 18.1]:

Synthesis of (1r,4r)-N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-4-hydroxycyclohexane-1- carboxamide [INT 18-a]: [00326] To a mixture of (1r,4r)-4-hydroxycyclohexane-1-carboxylic acid (1.13 g, 7.87 mmol), EDCI (2.28 g, 11.8 mmol), and HOBT (1.59 g, 11.8 mmol) in CH₂Cl₂ (20 mL) was added (1S)- 1-(4-bromophenyl)-2,2,2-trifluoroethan-1-amine [INT 6.1] (2 g, 7.87 mmol) and the mixture was stirred at 25 °C for 16 hours. The reaction was quenched by adding water (100 mL) and was extracted with CH₂Cl₂ (100 mL × 3). The combined organic layers were washed with saturated NaHCO₃ aqueous (200 mL × 2) and brine (200 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product which was purified by flash chromatography on silica gel (50%-100% EtOAc in petroleum ether) to give (1r,4r)-N- [(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-4-hydroxycyclohexane-1-carboxamide [INT 18- a] (1.80 g, 60.2% yield) as a white solid. m/z: [M + H]+ Calcd for C15H18BrF3NO2380.0, 382.0; Found 381.7. Synthesis of (1r,4r)-N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-4- [(tertbutyldimethylsilyl)oxy]cyclohexane-1-carboxamide [INT 18-b]: [00327] A suspension of (1r,4r)-N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-4- hydroxycyclohexane-1-carboxamide [INT 18-a] (500 mg, 1.31 mmol), imidazole (178 mg, 2.62 mmol) and tert-butyl(chloro)dimethylsilane (295 mg, 1.96 mmol) in CH2Cl2 (5 mL) was stirred at 25 °C for 12 hours. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (30 mL × 2). The combined organic layers were washed by saturated Na₂CO₃ (100 mL × 2) and brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product which was purified by flash chromatography on silica gel (0-5% EtOAc in petroleum ether) to give (1r,4r)-N-[(1S)-1-(4-bromophenyl)-2,2,2- trifluoroethyl]-4-[(tertbutyldimethylsilyl)oxy]cyclohexane-1-carboxamide [INT 18-b] (440 mg, 68.0% yield) as a white solid. m/z: [M + H]+ Calcd for C21H32BrF3NO2Si 494.1, 496.1; Found 496.0. ¹H NMR (400 MHz, CHLOROFORM-d) į = 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). (1r,4r)-N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-4-[(tert-butyldimethylsilyl)oxy]-N- methylcyclo hexane-1-carboxamide [INT 18.1]: [00328] A suspension of (1r,4r)-N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-4-[(tert- butyldimethylsilyl)oxy] cyclohexane-1-carboxamide [INT 18-b] (1.15 g, 2.32 mmol) and Cs2CO3 (2.26 g, 6.96 mmol) in DMF (3 mL) was stirred at 20 °C for 1 hour. Then MeI (987 mg, 6.96 mmol) was added and the reaction mixture was stirred at 20 °C for 3 hours. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (30 mL × 2). The combined organic layers were washed with water (50 mL × 2) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography on silica gel (0-3% EtOAc in Petroleum ether) to give (1r,4r)-N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-4- [(tert-butyldimethylsilyl)oxy]-N-methylcyclo hexane-1-carboxamide [INT 18.1] (495 mg, 42.3 % yield) as a white solid. m/z: [M + H]+ Calcd for C22H34BrF3NO2Si 508.1, 510.1; Found 510.1. ¹H NMR (400 MHz, CHLOROFORM-d) į = 7.53 (d, J=8.4 Hz, 2H), 7.23 (d, J=8.4 Hz, 2H), 6.63 (q, J=8.8 Hz, 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). 157 Synthesis of Tert-butyl N-[(4-{[(1S)-1-(4-bromophenyl)-2,2,2- trifluoroethyl](methyl)carbamoyl}cyclohexyl)methyl]- carbamate [Intermediate 19.1]:

Tert-butyl N-[(4-{[(1S)-1-(4-bromophenyl)-2,2,2- trifluoroethyl]carbamoyl}cyclohexyl)methyl]carbamate [INT 19-a]: [00329] To a mixture of 4-({[(tert-butoxy)carbonyl]amino}methyl)cyclohexane-1-carboxylic acid (1.92 g, 7.47 mmol), EDCI (2.16 g, 11.2 mmol), and HOBT (1.51 g, 11.2 mmol) in CH2Cl2 (20 mL) was added (1S)-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 hours. The reaction was quenched by adding saturated Na2CO3 (100 mL) solution and extracted with EtOAc (50 mL ×^3). The combined organic layers were washed with brine (200 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product which was purified by flash chromatography on silica gel (0 - 10% EtOAc in CH₂Cl₂) to give tert-butyl N-[(4-{[(1S)-1- (4-bromophenyl)-2,2,2-trifluoroethyl]carbamoyl}cyclohexyl)methyl]carbamate [INT 19-a] (2.53 g, 5.13 mmol, 68.7% yield) as a white solid. m/z: [M - t-Bu + H]+ Calcd for C17H21BrF3N2O3 437.1, 439.1; Found 436.9.¹H NMR (400MHz, CD₃OD) į = 7.58 (d, J=8.4 Hz, 2H), 7.40 (d, J=8.4 Hz, 2H), 5.68 (q, J=8.0 Hz, 1H), 2.89 (d, J=6.4 Hz, 2H), 2.38 - 2.55 (m, 1H), 1.89 - 1.72 (m, 4H), 1.47 - 1.40 (m, 12H), 1.07 - 0.90 (m, 2H). Tert-butyl N-[(4-{[(1S)-1-(4-bromophenyl)-2,2,2- trifluoroethyl]carbamoyl}cyclohexyl)methyl]carbamate [INT 19.1]: [00330] A suspension of tert-butyl N-[(4-{[(1S)-1-(4-bromophenyl)-2,2,2- trifluoroethyl]carbamoyl}cyclohexyl) methyl]carbamate [INT 19-a] (1.00 g, 2.02 mmol) and Cs₂CO₃ (1.31 g, 4.04 mmol) in DMF (15 mL) was stirred for 1 hour at 20 °C. Then MeI (860 mg, 6.06 mmol) was added and the resulting mixture was stirred for 3 hours at 20 °C. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (50 mL × 2). The combined organic layers were washed with water (100 mL × 2) and brine(100 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue which was purified by Prep-HPLC (column: YMC Triart C18250 * 50 mm * 7 um, table: 44 - 84% B (A = water (0.05% ammonia hydroxide v/v), B = acetonitrile), flow rate: 60 mL/min, UV Detector 220 nm) to afford tert-butyl N-[(4-{[(1S)-1-(4-bromophenyl)-2,2,2- trifluoroethyl](methyl)carbamoyl}cyclohexyl)methyl]- carbamate [INT 19.1] (380 mg, 0.749 mmol, 37.2%) as a white solid. m/z: [M - t-Bu + H]+ Calcd for C18H23BrF3N2O3451.1, 453.1; Found 452.8. ¹H NMR (400MHz, CDCl₃) į = 7.53 (d, J=8.8 Hz, 2H), 7.24 (d, J=8.4 Hz, 2H), 6.63 (q, J=8.8 Hz, 1H), 4.58 (br s, 1H), 3.01 (t, J=6.4 Hz, 2H), 2.86 (s, 3H), 2.57 - 2.45 (m, 1H), 1.94 - 1.77 (m, 4H), 1.67 - 1.54 (m, 3H), 1.45 (s, 9H), 1.11 - 0.91 (m, 2H). Synthesis of N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-4-(1,3-dioxo-2,3-dihydro-1H- isoindol-2-yl)-N-methylcyclohexane-1-carboxamide [Intermediate 20.1]:

Tert-butyl N-(4-{[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]carbamoyl}cyclohexyl)carbamate [INT 20-a]: [00331] To a mixture of 4-{[(tert-butoxy)carbonyl]amino}cyclohexane-1-carboxylic acid (1.43 g, 5.90 mmol), EDCI (1.69 g, 8.85 mmol), and HOBT (1.19 g, 8.85 mmol) in CH₂Cl₂ (20 mL) was added (1S)-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 hours. The reaction mixture was quenched with water (30 mL) and extracted with EtOAc (100 mL × 2). The combined organic layers were washed with brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product which was purified by flash chromatography on silica gel (0 - 25% EtOAc in petroleum ether) to give tert-butyl N-(4-{[(1S)-1-(4- bromophenyl)-2,2,2-trifluoroethyl]carbamoyl}cyclohexyl)carbamate [INT 20-a] (2.70 g, 95.7% yield) as a white solid. m/z: [M - t-Bu + H]+ Calcd for C16H19BrF3N2O3423.1, 425.1; Found 425.0. 159 4-amino-N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]cyclohexane-1-carboxamide hydrochloride [INT 20-b]: [00332] A solution of tert-butyl N-(4-{[(1S)-1-(4-bromophenyl)-2,2,2- trifluoroethyl]carbamoyl}cyclohexyl) carbamate [INT 20-a] (2.7 g, 5.63 mmol) in 4 M HCl/dioxane (30 mL) was stirred at 25 ºC for 1 hour. The reaction mixture was concentrated under reduced pressure to give the crude 4-amino-N-[(1S)-1-(4-bromophenyl)-2,2,2- trifluoroethyl]cyclohexane-1-carboxamide hydrochloride [INT 20-b] (2.20 g, 94.0% yield) as a white solid. m/z: [M + H]+ Calcd for C15H19BrF3N2O 379.1, 381.1; Found 381.1. N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-4-(1,3-dioxo-2,3-dihydro-1Hisoindol-2- yl)cyclohexane-1-carboxamide [INT 20-c]: [00333] A mixture of 4-amino-N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]cyclohexane- 1-carboxamide [INT 20-b] (2.00 g, 5.27 mmol), ethyl 1,3-dioxo-2,3-dihydro-1H-isoindole-2- carboxylate (1.73 g, 7.90 mmol) and Na2CO3 (1.67 g, 15.8 mmol) in THF (20 mL) was stirred at 25 ºC for 1 hour. The reaction was concentrated under reduced pressure to give the crude product. The crude product was triturated with (EtOAc/PE, V/V = 1:1, 15 mL) to give N-[(1S)- 1-(4-bromophenyl)-2,2,2-trifluoroethyl]-4-(1,3-dioxo-2,3-dihydro-1Hisoindol-2-yl)cyclohexane- 1-carboxamide [INT 20-c] (1.30 g, 48.5% yield) as a white solid. m/z: [M + H]+ Calcd for C23H21BrF3N2O3509.1, 511.1; Found 509.1. N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-4-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-N- methylcyclohexane-1-carboxamide [INT 20.1]: [00334] A mixture of N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-4-(1,3-dioxo-2,3- dihydro-1H-isoindol-2-yl)cyclohexane-1-carboxamide [INT 20-c] (1.10 g, 2.15 mmol) and Cs2CO3 (1.40 g, 4.30 mmol) in DMF (12 mL) was stirred at 25 °C for 1 hour. CH3I (1.51 g, 10.7 mmol) was added and the reaction mixture was stirred at 25 ºC for 1 hour. The reaction was quenched by adding water (30 mL) and a suspension formed. The precipitate was filtered. The filtrate was extracted with EtOAc (50 mL × 2). The combined organic layers were washed with brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product which was purified by flash chromatography on silica gel (0 - 25% EtOAc in petroleum ether) to give N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-4-(1,3- dioxo-2,3-dihydro-1H-isoindol-2-yl)-N-methylcyclohexane-1-carboxamide [INT 20.1] (183 mg, 16.3% yield) as a white solid. m/z: [M + H]+ Calcd for C24H23BrF3N2O3523.1, 525.1; Found 525.2. Synthesis of N-[1-(4-bromophenyl)ethyl]-N-methylcyclobutanecarboxamide [Intermediate 21.1]:

[00335] To a mixture of cyclobutanecarboxylic acid (389 mg, 3.89 mmol) and HATU (2.21 g, 5.83 mmol) in DCM (15 mL) was added DIPEA (1.49 g, 11.6 mmol) and [1-(4- bromophenyl)ethyl](methyl)amine [INT 12.1] (1.00 g, 4.67 mmol). The reaction mixture was stirred at 20 °C for 16 hours. The reaction mixture was concentrated under reduced pressure to afford the crude product which was purified by Prep-HPLC (column: Phenomenex Gemini-NX 80 * 40 mm * 3 um, table: 22 - 62% B (A = water (0.05% ammonia hydroxide )), B = acetonitrile), flow rate: 25 mL/min, UV Detector 220 nm) to afford N-[1-(4-bromophenyl)ethyl]- N-methylcyclobutanecarboxamide [INT 21.1] (150 mg, 13.0% yield) as an off-white dry powder. m/z: [M + H]+ Calcd for C14H19BrNO 296.1, 298.1; Found 298.1. Synthesis of N-[1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N- methylacetamide [Intermediate

