Substituted pyridines and pyrimidines

Abstract

The present disclosure describes compounds of Formula I or II, or a pharmaceutically acceptable salt thereof, pharmaceutical compositions comprising the compounds, methods of preparation, and methods of use. The compounds of the disclosure can inhibit the interaction between SLC15A4 and TASL, and are believed to be useful for treating an autoimmune disease, such as systemic lupus erythematosus, or an inflammatory condition.

Description

Attorney Docket No.: 064105-501001WO SUBSTITUTED PYRIDINES AND PYRIMIDINES CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. provisional application no.63 / 667,523, filed July 3, 2024, and U.S. provisional application no.63 / 770,761, filed March 12, 2025, which are each incorporated herein in their entireties for all purposes. BACKGROUND

[0002] Dysregulation of pathogen-recognition pathways of the innate immune system is associated with multiple autoimmune disorders. Due to the intricacies of the molecular network involved, the identification of pathway- and disease-specific therapeutics has been challenging.

[0003] Endolysosomal toll-like receptors, e.g., TLR7, TLR8, and TLR9, are critical for detecting pathogens and initiating immune responses. However, their aberrant activation is associated with autoimmune diseases, including systemic lupus erythematosus (SLE). Interferon regulatory factor 5 (IRF5) belongs to a family of transcription factors originally implicated in antiviral responses and interferon production. It is believed that IRF5 plays a central role in inflammation by induction of proinflammatory cytokines. This is also supported by genome-wide association studies (GWAS) where genetic variants within or near IRF5 are robustly associated with SLE. Recently, the mechanism of endolysosomal TLR pathway activation of IRF5 has been reported in several studies. First, the discovery of the endolysosomal solute carrier family 15 member 4 (SLC15A4) was implicated in TLR7 / 8 / 9- mediated immune responses, and genetic loss of function mutant (aka ‘feeble’) and haploinsufficiency can completely protect against murine SLE disease models. Indeed, SLC15A4 loss results in a defect in IRF5 activation and dampened proinflammatory cytokine production. Second, the discovery of a previously uncharacterized protein encoded by the X- linked CXorf21 gene (also known as TASL for TLR Adaptor interacting with SLC15A4 on the Lysosome) to be a key adaptor protein of IRF5 signaling axis. TASL interacts with both SLC15A4 (via its N-terminus) and IRF5 (via its C-terminus), forming a complex that brings IRF5 close to the endolysosome where endolysosomal TLR components can induce its phosphorylation. Cells deficient in TASL can no longer activate IRF5 downstream of endolysosomal TLR stimulation, phenocopying SLC15A4 deficient cells. This uniquemolecular positioning of the SLC15A4-TASL-IRF5 complex within the endolysosomal TLR pathway may permit the opportunity to selectively inactivate IRF5 without affecting ligand- receptor interaction of upstream TLR signaling (MAPK and NF^B). Therefore, agents which can disrupt the SLC15A4-TASL-IRF5 signaling axis may have benefit in treating human autoimmune disorders, including SLE.

[0004] PCT application publication WO 2024 / 089045 reported synthesis and evaluation of a small number of quinoline amide compounds on disrupting the SLC15A4-TASL interaction. Compound C5 has been evaluated mechanistically with regard to its ability to disrupt the SLC15A4-TASL adapter module. See, Boeszermenyi, A. et al. Nature Communications 2023, 14: 6626, pages 1-12.

[0005] There is an urgent need for new treatments and therapeutic modalities against autoimmune diseases, in particular against systemic lupus erythematosus, as well as inflammation conditions. The present invention addresses this problem through provision of new chemical entities useful in the treatment or prevention of autoimmune diseases, in particular against systemic lupus erythematosus, as well as inflammation conditions. BRIEF SUMMARY

[0006] The present disclosure provides a compound of Formula I:or pharmaceutically acceptable salt thereof, wherein R1is a C3-C8cycloalkyl, heterocyclyl, C6-C10aryl, or heteroaryl, which are each substituted by 0, 1, 2, or 3 R1a; R2is a C3-C8cycloalkyl, heterocyclyl, C6-C10aryl, or heteroaryl, which are each substituted by 0, 1, 2, or 3 R2a; R3is -(C0-C3 alkylene)(C3-C8 cycloalkyl), -(C0-C3 alkylene)(heterocyclyl), -(C0-C3 alkylene)(C6-C10 aryl), or -(C0-C3 alkylene)(heteroaryl), which are each substituted by 0, 1, 2, or 3 R3a; X1is C-X1aor N; X2is C-X2aor N;X1aand X2ais independently H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1- C6 aminoalkyl, C1-C6 sulfonylalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, halogen, or -CN; Y1is -S(O)NH-, -S(O)2NH-, -S(O)(=NRY)NH-, -NHS(O)-, -NHS(O)2-, or -NHS(O)(=NRY)-; RYis H or C1-C6 alkyl; each R1a, R2a, and R3ais independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, C3-C6cycloalkyl, heterocyclyl, C6-C10aryl, heteroaryl, halogen, -OR1b, -NR1cR1d, -CN, -C(O)R1b, -C(O)NR1cR1d, -OC(O)NR1cR1d, -N(R1b)C(O)NR1cR1d, or -S(O)2NR1cR1d; and each R1b, R1c, and R1dis independently H, C1-C6alkyl, C1-C6haloalkyl, –(C0-C3alkylene)(C3-C8cycloalkyl), –(C0-C3alkylene)(heterocyclyl), –(C0-C3alkylene)(C6-C10aryl), or –(C0-C3 alkylene)(heteroaryl).

[0007] The present disclosure also provides a compound of Formula II:or pharmaceutically acceptable salt thereof, wherein R1is a C3-C8 cycloalkyl, heterocyclyl, C6-C10 aryl, or heteroaryl, which are each substituted by 0, 1, 2, or 3 R1a; R2is a C3-C8cycloalkyl, heterocyclyl, C6-C10aryl, or heteroaryl, which are each substituted by 0, 1, 2, or 3 R2a; R3is -(C0-C3 alkylene)(nitrogen-containing heterocyclyl), which is substituted by 0, 1, 2, or 3 R3a; X1is C-X1aor N; X2is C-X2aor N; X1aand X2ais independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1- C6aminoalkyl, C1-C6sulfonylalkyl, C1-C6haloalkyl, C1-C6haloalkoxy, halogen, or -CN; Y2is -C(O)NH- or -NHC(O)-; each R1a, R2a, and R3ais independently C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, C3-C6cycloalkyl, heterocyclyl, C6-C10aryl, heteroaryl, halogen, -OR1b, -NR1cR1d, -CN, -C(O)R1b, -C(O)NR1cR1d, -OC(O)NR1cR1d, -N(R1b)C(O)NR1cR1d, or -S(O)2NR1cR1d; and each R1b, R1c, and R1dis independently H, C1-C6 alkyl, C1-C6 haloalkyl, –(C0-C3 alkylene)(C3-C8cycloalkyl), –(C0-C3alkylene)(heterocyclyl), –(C0-C3alkylene)(C6- C10 aryl), or –(C0-C3 alkylene)(heteroaryl).

[0008] Also provided herein is a pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof of the present disclosure.

[0009] Further provided herein is a method of inhibiting binding between SLC15A4 and TASL in an immune cell, comprising administering to the immune cell an effective amount of a compound or pharmaceutically acceptable salt thereof of the present disclosure, or a pharmaceutical composition of the present disclosure.

[0010] Further provided herein is a method of treating an autoimmune disorder or an inflammatory condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof of the present disclosure, or a pharmaceutical composition of the present disclosure. DETAILED DESCRIPTION I. GENERAL

[0011] The disclosure relates generally to substituted, e.g., tetrasubstituted or trisubstituted pyridine and pyrimidine compounds, pharmaceutically acceptable salts thereof, and methods and uses thereof, for interfering with SLC15A4-TASL complex formation. The following description sets forth exemplary methods, parameters and the like. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure but is instead provided as a description of exemplary embodiments. II. DEFINITIONS

[0012] As used in the present specification, the following words, phrases and symbols are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

[0013] A dash (“-”) that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -CONH2 is attached through the carbon atom. Adash at the front or end of a chemical group is a matter of convenience; chemical groups can be depicted with or without one or more dashes without losing their ordinary meaning. A wavy line drawn through a line in a structure indicates a point of attachment of a group.

[0014] A squiggly line on a chemical group as shown below, for example, indicates a point of attachment, i.e., it shows the broken bond by which the group is connected to another described group.

[0015] The prefix “Cu-Cv” indicates that the following group has from u to v carbon atoms. For example, “C1-C8alkyl” indicates that the alkyl group has from 1 to 8 carbon atoms.

[0016] “Alkyl” refers to a monovalent unbranched or branched saturated hydrocarbon chain. For example, an alkyl group can have 1 to 20 carbon atoms (i.e., C1-C20 alkyl), 1 to 8 carbon atoms (i.e., C1-C8alkyl), 1 to 6 carbon atoms (i.e., C1-C6alkyl), or 1 to 3 carbon atoms (i.e., C1-C3alkyl). Examples of suitable alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i- butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1- butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (- CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), and 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3. Other alkyl groups include, but are not limited to, heptyl, octyl,nonyl, decyl, undecyl, dodecyl, pentadcyl, hexadecyl, heptadecyl and octadecyl.

[0017] “Alkylene” or “alkylene chain” refers to a straight or branched divalent hydrocarbon (alkyl) chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, respectively. Alkylenes can have from one to twelve carbon atoms, e.g., methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single or double bond. The points of attachment of thealkylene chain to the rest of the molecule can be through one carbon or any two carbons within the chain. “Optionally substituted alkylene” refers to alkylene or substituted alkylene.

[0018] “Alkenyl” refers to an unbranched or branched hydrocarbon chain containing at least two carbon atoms and at least one carbon-carbon double bond. As used herein, alkenyl can have from 2 to 20 carbon atoms (i.e., C2-20 alkenyl), 2 to 8 carbon atoms (i.e., C2-8 alkenyl), 2 to 6 carbon atoms (i.e., C2-6 alkenyl), or 2 to 4 carbon atoms (i.e., C2-4 alkenyl). Alkenyl can include any number of carbons, such as C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, or any range therein. Alkenyl groups can have any suitable number of double bonds, including, but not limited to, 1, 2, 3, 4, 5 or more. Examples of alkenyl groups include, but are not limited to, vinyl (ethenyl), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1-pentenyl, 2-pentenyl, isopentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl, 2,4-hexadienyl, or 1,3,5-hexatrienyl.

[0019] “Alkynyl” refers to an unbranched or branched hydrocarbon chain containing at least one carbon-carbon triple bond. For example, an alkynyl group can have from 2 to 20 carbon atoms (i.e., C2-20 alkynyl), 2 to 8 carbon atoms (i.e., C2-8 alkynyl), 2 to 6 carbon atoms (i.e., C2-6alkynyl), or 2 to 4 carbon atoms (i.e., C2-4alkynyl). The term “alkynyl” also includes those groups having one triple bond and one double bond. Examples of C2-6alkynyl include, but are not limited to, ethynyl, prop-1-ynyl, but-1-ynyl, pent-1-ynyl, pent-4-ynyl and penta-1,4-diynyl.

[0020] “Alkoxy” means a group having the formula –O-alkyl, in which an alkyl group, as defined above, is attached to the parent molecule via an oxygen atom. The alkyl portion of an alkoxy group can have 1 to 20 carbon atoms (i.e., C1-C20 alkoxy), 1 to 12 carbon atoms (i.e., C1-C12alkoxy), 1 to 8 carbon atoms (i.e., C1-C8alkoxy), 1 to 6 carbon atoms (i.e., C1-C6alkoxy) or 1 to 3 carbon atoms (i.e., C1-C3 alkoxy). Examples of suitable alkoxy groups include, but are not limited to, methoxy (-O-CH3 or –OMe), ethoxy (-OCH2CH3 or -OEt), isopropoxy (-O-CH(CH3)2), t-butoxy (-O-C(CH3)3or –OtBu) and the like. Other examples of suitable alkoxy groups include, but are not limited to, sec-butoxy, tert-butoxy, pentoxy, hexoxy, and the like.

[0021] “Aminoalkyl” is an alkyl group, as defined above, in which one or more hydrogen atoms of the alkyl group is replaced with an amine group (-NR2, where R = H or alkyl). The alkyl portion of an aminoalkyl group can have 1 to 20 carbon atoms (i.e., C1-C20 aminoalkyl),1 to 12 carbon atoms (i.e., C1-C12aminoalkyl), 1 to 8 carbon atoms (i.e., C1-C8aminoalkyl), 1 to 6 carbon atoms (i.e., C1-C6 aminoalkyl) or 1 to 3 carbon atoms (i.e., C1-C3 aminoalkyl). The alkyl groups can be substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9 or more amines. Examples of suitable aminoalkyl groups include, but are not limited to, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, -CH2CH2N(CH3)2, and -CH2CH2CH2N(CH3)2.

[0022] “Sulfonylalkyl” is an alkyl group, as defined above, in which one or more hydrogen atoms of the alkyl group is replaced with a sulfonyl group (-SO2R, where R = H or alkyl). The alkyl portion of an sulfonylalkyl group can have 1 to 20 carbon atoms (i.e., C1-C20 sulfonylalkyl), 1 to 12 carbon atoms (i.e., C1-C12sulfonylalkyl), 1 to 8 carbon atoms (i.e., C1- C8sulfonylalkyl), 1 to 6 carbon atoms (i.e., C1-C6sulfonylalkyl) or 1 to 3 carbon atoms (i.e., C1-C3 sulfonylalkyl). The alkyl groups can be substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9 or more sulfonyl groups. Examples of suitable sulfonylalkyl groups include, but are not limited to, -CH2SO2CH3, -CH2CH2SO2CH3, -CH2CH2SO2CH2CH3, and -CH2CH2CH2SO2CH3.

[0023] “Halo” or “halogen” as used herein refers to fluoro (-F), chloro (-Cl), bromo (-Br) and iodo (-I).

[0024] “Haloalkyl” is an alkyl group, as defined above, in which one or more hydrogen atoms of the alkyl group is replaced with a halogen atom. The alkyl portion of a haloalkyl group can have 1 to 20 carbon atoms (i.e., C1-C20 haloalkyl), 1 to 12 carbon atoms (i.e., C1- C12haloalkyl), 1 to 8 carbon atoms (i.e., C1-C8haloalkyl), 1 to 6 carbon atoms (i.e., C1-C6alkyl) or 1 to 3 carbon atoms (i.e., C1-C3alkyl). The alkyl groups can be substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9 or more halogens. Examples of suitable haloalkyl groups include, but are not limited to, -CF3, -CHF2, -CFH2, -CH2CF3, fluorochloromethyl, difluorochloromethyl, 1,1,1- trifluoroethyl and pentafluoroethyl.

[0025] “Haloalkoxy” refers to an alkoxy group where some or all of the hydrogen atoms are substituted with halogen atoms. As for an alkyl group, haloalkoxy groups can have any suitable number of carbon atoms, such as C1-6. The alkoxy groups can be substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9 or more halogens. When all the hydrogens are replaced with a halogen, for example by fluorine, the compounds are per-substituted, for example, perfluorinated. Haloalkoxy includes, but is not limited to, trifluoromethoxy, 2,2,2,-trifluoroethoxy, perfluoroethoxy, etc.

[0026] “Cycloalkyl” refers to a saturated or partially saturated cyclic alkyl group having a single ring or multiple rings, such as 2, 3, 4 or more, wherein the multiple rings can be fused, bridged, spiro, or any combination thereof. As used herein, cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C3-20cycloalkyl), 3 to 12 ring carbon atoms (i.e., C3-12cycloalkyl), 3 to 10 ring carbon atoms (i.e., C3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C3-8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C3-6 cycloalkyl). Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyl groups also include partially unsaturated ring systems containing one or more double bonds, including fused ring systems with one aromatic ring and one non-aromatic ring, but not fully aromatic ring systems.

[0027] “Alkylene-cycloalkyl” refers to a radical having an alkylene component and a cycloalkyl component, where the alkylene component links the cycloalkyl component to the point of attachment. The alkylene component is as defined above to link to the cycloalkyl component and to the point of attachment. In some instances, the alkylene component can be absent. The alkylene component can include any number of carbons, such as C1-6, C1-2, C1-3, C1-4, C1-5, C2-3, C2-4, C2-5, C2-6, C3-4, C3-5, C3-6, C4-5, C4-6 and C5-6. The cycloalkyl component is as defined within. Exemplary alkylene-cycloalkyl groups include, but are not limited to, - CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl and -CH2-cyclohexyl. “Substituted” alkylene-cycloalkyl groups include those having substitutions on the alkylene component and substitutions on the cycloalkyl component.

[0028] “Heterocycle” or “heterocyclyl” or “heterocycloalkyl” refer to a saturated or partially unsaturated cyclic alkyl group, with one or more ring heteroatoms independently selected from nitrogen, oxygen, sulfur and silicon. A heterocyclyl can be a single ring or multiple rings, such as 2, 3, 4 or more, wherein the multiple rings can be fused, bridged, spiro, or any combination thereof. As used herein, heterocyclyl has 3 to 20 ring atoms (i.e., 3 to 20 membered heterocyclyl), 3 to 12 ring atoms (i.e., 3 to 12 membered heterocyclyl), 3 to 10 ring atoms (i.e., 3 to 10 membered heterocyclyl), 3 to 8 ring atoms (i.e., 3 to 8 membered heterocyclyl), 4 to 12 ring carbon atoms (i.e., 4 to 12 membered heterocyclyl), 4 to 8 ring atoms (i.e., 4 to 8 membered heterocyclyl), or 4 to 6 ring atoms (i.e., 4 to 6 membered heterocyclyl). Examples of heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, dioxolanyl, azetidinyl, and morpholinyl.

[0029] “Alkylene-heterocyclyl” refers to a radical having an alkylene component and a heterocyclyl component, where the alkylene component links the heterocyclyl component to the point of attachment. The alkylene component is as defined above to link to the heterocyclyl component and to the point of attachment. The alkylene component can include any number of carbons, such as C0-6, C1-2, C1-3, C1-4, C1-5, C1-6, C2-3, C2-4, C2-5, C2-6, C3-4, C3-5, C3-6, C4-5, C4-6 and C5-6. In some instances, the alkylene component can be absent. The heterocyclyl component is as defined above. “Substituted” alkylene-heterocyclyl groups include those having substitutions on the alkylene component and substitutions on the heterocyclyl component.

[0030] “Aryl” means an aromatic hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. For example, an aryl group can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 10 carbon atoms. Exemplary aryl groups include, but are not limited to, radicals derived from benzene (e.g., phenyl), naphthalene, anthracene, biphenyl, and the like.

[0031] “Alkylene-aryl” refers to a radical having an alkylene component and an aryl component, where the alkylene component links the aryl component to the point of attachment. The alkylene component is as defined above to link to the aryl component and to the point of attachment. The alkylene component can include any number of carbons, such as C0-6, C1-2, C1-3, C1-4, C1-5, C1-6, C2-3, C2-4, C2-5, C2-6, C3-4, C3-5, C3-6, C4-5, C4-6 and C5-6. In some instances, the alkylene component can be absent. The aryl component is as defined above. Examples of alkylene-aryl groups include, but are not limited to, benzyl and ethylene- benzene. “Substituted” alkylene-aryl groups include those having substitutions on the alkylene component and substitutions on the aryl component.

[0032] “Heteroaryl” refers to an aromatic group, including groups having an aromatic tautomer or resonance structure, having a single ring, multiple rings, or multiple fused rings, with at least one heteroatom in the ring, i.e., one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the nitrogen or sulfur can be oxidized. Thus, the term includes rings having one or more annular O, N, S, S(O), S(O)2, and N-oxide groups. The term includes rings having one or more annular C(O) groups. As used herein, heteroaryl include 5 to 20 ring atoms (i.e., 5- to 20-membered heteroaryl), 5 to 12 ring atoms (i.e., 5- to 12-membered heteroaryl), or 5 to 10 ring atoms (i.e., 5- to 10-membered heteroaryl), and 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur,and oxidized forms of the heteroatoms. Examples of heteroaryl groups include, but are not limited to, pyridin-2(1H)-one, pyridazin-3(2H)-one, pyrimidin-4(3H)-one, quinolin-2(1H)- one, pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Heteroaryl does not encompass or overlap with aryl as defined above.

[0033] “Alkylene-heteroaryl” refers to a radical having an alkylene component and a heteroaryl component, where the alkylene component links the heteroaryl component to the point of attachment. The alkylene component is as defined above to link to the heteroaryl component and to the point of attachment. The alkylene component can include any number of carbons, such as C0-6, C1-2, C1-3, C1-4, C1-5, C1-6, C2-3, C2-4, C2-5, C2-6, C3-4, C3-5, C3-6, C4-5, C4-6and C5-6. In some instances, the alkylene component can be absent. The heteroaryl component is as defined within. “Substituted” alkylene-heteroaryl groups include those having substitutions on the alkylene component and substitutions on the heteroaryl component.

[0034] “Substituted” as used herein refers to wherein one or more hydrogen atoms of the group are independently replaced by one or more substituents (e.g., 1, 2, 3, or 4 or more) as indicated.

[0035] A “compound of the present disclosure” includes compounds disclosed herein, for example a compound of the present disclosure includes compounds of Formula I and II, including the compounds of the Examples. In some embodiments, a “compound of the present disclosure” includes compounds of Formula I, Ia, II, and IIa.

[0036] “Treatment” or “treating” as used herein is an approach for obtaining beneficial or desired results including clinical results. Beneficial or desired clinical results may include one or more of the following: (a) inhibiting the disease or condition (e.g., decreasing one or more symptoms resulting from the disease or condition, and / or diminishing the extent of the disease or condition); (b) slowing or arresting the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and / or preventing or delaying the spread (e.g., metastasis) of the disease or condition); and / or (c) relieving the disease, that is, causing the regression of clinical symptoms (e.g., ameliorating the disease state, providing partial or total remission of the disease or condition, enhancing effect of another medication, delaying the progression of the disease, increasing the quality of life, and / or prolonging survival.

[0037] The term “therapeutically effective amount,” as used herein, is the amount of compound disclosed herein present in a formulation described herein that is needed to provide a desired level of drug in the bloodstream of a subject to be treated to give an anticipated physiological response or desired biological effect when such a formulation is administered by the chosen route of administration. The precise amount will depend upon numerous factors, for example the particular compound disclosed herein, the specific activity of the formulation, the delivery device employed, the physical characteristics of the formulation, its intended use, as well as subject considerations such as severity of the disease state, subject cooperation, etc., and can readily be determined by one skilled in the art based upon the information provided herein.

[0038] “Administering” refers to oral administration, administration as a suppository, topical contact, parenteral, intravenous, intraperitoneal, intramuscular, intralesional, intranasal or subcutaneous administration, intrathecal administration, or the implantation of a slow-release device e.g., a mini-osmotic pump, to the subject. The administration can be carried out according to a schedule specifying frequency of administration, dose for administration, and other factors.

[0039] A “subject” or “patient” is meant to describe a human or vertebrate animal including a dog, cat, pocket pet, marmoset, horse, cow, pig, sheep, goat, elephant, giraffe, chicken, lion, monkey, owl, rat, squirrel, slender loris, and mouse. A “pocket pet” refers to a group of vertebrate animals capable of fitting into a commodious coat pocket such as, for example, hamsters, chinchillas, ferrets, rats, guinea pigs, gerbils, rabbits and sugar gliders. III. COMPOUNDS

[0040] In some embodiments of the compound of the present disclosure or pharmaceutically acceptable salt thereof, the compound is a compound of Formula I:or pharmaceutically acceptable salt thereof, whereinR1is a C3-C8cycloalkyl, heterocyclyl, C6-C10aryl, or heteroaryl, which are each substituted by 0, 1, 2, or 3 R1a; R2is a C3-C8 cycloalkyl, heterocyclyl, C6-C10 aryl, or heteroaryl, which are each substituted by 0, 1, 2, or 3 R2a; R3is -(C0-C3 alkylene)(C3-C8 cycloalkyl), -(C0-C3 alkylene)(heterocyclyl), -(C0-C3 alkylene)(C6-C10 aryl), or -(C0-C3 alkylene)(heteroaryl), which are each substituted by 0, 1, 2, or 3 R3a; X1is C-X1aor N; X2is C-X2aor N; X1aand X2ais independently H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1- C6aminoalkyl, C1-C6sulfonylalkyl, C1-C6haloalkyl, C1-C6haloalkoxy, halogen, or -CN; Y1is -S(O)NH-, -S(O)2NH-, -S(O)(=NRY)NH-, -NHS(O)-, -NHS(O)2-, or -NHS(O)(=NRY)-; RYis H or C1-C6alkyl; each R1a, R2a, and R3ais independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 cycloalkyl, heterocyclyl, C6-C10 aryl, heteroaryl, halogen, -OR1b, -NR1cR1d, -CN, -C(O)R1b, -C(O)NR1cR1d, -OC(O)NR1cR1d, -N(R1b)C(O)NR1cR1d, or -S(O)2NR1cR1d; and each R1b, R1c, and R1dis independently H, C1-C6 alkyl, C1-C6 haloalkyl, –(C0-C3 alkylene)(C3-C8cycloalkyl), –(C0-C3alkylene)(heterocyclyl), –(C0-C3alkylene)(C6-C10aryl), or –(C0-C3alkylene)(heteroaryl).

[0041] In some embodiments of the compound of Formula I, or pharmaceutically acceptable salt thereof, Y1is -S(O)2NH-.

[0042] In some embodiments of the compound of the present disclosure or pharmaceutically acceptable salt thereof, the compound is a compound of Formula II:or pharmaceutically acceptable salt thereof, whereinR1is a C3-C8cycloalkyl, heterocyclyl, C6-C10aryl, or heteroaryl, which are each substituted by 0, 1, 2, or 3 R1a; R2is a C3-C8 cycloalkyl, heterocyclyl, C6-C10 aryl, or heteroaryl, which are each substituted by 0, 1, 2, or 3 R2a; R3is –(C0-C3 alkylene)(nitrogen-containing heterocyclyl), which is substituted by 0, 1, 2, or 3 R3a; X1is C-X1aor N; X2is C-X2aor N; X1aand X2ais independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1- C6aminoalkyl, C1-C6sulfonylalkyl, C1-C6haloalkyl, C1-C6haloalkoxy, halogen, or -CN; Y2is -C(O)NH- or -NHC(O)-; each R1a, R2a, and R3ais independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, C3-C6cycloalkyl, heterocyclyl, C6-C10aryl, heteroaryl, halogen, -OR1b, -NR1cR1d, -CN, -C(O)R1b, -C(O)NR1cR1d, -OC(O)NR1cR1d, -N(R1b)C(O)NR1cR1d, or -S(O)2NR1cR1d; and each R1b, R1c, and R1dis independently H, C1-C6alkyl, C1-C6haloalkyl, –(C0-C3alkylene)(C3-C8cycloalkyl), –(C0-C3alkylene)(heterocyclyl), –(C0-C3alkylene)(C6- C10 aryl), or –(C0-C3 alkylene)(heteroaryl).

[0043] In some embodiments of the compound of Formula II, or pharmaceutically acceptable salt thereof, Y2is -C(O)NH-.

[0044] In some embodiments of the compound of Formula I or II, or pharmaceutically acceptable salt thereof, X2is CH. In some embodiments of the compound of the present disclosure or pharmaceutically acceptable salt thereof, X2is N.

[0045] In some embodiments of the compound of Formula I or II, or pharmaceutically acceptable salt thereof, X1is C-X1a; X1ais H, halogen, or -CN; and X2is N.

[0046] In some embodiments of the compound of Formula I or II, or pharmaceutically acceptable salt thereof, X1is C-X1a; X1ais H, halogen, or -CN; X2is N; and Y2is -C(O)NH-.

[0047] In some embodiments of the compound of Formula I or II, or pharmaceutically acceptable salt thereof, R2is a C6-C10aryl or heteroaryl, which are each substituted by 0, 1, 2, or 3 R2a. In some embodiments of the compound of Formula I or II, or pharmaceutically acceptable salt thereof, R2is a C6-C10 aryl, which is substituted by 0, 1, 2, or 3 R2a. In someembodiments of the compound of Formula I or II, or pharmaceutically acceptable salt thereof, R2is a heteroaryl, which is substituted by 0, 1, 2, or 3 R2a. In some embodiments of the compound of Formula I or II, or pharmaceutically acceptable salt thereof, R2is a 5- to 6- membered heteroaryl, which is substituted by 0, 1, 2, or 3 R2a. In some embodiments of the compound of Formula I or II, or pharmaceutically acceptable salt thereof, R2is phenyl or pyridyl, which are each substituted by 0, 1, 2, or 3 R2a.

[0048] In some embodiments of the compound of Formula I or II, or pharmaceutically acceptable salt thereof, R2is:.

[0049] In some embodiments of the compound of Formula I or pharmaceutically acceptable salt thereof, the compound has the structure of Formula Ia:or pharmaceutically acceptable salt thereof, wherein variable n is 0, 1, 2, or 3.

[0050] In some embodiments of the compound of Formula II or pharmaceutically acceptable salt thereof, the compound has the structure of Formula IIa:or pharmaceutically acceptable salt thereof, wherein variable n is 0, 1, 2, or 3.

[0051] In some embodiments of the compound of the present disclosure, e.g., a compound of Formula I, Ia, II, or IIa, or pharmaceutically acceptable salt thereof, unless otherwise indicated, the heteroaryl in each instance is 5- to 10-membered ring having 1, 2, 3, or 4 heteroatoms selected from N, O, and S; and the heterocyclyl in each instance is 3- to 12- membered ring having 1, 2, 3, or 4 heteroatoms selected from N, O, and S.

[0052] In some embodiments of the compound of the present disclosure, e.g., a compound of Formula I, Ia, II, or IIa, or pharmaceutically acceptable salt thereof, X1is C-X1a. In some embodiments of the compound of the present disclosure or pharmaceutically acceptable salt thereof, X1is C-CN. In some embodiments of the compound of the present disclosure or pharmaceutically acceptable salt thereof, X1is C-F. In some embodiments of the compound of the present disclosure or pharmaceutically acceptable salt thereof, X1is CH. In some embodiments of the compound of the present disclosure or pharmaceutically acceptable salt thereof, X1is N.

[0053] In some embodiments of the compound of the present disclosure or pharmaceutically acceptable salt thereof, X1ais H, C1-C6 alkyl, C1-C6 haloalkyl, halogen, or - CN. In some embodiments of the compound of the present disclosure or pharmaceutically acceptable salt thereof, X1ais H, halogen, or -CN. In some embodiments of the compound of the present disclosure or pharmaceutically acceptable salt thereof, X1ais H, F, or -CN.

[0054] In some embodiments of the compound of the present disclosure or pharmaceutically acceptable salt thereof, X1aand X2ais independently H, C1-C6alkyl, C1-C6haloalkyl, halogen, or -CN. In some embodiments of the compound of the present disclosure or pharmaceutically acceptable salt thereof, X1aand X2ais independently H, halogen, or -CN. In some embodiments of the compound of the present disclosure or pharmaceutically acceptable salt thereof, X1aand X2ais independently H, F, or -CN.

[0055] In some embodiments of the compound of the present disclosure, e.g., a compound of Formula I, Ia, II, or IIa, or pharmaceutically acceptable salt thereof, R1is heterocyclyl or heteroaryl, which are each substituted by 0, 1, 2, or 3 R1a. In some embodiments of the compound of the present disclosure or pharmaceutically acceptable salt thereof, R1is a 4- to 7-membered heterocyclyl or 5- to 6-membered heteroaryl, which are each substituted by 0, 1, 2, or 3 R1a. In some embodiments of the compound of the present disclosure or pharmaceutically acceptable salt thereof, R1is a 5- to 6-membered heteroaryl, which is substituted by 0, 1, 2, or 3 R1a. In some embodiments of the compound of the presentdisclosure or pharmaceutically acceptable salt thereof, R1is a pyrazolyl, pyridyl, pyridazinyl, pyrimidyl, or pyrazinyl, which are each substituted by 0, 1, 2, or 3 R1a. In some embodiments of the compound of the present disclosure or pharmaceutically acceptable salt thereof, R1is a pyrazolyl, pyridyl, or pyrimidyl, which are each substituted by 0, 1, 2, or 3 R1a.

[0056] In some embodiments of the compound of the present disclosure e.g., a compound of Formula I, Ia, II, or IIa, or pharmaceutically acceptable salt thereof, each R1ais independently C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, halogen, -OR1b, -NR1cR1d, or -CN; and each R1b, R1c, and R1dis independently H and C1-C6alkyl.

[0057] In some embodiments of a compound of Formula I, Ia, II, or IIa, or pharmaceutically acceptable salt thereof, R1is.

[0058] In some embodiments of a compound of Formula I, Ia, II, or IIa, or pharmaceutically acceptable salt thereof, R1is.

[0059] In some embodiments of the compound of the present disclosure, e.g., a compound of Formula I, Ia, II, or IIa, or pharmaceutically acceptable salt thereof, each R2aisindependently C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, C3-C6cycloalkyl, halogen, -OR1b, -NR1cR1d, or -CN. In some embodiments of the compound of the present disclosure or pharmaceutically acceptable salt thereof, R2ais C1-C6 haloalkyl. In some embodiments of the compound of the present disclosure or pharmaceutically acceptable salt thereof, R2ais -OCH2CF3.

[0060] In some embodiments of the compound of Formula I or II, or pharmaceutically acceptable salt thereof, R2is:

[0061] In some embodiments of the compound of Formula I or II, or pharmaceutically acceptable salt thereof, R2is:

[0062] In some embodiments of the compound of Formula I or II, or pharmaceutically acceptable salt thereof, R2is:.

[0063] In some embodiments of the compound of the present disclosure, e.g., a compound of Formula I, Ia, II, or IIa, or pharmaceutically acceptable salt thereof, R3is heterocyclyl, substituted by 0, 1, 2, or 3 R3a.

[0064] In some embodiments of the compound of the present disclosure, e.g., a compound of Formula I, Ia, II, or IIa, or pharmaceutically acceptable salt thereof, R3is piperidinyl, substituted by 0, 1, 2, or 3 R3a.

[0065] In some embodiments of the compound of the present disclosure, e.g., a compound of Formula I, Ia, II, or IIa, or pharmaceutically acceptable salt thereof, each R3ais independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, halogen, -CN, -C(O)R1b, or -C(O)NR1cR1d. In some embodiments of the compound of the present disclosure or pharmaceutically acceptable salt thereof, each R3ais independently C1- C6 alkyl, C1-C6 haloalkyl, halogen, or -OR1b. In some embodiments of the compound of the present disclosure or pharmaceutically acceptable salt thereof, each R3ais independently C1- C6alkyl, halogen, or -OR1b. In some embodiments of the compound of the present disclosure or pharmaceutically acceptable salt thereof, each R3ais independently C1-C6 alkyl.

[0066] In some embodiments of the compound of the present disclosure or pharmaceutically acceptable salt thereof, R3is.

[0067] In some embodiments of a compound of Formula I, Ia, II, or IIa, or pharmaceutically acceptable salt thereof, R3is

[0068] In some embodiments of a compound of Formula I, Ia, II, or IIa, or pharmaceutically acceptable salt thereof, R3is

[0069] In some embodiments of the compound of the present disclosure or pharmaceutically acceptable salt thereof, R3is

[0070] In some embodiments of a compound of Formula I, Ia, II, or IIa, or pharmaceutically acceptable salt thereof, R3is

[0071] In some embodiments of a compound of Formula I, Ia, II, or IIa, or pharmaceutically acceptable salt thereof, R3is.

[0072] In some embodiments of a compound of Formula I, Ia, II, or IIa, or pharmaceutically acceptable salt thereof, R3is

[0073] In some embodiments of the compound of the present disclosure or pharmaceutically acceptable salt thereof, R3is

[0074] In some embodiments of the compound of the present disclosure or pharmaceutically acceptable salt thereof, variable n is 1 or 2. In some embodiments of thecompound of the present disclosure or pharmaceutically acceptable salt thereof, variable n is 1. In some embodiments of the compound of the present disclosure or pharmaceutically acceptable salt thereof, variable n is 2.

[0075] In some embodiments of the compound of the present disclosure, e.g., a compound of Formula I, Ia, II, or IIa, or pharmaceutically acceptable salt thereof, the compound is any one of the following: Table 1. Compounds

[0076] Provided are also compounds described herein or pharmaceutically acceptable salts, isomers, or a mixture thereof, in which from 1 to n hydrogen atoms attached to a carbon atom can be replaced by a deuterium atom or D, in which n is the number of hydrogen atoms in the molecule. As known in the art, the deuterium atom is a non-radioactive isotope of the hydrogen atom. Such compounds can increase resistance to metabolism, and thus can be useful for increasing the half-life of the compounds described herein or pharmaceutically acceptable salts, isomer, or a mixture thereof when administered to a mammal. See, e.g., Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” TRENDS PHARMACOL. SCI., 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogen atoms have been replaced by deuterium.

[0077] Examples of isotopes that can be incorporated into the disclosed compounds also include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as2H,3H,11C,13C,14C,13N,15N,15O,17O,18O,31P,32P,35S,18F,36Cl,123I, and125I, respectively. Substitution with positron emitting isotopes, such as11C,18F,15O and13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds of Formula I can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Examples as set out below using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.

[0078] Furthermore, the compounds of Formula I or pharmaceutically acceptable salt thereof may exist in the form of different isomers, in particular stereoisomers (including, e.g., geometric isomers (or cis / trans isomers), enantiomers and diastereomers) or tautomers(including, in particular, prototropic tautomers, such as keto / enol tautomers or thione / thiol tautomers). All such isomers of the compounds of Formula I are contemplated as being part of the present disclosure, either in admixture or in pure or substantially pure form. As for stereoisomers, the invention embraces the isolated optical isomers of the compounds according to the invention as well as any mixtures thereof (including, in particular, racemic mixtures / racemates). The racemates can be resolved (i.e., separated) by physical methods, such as, e.g., fractional crystallization, separation or crystallization of diastereomeric derivatives, or separation by chiral column chromatography. The individual optical isomers can also be obtained from the racemates via salt formation with an optically active acid followed by crystallization. The present disclosure further encompasses any tautomers of the compounds of formula (I) and / or II. It will be understood that some compounds may exhibit tautomerism. In such cases, the formulae provided herein expressly depict only one of the possible tautomeric forms. The formulae and chemical names as provided herein are intended to encompass any tautomeric form of the corresponding compound and not to be limited merely to the specific tautomeric form depicted by the drawing or identified by the name of the compound.

[0079] The compounds of the embodiments disclosed herein, or their pharmaceutically acceptable salts can contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids. The present disclosure is meant to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high-pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included. Where compounds are represented in their chiral form, it is understood that the embodiment encompasses, but is not limited to, the specific diastereomerically or enantiomerically enriched form. Where chirality is not specified but is present, it is understood that theembodiment is directed to either the specific diastereomerically or enantiomerically enriched form; or a racemic or scalemic mixture of such compound(s). As used herein, “scalemic mixture” is a mixture of stereoisomers at a ratio other than 1:1.

[0080] “Racemates” refers to a mixture of enantiomers. The mixture can comprise equal or unequal amounts of each enantiomer.

[0081] “Stereoisomer” and “stereoisomers” refer to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers. The compounds can exist in stereoisomeric form if they possess one or more asymmetric centers or a double bond with asymmetric substitution and, therefore, can be produced as individual stereoisomers or as mixtures. Unless otherwise indicated, the description is intended to include individual stereoisomers as well as mixtures. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see, e.g., Chapter 4 of ADVANCEDORGANICCHEMISTRY, 4th ed., J. March, John Wiley & Sons, New York, 1992).

[0082] Provided are also pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, polymorphs, and prodrugs of the compounds described herein. “Pharmaceutically acceptable” or “physiologically acceptable” refer to compounds, salts, formulations, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.

[0083] The compounds described herein can be prepared and / or formulated as pharmaceutically acceptable salts or when appropriate as a free base. Pharmaceutically acceptable salts are non-toxic salts of a free base form of a compound that possess the desired pharmacological activity of the free base. These salts can be derived from inorganic or organic acids or bases. For example, a compound that contains a basic nitrogen can be prepared as a pharmaceutically acceptable salt by contacting the compound with an inorganic or organic acid. Non-limiting examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates,sulfonates, methylsulfonates, propylsulfonates, besylates, xylenesulfonates, naphthalene-1- sulfonates, naphthalene-2-sulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates, and mandelates. Lists of other suitable pharmaceutically acceptable salts are found in REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY, 21stEdition, Lippincott Wiliams and Wilkins, Philadelphia, Pa., 2006.