Synthesis of N-[(E)-(4-bromophenyl)-methylidene]-2-methylpropane-2-sulfinamide [INT 22-a]: [00336] 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 stirring for 15 min, sodium hydroxide (1.1 g, 27.5 mmol) was added and the reaction mixture was stirred at 25 ºC for 12 hours. Sodium sulfate (1.3 g) and celite (1.3 g) were added to the mixture and the suspension was stirred for 15 min. The mixture was filtered and concentrated under reduced pressure to give N-[(E)-(4-bromophenyl)-methylidene]-2-methylpropane-2-sulfinamide [INT 22-a] (7.35 g, 94.4% yield) as a colorless gum. ¹H NMR (400MHz, DMSO-d6) į = 8.55 (s, 1H), 7.89 (d, J=8.4 Hz, 2H), 7.76 (d, J=8.4 Hz, 2H), 1.19 (s, 9H). Synthesis of N-[1-(4-bromophenyl)-2,2,2-trifluoroethyl]-2-methylpropane-2-sulfinamide [INT 22-b]: [00337] To a solution of tetrabutylazanium acetate (3.64 g, 12.1 mmol) and N-[(E)-(4- bromophenyl)methylidene]-2-methylpropane-2-sulfinamide [INT 22-a] (3.5 g, 12.1 mmol) in DMF (30 mL) was added trimethyl-(trifluoromethyl)silane (4.29 g, 30.2 mmol) at 0 °C. The mixture was stirred at 0 - 5 °C for 3 hours. The mixture was poured into water (100 mL) and a precipitate was collected by filtration and dried under reduced pressure to give N-[1-(4- bromophenyl)-2,2,2-trifluoroethyl]-2-methylpropane-2-sulfinamide [INT 22-b] (3.50 g, 80.8% yield) as an off white solid. ¹H NMR (400MHz, DMSO-d₆) į = 7.65 (d, J=8.8 Hz, 2H), 7.59 (d, J=8.8 Hz, 2H), 6.48 (d, J=9.6 Hz, 1H), 5.27 (q, J=8.8 Hz, 1H), 1.14 (s, 9H). Synthesis of 1-(4-bromophenyl)-2,2,2-trifluoroethan-1-amine [INT 22-c]: [00338] To a suspension of N-[1-(4-bromophenyl)-2,2,2-trifluoroethyl]-2-methylpropane-2- sulfinamide [INT 22-b] (3.5 g, 9.77 mmol) in methanol (20 mL) was added 4M HCl/dioxane (9.75 mL, 39.0 mmol). The reaction mixture was stirred at 20 ºC for 1 hour. The reaction was concentrated. The residue was diluted with water (20 mL) and adjusted with 1 N NaOH solution to pH = 10. The mixture was extracted with EtOAc (50 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the crude of 1-(4-bromophenyl)-2,2,2-trifluoroethan-1-amine [INT 22- c] (2.7 g, ~80% purity, 87.0% yield) as a brown oil. ¹H NMR (400MHz, DMSO-d₆) į = 7.60 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H), 4.54 (q, J=8.4 Hz, 1H), 2.78 (br s, 2H). Synthesis of N-[1-(4-bromophenyl)-2,2,2-trifluoroethyl]acetamide [INT 22-d]: [00339] To a solution of 1-(4-bromophenyl)-2,2,2-trifluoroethan-1-amine [INT 22-c] (2.7 g, ~80% purity, 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 ºC for 12 hours. The reaction was diluted with CH₂Cl₂ (50 mL) and water (50 mL). The organic phase was separated, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the crude product which was purified by flash chromatography on silica gel (0-50% ethyl acetate in petroleum ether) to give N-[1-(4-bromophenyl)-2,2,2- trifluoroethyl]acetamide [INT 22-d] (2.50 g, 99.6% yield) as an off- white solid. ¹H NMR (400MHz, DMSO-d6) į = 9.15 (d, J=10.0 Hz, 1H), 7.65 (d, J=8.8 Hz, 2H), 7.53 (d, J=8.4 Hz, 2H), 5.91 - 5.74 (m, 1H), 1.97 (s, 3H). 162 Synthesis of N-[1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N- methylacetamide [INT 22.1]: [00340] To a mixture of sodium hydride (671 mg, 16.8 mmol, 60%) in THF (30 mL) was added N-[1-(4-bromophenyl)-2,2,2-trifluoroethyl]acetamide [INT 22-d] (2.5 g, 8.44 mmol) at 0 ºC. After stirring at 0 ºC for 30 min. iodomethane (3.59 g, 25.3 mmol) was added and the reaction mixture was allowed to warm to 20 ºC and stir at 20 °C for 12 hours under N₂ atmosphere. The reaction was quenched by adding saturated NH4Cl (150 mL) and was extracted with EtOAc (100 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the crude product which was purified by flash chromatography on silica gel (0-20% ethyl acetate in petroleum ether) to give N-[1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N- methylacetamide [INT 22.1] (1.83 g, 70.1% yield) as a brown oil. m/z: [M + H]+ Calcd for C11H12BrF3NO 310.0, 312.0; Found 311.7.¹H NMR (400MHz, DMSO-d6) į= 7.71 - 7.66 (m, 2H), 7.37 - 7.31 (m, 2H), 6.62 - 6.06 (m, 1H), 2.97 (s, 1H), 2.83 (s, 2H), 2.16 (s, 2H), 1.91 (s, 1H). Synthesis of (S)-N-(1-(4-aminophenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H- thiopyran-4-carboxamide 1,1-dioxide hydrochloride [Intermediate 23.1]:

Tert-butyl (S)-(4-(2,2,2-trifluoro-1-(N-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4- carboxamido)ethyl)phenyl)carbamate [INT 23-a]: [00341] A solution of N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-methyl-1,1-dioxo- 1^^-thiane-4-carboxamide [INT 5.1] (5 g, 11.6 mmol), tert-butyl carbamate (2.03 g, 17.4 mmol), xantphos (1.34 g, 2.32 mmol), caesium carbonate (11.3 g, 34.8 mmol), and tris(dibenzylideneacetone) dipalladium (1.06 g, 1.16 mmol) in dioxane (50 mL) was stirred at 100 °C for 1 h under N2 atmosphere. The reaction was quenched by adding water (60 mL) and was extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was purified by flash chromatography on silica gel (EtOAc/PE = 0/1 to 1/2) to give tert-butyl (S)-(4-(2,2,2-trifluoro-1-(N-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4- carboxamido)ethyl)phenyl)carbamate [INT 23-a] (3.43 g, 7.38 mmol, 63.7% yield) as a yellow solid. m/z: [M - 56]+ Calcd for C16H20F3N2O5S 409.1; Found 409.1. (S)-N-(1-(4-aminophenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4- carboxamide 1,1-dioxide hydrochloride [INT 23.1]: [00342] A solution of tert-butyl (S)-(4-(2,2,2-trifluoro-1-(N-methyl-1,1-dioxidotetrahydro- 2H-thiopyran-4-carboxamido)ethyl)phenyl)carbamate [INT 23-a] (4.7 g, 7.38 mmol) in 4 M HCl in dioxane (60 mL) was stirred at 25 °C for 16 h. The reaction was concentrated under reduced pressure to give the crude product, which was triturated with EtOAc (100 mL) at 25 °C for 12 h. A precipitate was filtered and dried under reduced pressure to give (S)-N-(1-(4- aminophenyl)-2,2,2-trifluoroethyl)-N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1- dioxide hydrochloride [INT 23.1] (2.47 g, 6.16 mmol, 83.7% yield) as a light yellow solid. m/z: [M + H]+ Calcd for C15H20F3N2O3S 365.1; Found 365.1. Synthesis of 3-bromo-1,5-naphthyridine [Intermediate 24.1]:

[00343] To a solution of 5-bromopyridin-3-amine [INT 24-a] (3 g, 17.3 mmol), propane- 1,2,3-triol (7.95 g, 86.4 mmol), and sodium 3-nitrobenzenesulfonate (7.79 g, 34.6 mmol) in H₂O (18 mL) was added H₂SO₄ (12 mL) and the reaction mixture was stirred at 135 ºC for 16 hours. The reaction was cooled to 25 °C, poured into ice water (100 mL), basified with 2 N NaOH to pH = 11, and extracted with EtOAc (100 mL × 2). The combined organic layers were washed with brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product, which was purified by flash chromatography on silica gel (0 - 30% EtOAc in petroleum ether) to give 3-bromo-1,5-naphthyridine [INT 24.1] (1 g, 4.81 mmol, 27.7% yield) as a yellow solid. m/z: [M + H]+ Calcd for C8H6BrN2209.0, 211; Found 209.0. ¹H NMR (400MHz, DMSO-d6) į = 9.06 (d, J=2.0 Hz, 1H), 9.03 (dd, J=1.6, 4.0 Hz, 1H), 8.74 - 8.70 (m, 1H), 8.45 (d, J=8.4 Hz, 1H), 7.83 (dd, J=4.0, 8.4 Hz, 1H). Synthesis of (1r,4S)-N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)-4-(hydrazinecarbonyl)-N-methylcyclohexane-1-carboxamide [Intermediate

[00344] A mixture of methyl (1S,4r)-4-(((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3- yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexane-1-carboxylate [Compound 1.7] (200 mg, 369 μmol) and hydrazine hydrate (2 ml, 39.9 μmol) in EtOH (2 mL) was stirred at 25 °C for 2 hours. The reaction was concentrated under reduced pressure to give (1r,4S)-N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)- 4-(hydrazinecarbonyl)-N-methylcyclohexane-1-carboxamide [INT 25.1] (199 mg, 100.0% yield) as a yellow oil. m/z: [M + H]+ Calcd for C28H32F3N6O2541.2; Found 541.3. Synthesis of (1r,4S)-4-(((((Z)-1-aminoethylidene)amino)oxy)carbonyl)-N-((S)-1-(4-((4- cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N- methylcyclohexane-1-carboxamide [Intermediate 26.1]:

[00345] To a mixture of (1S,4r)-4-(((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3- yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclohexane-1-carboxylic acid [Compound 6.1] (200 mg, 379 μmol) and (Z)-N'-hydroxyacetimidamide (140 mg, 1.89 mmol) in CH2Cl2 (2 mL) was added EDCI (108 mg, 568 μmol) and HOBT (76.7 mg, 568 μmol). The reaction mixture was stirred at 20 °C for 2 hours. The reaction mixture was diluted with CH₂Cl₂ (20 mL) and washed with water (10 mL) and brine (10 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give a mixture of (1S,4r)-4-(((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)(methyl)carbamoyl)cyclohexane-1-carboxylic acid [Compound 1.6] and (1r,4S)- 4-(((((Z)-1-aminoethylidene)amino)oxy)carbonyl)-N-((S)-1-(4-((4-cyclopropyl-1,5- naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylcyclohexane-1-carboxamide [INT 26.1] (170 mg, 77.3 % yield). m/z: [M + H]+ Calcd for C30H34F3N6O3583.3; Found 583.4. Synthesis of 1-(5-methyl-1,3,4-oxadiazol-2-yl)azetidine-3-carboxylic acid [Intermediate 27.1]:

Methyl 1-(3-methyl-1,2,4-oxadiazol-5-yl)azetidine-3-carboxylate [INT 27-b]: [00346] Methyl azetidine-3-carboxylate hydrochloride (1 g, 6.59 mmol), N,N- diisopropylethylamine (1.92 g, 14.9 mmol) and 3-methyl-5-(trichloromethyl)-1,2,4-oxadiazole [INT 27-a] (1.20 g, 5.99 mmol) were dissolved in NMP (3 mL). The mixture was stirred for 10 hr at 80 °C. The reaction mixture was purified by HPLC (see conditions below) to obtain methyl 1-(3-methyl-1,2,4-oxadiazol-5-yl)azetidine-3-carboxylate [INT 27-b] (157 mg, 0.800 mmol, 13.3% yield) as a yellow solid. m/z: [M + H]+ Calcd for C8H12N3O3198.1; Found 198.0. [00347] HPLC conditions: System - Agilent 1260 Infinity II LC coupled to an Agilent 6120B Single Quadrupole LC/MS System. Column - Description: Chromatorex SBM 100-5T 5 ^m C18(2) 100 Å, LC Column 100 x 19 mm, Waters, Sun Fire. Stationary Phase: C18. Solid Support: Fully Porous Silica. Separation Mode: Reversed Phase. Mobile Phase - Mobile phase A: water. Mobile phase B: acetonitrile. Flow rate: 30ml/min; loading pump 4ml/min B. Gradient conditions: 0-0-50-100% (B) 0-2-10-11.2 min. Lithium(1+) 1-(3-methyl-1,2,4-oxadiazol-5-yl)azetidine-3-carboxylate [INT 27.1]: [00348] Methyl 1-(3-methyl-1,2,4-oxadiazol-5-yl)azetidine-3-carboxylate [INT 27-b] (0.154 g, 0.7809 mmol) was dissolved in a mixture of THF (1 mL) and water (1 mL ). Lithium(1+) hydrate hydroxide (49.0 mg, 1.17 mmol) was then added and the mixture was stirred for 10 hr at 20 °C. The mixture was evaporated in vacuo at 50 °C to obtain lithium(1+) 1-(3-methyl-1,2,4- oxadiazol-5-yl)azetidine-3-carboxylate [INT 27.1] (137 mg, 0.7284 mmol, 93.3% yield) as a yellow solid. m/z: [M + H]+ Calcd for C7H10N3O3184.1; Found 184.0. Synthesis of (1r,4S)-4-((tert-butyldimethylsilyl)oxy)-N-((S)-1-(4-((4-cyclopropyl-1,5- naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methylcyclohexane-1- carboxamide [Intermediate 28.1]:

[00349] To a suspension of (1r,4S)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-((tert- butyldimethylsilyl)oxy)-N-methylcyclohexane-1-carboxamide [INT 18.1] (100 mg, 196 μmol), 4-cyclopropyl-1,5-naphthyridin-3-amine [INT 1.1] (43.5 mg, 235 μmol), Cs₂CO₃ (127 mg, 392 μmol), and xantphos (22.6 mg, 39.2 μmol) in dioxane (3 mL) was added Pd2(dba)3 (17.9 mg, 19.6 μmol). The resulting mixture was stirred at 100 °C for 2 h under N2. The reaction was concentrated under reduced pressure to give the crude product, which was purified by flash chromatography on silica gel (MeOH/Dichloromethane = 0/1 to 2/8) to give (1r,4S)-4-((tert- butyldimethylsilyl)oxy)-N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)-N-methylcyclohexane-1-carboxamide [INT 28.1] (98.0 mg, 159 μmol, 81.6% yield) as a yellow oil. m/z: [M + H]+ Calcd for C33H44F3N4O2Si 613.3; Found 613.3. ¹H NMR (400 MHz, CDCl₃) į = 8.99 - 8.91 (m, 2H), 8.30 (dd, J=1.6, 8.8 Hz, 1H), 7.50 (dd, J=4.4, 8.4 Hz, 1H), 7.32 (br d, J=8.4 Hz, 2H), 7.12 (d, J=8.4 Hz, 2H), 6.65 (q, J=8.8 Hz, 1H), 6.45 (s, 1H), 3.69 - 3.60 (m, 1H), 2.93 (s, 3H), 2.60 - 2.47 (m, 1H), 2.11 - 1.76 (m, 6H), 1.42 - 1.21 (m, 5H), 1.15 - 1.03 (m, 2H), 0.91 (s, 9H), 0.08 (s, 6H). Synthesis of (S)-N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)-4-(1,3-dioxoisoindolin-2-yl)-N-methylcyclohexane-1-carboxamide [Intermediate 28.2]:

[00350] To a mixture of (S)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-(1,3- dioxoisoindolin-2-yl)-N-methylcyclohexane-1-carboxamide [INT 20.1] (200 mg, 382 μmol), 4- cyclopropyl-1,5-naphthyridin-3-amine [INT 1.1] (70.7 mg, 382 μmol) , Cs2CO3 (248 mg, 764 μmol), and Xantphos (44.2 mg, 76.4 μmol) in dioxane (1 mL) was added Pd2(dba)3 (34.9 mg, 38.2 μmol) at 25 ºC. The mixture was stirred at 100 ºC under N2 for 1 h, after which it was combined with another batch of the same reaction (191 μmol scale), 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 give the crude product, which was purified by flash chromatography on silica gel (EtOAc/PE = 0/1 to 1/1) to give two (S)-N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)- 2,2,2-trifluoroethyl)-4-(1,3-dioxoisoindolin-2-yl)-N-methylcyclohexane-1-carboxamide [INT 28.2] products (product 1; 106 mg, 168 μmol, LCMS rt = 0.814 min and product 2; 110 mg, 175 μmol, LCMS rt = 0.811 min, 59.9% yield c bi d) llow solid. Synthesis of (1s,4R)-N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)-4-(1,3-dioxoisoindolin-2-yl)-N-methylcyclohexane-1-carboxamide [Intermediate 28.3]:

[00351] To a mixture of (1s,4R)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-(1,3- dioxoisoindolin-2-yl)-N-methylcyclohexane-1-carboxamide [INT 5.6] (590 mg, 1.12 mmol), 4- cyclopropyl-1,5-naphthyridin-3-amine [INT 1.1] (207 mg, 1.12 mmol), Cs2CO3 (729 mg, 2.24 mmol), and Xantphos (129 mg, 224 μmol) in dioxane (15 mL) was added Pd2(dba)3 (102 mg, 112 μmol) and the mixture was stirred at 100 ºC under N2 for 1 h. The reaction was concentrated under reduced pressure to give the crude product, which was purified by flash chromatography on silica gel (CH3OH/CH2Cl2 = 0/1 to 1/20) to give (1s,4R)-N-((S)-1-(4-((4- cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-4-(1,3-dioxoisoindolin-2- yl)-N-methylcyclohexane-1-carboxamide [INT 28.3] (380 mg, 605 μmol, 54.1% yield) as a yellow solid. m/z: [M + H]+ Calcd for C35H33F3N5O3628.2; Found 628.3. ¹H NMR (400 MHz, CDCl3) į = 9.11 - 8.86 (m, 2H), 8.35 (br d, J=7.6 Hz, 1H), 7.82 (dd, J=3.1, 5.4 Hz, 2H), 7.69 (dd, J=3.0, 5.4 Hz, 2H), 7.51 (br dd, J=4.3, 8.3 Hz, 1H), 7.38 (br d, J=8.2 Hz, 2H), 7.14 (br d, J=8.6 Hz, 2H), 6.89 - 6.63 (m, 1H), 6.56 (br s, 1H), 4.25 - 4.15 (m, 1H), 3.08 - 2.98 (m, 1H), 2.93 (s, 3H), 2.91 - 2.62 (m, 2H), 2.22 - 2.07 (m, 3H), 1.82 - 1.63 (m, 4H), 1.34 (br d, J=6.5 Hz, 2H), 1.06 (br d, J=4.2 Hz, 2H).