[0084] Examples of “pharmaceutically acceptable salts” of the compounds disclosed herein also include salts derived from an appropriate base, such as an alkali metal (for example, sodium, potassium), an alkaline earth metal (for example, magnesium), ammonium and NX4+(wherein X is C1−C4alkyl). Also included are base addition salts, such as sodium or potassium salts. IV. COMPOSITIONS

[0085] Also provided herein is a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0086] As used herein, “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes, but is not limited to, any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and combinations thereof. The use of pharmaceutically acceptable carriers and pharmaceutically acceptable excipients for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic formulations is contemplated. Supplementary active ingredients can also be incorporated into the formulations. The carrier(s) must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and physiologically innocuous to the recipient thereof.

[0087] The compounds disclosed herein can be formulated with conventional carriers and excipients. Tablets can contain, for instance, excipients, glidants, fillers, binders, or a combination thereof. Aqueous formulations are prepared in sterile form, and when intended for delivery by other than oral administration generally will be isotonic. Exemplary excipients include, but are not limited to, those set forth in the “HANDBOOK OFPHARMACEUTICAL EXCIPIENTS” (1986). Excipients can include, for example, ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextran, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid, and combinations thereof. In some embodiments, the formulation is basic. In some embodiments, the formulation is acidic. In some embodiments, the formulation has a neutral pH. In some embodiments, the pH of the formulations is from 2 to 11 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 2-3, 2-4, 2-5, 2-6, 2- 7, 2-8, 2-9, 2-10, 3-4, 3-5, 3-6, 3-7, 3-8, 3-9, 3-10, 4-5, 4-6, 4-7, 4-8, 4-9, 4-10, 4-11, 5-6, 5-7, 5-8, 5-9, 5-10, 5-11, 6-7, 6-8, 6-9, 6-10, 6-11, 7-8, 7-9, 7-10, 7-11, 8-9, 8-10, 8-11, 9-10, or 9- 11).

[0088] In some embodiments, the compounds disclosed herein have pharmacokinetic properties (e.g., oral bioavailability) suitable for oral administration of the compounds. Formulations suitable for oral administration can, for instance, be presented as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non- aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient can also be administered, for instance, as a bolus, electuary, or paste.

[0089] A tablet can be made by compression or molding, optionally with at least accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as, for instance, a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active, dispersing agent, or a combination thereof. Molded tablets can be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. The tablets can optionally be coated or scored and optionally are formulated so as to provide slow or controlled release of the active ingredient therefrom.

[0090] Formulations for oral use can be also presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin, or olive oil.

[0091] For diseases of the eye or other external tissues (e.g., mouth and skin), the formulations can be applied as a topical ointment or cream containing the active ingredient(s) in an amount of, for example, 0.075 to 20% w / w (including active ingredient(s) in a range from 0.1% to 20% in increments of 0.1% w / w such as 0.6% w / w, 0.7% w / w, etc.), from 0.2%to 15% w / w, or from 0.5% to 10% w / w. When formulated in an ointment, the active ingredients can be employed in some embodiments with either a paraffinic or a water- miscible ointment base. Alternatively, the active ingredients can be formulated in a cream with an oil-in-water cream base.

[0092] In some embodiments, the aqueous phase of the cream base can include, for example, from 30% to 90% (e.g., 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%) w / w of a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof. In some embodiments, the cream base can include, for instance, a compound that enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include, but are not limited to, dimethyl sulfoxide and related analogs. In some embodiments, the cream or emulsion does not include water.

[0093] The oily phase of the emulsions can be constituted from known ingredients in a known manner. In some embodiments, the phase comprises merely an emulsifier (otherwise known as an emulgent). In some embodiments, the phase comprises a mixture of at least one emulsifier with a fat, an oil, or a combination thereof. In some embodiments, a hydrophilic emulsifier is included together with a lipophilic emulsifier that acts as a stabilizer. Together, the emulsifier(s) with or without stabilizer(s) can make up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base that can form the oily dispersed phase of the cream formulations.

[0094] Emulgents and emulsion stabilizers suitable for use in the formulation can include, but are not limited to, TWEEN®60, TWEEN® 80, SPAN®80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate, sodium lauryl sulfate, captisol (and other beta cyclodextrin vehicles), and combinations thereof.

[0095] The choice of suitable oils or fats for the formulation can be based on achieving the desired cosmetic properties. In some embodiments, the cream can be a non-greasy, non- staining, and washable product with suitable consistency to avoid leakage from tubes or other containers. In some embodiments, esters can be included, such as, for example, straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate, a blend of branched chain esters known asCRODAMOL® CAP, or a combination thereof. In some embodiments, high melting point lipids such as white soft paraffin and / or liquid paraffin or other mineral oils can be included.

[0096] Effective dose of active ingredient depends at least on the nature of the condition being treated, toxicity, whether the compound is being used prophylactically (lower doses) or against an active viral infection, the method of delivery, and the pharmaceutical composition, and will be determined by the clinician using conventional dose escalation studies. In some embodiments, the effective dose is from 0.0001 to 100 mg / kg body weight per day; for instance, from 10 to 30 mg / kg body weight per day; from 15 to 25 mg / kg body weight per day; from 10 to 15 mg / kg body weight per day; or from 20 to 30 mg / kg body weight per day. For example, the daily candidate dose for an adult human of approximately 70 kg body weight can range from 1 mg to 2000 mg (e.g., from 5 mg to 500 mg, from 500 mg to 1000 mg, from 1000 mg to 1500 mg, from 1500 mg to 2000 mg), and can take the form of single or multiple doses. For example, the daily candidate dose for an adult human of approximately 70 kg body weight can range from 1 mg to 1000 mg (e.g., from 5 mg to 500 mg), and can take the form of single or multiple doses. V. KITS

[0097] Also provided herein are kits that includes a compound disclosed herein or a pharmaceutically acceptable salt thereof. In some embodiments the kits described herein can comprise a label and / or instructions for use of the compound in the treatment of a disease or condition in a subject (e.g., human) in need thereof.

[0098] In some embodiments, the kit can also comprise one or more additional therapeutic agents and / or instructions for use of additional therapeutic agents in combination with the compound disclosed herein in the treatment of the disease or condition in a subject (e.g., human) in need thereof.

[0099] In some embodiments, the kits provided herein comprise individual dose units of a compound as described herein, or a pharmaceutically acceptable salt, racemate, enantiomer, diastereomer, tautomer, polymorph, pseudopolymorph, amorphous form, hydrate or solvate thereof. Examples of individual dosage units can include pills, tablets, capsules, prefilled syringes or syringe cartridges, IV bags, inhalers, nebulizers etc., each comprising a therapeutically effective amount of the compound in question, or a pharmaceutically acceptable salt, racemate, enantiomer, diastereomer, tautomer, polymorph, pseudopolymorph,amorphous form, hydrate or solvate thereof. In some embodiments, the kit can contain a single dosage unit and in others multiple dosage units are present, such as the number of dosage units required for a specified regimen or period.

[0100] Also provided are articles of manufacture that include a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or tautomer thereof; and a container. In some embodiments, the container of the article of manufacture is a vial, jar, ampoule, preloaded syringe, blister package, tin, can, bottle, box, an intravenous bag, an inhaler, or a nebulizer. VI. ADMINISTRATION

[0101] One or more of the compounds of Formula I or pharmaceutically acceptable salt thereof (herein referred to as the active ingredients) are administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), and the like. It will be appreciated that the route may vary with for example the condition of the recipient. An advantage of the compounds herein is that they are orally bioavailable and can be dosed orally.

[0102] The compounds of the present disclosure can be administered by any route appropriate to the condition to be treated.

[0103] Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), and the like. It will be appreciated that the route may vary with for example the condition of the recipient. An advantage of certain compounds disclosed herein is that they are orally bioavailable and can be dosed orally.

[0104] A compound of the present disclosure may be administered to an individual in accordance with an effective dosing regimen for a desired period of time or duration, such as at least about one month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer. In some embodiments, the compound is administered on a daily or intermittent schedule for the duration of the individual’s life.

[0105] The dosage or dosing frequency of a compound of the present disclosure may be adjusted over the course of the treatment, based on the judgment of the administering physician.

[0106] The compound may be administered to an individual (e.g., a human) in an effective amount. In some embodiments, the compound is administered once daily.

[0107] The compound can be administered by any useful route and means, such as by oral or parenteral (e.g., intravenous) administration. Therapeutically effective amounts of the compound may include from about 0.00001 mg / kg body weight per day to about 10 mg / kg body weight per day, such as from about 0.0001 mg / kg body weight per day to about 10 mg / kg body weight per day, or such as from about 0.001 mg / kg body weight per day to about 1 mg / kg body weight per day, or such as from about 0.01 mg / kg body weight per day to about 1 mg / kg body weight per day, or such as from about 0.05 mg / kg body weight per day to about 0.5 mg / kg body weight per day, or such as from about 0.3 mg to about 30 mg per day, or such as from about 30 mg to about 300 mg per day.

[0108] A compound of the present disclosure may be combined with one or more additional therapeutic agents in any dosage amount of the compound of the present disclosure (e.g., from about 1 mg to about 1000 mg of compound). VII. METHODS

[0109] Without being bound by the theory, as TASL is regulated by proteostatic interaction with SLC15A4, the compound of Formula I and / or II described herein inhibits interaction of TASL protein with SLC15A4. Accordingly, in some embodiments, the method of the present disclosure is a method of inhibiting binding between SLC15A4 and TASL in an immune cell, comprising administering to the immune cell an effective amount of a compound or pharmaceutically acceptable salt thereof of the present disclosure or a pharmaceutical composition of the present disclosure.

[0110] Any immune cell can be used in a method of the present disclosure. In some embodiments, the immune cell is a B-cell, neutrophil, dendritic cell, or monocyte.

[0111] It has been reported in the literature that SLC15A4 and / or TASL play a role in autoimmune diseases (including systemic lupus erythematosus) and inflammatory conditions(including inflammatory bowel disease, psoriasiform dermatitis and endosomal TLR- dependent inflammation.)

[0112] Accordingly, in some embodiments, a method of the present disclosure is a method of treating an autoimmune disorder or an inflammatory condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof of the present disclosure, or a pharmaceutical composition of the present disclosure. In some embodiments, the autoimmune disorder comprises systemic lupus erythematosus (SLE).

[0113] Genetic studies of systemic lupus erythematosus (SLE) in human cells suggest SLC15A4 has a causative role in this disorder. The genetic association of SLC15A4 and TASL with SLE was identified in a cohort of European ancestry and separately in a cohort of a Chinese Han population. He, C.-F. and coworkers identified through GWAS the genetic association of SLC15A4 with SLE-related discoid rash in a Chinese Han population. Langefeld and coworkers identified through GWAS the genetic association of SLC15A4 with SLE in a cohort of European ancestry.

[0114] Further, there is a body of evidence based on genetic studies of systemic lupus erythematosus (SLE) in human cells indicating the role TASL in this disorder. Odhams et al. proposed that genetic variants of TASL (CXorf21) associated with SLE lead to increased TASL expression in an interferon- and sex specific manner.

[0115] Mouse models have showed the importance of TASL / SLC15A4 in systemic lupus erythematosus. A protective role was suggested for SLC15A4 deficiency in the development of SLE in a mouse model using the C57BL / 6-Fas(lpr) strain. SLC15A4-deficiency was protective in two models of SLE (pristane-induced and C57BL / 6lpr7lpr mice) and that SLC15A4 was required in B cells for endosomal TLR function. SLC15A4-deficiency was protective in a mercury-induced model of SLE.

[0116] Accordingly, the compounds of the present disclosure are believed to be useful in the treatment or prevention of autoimmune disorders, in particular systemic lupus erythematosus.

[0117] Based on the role of SLC15A4 and / or TASL in IRF5 activation, the compounds of the present disclosure are also expected to be useful in the treatment of prevention of autoimmune disorders, preferably selected from systemic lupus erythematosus, rheumatoidarthritis, scleroderma, Sjogren’s syndrome, polymyositis / dermatomyositis, primary biliary cirrhosis, multiple sclerosis, oral ulcers, periodontitis, Behçet’s disease, myasthenia gravis, and ankylosing spondylitis.

[0118] Further genetic studies demonstrate the role of SLC15A4 and / or TASL in inflammatory conditions. Heinz and coworkers have shown essential role of SLC15A4-TASL and their relationship in human cell lines and primary cells for endosomal TLR function.

[0119] There is further a body of evidence based on the studies in mouse models indicating the role of SLC15A4 and / or TASL in inflammatory conditions. SLC15A4 was identified as an essential component in endosomal TLR function in plasmacytoid dendritic cells. SLC15A4 deficiency has been found to impair CpG-induced production of inflammatory cytokines from dendritic cells. Furthermore, SLC15A4 deficiency was found to be protective in a mouse model of inflammatory bowel disease. SLC15A4-deficient mice also showed defective cytokine production upon activation of the NOD-like receptor NOD1. An important role was suggested for SLC15A4 in pDCs in controlling viral persistence, as evidenced in a model of LCMV infection.

[0120] Based on the role of SLC15A4 and / or TASL in IRF5 activation, the compounds of the present disclosure are also expected to be useful in the treatment of prevention of inflammatory condition, preferably selected from inflammatory bowel disease, psoriasiform dermatitis, endosomal TLR-dependent inflammation, ulcerative colitis, Crohn’s disease, endosomal TLR-induced hyperinflammation, macrophage activation syndrome, allergic airway inflammation, and sarcoidosis, preferably wherein the inflammatory condition is selected from inflammatory bowel disease, psoriasiform dermatitis, and endosomal TLR- dependent inflammation. In some embodiments, the inflammatory condition comprises inflammatory bowel disease.

[0121] Accordingly, the compounds of the present disclosure are believed to be useful in treatment or prevention of an inflammatory condition.

[0122] Thus, in one embodiment, the present disclosure relates to the compound of Formula I and / or II or its pharmaceutically acceptable salt, or the pharmaceutical composition of the present disclosure, for use in treatment or prevention of an autoimmune disorder or an inflammatory condition. In one embodiment, the present disclosure relates to the compound of Formula I and / or II or its pharmaceutically acceptable salt, or the pharmaceutical composition of the present disclosure, for use in treatment or prevention of an autoimmunedisorder. In one embodiment, the present disclosure relates to the compound of Formula I and / or II or its pharmaceutically acceptable salt, or the pharmaceutical composition of the present disclosure, for use in treatment or prevention of an inflammatory condition.

[0123] In some embodiments, the autoimmune disorder or inflammatory condition is selected from systemic lupus erythematosus, cutaneous lupus erythematosus (CLE), acute cutaneous lupus erythematosus, subacute cutaneous lupus erythematosus, chronic cutaneous lupus erythematosus, discoid lupus erythematosus, lupus nephritis, endosomal TLR- dependent hyperinflammation, macrophage activation syndrome, rheumatoid arthritis, scleroderma / systemic sclerosis, sarcoidosis, Sjogren’s syndrome, inflammatory myopathy, polymyositis, dermatomyositis, necrotizing autoimmune myositis, inclusion body myositis, juvenile dermatomyositis, primary biliary cirrhosis, multiple sclerosis, ankylosing spondylitis, oral ulcers, periodontitis, Behçet’s disease (syndrome), psoriasis, psoriatic arthritis, Raynaud's disease, myasthenia gravis, irritable bowel syndrome, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, psoriasiform dermatitis, allergic airway inflammation, allergic blepharitis, atopic dermatitis, bullous pemphigoid, epidermolysis bullosa, prurigo nodularis, severe stress, thyroid disease, tinea cruris, rosacea, cutaneous amyloidosis, autoimmune atrophic gastritis, chronic pancreatitis, erythromelalgia, fibromyalgia, gout, headaches, herniated disc, interstitial cystitis, polymyalgia rheumatica, sacroiliac joint dysfunction, transverse myelitis, Steven Johnson's syndrome, toxic epidermal necrolysis, appendicitis, bursitis, phlebitis psoriasis, graft-versus-host disease, reactive airway disorder, asthma, airway infection, autoinflammatory disease, celiac disease, chronic prostatitis, diverticulitis, glomerulonephritis, hidradenitis suppurativa, hypersensitivities, intestinal disorder, epithelial intestinal disorder, otitis, pelvic inflammatory disease, and vasculitis.

[0124] In some embodiments, the autoimmune disorder is selected from systemic lupus erythematosus, rheumatoid arthritis, scleroderma, Sjogren’s syndrome, polymyositis / dermatomyositis, primary biliary cirrhosis, multiple sclerosis, oral ulcers, periodontitis, Behçet’s disease, myasthenia gravis, and ankylosing spondylitis. In some embodiments, the autoimmune disorder is systemic lupus erythematosus.

[0125] In some embodiments, the inflammatory condition is selected from inflammatory bowel disease, psoriasiform dermatitis, endosomal TLR-dependent inflammation, ulcerative colitis, Crohn’s disease, endosomal TLR-induced hyperinflammation, macrophage activationsyndrome, allergic airway inflammation, and sarcoidosis. In some embodiments, the inflammatory condition is selected from inflammatory bowel disease, psoriasiform dermatitis, and endosomal TLR-dependent inflammation.

[0126] In some embodiments, the present disclosure relates to use of the compound of Formula I and / or II or its pharmaceutically acceptable salt, or the pharmaceutical composition of the present disclosure, in the manufacture of a medicament for use in the treatment or prevention of an autoimmune disorder or an inflammatory condition. In one embodiment, the present disclosure relates to use of the compound of Formula I and / or II or its pharmaceutically acceptable salt, or the pharmaceutical composition of the present disclosure, in the manufacture of a medicament for use in the treatment or prevention of an autoimmune disorder. In one embodiment, the present disclosure relates to use of the compound of Formula I and / or II or its pharmaceutically acceptable salt, or the pharmaceutical composition of the present disclosure, in the manufacture of a medicament for use in the treatment or prevention of an inflammatory condition.

[0127] In some embodiments, the present disclosure relates to the method of treating an autoimmune disorder, the method comprising administering the compound of Formula I and / or II or its pharmaceutically acceptable salt, or the pharmaceutical composition of the present disclosure, to a subject in need thereof. It is to be understood that said compound or its salt or said pharmaceutical composition is to be administered in a therapeutically effective amount as described herein.

[0128] In one embodiment, the present disclosure relates to the method of treating an inflammatory condition, the method comprising administering the compound of Formula I and / or II or its pharmaceutically acceptable salt, or the pharmaceutical composition of the present disclosure, to a subject in need thereof. It is to be understood that said compound or its salt or said pharmaceutical composition is to be administered in a therapeutically effective amount, preferably as described herein.

[0129] It is to be noted that the compound of Formula I and / or II or its salt has been shown by the present inventors to inhibit SLC15 peptide transporter (i.e., SLC15A4). Accordingly and preferably, it is expected that the therapeutic effect of the compound of Formula I and / or II or its salt is based on the inhibition of SLC15 peptide transporter (i.e., SLC15A4). Accordingly, in one embodiment the present disclosure relates to the compound of Formula I and / or II or its salt, or the pharmaceutical composition of the present disclosure for use in thetreatment or prevention of an autoimmune disorder, wherein said compound or said pharmaceutical composition inhibits SLC15 peptide transporter. Given the ability of the compound of the present disclosure, or its salt, to inhibit the SLC15 peptide transporter, said compound is particularly useful in the treatment of the autoimmune disorder, wherein the autoimmune disorder is a disorder associated with SLC15 peptide transporter. Accordingly, the present disclosure in one embodiment relates to the compound of Formula I and / or II or its salt, or the pharmaceutical composition of the present disclosure wherein said compound or said pharmaceutical composition for use in the treatment or prevention of an autoimmune disorder, wherein the autoimmune disorder is a disorder associated with SLC15 peptide transporter.

[0130] The compounds provided in the present disclosure are also useful in treatment or prevention of other lupus diseases such as cutaneous or neonatal lupus erythematosus. VIII. EXAMPLES

[0131] The following examples are provided to further aid in understanding the embodiments disclosed in the application, and presuppose an understanding of conventional methods well known to those persons having ordinary skill in the art to which the examples pertain. The particular materials and conditions described hereunder are intended to exemplify particular aspects of embodiments disclosed herein and should not be construed to limit the reasonable scope thereof.

[0132] Many general references providing commonly known chemical synthetic schemes and conditions useful for synthesizing the disclosed compounds are available (see, e.g., Smith, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7thedition, Wiley-Interscience, 2013.)

[0133] Compounds as described herein can be purified by any of the means known in the art, including chromatographic means, such as high performance liquid chromatography (HPLC), preparative thin layer chromatography, flash column chromatography and ion exchange chromatography. Any suitable stationary phase can be used, including normal and reversed phases as well as ionic resins. For example, disclosed compounds can be purified via silica gel chromatography. See, e.g., Introduction to Modern Liquid Chromatography, 3rded., ed. L. R. Snyder, J. J. Kirkland, J. W. Dolan. John Wiley and Sons, 2011; and Thin Layer Chromatography, E. Stahl (ed.), Springer-Verlag, New York, 1969.

[0134] Compounds were characterized using standard instrumentation methods. Identification of the compound was carried out by hydrogen nuclear magnetic resonance spectrum (1H-NMR) and mass spectrum (MS).1H-NMR was measured at 400 MHz, unless otherwise specified. In some cases, exchangeable hydrogen could not be clearly observed depending on the compound and measurement conditions. The designation br. or broad, used herein, refers to a broad signal. LCMS were performed according to the following. HPLC preparative chromatography was carried out according to the following conditions, unless otherwise specified.

[0135] General LCMS conditions:

[0136] LCMS (Shimadzu), column: YMC-Triart C18, 50×4.6mm, 5 μm, mobile phase: Solvent A: Solvent A: H2O / MeCN / NH4OH = 90 / 10 / 0.05; Solvent B: MeCN, Flow rate: 3mL / min, temperature: 40℃; gradient: 0.01min @ 20% B, 1.79min gradient (20-95% B), then 0.7min @ 95% B.

[0137] LCMS (Shimadzu), column: YMC-Triart C18, 50×4.6mm, 5 μm, RP-18e, 50×4.6 mm, mobile phase: Solvent A: H2O (10mmol / L NH4HCO3) / MeCN= 90 / 10 Solvent B: H2O / MeCN= 10 / 90, Flow rate: 2.5 mL / min, temperature: 40℃; gradient: 0.01min @ 20% B, 1.79min gradient (20-95% B), then 0.7min @ 95% B.

[0138] LCMS (Shimadzu), column: YMC-Triart C18, 50×4.6mm, 5 μm, RP-18e, 50×4.6 mm, mobile phase: Solvent Solvent A: H2O / MeCN / FA = 90 / 10 / 0.05 Solvent B: MeCN, Flow rate: 2.5 mL / min, temperature: 40℃; gradient: 0.01min @ 20% B, 1.79min gradient (20-95% B), then 0.7min @ 95% B.

[0139] General preparatory HPLC conditions: HPLC purifications were performed on a SHIMADZU LC-8A, Shimadzu LH-40 or Shimadzu LC-8A; Column: YMC-Triart C18, 250X20 mm, 5 μm, YMC-Triart C8, 250X20 mm, 5 μm, YMC-Pack ODS-AQ, 250X20 mm, 5 μm or Xbridge Prep C185 μm OBD etc., 250X20 mm, 5 μm with UV detection which were controlled by LC solution Chemstation software. H2O (FA / TFA) or H2O NH4OH / NH4HCO3) and MeOH (MeCN) as mobile phase at the indicated flow rate (15-20 mL / min) at room temperature.

[0140] The Examples provided herein describe the synthesis of compounds disclosed herein as well as intermediates used to prepare the compounds. It is to be understood thatindividual steps described herein may be combined. It is also to be understood that separate batches of a compound may be combined and then carried forth in the next synthetic step.

[0141] Representative syntheses of compounds of the present disclosure are described in schemes below, and the particular examples that follow.

[0142] Abbreviations. Certain abbreviations and acronyms are used in describing the experimental details. Although most of these would be understood by one skilled in the art, the following table contains a list of many of these abbreviations and acronyms. Table 2. List of abbreviations and acronyms.General Procedures

[0143] General Procedure I: Sulfonamide Formation: To a stirred solution of 2,6- dichloropyridine-4-sulfonyl chloride (1 eq.) and the corresponding amine (1.5 eq.) in THF (16 mL) was added DIEA (3 eq.). The reaction mixture was stirred at ambient temperature for 2 h. Upon completion, the reaction mixture was quenched with water and extracted with EtOAc. The organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography.

[0144] General Procedure II: Suzuki Coupling: To a solution of the corresponding 2,6- dichloro-N-4-sulfonamide (1 eq.) and the corresponding boron ester or boric acid (1 eq. or 0.8 eq.) in 1,4-dioxane (10 mL) and water (2 mL), Na2CO3 (2.00 eq.) and Pd(dppf)Cl2^DCM (0.10 eq.) were added at ambient temperature. The resulting mixture was subsequently degassed by bubbling nitrogen for 3 minutes. The reaction mixture was then heated at 80 °C for 2 hours or, alternatively, at 100 °C overnight. Upon completion, the mixture was cooled to ambient temperature, diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reversed-phase flash chromatography.

[0145] General Procedure III: Boc / PMB / DMB Deprotection: The corresponding Boc / PMB / DMB-protected amine (1.00 eq.) was dissolved in anhydrous CH2Cl2 (6 mL / mmol), and TFA (2 mL / mmol) was added. The mixture was stirred at 25 °C for 2 h. Upon completion, the mixture was concentrated in vacuo and the residue dissolved in MeCN, and the pH adjusted to 8 with ammonia (7 M in THF, 1 mL). The mixture was concentration in vacuo and the residue purified by prep-HPLC.

[0146] General Procedure IV: Ester Hydrolysis: To a solution of the corresponding ester (1.00 eq.) in water (2 mL) and THF (2 mL) was added LiOH^H2O (2.00 eq.), and the reaction was stirred at ambient temperature for 2 h. Upon completion, the mixture was concentrated in vacuo and the residue diluted with DMSO, filtered, and purified by reversed phase flash chromatography (C18 silica).

[0147] General Procedure V: HATU Coupling: To a solution of the corresponding-3- fluoro-pyridine-4-carboxylic acid (1.00 eq.) and the corresponding amine (1.50 eq.) in DMF (10 mL) were added HATU (1.50 eq.) and DIEA (3.00 eq.) at 0 °C. The reaction was stirred at ambient temperature for 1~ 16 h under N2atmosphere. Upon completion, the mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed withbrine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by reversed phase flash chromatography (C18 silica). Example 1. N-[3-(2-methyl-1-piperidyl)propyl]-2-phenyl-6-[4-(2,2,2- trifluoroethoxy)phenyl]pyridine-4-carboxamide

[0148] Scheme 1

[0149] Step 1: To a solution of methyl 2,6-dichloropyridine-4-carboxylate (1.0 eq, 2.2 g, 10.7 mmol) in 1,4-dioxane (30 mL) and water (5 mL) was added K3PO4 (2.50 eq, 5.67 g, 26.7 mmol), [4-(2,2,2-trifluoroethoxy)phenyl]boronic acid (0.9 eq, 2.1 g, 9.61 mmol) and Pd(dppf)Cl2(0.1 eq, 0.872 g, 1.07 mmol). The mixture was stirred at 100 °C for 12 h under N2 atmosphere. The mixture was quenched with Sat. NH4Cl solution (30 mL), extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (PE: ethyl acetate=0~50%) to afford the desired product methyl 2-chloro-6-[4-(2,2,2-trifluoroethoxy)phenyl]pyridine-4-carboxylate (2.00 g,4.63 mmol, 43.3 % yield) as a yellow solid. LC purity: 80% (UV at 254 nm); Mass calculated for C15H11ClF3NO3[M+1]+, 346.0, found 346.3 [M+1]; Retention time: 2.001 min.

[0150] Step 2: To a solution of methyl 2-chloro-6-[4-(2,2,2- trifluoroethoxy)phenyl]pyridine-4-carboxylate (1.00 eq, 200 mg, 0.579 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was added K2CO3(2.00 eq, 160 mg, 1.16 mmol), phenylboronic acid (1.20 eq, 85 mg, 0.694 mmol) and Pd(dppf)Cl2 (0.100 eq, 47 mg, 0.0579 mmol). The mixture was stirred at 100 °C for 12 h under N2 atmosphere. The mixture was diluted withsat. NH4Cl solution (10 mL), extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (PE: ethyl acetate=0~50%) to afford the desired product methyl 2-phenyl-6-[4-(2,2,2- trifluoroethoxy)phenyl]pyridine-4-carboxylate (120 mg, 0.279 mmol, 48.2 % yield) as a yellow solid. LC purity: 80% (UV at 254 nm); Mass calculated for C21H16F3NO3 [M+1]+, 388.1, found 388.4; Retention time: 2.214 min.

[0151] Step 3: To a solution of methyl-2-phenyl-6-[4-(2,2,2- trifluoroethoxy)phenyl]pyridine-4-carboxylate (1.00 eq, 100 mg, 0.258 mmol) in THF (3 mL) and water (1 mL) was added LiOH (4.00 eq, 25 mg, 1.03 mmol). The mixture was stirred at 50°C for 4 h. The reaction was allowed to cool to ambient temperature and concentrated in vacuo. The residue was dissolved in H2O (5 mL) and the pH adjusted to 3 with 1N HCl. The reaction mixture was extracted with ethyl acetate (10 mL x 3), the combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford the crude product 2-phenyl-6-[4-(2,2,2-trifluoroethoxy)phenyl]pyridine-4- carboxylic acid (70 mg, 0.150 mmol, 58.1% yield) as a yellow oil, which can be used to next step directly without further purification. (DCM / MeOH=15:1, Rf=0.4).

[0152] Step 4: To a solution of 2-phenyl-6-[4-(2,2,2-trifluoroethoxy)phenyl]pyridine-4- carboxylic acid (1.00 eq, 126 mg, 0.337 mmol) in DMF (5 mL) was added 3-(2-methyl-1- piperidyl)propan-1-amine (1.20 eq, 63 mg, 0.405 mmol), DIEA (1.50 eq, 0.088 mL, 0.506 mmol) and HATU (3.00 eq, 385 mg, 1.01 mmol). The mixture was stirred at 25°C for 2 h. The reaction mixture was concentrated in vacuo to give the crude product as a yellow oil. The residue was purified by pre-HPLC (gradient of CH3CN / H2O containing 0.1%FA) to afford the product the title compound (78 mg, 0.147 mmol, 43.59 % yield) as a yellow solid. LC purity: 96.85% (UV at 254 nm); Mass calculated for C29H32F3N3O2 [M+1]+, 512.2, found 512.5; Retention time: 1.345 min,1H NMR(400 MHz, CDCl3) δ 8.87 (s, 1H), 8.29 – 8.23 (m, 6H), 7.45 (dt, J = 26.2, 7.2 Hz, 3H), 7.03 (d, J = 8.8 Hz, 2H), 4.39 (q, J = 8.1 Hz, 2H), 3.60 (s, 2H), 3.46 – 3.02 (m, 3H), 2.85 (s, 2H), 2.16 (q, J = 15.8 Hz, 2H), 1.85 (s, 3H), 1.75 (d, J = 6.3 Hz, 2H), 1.51 (s, 1H), 1.33 (d, J = 6.4 Hz, 3H). Example 2. N-(1-methyl-3-piperidyl)-2-(1-methylpyrazol-4-yl)-6-[4-(2,2,2- trifluoroethoxy)phenyl]pyridine-4-carboxamide

[0153] Scheme 2

[0154] Step 1: To a solution of 2,6-dichloropyridine-4-carboxylic acid (1.00 eq, 1.00 g, 5.21 mmol) and 1-methylpiperidin-3-amine (1.50 eq, 892 mg, 7.81 mmol) in DMF (10 mL) was added DIEA (4.00 eq, 3.6 mL, 20.8 mmol) and HATU (1.50 eq, 2.97 g, 7.81 mmol) at ambient temperature. The reaction mixture was stirred overnight under N2at 25 °C. The reaction mixture was diluted with water (30 mL), extracted with ethyl acetate (20 mL x 3). The combined the organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (MeOH in DCM= 0 to 10%) to afford 2,6-dichloro-N-(1- methyl-3-piperidyl) pyridine-4-carboxamide (1.20 g, 48.0 % yield) as a white solid. Mass calculated for C12H15Cl2N3O [M+1]+, 288.1, found 288.0.

[0155] Step 2: To a solution of 2,6-dichloro-N-(1-methyl-3-piperidyl)pyridine-4- carboxamide (1.00 eq, 1.21 g, 4.20 mmol) in 1,4-Dioxane (15 mL) ) and Water (4 mL) were added [4-(2,2,2-trifluoroethoxy)phenyl]boronic acid (0.800 eq, 739 mg, 3.36 mmol), K2CO3(3.00 eq, 1741 mg, 12.6 mmol) and Pd(dppf)Cl2 (0.100 eq, 307 mg, 0.420 mmol) under N2. The reaction was stirred at 60 ℃ for 2 hr. The reaction was diluted with ethyl acetate and water. The organic layers were separated, washed with brine, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (ethyl acetate in PE=0 to 50%) to afford 2-chloro-N-(1-methyl-3-piperidyl)-6-[4-(2,2,2- trifluoroethoxy)phenyl]pyridine-4-carboxamide (700 mg, 39.0 % yield) as a white solid. Mass calculated for C20H21ClF3N3O2[M+1]+, 428.1, found 428.0.

[0156] Step 3: To a solution of 2-chloro-N-(1-methyl-3-piperidyl)-6-[4-(2,2,2- trifluoroethoxy)phenyl]pyridine-4-carboxamide (1.00 eq, 200 mg, 0.467 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (1.50 eq, 146 mg, 0.701 mmol) in dioxane (5 mL) and water (1 mL) was added K2CO3 (2.00 eq, 129 mg, 0.935 mmol) and Pd(dppf)Cl2 (0.100 eq, 34 mg, 0.0467 mmol). The reaction mixture was stirred overnight at 80 ℃ under N2. The reaction was allowed to cool to room temperature and filtered through a pad of celite. The filtrate was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by prep- TLC and prep-HPLC to give the title compound (50 mg, 22.3 % yield) as a white solid. Mass calculated for C24H26F3N5O2 [M+1]+, 474.2, found 474.0; Retention time: 0.952 min.1H NMR (400 MHz, MeOD) δ 8.42 (s, 1H), 8.29 (s, 1H), 8.20 – 8.08 (m, 3H), 7.98 (s, 1H), 7.87 (s, 1H), 7.15 (d, J = 8.8 Hz, 2H), 4.62 (q, J = 8.4 Hz, 2H), 4.29 (t, J = 9.8 Hz, 1H), 3.98 (s, 3H), 3.39 (d, J = 11.1 Hz, 1H), 3.17 (d, J = 18.6 Hz, 1H), 2.71 (s, 5H), 2.05 (dd, J = 12.5, 8.9 Hz, 2H), 1.84 (dd, J = 21.4, 10.6 Hz, 1H), 1.74 – 1.64 (m, 1H). Example 2-(2-aminopyrimidin-5-yl)-3-cyano-N-(1-methylpiperidin-3-yl)-6-(4- (2,2,2- phenyl)isonicotinamide

[0157] Scheme 3

[0158] Step 1: To a solution of 1-(4-hydroxyphenyl)ethanone (1.00 eq, 5.00 g, 36.7 mmol) in DMF (75 mL) at 0 °C was added NaH (1.20 eq, 1.76 g, 44.1 mmol). The reaction mixture was allowed to stir at 0 °C for 30 min, then 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.10 eq, 9.38 g, 40.4 mmol) was added. The resulting mixture was stirred at ambient temperature for 2h. The mixture was quenched with sat. NH4Cl solution, and the pH adjusted to 3 with 1N HCl solution. The mixture was extracted with EtOAc (30 mL × 3) and the combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:PE = 10-20%) to afford 1-[4-(2,2,2-trifluoroethoxy)phenyl]ethanone (7.00 g, 32.1 mmol, 87 % yield) as a white solid. LC purity: 95% (UV at 254 nm) / MS: 444[M+1]; Retention time: 1.327 min;1H NMR (400 MHz, CDCl3) δ 8.01 – 7.93 (m, 2H), 7.04 – 6.96 (m, 2H), 4.42 (q, J = 8.0 Hz, 2H), 2.57 (s, 3H).

[0159] Step 2: To a solution of 1-[4-(2,2,2-trifluoroethoxy)phenyl]ethanone (1.00 eq, 7.00 g, 32.1 mmol) in ethanol (75 mL) at 0 °C was added NaOEt (1.20 eq, 1.54 g, 38.5 mmol).The resulting mixture was stirred at 0 °C for 30 min and diethyl oxalate (1.10 eq, 4.8 mL, 35.3 mmol) was added, the reaction mixture was stirred at 80 °C for 1h. Upon completion, the reaction mixture was poured into sat. NH4Cl solution (50 mL), and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column flash (ethyl acetate:PE = 10-20%) to afford ethyl 2,4-dioxo-4-[4-(2,2,2-trifluoroethoxy)phenyl]butanoate (9.00 g,28.3 mmol, 88 % yield) as a white solid. LC purity: 90% (UV at 254 nm) / MS: 319 [M+1]; Retention time: 1.697 min.

[0160] Step 3: To a solution of ethyl 2,4-dioxo-4-[4-(2,2,2- trifluoroethoxy)phenyl]butanoate (1.00 eq, 2.00 g, 6.28 mmol) in ethanol (30 mL) was added 2-cyanoacetamide (1.00 eq, 0.49 mL, 6.28 mmol) and TEA (1.00 eq, 0.88 mL, 6.28 mmol), the resulting mixture was stirred at 70 °C for 2h. Upon completion, the reaction mixture was poured into sat. NH4Cl solution (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column flash (ethyl acetate:PE = 20- 40%) to afford ethyl 3-cyano-2-hydroxy-6-[4-(2,2,2-trifluoroethoxy)phenyl]pyridine-4- carboxylate (1.80 g, 4.91 mmol, 78 % yield) as a yellow solid. LC purity: 95% (UV at 254 nm) / MS: 367[M+1]; Retention time: 1.370 min.

[0161] Step 4: A solution of ethyl 3-cyano-2-hydroxy-6-[4-(2,2,2- trifluoroethoxy)phenyl]pyridine-4-carboxylate (1.00 eq, 1.50 g, 4.10 mmol) in phenylphosphonic dichloride (10 mL) was stirred at 160 °C for 2h. Upon completion, the reaction was allowed to cooled to ambient temperature and quenched with water (20 mL). The mixture was extracted with EtOAc (10 mL × 3) and the combined organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column flash (ethyl acetate:PE = 10 - 20%) to afford ethyl 2-chloro-3-cyano-6-[4-(2,2,2- trifluoroethoxy)phenyl]pyridine-4-carboxylate (1.30 g, 3.38 mmol, 82.5 % yield) as a brown solid. LC purity: 90% (UV at 254 nm) / MS: 385[M+1]; Retention time: 1.893 min.1H NMR (400 MHz, CDCl3) δ 8.23 (s, 1H), 8.12 (d, J = 8.9 Hz, 2H), 7.08 (d, J = 8.9 Hz, 2H), 4.54 (q, J = 7.1 Hz, 2H), 4.45 (q, J = 8.0 Hz, 2H), 1.49 (t, J = 7.1 Hz, 3H).

[0162] Step 5: To a solution of ethyl 2-chloro-3-cyano-6-[4-(2,2,2- trifluoroethoxy)phenyl]pyridine-4-carboxylate (1.00 eq, 256 mg, 0.666 mmol) in 1,4-Dioxane (3 mL) and water (1 mL) was added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (1.20 eq, 177 mg, 0.800 mmol), K2CO3(2.00 eq, 184 mg, 1.33 mmol), Pd(dppf)Cl2-DCM (0.100 eq, 54 mg, 0.067 mmol). The mixture was stirred at 80 °C for 3 hours under N2 atmosphere. The mixture was quenched with saturated NH4Cl solution (30 mL), extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (PE : ethyl acetate=0~50%) to afford the desired product ethyl 2-(2-aminopyrimidin-5-yl)-3-cyano-6-[4-(2,2,2- trifluoroethoxy)phenyl]pyridine-4-carboxylate (60 mg, 0.108 mmol, 16.3 % yield) as a yellow solid. LC purity: 80% (UV at 254 nm) / MS: 444[M+1]; Retention time: 1.699 min.