Synthesis of (1r,4S)-N-((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)-4-(1,3-dioxoisoindolin-2-yl)-N-methylcyclohexane-1-carboxamide [Intermediate 28.4]:

[00352] To a mixture of (1r,4S)-N-((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-4-(1,3- dioxoisoindolin-2-yl)-N-methylcyclohexane-1-carboxamide [INT 5.7] (1 g, 1.91 mmol), 4- cyclopropyl-1,5-naphthyridin-3-amine [INT 1.1] (353 mg, 1.91 mmol), Cs2CO3 (1.24 g, 3.82 mmol), and Xantphos (221 mg, 382 μmol) in dioxane (10 mL) was added Pd2(dba)3 (174 mg, 191 μmol) and the mixture was stirred at 100 ºC under N2 for 1 h. The reaction was concentrated under reduced pressure to give the crude product, which was purified by flash chromatography on silica gel (CH3OH/CH2Cl2 = 0/1 to 1/20) to give (1r,4S)-N-((S)-1-(4-((4- cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-4-(1,3-dioxoisoindolin-2- yl)-N-methylcyclohexane-1-carboxamide [INT 28.4] (1.10 g, 1.75 mmol, 92.4% yield) as a yellow solid. m/z: [M + H]+ Calcd for C35H33F3N5O3628.2; Found 628.2. ¹H NMR (400 MHz, CDCl₃) į = 9.02 - 8.85 (m, 2H), 8.28 (dd, J=1.7, 8.4 Hz, 1H), 7.82 (dd, J=3.0, 5.4 Hz, 2H), 7.70 (dd, J=3.1, 5.4 Hz, 2H), 7.47 (dd, J=4.2, 8.4 Hz, 1H), 7.32 (br d, J=8.4 Hz, 2H), 7.13 - 7.04 (m, 2H), 6.65 (q, J=9.1 Hz, 1H), 6.49 (s, 1H), 4.35 - 4.12 (m, 1H), 2.96 (s, 3H), 2.78 - 2.63 (m, 1H), 2.41 - 2.26 (m, 2H), 2.11 - 1.99 (m, 2H), 1.96 - 1.75 (m, 5H), 1.27 (br dd, J=2.0, 8.5 Hz, 2H), 1.15 - 0.98 (m, 2H).

Synthesis of methyl (1S,3r)-3-(((S)-1-(4-((4-cyclopropyl-1,5-naphthyridin-3- yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclobutane-1-carboxylate [Intermediate 28.5]:

[00353] A mixture of 4-cyclopropyl-1,5-naphthyridin-3-amine [INT 1.1] (50 mg, 269 μmol), methyl (1S,3r)-3-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamoyl)cyclobutane- 1-carboxylate [INT 5.8] (160 mg, 207 μmol), tris(dibenzylideneacetone) dipalladium (24.6 mg, 26.9 μmol), xantphos (31.1 mg, 53.8 μmol), and caesium carbonate (262 mg, 807 μmol) in dioxane (3 mL) was stirred at 100 °C for 2 hours under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by flash chromatography on silica gel (DCM/MeOH = 1/0 to 20/1) to give methyl (1S,3r)-3-(((S)-1-(4- ((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2- trifluoroethyl)(methyl)carbamoyl)cyclobutane-1-carboxylate [INT 28.5] (100 mg, 196 μmol, 72.9% yield) as a yellow gum. m/z: [M + H]+ Calcd for C27H28F3N4O3513.2; Found 513.2. ¹H NMR (400 MHz, CDCl₃) į = 8.95 (s, 2H), 8.29 (d, J=8.0 Hz, 1H), 7.55 - 7.45 (m, 1H), 7.40 - 7.29 (m, 2H), 7.11 (d, J=8.4 Hz, 2H), 6.60 (q, J=8.8 Hz, 1H), 6.43 (s, 1H), 3.73 (s, 3H), 3.56 - 3.43 (m, 1H), 3.27 - 3.11 (m, 1H), 2.89 - 2.44 (m, 7H), 2.14 - 2.02 (m, 1H), 1.33 - 1.25 (m, 2H), 1.14 - 1.03 (m, 2H).

(S)-N-(1-(4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-4- ((1,3-dioxoisoindolin-2-yl)methyl)-N-methylcyclohexane-1-carboxamide [Intermediate 28.6]:

[00354] To a suspension of N-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-4-[(1,3-dioxo- 2,3-dihydro-1H-isoindol-2-yl)methyl]-N-methylcyclohexane-1- carboxamide [INT 5.11] (63 mg, 117 μmol), 4-cyclopropyl-1,5-naphthyridin-3-amine [INT 1.1] (23.7 mg, 128 μmol), Cs2CO3 (76.2 mg, 234 μmol), and xantphos (13.5 mg, 23.4 μmol) in dioxane (3 mL) was added Pd₂(dba)₃ (10.7 mg, 11.7 μmol) .The resulting mixture was stirred at 100 °C for 2 h under N₂.The reaction was quenched by adding Na₂CO₃ (20 mL) and was extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to give the crude product (S)-N-(1- (4-((4-cyclopropyl-1,5-naphthyridin-3-yl)amino)phenyl)-2,2,2-trifluoroethyl)-4-((1,3- dioxoisoindolin-2-yl)methyl)-N-methylcyclohexane-1-carboxamide [INT 28.6] (75.0 mg, 116 μmol) as a yellow solid. m/z: [M + H]+ Calcd for C36H35F3N5O3642.3; Found 642.1. Exemplary Compounds of Formula (I) [00355] The following compounds in Table 1 were synthesized according to Schemes 1-15 as described above with the identified intermediates.

Table 1.

173

177

180

182

183

185

186

187

188

189

191

193

194

195

197

198

199

200

202

207

209

210

211

212

213

Intermediates Used in the Preparation of Compounds of Formula (I) [00356] The intermediates provided in Table 2 can be prepared from readily available starting materials using modifications to the specific synthesis protocols for the exemplified intermediates, as described above, that would be well known to those of skill in the art. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by those skilled in the art by routine optimization procedures. 218 Table 2.

219

220

221

223

224

225

226

228

229

Example 2. MALT1 Biochemical Assay [00357] Inhibitor potency was evaluated by measuring enzymatic activity of full length MALT1 at varying concentrations of compound. The enzymatic assay consists of a single substrate reaction that monitors the release of a fluorescent dye upon cleavage of the peptide substrate. The peptide substrate has the following sequence: Ac-Leu-Arg-Ser-Arg-Rh110-dPro (custom synthesis from WuXi AppTec, Shanghai, China). The assay buffer consists 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 (KM) of 150 μM. The assay was performed in a 384-well F-bottom polypropylene, black microplate (Greiner Bio_One, Catalog no.781209) at 15 nM enzyme and 30 μM peptide substrate. The reaction was quenched after 60 minutes with the addition of iodoacetate at a final concentration of 10 mM. Total fluorescence was measured using an Envision (PerkinElmer) with fluorescence excitation at 485 nm and emission at 520 nm. [00358] For potency determination, 1 μL of serially diluted compound (in 100% DMSO) was pre-incubated with 40 μL of enzyme for 30 minutes. The reaction was initiated with the addition of 10 μL of peptide substrate. The relative fluorescence units were transformed to percent inhibition by using 0% and 100% inhibition controls as reference. The 100% inhibition control consisted of 1 μM final concentration of (S)-1-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)- 3-(2-chloro-7-(1-methoxyethyl)pyrazolo[1,5-a]pyrimidin-6-yl)urea (IC50 = 15 nM), while the 0% inhibition control consisted of 2% DMSO. IC₅₀ values were calculated by fitting the concentration-response curves to a four-parameter logistic equation in GraphPad Prism. [00359] Results from this assay are summarized in Table 3 below. In this table, “A” indicates IC50 of less than 0.1 ^M; “B” indicates IC50 from 0.1 ^M up to 1 ^M; and “C” indicates IC50 of greater than 1 ^M. “N/A” indicates not tested. For a compound that was tested in more than one experiment, the result shown represents the mean value. Table 3.