[0163] Step 6: To a solution of ethyl 2-(2-aminopyrimidin-5-yl)-3-cyano-6-[4-(2,2,2- trifluoroethoxy)phenyl]pyridine-4-carboxylate (1.00 eq, 60 mg, 0.136 mmol) in THF (3 mL), water (1 mL), and methanol (1 mL) was added LiOH (4.00 eq, 13 mg, 0.542 mmol). The mixture was stirred 25 °C for 3 hours. Upon completion, the reaction mixture was concentrated to give the residue. The crude mixture was dissolved in H2O (5 mL), and the pH adjusted to 3 with 1N HCl. The aqueous layer was extracted with ethyl acetate (10 mL x 3) and the combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford the crude product 2-(2-aminopyrimidin-5-yl)-3-cyano-6-[4- (2,2,2-trifluoroethoxy)phenyl]pyridine-4-carboxylic acid (40 mg, 0.0770 mmol, 56.8 % yield) as a yellow oil. The material was used in the next step without further purification. LC purity: 80% (UV at 254 nm) / MS: 416 [M+1]; Retention time: 1.320 min.

[0164] Step 7: To a solution of 2-(2-aminopyrimidin-5-yl)-3-cyano-6-[4-(2,2,2- trifluoroethoxy)phenyl]pyridine-4-carboxylic acid (1.00 eq, 40 mg, 0.0963 mmol) in DMF (3 mL) was added DIEA (3.00 eq, 0.050 mL, 0.289 mmol), (3S)-1-methylpiperidin-3-amine (1.30 eq, 14 mg, 0.125 mmol) and HATU (1.50 eq, 55 mg, 0.144 mmol). The reaction mixture was stirred 25 °C for 2 hours. The mixture was quenched with NH4Cl solution (10 mL), extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by HPLC to afford the title compound (10 mg, 0.0195 mmol, 20 % yield) as a yellow solid. LC purity: 98.75% (UV at 254 nm) / MS: 512.1 [M+1]; Retention time: 0.856 min.1H NMR(400 MHz, MeOD) δ 8.97 (s, 2H), 8.27 (d, J = 9.0 Hz, 2H), 8.06 (s, 1H), 7.20 (d, J = 9.0 Hz, 2H), 4.66 (d,J = 8.4 Hz, 2H), 4.31 (s, 1H), 3.80 (d, J = 10.6 Hz, 2H), 3.55 (d, J = 12.4 Hz, 2H), 2.97 (s, 3H), 2.23 – 2.13 (m, 2H), 1.93 (s, 1H), 1.67 (d, J = 13.1 Hz, 1H).Example 4. N-(1-methyl-3-piperidyl)-2-(1-methylpyrazol-4-yl)-6-[4-(2,2,2- trifluoroethoxy)phenyl]pyrimidine-4-carboxamide

[0165] Scheme 4.

[0166] Step 1: To a solution of methyl 2,6-dichloropyrimidine-4-carboxylate (1.00 eq, 500 mg, 2.42 mmol) in 1,4-dioxane (4 mL) and water (1 mL) was added K2CO3(2.00 eq, 668 mg, 4.83 mmol), [4-(2,2,2-trifluoroethoxy)phenyl]boronic acid (1.20 eq, 638 mg, 2.90 mmol), Pd(dppf)Cl2 (0.100 eq, 197 mg, 0.242 mmol). The mixture was stirred 80 ℃ for 1 h under N2 atmosphere. The mixture was diluted with sat. NH4Cl solution (30 mL), extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and in vacuo. The residue was purified by column chromatography on silica gel (PE: ethyl acetate =0~50%) to afford methyl 2-chloro-6-[4- (2,2,2-trifluoroethoxy)phenyl]pyrimidine-4-carboxylate (300 mg, 0.779 mmol, 32.2 % yield) as a yellow oil. LC purity: 90% (UV at 254 nm); Mass calculated for C14H10ClF3N2O3 [M+1]+, 347.0, found 347.2; Retention time: 1.815 min.1HNMR(400 MHz, DMSO-d6) δ 8.51 (s, 1H), 8.31 (d, J = 8.9 Hz, 2H), 7.26 (d, J = 8.9 Hz, 2H), 4.93 (q, J = 8.8 Hz, 2H), 3.96 (s, 3H).

[0167] Step 2: To a solution of methyl 2-chloro-6-[4-(2,2,2- trifluoroethoxy)phenyl]pyrimidine-4-carboxylate (1.00 eq, 300 mg, 0.865 mmol) in 1,4- dioxane (4 mL), water (1 mL) was added K2CO3(2.00 eq, 239 mg, 1.73 mmol), 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (1.20 eq, 216 mg, 1.04 mmol), and Pd(dppf)Cl2(0.100 eq, 71 mg, 0.0865 mmol). The mixture was stirred 100 ℃ for 3 h under N2atmosphere. The mixture was quenched with sat. NH4Cl solution (20 mL), extracted withEtOAc (30 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by reversed combi flash (gradient of CH3CN / H2O containing 0.1%FA) to afford the product 2- (1-methylpyrazol-4-yl)-6-[4-(2,2,2-trifluoroethoxy)phenyl]pyrimidine-4-carboxylic acid (300 mg,0.714 mmol, 82.5 % yield) as a yellow oil. LC purity:90 % (UV at 254 nm); Mass calculated for C17H13F3N4O3 [M+1]+, 379.1, found 379.3; Retention time: 1.416 min.

[0168] Step 3: To a solution of 2-(1-methylpyrazol-4-yl)-6-[4-(2,2,2- trifluoroethoxy)phenyl]pyrimidine-4-carboxylic acid (1.00 eq, 90 mg, 0.238 mmol) in DMF (3 mL) was added 1-methylpiperidin-3-amine (1.20 eq, 33 mg, 0.285 mmol), DIEA (3.00 eq, 0.12 mL, 0.714 mmol), HATU (1.50 eq, 136 mg, 0.357 mmol). The mixture was stirred at 25 °C for 12 h. The mixture was diluted with sat. NH4Cl solution (5 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by prep-HPLC (gradient of CH3CN / H2O containing 0.1%FA) to afford the title compound (37 mg,0.0763 mmol, 32.05 % yield) as a yellow solid. LC purity: 99.13% (UV at 254 nm); Mass calculated for C23H25F3N6O2 [M+1]+, 475.2, found 475.4; Retention time: 0.932 min.1H NMR (400 MHz, DMSO-d6) δ 9.88 (s, 1H), 9.01 (d, J = 8.6 Hz, 1H), 8.65 (s, 1H), 8.37 (d, J = 7.0 Hz, 3H), 8.17 (s, 1H), 7.26 (d, J = 7.3 Hz, 2H), 4.92 (d, J = 8.7 Hz, 2H), 4.28 (s, 1H), 3.96 (s, 3H), 3.52 (dd, J = 27.9, 12.0 Hz, 2H), 3.03 (d, J = 10.3 Hz, 1H), 2.87 (s, 4H), 1.97 (d, J = 11.5 Hz, 2H), 1.76 (t, J = 9.8 Hz, 2H). Example 5. N-(1-methyl-3-piperidyl)-2-(4-methylpyrazol-1-yl)-6-[4-(2,2,2- trifluoroethoxy)phenyl]pyridine-4-carboxamide

[0169] Scheme 5.

[0170] Step 1: To a solution of tert-butyl 2,6-dichloropyridine-4-carboxylate (1.00 eq, 5 g, 20.2 mmol) in 1,4-dioxane (50 mL) and water (10 mL) was added [4-(2,2,2- trifluoroethoxy)phenyl]boronic acid (0.600 eq, 2.66 g, 12.1 mmol), K2CO3(3.00 eq, 8.36 g, 60.5 mmol), and Pd(dppf)Cl2(0.05 eq, 0.74 g, 1.01 mmol). The mixture was stirred at 80 °C for 30 min under N2 atmosphere. Upon completion, the reaction mixture was quenched with sat. NH4Cl solution (20 mL), and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by reversed combi flash (gradient of CH3CN / H2O containing 0.1%FA) to afford tert-butyl 2-chloro-6-[4-(2,2,2- trifluoroethoxy)phenyl]pyridine-4-carboxylate (3.30 g, 8.51 mmol, 42.2 % yield) as a yellow solid. LC purity: 90% (UV at 254 nm); Mass calculated for C18H17ClF3NO3[M+1]+, 388.1, found 388.1; Retention time: 2.296 min.

[0171] Step 2: To a solution of tert-butyl 2-chloro-6-[4-(2,2,2- trifluoroethoxy)phenyl]pyridine-4-carboxylate (1.00 eq, 1.00 g, 2.58 mmol) in DCM (5 mL) was added TFA (10.0 eq, 2.0 mL, 25.8 mmol). The mixture was stirred at 25 °C for 30 min. Upon completion, the reaction mixture was concentrated in vacuo to afford 2-chloro-6-[4- (2,2,2-trifluoroethoxy)phenyl]pyridine-4-carboxylic acid (0.80 g, 2.41 mmol, 93.5 % yield) as a yellow oil. The crude material was used in the next step without further purification. LC purity: 90% (UV at 254 nm); Mass calculated for C14H9ClF3NO3 [M+1]+, 332.0, found 331.6; Retention time: 1.532 min.

[0172] Step 3: To a solution of 2-chloro-6-[4-(2,2,2-trifluoroethoxy)phenyl]pyridine-4- carboxylic acid (1.00 eq, 1.00 g, 3.01 mmol) in DCM (10 mL) was added 1-methylpiperidin-3-amine (1.50 eq, 0.35 mL, 4.52 mmol), DIEA (3.00 eq, 1.6 mL, 9.04 mmol) and HATU (1.50 eq, 1720 mg, 4.52 mmol). The mixture was stirred at 25 °C for 2 h. Upon completion the reaction mixture was quenched with sat. NH4Cl solution (20 mL) and extracted with DCM (10 mL x 3). The combined organic layer was washed by brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0~10% MeOH / DCM) to afford 2-chloro-N-(1-methyl-3- piperidyl)-6-[4-(2,2,2-trifluoroethoxy)phenyl]pyridine-4-carboxamide (1.20 g, 2.80 mmol, 93.0 % yield) as a yellow oil. LC purity: 90% (UV at 254 nm); Mass calculated for C20H21ClF3N3O2 [M+1]+, 428.1, found 428.4; Retention time: 0.832 min.

[0173] Step 4: To a solution of 2-chloro-N-(1-methyl-3-piperidyl)-6-[4-(2,2,2- trifluoroethoxy)phenyl]pyridine-4-carboxamide (1.00 eq, 103 mg, 0.242 mmol) in DMF (2 mL) was added 4-methyl-1H-pyrazole (1.20 eq, 24 mg, 0.290 mmol), Cs2CO3 (3.00 eq, 236 mg, 0.725 mmol), CuI (0.200 eq, 9.2 mg, 0.0483 mmol) and cis-1,2-diaminocyclohexane (0.200 eq, 5.5 mg, 0.0483 mmol) at ambient temperature. The mixture was stirred at 120 °C for 16 h under N2 atmosphere. Upon completion the reaction mixture was filtered and purified by prep-HPLC (gradient of CH3CN / H2O containing 0.1% FA) to afford the title compound (5.4 mg, 0.0114 mmol, 4.7 % yield) as a brown solid. LC purity: 95% (UV at 254 nm); Mass calculated for C24H26F3N5O2[M+1]+, 474.2, found 474.2. Retention time: 1.616 min.1H NMR (400 MHz, MeOD) δ 8.54 (s, 1H), 8.19 (d, J = 8.7 Hz, 2H), 8.09 (d, J = 33.3 Hz, 2H), 7.63 (s, 1H), 7.17 (d, J = 8.8 Hz, 2H), 4.64 (q, J = 8.4 Hz, 2H), 4.32 (t, J = 11.9 Hz, 1H), 3.75 (d, J = 10.2 Hz, 1H), 3.56 (d, J = 11.5 Hz, 1H), 2.99 (d, J = 13.1 Hz, 1H), 2.95 (s, 3H), 2.89 (t, J = 11.7 Hz, 1H), 2.20 (s, 3H), 2.14 (d, J = 13.9 Hz, 2H), 1.90 (dd, J = 27.9, 13.6 Hz, 1H), 1.72 (dt, J = 18.3, 12.1 Hz, 1H). Example 6.2-(4-methylimidazol-1-yl)-N-(1-methyl-3-piperidyl)-6-[4-(2,2,2- trifluoroethoxy)phenyl]pyridine-4-carboxamide

[0174] Scheme 6.

[0175] Step 1: To a solution of 2-chloro-N-(1-methyl-3-piperidyl)-6-[4-(2,2,2- trifluoroethoxy)phenyl]pyridine-4-carboxamide (1.00 eq, 100 mg, 0.234 mmol) in DMF (2 mL) was added 4-methylimidazole (1.20 eq, 23 mg, 0.280 mmol), Cs2CO3 (3.00 eq, 228 mg, 0.701 mmol), CuI (0.200 eq, 8.9 mg, 0.047 mmol) and (1R,2R)-(-)-1,2-diaminocyclohexane (0.200 eq, 5.3 mg, 0.047 mmol) at ambient temperature. The mixture was stirred at 120 °C for 16 h under N2 atmosphere. Upon completion, the reaction mixture was filtered, and concentrated in vacuo. The residue was purified by prep-HPLC (gradient of CH3CN / H2O containing 0.1%FA) to afford the title compound (17 mg, 0.0349 mmol, 14.9 % yield) as a brown solid. LC purity: 95% (UV at 254 nm); Mass calculated for C24H26F3N5O2 [M+1]+, 474.2, found 474.4. Retention time: 1.616 min.1H NMR (400 MHz, MeOD) δ 9.80 (s, 1H), 8.40 (s, 1H), 8.27 (d, J = 8.9 Hz, 2H), 8.22 (s, 1H), 8.14 (s, 1H), 7.19 (d, J = 8.8 Hz, 2H), 4.65 (d, J = 8.4 Hz, 2H), 4.35 (t, J = 11.7 Hz, 1H), 3.75 (d, J = 11.3 Hz, 1H), 3.56 (d, J = 11.7 Hz, 1H), 2.98 (s, 1H), 2.95 (s, 3H), 2.94 – 2.90 (m, 1H), 2.48 (s, 3H), 2.16 (t, J = 14.5 Hz, 2H), 1.93 (d, J = 14.5 Hz, 1H), 1.82 – 1.69 (m, 1H). Example 7.2-(3-hydroxy-3-methyl-pyrrolidin-1-yl)-N-(1-methyl-3-piperidyl)-6-[4-(2,2,2- trifluoroethoxy)phenyl]pyridine-4-carboxamide

[0176] Scheme 7.

[0177] Step 1: To a solution of 2-chloro-N-(1-methyl-3-piperidyl)-6-[4-(2,2,2- trifluoroethoxy)phenyl]pyridine-4-carboxamide (1.00 eq, 100 mg, 0.234 mmol) and 3- methylpyrrolidin-3-ol (1.20 eq, 28 mg, 0.280 mmol) in1,4-dioxane (1mL) was added XantPhos (0.200 eq, 27 mg, 0.047mmol), Cs2CO3(2.00 eq, 152 mg, 0.467 mmol) and Pd2dba3(0.100 eq, 21 mg, 0.023 mmol). The reaction mixture was stirred at 90 °C overnight under N2 atmosphere. Upon completion, the reaction mixture was filtered, the filtrate taken up in water (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by prep-TLC and prep-HPLC (gradient of CH3CN / H2O containing 0.1%FA) to give the title compound (23 mg,0.0449 mmol, 19.2 %yield) as a white solid. LC purity: 98% (UV at 254 nm); Mass calculated for C25H31F3N4O3[M+1]+, 493.2 , found 493.0; Retention time: 0.969 min.1H NMR (400 MHz, MeOD) δ 8.15 – 8.00 (m, 2H), 7.36 (d, J = 0.9 Hz, 1H), 7.20 – 7.02 (m, 2H), 6.71 (d, J = 0.9 Hz, 1H), 4.59 (q, J = 8.5 Hz, 2H), 4.26 – 4.13 (m, 1H), 3.77 – 3.57 (m, 3H), 3.52 – 3.42 (m, 1H), 3.03 (d, J = 8.9 Hz, 1H), 2.79 (d, J = 7.4 Hz, 1H), 2.41 (s, 3H), 2.24 (dd, J = 36.8, 6.9 Hz, 2H), 2.14 – 2.01 (m, 2H), 1.88 (ddd, J = 16.4, 12.4, 7.8 Hz, 2H), 1.72 (ddd, J = 20.7, 12.2, 8.7 Hz, 1H), 1.61 – 1.43 (m, 4H). Example 8.2-(4-methyloxazol-2-yl)-N-(1-methyl-3-piperidyl)-6-[4-(2,2,2- trifluoroethoxy)phenyl]pyridine-4-carboxamide

[0178] Scheme 8.

[0179] Step 1: To a solution of 4-methyloxazole (2.00 eq, 107 mg, 1.29 mmol) in THF (5 mL) was added n-BuLi (2.50 eq, 0.64 mL, 1.61 mmol) at -78 °C under N2 atmosphere. The solution was stirred at this temperature for 10 minutes, followed addition of ZnCl2 (6.00 eq, 3.9 mL, 3.87 mmol) in THF added dropwise. The resulting solution was stirred for 15 minutes at - 78 °C allowed to warm to ambient temperature. The reaction mixture was added to a solution of tert-butyl 2-chloro-6-[4-(2,2,2-trifluoroethoxy)phenyl]pyridine-4-carboxylate (1.00 eq, 250 mg, 0.645 mmol) and Pd(PPh3)2Cl2 (0.1 eq, 45 mg, 0.065 mmol) in THF (2 mL) dropwise under N2atmosphere. The resulting mixture was stirred at 60 °C for 1h. Upon completion, the reaction mixture was quenched with sat. NH4Cl solution (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4,filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE: ethyl acetate=20 ~ 30%) to afford tert-butyl 2-(4-methyloxazol-2-yl)-6-[4-(2,2,2-trifluoroethoxy)phenyl]pyridine-4-carboxylate (250 mg,0.575 mmol, 89.3 % yield) as a white solid. LC purity: 100% (UV at 254 nm); Mass calculated for C22H21F3N2O4 [M+1]+, 435.2, found 435.4; Retention time: 2.255 min.

[0180] Step 2: To a solution of tert-butyl 2-(4-methyloxazol-2-yl)-6-[4-(2,2,2- trifluoroethoxy)phenyl]pyridine-4-carboxylate (1.00 eq, 250 mg, 0.575 mmol) in DCM (5 mL) was added TFA (13.6 eq, 2.0 mL, 7.83 mmol), the mixture was stirred at ambient temperature for 2 h. Upon completion, the reaction mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (MeOH in DCM=3 ~ 8%) to afford 2-(4-methyloxazol-2-yl)-6-[4-(2,2,2-trifluoroethoxy)phenyl]pyridine-4- carboxylic acid (200 mg,0.529 mmol, 91.9 % yield) as a white solid. LC purity: 98% (UV at 254 nm); Mass calculated for C18H13F3N2O4[M+1]+, 379.1, found 379.0; Retention time: 1.770 min.

[0181] Step 3: To a solution of 2-(4-methyloxazol-2-yl)-6-[4-(2,2,2- trifluoroethoxy)phenyl]pyridine-4-carboxylic acid (1.00 eq, 50 mg, 0.132 mmol) in DCM (2 mL) was added DIEA (5.00 eq, 0.12 mL, 0.661 mmol) and HATU (1.50 eq, 75 mg, 0.198 mmol), the resulting mixture was stirred at ambient temperature for 10 min.1- methylpiperidin-3-amine dihydrochloride (1.50 eq, 37 mg, 0.198 mmol) was added and allowed to stir at ambient temperature for 2h. The mixture was quenched with H2O (10 mL) and extracted with DCM (10 mL x 2). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by prep-HPLC (gradient of CH3CN / H2O containing 0.1%FA) to afford the title compound (36 mg,0.0758 mmol, 57.4 % yield) as a white solid. LC purity: 99% (UV at 254 nm); Mass calculated for C24H25F3N4O3 [M+1]+, 475.2, found 475.4; Retention time: 1.048 min.1H NMR (400 MHz, MeOD) δ 8.32 (d, J = 1.3 Hz, 1H), 8.29 – 8.21 (m, 3H), 7.85 (d, J = 1.2 Hz, 1H), 7.18 (dd, J = 9.2, 2.3 Hz, 2H), 4.64 (q, J = 8.4 Hz, 2H), 4.40 – 4.25 (m, 1H), 3.83 – 3.71 (m, 1H), 3.61 – 3.51 (m, 1H), 3.02 – 2.92 (m, 4H), 2.87 (t, J = 11.7 Hz, 1H), 2.30 (d, J = 1.1 Hz, 3H), 2.21 – 2.10 (m, 2H), 1.96 – 1.81 (m, 1H), 1.78 – 1.65 (m, 1H). Example 9.2-(1-methylimidazol-4-yl)-N-(1-methyl-3-piperidyl)-6-[4-(2,2,2- trifluoroethoxy)phenyl]pyridine-4-carboxamide

[0182] Scheme 9.

[0183] Step 1: To a solution of tert-butyl 2-chloro-6-[4-(2,2,2- trifluoroethoxy)phenyl]pyridine-4-carboxylate (1.00 eq, 100 mg, 0.258 mmol) in DMF (5 mL) was added tributyl-(1-methylimidazol-4-yl)stannane (1.10 eq, 105 mg, 0.284 mmol) and Pd(PPh3)4(0.100 eq, 30 mg, 0.0258 mmol) at ambient temperature. The mixture was stirred at 120 ℃ for 16 h under N2 atmosphere. The reaction mixture was quenched with KF solution (1M, 10 mL) and filtered. The aqueous mixture was extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (20 mL), and dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (Eluent of 0~30 % EtOAc / PE) to afford tert-butyl 2-(1-methylimidazol-4-yl)-6-[4- (2,2,2-trifluoroethoxy)phenyl]pyridine-4-carboxylate (100 mg,0.162 mmol, 62.2% yield) as a yellow solid. LC purity: 95% (UV at 254 nm); Mass calculated for C22H22F3N3O3 [M+1]+, 433.2, found 434.1; Retention time: 1.504 min.

[0184] Step 2: To a solution of tert-butyl 2-(1-methylimidazol-4-yl)-6-[4-(2,2,2- trifluoroethoxy)phenyl]pyridine-4-carboxylate (1.00 eq, 160 mg, 0.369 mmol) in 1,4-dioxane (3 mL) was added 3N HCl solution (5.00 eq, 0.62 mL, 1.85 mmol) at 0 ℃. The mixture was stirred at 25 ℃ for 6 h under N2atmosphere. The reaction mixture was concentrated in vacuo to afford 2-(1-methylimidazol-4-yl)-6-[4-(2,2,2-trifluoroethoxy)phenyl]pyridine-4-carboxylic acid (130 mg,0.345 mmol, 93.3 % yield). The crude product was used in the next step without further purification. LC purity: 95% (UV at 254 nm); Mass calculated for C18H14F3N3O3[M+1]+, 378.1, found 378.0; Retention time: 0.804 min.

[0185] Step 3: To a solution of 2-(1-methylimidazol-4-yl)-6-[4-(2,2,2- trifluoroethoxy)phenyl]pyridine-4-carboxylic acid (1.00 eq, 130 mg, 0.345 mmol) in DCM (3 mL) was added DIEA (3.00 eq, 0.18 mL, 1.03 mmol), 1-methylpiperidin-3-amine (1.10 eq,43 mg, 0.379 mmol) and HATU (1.50 eq, 197 mg, 0.517 mmol) at RT. The mixture was stirred at 25 ℃ for 1 hour. The reaction mixture was quenched with sat. NH4Cl solution (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed by brine (20 mL), and dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by pre-HPLC (gradient of CH3CN / H2O containing 0.1%FA) to afford the title compound (27 mg, 0.0565 mmol, 16.4 % yield) as a yellow solid. LC purity: 95% (UV at 254 nm); Mass calculated for C24H26F3N5O2[M+1]+, 474.2, found 474.1; Retention time: 0.504 min.1H NMR (400 MHz, DMSO-d6) δ 8.74 (d, J = 7.6 Hz, 1H), 8.21 (d, J = 8.8 Hz, 2H), 8.15 (s, 1H), 8.04 (s, 1H), 7.92 (s, 1H), 7.74 (s, 1H), 7.22 (d, J = 8.8 Hz, 2H), 4.87 (q, J = 8.8 Hz, 2H), 4.10 (d, J = 7.1 Hz, 1H), 3.76 (s, 3H), 3.13 (d, J = 9.1 Hz, 1H), 2.96 (d, J = 10.3 Hz, 1H), 2.47 (s, 3H), 2.32 (s, 2H), 1.91 – 1.80 (m, 2H), 1.64 (d, J = 11.7 Hz, 1H), 1.47 (dd, J = 21.2, 10.2 Hz, 1H). Example 10.2-(5-Methyloxazol-2-yl)-N-(1-methyl-3-piperidyl)-6-[4-(2,2,2- trifluoroethoxy)phenyl]pyridine-4-carboxamide

[0186] Scheme 10.

[0187] Step 1: To a solution of 2-chloro-N-(1-methyl-3-piperidyl)-6-[4-(2,2,2- trifluoroethoxy)phenyl]pyridine4carboxamide(1.00eq, 200 mg, 0.467 mmol) in methanol (5 mL) was added TEA (2.00eq, 0.13 mL, 0.935 mmol), Pd(dppf)Cl2(0.100 eq, 34 mg, 0.0467 mmol) at ambient temperature. The mixture was stirred at 70 ℃ for 2 h under CO atmosphere. Upon completion, the mixture was concentrated in vacuo. The residue was purified by reversed combi flash (gradient of CH3CN / H2O containing 0.1%FA) to get methyl4-[(1-methyl-3-piperidyl)carbamoyl]-6-[4-(2,2,2-trifluoroethoxy)phenyl]pyridine-2- carboxylate (140 mg,0.310 mmol, 66.3 % yield) as a yellow solid. LC purity: 95% (UV at 254 nm); Mass calculated for C22H24F3N3O4 [M+1]+, 452.2, found 452.1; Retention time: 1.112 min.

[0188] Step 2: To a solution of methyl 4-[(1-methyl-3-piperidyl)carbamoyl]-6-[4-(2,2,2- trifluoroethoxy)phenyl]pyridine-2-carboxylate (1.00 eq, 130 mg, 0.288 mmol) in Methanol (5 mL) and Water (1 mL) was added LiOH (10.0 eq, 69 mg, 2.88 mmol) at RT. The mixture was stirred at 25 ℃ for 2 h. The mixture was concentrated in vacuo. The residue was purified by reversed combi flash (gradient of CH3CN / H2O containing 0.1%FA) to give 4-[(1-methyl- 3-piperidyl)carbamoyl]-6-[4-(2,2,2-trifluoroethoxy)phenyl]pyridine-2-carboxylic acid (100 mg,0.229 mmol, 79.4 % yield) as a white solid. LC purity: 95% (UV at 254 nm); Mass calculated for C21H22F3N3O4 [M+1]+, 438.2, found 438.3; Retention time: 1.112 min.

[0189] Step 3: To a solution of 4-[(1-methyl-3-piperidyl)carbamoyl]-6-[4-(2,2,2- trifluoroethoxy)phenyl]pyridine-2-carboxylic acid (1.00 eq, 70 mg, 0.160 mmol) in CH3CN (5 mL) was added propargylamine (1.20 eq, 0.012 mL, 0.192 mmol), TCFH (1.20 eq, 54 mg, 0.192 mmol) and NMI (3.00 eq, 39 mg, 0.480 mmol) at ambient temperature. The mixture was stirred at 25 ℃ for 2 h. The mixture was concentrated in vacuo. The residue was purified by reversed combi flash (gradient of CH3CN / H2O containing 0.1%FA) to get N-4-(1-methyl- 3-piperidyl)-N-2-prop-2-ynyl-6-[4-(2,2,2-trifluoroethoxy)phenyl]pyridine-2,4-dicarboxamide (60 mg,0.126 mmol, 79.0 % yield) as a yellow solid. LC purity: 95% (UV at 254 nm); Mass calculated for C21H22F3N3O4[M+1]+, 475.2, found 475.1; Retention time: 1.112 min.

[0190] Step 4: To a solution of N-4-(1-methyl-3-piperidyl)-N-2-prop-2-ynyl-6-[4-(2,2,2- trifluoroethoxy)phenyl]pyridine-2,4-dicarboxamide (1.00 eq, 60 mg, 0.126 mmol) in DCE (3 mL) was added trifluoromethanesulfonic acid (10.0 eq, 0.11 mL, 1.26 mmol) at ambient temperature. The mixture was stirred at 70 ℃ for 2 h. The mixture was concentrated in vacuo. The residue was purified by prep-HPLC (gradient of CH3CN / H2O containing 0.1%FA) to afford the title compound (4.9 mg,0.0102 mmol, 8.1 % yield) as a yellow solid. LC purity: 95% (UV at 254 nm); Mass calculated for C21H22F3N3O4[M+1]+, 475.2, found 475.1; Retention time: 1.369 min.1H NMR (400 MHz, DMSO-d6) δ 8.76 (d, J = 7.5 Hz, 1H), 8.32 (d, J = 3.8 Hz, 2H), 8.22 (d, J = 8.9 Hz, 2H), 7.26 (d, J = 8.9 Hz, 2H), 7.14 (d, J = 1.2 Hz, 1H), 4.87 (t, J = 8.8 Hz, 2H), 4.00 (s, 1H), 2.89 (s, 1H), 2.67 (s, 1H), 2.47 (d, J = 0.9 Hz, 3H), 2.33 (s, 1H), 2.23 (s, 3H), 1.87 (s, 2H), 1.72 (s, 1H), 1.57 (s, 1H), 1.37 (s, 1H).Example 11.2-(2-aminopyrimidin-5-yl)-N-[ -1-methyl-3-piperidyl]-6-[4-(2,2,2- trifluoroethoxy)phenyl]pyridine-4-

[0191] Scheme 11.

[0192] Step 1: To a solution of tert-butyl-2-chloro-6-[4-(2,2,2-trifluoroethoxy) phenyl]pyridine-4-carboxylate (1.00 eq, 500 mg, 1.29 mmol) in 1,4-dioxane (10mL) and water (1mL) was added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (1.20 eq, 342 mg, 1.55 mmol), K2CO3 (2.50 eq, 446 mg, 3.22 mmol) and Pd(dppf)Cl2 (0.100 eq, 94 mg, 0.129 mmol) under N2 atmosphere. The reaction was stirred at 100 °C for 2h. Upon completion, the mixture was poured into sat. NH4Cl solution (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (MeOH in DCM=4 ~ 7%) to afford tert-butyl 2-(2- aminopyrimidin-5-yl)-6-[4-(2,2,2-trifluoroethoxy)phenyl]pyridine-4-carboxylate (350 mg, 0.784 mmol, 60.8 % yield) as a white solid. LC purity: 95% (UV at 254 nm); Mass calculated for C22H21F3N4O3 [M+1]+, 447.2, found 447.3; Retention time: 1.866 min.

[0193] Step 2: To a solution of tert-butyl 2-(2-aminopyrimidin-5-yl)-6-[4-(2,2,2- trifluoroethoxy)phenyl]pyridine-4-carboxylate (1.00 eq, 350 mg, 0.784 mmol) in DCM (5 mL) was added TFA (3.0 mL, 11.7 mmol) and allowed to stir at ambient temperature for 2 h. Upon completion, the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel (MeOH in DCM=3 ~ 8%) to afford 2-(2- aminopyrimidin-5-yl)-6-[4-(2,2,2-trifluoroethoxy)phenyl]pyridine-4-carboxylic acid (250mg, 0.641 mmol, 81.7 % yield) as a white solid. LC purity: 80% (UV at 254 nm); Mass calculated for C18H13F3N4O3 [M+1]+, 391.1, found 390.7; Retention time: 1.189 min.

[0194] Step 3: To a solution of 2-(2-aminopyrimidin-5-yl)-6-[4-(2,2,2- trifluoroethoxy)phenyl]pyridine-4-carboxylic acid (1.00 eq, 100 mg, 0.256 mmol) in DMF (5 mL) was added (3S)-1-methylpiperidin-3-amine (1.00 eq, 29 mg, 0.256 mmol), HATU (1.00 eq, 97 mg, 0.256 mmol) and DIEA (3.00 eq, 34 mg, 0.768 mmol), the reaction was stirred rt for 2 h, The reaction was monitored by LCMS. The reaction mixture was quenched with H2O (20 mL), and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (90 mL), and dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by prep-HPLC (gradient of CH3CN / H2O containing 0.1%FA)to afford the title compound (47 mg,0.0930 mmol, 36.3 % yield) as a white solid. LC purity: 97% (UV at 254 nm); Mass calculated for C24H25F3N6O2 [M+1]+, 487.2, found 487.3; Retention time: 0.886 min.1H NMR (400 MHz, MeOD) δ 9.08 (s, 2H), 8.39 (s, 1H), 8.19 (d, J = 8.8 Hz, 2H), 8.10 (s, 1H), 8.03 (s, 1H), 7.16 (d, J = 8.9 Hz, 2H), 4.63 (q, J = 8.4 Hz, 2H), 4.29 (dd, J = 12.0, 8.3 Hz, 1H), 3.43 (d, J = 10.8 Hz, 1H), 3.31 (s, 1H), 3.19 (s, 1H), 2.76 (s, 1H), 2.73 (s, 3H), 2.16 – 1.97 (m, 2H), 1.96 – 1.78 (m, 1H), 1.75 – 1.54 (m, 1H). Example 12.2-(2-aminopyrimidin-5-yl)-N-[ -1-methyl-3-piperidyl]-6-[4-(2,2,2-trifluoroethoxy)phenyl]pyridine-4-

[0195] Scheme 12.

[0196] Step 1: To a solution of 2,6-dichloropyridine-4-sulfonyl chloride (1.00 eq, 250 mg, 1.01 mmol) in DCM (5 mL) was added TEA (3.00 eq, 0.42 mL, 3.04 mmol) and (3S)-1- methylpiperidin-3-amine (1.20 eq, 139 mg, 1.22 mmol) at 0 °C. The reaction mixture was stirred at ambient temperature for 30 min. Upon completion, the reaction mixture was quenched with sat. NH4Cl solution (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (90 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column flash (silica gel, 0-10 % MeOH in DCM) to afford 2,6-dichloro-N-[(3S)-1-methyl-3-piperidyl]pyridine-4-sulfonamide (290 mg,0.805 mmol, 79.4 % yield) as a white solid. LC purity: 90% (UV at 254 nm); Mass calculated for C11H15Cl2N3O2S [M+1]+,324.0, found 324.0; Retention time: 0.405 min.

[0197] Step 2: To a solution of 2,6-dichloro-N-[(3S)-1-methyl-3-piperidyl]pyridine-4- sulfonamide (1.00 eq, 250 mg, 0.771 mmol) in dioxane (5 mL) and water (1 mL) was added K2CO3 (3.00 eq, 491 mg, 2.31 mmol), [4-(trifluoromethoxy)phenyl]boronic acid (0.999 eq, 159 mg, 0.770 mmol), and Pd(dppf)Cl2(0.198 eq, 128 mg, 0.153 mmol). The reaction was stirred at 100 °C for 16 h under N2 atmosphere. Upon completion, the reaction mixture was quenched with sat. NH4Cl solution (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (12 g, SepaFlash®Silica Flash Column, eluent of 70 % ethyl acetate / PE) to afford 2-chloro-N-[(3S)-1-methyl-3-piperidyl]-6-[4-(2,2,2-trifluoroethoxy)phenyl]pyridine-4- sulfonamide (230 mg,0.471 mmol, 61.1 % yield) as a yellow solid. LC purity: 64% (UV at 254 nm); Mass calculated for C19H21ClF3N3O3S [M+1]+, 464.1, found 464.0; Retention time: 1.36 min.

[0198] Step 3: To a solution of 2-chloro-N-[(3S)-1-methyl-3-piperidyl]-6-[4-(2,2,2- trifluoroethoxy)phenyl]pyridine-4-sulfonamide (1.00 eq, 100 mg, 0.216 mmol) in 1,4- dioxane (5 mL) was added water (1 mL) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyrimidin-2-amine (1.00 eq, 48 mg, 0.216 mmol), K2CO3(3.00 eq, 89 mg, 0.647 mmol), and Pd(dppf)Cl2(0.100 eq, 16 mg, 0.0216 mmol). The reaction was stirred at 100 °C for 12 h under N2 atmosphere. Upon completion, the reaction mixture was quenched with sat. NH4Cl solution (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (90 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by reversed phase column chromatography (gradient of CH3CN / H2O containing 0.1%FA) to afford the title compound (29 mg,0.0549 mmol, 25.5 %yield) as a white solid. LC purity: 97% (UV at 254 nm); Mass calculated for C23H25F3N6O3S [M+1]+, 523.2, found 523.2; Retention time: 1.194 min.1H NMR (400 MHz, MeOD) δ 8.34 (s, 1H), 8.17 (d, J = 8.8 Hz, 2H), 8.14 (s, 1H), 7.97 (s, 1H), 7.84 (s, 1H), 7.17 (d, J = 8.8 Hz, 2H), 4.64 (q, J = 8.4 Hz, 2H), 3.98 (s, 3H), 3.42 (s, 1H), 3.15 (d, J = 12.3 Hz, 1H), 2.96 (d, J = 11.4 Hz, 1H), 2.55 (s, 3H), 2.53 – 2.43 (m, 1H), 1.88 – 1.70 (m, 2H), 1.70 – 1.52 (m, 1H), 1.45 – 1.27 (m, 1H). Example 13.2-(4-Aminopyrazol-1-yl)-N-[ -1-methyl-3-piperidyl]-6-[4-(2,2,2-trifluoroethoxy)phenyl]pyridine-4-

[0199] Scheme 13.

[0200] Step 1: To a solution of 2-chloro-N-[(3S)-1-methyl-3-piperidyl]-6-[4-(2,2,2- trifluoroethoxy)phenyl]pyridine-4-carboxamide (1.00 eq, 100 mg, 0.234 mmol) in DMF (10 mL) at ambient temperature was added ethyl 1H-pyrazole-4-carboxylate (1.20 eq, 39 mg, 0.280 mmol) and t-BuOK(3.00 eq, 79 mg, 0.701 mmol). The reaction mixture was allowed to stir at 120 °C for 12 h under N2 atmosphere. The reaction mixture was quenched with sat. NH4Cl solution (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), and dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by reversed combi flash (gradient of CH3CN / H2O containing 0.1%FA) to obtain the product ethyl 1-[4-[[(3S)-1-methyl-3- piperidyl]carbamoyl]-6-[4-(2,2,2-trifluoroethoxy)phenyl]-2-pyridyl]pyrazole-4-carboxylate(100 mg,0.188 mmol, 80.5 % yield) as a white solid. LC purity: 90% (UV at 254 nm); Mass calculated for C26H28F3N5O4 [M+1]+,532.2, found 532.2; Retention time: 1.503 min.

[0201] Step 2: To a solution of ethyl 1-[4-[[(3S)-1-methyl-3-piperidyl]carbamoyl]-6-[4- (2,2,2-trifluoroethoxy)phenyl]-2-pyridyl]pyrazole-4-carboxylate (1.00 eq, 100 mg, 0.188 mmol) in THF (3 mL) and water (1 mL) was added LiOH (10.0 eq, 45 mg, 1.88 mmol) at rt. The reaction mixture was stirred at 25 °C for 2 h. Upon completion, the reaction mixture was concentrated in vacuo. The residue was dissolved in H2O (3 mL) and the pH adjusted to 4 with HCl (1N) solution. The aqueous layer was extracted with EtOAc (10 mL x 3) and the combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue product was purified by reversed combi flash (gradient of CH3CN / H2O containing 0.1%FA) to obtain the product 1-[4-[[(3S)-1-methyl-3-piperidyl]carbamoyl]-6-[4- (2,2,2-trifluoroethoxy)phenyl]-2-pyridyl]pyrazole-4-carboxylic acid (90 mg,0.179 mmol, 95.0 % yield) as a white solid. LC purity: 90% (UV at 254 nm); Mass calculated for C24H24F3N5O4[M+1]+, 504.2, found 504.1; Retention time: 1.003 min.