Example 3. Jurkat IL-2 Assay [00360] Inhibition was determined in a cell-based assay using Jurkat (ATCC, clone E6.1), an immortalized T-cell line, exposed to a dose response of compound and assessed for viability, and Il-2 inhibition by ELISA. Cells were cultured in RPMI/10% FBS (Invitrogen 11875093, Atlanta Biologicals S12450H), maintained below 3E6/mL and only used in assays while below passage 25. Compounds were stamped by ECHO onto 384w plates (PerkinElmer Culturplate, 6007680). The cells were plated in fresh media on top of compound and incubated for 30 minutes before stimulation 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 compound, cells were lysed with CTG reagent (Promega, G7570), and measured by luminometer. IL-2 curves were calculated as percent of DMSO (100%) and signal-inhibiting (0%, (S)-1-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-3-(2-chloro-7-(1- methoxyethyl)pyrazolo[1,5-a]pyrimidin-6-yl)urea) controls. IC50s calculated using 4-parameter fit in GraphPad Prism. [00361] Results from this assay are summarized in Table 4 below. In this table, “A” indicates IC₅₀ of less than 0.1 ^M; “B” indicates IC₅₀ from 0.1 ^M up to 1 ^M; and “C” indicates IC₅₀ of greater than 1 ^M. “N/A” indicates not tested. For a compound that was tested in more than one experiment, the result shown represents the mean value. Table 4.

Equivalents and Scope [00362] In the claims, articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process. [00363] Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is/are referred to as comprising particular elements and/or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and/or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms “comprising” and “containing” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub–range within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise. [00364] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the invention can be excluded from any claim, for any reason, whether or not related to the existence of prior art. [00365] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims.

Claims

CLAIMS 1. A compound represented by Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is selected from the group consisting of C_1-6alkyl, C_1-6alkoxy, C_3-6cycloalkyl, and 5-10 membered heterocyclyl, wherein the C_1-6alkyl, C_3-6cycloalkyl, and 5-10 membered heterocyclyl may be optionally 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, that ring nitrogen atom may optionally be substituted by R^1b, and wherein if the 5-10 membered heterocyclyl contains a substitutable ring sulfur atom, that ring sulfur atom may be optionally substituted with two O atoms; R² is CH3 or CF3; R³ is hydrogen; or R³ is selected from the group consisting of C1-6alkyl, C1-6alkoxy, C3-7cycloalkyl, 5-6 membered heterocyclyl, 5-6 membered heterocyclyl-C1-3alkyl-, 5-6 membered heterocyclyl-O-, phenyl, and 5-6 membered heteroaryl, any of which may be optionally substituted with one, two or three substituents each independently selected from R^3a; R^4a, R^4b, and R^4c are independently selected from the group consisting of hydrogen, halogen, cyano, C_1-4alkyl, haloC_1-4alkyl, C_1-4alkoxy, haloC_1-4alkoxy, amino, hydroxy, hydroxymethyl, C_3-4cycloalkyl, C_1-4alkoxyC_1-4alkyl, -CONR^CR^D, and S(O)₂NH₂; wherein the C_{3- 4}cycloalkyl may be optionally substituted with one, two or three substituents each independently methyl or fluoro; R^1a is independently, for each occurrence, selected from the group consisting of cyano, halogen, hydroxyl, oxo, C1-6alkyl, -C(O)OR^A, -C(O)N(R^A)2, -N(R^A)2, C1-6alkoxy, 5-6 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the C1-6alkyl is optionally substituted with - N(R^A)2, wherein the 5-6 membered heterocyclyl or 5-6 membered heteroaryl may be optionally substituted with C1-6alkyl or oxo, and wherein if the 5-6 membered heterocyclyl or 5-6 membered heteroaryl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by R^B; R^1b is selected from the group consisting of C1-6alkyl, -C(O)OR^A, -C(O)C1-6alkyl, -C(O)C3- 6cycloalkyl, -C(O)N(R^A)2, -S(O)2C1-6alkyl, and 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl is optionally substituted with C1-6alkyl; R^3a is independently, for each occurrence, selected from the group consisting of halogen, C1- 4alkyl, C1-4haloalkyl, C1-4alkoxy, C1-4haloalkoxy, hydroxy, C1-4alkenyl, cyano, azido, -NR^CR^D, C3-6cycloalkyl, C1-4alkoxyC1-4alkoxy, 5-6 membered heterocyclyl-O-, 5-6 membered heterocyclyl, and phenyl, wherein C_3-6cycloalkyl, 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; R^p is independently, for each occurrence, selected from the group consisting of halogen, C_{1- 4}alkyl, C_1-4haloalkyl, hydroxy, C_1-4alkoxy, C_1-4alkoxyC_1-4alkyl, NR^CR^D, and aminoC_1-3alkyl; R^A is independently, for each occurrence, selected from the group consisting of hydrogen, C1-6alkyl, -C(O)C1-6alkyl, and -C(O)OC1-6alkyl; R^B is selected from the group consisting of C1-6alkyl, C3-6cycloalkyl, and -C(O)OC1-6alkyl; and R^C and R^D are independently, for each occurrence, selected from the group consisting of hydrogen, C1-6alkyl, haloC1-6alkyl, and C3-4cycloalkyl, or R^C and R^D together with the nitrogen atom to which they are attached form 4-6 membered heterocyclyl or 4-6 membered heteroaryl, wherein the 4-6 membered heterocyclyl or 4-6 membered heteroaryl may contain a further nitrogen atom or an oxygen atom and is optionally substituted with one or two fluoro. 2. The compound of claim 1, wherein R² is CF₃. 3. The compound of claim 1, wherein R² is CH₃. 4. The compound of any one of claims 1-3, wherein R³ is C_3-7cycloalkyl. 5. The compound of any one of claims 1-4, wherein R³ is cyclopropyl. 6. The compound of any one of claims 1-3, wherein R³ is C1-6alkyl. 7. The compound of any one of claims 1-3 or 6, wherein R³ is propyl or isopropyl.