[0202] Step 3: To a solution of 1-[4-[[(3S)-1-methyl-3-piperidyl]carbamoyl]-6-[4-(2,2,2- trifluoroethoxy)phenyl]-2-pyridyl]pyrazole-4-carboxylic acid (1.00 eq, 90 mg, 0.179 mmol) in toluene (3 mL) was added DPPA (1.20 eq, 59 mg, 0.215 mmol), TEA (3.00 eq, 0.075 mL, 0.536 mmol) and BnOH (2.00 eq, 0.037 mL, 0.358 mmol). The reaction mixture was stirred at 90 °C for 2 h. The reaction mixture was quenched with sat. NH4Cl solution (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (DCM:MeOH=0 ~10%) to obtain the product benzyl N-[1-[4-[[(3S)-1-methyl-3-piperidyl]carbamoyl]-6-[4-(2,2,2- trifluoroethoxy)phenyl]-2-pyridyl]pyrazol-4-yl]carbamate (50 mg,0.0822 mmol, 46.0 % yield) as a white solid. LC purity: 90% (UV at 254 nm); Mass calculated for C31H31F3N6O4 [M+1]+, 609.2, found 609.1; Retention time: 1.668 min.

[0203] Step 4: To a solution of benzyl N-[1-[4-[[(3S)-1-methyl-3-piperidyl]carbamoyl]-6- [4-(2,2,2-trifluoroethoxy)phenyl]-2-pyridyl]pyrazol-4-yl]carbamate (1.00 eq, 50 mg, 0.0822 mmol) in Methanol (10 mL) at rt was added Pd / C (1.00 eq, 8.7 mg, 0.0822 mmol), the reaction mixture was stirred at 25 ℃ for 2 h under H2 atmosphere. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by prep-HPLC (gradient of CH3CN / H2O containing 0.1%FA) to the title compound (4.7 mg, 0.00934 mmol, 11.4 %yield) as a white solid. LC purity: 95% (UV at 254 nm); Mass calculated for C23H25F3N6O2[M+1]+, 473.2, found 474.7; Retention time: 1.803 min.1HNMR(400 MHz, MeOD) δ 8.81 (s, 1H), 8.23 (d, J = 5.1 Hz, 2H), 8.14 (d, J = 12.2 Hz, 1H), 7.83 (s, 1H), 7.26 (t, J = 7.9 Hz, 1H), 7.19 (d,J = 8.8 Hz, 2H), 4.64 (dt, J = 8.4, 6.0 Hz, 2H), 4.33 (s, 1H), 3.75 (d, J =10.7 Hz, 1H), 3.55 (d, J = 13.2 Hz, 1H), 2.93 (d, J = 13.9 Hz, 4H), 2.14 (d, J = 13.9 Hz, 2H), 1.99 – 1.65 (m, 2H). Example 14. N-[(3S)-1-methyl-3-piperidyl]-2-(3-sulfamoylazetidin-1-yl)-6-[4-(2,2,2- trifluoroethoxy)phenyl]pyridine-4-carboxamide

[0204] Scheme 14.

[0205] Step 1: To a solution of 1-(4-methoxyphenyl)-N-[(4-methoxyphenyl)methyl] methanamine (1.00 eq, 101 mg, 0.391 mmol) in DCM (5 mL) at 0 °C was added TEA (3.00 eq, 0.16 mL, 1.17 mmol) and tert-butyl 3-chlorosulfonylazetidine-1-carboxylate (1.00 eq, 0.090 mL, 0.391 mmol). The mixture was stirred at ambient temperature for 30 min. Upon completion, the reaction mixture was purified by column chromatography on silica gel (PE: ethyl acetate=20~25%) to afford tert-butyl 3-[bis[(4- methoxyphenyl)methyl]sulfamoyl]azetidine-1-carboxylate (130 mg, 0.273 mmol, 69.8 % yield) as a white solid. LC purity: 95% (UV at 254 nm); Mass calculated for C19H24N2O4S [M-Boc+1]+, 377.2, found 377.3; Retention time: 1.676 min.

[0206] Step 2: To a solution of tert-butyl 3-[bis[(4-methoxyphenyl)methyl] sulfamoyl]azetidine-1-carboxylate (1.00 eq, 130 mg, 0.273 mmol) in CH3CN (2 mL) was added TsOH (1.00 eq, 47 mg, 0.273 mmol). The mixture was stirred at ambient temperature for 16 h. Upon completion, the reaction mixture was filtered and the filter cake was washed with DCM (2 mL), and dried in vacuo to afford N,N-bis[(4-methoxyphenyl)methyl]azetidine- 3-sulfonamide (80 mg, 0.213 mmol, 77.9 % yield) as a white solid. The product was used in the next step without further purification. LC purity: 80% (UV at 254 nm); Mass calculated for C19H24N2O4S [M+1]+, 377.2, found 377.3; Retention time: 0.842 min.

[0207] Step 3: To a solution of 2-chloro-N-[(3S)-1-methyl-3-piperidyl]-6-[4-(2,2,2- trifluoroethoxy)phenyl]pyridine-4-carboxamide (1.00 eq, 50 mg, 0.117 mmol) in 1,4-dioxane (3 mL) was added N,N-bis[(4-methoxyphenyl)methyl]azetidine-3-sulfonamide (1.20 eq, 53 mg, 0.140 mmol), Cs2CO3 (2.00 eq, 76 mg, 0.234 mmol), RuPhos (0.200 eq, mg, 0.0234 mmol) and RuPhos-Pd-G3 (0.100 eq, mg, 0.0117 mmol). The reaction mixture was stirred at 100 °C for 2h under N2atmosphere. Upon completion, the reaction mixture was quenched with sat. NH4Cl solution (5 mL), and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (MeOH in DCM=0~10%) to afford 2-[3-[bis[(4-methoxyphenyl)methyl]sulfamoyl]azetidin-1-yl]-N- [(3S)-1-methyl-3-piperidyl]-6-[4-(2,2,2-trifluoroethoxy)phenyl]pyridine-4-carboxamide (50 mg,0.0651 mmol, 55.7 % yield) as a white solid. LC purity: 90% (UV at 254 nm); Mass calculated for C39H44F3N5O6S [M+1]+, 768.3, found 768.2; Retention time: 1.803 min.

[0208] Step 4: A solution of 2-[3-[bis[(4-methoxyphenyl)methyl]sulfamoyl]azetidin-1-yl]- N-[(3S)-1-methyl-3-piperidyl]-6-[4-(2,2,2-trifluoroethoxy)phenyl]pyridine-4-carboxamide (1.00 eq, 40 mg, 0.0521 mmol) in TFA (100 eq, 0.40 mL, 5.21 mmol) was stirred at 25 °C for 2 h under N2 atmosphere. Upon completion, the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (gradient of CH3CN / H2O containing 0.1%FA) to afford the title compound (3.9 mg, 0.00737 mmol, 14.0 % yield) as a white solid. LC purity: 95% (UV at 254 nm); Mass calculated for C23H28F3N5O4S [M+1]+, 528.2, found 527.7; Retention time: 1.803 min.1HNMR(400 MHz, MeOD) δ 8.40 (s, 1H), 8.05 (d, J = 8.8 Hz, 2H), 7.49 (s, 1H), 7.10 (d, J = 8.9 Hz, 2H), 6.73 (s, 1H), 4.59 (q, J = 8.5 Hz, 2H), 4.43 (t, J = 8.6 Hz, 2H), 4.35 (dd, J = 8.8, 5.3 Hz, 2H), 4.27 (dd, J =13.6, 8.3 Hz, 2H), 3.33 (s, 1H), 3.13 (s, 1H), 2.68 (s, 5H), 2.01 (d, J = 4.0 Hz, 2H), 1.73 (dd, J = 71.9, 10.7 Hz, 2H).Example 15. N-[3-(2-Methyl-1-piperidyl)propyl]-2-(1-methylpyrazol-4-yl)-6-[4-(2,2,2- trifluoroethoxy)phenyl]pyridine-4-carboxamide

[0209] The title compound was made in an analogous fashion to the procedure described in Example 1 in 44.3 % yield. Mass calculated for C27H32F3N5O2 [M+1]+, 516.6, found 516.6;1H NMR (400 MHz, CDCl3) δ 8.29 (s, 1H), 8.10 – 8.05 (m, 4H), 7.93 (s, 1H), 7.81 (s, 1H), 6.98 (d, J = 8.9 Hz, 2H), 4.36 (q, J = 8.1 Hz, 2H), 3.90 (s, 3H), 3.54 (d, J = 5.4 Hz, 2H), 3.30 (s, 3H), 2.94 (d, J = 6.3 Hz, 2H), 2.12 (d, J = 6.1 Hz, 2H), 1.93 – 1.81 (m, 3H), 1.79 – 1.70 (m, 2H), 1.54 (s, 1H), 1.32 (d, J = 6.4 Hz, 3H). Example 16.2-(2-aminopyrimidin-5-yl)-N-(1-methyl-3-piperidyl)-6-[4-(2,2,2- trifluoroethoxy)phenyl]pyridine-4-carboxamide

[0210] The title compound was made in an analogous fashion to the procedure described in Example 2 in 3.3 % yield. Mass calculated for C24H25F3N6O2 [M+1]+, 487.5, found 487.5;1H NMR (400 MHz, MeOD) δ: 9.12 (d, J = 4.8 Hz, 2H), 8.20 (d, J = 8.5 Hz, 2H), 8.08 (d, J = 27.8 Hz, 2H), 7.18 (d, J = 8.4 Hz, 2H), 4.63 (q, J = 8.4 Hz, 2H), 4.32 (s, 1H), 3.77 (d, J = 12.5 Hz, 1H), 3.56 (d, J = 12.1 Hz, 1H), 3.27 – 3.23 (m, 1H), 2.96 (s, 3H), 2.85 (d, J = 8.3 Hz, 1H), 2.15 (d, J = 14.7 Hz, 2H), 1.81 (dd, J = 75.0, 13.6 Hz, 2H). Example 17.2-(4-fluoropyrazol-1-yl)-N-(1-methyl-3-piperidyl)-6-[4-(2,2,2- trifluoroethoxy)phenyl]pyridine-4-carboxamide

[0211] The title compound was made in an analogous fashion to the procedure described in Example 5 in 9.0 % yield. Mass calculated for C23H23F4N5O2 [M+1]+, 478.6, found 478.6;1H NMR (400 MHz, MeOD) δ: 8.72 (s, 1H), 8.26 – 8.17 (m, 3H), 8.11 (s, 1H), 7.76 (d, J = 4.0 Hz, 1H), 7.18 (d, J = 7.3 Hz, 2H), 4.63 (q, J = 8.4 Hz, 2H), 4.42 – 4.21 (m, 1H), 3.83 – 3.70 (m, 1H), 3.61 – 3.50 (m, 1H), 3.13 – 2.94 (m, 4H), 2.93 – 2.82 (m, 1H), 2.24 – 2.07 (m, 2H), 1.97 – 1.84 (m, 1H), 1.82 – 1.60 (m, 1H). Example 18. N-(1-Methyl-3-piperidyl)-2-(1H-pyrazol-4-yl)-6-[4-(2,2,2- trifluoroethoxy)phenyl]pyridine-4-carboxamide

[0212] The title compound was made in an analogous fashion to the procedure described in Example 2 in 14.2 % yield. Mass calculated for C23H24F3N5O2 [M+1]+, 460.5, found 460.5;1H NMR (400 MHz, DMSO-d6) δ 9.68 (s, 1H), 8.87 (d, J = 7.6 Hz, 1H), 8.33 (s, 2H), 8.21 (d, J = 8.9 Hz, 2H), 7.99 (s, 1H), 7.89 (s, 1H), 7.23 (d, J = 8.9 Hz, 2H), 4.88 (d, J = 8.9 Hz, 2H), 4.21 (d, J = 7.6 Hz, 2H), 3.60 (d, J = 11.9 Hz, 1H), 3.45 (d, J = 12.5 Hz, 1H), 2.86 (d, J = 4.4 Hz, 3H), 2.82 – 2.73 (m, 1H), 2.00 (d, J = 12.0 Hz, 2H), 1.80 – 1.69 (m, 1H), 1.58 (dd, J = 22.2, 12.7 Hz, 1H). Example 19.2-(3-hydroxy-3-methyl-azetidin-1-yl)-N-(1-methyl-3-piperidyl)-6-[4-(2,2,2- trifluoroethoxy)phenyl]pyridine-4-carboxamide

[0213] The title compound was made in an analogous fashion to the procedure described in Example 7 in 14.3 % yield. Mass calculated for C24H29F3N4O3 [M+1]+, 479.5, found 479.5;1H NMR (400 MHz, MeOD) δ: 8.13 – 7.95 (m, 2H), 7.43 (d, J = 1.0 Hz, 1H), 7.09 (d, J = 8.9 Hz, 2H), 6.68 (d, J = 1.0 Hz, 1H), 4.59 (q, J = 8.5 Hz, 2H), 4.22 – 4.12 (m, 1H), 4.00 (dd, J = 21.8, 8.5 Hz, 4H), 3.05 (d, J = 12.5 Hz, 1H), 2.91 – 2.73 (m, 1H), 2.43 (s, 3H), 2.31 (d, J = 7.8 Hz, 2H), 1.99 – 1.83 (m, 2H), 1.71 (tt, J = 13.9, 7.0 Hz, 1H), 1.61 – 1.47 (m, 4H). Example 20.2-[ -3-hydroxypyrrolidin-1-yl]-N-(1-methyl-3-piperidyl)-6-[4-(2,2,2-pyridine-4-carboxamide

[0214] The title compound was made in an analogous fashion to the procedure described in Example 7 in 20.1 % yield. Mass calculated for C24H29F3N4O3 [M+1]+, 479.5, found 479.5;1H NMR (400 MHz, MeOD) δ: 8.48 (s, 1H), 8.08 (d, J = 8.7 Hz, 2H), 7.36 (s, 1H), 7.08 (d, J = 8.7 Hz, 2H), 6.74 (s, 1H), 4.59 (dd, J = 16.9, 8.4 Hz, 3H), 4.23 (s, 1H), 3.80 – 3.53 (m, 4H), 3.24 (d, J = 4.3 Hz, 1H), 3.01 (d, J = 6.4 Hz, 1H), 2.66 – 2.40 (m, 5H), 2.25 – 2.13 (m, 1H), 2.00 (t, J = 30.2 Hz, 3H), 1.79 (d, J = 10.7 Hz, 1H), 1.60 (d, J = 10.4 Hz, 1H). Example 21.2-(4-fluorophenyl)-N-(1-methyl-3-piperidyl)-6-[4-(2,2,2- trifluoroethoxy)phenyl]pyridine-4-carboxamide

[0215] The title compound was made in an analogous fashion to the procedure described in Example 2 in 21.7 % yield. Mass calculated for C26H25F4N3O2[M+1]+, 488.5, found 488.5;1H NMR (400 MHz, MeOD) δ: 8.30 – 8.19 (m, 4H), 8.12 (d, J = 5.8 Hz, 2H), 7.32 – 7.23 (m, 2H), 7.21 – 7.14 (m, 2H), 4.63 (q, J = 8.4 Hz, 2H), 4.33 (t, J = 11.9 Hz, 1H), 3.77 (d, J = 11.4 Hz, 1H), 3.63 – 3.46 (m, 1H), 3.15 – 2.80 (m, 5H), 2.15 (d, J = 14.8 Hz, 2H), 1.91 (dd, J = 27.9, 14.0 Hz, 1H), 1.72 (dd, J = 21.3, 12.4 Hz, 1H). Example 22. N-[(3R)-1-methyl-3-piperidyl]-2-(1-methylpyrazol-4-yl)-6-[4-(2,2,2- trifluoroethoxy)phenyl]pyridine-4-carboxamide

[0216] The title compound was made in an analogous fashion to the procedure described in Example 2 in 29.4 % yield. Mass calculated for C24H26F4N5O2[M+1]+, 473.5, found 473.5;1H NMR (400 MHz, MeOD) δ: 8.30 (s, 1H), 8.21 – 8.08 (m, 3H), 7.99 (s, 1H), 7.89 (s, 1H), 7.15 (d, J = 8.9 Hz, 2H), 4.65 – 4.58 (m, 2H), 4.32 (t, J = 10.0 Hz, 1H), 3.98 (s, 3H), 3.51 (d, J = 11.0 Hz, 1H), 3.34 (d, J = 7.7 Hz, 1H), 2.86 (d, J = 34.0 Hz, 5H), 2.09 (d, J = 10.8 Hz, 2H), 1.94 – 1.82 (m, 1H), 1.79 – 1.6 (m, 1H). Example 23. N-[(3S)-1-methyl-3-piperidyl]-2-(1-methylpyrazol-4-yl)-6-[4-(2,2,2- trifluoroethoxy)phenyl]pyridine-4-carboxamide

[0217] The title compound was made in an analogous fashion to the procedure described in Example 2 in 31.4 % yield. Mass calculated for C24H26F4N5O2 [M+1]+, 474.5, found 474.5;1H NMR (400 MHz, MeOD) δ: 8.30 (s, 1H), 8.20 – 8.11 (m, 3H), 7.99 (s, 1H), 7.89 (s, 1H), 7.15 (d, J = 8.8 Hz, 2H), 4.65 – 4.59 (m, 2H), 4.31 (t, J = 9.8 Hz, 1H), 3.98 (s, 3H), 3.47 (s, 1H), 3.25 (d, J = 6.9 Hz, 1H), 2.83 (d, J = 29.5 Hz, 5H), 2.08 (d, J = 10.6 Hz, 2H), 1.87 (dd, J = 11.2, 3.8 Hz, 1H), 1.78 – 1.67 (m, 1H). Example 24.2-[1-(difluoromethyl)pyrazol-4-yl]-N-(1-methyl-3-piperidyl)-6-[4-(2,2,2- trifluoroethoxy)phenyl]pyrimidine-4-carboxamide

[0218] The title compound was made in an analogous fashion to the procedure described in Example 4 in 9.4 % yield. Mass calculated for C23H23F5N6O2 [M+1]+, 511.5, found 511.5;1H NMR (400 MHz, MeOD) δ: 9.59 (s, 1H), 9.20 (s, 1H), 9.05 (d, J = 8.3 Hz, 1H), 8.71 (s, 1H), 8.42 (d, J = 8.2 Hz, 2H), 8.27 (s, 1H), 7.95 (t, J = 58.8 Hz, 1H), 7.24 (d, J = 8.7 Hz, 2H), 4.91 (q, J = 8.9 Hz, 2H), 3.61 – 3.52 (m, 1H), 2.88-2.80 (m, 4H), 2.65 (s, 1H), 2.31 (s, 1H), 2.01 – 1.67 (m, 5H). Example 25.2-(1,5-dimethylpyrazol-4-yl)-N-(1-methyl-3-piperidyl)-6-[4-(2,2,2- trifluoroethoxy)phenyl]pyrimidine-4-carboxamide

[0219] The title compound was made in an analogous fashion to the procedure described in Example 4 in 33.0 % yield. Mass calculated for C24H27F3N6O2 [M+1]+, 489.5, found 489.5;1H NMR (400 MHz, DMSO-d6) δ: 9.58 (s, 1H), 8.42 (s, 1H), 8.29 (d, J = 8.6 Hz, 2H), 8.11 (s, 1H), 7.24 (d, J = 8.5 Hz, 2H), 4.88 (q, J = 8.6 Hz, 2H), 4.32-4.16 (m, 1H), 3.82 (s, 3H), 3.50 (s, 1H), 3.02 – 2.89 (m, 2H), 2.87 – 2.77 (m, 6H), 1.98-1.63 (m, 5H). Example 26.2-(1,3-dimethylpyrazol-4-yl)-N-(1-methyl-3-piperidyl)-6-[4-(2,2,2- trifluoroethoxy)phenyl]pyrimidine-4-carboxamide

[0220] The title compound was made in an analogous fashion to the procedure described in Example 4 in 16 % yield. Mass calculated for C24H27F3N6O2[M+1]+, 489.5, found 489.5;1H NMR (400 MHz, DMSO-d6) δ: 9.55 (s, 1H), 8.77 (d, J = 8.3 Hz, 1H), 8.56 (s, 1H), 8.28 (d, J = 8.7 Hz, 2H), 8.08 (s, 1H), 7.20 (d, J = 8.5 Hz, 2H), 4.85 (q, J = 8.6 Hz, 2H), 4.23 – 4.14 (s, 1H), 3.82 (s, 3H), 2.82 – 2.74 (m, 4H), 2.62 – 2.56 (m, 4H), 1.95 – 1.61 (m, 5H). Example 27.2-(3-aminopyrazol-1-yl)-N-(1-methyl-3-piperidyl)-6-[4-(2,2,2- trifluoroethoxy)phenyl]pyridine-4-carboxamide

[0221] The title compound was made in an analogous fashion to the procedure described in Example 5 in 3.6 % yield. Mass calculated for C23H25F3N6O2 [M+1]+, 475.5, found 475.5;1H NMR (400 MHz, MeOD) δ: 8.50 (d, J = 2.7 Hz, 1H), 8.17 (d, J = 8.9 Hz, 2H), 7.93 (d, J = 9.2 Hz, 2H), 7.15 (d, J = 8.9 Hz, 2H), 5.97 (d, J = 2.7 Hz, 1H), 4.66 – 4.60 (m, 2H), 4.26 (dd, J = 9.0, 5.1 Hz, 1H), 3.38 (d, J = 9.4 Hz, 1H), 3.13 (d, J = 1.6 Hz, 1H), 2.70 (s, 3H), 2.01 (dd, J = 14.1, 10.1 Hz, 2H), 1.83 (dd, J = 11.1, 3.6 Hz, 1H), 1.66 (d, J = 10.4 Hz, 1H), 1.41 – 1.29 (m, 2H). Example 28.2-(1,3-dimethylpyrazol-4-yl)-N-(1-methyl-3-piperidyl)-6-[4-(2,2,2- trifluoroethoxy)phenyl]pyridine-4-carboxamide

[0222] The title compound was made in an analogous fashion to the procedure described in Example 2 in 12.9 % yield. Mass calculated for C25H28F3N5O2 [M+1]+, 488.5, found 488.5;1H NMR (400 MHz, MeOD) δ: 8.21 – 8.10 (m, 3H), 7.97 (s, 1H), 7.80 (s, 1H), 7.15 (d, J = 8.9 Hz, 2H), 4.62 (q, J = 8.4 Hz, 2H), 4.22 (dd, J = 11.6, 7.4 Hz, 1H), 3.90 (s, 3H), 3.13 (s, 1H), 2.86 (s, 1H), 2.64 (s, 3H), 2.47 (s, 3H), 2.39 (s, 2H), 2.05 – 1.85 (m, 2H), 1.83 – 1.68 (m, 1H), 1.57 (d, J = 10.1 Hz, 1H). Example 29.2-(1,5-dimethylpyrazol-4-yl)-N-(1-methyl-3-piperidyl)-6-[4-(2,2,2- trifluoroethoxy)phenyl]pyridine-4-carboxamide

[0223] The title compound was made in an analogous fashion to the procedure described in Example 2 in 8.8 % yield. Mass calculated for C25H28F3N5O2[M+1]+, 488.5, found 488.5;1H NMR (400 MHz, DMSO-d6) δ: 8.17 (t, J = 9.6 Hz, 2H), 8.04 (s, 2H), 7.89 (s, 1H), 7.23(d, J = 8.9 Hz, 2H), 4.87 (q, J = 8.8 Hz, 2H), 4.11 (s, 1H), 3.82 (s, 3H), 3.02 (d, J = 76.9 Hz, 2H), 2.73 (s, 3H), 2.50 – 2.42 (m, 5H), 1.95 – 1.39 (m, 4H). Example 30.2-(1-methylpyrazol-4-yl)-N-[(3R)-1-methylpyrrolidin-3-yl]-6-[4-(2,2,2- trifluoroethoxy)phenyl]pyridine-4-carboxamide

[0224] The title compound was made in an analogous fashion to the procedure described in Example 2 in 15.4 % yield. Mass calculated for C23H24F3N5O2[M+1]+, 460.5, found 460.5;1H NMR (400 MHz, MeOD) δ: 8.29 (s, 1H), 8.17 (d, J = 8.9 Hz, 2H), 8.12 (s, 1H), 7.99 (d, J = 1.2 Hz, 1H), 7.88 (d, J = 1.2 Hz, 1H), 7.15 (d, J = 8.9 Hz, 2H), 4.68 (d, J = 7.8 Hz, 1H), 4.62 (q, J = 8.5 Hz, 2H), 3.98 (s, 3H), 3.75 – 3.58 (m, 2H), 3.53 – 3.44 (m, 1H), 3.39 – 3.32 (m, 1H), 2.95 (s, 3H), 2.58 (dd, J = 14.1, 5.9 Hz, 1H), 2.28 (dd, J = 13.6, 5.4 Hz, 1H). Example 31.2-(1-methylpyrazol-4-yl)-N-[ -1-methylpyrrolidin-3-yl]-6-[4-(2,2,2-trifluoroethoxy)phenyl]pyridine-4-

[0225] The title compound was made in an analogous fashion to the procedure described in Example 2 in 63.8 % yield. Mass calculated for C23H24F3N5O2[M+1]+, 460.5, found 460.5;1H NMR (400 MHz, MeOD) δ: δ 10.04 (d, J = 28.4 Hz, 1H), 9.04 (dd, J = 33.8, 6.0 Hz, 1H), 8.22 (d, J = 8.9 Hz, 2H), 8.12 (d, J = 2.3 Hz, 1H), 8.02 (d, J = 6.1 Hz, 1H), 7.86 (d, J = 4.8 Hz, 1H), 7.22 (d, J = 8.8 Hz, 2H), 4.88 (q, J = 8.9 Hz, 2H), 4.66 (m, 1H), 3.93 (s, 3H), 3.80 – 3.59 (m, 2H), 3.44 – 3.25 (m, 1H), 3.17 – 3.07 (m, 1H), 2.92 (dd, J = 15.8, 4.5 Hz, 3H), 2.54 (s, 1H), 2.33 – 2.15 (m, 1H)Example 32.2-((S)-3-hydroxypyrrolidin-1-yl)-N-((R)-1-methylpiperidin-3-yl)-6-(4- (2,2,2-trifluoroethoxy)phenyl)isonicotinamid

[0226] The title compound was made in an analogous fashion to the procedure described in Example 7 in 15.2 % yield. Mass calculated for C24H29F3N4O3[M+1]+, 479.5, found 479.5;1H NMR (400 MHz, DMSO-d6) δ: 9.59 (s, 1H), 8.70 (d, J = 7.6 Hz, 1H), 8.07 (d, J = 8.7 Hz, 2H), 7.39 (s, 1H), 7.17 (d, J = 8.4 Hz, 2H), 6.69 (s, 1H), 4.84 (q, J = 8.9 Hz, 2H), 4.43 (s, 1H), 4.22 – 4.11 (m, 1H), 2.90 – 2.81 (m, 5H), 2.79 – 2.69 (m, 1H), 2.67 (s, 1H), 2.33 (s, 1H), 2.10 – 1.51 (m, 8H). Example 33. (R)-2-(3-hydroxyazetidin-1-yl)-N-(1-methylpiperidin-3-yl)-6-(4-(2,2,2- trifluoroethoxy)phenyl)isonicotinamide

[0227] The title compound was made in an analogous fashion to the procedure described in Example 7 in 23.1 % yield. Mass calculated for C23H27F3N4O3[M+1]+, 465.5, found 465.5;1H NMR (400 MHz, DMSO-d6) δ: 9.41 (s, 1H), 8.54 (d, J = 7.5 Hz, 1H), 7.86 (d, J = 8.6 Hz, 2H), 7.28 (s, 1H), 6.99 (d, J = 8.5 Hz, 2H), 6.46 (s, 1H), 4.66 (q, J = 8.8 Hz, 2H), 4.48 – 4.42 (m, 1H), 4.09 (t, J = 7.6 Hz, 2H), 4.04 – 3.93 (s, 1H), 3.62 – 3.55 (m, 3H), 2.75 – 2.61 (m, 4H), 2.04 – 1.20 (m, 4H). Example 34. (R)-2-(5-formyl-1-methyl-1H-pyrazol-4-yl)- (1-methylpiperidin-3-yl)-6-(4-(2,2,2-trifluoroethoxy)phenyl)isonicotinamide

[0228] The title compound was made in an analogous fashion to the procedure described in Example 2 in 41.0 % yield. Mass calculated for C25H26F3N5O3 [M+1]+, 502.2, found 502.2;1H NMR (400 MHz, DMSO-d6) δ: 10.58 (s, 1H), 9.53 (s, 1H), 8.85 (d, J = 7.4 Hz, 1H), 8.20 – 7.99 (m, 5H), 7.17 (d, J = 8.4 Hz, 2H), 4.79 (q, J = 8.9 Hz, 2H), 4.16-4.03 (s, 4H), 3.50 (d, J = 12.6 Hz, 2H), 2.87 – 2.67 (m, 5H), 1.90 (d, J = 12.9 Hz, 2H), 1.80 – 1.41 (m, 2H). Example 35.2-((S)-3-hydroxypyrrolidin-1-yl)-N-((S)-1-methylpiperidin-3-yl)-6-(4-(2,2,2- trifluoroethoxy)phenyl)isonicotinamide

[0229] The title compound was made in an analogous fashion to the procedure described in Example 7 in 15.5% yield. Mass calculated for C24H29F3N4O3[M+1]+, 479.5, found 479.5;1H NMR (400 MHz, DMSO-d6) δ: 9.58 (s, 1H), 8.70 (d, J = 7.7 Hz, 1H), 8.07 (d, J = 8.7 Hz, 2H), 7.40 (s, 1H), 7.17 (d, J = 8.4 Hz, 2H), 6.69 (s, 1H), 4.84 (q, J = 8.8 Hz, 2H), 4.43 (s, 1H), 4.16 (s, 2H), 2.85 (d, J = 4.9 Hz, 5H), 2.67 (s, 1H), 2.33 (s, 1H), 2.10 – 1.52 (m, 9H). Example 36. (R)-2-(2-aminopyrimidin-5-yl)-N-(1-methylpiperidin-3-yl)-6-(4-(2,2,2- trifluoroethoxy)phenyl)isonicotinamide

[0230] The title compound was made in an analogous fashion to the procedure described in Example 11 in 25.8 % yield. Mass calculated for C24H25F3N6O2 [M+1]+, 487.5, found 487.5;1H NMR (400 MHz, MeOD) δ: 9.16 (s, 2H), 8.20 (d, J = 8.8 Hz, 2H), 8.13 (s, 1H), 8.07 (s, 1H), 7.17 (d, J = 8.9 Hz, 2H), 4.63 (q, J = 8.4 Hz, 2H), 4.39 – 4.25 (m, 1H), 3.83 – 3.71 (m, 1H), 3.61 – 3.52 (m, 1H), 3.01 – 2.93 (m, 4H), 2.87 (t, J = 11.7 Hz, 1H), 2.27 – 2.11 (m, 2H), 1.96 – 1.82 (m, 1H), 1.81 – 1.64 (m, 1H). Example 37. (S)-2-(4-methyl-1H-pyrazol-1-yl)-N-(1-methylpiperidin-3-yl)-6-(4-(2,2,2- trifluoroethoxy)phenyl)isonicotinamide

[0231] The title compound was made in an analogous fashion to the procedure described in Example 5 in 5.4% yield. MASS calculated for C24H26F3N5O2[M+1]+, 474.5, found 474.5;1H NMR (400 MHz, MeOD) δ 8.54 (s, 1H), 8.19 (d, J = 8.7 Hz, 2H), 8.11 (s, 1H), 8.05 (s, 1H), 7.63 (s, 1H), 7.17 (d, J = 8.8 Hz, 2H), 4.64 (q, J = 8.4 Hz, 2H), 4.32 (t, J = 11.9 Hz, 1H), 3.75 (d, J = 10.2 Hz, 1H), 3.56 (d, J = 11.5 Hz, 1H), 2.99 (d, J = 13.1 Hz, 1H), 2.95 (s, 3H), 2.89 (t, J = 11.7 Hz, 1H), 2.20 (s, 3H), 2.14 (d, J = 13.9 Hz, 2H), 1.90 (m, 1H), 1.72 (m, 1H). Example 38. (S)-2-(5-formyl-1-methyl-1H-pyrazol-4-yl)- (1-methylpiperidin-3-yl)-6-(4-(2,2,2-trifluoroethoxy)phenyl)isonicotinamide

[0232] The title compound was made in an analogous fashion to the procedure described in Example 2 in 22.0 % yield. MS calculated for C25H26F3N5O3 [M+1]+, 502.2, found 502.2;1H NMR (400 MHz, MeOD) δ:1H NMR (400 MHz, MeOD) δ 7.91-8.18 (m, 5H), 7.18 (m, 2H),6.21 (s, 1H), 4.64 (m, 2H), 4.32 (m, 1H), 3.95 (m, 2H), 3.75 (m, 1H), 3.56 (m, 1H), 2.85 (s, 3H), 2.80 (m, 1H), 2.14 (m, 2H), 2.02 (m, 1H), 1.85 (m, 1H), 1.65 (m, 1H), 1.27 (m, 1H). Example 39. (S)-2-(1,5-dimethyl-1H-pyrazol-4-yl)-N-(1-methylpiperidin-3-yl)-6-(4- (2,2,2-trifluoroethoxy)phenyl)isonicotinamide

[0233] The title compound was made in an analogous fashion to the procedure described in Example 2 in 5.2 % yield. Mass calculated for C25H26F3N5O3 [M+1]+, 488.5, found 488.5;1H NMR (400 MHz, MeOD) δ: 8.17 (m, 2H), 7.91 (s, 2H), 7.85 (s, 1H), 7.23 (m, 2H), 4.87 (q, J = 8.8 Hz, 2H), 4.11 (s, 1H), 3.82 (s, 3H), 3.02 (d, J = 76.9 Hz, 2H), 2.73 (s, 3H), 2.50 – 2.42 (m, 5H), 1.95 – 1.39 (m, 4H). Example 40. (S)-2-(3-hydroxyazetidin-1-yl)-N-(1-methylpiperidin-3-yl)-6-(4-(2,2,2- trifluoroethoxy)phenyl)isonicotinamide

[0234] The title compound was made in an analogous fashion to the procedure described in Example 7 in 18.4 % yield. Mass calculated for C23H27F3N4O3[M+1]+, 465.5, found 465.5;1H NMR (400 MHz, MeOD) δ: 7.95 (d, J = 8.3 Hz, 2H), 7.36 (s, 1H), 7.11 (d, J = 8.4 Hz, 2H), 6.74 (s, 1H), 4.76-4.70 (m, 1H), 4.62 – 4.56 (m, 2H), 4.40 (t, J = 7.8 Hz, 2H), 4.29 – 4.20 (m, 1H), 3.99 – 3.90 (m, 3H), 3.72 – 3.65 (m, 1H), 3.52 (d, J = 14.4 Hz, 1H), 2.97 – 2.88 (m, 4H), 2.80 (t, J = 11.7 Hz, 1H), 2.17 – 1.61 (m, 5H). Example 41. N-((3R,5S)-5-hydroxy-1-methylpiperidin-3-yl)-2-(1-methyl-1H-pyrazol-4- yl)-6-(4-(2,2,2-trifluoroethoxy)phenyl)isonicotinamide

[0235] The title compound was made in an analogous fashion to the procedure described in Example 2 in 47.5 % yield. Mass calculated for C24H26F3N5O3[M+1]+, 490.5, found 490.5;1H NMR (400 MHz, MeOD) δ: 8.28 (s, 1H), 8.15 (d, J = 8.9 Hz, 2H), 8.11 (s, 1H), 7.95 (d, J = 1.2 Hz, 1H), 7.83 (d, J = 1.2 Hz, 1H), 7.15 (d, J = 8.9 Hz, 2H), 4.65 – 4.59 (m, 2H), 4.38 (s, 1H), 4.04 (s, 1H), 3.97 (s, 3H), 3.11 (dd, J = 27.5, 10.7 Hz, 2H), 2.65 (s, 1H), 2.61 (s, 3H), 2.59 – 2.37 (m, 1H), 2.20 (d, J = 7.7 Hz, 1H), 1.72 (s, 1H). Example 42. (S)-2-(1-methyl-1H-pyrazol-4-yl)-N-(1-methylpiperidin-3-yl)-6-(4-(2,2,2- trifluoroethoxy)phenyl)pyridine-4-sulfonamide

[0236] The title compound was made in an analogous fashion to the procedure described in Example 12 in 28.0 % yield. Mass calculated for C23H26F3N5O3S [M+1]+, 510.5, found 510.5;1H NMR (400 MHz, MeOD) δ: 8.34 (s, 1H), 8.17 (d, J = 8.8 Hz, 2H), 8.14 (s, 1H), 7.97 (s, 1H), 7.84 (s, 1H), 7.17 (d, J = 8.8 Hz, 2H), 4.64 (q, J = 8.4 Hz, 2H), 3.98 (s, 3H), 3.42 (s, 1H), 3.15 (d, J = 12.3 Hz, 1H), 2.96 (d, J = 11.4 Hz, 1H), 2.55 (s, 3H), 2.53 – 2.43 (m, 1H), 1.88 – 1.70 (m, 2H), 1.70 – 1.52 (m, 1H), 1.45 – 1.27 (m, 1H). Example 43. (R)-6'-amino-N-(1-methylpiperidin-3-yl)-6-(4-(2,2,2- trifluoroethoxy)phenyl)-[2,3'-bipyridine]-4-carboxamide

[0237] The title compound was made in an analogous fashion to the procedure described in Example 11 in 11.4 % yield. Mass calculated for C25H26F3N5O2 [M+1]+, 486.5, found 486.5;1H NMR (400 MHz, MeOD) δ: 9.08 (s, 2H), 8.20 (d, J = 8.9 Hz, 2H), 8.09 (s, 1H), 8.03 (s, 1H), 7.18 (d, J = 8.9 Hz, 2H), 4.64 (q, J = 8.4 Hz, 2H), 3.49 – 3.38 (m, 1H), 3.18 – 3.09 (m, 1H), 3.01 – 2.88 (m, 1H), 2.64 – 2.35 (m, 5H), 1.88 – 1.70 (m, 2H), 1.67 – 1.55 (m, 1H), 1.40 – 1.27 (m, 1H). Example 44. N-((3S,5R)-5-hydroxy-1-methylpiperidin-3-yl)-2-(1-methyl-1H-pyrazol-4- yl)-6-(4-(2,2,2-trifluoroethoxy)phenyl)isonicotinamide

[0238] The title compound was made in an analogous fashion to the procedure described in Example 2 in 42.8 % yield. Mass calculated for C24H26F3N5O3 [M+1]+, 490.5, found 490.5;1H NMR (400 MHz, MeOD) δ: 9.08 (s, 2H), 8.40 (s, 1H), 8.20 (d, J = 8.9 Hz, 2H), 8.09 (s, 1H), 8.03 (s, 1H), 7.18 (d, J = 8.9 Hz, 2H), 4.64 (q, J = 8.4 Hz, 2H), 3.49 – 3.38 (m, 1H), 3.18 – 3.09 (m, 1H), 3.01 – 2.88 (m, 1H), 2.64 – 2.35 (m, 5H), 1.88 – 1.70 (m, 2H), 1.67 – 1.55 (m, 1H), 1.40 – 1.27 (m, 1H). Example 45. (R)-2-(2-aminopyrimidin-5-yl)-N-(1-methylpiperidin-3-yl)-6-(4-(2,2,2- trifluoroethoxy)phenyl)pyridine-4-sulfonamide

[0239] The title compound was made in an analogous fashion to the procedure described in Example 12 in 47.1 % yield. Mass calculated for C23H25F3N6O3S [M+1]+, 523.5, found 523.5;1H NMR (400 MHz, MeOD) δ: 9.08 (s, 2H), 8.20 (d, J = 8.9 Hz, 2H), 8.09 (s, 1H), 8.03 (s, 1H), 7.18 (d, J = 8.9 Hz, 2H), 4.64 (q, J = 8.4 Hz, 2H), 3.49 – 3.38 (m, 1H), 3.18 – 3.09 (m, 1H), 3.01 – 2.88 (m, 1H), 2.64 – 2.35 (m, 5H), 1.88 – 1.70 (m, 2H), 1.67 – 1.55 (m, 1H), 1.40 – 1.27 (m, 1H). Example 46. (R)-2-(1-methyl-1H-pyrazol-4-yl)-N-(1-methylpiperidin-3-yl)-6-(4-(2,2,2- trifluoroethoxy)phenyl)pyridine-4-sulfonamide

[0240] The title compound was made in an analogous fashion to the procedure described in Example 12 in 50.6 % yield. Mass calculated for C23H26F3N5O3S [M+1]+, 510.5, found 510.5;1H NMR (400 MHz, MeOD) δ: 8.34 (s, 1H), 8.17 (d, J = 8.8 Hz, 2H), 8.14 (s, 1H), 7.97 (d, J = 1.0 Hz, 1H), 7.84 (d, J = 1.0 Hz, 1H), 7.17 (d, J = 8.9 Hz, 2H), 4.63 (q, J = 8.4 Hz, 2H), 3.98 (s, 3H), 3.50 – 3.37 (m, 1H), 3.13 (d, J = 7.9 Hz, 1H), 2.94 (d, J = 11.6 Hz, 1H), 2.60 – 2.35 (m, 5H), 1.86 – 1.70 (m, 2H), 1.65 – 1.54 (m, 1H), 1.41 – 1.27 (m, 1H). Example 47. (S)-6'-amino-N-(1-methylpiperidin-3-yl)-6-(4-(2,2,2- trifluoroethoxy)phenyl)-[2,3'-bipyridine]-4-carboxamide

[0241] The title compound was made in an analogous fashion to the procedure described in Example 11 in 23.3 % yield. Mass calculated for C25H26F3N5O2[M+1]+, 486.5, found 486.5;1H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J = 2.3 Hz, 1H), 8.55 (d, J = 7.9 Hz, 1H), 8.24 (dd, J = 12.8, 5.7 Hz, 3H), 8.05 (d, J = 5.4 Hz, 2H), 7.22 (d, J = 8.9 Hz, 2H), 6.58 (d, J = 8.7 Hz, 1H), 6.36 (s, 2H), 4.86 (t, J = 8.9 Hz, 2H), 4.00 (d, J = 7.6 Hz, 1H), 2.88 (d, J = 7.8 Hz, 1H), 2.69 (d, J = 10.6 Hz, 2H), 2.21 (s, 3H), 1.87 (d, J = 8.9 Hz, 2H), 1.73 (d, J = 13.2 Hz, 1H), 1.55 (d, J = 11.9 Hz, 1H), 1.34 (dd, J = 11.6, 3.4 Hz, 1H). Example 48. (S)-2-(1,5-dimethyl-1H-pyrazol-4-yl)-N-(1-methylpiperidin-3-yl)-6-(4- (2,2,2-trifluoroethoxy)phenyl)pyrimidine-4-carboxamide

[0242] The title compound was made in an analogous fashion to the procedure described in Example 4 in 24.4% yield. Mass calculated for C24H27F3N6O2 [M+1]+, 489.5, found 489.5;1H NMR (400 MHz, MeOD) δ: 8.39 (s, 1H), 8.28 (d, J = 6.7 Hz, 2H), 8.19 (s, 1H), 7.19 (d, J = 7.7 Hz, 2H), 4.70 – 4.59 (m, 2H), 4.39 – 4.30 (m, 1H), 3.90 – 3.85 (m, 4H), 3.47 – 3.43 (m, 1H), 3.13 – 3.08 (m, 1H), 2.92 (s, 3H), 2.86 (s, 3H), 2.21- 1.52 (m, 5H) Example 49. (S)-2'-amino-N-(1-methylpiperidin-3-yl)-6-(4-(2,2,2- trifluoroethoxy)phenyl)-[2,5'-bipyrimidine]-4-carboxamide

[0243] The title compound was made in an analogous fashion to the procedure described in Example 4 in 22.0% yield. Mass calculated for C23H24F3N7O2 [M+1]+, 488.5, found 488.5;1H NMR (400 MHz, MeOD) δ: 9.46 (s, 2H), 8.41 – 8.23 (m, 3H), 7.22 (d, J = 8.5 Hz, 2H), 5.35- 5.30 (m, 1H), 4.67 (q, J = 8.3 Hz, 2H), 4.41-4.31 (m, 1H), 3.70-3.64 (m, 1H), 3.58-3.53 (m, 1H), 3.47 (s, 1H), 3.12 (s, 1H), 2.95 (s, 3H), 2.20-2.10 (m, 2H), 2.05-1.98 (m, 2H), 1.9-1.82 (m, 1H), 1.63-1.54 (s, 1H). Example 50. (R)-2-(2-aminopyrimidin-5-yl)-N-(piperidin-3-yl)-6-(4-(2,2,2- trifluoroethoxy)phenyl)isonicotinamide

[0244] The title compound was made in an analogous fashion to the procedure described in Example 11 in 60.7 % yield. Mass calculated for C23H23F3N6O2[M+1]+, 473.5, found 473.5;1H NMR (400 MHz, MeOD) δ: 9.07 (s, 2H), 8.19 (d, J = 8.8 Hz, 2H), 8.10 (s, 1H), 8.03 (s, 1H), 7.16 (d, J = 8.8 Hz, 2H), 4.63 (q, J = 8.4 Hz, 2H), 4.39 – 4.22 (m, 1H), 3.56 (dd, J = 12.3, 3.7 Hz, 1H), 3.36 (s, 1H), 2.97 (dd, J = 20.5, 8.9 Hz, 2H), 2.27 – 2.04 (m, 2H), 1.96 – 1.73 (m, 2H) Example 51. (S)-2-(2-aminopyrimidin-5-yl)-N-(piperidin-3-yl)-6-(4-(2,2,2- trifluoroethoxy)phenyl)isonicotinamide

[0245] The title compound was made in an analogous fashion to the procedure described in Example 11 in 64.2 % yield. Mass calculated for C23H23F3N6O2 [M+1]+, 473.5, found 473.5;1H NMR (400 MHz, MeOD) δ: 9.07 (s, 2H), 8.19 (d, J = 8.8 Hz, 2H), 8.10 (s, 1H), 8.03 (s, 1H), 7.16 (d, J = 8.8 Hz, 2H), 4.63 (q, J = 8.4 Hz, 2H), 4.38 – 4.25 (m, 1H), 3.58 (dd, J = 12.1, 3.5 Hz, 1H),3.36 (d, J = 12.8 Hz, 1H), 3.04 – 2.93 (m, 2H), 2.22 – 2.06 (m, 2H), 1.94 – 1.75 (m, 2H). Example 52. (S)-2-(4-amino-1H-pyrazol-1-yl)-N-(1-methylpiperidin-3-yl)-6-(4-(2,2,2- trifluoroethoxy)phenyl)isonicotinamide

[0246] The title compound was made in an analogous fashion to the procedure described in Example 13 in 11.4 % yield. Mass calculated for C23H25F3N6O2[M+1]+, 475.5, found 475.5;1H NMR (400 MHz, MeOD) δ: 8.81 (s, 1H), 8.23 (d, J = 5.1 Hz, 2H), 8.14 (d, J = 12.2 Hz, 1H), 7.83 (s, 1H), 7.26 (t, J = 7.9 Hz, 1H), 7.19 (d, J = 8.8 Hz, 2H), 4.64 (dt, J = 8.4, 6.0 Hz, 2H), 4.33 (s, 1H), 3.75 (d, J =10.7 Hz, 1H), 3.55 (d, J = 13.2 Hz, 1H), 2.93 (d, J = 13.9 Hz, 4H), 2.14 (d, J = 13.9 Hz, 2H), 1.99 – 1.65 (m, 2H). Example 53. (R)-N -[1-methylpiperidin3-yl]-2-(3-sulfamoylazetidin-1-yl)-6-[4-(2,2,2- trifluoroethoxy)phenyl]pyridine-4-carboxamide

[0247] The title compound was made in an analogous fashion to the procedure described in Example 14 in 36.8 % yield. Mass calculated for C23H28F3N5O4S [M+1]+, 528.5, found 528.5;1H NMR (400 MHz, MeOD) δ: 8.04 (d, J = 8.8 Hz, 2H), 7.48 (s, 1H), 7.10 (d, J = 8.9 Hz, 2H), 6.73 (s, 1H), 4.60 (q, J = 8.5 Hz, 2H), 4.44 (t, J = 8.6 Hz, 2H), 4.39 – 4.33 (m, 2H), 4.33 – 4.22 (m, 2H), 3.77 – 3.66 (m, 1H), 3.60 – 3.50 (m, 1H), 2.99 – 2.90 (m, 4H), 2.84 (t, J = 11.7 Hz, 1H), 2.19 – 2.04 (m, 2H), 1.97 – 1.81 (m, 1H), 1.76 – 1.60 (m, 1H). Example 54. (S)-6-(2-aminopyrimidin-5-yl)-N-(piperidin-3-yl)-6'-(2,2,2-trifluoroethoxy)- [2,3'-bipyridine]-4-sulfonamide

[0248] Scheme 15

[0249] Step 1: Tert-butyl (S)-3-((2,6-dichloropyridine)-4-sulfonamido)piperidine-1- carboxylate was synthesized according to General Procedure I using tert-butyl (S)-3- aminopiperidine-1-carboxylate (367 mg, 1.83 mmol). The crude product was purified by column chromatography on silica gel (PE in EtOAc =60%) to afford a yellow solid (410 mg,1.0 mmol, 82.1% yield). LC purity: 92% (UV at 254 nm); Mass calculated for C15H21Cl2N3O4S [M+1]+, 410.0, found 410.0; Retention time: 0.602 min.

[0250] Step 2: Tert-butyl (S)-3-((2-(2-aminopyrimidin-5-yl)-6-chloropyridine)-4- sulfonamido)piperidine-1-carboxylate was synthesized according to General Procedure II using tert-butyl (S)-3-((2,6-dichloropyridine)-4-sulfonamido)piperidine-1-carboxylate (1.00 eq, 200 mg, 0.49 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2- amine (1.00 eq, 108 mg, 0.49 mmol) at 100 °C overnight. The crude product was purified by reversed phase flash chromatography (C18 silica) using a gradient of 20% to 70% ACN in water (with 10 mmol / L NH4HCO3) to afford a yellow solid (110 mg, 0.234 mmol, 48.1% yield). LC purity: 88% (UV at 254 nm); Mass calculated for C19H25ClN6O4S [M+1]+, 469.1, found 469.1; Retention time: 0.808 min.

[0251] Step 3: Tert-butyl (S)-3-((6-(2-aminopyrimidin-5-yl)-6'-(2,2,2-trifluoroethoxy)- [2,3'-bipyridine])-4-sulfonamido)piperidine-1-carboxylate was synthesized according to General Procedure II using tert-butyl (S)-3-((2-(2-aminopyrimidin-5-yl)-6-chloropyridine)- 4-sulfonamido)piperidine-1-carboxylate (1.00 eq, 100 mg, 0.21 mmol) and 5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (1.00 eq, 65 mg, 0.21 mmol) at 100 °C overnight. The crude product was purified by reversed phase flash chromatography (C18 silica) using a gradient of 20% to 70% ACN in water (with 10 mmol / L NH4HCO3) to afford a yellow solid (100 mg, 0.164 mmol, 76.9% yield). LC purity: 71% (UV at 254 nm); Mass calculated for C26H30F3N7O5S [M+1]+, 610.2, found 610.2; Retention time: 0.667 min.

[0252] Step 4: To a stirred solution of tert-butyl (S)-3-((6-(2-aminopyrimidin-5-yl)-6'- (2,2,2-trifluoroethoxy)-[2,3'-bipyridine])-4-sulfonamido)piperidine-1-carboxylate (1.00 eq, 95 mg, 0.16 mmol) in HFIP (2 mL) was added AlCl3(3.00 eq, 62 mg, 0.47 mmol) in several portions at 0 °C. The reaction was stirred at ambient temperature for 1 h under nitrogen atmosphere. Upon completion, the mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (conditions: Column: Xselect CSH Prep C18 OBD Column, 30X150 mm, 5 μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 8% B to 38% B in 8 min; Wavelength: 254 nm / 220 nm; RT1 (min): 7.3). The fraction was collected and concentrated in vacuo, and the residue was re-dissolved in CH3CN and H2O, and then waslyophilized to afford the title compound (12.8 mg, 0.025 mmol, 16.1% yield) as a white solid. LC purity: 99.8% (UV at 254 nm); Mass calculated for C24H27FN6O2 [M+1]+, 510.1, found 510.1; Retention time: 0.658 min.1H NMR (400 MHz, DMSO-d6) δ 9.10 (s, 2H), 9.05 (d, J = 2.5 Hz, 1H), 8.64 (dd, J = 8.7, 2.5 Hz, 1H), 8.30 (m, 1H), 8.16 (dd, J = 8.8, 1.3 Hz, 2H), 7.23 – 7.15 (m, 3H), 5.11 (q, J = 9.0 Hz, 2H), 3.20 (m, 2H), 2.84 (m, 1H), 2.71 (m, 1H), 2.37 (m, 2H), 1.69 (m, 1H), 1.55 (m, 1H), 1.31 (m, 2H). Example 55. (S)-2-(5-amino-6-fluoropyrazin-2-yl)-N-(piperidin-3-yl)-6-(4-(2,2,2- trifluoroethoxy)phenyl)pyridine-4-sulfonamide

[0253] Scheme 16

[0254] Step 1: To a solution of 3-chloro-5-iodo-pyrazin-2-amine (1.00 eq, 2 g, 7.83 mmol) in DMF (20 mL) was added sodium hydride (1.50 eq, 0.47 g, 11.75 mmol, 60% dispersion in mineral oil) at 0 °C in several portions under N2 atmosphere. The reaction was stirred at ambient temperature for 1 h. A solution of 4-methoxybenzyl chloride (1.00 eq, 1187 mg, 7.83 mmol) in DMF (20 mL) was added dropwise at 0 °C and the reaction was stirred at ambient temperature for 2 h. Upon completion, the mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was added DMSO, filtered and purified by reversed phase flash chromatography (C18 silica) using a gradient of 20% to 70%ACN in water (with 10 mmol / L NH4HCO3) to afford 3-chloro-5-iodo-N-[(4- methoxyphenyl)methyl]pyrazin-2-amine (1.20 g, 3.19 mmol, 40.8% yield) as a yellow solid. LC purity: 99.8% (UV at 254 nm); Mass calculated for C12H11ClIN3O [M+1]+, 376.0, found 376.0; Retention time: 1.096 min.

[0255] Step 2: To a solution of 3-chloro-5-iodo-N-[(4-methoxyphenyl)methyl]pyrazin-2- amine (1.00 eq, 1.20 g, 3.19 mmol) in DMSO (10 mL) were added DIEA (3.00 eq, 1.24 g, 9.58 mmol) and KF (1.50 eq, 278 mg, 4.79 mmol) at ambient temperature. The reaction was stirred at 120 °C overnight under N2atmosphere. Upon completion, the mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE / EtOAc, 1 / 1) to afford 3-fluoro-5- iodo-N-[(4-methoxyphenyl)methyl]pyrazin-2-amine (580 mg, 1.50 mmol, 47% yield) as a yellow solid. LC purity: 93.2% (UV at 254 nm); Mass calculated for C12H11FIN3O [M+1]+, 360.0, found 359.9; Retention time: 0.956 min.

[0256] Step 3: To a solution of 3-fluoro-5-iodo-N-[(4-methoxyphenyl)methyl]pyrazin-2- amine (1.00 eq, 470 mg, 1.31 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2- dioxaborolane) (4.00 eq, 1.33 g, 5.23 mmol) in 1,4-dioxane (5 mL) were added Pd(dppf)Cl2^DCM (0.20 eq, 214 mg, 0.26 mmol) and potassium acetate (3.00 eq, 385 mg, 3.93 mmol) at ambient temperature. The reaction was stirred overnight at 80 °C under N2atmosphere. The mixture was filtered, and the filtrate was concentrated in vacuo to afford the crude product which was used in next step directly without further purification.

[0257] Step 4: Tert-butyl (S)-3-((2-chloro-6-(4-(2,2,2-trifluoroethoxy)phenyl)pyridine)-4- sulfonamido)piperidine-1-carboxylate was synthesized according to General Procedure II using tert-butyl (S)-3-((2,6-dichloropyridine)-4-sulfonamido)piperidine-1-carboxylate (preparation in Example 55, Step 1, 1.00 eq, 200 mg, 0.49 mmol) and (4-(2,2,2- trifluoroethoxy)phenyl)boronic acid (1.00 eq, 107 mg, 0.49 mmol) at 80 °C for 2 h under N2 atmosphere. The crude product was purified by reversed-phase chromatography using a gradient of 20% to 70% ACN in water (with 10 mmol / L NH4HCO3) to afford a yellow solid (150 mg, 0.272 mmol, 55.9% yield). LC purity: 86% (UV at 254 nm); Mass calculated for C23H27ClF3N3O5S [M+1]+, 550, found 550; Retention time: 0.789 min.

[0258] Step 5: Tert-butyl (S)-3-((2-(6-fluoro-5-((4-methoxybenzyl)amino)pyrazin-2-yl)-6- (4-(2,2,2-trifluoroethoxy)phenyl)pyridine)-4-sulfonamido)piperidine-1-carboxylate wassynthesized according to General Procedure II using tert-butyl (S)-3-((2-chloro-6-(4-(2,2,2- trifluoroethoxy)phenyl)pyridine)-4-sulfonamido)piperidine-1-carboxylate (1.00 eq, 150 mg, 0.27 mmol) and 3-fluoro-N-(4-methoxybenzyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyrazin-2-amine (1.50 eq, 735 mg, 0.41 mmol) at 80 °C overnight under N2atmosphere. The crude product was purified by reversed phase flash chromatography (C18 silica) using a gradient of 20% to 70% ACN in water (with 10 mmol / L NH4HCO3) to afford a yellow solid (60 mg, 0.080 mmol, 29.5% yield). LC purity: 86.8% (UV at 254 nm); Mass calculated for C35H38F4N6O6S [M+1]+, 747.3, found 747.3; Retention time: 1.117 min.

[0259] Step 6: The title compound was synthesized according to Procedure III using tert- butyl (S)-3-((2-(6-fluoro-5-((4-methoxybenzyl)amino)pyrazin-2-yl)-6-(4-(2,2,2- trifluoroethoxy)phenyl)pyridine)-4-sulfonamido)piperidine-1-carboxylate (1.00 eq, 55 mg, 0.074 mmol). The crude product was purified by prep-HPLC (conditions: Column: Xselect CSH Prep C18 OBD Column, 30X150 mm, 5 μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 13% B to 43% B in 7 min; Wavelength: 254 nm / 220 nm; RT1 (min): 6.3). The fraction was collected and concentrated in vacuo, and the residue was re-dissolved in CH3CN and H2O, and then was lyophilized to afford a white solid (11 mg, 0.019 mmol, 25.9% yield). LC purity: 95.9% (UV at 254 nm); Mass calculated for C22H22F4N6O3S [M+1]+, 521.7, found 521.7; Retention time: 1.250 min.1H NMR (400 MHz, DMSO-d6) δ 9.02 (d, J = 4.7 Hz, 1H), 8.32 – 8.21 (m, 3H), 8.14 (s, 2H), 7.45 (s, 2H), 7.30 – 7.21 (m, 2H), 4.89 (q, J = 8.8 Hz, 2H), 3.19 – 3.06 (m, 1H), 2.83 (m, 1H), 2.71 (m, 1H), 2.32 (m, 2H), 1.66 (m, 1H), 1.56 – 1.51 (m, 1H), 1.29 (m, 2H). Example 56. -2-(5-aminopyrazin-2-yl)-3-fluoro-N-(1-methylpiperidin-3-yl)-6-(4-(2,2,2- phenyl)isonicotinamide

[0260] Scheme 17

[0261] Step 1: Methyl 2-(5-aminopyrazin-2-yl)-6-chloro-3-fluoroisonicotinate was synthesized according to General Procedure II using methyl 2,6-dichloro-3- fluoroisonicotinate (1.00 eq, 1 g, 4.46 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)pyrazin-2-amine (0.80 eq, 789 mg, 3.57 mmol) at 80 °C for 2 h under N2 atmosphere. The crude product was purified by reversed phase flash chromatography (C18 silica) using a gradient of 20% to 70% ACN in water (with 10 mmol / L NH4HCO3) to afford a yellow solid (480 mg, 1.696 mmol, 47.5% yield). LC purity: 84% (UV at 254 nm); Mass calculated for C11H8ClFN4O2[M+1]+283, found 283; Retention time: 0.812 min.

[0262] Step 2: Methyl 2-(5-aminopyrazin-2-yl)-3-fluoro-6-(4-(2,2,2- trifluoroethoxy)phenyl)isonicotinate was synthesized according to General Procedure II using methyl 2-(5-aminopyrazin-2-yl)-6-chloro-3-fluoroisonicotinate (1.00 eq, 480 mg, 1.69 mmol) and (4-(2,2,2-trifluoroethoxy)phenyl)boronic acid (1.50 eq, 560 mg, 2.54 mmol) at 80 °C for 2 h under N2 atmosphere. The crude product was purified by reversed phase flash chromatography (C18 silica) using a gradient of 20% to 70% ACN in water (with 10 mmol / L NH4HCO3) to afford (400 mg, 0.164 mmol, 94.5% yield) a yellow solid (400 mg, 0.164 mmol, 94.5% yield). LC purity: 84% (UV at 254 nm); Mass calculated for C19H14F4N4O3 [M+1]+, 423.1, found 423; Retention time: 0.898 min.

[0263] Step 3: 2-(5-Aminopyrazin-2-yl)-3-fluoro-6-(4-(2,2,2- trifluoroethoxy)phenyl)isonicotinic acid was synthesized according to General Procedure IV using methyl 2-(5-aminopyrazin-2-yl)-3-fluoro-6-(4-(2,2,2- trifluoroethoxy)phenyl)isonicotinate (1.00 eq, 400 mg, 0.95 mmol). The crude product was purified by reversed phase flash chromatography (C18 silica) using a gradient of 20% to 50%ACN in water (with 10 mmol / L NH4HCO3) to afford (350 mg, 0.855 mmol, 90.6% yield) a light yellow solid. LC purity: 90% (UV at 254 nm); Mass calculated for C18H12F4N4O3 [M+1]+, 409.1, found 409; Retention time: 0.688 min.

[0264] Step 4: To a solution of 2-(5-aminopyrazin-2-yl)-3-fluoro-6-(4-(2,2,2- trifluoroethoxy)phenyl)isonicotinic acid (1.00 eq, 40 mg, 0.098 mmol) and (3S)-1- methylpiperidin-3-amine (3.00 eq, 34 mg, 0.29 mmol) in DMF (2 mL) were added NMI (3.00 eq, 24 mg, 0.29 mmol) and TCFH (1.50 eq, 41 mg, 0.15 mmol) at ambient temperature. The solution was stirred overnight at ambient temperature under N2atmosphere. The solution was filtered and purified directly by prep-HPLC (Column: Xbridge Prep OBD C18 Column, 30X150 mm, 5 μm; Mobile Phase A: Water (10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 24% B to 54% B in 10 min; Wavelength: 254 nm / 220 nm; RT1 (min): 8.65) to afford the title compound (16.1 mg, 0.032 mmol, 32.3% yield) as a white solid. LC purity: 99.3% (UV at 254 nm); Mass calculated for C24H24F4N6O2 [M+1]+, 505.2, found 505.2; Retention time: 1.400 min.1H NMR (400 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.59 (d, J = 8.0 Hz, 1H), 8.16 (d, J = 8.4 Hz, 2H), 8.00 (s, 1H), 7.94 (d, J = 3.6 Hz, 1H), 7.20 (d, J = 8.4 Hz, 2H), 6.90 (s, 2H), 4.86 (q, J = 8.9 Hz, 2H), 3.96 (m, 1H), 2.80 (m, 1H), 2.30 (m, 1H), 2.19 (s, 3H), 1.92 (m, 2H), 1.78 (m, 1H), 1.69 (m, 1H), 1.53 (m, 1H), 1.31 (m, 1H). Example 57. (R)-2-(2-aminopyrimidin-5-yl)-N-(1-methylpyrrolidin-3-yl)-6-(4-(2,2,2- trifluoroethoxy)phenyl)pyridine-4-sulfonamide

[0265] Scheme 18

[0266] Step 1: To a solution of 4-bromo-2,6-dichloro-pyridine (1.00 eq, 500 mg, 2.20 mmol) and benzyl mercaptan (1.02 eq, 0.27 mL, 2.25 mmol) in DMF (10 mL) were addedTEA (3 eq, 669 mg, 6.61 mmol), Pd2(dba)3(0.05 eq, 101 mg, 0.11 mmol) and xantphos (0.1 eq, 128 mg, 0.22 mmol). The reaction was stirred at 80 °C for 2 h under N2 atmosphere. Upon completion, the mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was added DMSO, filtered and purified via phase flash chromatography (C18 silica gel) using a gradient of 40% to 90% ACN in water (with 0.05%TFA) to afford 4-benzylsulfanyl-2,6-dichloro-pyridine (500 mg,1.85 mmol, 84.0% yield) as a yellow solid. LC purity: 90% (UV at 254 nm); Mass calculated for C12H9Cl2NS [M+1]+, 270.0, found 270.0; Retention time: 0.988 min.

[0267] Step 2: To a solution of 4-benzylsulfanyl-2,6-dichloro-pyridine (1.00 eq, 500 mg, 1.85 mmol) in acetic acid (9 mL) and water (1 mL) was added NCS (3.00 eq, 742 mg, 5.55 mmol) at 0 °C. The reaction was stirred at room temperature for 3 h under N2 atmosphere. Upon completion, the reaction was then quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, concentrated in vacuo to afford 2,6-dichloropyridine-4-sulfonyl chloride (450 mg, 1.83 mmol, 98.6% yield) as a light yellow oil. LC purity: 80% (UV at 220 nm); Mass calculated for Chemical Formula: C5H2Cl3NO2S [M+1]+, 245.9, found 226 (sulfonic acid); Retention time: 0.535 min.

[0268] Step 3: To a solution of KHF2 (2.00 eq, 285 mg, 3.65 mmol) in water (3mL), a solution of 2,6-dichloropyridine-4-sulfonyl chloride (1.00 eq, 450 mg, 1.83 mmol) and TBAC (0.10 eq, 51 mg, 0.18 mmol) in DCM (9 mL) was added dropwise. The reaction was stirred at 25 °C for 15 h under N2 atmosphere. The mixture was then quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, concentrated in vacuo. The residue was purified by column chromatography on silica gel with petroleum ether / dichloromethane (3 / 1) to afford 2,6- dichloropyridine-4-sulfonyl fluoride (113 mg, 1.03 mmol, 25.4% yield) as a light yellow oil. LC purity: 90% (UV at 254 nm); Mass calculated for Chemical Formula: C5H2Cl2FNO2S [M+1]+, 229.9, found 228 (sulfonic acid); Retention time: 0.482 min.

[0269] Step 4: To a solution of 2,6-dichloropyridine-4-sulfonyl fluoride (1.00 eq, 100 mg, 0.44 mmol), [4-(2,2,2-trifluoroethoxy)phenyl]boronic acid (0.80 eq, 76 mg, 0.35 mmol) and CsOAc (2.00 eq, 167 mg, 0.87 mmol) in THF (5 mL) was added Pd(dppf)Cl2(0.10 eq, 32 mg, 0.044 mmol) at ambient temperature. The reaction was stirred at 35 °C for 3 h under N2atmosphere. The solution was diluted with ethyl acetate. The solid was filtered out and the filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel with petroleum ether / ethyl acetate (6 / 1) to afford 2-chloro-6-[4-(2,2,2- trifluoroethoxy)phenyl]pyridine-4-sulfonyl fluoride (50 mg, 0.13 mmol, 29.6% yield) as a light yellow solid. LC purity: 95% (UV at 254 nm); Mass calculated for Chemical Formula: C13H8ClF4NO3S [M+1]+, 370.0, found 370.0; Retention time:1.052 min.

[0270] Step 5: To a solution of 2-chloro-6-[4-(2,2,2-trifluoroethoxy)phenyl]pyridine-4- sulfonyl fluoride (1.00 eq, 500 mg, 1.35 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyrimidin-2-amine (1.50 eq, 448 mg, 2.03 mmol) and K3PO4.7H2O (2.00 eq, 914 mg, 2.70 mmol) in THF (10 mL) was added Pd(dtbpf)Cl2(0.10 eq, 88 mg, 0.13 mmol). The reaction was stirred for overnight at ambient temperature under N2atmosphere. Upon completion, the mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford the crude product which was used for the next step directly without further purification. LC purity: 70% (UV at 254 nm); Mass calculated for C17H12F4N4O3S [M+1]+, 429.1, found 429.05; Retention time: 1.038 min.

[0271] Step 6: To a solution of 2-(2-aminopyrimidin-5-yl)-6-[4-(2,2,2- trifluoroethoxy)phen-yl]pyridine-4-sulfonyl fluoride (1.00 eq, 60 mg, 0.14 mmol), (R)-1- methylpyrrolidin-3-amine (2.00 eq, 28 mg, 0.280 mmol) and DABCO (1.5 eq, 24 mg, 0.21 mmol) in THF (5 mL) was added Ca(NTf2)2 (1.10 eq, 92 mg, 0.15 mmol). The reaction was stirred at ambient temperature for 3 h under N2atmosphere. Upon completion, the mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE / EtOAc, 1 / 2) to afford the crude product a yellow solid. The solid was then quenched with aq. NaOH (2 M) and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by Prep-HPLC (Column: Xselect CSH Prep C18 OBD Column, 30X150 mm, 5 μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 9% B to 39% B in 8 min; Wavelength: 254 nm / 220 nm; RT1 (min): 7.5). The fraction was collected and concentrated in vacuo, and the residue was re-dissolved in CH3CN and H2O, and then was lyophilized to afford the title compound to afford the title compound (5.2 mg, 0.010 mmol, 7.3% yield) as a white solid. LC purity: 99% (UV at 254 nm); Mass calculated forC22H23F3N6O3S [M+1]+, 509.2, found 509.1; Retention time:0.682 min.1H NMR (400 MHz, DMSO-d6) δ 9.09 (s, 2H), 8.23 (d, J = 8.6 Hz, 2H), 8.07 (d, J = 7.4 Hz, 2H), 7.25 (d, J = 8.5 Hz, 2H), 7.18 (s, 2H), 4.94 – 4.83 (m, 2H), 3.88 – 3.77 (m, 1H), 2.50 – 2.38 (m, 2H), 2.26 (m, 2H), 2.15 (s, 3H), 2.02 – 1.89 (m, 1H), 1.56 – 1.44 (m, 1H). Example 58. (S)-2-(5-aminopyrazin-2-yl)-6-(4-ethoxyphenyl)-3-fluoro-N-(1- methylpiperidin-3-yl)isonicotinamide

[0272] Scheme 19

[0273] Step 1: To a solution of 2-chloro-5-fluoro-pyridine-4-carboxylic acid (1.00 eq, 200 mg, 1.14 mmol) in MeOH (3 mL) was added SOCl2 (1.50 eq, 203 mg, 1.71 mmol) at 0 °C. The reaction was stirred for 2 h at 80 °C under N2 atmosphere, then cooled to ambient temperature and concentrated in vacuo. The residue was dissolved in EtOAc, washed with saturated aqueous NaHCO3 solution and then with brine. The organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel with petroleum ether / ethyl acetate (10 / 1) to afford methyl 2- chloro-5-fluoro-pyridine-4-carboxylate (180 mg, 0.95 mmol, 83.3% yield) as a white solid. LC purity: 99.3% (UV at 254 nm); Mass calculated for C7H5ClFNO2 [M+1]+, 190, found190. Retention time: 0.692 min.1H NMR (400 MHz, CDCl3) δ 8.42 (d, J = 1.8 Hz, 1H), 7.82 (d, J = 5.0 Hz, 1H), 4.01 (s, 3H).

[0274] Step 2: Methyl 2-(4-ethoxyphenyl)-5-fluoroisonicotinate was synthesized according to General Procedure II using methyl 2-chloro-5-fluoro-pyridine-4-carboxylate (1.00 eq, 170 mg, 0.89 mmol) and (4-ethoxyphenyl)boronic acid (1.20 eq, 179 mg, 1.08 mmol) at 80 °C for 2 h under N2 atmosphere. The crude product was purified by reversed phase flash chromatography (C18 silica) using a gradient of 20% to 70% ACN in water (with 10 mmol / L NH4HCO3) to afford an off-white solid (210 mg, 0.761 mmol, 85% yield). LC purity: 98.4% (UV at 254 nm); Mass calculated for C15H14FNO3 [M+1]+, 276.1, found 276.1; Retention time: 1.097 min.

[0275] Step 3: To a solution of methyl 2-(4-ethoxyphenyl)-5-fluoroisonicotinate (1.00 eq, 200 mg, 0.72 mmol) in DCM (4mL) was added m-CPBA (2.00 eq, 251 mg, 1.45 mmol) at 0 °C. The reaction was stirred overnight at ambient temperature under N2 atmosphere. The mixture was diluted with DCM, washed with NaHCO3, brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo to afford 2-(4-ethoxyphenyl)-5-fluoro- 4-(methoxycarbonyl)pyridine 1-oxide (210 mg, 0.72 mmol, 99% yield) as a yellow solid. LC purity: 87.9% (UV at 254 nm); Mass calculated for C15H14FNO4[M+1]+, 292.1, found 292. Retention time: 0.740 min.

[0276] Step 4: To a solution of 2-(4-ethoxyphenyl)-5-fluoro-4-(methoxycarbonyl)pyridine 1-oxide (1.00 eq, 260 mg, 0.89 mmol) in toluene (4 mL) were added N,N-dimethylaniline (5.00 eq, 541 mg, 4.46 mmol) and POCl3(5.00 eq, 684 mg, 4.46 mmol) at 0 °C. The reaction was stirred at 100 °C for 1 h under N2 atmosphere. The mixture was concentrated in vacuo and the residue was purified by reverse chromatography using a gradient of 30% to 60% ACN in water (with 10 mmol / L NH4HCO3) to afford methyl 2-chloro-6-(4-ethoxyphenyl)-3- fluoroisonicotinate (140 mg, 0.45 mmol, 50% yield) as a yellow solid. LC purity: 97.2% (UV at 254 nm); Mass calculated for C15H13ClFNO3 [M+1]+, 310.1, found 310. Retention time: 1.085 min.

[0277] Step 5: 2-Chloro-6-(4-ethoxyphenyl)-3-fluoroisonicotinic acid was synthesized according to General Procedure IV using methyl 2-chloro-6-(4-ethoxyphenyl)-3- fluoroisonicotinate (1.00 eq, 140 mg, 0.45 mmol). The crude product was purified by reversed phase flash chromatography (C18 silica) using a gradient of 0% to 70% ACN in water (with 10 mmol / L NH4HCO3) to afford a yellow solid (120 mg, 0.405 mmol, 89%yield). LC purity: 98.8% (UV at 254 nm); Mass calculated for C14H11ClFNO3[M+1]+, 296, found 296; Retention time: 0.637 min.

[0278] Step 6: (S)-2-Chloro-6-(4-ethoxyphenyl)-3-fluoro-N-(1-methylpiperidin-3- yl)isonicotinamide was synthesized according to General Procedure V using 2-chloro-6-(4- ethoxyphenyl)-3-fluoroisonicotinic acid (1.00 eq, 950 mg, 3.21 mmol) and (S)-1- methylpiperidin-3-amine (1.50 eq, 550 mg, 4.82 mmol). The crude product was purified by reversed phase flash chromatography (C18 silica) using a gradient of 20% to 70% ACN in water (with 10 mmol / L NH4HCO3) to afford a yellow solid (1 g, 2.551 mmol, 79.4% yield). LC purity: 96% (UV at 254 nm); Mass calculated for C20H23ClFN3O2 [M+1]+, 392.1, found 392.1; Retention time: 1.053 min.

[0279] Step 7: The title compound was synthesized according to General Procedure II using (S)-2-chloro-6-(4-ethoxyphenyl)-3-fluoro-N-(1-methylpiperidin-3-yl)isonicotinamide (1.00 eq, 80 mg, 0.20 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazin-2- amine at 80 °C under N2atmosphere. The crude product was concentrated in vacuo and the residue was dissolved into DMSO, filtered and purified by prep-HPLC (Column: XBridge Prep OBD C18 Column, 30X150 mm, 5 μm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 22% B to 52% B in 8 min; Wavelength: 254 nm / 220 nm; RT1 (min): 7.2). The fraction was collected and concentrated in vacuo, and the residue was re-dissolved in CH3CN and H2O, and then was lyophilized to afford an off-white solid (39 mg, 0.08 mmol, 42% yield). LC purity: 95% (UV at 254 nm); Mass calculated for C24H27FN6O2[M+1]+, 451.2, found 451.2; Retention time: 1.426 min.1H NMR (400 MHz, DMSO-d6) δ 8.66 (d, J = 1.4 Hz, 1H), 8.57 (d, J = 7.9 Hz, 1H), 8.19 – 8.06 (m, 2H), 7.99 (d, J = 1.4 Hz, 1H), 7.88 (d, J = 3.8 Hz, 1H), 7.11 – 6.99 (m, 2H), 6.89 (s, 2H), 4.10 (q, J = 6.9 Hz, 2H), 3.95 (m, 1H), 2.80 (m, 1H), 2.70 – 2.60 (m, 1H), 2.19 (s, 3H), 1.92 (m, 2H), 1.79 (m, 1H), 1.75 – 1.65 (m, 1H), 1.61 – 1.47 (m, 1H), 1.36 (t, J = 7.0 Hz, 3H), 1.34 – 1.20 (m, 1H). Example 59. -2-(5-amino-6-fluoropyrazin-2-yl)-6-(4-ethoxyphenyl)-3-fluoro-N-(1-methylpiperidin-3-yl)isonicotinamide

[0280] Scheme 20

[0281] Step 1: (S)-6-(4-ethoxyphenyl)-3-fluoro-2-(6-fluoro-5-((4-methoxybenzyl)amino)- pyrazin-2-yl)-N-(1-methylpiperidin-3-yl)isonicotinamide was synthesized according to General Procedure II using (S)-2-chloro-6-(4-ethoxyphenyl)-3-fluoro-N-(1- methylpiperidin-3-yl)isonicotinamide (preparation in Example 58, Step 6, 1.00 eq, 150 mg, 0.38 mmol) and 3-fluoro-N-(4-methoxybenzyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyrazin-2-amine (preparation in Example 55, Step 3, 2.00 eq, 273 mg, 0.76 mmol) at 80 °C overnight under N2atmosphere. The crude product was purified by reversed phase flash chromatography (C18 silica) using a gradient of 20% to 70% ACN in water (with 10 mmol / L NH4HCO3) to afford a yellow solid(200 mg, 0.339 mmol, 89.5% yield). LC purity: 88% (UV at 254 nm); Mass calculated for C32H34F2N6O3[M+1]+, 589.3, found 589.2; Retention time: 1.283 min.

[0282] Step 2: The title compound was synthesized according to General Procedure III using (S)-6-(4-ethoxyphenyl)-3-fluoro-2-(6-fluoro-5-((4-methoxybenzyl)amino)pyrazin-2- yl)-N-(1-methylpiperidin-3-yl)isonicotinamide (1.00 eq, 180 mg, 0.30 mmol). The crude product was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30X150 mm, 5 μm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 28% B to 58% B in 8 min; Wavelength: 254 nm / 220 nm; RT1 (min): 7.52). The fraction was collected and concentrated in vacuo, and the residue was re-dissolved in CH3CN and H2O, and then was lyophilized to afford an off-white solid (38 mg, 0.08 mmol, 26.7% yield). LC purity: 99% (UV at 254 nm); Mass calculated for C24H26F2N6O2 [M+1]+, 469.2, found 459.2; Retention time: 1.653 min.1H NMR (400 MHz, DMSO-d6) δ 8.67 (d, J = 4.7 Hz, 1H), 8.59 (d, J = 7.9 Hz, 1H), 8.17 – 8.06 (m, 2H), 7.91 (d, J = 3.9 Hz, 1H), 7.35 (s, 2H), 7.13 – 6.99 (m, 2H), 4.10 (q, J = 7.0 Hz, 2H), 3.94 (m, 1H), 2.80 (m, 1H), 2.56 (m, 1H), 2.19 (s, 3H), 1.91 (m, 2H), 1.79 (m, 1H), 1.70 (m, 1H), 1.65 – 1.47 (m, 1H), 1.36 – 1.21 (m, 4H). Example 60. (S)-6-(5-aminopyrazin-2-yl)-6'-(2,2-difluoroethoxy)-N-(1-methylpyrrolidin- 3-yl)-[2,3'-bipyridine]-4-sulfonamide

[0283] Scheme 21

[0284] Step 1: (S)-2,6-dichloro-N-(1-methylpyrrolidin-3-yl)pyridine-4-sulfonamide was synthesized according to General Procedure I using (S)-1-methylpyrrolidin-3-amine (1.50 eq., 244 mg, 2.43 mmol). The crude product was purified by column chromatography on silica gel (PE in EtOAc=60%) to afford a yellow solid (500 mg, 1.612 mmol, 87.6% yield). LC purity: 88% (UV at 254 nm); Mass calculated for C10H13Cl2N3O2S [M+1]+, 310.0, found 310.0; Retention time: 0.595 min.