8. The compound of any one of claims 1-3, wherein R³ is C1-6alkyl, wherein R³ is substituted with C1-4alkoxy. 9. The compound of any one of claims 1-3 and 8, wherein R³ is

. 10. The compound of any one of claims 1-3, wherein R³ is hydrogen. 11. The compound of any one of claims 1-10, wherein R^4a, R^4b, and R^4c are hydrogen. 12. The compound of any one of claims 1-10, wherein R^4b and R^4c are hydrogen and R^4a is C1- 6alkyl, haloC1-4alkyl, or C1-4alkoxy. 13. The compound of any one of claims 1-10 and 12, wherein R^4b and R^4c are hydrogen and R^4a is C1-6alkyl. 14. The compound of any one of claims 1-10, 12, and 13, wherein R^4b and R^4c are hydrogen and R^4a is CH3. 15. The compound of any one of claims 1-10 and 12, wherein R^4b and R^4c are hydrogen and R^4a is haloC_1-4alkyl. 16. The compound of any one of claims 1-10, 12, and 15, wherein R^4b and R^4c are hydrogen and R^4a is CF₃. 17. The compound of any one of claims 1-10 and 12, wherein R^4b and R^4c are hydrogen and R^4a is C1-4alkoxy. 18. The compound of any one of claims 1-10, 12, and 17, wherein R^4b and R^4c are hydrogen and R^4a is -O-CH3. 19. The compound of any one of claims 1-10, wherein R^4a and R^4c are hydrogen and R^4b is C1- 4alkyl or C1-4alkoxy.

20. The compound of any one of claims 1-10 and 19, wherein R^4a and R^4c are hydrogen and R^4b is C1-4alkoxy. 21. The compound of any one of claims 1-10, 19, and 20, wherein R^4a and R^4c are hydrogen and R^4b is -O-CH3. 22. The compound of any one of claims 1-10 and 19, wherein R^4a and R^4c are hydrogen and R^4b is C_1-4alkyl. 23. The compound of any one of claims 1-10, 19, and 22, wherein R^4a and R^4c are hydrogen and R^4b is CH₃. 24. A compound represented by Formula (Ia):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is C1-6alkyl, C3-6cycloalkyl, or 5-10 membered heterocyclyl, wherein the 3-6 membered cycloalkyl may be optionally 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, that ring nitrogen atom may optionally be substituted by R^1b, and wherein if the 5-10 membered heterocyclyl contains a substitutable ring sulfur atom, that ring sulfur atom may be optionally substituted with two O atoms; R^1a is independently, for each occurrence, selected from the group consisting of cyano, halogen, hydroxyl, C_1-6alkyl, -C(O)OR^A, -C(O)N(R^A)₂, -N(R^A)₂, C_1-6alkoxy, 5-6 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the C_1-6alkyl is optionally substituted with - N(R^A)₂, wherein the 5-6 membered heterocyclyl or 5-6 membered heteroaryl may be optionally substituted with C_1-6alkyl or oxo, and wherein if the 5-6 membered heterocyclyl or 5-6 membered heteroaryl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by R^B; R^1b is selected from the group consisting of C1-6alkyl, -C(O)OR^A, -C(O)C1-6alkyl, -C(O)C3- 6cycloalkyl, -C(O)N(R^A)2, -S(O)2C1-6alkyl, and 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl is optionally substituted with C1-6alkyl; R^A is independently, for each occurrence, hydrogen, C1-6alkyl, -C(O)C1-6alkyl, and - C(O)OC1-6alkyl; and R^B is C1-6alkyl. 25. The compound of any one of claims 1-24, wherein R¹ is C_1-6alkyl. 26. The compound of any one of claims 1-25, wherein R¹ is CH₃. 27. The compound of any one of claims 1-24, wherein R¹ is C_3-6cycloalkyl, wherein R¹ may be optionally substituted on one or more available carbons by one, two, three, or more substituents each independently selected from R^1a. 28. The compound of any one of claims 1-24 and 27, wherein R¹ is C3-6cycloalkyl. 29. The compound of any one of claims 1-24, 27, and 28, wherein R¹ is selected from the group consisting

. 30. The compound of any one of claims 1-24 and 27, wherein R¹ is C3-6cycloalkyl, wherein R¹ is substituted on one or more available carbons by one, two, three, or more substituents each independently selected from R^1a. 31. The compound of any one of claims 1-24, 27, and 30, wherein

32. The compound of any one of claims 1-24, 27, 30, and 31, wherein R^1a is selected from the

. 33. The compound of any one of claims 1-24, 27 and 30-32, wherein R¹ is selected from the

34. The compound of any one of claims 1-23, wherein R¹ is selected from the group consisting

35. The compound of any one of claims 1-24, wherein R¹ is 5-10 membered heterocyclyl, wherein if R¹ contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by R^1b, and wherein if the 5-10 membered heterocyclyl contains a substitutable ring sulfur atom, that ring sulfur atom may be optionally substituted with two O atoms. 36. The compound of any one of claims 1-24 and 35, wherein R¹ is 5-10 membered heterocyclyl. 37. The compound of any one of claims 1-26, 37, and 38, wherein R¹ is selected from the group

38. The compound of any one of claims 1-24 and 35, wherein

39. The compound of any one of claims 1-24 and 35, wherein R¹ is selected from the group

40. The compound of any one of claims 1-24, 35, and 39, wherein R^1b is selected from the

. 41. The compound of any one of claims 1-24, 35, 39, and 40, wherein R¹ is selected from the

. 42. The compound of any one of claims 1-24 and 35, wherein R¹ is selected from the group

. 44. The compound of claim 24, wherein R¹ is selected from the group consisting of CH3,

. 45. A compound selected from any compound set forth in Table 1, or a pharmaceutically acceptable salt thereof. 46. A pharmaceutical composition comprising a compound of any one of claims 1-45 and a pharmaceutically acceptable carrier. 47. A method of treating a cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-45 or a pharmaceutical composition of claim 46.

48. A method of treating an autoimmune or inflammatory disorder or disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-45 or a pharmaceutical composition of claim 46. 49. The method of claim 48, wherein the autoimmune or inflammatory disorder or disease is selected from the group consisting of acute graft-versus-host disease, chronic graft-versus-host disease, lupus, scleroderma, psoriatic arthritis, primary sclerosing cholangitis, rheumatoid arthritis, and an inflammatory bowel disease.