[0285] Step 2: (S)-2-(5-aminopyrazin-2-yl)-6-chloro-N-(1-methylpyrrolidin-3-yl)pyridine- 4-sulfonamide was synthesized according to General Procedure II using (S)-2,6-dichloro-N- (1-methylpyrrolidin-3-yl)pyridine-4-sulfonamide (1.00 eq, 300 mg, 0.96 mmol) and 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazin-2-amine (0.90 eq, 192 mg, 0.87 mmol) at 80 °C for 2 h under N2atmosphere. The crude product was purified by reversed phase flash chromatography (C18 silica) using a gradient of 40% to 60% ACN in water (with 10 mmol / L NH4HCO3) to afford a brown solid (224 mg, 0.607 mmol, 62% yield). LC purity: 96% (UV at 254 nm); Mass calculated for C14H17ClN6O2S [M+1]+, 369.0, found 369.0; Retention time: 0.493 min.

[0286] Step 3: The title compound was synthesized according to General Procedure II using (S)-2-(5-aminopyrazin-2-yl)-6-chloro-N-(1-methylpyrrolidin-3-yl)pyridine-4- sulfonamide (1.00 eq, 100 mg, 0.27 mmol) and (6-(2,2-difluoroethoxy)pyridin-3-yl)boronicacid (1.31 eq, 72 mg, 0.35 mmol) at 80 °C for 2 h under N2atmosphere. The crude product was purified by reversed phase flash chromatography (C18 silica) using a gradient of 40% to 60% ACN in water (with 10 mmol / L NH4HCO3) to afford a crude product. This crude product was further purified by Prep-HPLC (conditions: Column: XBridge Prep RP OBD C18 Column, 30X150 mm, 5 μm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 26% B to 50% B in 10 min; Wavelength: 254 nm / 220 nm; RT1 (min): 8.38). The fraction was collected and concentrated in vacuo, and the residue was re-dissolved in CH3CN and H2O, and then was lyophilized to afford an off-white solid (16 mg, 0.03 mmol, 11% yield). LC purity: 99% (UV at 254 nm); Mass calculated for C21H23F2N7O3S [M+1]+492.0, found 492.0; Retention time: 0.946 min.1H NMR (400 MHz, DMSO-d6) δ 9.08 (dd, J = 18.8, 1.9 Hz, 2H), 8.62 (dd, J = 8.7, 2.5 Hz, 1H), 8.36 (d, J = 1.5 Hz, 1H), 8.24 (s, 1H), 8.15 (d, J = 1.5 Hz, 1H), 8.01 (d, J = 1.4 Hz, 1H), 7.12 (d, J = 8.7 Hz, 1H), 7.03 (s, 2H), 6.45 (t, J = 3.5 Hz, 1H), 4.82 – 4.52 (m, 2H), 3.80 (t, J = 7.7 Hz, 1H), 2.54 – 2.52 (m, 1H), 2.44 – 2.32 (m, 1H), 2.31 – 2.18 (m, 2H), 2.13 (s, 3H), 2.00 – 1.86 (m, 1H), 1.55 – 1.42 (m, 1H). Example 61. (S)-2-(5-aminopyrazin-2-yl)-6-(4-(2,2-difluoroethoxy)phenyl)-N-(1- methylpyrrolidin-3-yl)pyridine-4-sulfonamide

[0287] Scheme 22

[0288] Step 1: The title compound was synthesized according to General Procedure II using (S)-2-(5-aminopyrazin-2-yl)-6-chloro-N-(1-methylpyrrolidin-3-yl)pyridine-4- sulfonamide (preparation in Example 60, Step 2, 1.00 eq, 100 mg, 0.27 mmol) and (4-(2,2- difluoroethoxy)phenyl)boronic acid (1.30 eq, 71 mg, 0.35 mmol). The crude product was purified by reversed phase flash chromatography (C18 silica) using a gradient of 40% to 65% ACN in water (with 10 mmol / L NH4HCO3) to afford a crude product. This crude product was further purified by Prep-HPLC (conditions: Column: XBridge Prep OBD C18 Column, 30X150 mm, 5 μm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN;Flow rate: 60 mL / min; Gradient (B%): 24% B to 54% B in 10 min; Wavelength: 254 nm / 220 nm; RT1 (min): 8.65). The fraction was collected and concentrated in vacuo, and the residue was re-dissolved in CH3CN and H2O, and then was lyophilized to afford an off-white solid (27 mg, 0.05 mmol, 19% yield). LC purity: 99% (UV at 254 nm); Mass calculated for C22H24F2N6O3S [M+1]+, 491.1, found 491.1; Retention time: 0.968 min.1H NMR (400 MHz, DMSO-d6) δ 9.09 (s, 1H), 8.31 (s, 1H), 8.23 (d, J = 8.4 Hz, 3H), 8.10 (s, 1H), 8.02 (s, 1H), 7.21 (d, J = 8.4 Hz, 2H), 7.01 (s, 2H), 6.45 (t, J = 3.5 Hz, 1H), 4.44 (m, 2H), 3.78 (m, 1H), 2.47 – 2.42 (m, 2H) , 2.31 – 2.19 (m, 2H), 2.13 (s, 3H), 2.01 – 1.81 (m, 1H), 1.70 – 1.26 (m, 1H). Example 62. (R)-6-(5-amino-6-fluoropyrazin-2-yl)-6'-ethoxy-N-(1-methylpyrrolidin-3- yl)-[2,3'-bipyridine]-4-sulfonamide

[0289] Scheme 23

[0290] Step 1: (R)-2,6-Dichloro-N-(1-methylpyrrolidin-3-yl)pyridine-4-sulfonamide was synthesized according to General Procedure I using (R)-1-methylpyrrolidin-3-amine (1.50 eq, 305 mg, 3.04 mmol). The crude product was purified by column chromatography on silica gel (0 to 10% MeOH in DCM) to afford a white solid (500 mg, 1.612 mmol, 79% yield). LC purity: 86% (UV at 254 nm); Mass calculated for C10H13Cl2N3O2S [M+1]+, 310.0, found 310.0; Retention time: 0.579 min.

[0291] Step 2: (R)-6-Chloro-6'-ethoxy-N-(1-methylpyrrolidin-3-yl)-[2,3'-bipyridine]-4- sulfonamide was synthesized according to General Procedure II using (R)-2,6-dichloro-N- (1-methylpyrrolidin-3-yl)pyridine-4-sulfonamide (1.00 eq, 140 mg, 0.45 mmol) and 2- ethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.90 eq, 101 mg, 0.40 mmol). The crude product was purified by reversed phase flash chromatography (C18 silica) using a gradient of 0% to 40% ACN in water (with 10 mmol / L NH4HCO3) to afford a yellow solid (108 mg, 0.272 mmol, 60% yield). LC purity: 79% (UV at 254 nm); Mass calculated for C17H21ClN4O3S [M+1]+, 397.1, found 397.1; Retention time: 0.817 min.

[0292] Step 3: (R)-6'-ethoxy-6-(6-fluoro-5-((4-methoxybenzyl)amino)pyrazin-2-yl)-N-(1- methylpyrrolidin-3-yl)-[2,3'-bipyridine]-4-sulfonamide was synthesized according to General Procedure II using (R)-6-Chloro-6'-ethoxy-N-(1-methylpyrrolidin-3-yl)-[2,3'- bipyridine]-4-sulfonamide (1.00 eq, 100 mg, 0.25 mmol) and 3-fluoro-N-(4-methoxybenzyl)- 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazin-2-amine (1.20 eq, 109 mg, 0.30 mmol) at 80 °C for 2 h under N2atmosphere. The crude product was purified by reversed phase flash chromatography (C18 silica) using a gradient of 80% to 100% ACN in water (with 10 mmol / L NH4HCO3) to afford a yellow solid (58 mg, 0.09 mmol, 38% yield). LC purity: 56% (UV at 254 nm); Mass calculated for C29H32FN7O4S [M+1]+, 594.3, found 594.3; Retention time: 0.985 min.

[0293] Step 4: The title compound was synthesized according to General Procedure III using (R)-6'-ethoxy-6-(6-fluoro-5-((4-methoxybenzyl)amino)pyrazin-2-yl)-N-(1-methylpyr- rolidin-3-yl)-[2,3'-bipyridine]-4-sulfonamide (1.00 eq, 50 mg, 0.08 mmol). The crude product was purified by Prep-HPLC (conditions: Column: XBridge Prep OBD C18 Column, 30X150 mm, 5μm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 24% B to 54% B in 10 min; Wavelength: 254 nm / 220 nm; RT1 (min): 8.65). The fraction was collected and concentrated in vacuo, and the residue was re-dissolved in CH3CN and H2O, and lyophilized to afford a white solid (6.3 mg, 0.01 mmol, 15.5% yield). LC purity: 98% (UV at 254 nm); Mass calculated for C21H24FN7O3S [M+1]+ 474.1, found 474.1; Retention time: 1.403 min.1H NMR (400 MHz, DMSO-d6) δ 9.07 – 9.01 (m, 2H), 8.55 (dd, J = 8.7, 2.6 Hz, 1H), 8.27 (s, 1H), 8.18 – 8.12 (m, 2H), 7.46 (s, 2H), 6.98 (d, J = 8.7 Hz, 1H), 4.52 – 4.26 (m, 2H), 3.89 – 3.71 (m, 1H), 2.55 (m, 1H), 2.47 – 2.38 (m, 1H), 2.32 – 2.19 (m, 2H), 2.14 (s, 3H), 2.01 – 1.87 (m, 1H), 1.56 – 1.42 (m, 1H), 1.37 (t, J = 7.0 Hz, 3H).Example 63. (S)-6-(5-amino-6-fluoropyrazin-2-yl)-5-fluoro-N-(1-methylpiperdin-3-yl)- 6'-(2,2,2-trifluoroethoxy)-[2,3'-bipyridine]-4-carboxamide

[0294] Scheme 24

[0295] Step 1: To a mixture of methyl 2,6-dichloro-3-fluoro-pyridine-4-carboxylate (1 eq, 800 mg, 3.57 mmol), 3-fluoro-N-(4-methoxybenzyl)-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyrazin-2-amine (preparation in Example 55, Step 3, 0.80 eq, 1026 mg, 2.86 mmol) and Na2CO3 (2.00 eq, mg, 7.14 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was added Pd(dtbpf)Cl2(0.1 eq, 232 mg, 0.357 mmol) at ambient temperature. The reaction was stirred at 40 °C for 2 h under N2atmosphere. Upon completion, the mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE / EtOAc, 3 / 2) to afford methyl 6-chloro-3-fluoro- 2-(6-fluoro-5-((4-methoxybenzyl)amino)pyrazin-2-yl)isonicotinate (480 mg, 1.14 mmol, 31.9% yield) as a yellow solid. LC purity: 83% (UV at 254 nm); Mass calculated for C19H15ClF2N4O3[M+1]+, 421.1, found 421.1; Retention time: 0.766 min.

[0296] Step 2: Methyl 5-fluoro-6-(6-fluoro-5-((4-methoxybenzyl)amino)pyrazin-2-yl)-6'- (2,2,2-trifluoroethoxy)-[2,3'-bipyridine]-4-carboxylate was synthesized according to General Procedure II using methyl 6-chloro-3-fluoro-2-(6-fluoro-5-((4- methoxybenzyl)amino)pyrazin-2-yl)isonicotinate (1.00 eq, 250 mg, 0.594 mmol) and 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (1.20 eq, 216 mg, 0.71 mmol) at 80 °C for 2 h under N2 atmosphere. The crude product was purified by column chromatography on silica gel (PE / EtOAc, 1 / 1) to afford a yellow solid (280 mg, 0.50mmol, 83.9% yield). LC purity: 80% (UV at 254 nm); Mass calculated for C26H20F5N5O4[M+1]+, 562.1, found 562.2; Retention time: 0.994 min.

[0297] Step 3: 5-Fluoro-6-(6-fluoro-5-((4-methoxybenzyl)amino)pyrazin-2-yl)-6'-(2,2,2- trifluoroethoxy)-[2,3'-bipyridine]-4-carboxylic acid was synthesized according to General Procedure IV using methyl 5-fluoro-6-(6-fluoro-5-((4-methoxybenzyl)amino)pyrazin-2-yl)- 6'-(2,2,2-trifluoroethoxy)-[2,3'-bipyridine]-4-carboxylate (1.00 eq, 270 mg, 0.48 mmol). The crude product was purified by reversed phase flash chromatography (C18 silica) using a gradient of 20% to 50% ACN in water (with 10 mmol / L NH4HCO3) to afford a yellow solid(220 mg, 0.40 mmol, 83.6% yield). LC purity: 80% (UV at 254 nm); Mass calculated for C25H18F5N5O4[M+1]+, 548.1, found 548.2; Retention time: 0565 min.

[0298] Step 4: (S)-5-fluoro-6-(6-fluoro-5-((4-methoxybenzyl)amino)pyrazin-2-yl)-N-(1- methylpiperidin-3-yl)-6'-(2,2,2-trifluoroethoxy)-[2,3'-bipyridine]-4-carboxamide was synthesized according to General Procedure V using 5-fluoro-6-(6-fluoro-5-((4- methoxybenzyl)amino)pyrazin-2-yl)-6'-(2,2,2-trifluoroethoxy)-[2,3'-bipyridine]-4-carboxylic acid (1.00 eq, 40 mg, 0.073 mmol), (S)-1-methylpiperidin-3-amine (1.50 eq, 13 mg, 0.11 mmol). Upon completion, the mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford the crude product which was used in the next step directly without further purification. LC purity: 80% (UV at 254 nm); Mass calculated for: C31H30F5N7O3 [M+1]+, 644.2, found 644.1; Retention time:0.646 min.

[0299] Step 5: The title compound was synthesized according to General Procedure III using (S)-5-fluoro-6-(6-fluoro-5-((4-methoxybenzyl)amino)pyrazin-2-yl)-N-(1- methylpiperidin-3-yl)-6'-(2,2,2-trifluoroethoxy)-[2,3'-bipyridine]-4-carboxamide (1.00 eq, 34 mg, 0.053 mmol). The crude product was purified by Prep-HPLC (conditions: XBridge Prep RP OBD C18 Column, 30X75 mm, 5 μm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 20% B to 80% B in 9 min; Wavelength: 254 nm / 220 nm; RT1 (min): 6.03). The fraction was collected and concentrated in vacuo, and the residue was re-dissolved in CH3CN and H2O, and then was lyophilized to afford a light yellow solid (6.6 mg, 0.0125 mmol, 23.7% yield). LC purity: 99% (UV at 254 nm); Mass calculated for Chemical Formula: C23H22F5N7O2 [M+1]+, 524.2, found 524.2; Retention time:1.048 min.1H NMR (400 MHz, DMSO-d6) δ 8.99 (d, J = 2.5 Hz, 1H), 8.72 (d, J = 4.6 Hz, 1H), 8.64 (d, J = 7.9 Hz, 1H), 8.58 (dd, J = 8.6, 2.5 Hz, 1H), 8.06 (d, J = 3.9Hz, 1H), 7.38 (s, 2H), 7.13 (d, J = 8.7 Hz, 1H), 3.95 (m, 1H), 2.79 (m, 1H), 2.56 (m, 1H), 2.19 (s, 3H), 1.93 (m, 2H), 1.80 (m, 1H), 1.74 – 1.65 (m, 1H), 1.60 – 1.46 (m, 1H), 1.37 – 1.21 (m, 1H). Example 64. (R)-6-(5-amino-6-fluoropyrazin-2-yl)-6'-(2,2-difluoroethoxy)-5-fluoro-N- (piperidin-3-yl)-[2,3'-bipyridine]-4-carboxamide

[0300] Scheme 25

[0301] Step 1: Methyl 6'-(2,2-difluoroethoxy)-5-fluoro-6-(6-fluoro-5-((4-methoxybenzyl)- amino)pyrazin-2-yl)-[2,3'-bipyridine]-4-carboxylate was synthesized according to General Procedure II using methyl 6-chloro-3-fluoro-2-(6-fluoro-5-((4- methoxybenzyl)amino)pyrazin-2-yl)isonicotinate (preparation in Example 63, Step 1, 1.00 eq, 150 mg, 0.36 mmol) and (6-(2,2-difluoroethoxy)pyridin-3-yl)boronic acid (1.5 eq, 109 mg, 0.535 mmol) at 80 °C for 2 h under N2 atmosphere. The crude product was purified by column chromatography on silica gel with petroleum ether / ethyl acetate (1 / 1) to afford a yellow solid (160 mg, 0.25 mmol, 70.2% yield). LC purity: 80% (UV at 254 nm); Mass calculated for C26H21F4N5O4 [M+1]+, 544.2, found 544.05; Retention time: 0.740 min.

[0302] Step 2: 6'-(2,2-Difluoroethoxy)-5-fluoro-6-(6-fluoro-5-((4- methoxybenzyl)amino)pyr-azin-2-yl)-[2,3'-bipyridine]-4-carboxylic acid was synthesized according to General Procedure IV using methyl 6'-(2,2-difluoroethoxy)-5-fluoro-6-(6- fluoro-5-((4-methoxybenzyl)-amino)pyrazin-2-yl)-[2,3'-bipyridine]-4-carboxylate (1 eq, 160 mg, 0.294 mmol) in THF (3 mL) and LiOH (10 eq, 71 mg, 2.94 mmol) in water (1 mL). The crude product was added DMSO, filtered and purified via phase flash chromatography (C18 silica gel) using a gradient of 20% to 50% ACN in water (with 10 mmol / L NH4HCO3) toafford a yellow solid (150 mg, 0.283 mmol, 96.2% yield). LC purity: 90% (UV at 254 nm); Mass calculated for Chemical Formula: C25H19F4N5O4 [M+1]+, 530.1, found 530.2; Retention time: 0530 min.

[0303] Step 3: Tert-butyl (R)-3-(6'-(2,2-difluoroethoxy)-5-fluoro-6-(6-fluoro-5-((4- methoxybenzyl)amino)pyrazin-2-yl)-[2,3'-bipyridine]-4-carboxamido)piperidine-1- carboxylate was synthesized according to General Procedure V using 6'-(2,2- difluoroethoxy)-5-fluoro-6-(6-fluoro-5-((4-methoxybenzyl)amino)pyr-azin-2-yl)-[2,3'- bipyridine]-4-carboxylic acid (1.00 eq, 40 mg, 0.076 mmol) and tert-butyl (R)-3- aminopiperidine-1-carboxylate (1.50 eq, 23 mg, 0.113 mmol). The reaction was stirred at ambient temperature for 2 h. The crude product was used in the next step without further purification. LC purity: 90% (UV at 254 nm); Mass calculated for Chemical Formula: C35H37F4N7O5 [M+1]+, 712.3, found 712.15; Retention time: 0.852 min.

[0304] Step 4: The title compound was synthesized according to General Procedure III using tert-butyl (R)-3-(6'-(2,2-difluoroethoxy)-5-fluoro-6-(6-fluoro-5-((4-methoxybenzyl)- amino)pyrazin-2-yl)-[2,3'-bipyridine]-4-carboxamido)piperidine-1-carboxylate (1.00 eq, 60 mg, 0.084 mmol) in DCM (10 mL) was added TFA (2 mL) dropwise. The resulting solution was stirred for 1 h at 50 °C and concentrated in vacuo. The crude product was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30X150 mm, 5 μm; Mobile Phase A: Water (10nmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient (B%): 19% B to 49% B in 10 min; Wavelength: 254 nm / 220 nm; RT1 (min): 9.25). The product was concentrated in vacuo and lyophilized to afford the title compound (7.3 mg, 0.0146 mmol, 17.3% yield) as a light yellow solid. LC purity: 98% (UV at 254 nm); Mass calculated for Chemical Formula: C22H21F4N7O2 [M+1]+, 492.2, found 492.1; Retention time:1.703 min.1H NMR (400 MHz, DMSO-d6) δ 8.98 (d, J = 2.5 Hz, 1H), 8.72 (d, J = 4.7 Hz, 1H), 8.61 – 8.51 (m, 2H), 8.05 (d, J = 3.8 Hz, 1H), 7.39 (s, 2H), 7.11 – 7.04 (m, 1H), 6.62 – 6.22 (m, 1H), 4.72 – 4.60 (m, 2H), 3.81 (dd, J = 8.7, 4.4 Hz, 1H), 3.01 (m, 1H), 2.77 (m, 1H), 2.50 – 2.38 (m, 2H), 1.89 (m, 1H), 1.67 – 1.60 (m, 1H), 1.53 – 1.38 (m, 2H).. Example 65.6-(5-amino-6-fluoropyrazin-2-yl)-6'-(2,2-difluoroethoxy)- -4-fluoropiperidin-3-yl)-[2,3'-bipyridine]-4-sulfonamide

[0305] Scheme 26

[0306] The title compound (14 mg) was prepared in a 9.1% overall yield as a white solid, following a procedure analogous to that described in Example 62, using tert-butyl (3R,4R)-3- amino-4-fluoropiperidine-1-carboxylate in Step 1. Prep-HPLC conditions: Column: XBridge Prep OBD C18 Column, 30X150 mm, 5 μm; Mobile Phase A: Water (10 mmol / L NH4HCO3+0.1%NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 30% B to 50% B in 8 min; Wavelength: 254 nm / 220 nm; RT1 (min): 8.12. LC purity: 99% (UV at 254 nm); Mass calculated for C21H21F4N7O3S [M+1]+, 528.1, found 528.1; Retention time:0.937 min.1H NMR (400 MHz, DMSO-d6) δ 9.07 – 9.01 (m, 2H), 8.61 (dd, J = 8.7, 2.5 Hz, 1H), 8.17 (dd, J = 9.6, 1.4 Hz, 2H), 7.46 (s, 2H), 7.12 (d, J = 8.7 Hz, 1H), 6.59 – 6.32 (m, 1H), 4.75 – 4.62 (m, 2H), 4.42 – 4.18 (m, 1H), 3.29 – 3.16 (m, 1H), 2.95 – 2.74 (m, 2H), 2.38 – 2.19 (m, 2H), 1.92 (m, 1H), 1.46 – 1.31 (m, 1H). Example 66.2-(5-amino-6-fluoropyrazin-2-yl)-N-(2-azabicyclo [2.2.2] octan-4-yl)-6-(4- (2,2-difluoroethoxy) phenyl)-3-fluoroisonicotinamide

[0307] Scheme 27

[0308] Step 1 & 2: 6-(4-(2,2-difluoroethoxy)phenyl)-2-(5-((2,4-dimethoxybenzyl)amino)- 6-fluoropyrazin-2-yl)-3-fluoroisonicotinic acid was prepared following a procedure analogous to that described in Example 63 (Step 1 and Step 2), using 2-(4-(2,2- difluoroethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in Step 1.

[0309] Step 3: tert-Butyl 4-(6-(4-(2,2-difluoroethoxy)phenyl)-2-(5-((2,4- dimethoxybenzyl)amino)-6-fluoropyrazin-2-yl)-3-fluoroisonicotinamido)-2- azabicyclo[2.2.2]octane-2-carboxylate was synthesized according to General Procedure V using 6-(4-(2,2-difluoroethoxy)phenyl)-2-(5-((3,4-dimethylbenzyl)amino)-6-fluoropyrazin-2- yl)-3-fluoroisonicotinic acid (1.00 eq, 60 mg, 0.11 mmol) and tert-butyl 4-amino-2- azabicyclo[2.2.2]octane-2-carboxylate (1.20 eq, 31 mg, 0.14 mmol). The reaction was stirred at ambient temperature for 2 h. The crude product was added DMSO, filtered and purified via phase flash chromatography (C18 silica gel) using a gradient of 0% to 100% ACN in water (with 10 mmol / L NH4HCO3) to afford a white solid (70 mg, 0.095 mmol, 83.7% yield). LC purity: 85% (UV at 254 nm); Mass calculated for C38H40F4N6O5 [M+1]+,737.3, found 737.4; Retention time: 1.236 min.

[0310] Step 4: The title compound was synthesized according to General Procedure III using tert-butyl 4-(6-(4-(2,2-difluoroethoxy)phenyl)-2-(5-((2,4-dimethoxybenzyl)amino)-6- fluoropyrazin-2-yl)-3-fluoroisonicotinamido)-2-azabicyclo[2.2.2]octane-2-carboxylate (1.00 eq, 70 mg, 0.095 mmol) in DCM (2 mL) at 50 °C for 1 h under N2atmosphere. The crude product was added DMSO, filtered and purified by Prep HPLC (Column: Xbridge Prep OBD Shield RP18, 30X150 mm, 5 μm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 20% B to 50% B in 10 min; Wavelength: 254 nm / 220 nm; RT1 (min): 8.48). The fraction was collected and concentratedunder vacuo, and the residue was re-dissolved in CH3CN and H2O and lyophilized to afford a white solid (19 mg, 0.035 mmol, 38.7% yield). LC purity: 97.6% (UV at 254 nm); Mass calculated for C25H24F4N6O2 [M+1]+, 517.2, found 517.5; Retention time: 0.652 min.1H NMR (400 MHz, DMSO-d6) δ 8.67 (d, J = 4.6 Hz, 1H), 8.24 – 8.10 (m, 3H), 7.88 (m, 1H), 7.35 (s, 2H), 7.14 (d, J = 8.9 Hz, 2H), 6.43 (m, 1H), 4.41 (m, 2H), 3.87 (m, 1H), 3.12 (s, 2H), 2.69 (m, 1H), 2.10 – 1.90 (m, 4H), 1.83 (m, 2H), 1.69 (m, 2H). Example 67. (R)-N-(2-(2-aminopyrimidin-5-yl)-3-fluoro-6-(4-(2,2,2- trifluoroethoxy)phenyl)pyridin-4-yl)piperidine-3-carboxamide

[0311] Scheme 28

[0312] Step 1 and Step 2: The tert-butyl (5-(4-amino-3-fluoro-6-(4-(2,2,2- trifluoroethoxy)phenyl)pyridin-2-yl)pyrimidin-2-yl)(tert-butoxycarbonyl)carbamate was prepared from 2,6-dichloro-3-fluoropyridin-4-amine in a 4.5% overall yield, following a procedure analogous to that described in Example 56.

[0313] Step 3: To a solution of (R)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (2.00 eq, 107 mg, 0.466 mmol) and tert-butyl (5-(4-amino-3-fluoro-6-(4-(2,2,2- trifluoroethoxy)phenyl)pyridin-2-yl)pyrimidin-2-yl)(tert-butoxycarbonyl)carbamate (1.00 eq, 135 mg, 0.23 mmol) in MeCN (5mL) were added TCFH (2.00 eq, 131 mg, 0.47 mmol) and NMI (8.00 eq, 153 mg, 1.86 mmol) at ambient temperature. The reaction was stirred for 4 days at 80 °C under N2 atmosphere. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by reversed phase column to afford tert-butyl (R)-3-((2-(2-(bis(tert-butoxycarbonyl)amino)pyrimi-din-5-yl)-3-fluoro-6-(4-(2,2,2- trifluoroethoxy)phenyl)-pyridin-4-yl)carbamoyl)piperi-dine-1-carboxylate (75 mg, 0.095mmol, 40.7% yield) as a white solid. LC purity: 69% (UV at 254 nm); Mass calculated for C38H46F4N6O8 [M+1]+, 791.3, found 791.2; Retention time: 1.418 min.

[0314] Step 4: To a solution of tert-butyl (R)-3-((2-(2-(bis(tert- butoxycarbonyl)amino)pyrimi-din-5-yl)-3-fluoro-6-(4-(2,2,2-trifluoroethoxy)phenyl)-pyridin- 4-yl)carbamoyl)piperi-dine-1-carboxylate (1.00 eq, 95 mg, 0.12 mmol) in 1,4-dioxane (5mL) was added HCl (dioxane) (5.0 mL, 4 M in dioxane). The reaction was stirred at ambient temperature overnight. The mixture was concentrated in vacuo to afford the crude product which was purified by prep-HPLC (Column: Xselect CSH Prep C18 OBD Column, 30X150 mm, 5 μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 8% B to 38% B in 8 min; Wave Length: 254 nm / 220 nm; RT1 (min): 7.2). The fraction was collected and concentrated in vacuo, and the residue was re- dissolved in CH3CN and H2O, and then was lyophilized to afford the title compound (45 mg, 0.083 mmol, 68.8% yield) as a white solid. LC purity: 99.3% (UV at 254 nm); Mass calculated for C23H22F4N6O2[M+1]+, 491.2, found 491.2; Retention time: 0.762 min.1H NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 8.85 (s, 2H), 8.59 (d, J = 4.9 Hz, 1H), 8.36 (s, 1H), 8.04 – 7.95 (m, 2H), 7.23 – 7.14 (m, 2H), 7.11 (s, 2H), 4.90 – 4.79 (m, 2H), 3.08 (m, 1H), 3.01 – 2.77 (m, 3H), 2.72 (m, 1H), 1.94 (m, 1H), 1.79 – 1.67 (m, 2H), 1.53 (m, 1H). Example 68. (S)-6-(5-amino-6-fluoropyrazin-2-yl)-6'-ethoxy-5-fluoro-N-(1- methylpiperidin-3-yl)-[2,3'-bipyridine]-4-carboxamide

[0315] Scheme 29

[0316] Step 1: To a mixture of methyl 2,6-dichloro-3-fluoroisonicotinate (1.00 eq, 800 mg, 3.57 mmol), 3-fluoro-N-(4-methoxybenzyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyrazin-2-amine (0.80 eq, 1026 mg, 2.86 mmol) and Na2CO3 (2.00 eq, 757 mg, 7.14 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was added Pd(dtbpf)Cl2(0.10 eq, 232 mg, 0.357 mmol). The reaction was stirred at 40 °C for 2 h under N2atmosphere. The reaction was then diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel with petroleum ether / ethyl acetate (3 / 2) to give methyl 6-chloro-3-fluoro-2-(6-fluoro-5-((4- methoxybenzyl)amino)pyrazin-2-yl)isonicotinate (480 mg, 1.14 mmol, 39.8% yield) as a yellow solid. LC purity: 83% (UV at 254 nm); Mass calculated for C19H15ClF2N4O3[M+1]+ 421.1, found 421.1; Retention time: 0.766 min.

[0317] Step 2: To a solution of methyl 6-chloro-3-fluoro-2-(6-fluoro-5-((4- methoxybenzyl)amino)pyrazin-2-yl)isonicotinate (1.00 eq, 300 mg, 0.71 mmol) in water (2mL) and THF (2 mL) was added LiOH^H2O (2.00 eq, 60 mg, 1.43 mmol) at room temperature. The reaction was stirred for 2 h at room temperature. The resulting mixture was concentrated in vacuo and the residue was added DMSO, filtered, and the filtrate was purified via reversed phase flash chromatography (C18 silica gel) using a gradient of 30% to 70% ACN in water (with 10 mmol / L NH4HCO3) to afford the 6-chloro-3-fluoro-2-(6-fluoro-5-((4- methoxybenzyl)amino)pyrazin-2-yl)isonicotinic acid (250 mg, 0.62 mmol, 86% yield) as a yellow solid. LC purity: 73% (UV at 254 nm); Mass calculated for C + 18H13ClF2N4O3 [M+1] 407.0, found 407.0; Retention time: 0.623 min.

[0318] Step 3: To a solution of (3S)-1-methylpiperidin-3-amine (2.00 eq, 180 mg, 1.57 mmol) and afford the 6-chloro-3-fluoro-2-(6-fluoro-5-((4-methoxybenzyl)amino)pyrazin-2- yl)isonicotinic acid (1.00 eq, 320 mg, 0.79 mmol) in DMF (3mL) was added HATU (2.00 eq, 598 mg, 1.57 mmol) and DIEA (3.00 eq, 304 mg, 2.36 mmol) at 0 ℃. The reaction was stirred for 1 h at room temperature. The resulting mixture was purified via reversed phase flash chromatography (C18 silica gel) using a gradient of 50% to 80% ACN in water (with 10 mmol / L NH4HCO3) to afford (S)-6-chloro-3-fluoro-2-(6-fluoro-5-((4- methoxybenzyl)amino)pyrazin-2-yl)-N-(1-methylpiperidin-3-yl)isonicotinamide (190 mg, 0.32 mmol, 41% yield) as a yellow solid. LC purity: 85% (UV at 254 nm); Mass calculated for C24H25ClF2N6O2[M+1]+, 503.0, found 503.0; Retention time: 1.085 min.

[0319] Step 4: To a solution of (S)-6-chloro-3-fluoro-2-(6-fluoro-5-((4- methoxybenzyl)amino)pyrazin-2-yl)-N-(1-methylpiperidin-3-yl)isonicotinamide and (6- ethoxy-3-pyridyl)boronic acid (2.00 eq, 53 mg, 0.32 mmol) in 1,4-dioxane (2 mL) and water (0.20 mL) was added Na2CO3(3.00 eq, 51 mg, 0.48 mmol) and Pd(dppf)Cl2(0.10 eq, 13 mg, 0.02 mmol) at room temperature under N2. The reaction was stirred at 80 ℃ for 2 h under N2. The reaction was then diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reversed phase flash chromatography (C18 silica) using a gradient of 20% to 30% ACN in water (with 10 mmol / L NH4HCO3) to afford (S)-6'-ethoxy- 5-fluoro-6-(6-fluoro-5-((4-methoxybenzyl)amino)pyrazin-2-yl)-N-(1-methylpiperidin-3-yl)- [2,3'-bipyridine]-4-carboxamide (80 mg, 0.13 mmol, 82% yield) as a yellow solid. LC purity: 96% (UV at 254 nm); Mass calculated for C31H33F2N7O3 [M+1]+, 590.1, found 590.1; Retention time: 1.223 min.

[0320] Step 5: To a solution of 6-(6-ethoxy-3-pyridyl)-3-fluoro-2-[6-fluoro-5-[(4- methoxyphenyl)methylamino]pyrazin-2-yl]-N-[(3S)-1-methyl-3-piperidyl]pyridine-4- carboxamide (1.00 eq, 80 mg, 0.14 mmol) in DCM (5mL) was added TFA (1.0 mL) and stirred at 50 ℃ for 2 h. The resulting mixture was concentrated in vacuo. The residue was dissolved in MeCN and treated with 1 mL ammonium hydroxide at 0 °C, stirred for 30 min and concentrated in vacuo. The residue was purified by Prep-HPLC using the following conditions: Column: XBridge Prep Shield RP18 OBD C18 Column, 30X150 mm, 5 μm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 25% B to 55% B in 10 min; Wavelength: 254 nm / 220 nm; RT1 (min): 7.4. LC purity: 96% (UV at 254 nm). The fraction was collected and concentrated in vacuo and the residue was re-dissolved in CH3CN and H2O, and lyophilized to afford the title compound (14 mg, 0.03 mmol, 22 % yield) as an off-white solid. Mass calculated for C23H25F2N7O2 [M+1]+, 470.2, found 470.2; Retention time: 4.371 min.1H NMR (400 MHz, DMSO) δ 8.95 (d, J = 2.4 Hz, 1H), 8.71 (d, J = 4.7 Hz, 1H), 8.62 (d, J = 7.9 Hz, 1H), 8.47 (dd, J = 8.7, 2.5 Hz, 1H), 8.01 (d, J = 3.8 Hz, 1H), 7.38 (s, 2H), 6.93 (d, J = 8.7 Hz, 1H), 4.39 (q, J = 7.0 Hz, 2H), 4.19-3.90 (m, 1H), 2.80 (d, J = 10.2 Hz, 1H), 2.56 (m, 1H), 2.19 (s, 3H), 1.93 (q, J = 11.1 Hz, 2H), 1.83-1.75 (m, 1H), 1.69 (m, 1H), 1.52 (dd, J = 14.1, 10.0 Hz, 1H), 1.36 (t, J = 7.1 Hz, 3H), 1.31 (s, 1H). Example 69.2-(5-amino-6-fluoropyrazin-2-yl)-N-(2-azabicyclo[2.2.2]octan-4-yl)-6-(4- difluoroethoxy)phenyl)pyridine-4-sulfonamide

[0321] Scheme 30

[0322] The title compound (10 mg) was prepared in a 4.5% overall yield as a white solid, following a procedure analogous to that described in Example 62, using tert-butyl 4-amino- 2-azabicyclo[2.2.2]octane-2-carboxylate in Step 1. Prep-HPLC conditions: Column: Xbridge Prep OBD Shield RP18, 30X150 mm, 5 μm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 26% B to 56% B in 10 min; Wavelength: 254 nm / 220 nm; RT1 (min): 8.48. LC purity: 97.6% (UV at 254 nm); Mass calculated for C24H25F3N6O3 [M+1]+, 535.2, found 535.2; Retention time: 1.595 min.1H NMR (400 MHz, DMSO-d6) δ 9.02 (d, J = 4.6 Hz, 1H), 8.33 – 8.08 (m, 4H), 7.46 (s, 2H), 7.22 (d, J = 8.4 Hz, 2H), 6.46 (t, J = 54.5 Hz, 1H), 4.44 (t, J = 14.8 Hz, 2H), 3.32 (m, 2H), 2.79 (s, 1H), 1.85 – 1.40 (m, 8H). Example 70.6-(5-amino-6-fluoropyrazin-2-yl)-6'-ethoxy-N-((3R,4R)-4-fluoropiperidin- 3-yl)-[2,3'- 4-sulfonamide

[0323] Scheme 31

[0324] The title compound (27 mg) was prepared in a 18% overall yield as a white solid, following a procedure analogous to that described in Example 62, using tert-butyl (3R,4R)-3- amino-4-fluoropiperidine-1-carboxylate in Step 1. Prep-HPLC conditions: Column: XBridge Prep OBD C18 Column, 30X150 mm, 5 μm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 23% B to 53% B in 10 min; Wavelength: 254 nm / 220 nm; RT1 (min): 7.6. LC purity: 98.7% (UV at 254 nm); Mass calculated for C21H23F2N7O3S [M+1]+, 492.2, found 492.2; Retention time: 1.178 min.1H NMR (400 MHz, DMSO-d6) 9.02 (dd, J = 8.5, 3.6 Hz, 2H), 8.53 (dd, J = 8.7, 2.6 Hz, 1H), 8.14 (dd, J = 13.8, 1.4 Hz, 2H), 7.45 (s, 2H), 6.98 (d, J = 8.7 Hz, 1H), 4.42 (q, J = 7.0 Hz, 2H), 4.39 – 4.16 (m, 1H), 3.21 (m, 2H), 2.93 – 2.77 (m, 2H), 2.30 – 2.19 (m, 1H), 1.93 (m, 1H), 1.37 (t, J = 7.0 Hz, 4H), 1.23 – 1.10 (m, 1H). Example 71.2-(5-amino-6-fluoropyrazin-2-yl)-6-(4-(2,2-difluoroethoxy)phenyl)-3- fluoro-N-( -2-methyl-2-azabicyclo[2.2.1]heptan-4-yl)isonicotinamide Example 72.2-(5-amino-6-fluoropyrazin-2-yl)-6-(4-(2,2-difluoroethoxy)phenyl)-3- fluoro-N-((4R)-2-methyl-2-azabicyclo[2.2.1]heptan-4-yl)isonicotinamide

[0325] Scheme 32

[0326] Step 1: Methyl 6-(4-(2,2-difluoroethoxy)phenyl)-3-fluoro-2-(6-fluoro-5-((4- methoxybenzyl)amino)pyrazin-2-yl)isonicotinate was synthesized according to General Procedure II using methyl 6-chloro-3-fluoro-2-(6-fluoro-5-((4- methoxybenzyl)amino)pyrazin-2-yl)isonicotinate (preparation in Example 63, Step 1, 1.00 eq, 2000 mg, 4.75 mmol) and 2-(4-(2,2-difluoroethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (1.20 eq, 1620 mg, 5.7 mmol) at 80 °C for 2 h under N2atmosphere. The crude product was added DMSO, filtered and purified via phase flash chromatography (C18 silica gel) using a gradient of 60% to 90% ACN in water (with 10 mmol / L NH4HCO3.) to afford a yellow solid (1700 mg, 3.13 mmol, 65.9% yield). LC purity: 90% (UV at 254 nm); Mass calculated for Chemical Formula: C27H22F4N4O4[M+1]+, 543.2, found 543.3; Retention time: 0.978 min.

[0327] Step 2: 6-(4-(2,2-Difluoroethoxy)phenyl)-3-fluoro-2-(6-fluoro-5-((4- methoxybenzyl)-amino)pyrazin-2-yl)isonicotinic acid was synthesized according to General Procedure IV using methyl 6-(4-(2,2-difluoroethoxy)phenyl)-3-fluoro-2-(6-fluoro-5-((4- methoxybenzyl)amino)pyrazin-2-yl)isonicotinate (1.00 eq, 800 mg, 1.47 mmol) in THF (12 mL) and water (4 mL) was added LiOH (10.00 eq, 335 mg, 14 mmol). The crude product wasadded DMSO, filtered and purified via phase flash chromatography (C18 silica gel) using a gradient of 20% to 50% ACN in water (with 10 mmol / L NH4HCO3.) to afford a yellow solid (510 mg, 0.97 mmol, 65.4% yield). LC purity: 95% (UV at 254 nm); Mass calculated for Chemical Formula: C26H20F4N4O4[M+1]+, 529.1, found 529.15; Retention time: 0.598 min.

[0328] Step 3: Tert-butyl 4-(6-(4-(2,2-difluoroethoxy)phenyl)-3-fluoro-2-(6-fluoro-5-((4- methoxybenzyl)amino)pyrazin-2-yl)isonicotinamido)-2-azabicyclo[2.2.1]heptane-2- carboxylate was synthesized according to General Procedure V using 6-(4-(2,2- difluoroethoxy)phenyl)-3-fluoro-2-(6-fluoro-5-((4-methoxybenzyl)amino)pyrazin-2- yl)isonicotinic acid (1.00 eq, 100 mg, 0.19 mmol) and tert-butyl 4-amino-2- azabicyclo[2.2.1]heptane-2-carboxylate (1.10 eq, 44 mg, 0.21 mmol). The crude product was diluted with DMSO, filtered and purified via phase flash chromatography (C18 silica gel) using a gradient of 20% to 80% ACN in water (with 10 mmol / L NH4HCO3) to afford a yellow solid (130 mg, 0.18 mmol, 95.1% yield). LC purity: 88% (UV at 254 nm); Mass calculated for C37H38F4N6O5[M+1]+, 723.3, found 723.4; Retention time: 1.001 min.

[0329] Step 4: To a solution of tert-butyl 4-(6-(4-(2,2-difluoroethoxy)phenyl)-3-fluoro-2- (6-fluoro-5-((4-methoxybenzyl)amino)pyrazin-2-yl)isonicotinamido)-2-azabicyclo- [2.2.1]heptane-2-carboxylate (1.00 eq, 130 mg, 0.18 mmol) in 1,4-dioxane (3 mL) was added HCl (3.0 mL, 4.0 M in dioxane) at 0 ℃. The reaction was stirred at ambient temperature for 1 h under N2 atmosphere. The resulting solution was concentrated in vacuo to afford the crude N-(2-azabicyclo[2.2.1]heptan-4-yl)-6-(4-(2,2-difluoroethoxy)phenyl)-3-fluoro-2-(6-fluoro-5- ((4-methoxybenzyl)amino)pyrazin-2-yl)isonicotinamide as a yellow solid which was used for the next step without further purification. LC purity: 92% (UV at 254 nm); Mass calculated for C32H30F4N6O3 [M+1]+, 623.2, found 623.0; Retention time: 0.625 min.

[0330] Step 5: To a solution of N-(2-azabicyclo[2.2.1]heptan-4-yl)-6-(4-(2,2- difluoroethoxy)phenyl)-3-fluoro-2-(6-fluoro-5-((4-methoxybenzyl)amino)pyrazin-2- yl)isonicotinamide (1.00 eq, 110 mg, 0.18 mmol) in methanol and the pH value of the solution was adjusted to 9 ~ 10 with DIEA. Then a solution of (CH2O)n (1.20 eq, 6.4 mg, 0.21 mmol) was added, and the pH value of the solution was adjusted to 5 ~ 6 with HOAc. The solution was stirred at ambient temperature for 0.5 h. Then NaBH3CN (5.00 eq, 55 mg, 0.88 mmol) was added in several portions and the mixture was stirred at 50 °C overnight. Upon completion, the mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, andconcentrated in vacuo. The residue was added DMSO, filtered and purified via phase flash chromatography (C18 silica gel) using a gradient of 20% to 60% ACN in water (with 0.1% FA) to afford 6-(4-(2,2-difluoroethoxy)phenyl)-3-fluoro-2-(6-fluoro-5-((4- methoxybenzyl)amino)pyrazin-2-yl)-N-(2-methyl-2-azabicyclo[2.2.1]heptan-4- yl)isonicotinamide (100 mg, 0.16 mmol, 88.9% yield) as a light yellow solid. LC purity: 90% (UV at 254 nm); Mass calculated for C33H32F4N6O3 [M+1]+, 637.2, found 637.3; Retention time: 0.704 min.

[0331] Step 6: 2-(5-Amino-6-fluoropyrazin-2-yl)-6-(4-(2,2-difluoroethoxy)phenyl)-3- fluoro-N-(2-methyl-2-azabicyclo[2.2.1]heptan-4-yl)isonicotinamide was synthesized according to General Procedure III using 6-(4-(2,2-difluoroethoxy)phenyl)-3-fluoro-2-(6- fluoro-5-((4-methoxybenzyl)amino)pyrazin-2-yl)-N-(2-methyl-2-azabicyclo-[2.2.1]heptan-4- yl)isonicotinamide (1.00 eq, 90 mg, 0.14 mmol) at 50 °C for 2 h under N2 atmosphere. The crude product was added DMSO, filtered and purified via phase flash chromatography (C18 silica gel) using a gradient of 40% to 100% ACN in water (with 10 mmol / L NH4HCO3) to afford a light yellow solid (50 mg, 0.092 mmol, 65.1% yield). LC purity: 93% (UV at 254 nm); Mass calculated for C25H24F4N6O2 [M+1]+, 517.2, found 517.3; Retention time: 0.768 min.

[0332] Step 7: 2-(5-Amino-6-fluoropyrazin-2-yl)-6-(4-(2,2-difluoroethoxy)phenyl)-3- fluoro-N-(2-methyl-2-azabicyclo[2.2.1]heptan-4-yl)isonicotinamide (1.00 eq, 50 mg, 0.097 mmol) was purified by Prep-chiral-HPLC (Column: CHIRALPAK IE, 2X25 cm, 5 μm; Mobile Phase A: Hex (0.5% 2M NH3-MeOH)--HPLC, Mobile Phase B: EtOH: DCM=1: 1-- HPLC; Flow rate: 20 mL / min; Gradient (B%): isocratic 40; Wavelength: 254 / 220 nm; RT1 (min): 14.794; RT2 (min): 19.459; Sample Solvent: EtOH--HPLC; Injection Volume: 0.9 mL; Number of Runs: 5). Pure fractions (The first peak compound and the second peak compound were arbitrarily assigned as the S and R isomers, respectively.) were evaporated to afford the title compound (2-(5-amino-6-fluoropyrazin-2-yl)-6-(4-(2,2- difluoroethoxy)phenyl)-3-fluoro-N-((4S)-2-methyl-2-azabicyclo[2.2.1]heptan-4- yl)isonicotinamide, 14 mg, 0.027 mmol, 27.6% yield) as an off-white solid and (2-(5-amino- 6-fluoropyrazin-2-yl)-6-(4-(2,2-difluoroethoxy)phenyl)-3-fluoro-N-((4R)-2-methyl-2- azabicyclo[2.2.1]heptan-4-yl)isonicotinamide, 14 mg, 0.027 mmol, 27.6% yield) as an off- white solid.

[0333] Example 71: LC purity: 97% (UV at 254 nm); Mass calculated for C25H24F4N6O2[M+1]+, 517.2, found 517.2; Retention time: 0.824 min.1H NMR (400 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.68 (d, J = 4.7 Hz, 1H), 8.19 – 8.12 (m, 2H), 7.94 (d, J = 3.8 Hz, 1H), 7.36 (s, 2H), 7.22 – 7.11 (m, 2H), 6.60 – 6.24 (m, 1H), 4.41 (m, 2H), 3.01 (m, 2H), 2.54 (m, 1H), 2.26 (s, 3H), 2.06 – 1.99 (m, 1H), 1.93 – 1.76 (m, 3H), 1.72 (m, 1H), 1.65 – 1.54 (m, 1H).

[0334] Example 72: LC purity: 97% (UV at 254 nm); Mass calculated for C25H24F4N6O2 [M+1]+, 517.2, found 517.2; Retention time: 0.830 min.1H NMR (400 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.68 (d, J = 4.6 Hz, 1H), 8.20 – 8.12 (m, 2H), 7.94 (d, J = 3.7 Hz, 1H), 7.36 (s, 2H), 7.20 – 7.11 (m, 2H), 6.63 – 6.26 (m, 1H), 4.41 (m, 2H), 3.01 (m, 2H), 2.54 (m, 1H), 2.27 (s, 3H), 2.06 – 1.99 (m, 1H), 1.93 – 1.78 (m, 3H), 1.73 (d, J = 8.8 Hz, 1H), 1.65 – 1.54 (m, 1H). Example 73.2-(5-amino-6-fluoropyrazin-2-yl)-6-(4-(2,2-difluoroethoxy)phenyl)-3- fluoro-N-(2-methyl-2-azabicyclo[2.2.2]octan-4-yl)isonicotinamide

[0335] Scheme 33

[0336] Step 1: To a solution of 3-chloro-5-iodopyrazin-2-amine (1.00 eq, 25 g, 97.88 mmol) and 2,4-dimethoxybenzaldehyde (1.20 eq, 19.5 g, 117.33 mmol) in DMF (200 mL) was added TMSCl (3.00 eq, 31.9 g, 293.63 mmol) at 0 °C and the reaction was stirred at 80 °C for 2 h under N2atmosphere. Upon completion, the reaction mixture was cooled to 0 °C and BH3(2.55 eq, 250 mmol, 250 mL, 1 M in THF) was added dropwise. The resulting mixture was stirred at ambient temperature for 2 h. The mixture was concentrated in vacuo and the crude product was purified by column chromatography on silica gel (PE in EtOAc=20%) to afford 3-chloro-N-(2,4-dimethoxybenzyl)-5-iodopyrazin-2-amine (32 g, 78.89 mmol, 80.5% yield) as a white solid. LC purity: 73% (UV at 254 nm); Mass calculated for C13H13ClIN3O2 [M+1]+, 406.0, found 406.0; Retention time: 0.944 min.

[0337] Step 2: To a solution of 3-chloro-N-(2,4-dimethoxybenzyl)-5-iodopyrazin-2-amine (1.00 eq, 30.00 g, 74.0 mmol) and KF (5.00 eq, 21.5 g, 370 mmol) in DMSO (300 mL) was added DIEA (5.00 eq, 47.7 g, 370 mmol) at ambient temperature and the reaction was stirred at 140 ℃ for 12 h under N2atmosphere. Upon completion, the reaction mixture was dilutedwith EtOAc and the organic layers were washed with sat. brine eight times, dried and concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE in EtOAc=20%) to afford N-(2,4-dimethoxybenzyl)-3-fluoro-5-iodopyrazin-2-amine (14.00 g, 34.5 mmol, 46% yield) as a white solid. LC purity: 75% (UV at 254 nm); Mass calculated for C13H13FIN3O2 [M+1]+, 390.0, found 390.0; Retention time: 1.740 min.

[0338] Step 3: To a stirred solution of N-(2,4-dimethoxybenzyl)-3-fluoro-5-iodopyrazin-2- amine (1.00 eq, 14.00 g, 36.0 mmol) and bis(pinacolato)diboron (2.00 eq, 18.3 g, 71.9 mmol) in 1,4-dioxane (50 mL) were added KOAc (2.00 eq, 7.05 g, 71.9 mmol) and Pd(dppf)Cl2(0.10 eq, 2.94 g, 3.60 mmol) under N2 atmosphere. The reaction was stirred at 80 ℃ for 12 h. The resulting mixture was filtered, and the filtrate was used in the next step without further purification. LC purity: 60% (UV at 254 nm); Mass calculated for C19H25BFN3O4[M+1]+, 390.2, found 390.2; Retention time: 1.948 min.

[0339] Step 4 to Step 6: 6-(4-(2,2-Difluoroethoxy)phenyl)-2-(5-((2,4-dimethoxybenzyl)- amino)-6-fluoropyrazin-2-yl)-3-fluoroisonicotinic acid was prepared as a white solid, following a procedure analogous to that described in Example 63 (Step 1 ~ Step 3).

[0340] Step 7: Tert-butyl 4-(6-(4-(2,2-difluoroethoxy)phenyl)-2-(5-((2,4- dimethoxybenzyl)-amino)-6-fluoropyrazin-2-yl)-3-fluoroisonicotinamido)-2- azabicyclo[2.2.2]octane-2-carboxylate was synthesized according to General Procedure V using tert-butyl 4-amino-2-azabicyclo[2.2.2]octane-2-carboxylate (1.20 eq, 29 mg, 0.13 mmol) and 6-(4-(2,2-Difluoroethoxy)phenyl)-2-(5-((2,4-dimethoxybenzyl)amino)-6- fluoropyrazin-2-yl)-3-fluoroisonicotinic acid (1.00 eq, 60 mg, 0.11 mmol). The crude product was purified by reversed phase flash chromatography (C18 silica gel) using a gradient of 50% to 90% ACN in water (with 10 mmol / L NH4HCO3) to afford a yellow oil (80 mg, 0.10 mmol, 94% yield). LC purity: 97% (UV at 254 nm); Mass calculated for C39H42F4N6O6[M+1]+, 767.5, found 767.5; Retention time: 1.252 min.

[0341] Step 8: To a solution of tert-butyl 4-(6-(4-(2,2-difluoroethoxy)phenyl)-2-(5-((2,4- dimethoxybenzyl)amino)-6-fluoropyrazin-2-yl)-3-fluoroisonicotinamido)-2-azabicy- clo[2.2.2]octane-2-carboxylate (1.00 eq, 60 mg, 0.08 mmol) in 1,4-dioxane (2 mL) was added 4M HCl in dioxane (2.0 mL) at ambient temperature. The reaction was stirred at ambient temperature for 1 h under N2 atmosphere. The mixture was concentrated in vacuo to afford crude N-(2-azabicyclo[2.2.2]octan-4-yl)-6-(4-(2,2-difluoroethoxy)phenyl)-2-(5-((2,4- dimethoxybenzyl)amino)-6-fluoropyrazin-2-yl)-3-fluoroisonicotinamide (60 mg, 0.07 mmol,95% yield) as a yellow solid which was used for the next step without further purification. LC purity: 83% (UV at 254 nm); Mass calculated for C34H34F4N6O4 [M+1]+, 667.3, found 667.3; Retention time: 1.058 min.

[0342] Step 9: To a solution of N-(2-azabicyclo[2.2.2]octan-4-yl)-6-(4-(2,2- difluoroethoxy)phenyl)-2-(5-((2,4-dimethoxybenzyl)amino)-6-fluoropyrazin-2-yl)-3- fluoroisonicotinamide (1.00 eq, 60 mg, 0.09 mmol) and (CH2O)n (1.20 eq, 3.2 mg, 0.11 mmol) in DCE (3 mL) were added AcOH (1.00 eq, 0.005 mL, 0.09mmol) and NaBH3CN (5.00 eq, 28 mg, 0.45 mmol) at room temperature. The reaction was stirred for 12 h at 50 ℃. Upon completion, the resulting mixture was concentrated in vacuo and purified by reversed phase flash chromatography (C18 silica gel) using a gradient of 50% to 90% ACN in water (with 10 mmol / L NH4HCO3) to afford 6-(4-(2,2-difluoroethoxy)phenyl)-2-(5-((2,4- dimethoxybenzyl)amino)-6-fluoropyrazin-2-yl)-3-fluoro-N-(2-methyl-2- azabicyclo[2.2.2]octan-4-yl)isonicotinamide (43 mg, 0.04 mmol, 49% yield) as a yellow oil. LC purity: 70% (UV at 254 nm); Mass calculated for C35H36F4N6O4[M+1]+, 681.5, found 681.5; Retention time: 1.240 min.

[0343] Step 10: To a solution of 6-(4-(2,2-difluoroethoxy)phenyl)-2-(5-((2,4- dimethoxybenzyl)amino)-6-fluoropyrazin-2-yl)-3-fluoro-N-(2-methyl-2-azabicyclo- [2.2.2]octan-4-yl)isonicotinamide (1.00 eq, 40 mg, 0.06 mmol) in DCM (2 mL) was added TFA (1.00 eq, 0.40 mL, 0.06 mmol) and stirred for 1 h at 50 ℃. The resulting mixture was treated with 1 mL NH3OH and concentrated in vacuo. The residue was purified by Prep HPLC (Column: XBridge Prep OBD C18 Column, 30X150 mm, 5μm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: MeOH; Flow rate: 60 mL / min; Gradient (B%): 39% B to 64% B in 10 min; Wavelength: 254 nm / 220 nm; RT1 (min): 8.22) to afford the title compound (10 mg, 0.02 mmol, 33% yield) as a white solid. LC purity: 97% (UV at 254 nm); Mass calculated for C26H26F4N6O2 [M+1]+, 531.2, found 531.2; Retention time: 1.479 min.1H NMR (400 MHz, DMSO-d6) δ 8.66 (d, J = 4.6 Hz, 1H), 8.25 (s, 1H), 8.19 – 8.10 (m, 2H), 7.88 (d, J = 3.8 Hz, 1H), 7.35 (s, 2H), 7.18 - 7.10 (m, 2H), 6.43 (t, J = 3.6 Hz, 1H), 4.40 (m, 2H), 2.87 (s, 2H), 2.43 (m, 1H), 2.27 (s, 3H), 2.03 – 1.89 (m, 4H), 1.84 (m, 2H), 1.59 – 1.47 (m, 2H). Example 74.6-(5-amino-6-fluoropyrazin-2-yl)-6'-ethoxy-5-fluoro-N-(2-methyl-2- azabicyclo[2.2.2]octan-4-yl)-[2,3'-bipyridine]-4-carboxamide

[0344] Scheme 34

[0345] Step 1: To a mixture of methyl 6-chloro-2-(5-((2,4-dimethoxybenzyl)amino)-6- fluoropyrazin-2-yl)-3-fluoroisonicotinate (preparation in Example 73, Step 4, 1.00 eq, 500 mg, 1.11 mmol), 2-ethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.20 eq, 334 mg, 1.34 mmol) and Na2CO3(2.00 eq, 235 mg, 2.22 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was added Pd(dppf)Cl2(0.12 eq, 97 mg, 0.13 mmol). The reaction was stirred at 80oC for 2 h under N2 atmosphere. The reaction was then diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel with petroleum ether / ethyl acetate (1 / 1) to give methyl 6-(5- ((2,4-dimethoxybenzyl)amino)-6-fluoropyrazin-2-yl)-6'-ethoxy-5-fluoro-[2,3'-bipyridine]-4- carboxylate (400 mg, 0.74 mmol, 66.3% yield) as a yellow solid. LC purity: 80% (UV at 254 nm); Mass calculated for Chemical Formula: C27H25F2N5O5[M+1]+, 538.2, found 538.2; Retention time: 0.994 min.

[0346] Step 2: To a solution of methyl 6-(5-((2,4-dimethoxybenzyl)amino)-6- fluoropyrazin-2-yl)-6'-ethoxy-5-fluoro-[2,3'-bipyridine]-4-carboxylate (1.00 eq, 400 mg, 0.74 mmol) in THF (3 mL) and water (1 mL) was added LiOH (10.04 eq, 178 mg, 7.43 mmol). The reaction was stirred for 1 h at ambient temperature. The mixture was evaporated and the residue was added DMSO, filtered and the filtrate was purified via reversed phase flash chromatography (C18 silica gel) using a gradient of 20% to 50% ACN in water (with 10mmol / L NH4HCO3.) to afford 6-(5-((2,4-dimethoxybenzyl)amino)-6-fluoropyrazin-2-yl)-6'- ethoxy-5-fluoro-[2,3'-bipyridine]-4-carboxylic acid (310 mg, 0.59 mmol, 79.8% yield) as a yellow solid. LC purity: 90% (UV at 254 nm); Mass calculated for Chemical Formula: C26H23F2N5O5[M+1]+, 524.2, found 524.2; Retention time: 0530 min.

[0347] Step 3: To a solution of 6-(6-ethoxy-3-pyridyl)-2-[5-[(4-ethyl-2-methoxy- phenyl)methylamino]-6-fluoro-pyrazin-2-yl]-3-fluoro-pyridine-4-carboxylic acid (1.00 eq, 80 mg, 0.15 mmol) and tert-butyl 4-amino-2-azabicyclo[2.2.2]octane-2-carboxylate (1.10 eq, 38 mg, 0.16 mmol) in DMF (5 mL) was treated with HATU (1.50 eq, 87 mg, 0.23 mmol) and DIEA (1.50 eq, 30 mg, 0.23 mmol). The reaction mixture was stirred at room temperature for 1h. The resulting mixture was purified by reversed-phase flash chromatography (with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 0 % to 80 % gradient in 18 min; detector, UV 254 nm) to afford tert-butyl 4-[[2-[5-[(2,4- dimethoxyphenyl)methylamino]-6-fluoro-pyrazin-2-yl]-6-(6-ethoxy-3-pyridyl)-3-fluoro- pyridine-4-carbonyl]amino]-2-azabicyclo[2.2.2]octane-2-carboxylate (70 mg, 0.09 mmol, 62 % yield) as a white solid. MS: m / z: C38H43F2N7O6 [M+H]+732, found [M+H]+732. Retention time: 1.135 min.

[0348] Step 4: To a solution of tert-butyl 4-[[2-[5-[(2,4-dimethoxyphenyl)methylamino]-6- fluoro-pyrazin-2-yl]-6-(6-ethoxy-3-pyridyl)-3-fluoro-pyridine-4-carbonyl]amino]-2- azabicyclo[2.2.2]octane-2-carboxylate (1.00 eq, 70 mg, 0.09 mmol) in 1,4-Dioxane (5 mL) was treated with 4M HCl in dioxane (5.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 1h. The resulting mixture was concentrated to afford crude product, which was used directly in the next step without further purification. MS: m / z: C33H35F2N7O4 [M+H]+632.3, found [M+H]+632.2. Retention time: 0.646 min.

[0349] Step 5: To a solution of N-(2-azabicyclo[2.2.2]octan-4-yl)-2-[5-[(2,4- dimethoxyphenyl)methylamino]-6-fluoro-pyrazin-2-yl]-6-(6-ethoxy-3-pyridyl)-3-fluoro- pyridine-4-carboxamide (1.00 eq, 60 mg, 0.09 mmol) in THF (1 mL) was added DIEA to adjust the pH value to 9 ~ 10. Then a solution of (CH2O)n (1.00 eq, 2.8 mg, 0.09 mmol) in THF (0.2 mL) and acetic acid (5.00 eq, 27 mg, 0.45 mmol) were added. The mixture was stirred at ambient temperature for 0.5 h. Then NaBH3CN (5.00 eq, 32 mg, 0.475 mmol) was added and the mixture was stirred at 50 °C overnight. The resulting mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue wasadded DMSO, filtered and the filtrate was purified via reversed phase flash chromatography (C18 silica) using a gradient of 20% to 60% ACN in water (with 0.1% FA) to afford 2-[5- [(2,4-dimethoxyphenyl)methylamino]-6-fluoro-pyrazin-2-yl]-6-(6-ethoxy-3-pyridyl)-3- fluoro-N-(2-methyl-2-azabicyclo[2.2.2]octan-4-yl)pyridine-4-carboxamide (40 mg, 0.06 mmol, 65 % yield) as a white solid. MS: m / z: C34H37F2N7O4 [M+H]+646, found [M+H]+646. Retention time: 0.672 min.

[0350] Step 6: To a solution of 2-[5-[(2,4-dimethoxyphenyl)methylamino]-6-fluoro- pyrazin-2-yl]-6-(6-ethoxy-3-pyridyl)-3-fluoro-N-(2-methyl-2-azabicyclo[2.2.2]octan-4- yl)pyridine-4-carboxamide (1.00 eq, 40 mg, 0.06 mmol) in DCM (3 mL) was added TFA (1 mL), and the resulting solution was stirred at room temperature for 2h. The resulting mixture was concentrated in vacuo. The residue was dissolved in MeCN and treated with 1 mL ammonium hydroxide at 0oC, stirred for 30 min and concentrated in vacuo. The residue was purified by Prep-HPLC using the following conditions: Column: XBridge Prep OBD C18 Column, 30X150 mm, 5μm; Mobile Phase A: Water (10nmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 24% B to 54% B in 8 min; Wave Length: 254nm / 220nm; RT1(min): 7.13. LC purity: 98.5% (UV at 254 nm). The fraction was collected and concentrated under vacuum, and the residue was re-dissolved in CH3CN and H2O, and then was lyophilized to afford 2-(5-amino-6-fluoro-pyrazin-2-yl)-6-(6-ethoxy-3- pyridyl)-3-fluoro-N-(2-methyl-2-azabicyclo[2.2.2]octan-4-yl)pyridine-4-carboxamide (9.5 mg,0.01 mmol, 30% yield) as an off-white solid. Mass calculated for C25H27F2N7O2 [M+1]+, 496.2, found 496.2; Retention time: 1.325 min.1H NMR (400 MHz, DMSO-d6) δ 8.95 (d, J = 2.5 Hz, 1H), 8.70 (d, J = 4.7 Hz, 1H), 8.47 (dd, J = 8.7, 2.6 Hz, 1H), 8.25 (s, 1H), 7.94 (d, J = 3.8 Hz, 1H), 7.37 (s, 2H), 6.92 (d, J = 8.6 Hz, 1H), 4.39 – 4.34 (m, 2H), 2.87 (s, 2H), 2.43 (m, 1H), 2.28 (s, 3H), 1.95 – 1.91 (m, 4H), 1.84 (m, 2H), 1.53 (m, 2H), 1.36 (t, J = 7.1 Hz, 3H). Example 75.2-(5-amino-6-fluoro-pyrazin-2-yl)-6-[6-(2,2-difluoroethoxy)-3-pyridyl]-3- fluoro-N-(2-methyl-2-azabicyclo[2.2.2]octan-4-yl)pyridine-4-carboxamide

[0351] Scheme 35

[0352] Intermediate 6'-(2,2-difluoroethoxy)-6-(5-((2,4-dimethoxybenzyl)amino)-6- fluoropyrazin-2-yl)-5-fluoro-[2,3'-bipyridine]-4-carboxylic acid was prepared in a 50.4% as a white solid, following a procedure analogous to that described in Example 72 (Step 5 and Step 6).

[0353] The title compound (9.4 mg) was prepared in a 13.6% overall yield as an off-white solid, following a procedure analogous to that described in Example 72 (Step 7 to Step 10), 6'-(2,2-difluoroethoxy)-6-(5-((2,4-dimethoxybenzyl)amino)-6-fluoropyrazin-2-yl)-5-fluoro- [2,3'-bipyridine]-4-carboxylic acid in Step 3. prep-HPLC conditions: XBridge Prep OBD C18 Column, 30X150 mm, 5 μm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 27% B to 57% B in 10 min; Wavelength: 254 nm / 220 nm; RT1 (min): 5.56. LC purity: 98.8% (UV at 254 nm); Mass calculated for C25H25F4N7O2[M+1]+, 532.2, found 532.1; Retention time: 1.429 min.1H NMR (400 MHz, DMSO-d6) δ 8.98 (d, J = 2.5 Hz, 1H), 8.70 (d, J = 4.6 Hz, 1H), 8.54 (dd, J = 8.7, 2.5 Hz, 1H), 8.26 (s, 1H), 7.98 (d, J = 3.8 Hz, 1H), 7.37 (s, 2H), 7.06 (d, J = 8.7 Hz, 1H), 6.43 (m, 1H), 4.65 (m, 2H), 2.87 (s, 2H), 2.43 (t, J = 2.8 Hz, 1H), 2.27 (m, 3H), 2.03 – 1.96 (m, 4H), 1.89 – 1.84 (m, 2H), 1.52 (m, 2H). Example 76.6-(5-amino-6-fluoropyrazin-2-yl)-6'-(2,2-difluoroethoxy)-N-(2-ethyl-2- azabicyclo[2.2.2]octan-4-yl)-5-fluoro-[2,3'-bipyridine]-4-carboxamide

[0354] Scheme 36

[0355] Step 1: 6-(5-amino-6-fluoropyrazin-2-yl)-N-(2-azabicyclo[2.2.2]octan-4-yl)-6'-(2,2- difluoroethoxy)-5-fluoro-[2,3'-bipyridine]-4-carboxamide was synthesized according to General Procedure III using tert-butyl 4-(6'-(2,2-difluoroethoxy)-6-(5-((3,4- dimethylbenzyl)amino)-6-fluoropyrazin-2-yl)-5-fluoro-[2,3'-bipyridine]-4-carboxamido)-2- azabicyclo[2.2.2]octane-2-carboxylate (1.0 eq, 70 mg, 0.09 mmol) made analogous to procedure Example 75 (Step 1 to Step 3). The crude product was purified by reversed phase flash chromatography using a gradient of 20% to 80% ACN in water (with 0.1% FA) to afford a white solid (50 mg, 0.11 mmol, 88 % yield). LC purity: 90% (UV at 254 nm); Mass calculated for C24H23F4N7O2 [M+1]+518, found 518; Retention time: 0.405 min.

[0356] Step 2: To a solution of 6-(5-amino-6-fluoropyrazin-2-yl)-N-(2- azabicyclo[2.2.2]octan-4-yl)-6'-(2,2-difluoroethoxy)-5-fluoro-[2,3'-bipyridine]-4- carboxamide (1.0 eq, 55 mg, 0.1 mmol) and acetaldehyde (1.0 eq, 4.7 mg, 0.1 mmol) in methanol (3 mL) was added HOAc (3.0 eq, 19 mg, 0.3 mmol) dropwise at 0 ºC. The resulting mixture was stirred for 10 minutes, then NaBH3CN (3.0 eq, 22 mg, 0.31 mmol) was added at 0 ºC and stirred at ambient temperature for 2h. Upon completion, the mixture was diluted with ice water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified directly by prep-HPLC Column (XBridge Prep OBD C18 Column, 30X150 mm, 5μm; Mobile Phase A: Water (10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 36% B to 66% B in 8 min; Wave Length: 254nm / 220nm; RT1(min): 7.45). The fraction was collected and concentrated in vacuo, and the residue was re-dissolved in CH3CN-H2O mixture and lyophilized to afford the title compound (13 mg, 0.02 mmol, 22 % yield) as an off-white solid. LC purity: 99.1% (UV at 254 nm); MS: m / z: Calc’d for C26H27F4N7O2[M+H]+546.2, found [M+H]+546.3; Retention time: 1.256 min.1H NMR (400 MHz, DMSO) δ 8.98 (d, J = 2.5 Hz, 1H), 8.71 (d, J = 4.7 Hz, 1H), 8.55 (dd, J = 8.7, 2.5 Hz, 1H), 8.26 (s, 1H), 8.00 (d, J = 3.8 Hz, 1H), 7.38 (s, 2H), 7.07 (d, J = 8.8 Hz, 1H),6.44 (t, J = 3.5 Hz, 1H), 4.66 – 4.61 (m, 2H), 2.89 (s, 2H), 2.56 (s, 1H), 2.03 – 1.50 (m, 9H), 0.99 (t, J = 7.1 Hz, 3H). Example 77.6-amino-6''-ethoxy-3',5-difluoro-N-(2-methyl-2-azabicyclo[2.2.2]octan-4- yl)-[3,2':6',3''-terpyridine]-4'-carboxamide

[0348] Scheme 37

[0357] Intermediate tert-butyl 4-(6-amino-6''-ethoxy-3',5-difluoro-[3,2':6',3''-terpyridine]- 4'-carboxamido)-2-azabicyclo[2.2.2]octane-2-carboxylate was prepared in a 19 % as a white solid, following a procedure analogous to that described in Example 73 (Step 4 to Step 7).

[0358] The title compound (14 mg) was prepared in a 18 % overall yield as a white solid, following a procedure analogous to that described in Example 76 (Step 1 and Step 2). Prep- HPLC conditions: Column: XBridge Prep OBD C18 Column, 30X150 mm, 5μm; Mobile Phase A: Water (10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 22% B to 52% B in 8min; Wave Length: 254nm / 220nm; RT1(min): 7.23. LC purity: 99.9% (UV at 254 nm); Mass calculated for C26H28F2N6O2[M+1]+, 495.0, found 495.0 [M+1]. Retention time: 0.565 min.1H NMR (400 MHz, DMSO) δ 8.95 (d, J = 2.5 Hz,1H), 8.53 – 8.44 (m, 2H), 8.23 (s, 1H), 8.03 (dd, J = 12.5, 1.8 Hz, 1H), 7.87 (d, J = 3.9 Hz, 1H), 6.92 (d, J = 8.7 Hz, 1H), 6.78 (s, 2H), 4.39 – 4.36 (m, 2H), 2.87 (s, 2H), 2.43 (t, J = 2.8 Hz, 1H), 2.27 (s, 3H), 2.03 – 1.89 (m, 4H), 1.85 (t, J = 9.4 Hz, 2H), 1.60 – 1.48 (m, 2H), 1.36 (t, J = 7.0 Hz, 3H). Example 78.6-(5-amino-6-fluoropyrazin-2-yl)-6'-cyclopropoxy-5-fluoro-N-(2-methyl-2- azabicyclo[2.2.2]octan-4-yl)-[2,3'-bipyridine]-4-carboxamide

[0351] Scheme 38

[0352] Intermediate tert-butyl 4-(6'-cyclopropoxy-6-(5-((2,4-dimethoxybenzyl)amino)-6- fluoropyrazin-2-yl)-5-fluoro-[2,3'-bipyridine]-4-carboxamido)-2-azabicyclo[2.2.2]octane-2- carboxylate was prepared in a 18.9% as a white solid, following a procedure analogous to that described in Example 73 (Step 5 to Step 7).

[0353] The title compound (9 mg) was prepared in a 10.8% overall yield as a white solid, following a procedure analogous to that described in Example 76 (Step 1 and Step 2). Prep- HPLC conditions: Column: XBridge Prep OBD C18 Column, 30X150 mm, 5μm; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 15% B to 38% B in 10 min; Wave Length: 254nm / 220nm; RT1(min): 8.66. LC purity: 99.7% (UV at 254 nm); Mass calculated for C26H28F2N6O2 [M+1]+, 508.2, found 508.2 [M+1]. Retention time: 1.315 min.1H NMR (400 MHz, DMSO) δ 8.85 (s, 1H), 8.63 (s, 1H), 8.42 (d, J = 8.8 Hz, 1H), 7.90 (d, J = 3.8 Hz, 1H), 7.06 (d, J = 8.7 Hz, 1H), 4.18 (s, 1H), 3.83 (d, J = 11.6 Hz, 1H), 3.33 (s, 1H), 3.21 (d, J = 11.7 Hz, 1H), 2.83 (s, 3H), 2.21 – 2.04 (m, 4H), 1.87 (dd, J = 22.1, 11.7 Hz, 4H), 1.18 (s, 1H), 0.81 (d, J = 6.5 Hz, 2H), 0.68 (s, 2H).Example 79.6-(5-amino-6-fluoropyrazin-2-yl)-6'-ethoxy-N-(2-ethyl-2- azabicyclo[2.2.2]octan-4-yl)-5-fluoro-[2,3'-bipyridine]-4-carboxamide

[0359] Scheme 39

[0360] Step 1: To a solution of tert-butyl 4-amino-2-azabicyclo[2.2.2]octane-2-carboxylate (1.0 eq, 2.5 g, 10.9 mmol) and DIEA (3.0 eq, 4.3 g, 33.1 mmol) in DCM (30mL) was added benzyl carbonochloridate (1.5 eq, 2.4 mL, 16.6 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. LCMS showed the reaction was completed. The resulting solution was diluted with dichloromethane (50 mL x 3). The solid was filtered out and the filtration was concentrated in vacuo. The crude product was purified by reversed phase flash chromatography using a gradient of 50% to 80% ACN in water (with 5mM NH4HCO3) to afford tert-butyl 4-(((benzyloxy)carbonyl)amino)-2- azabicyclo[2.2.2]octane-2-carboxylate (3500 mg, 9.7 mmol, 84.4 % yield) as a white solid. LC purity: 90% (UV at 254 nm); Mass calculated for C20H28N2O4 [M+1]+361.20, found 359.15; Retention time: 0.893 min.

[0361] Step 2: To a solution of tert-butyl 4-(((benzyloxy)carbonyl)amino)-2- azabicyclo[2.2.2]octane-2-carboxylate (1.0 eq, 3.5 g, 9.7 mmol) in 1,4-dioxane (10 mL) was added dropwise HCl-Dioxane (4M, 10 mL). The resulting mixture was stirred at room temperature for 2 h. LCMS showed the reaction was completed. The resulting solution was concentrated in vacuo. The crude product was purified by reversed phase flash chromatography using a gradient of 20% to 50% ACN in water (with 0.1% FA) to afford benzyl N-(2-azabicyclo[2.2.2]octan-4-yl)carbamate (2.5 g,9.6 mmol, 98.9 % yield) as a white solid. LC purity: 92% (UV at 254 nm); Mass calculated for C15H20N2O2[M+1]+261.1, found 261.1; Retention time: 0.476 min.

[0362] Step 3: To a solution of benzyl N-(2-azabicyclo[2.2.2]octan-4-yl)carbamate (1 eq, 1.5 g, 5.76 mmol) in MeCN (20mL) were added DIEA (3.0 eq, 2.2 g, 17.3 mmol) and bromoethane (1.5 eq, 0.7 mL, 8.6 mmol). The resulting solution was stirred at 80 °C for 2 h. The resulting solution was concentrated in vacuo and the crude product purified by reversed phase flash chromatography using a gradient of 20% to 50% ACN in water (with 5mM NH4HCO3) to afford benzyl (2-ethyl-2-azabicyclo[2.2.2]octan-4-yl)carbamate (1.0 g, 3.5 mmol, 55 % yield) as a white solid. LC purity: 92% (UV at 254 nm); Mass calculated for C17H24N2O2 [M+1]+289.2, found 289.2; Retention time: 0.501 min.

[0363] Step 4: To a solution of benzyl (2-ethyl-2-azabicyclo[2.2.2]octan-4-yl)carbamate (1.0 eq, 1.0 g, 3.5 mmol) in TFA (10 mL). The resulting solution was stirred at 60 °C for 2 h. The resulting solution was concentrated in vacuo. The product was used in the next step directly without further purification. Mass calculated for C9H18N2 [M+1]+155.2, found 155.2; Retention time: 0.501 min.

[0364] Step 5: To a solution of 6-(5-((2,4-dimethoxybenzyl)amino)-6-fluoropyrazin-2-yl)- 6'-ethoxy-5-fluoro-[2,3'-bipyridine]-4-carboxylic acid (preparation in Example 74, Step 2, 1.0 eq, 1.6 g, 3.1 mmol), 2-ethyl-2-azabicyclo[2.2.2]octan-4-amine (1.2 eq, 566 mg, 3.7 mmol) in DMF (20 mL) were added HATU (2.0 eq, 2.3 g, 6.1 mmol) and DIEA (3.0 eq, 1.2 g, 9.2 mmol). The resulting solution was stirred at room temperature for 2 h. Upon completion, the reaction was quenched with water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered, concentrated in vacuo. The crude product was used in the next step without further purification. LC purity: 80% (UV at 254 nm); Mass calculated for C + 35H39F2N7O4 [M+1] 660.3, found 660.3; Retention time: 0.967 min.

[0365] Step 6: To a crude solution of 6-(5-((2,4-dimethoxybenzyl)amino)-6-fluoropyrazin- 2-yl)-6'-ethoxy-N-(2-ethyl-2-azabicyclo[2.2.2]octan-4-yl)-5-fluoro-[2,3'-bipyridine]-4- carboxamide (1.0 eq, 1.3 g, 2.0 mmol) in DCM (10mL) was added drowpwise TFA (3mL). The resulting solution was stirred at room temperature for 1 h and was concentrated in vacuo. The crude product was purified by reversed phase flash chromatography using a gradient of 40% to 70% ACN in water (with 5mM NH4HCO3) to afford the title compound (736 mg,1.4 mmol, 72 % yield) as a light yellow solid. LC purity: 98% (UV at 254 nm); Mass calculated for C26H29F2N7O2[M+1]+510.2, found 510.2; Retention time: 1.350 min.1H NMR (400 MHz, DMSO) δ 8.94 (d, J = 2.5 Hz, 1H), 8.69 (d, J = 4.6 Hz, 1H), 8.46 (dd, J = 8.7, 2.6 Hz,1H), 8.25 (s, 1H), 7.95 (d, J = 3.7 Hz, 1H), 7.36 (s, 2H), 6.91 (d, J = 8.7 Hz, 1H), 4.43 – 4.33 (m, 2H), 2.89 (s, 2H), 2.56 (s, 2H), 2.48 (s, 1H), 2.04 – 1.80 (m, 7H), 1.58 – 1.46 (m, 2H), 1.39 – 1.31 (m, 3H), 1.03 – 0.95 (m, 3H). Example 80.6-(5-amino-6-fluoropyrazin-2-yl)-6'-ethoxy-5,5'-difluoro-N-(2-methyl-2- azabicyclo[2.2.2]octan-4-yl)-[2,3'-bipyridine]-4-carboxamide

[0366] Scheme 40

[0367] Step 1: To a stirred solution of 5-bromo-3-fluoropyridin-2-ol and iodoethane (1.0 eq, 1.6 g, 10.4 mmol) in Toluene (30 mL) was added Ag2CO3 (1.0 eq, 2.9 g, 10.4 mmol) at room temperature. The resulting mixture was heated to 150 °C and stirred for 30 min. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (3 X 500 mL). The combined organic layers were washed with saturated brine solution (300 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE: EtOAC= 0~20%) to afford 5-bromo-2-ethoxy-3- fluoropyridine (1.5 g, 6.8 mmol, 65 % yield) as a white solid. LC purity: 97% (UV at 254 nm); Mass calculated for C7H7BrFNO [M+1]+220.0, found 220.0; Retention time: 1.097 min.

[0368] Step 2: To a solution of 5-bromo-2-ethoxy-3-fluoropyridine (1.0 eq, 700 mg, 3.2 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.5 eq, 1.2 g, 4.7 mmol) in 1,4-dioxane (15 mL) were added KOAc (2.0 eq, 624 mg, 6.4 mmol) and Pd(dppf)Cl2(0.1 eq, 260 mg, 0.3 mmol) at room temperature. The reaction was stirred for 6 h at 90 °C under N2 atmosphere. Upon completion, the mixture was quenched with water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford 2-ethoxy-3-fluoro-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.8 g, 5.6 mmol, crude) as a brown oil. LC purity: 80% (UV at 254 nm); Mass calculated for C13H19BFNO3 [M+1]+268.0, found 268.0; Retention time:1.328 min.

[0369] Step 3: To a stirred solution of methyl 6-chloro-2-(5-((2,4- dimethoxybenzyl)amino)-6-fluoropyrazin-2-yl)-3-fluoroisonicotinate (preparation in Example 73, Step 4, 1.0 eq, 300 mg, 0.7 mmol) and 2-ethoxy-3-fluoro-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.0 eq, 178 mg, 0.7 mmol) in 1,4-dioxane (12 mL) and water (1.2 mL) was added Na2CO3 (1.0 eq, 71 mg, 0.7 mmol) and Pd(dtbpf)Cl2 (1.0 eq, 433 mg, 0.7 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was kept at 60 °C and stirred for 2 h. The resulting mixture was diluted with water (30 mL) and extracted with EA (3 X 200 mL). The combined organic layers were washed with brine solution (100 mL) and dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by reversed phase flash chromatography (C18 silica gel) using a gradient of 50% to 95% ACN in water (with 10 mmol / L NH4HCO3) to afford methyl 6-(5-((2,4-dimethoxybenzyl)amino)-6-fluoropyrazin-2-yl)-6'-ethoxy-5,5'-difluoro-[2,3'- bipyridine]-4-carboxylate (195 mg, 0.3 mmol, 52 % yield) as a yellow solid. LC purity: 93% (UV at 254 nm); Mass calculated for C27H24F3N5O5[M+1]+556.2, found 556.2; Retention time: 1.076 min.

[0370] Step 4: To a stirred solution of methyl 6-(5-((2,4-dimethoxybenzyl)amino)-6- fluoropyrazin-2-yl)-6'-ethoxy-5,5'-difluoro-[2,3'-bipyridine]-4-carboxylate (1.0 eq, 185 mg, 0.3 mmol) in water (2 mL) and THF (6 mL) was added LiOH (8.0 eq, 66 mg, 2.74 mmol) at room temperature. The mixture was concentrated in vacuo. The residue was taken up in water (10 mL) and the pH adjusted to 3 by the addition of 1M HCl. The resulting mixture was extracted with EA (3 X 80 mL). The combined organic layer was washed with brine solution (100 mL) and dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by reversed phase flash chromatography (C18 silica gel) using a gradient of 50%to 95% ACN in water (with 0.1% FA) to afford 6-(5-((2,4-dimethoxybenzyl)amino)-6- fluoropyrazin-2-yl)-6'-ethoxy-5,5'-difluoro-[2,3'-bipyridine]-4-carboxylic acid (155 mg, 0.3 mmol, 80 % yield) as a light yellow solid. LC purity: 96% (UV at 254 nm); Mass calculated for C26H22F3N5O5[M+1]+542.1, found 542.1; Retention time: 0.955 min.

[0371] Step 5: To a stirred solution of 6-(5-((2,4-dimethoxybenzyl)amino)-6- fluoropyrazin-2-yl)-6'-ethoxy-5,5'-difluoro-[2,3'-bipyridine]-4-carboxylic acid (1.0 eq, 80 mg, 0.1 mmol) and tert-butyl 4-amino-2-azabicyclo[2.2.2]octane-2-carboxylate (1.8 eq, 60 mg, 0.3 mmol) in MeCN (5 mL) was added TCFH (1.5 eq, 62 mg, 0.2 mmol) and NMI (5.0 eq, 61 mg, 0.7 mmol) at ambient temperature. The resulting mixture was stirred at ambient temperature for 1 h. The recation was concentrated in vacuo and the residue was purified by reversed phase flash chromatography (C18 silica gel) using a gradient of 70% to 95% ACN in water (with 10 mmol / L NH4HCO3) to afford tert-butyl 4-(6-(5-((2,4- dimethoxybenzyl)amino)-6-fluoropyrazin-2-yl)-6'-ethoxy-5,5'-difluoro-[2,3'-bipyridine]-4- carboxamido)-2-azabicyclo[2.2.2]octane-2-carboxylate (88 mg, 0.1 mmol, 77 % yield) as a light yellow solid. LC purity: 97% (UV at 254 nm); Mass calculated for C38H42F3N7O6 [M+1]+750.5, found 750.5; Retention time: 1.484 min.

[0372] Step 6: To a stirred solution of tert-butyl 4-(6-(5-((2,4-dimethoxybenzyl)amino)-6- fluoropyrazin-2-yl)-6'-ethoxy-5,5'-difluoro-[2,3'-bipyridine]-4-carboxamido)-2- azabicyclo[2.2.2]octane-2-carboxylate (1.0 eq, 88 mg, 0.1 mmol) in DCM (5 mL) was added TFA (1.0 mL) at ambient temperature. The resulting mixture was stirred at ambient temperature for 1 h. The resulting mixture was concentrated in vacuo. The residue was purified by reversed phase flash chromatography (C18 silica gel) using a gradient of 40% to 70% ACN in water (with 10 mmol / L NH4HCO3) to afford 6-(5-amino-6-fluoropyrazin-2-yl)- N-(2-azabicyclo[2.2.2]octan-4-yl)-6'-ethoxy-5,5'-difluoro-[2,3'-bipyridine]-4-carboxamide (60 mg, 0.1 mmol, 78 % yield) as a light yellow solid. LC purity: 77% (UV at 254 nm); Mass calculated for C24H24F3N7O2 [M+1]+500.2, found 500.2; Retention time: 0.915 min.

[0373] Step 7: To a stirred solution of 6-(5-amino-6-fluoropyrazin-2-yl)-N-(2- azabicyclo[2.2.2]octan-4-yl)-6'-ethoxy-5,5'-difluoro-[2,3'-bipyridine]-4-carboxamide (1.0 eq, 60 mg, 0.1 mmol) in Methanol (4 mL) were added AcOH (2.9 eq, 0.1 mL, 0.3 mmol) and formaldehyde (1.6 eq, 16 mg, 0.2 mmol). Then NaBH3CN (2.9 eq, 14 mg, 0.3 mmol) was added in the reaction system after the mixture was stirred for 30 min. The resulting mixture was stirred for 1 h at ambient temperature, then diluted with water (10 mL) and extractedwith EA (3 X 50 mL). The combined organic layer was washed with saturated NaCl solution (40 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo. The residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30 X 150 mm, 5 μm; Mobile Phase A: water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 23% B to 53% B in 8 min; Wavelength: 254 nm / 220 nm; RT1 (min): 7.29). The pure fractions were concentrated and lyophilized to afford the title compound (30 mg, 0.1 mmol, 47 % yield) as a white solid. LC purity: 99.9% (UV at 254 nm); Mass calculated for C25H26F3N7O2 [M+1]+, 514.2, found 514.2; Retention time: 0.925 min.1H NMR (400 MHz, DMSO) δ 8.79 (d, J = 2.0 Hz, 1H), 8.74 (d, J = 4.6 Hz, 1H), 8.50 - 8.36 (m, 1H), 8.26 (s, 1H), 8.01 (d, J = 3.7 Hz, 1H), 7.38 (s, 2H), 4.54 - 4.40 (m, 2H), 2.87 (s, 2H), 2.42 (t, J = 1.7 Hz, 1H), 2.27 (s, 3H), 2.02 - 1.89 (m, 4H), 1.89 - 1.70 (m, 2H), 1.60 - 1.45 (m, 2H), 1.39 (t, J = 7.0 Hz, 3H). Example 81.6-(5-amino-6-fluoropyrazin-2-yl)-6'-(cyclopropylmethoxy)-5-fluoro-N-(2- methyl-2-azabicyclo[2.2.2]octan-4-yl)-[2,3'-bipyridine]-4-carboxamide

[0374] Scheme 41

[0375] Intermediate tert-butyl 4-(6'-(cyclopropylmethoxy)-6-(5-((2,4- dimethoxybenzyl)amino)-6-fluoropyrazin-2-yl)-5-fluoro-[2,3'-bipyridine]-4-carboxamido)-2- azabicyclo[2.2.2]octane-2-carboxylate was prepared in a 77.4% as a yellow solid, following a procedure analogous to that described in Example 73 (Step 4 to Step 7).

[0376] The title compound (26.3 mg) was prepared in a 42% overall yield as a white solid, following a procedure analogous to that described in Example 76 (Step 1 and Step 2). Prep- HPLC conditions: Column: XBridge Prep OBD C 18 Column, 30 X 150 mm, 5 μm; MobilePhase A: water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 24% B to 54% B in 8 min; Wavelength: 254 nm / 220 nm; RT1 (min): 7.3. LC purity: 99.9% (UV at 254 nm); Mass calculated for C27H29F2N7O2 [M+1]+, 522.2, found 522.2; Retention time: 0.948 min.1H NMR (400 MHz, DMSO) δ 8.92 (d, J = 2.5 Hz, 1H), 8.69 (d, J = 4.7 Hz, 1H), 8.55 - 8.35 (m, 1H), 8.25 (s, 1H), 7.94 (d, J = 3.7 Hz, 1H), 7.36 (s, 2H), 6.94 (d, J = 8.7 Hz, 1H), 4.17 (d, J = 7.1 Hz, 2H), 2.87 (s, 2H), 2.42 (t, J = 2.9 Hz, 1H), 2.27 (s, 3H), 2.03 - 1.90 (m, 4H), 1.90 - 1.70 (m, 2H), 1.62 - 1.40 (m, 2H), 1.36 - 1.13 (m, 1H), 0.63 - 0.48 (m, 2H), 0.41 - 0.30 (m, 2H). Example 82.6-(5-amino-6-fluoropyrazin-2-yl)-6'-(ethoxy-d5)-5,5'-difluoro-N-(2-methyl- 2-azabicyclo[2.2.2]octan-4-yl)-[2,3'-bipyridine]-4-carboxamide

[0377] Scheme 83

[0378] Step 1: To a stirred solution of 5-bromo-3-fluoropyridin-2-ol (1.0 eq, 5.0 g, 26 mmol) and 1-iodoethane-1,1,2,2,2-d5(1.0 eq, 4.2 g, 26 mmol) in Toluene (30 mL) was added Ag2CO3 (1.0 eq, 7.2 g, 26 mmol) at room temperature. The resulting mixture was heated to 150 °C and stirred for 30 min. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (3 X 500 mL). The combined organic layer was washed with saturated NaCl solution (300 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate wasconcentrated in vacuo. The residue was purified by column chromatography on silica gel (PE: EtOAC = 0~20%) to afford 5-bromo-2-(ethoxy-d5)-3-fluoropyridine (4.1 g, 18.2 mmol, 70 % yield) as a yellow solid. LC purity: 78% (UV at 254 nm); Mass calculated for C7H2D5BrFNO [M+1]+225.0, found 225.0; Retention time: 0.556 min.

[0379] The title compound (21 mg) was prepared in 8.8% yield as a light yellow solid, following a procedure analogous to that described in Example 80 (Step 1 to Step 6). Prep- HPLC conditions: Column: X-Bridge Prep OBD C18 Column, 30X150 mm, 5 μm; Mobile Phase A: Water (10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 35% B to 60% B in 10 min; Wavelength: 254 nm / 220 nm; RT1 (min): 8.23. LC purity: 95.8% (UV at 254 nm); Mass calculated for C25H21D5F3N7O2[M+1]+, 519.2, found, 519.2; Retention time: 6.145 min.1H NMR (400 MHz, DMSO-d6) δ 8.79 (d, J= 2.0 Hz, 1H), 8.74 (d, J = 4.7 Hz, 1H), 8.44 (dd, J = 11.9, 2.1 Hz, 1H), 8.27 (s, 1H), 8.01 (d, J = 3.7 Hz, 1H), 7.38 (s, 2H), 2.88 (s, 2H), 2.44 (d, J = 2.9 Hz, 1H), 2.28 (s, 3H), 2.03 – 1.89 (m, 4H), 1.84 – 1.82 (m, 2H), 1.60 – 1.48 (m, 2H). Example 83.5-amino-6''-ethoxy-3',6-difluoro-N-(2-methyl-2-azabicyclo[2.2.2]octan-4- yl)-[2,2':6',3''-terpyridine]-4'-carboxamide

[0380] Scheme 43

[0381] Step 1: To a solution of 6-bromo-2-fluoropyridin-3-amine (1.0 eq, 400 mg, 2.1 mmol) and Sn2Me6(1.5 eq, 1300 mg, 3.9 mmol) in 1,4-dioxane (20 mL) was added Pd(PPh3)4 (0.1 eq, 302 mg, 0.2 mmol) under N2 at ambient temperature. The resulting mixture was heated to 100 ℃ and stirred for 2 h. The resulting mixture was concentrated in vacuo and diluted with sat. KF. The mixture was extracted with EA and the organic layers were washed with sat. KF, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified via silica gel chromatography using a gradient of 0 to 25% EA in PE to afford 2-fluoro-6-(trimethylstannyl)pyridin-3-amine (380 mg, 1.26 mmol, 65% yield) as a colorless oil. LC purity: 91.2% (UV at 254 nm); Mass calculated for C8H13FN2Sn [M+1]+276.6, found 276.6; Retention time: 0.952 min.

[0382] Step 2: To a solution of 2-fluoro-6-(trimethylstannyl)pyridin-3-amine (0.8 eq, 373 mg, 1.3 mmol) and methyl 2,6-dichloro-3-fluoroisonicotinate (1.0 eq, 380 mg, 1.7 mmol) in 1,4-dioxane (15 mL) was added PCy3 (0.3 eq, 142 mg, 0.5 mmol) and Pd(OAc)2 (0.2 eq, 77 mg, 0.3 mmol) at ambient temperature, and the mixture was stirred at 100 ℃ for 1 h under N2. The solvent was removed in vacuo and the resulting residue was purified via reversed phase flash chromatography using a gradient of 40% to 70% ACN in water (with 10 mmol / L NH4HCO3) to afford methyl 5'-amino-6-chloro-3,6'-difluoro-[2,2'-bipyridine]-4-carboxylate(130 mg, 0.3 mmol, 17% yield) as a yellow solid. LC purity: 65.0% (UV at 254 nm); Mass calculated for C12H8ClF2N3O2 [M+1]+, 300.0, found 300.0; Retention time: 1.096 min.

[0383] Step 3: To a solution of 2-ethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridine (1.5 eq, 162 mg, 0.6 mmol) and methyl 5'-amino-6-chloro-3,6'-difluoro-[2,2'- bipyridine]-4-carboxylate (1.0 eq, 130 mg, 0.4 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) waere added Na2CO3 (3.0 eq, 138 mg, 1.3 mmol) and Pd(dppf)Cl2 (0.1 eq, 35 mg, 0.04 mmol) under N2at ambient temperature. The reaction was stirred at 80 ℃ for 1 h, and the resulting mixture was purified via reversed phase flash chromatography using a gradient of 50% to 80% ACN in water (with 10 mmol / L NH4HCO3) to afford methyl 5-amino-6''-ethoxy- 3',6-difluoro-[2,2':6',3''-terpyridine]-4'-carboxylate (110 mg, 0.2 mmol, 56% yield) as a yellow oil. LC purity: 85.2% (UV at 254 nm); Mass calculated for C19H16F2N4O3[M+1]+, 387.1, found 387.1; Retention time: 1.031 min.

[0384] Step 4: To a solution of methyl 5-amino-6''-ethoxy-3',6-difluoro-[2,2':6',3''- terpyridine]-4'-carboxylate (1.0 eq, 110 mg, 0.3 mmol) in THF (1.5 mL) and water (1.5 mL) was added LiOH H2O (3.0 eq, 149 mg, 1.4 mmol) at ambient temperature. The reaction was stirred at ambient temperature for 1 h and was purified via reversed phase flash chromatography using a gradient of 20% to 70% ACN in water (with 10 mmol / L NH4HCO3) to afford 5-amino-6''-ethoxy-3',6-difluoro-[2,2':6',3''-terpyridine]-4'-carboxylic acid (90 mg, 0.2 mmol, 92% yield) as a yellow oil. LC purity: 90.9% (UV at 254 nm); Mass calculated for C18H14F2N4O3 [M+1]+, 373.0, found 373.0; Retention time: 0.513 min.

[0385] Step 5: The solution of 5-amino-6''-ethoxy-3',6-difluoro-[2,2':6',3''-terpyridine]-4'- carboxylic acid (1.0 eq, 75 mg, 0.2 mmol) and tert-butyl 4-amino-2-azabicyclo[2.2.2]octane- 2-carboxylate (1.5 eq, 68 mg, 0.3 mmol) in MeCN (2 mL) was added TCFH (2.0 eq, 392 mg, 1.4 mmol) and NMI (2.0 eq, 33 mg, 0.4 mmol) under at ambient temperature. The reaction was stirred at ambient temperature for 1 h. The resulting mixture was purified via reversed phase flash chromatography using a gradient of 50% to 80% ACN in water (with 10 mmol / L NH4HCO3) to afford tert-butyl 4-(5-amino-6''-ethoxy-3',6-difluoro-[2,2':6',3''-terpyridine]-4'- carboxamido)-2-azabicyclo[2.2.2]octane-2-carboxylate (60 mg, 0.1 mmol, 53% yield) as a yellow oil. LC purity: 96.6% (UV at 254 nm); Mass calculated for C30H34F2N6O4 [M+1]+581.1, found 581.1; Retention time: 1.226 min.

[0386] Step 6: The solution of tert-butyl 4-(5-amino-6''-ethoxy-3',6-difluoro-[2,2':6',3''- terpyridine]-4'-carboxamido)-2-azabicyclo[2.2.2]octane-2-carboxylate (1.0 eq, 60 mg, 0.1mmol) in DCM (2 mL) was added TFA (1.0 eq, 0.2 mL, 0.4 mmol), and the mixture was stirred for 1 h at ambient temperature. The resulting mixture was diluted with DCM and basified with NH4OH (0.5 mL). The mixture was concentrated and purified via reversed phase flash chromatography using a gradient of 50% to 80% ACN in water (with 10 mmol / L NH4HCO3) to afford 5-amino-N-(2-azabicyclo[2.2.2]octan-4-yl)-6''-ethoxy-3',6-difluoro- [2,2':6',3''-terpyridin e]-4'-carboxamide (45 mg, 0.1 mmol, 97% yield) as a yellow oil. LC purity: 93.9% (UV at 254 nm); Mass calculated for C25H26F2N6O2[M+1]+481.3, found 481.3; Retention time: 1.093 min.

[0387] Step 7: To a solution of 5-amino-N-(2-azabicyclo[2.2.2]octan-4-yl)-6''-ethoxy-3',6- difluoro-[2,2':6',3''-terpyridine]-4'-carboxamide (1.0 eq, 40 mg, 0.08 mmol) in methanol (2 mL) were added formaldehyde (1.6 eq, 4.0 mg, 0.1 mmol) and acetic acid (0.6 eq, 0.003 mL, 0.05 mmol), the resulting mixture was stirred at ambient temperature for 20 min. NaBH3CN (1.9 eq, 10 mg, 0.2 mmol) was added to above mixture and the reaction was stirred at ambient temperature for 1 h. Upon completion, the reaction mixture was diluted with water and extracted with EtOAc. The organic layers were washed with brine over 4 times, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by prep- HPLC (Column: XBridge Prep OBD C18 Column, 30X150 mm, 5 μm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 24% B to 54% B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 6.87). The pure fractions were concentrated and lyophilized to afford title compound (13 mg, 0.02 mmol, 32% yield) as a white solid. LC purity: 99.1% (UV at 254 nm); Mass calculated for C26H28F2N6O2 [M+1]+, 495.2, found 495.2; Retention time: 0.898 min.1H NMR (400 MHz, DMSO) δ 8.94 (d, J = 2.5 Hz, 1H), 8.45 (dd, J = 8.7, 2.6 Hz, 1H), 8.23 (s, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.90 (d, J = 3.7 Hz, 1H), 7.29 (dd, J = 11.2, 8.1 Hz, 1H), 6.92 (d, J = 8.6 Hz, 1H), 5.95 (s, 2H), 4.38 (q, J = 7.0 Hz, 2H), 2.87 (s, 2H), 2.54-2.43 (m, 1H), 2.28 (s, 3H), 1.95 (d, J = 10.0 Hz, 4H), 1.86 (d, J = 12.9 Hz, 2H), 1.52 (t, J = 9.4 Hz, 2H), 1.36 (t, J = 7.0 Hz, 3H). Example 84. (S)-6-(5-amino-6-fluoropyrazin-2-yl)-N-(1,3-dimethylpiperidin-3-yl)-6'- ethoxy-5-fluoro-[2,3'-bipyridine]-4-carboxamide Example 85. (R)-6-(5-amino-6-fluoropyrazin-2-yl)-N-(1,3-dimethylpiperidin-3-yl)-6'- ethoxy-5-fluoro-[2,3'-bipyridine]-4-carboxamide

[0388] Scheme 44

[0389] Step 1: To a solution of 6-(5-((2,4-dimethoxybenzyl)amino)-6-fluoropyrazin-2-yl)- 6'-ethoxy-5-fluoro-[2,3'-bipyridine]-4-carboxylic acid (preparation in Example 74, Step 2, 1.0 eq, 200 mg, 0.2 mmol) and tert-butyl 3-amino-3-methylpiperidine-1-carboxylate (1.1 eq, 54 mg, 0.2 mmol) in DMF (5 mL) were added HATU (2.0 eq, 174 mg, 0.5 mmol) and DIEA (2.0 eq, 59 mg, 0.5 mmol), and the reaction mixture was stirred at ambient temperature for 1 h, then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated to afford the crude tert- butyl 3-(6-(5-((2,4-dimethoxybenzyl)amino)-6-fluoropyrazin-2-yl)-6'-ethoxy-5-fluoro-[2,3'- bipyridine]-4-carboxamido)-3-methylpiperidine-1-carboxylate (200 mg, 0.1 mmol, 64% yield) as a black oil. LC purity: 52.9% (UV at 254 nm); Mass calculated for C37H43F2N7O6 [M+1]+720.3, found 720.3; Retention time: 1.081min.

[0390] Step 2: To a solution of crude tert-butyl 3-(6-(5-((2,4-dimethoxybenzyl)amino)-6- fluoropyrazin-2-yl)-6'-ethoxy-5-fluoro-[2,3'-bipyridine]-4-carboxamido)-3-methylpiperidine- 1-carboxylate (1.0 eq, 200 mg, 0.1 mmol) in DCM (2.5 mL) was added TFA (1.0 eq, 0.5 mL) and the reaction mixture was stirred at 50 ℃ for 1 h. The resulting mixture was treated with 2 mL NH4OH and concentrated. The residue was purified via reversed phase flash chromatography using a gradient of 22% to 52% ACN in water (with 10 mmol / L NH4HCO3) to afford 6-(5-amino-6-fluoropyrazin-2-yl)-6'-ethoxy-5-fluoro-N-(3-methylpiperidin-3-yl)- [2,3'-bipyridine]-4-carboxamide (60 mg, 0.1 mmol, 90 % yield) as a white solid. LC purity: 89.1% (UV at 254 nm); Mass calculated for C23H25F2N7O2 [M+1]+470.2, found 470.2; Retention time: 1.155 min.

[0391] Step 3: To a solution of 6-(5-amino-6-fluoropyrazin-2-yl)-6'-ethoxy-5-fluoro-N-(3- methylpiperidin-3-yl)-[2,3'-bipyridine]-4-carboxamide (1.0 eq, 70 mg, 0.2 mmol) andformaldehyde (1.5 eq, 17 mg, 0.2 mmol) in methanol (3 mL) was added acetic acid (5.0 eq, 45 mg, 0.7 mmol) and NaBH3CN (3.0 eq, 28 mg, 0.4 mmol) at ambient temperature. The reaction was stirred at ambient temperature for 1 h. The resulting mixture was diluted with ice-water and extracted with EtOAc. The organic layers were concentrated and the resulting residue was purified via reverse phase flash chromatography (C18 silica gel) using a gradient of 50% to 80% ACN in water (with 10 mmol / L NH4HCO3) to afford 6-(5-amino-6- fluoropyrazin-2-yl)-N-(1,3-dimethylpiperidin-3-yl)-6'-ethoxy-5-fluoro-[2,3'-bipyridine]-4- carboxamide (30 mg, 0.06 mmol, 42% yield) as a yellow solid. LC purity: 100% (UV at 254 nm); Mass calculated for C24H27F2N7O2 [M+1]+484.1, found 484.1; Retention time: 0.878 min.

[0392] Step 4: 6-(5-amino-6-fluoropyrazin-2-yl)-N-(1,3-dimethylpiperidin-3-yl)-6'-ethoxy- 5-fluoro-[2,3'-bipyridine]-4-carboxamide (1.0 eq, 30 mg, 0.06 mmol) was purified by prep- chiral-HPLC (Column: JW-CHIRAL ART Cellulose-SB, 20X250 mm, 5 um; Mobile Phase A: EtOH: DCM=1: 1--HPLC, Mobile Phase B: Hex (0.1% 2M NH3-MeOH)--HPLC; Flow rate: 20 mL / min; Gradient (B%): 80% B to 80% B in 26min% B; Wavelength: 220 / 254 nm; RT1(min): 9.03; RT2(min): 23.13; Sample Solvent: EtOH: DCM=1: 1--HPLC; Injection Volume: 1.0 mL; Number of Runs: 5). Pure fractions (The first peak compound and the second peak compound were arbitrarily assigned as the S and R isomers, respectively.) were evaporated to afford the title compound (S)-6-(5-amino-6-fluoropyrazin-2-yl)-N-(1,3- dimethylpiperidin-3-yl)-6'-ethoxy-5-fluoro-[2,3'-bipyridine]-4-carboxamide (10 mg, 0.02 mmol, 31% yield) as a white solid and (R)-6-(5-amino-6-fluoropyrazin-2-yl)-N-(1,3- dimethylpiperidin-3-yl)-6'-ethoxy-5-fluoro-[2,3'-bipyridine]-4-carboxamide (8.3 mg, 0.02 mmol, 26% yield) as a white solid.

[0393] Example 84: LC purity: 93.0% (UV at 254 nm); Mass calculated for C24H27F2N7O2[M+1]+, 484.2, found 484.2; Retention time: 1.420 min.1H NMR (400 MHz, DMSO) δ 8.88 (d, J = 2.5 Hz, 1H), 8.66 (d, J = 4.5 Hz, 1H), 8.42 (dd, J = 8.7, 2.5 Hz, 1H), 7.97 (d, J = 3.8 Hz, 1H), 6.92 (d, J = 8.7 Hz, 1H), 4.36 (q, J = 7.0 Hz, 2H), 2.75 (s, 1H), 2.14 (s, 4H), 2.01 (s, 2H), 1.68-1.61 (m, 1H), 1.50 (d, J = 7.2 Hz, 1H), 1.40 (s, 3H), 1.34 (t, J = 7.0 Hz, 3H), 1.26 (s, 2H).

[0394] Example 85: LC purity: 95.1% (UV at 254 nm); Mass calculated for C24H27F2N7O2 [M+1]+, 484.2, found 484.2; Retention time: 1.505 min.1H NMR (400 MHz, DMSO) δ 8.88 (d, J = 2.6 Hz, 1H), 8.66 (m, 1H), 8.42 (m, 1H), 7.97 (d, J = 3.8 Hz, 1H), 6.92 (d, J = 8.7 Hz,1H), 4.36 (q, J = 6.9 Hz, 2H), 2.37-2.17 (m, 7H), 1.66 (s, 1H), 1.52 (s, 1H), 1.40 (d, J = 2.7 Hz, 3H), 1.34 (m, 3H), 1.27 (m, 2H). Example 86. (S)-6-(5-amino-6-fluoropyrazin-2-yl)-N-(1,3-dimethylpiperidin-3-yl)-6'- ethoxy-5,5'-difluoro-[2,3'-bipyridine]-4-carboxamide

[0395] Scheme 45

[0396] Step 1: To a solution of tert-butyl (S)-(3-methylpiperidin-3-yl)carbamate (1.0 eq, 400 mg, 1.8 mmol) in DCM (5 mL) were added TEA (3.0 eq, 566 mg, 5.6 mmol) and CbzCl (1.5 eq, 478 mg, 2.8 mmol) at 0 ℃. The reaction was stirred at ambient temperature for 12 h. The resulting mixture was then concentrated and purified via reversed phase flash chromatography using a gradient of 40% to 70% ACN in water (with 10 mmol / L NH4HCO3) to afford benzyl (S)-3-((tert-butoxycarbonyl)amino)-3-methylpiperidine-1-carboxylate (600 mg, 1.6 mmol, 87% yield) as a white solid. LC purity: 94.3% (UV at 254 nm); Mass calculated for C19H28N2O4[M+1]+349.1, found 349.1; Retention time: 1.007 min.

[0397] Step 2: To a stirred solution of benzyl (S)-3-((tert-butoxycarbonyl)amino)-3- methylpiperidine-1-carboxylate (1.0 eq, 300 mg, 0.8 mmol) in 1,4-dioxane (4 mL) was added dropwise a solution of HCl in 1,4-dioxane (4.0 mL) at 0 ℃. The reaction was stirred at ambient temperature for 1 h. The resulting mixture was concentrated to afford crude benzyl (S)-3-amino-3-methylpiperidine-1-carboxylate (200 mg, 0.7 mmol, 84% yield) as a yellow solid which was used directly in the next step without further purification. LC purity: 90.3% (UV at 254 nm); Mass calculated for C14H20N2O2[M+1]+249.2, found 249.2; Retention time: 0.662 min.

[0398] Step 3: To solution of crude benzyl (S)-3-amino-3-methylpiperidine-1-carboxylate (1.2 eq, 110 mg, 0.4 mmol) and 6-(5-((2,4-dimethoxybenzyl)amino)-6-fluoropyrazin-2-yl)-6'- ethoxy-5,5'-difluoro-[2,3'-bipyridine]-4-carboxylic acid (preparation in Example 80, Step 4, 1.0 eq, 200 mg, 0.3 mmol) in DMF (5 mL) were added DIEA (2.0 eq, 95 mg, 0.7 mmol) and HATU (2.0 eq, 281 mg, 0.7 mmol). The reaction was stirred at ambient temperature for 1 h. The resulting mixture was diluted with water and extracted with EtOAc. The organic layers were washed, dried and concentrated. The residue was purified via silica gel chromatography using a gradient of 0 to 50% EtOAc in PE to afford benzyl (S)-3-(6-(5-((2,4- dimethoxybenzyl)amino)-6-fluoropyrazin-2-yl)-6'-ethoxy-5,5'-difluoro-[2,3'-bipyridine]-4- carboxamido)-3-methylpiperidine-1-carboxylate (100 mg, 0.1 mmol, 32% yield) as a yellow solid. LC purity: 92.5% (UV at 254 nm); Mass calculated for C40H40F3N7O6[M+1]+772.2, found 772.2; Retention time: 1.147 min.

[0399] Step 4: To a solution of benzyl (S)-3-(6-(5-((2,4-dimethoxybenzyl)amino)-6- fluoropyrazin-2-yl)-6'-ethoxy-5,5'-difluoro-[2,3'-bipyridine]-4-carboxamido)-3- methylpiperidine-1-carboxylate (1.0 eq, 100 mg, 0.1 mmol) in HFIP (1.0 eq, 5.0 mL) was added methanesulfonic acid (59.4 eq, 0.5 mL, 7.7 mmol) at 0 ℃. The reaction was stirred at ambient temperature for 1 h. The resulting mixture was poured into ice-cold water and adjusted to pH 8–9 with saturated aqueous sodium bicarbonate. The aqueous layer was extracted with with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified via reversed phase flash chromatography using a gradient of 60% to 90% ACN in water (with 10 mmol / L NH4HCO3) to afford (S)-6-(5-amino-6-fluoropyrazin-2-yl)-6'-ethoxy-5,5'-difluoro- N-(3-methylpiperidin-3-yl)-[2,3'-bipyridine]-4-carboxamide (40 mg, 0.1 mmol, 56% yield) as a yellow solid. LC purity: 89.2% (UV at 254 nm); Mass calculated for C23H24F3N7O2[M+1]+488.2, found 488.2; Retention time: 0.670 min.

[0400] Step 5: To a soluiton of (S)-6-(5-amino-6-fluoropyrazin-2-yl)-6'-ethoxy-5,5'- difluoro-N-(3-methylpiperidin-3-yl)-[2,3'-bipyridine]-4-carboxamide (1.0 eq, 40 mg, 0.1 mmol) and formaldehyde (1.6 eq, 10 mg, 0.1 mmol) in methanol (2 mL) was added acetic acid (3.0 eq, 15 mg, 0.3 mmol), and the solution was stirred for 10 min at 0 ℃ before NaBH3CN (2.9 eq, 15 mg, 0.2 mmol) was added. The resulting solution was stirred at ambient temperature for 1h. The resulting mixture was diluted with ice-water and extracted with DCM. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by Prep-HPLC(Column: XBridge Prep OBD C18 Column, 30X150 mm, 5μm; Mobile Phase A: Water (10 mmol / L NH4HCO3+0.05% NH3H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 45% B to 65% B in 8 min; Wavelength: 254 nm / 220 nm; RT1(min): 7.56). The pure fractions were concentrated and lyophilized to afford the title compound (20 mg, 0.04 mmol, 49% yield) as an off-white solid. LC purity: 98.4% (UV at 254 nm); Mass calculated for C24H26F3N7O2 [M+1]+, 502.1, found 502.1; Retention time: 1.148 min.1H NMR (400 MHz, DMSO) δ 8.78 (dd, J = 16.7, 3.4 Hz, 2H), 8.45 (dd, J = 11.9, 2.1 Hz, 1H), 8.06-7.98 (m, 2H), 7.38 (s, 2H), 4.49 (q, J = 7.0 Hz, 2H), 2.65 (d, J = 11.8 Hz, 1H), 2.23 (s, 1H), 2.16-2.04 (m, 5H), 1.73-1.65 (m, 1H), 1.55-1.29 (m, 9H). Example 87. (R)-6-(5-amino-6-fluoropyrazin-2-yl)-N-(1,3-dimethylpiperidin-3-yl)-6'- ethoxy-5,5'-difluoro-[2,3'-bipyridine]-4-carboxamide

[0401] Scheme 46

[0397] The title compound (9 mg) was prepared in a 9% overall yield as a white solid, following a procedure analogous to that described in Example 85 (Step 1 to Step 5). Prep- HPLC conditions: Column: Sunfire Prep C18 OBD Column, 30X150 mm, 5μm; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 10% B to 40% B in 8 min; Wave Length: 254nm / 220nm; RT1 (min): 7.8. LC purity: 99.1% (UV at 254 nm); Mass calculated for C24H26F3N7O2[M+1]+ 502.51, found 502.15; Retention time: 1.153 min.1H NMR (400 MHz, DMSO) δ 8.78 (dd, J = 14.4, 3.4 Hz, 2H), 8.45 (dd, J = 11.9, 2.1 Hz, 1H), 8.05 (t, J = 2.9 Hz, 2H), 7.39 (s, 2H), 4.49 (q, J = 7.1 Hz, 2H), 2.73 (d, J =44.1 Hz, 1H), 2.56 (d, J = 10.5 Hz, 1H), 2.22 (s, 4H), 2.13 (s, 1H), 1.78 – 1.65 (m, 1H), 1.62 – 1.21 (m, 9H). Example 88.5-amino-6''-ethoxy-N-(2-ethyl-2-azabicyclo[2.2.2]octan-4-yl)-3',5'',6- trifluoro-[2,2':6',3''-terpyridine]-4'-carboxamide

[0402] Scheme 47

[0403] Step 1: To a solution of 6-bromo-2-fluoropyridin-3-amine (1.0 eq, 4.0 g, 20.9 mmol) and Pd(PPh3)4(0.1 eq, 2.4 g, 2.0 mmol) in 1,4-Dioxane (40 mL) were added Sn2Me6(1.5 eq, 10.3 g, 31.4 mmol). The resulting mixture was stirred at 100°C for 2 h under nitrogen atmosphere. Upon completion, the reaction mixture was concentrated in vacuo and the residue extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with saturated aqueous KF (3x50 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography using a gradient of 0 to 30% EtOAc in PE to afford 2-fluoro-6-(trimethylstannyl)pyridin-3-amine (3.80 g,13.8 mmol, 66% yield) as a yellow solid. LC purity: 57.0% (UV at 254 nm); Mass calculated for C8H13FN2Sn[M+1]+, 277, found 277; Retention time: 0.838 min.

[0404] Step 2: To a solution of methyl 2,6-dichloro-3-fluoroisonicotinate (1.0 eq, 500 mg, 2.2 mmol) and methyl 2-fluoro-6-(trimethylstannyl)pyridin-3-amine (0.8 eq, 491 mg, 1.7mmol) in 1,4-Dioxane (6 mL) were added PCy3(0.3 eq, 18 mg, 0.6 mmol) and Pd(OAc)2(0.2 eq, 100 mg, 0.4 mmol). The resulting mixture was stirred at 70 °C under nitrogen atmosphere overnight. Upon completion, the reaction mixture was concentrated in vacuo and the residue was purified via reversed phase flash chromatography (C18 silica gel) using a gradient of 50% to 70% ACN in water (with 10 mmol / L NH4HCO3) to afford methyl 5'-amino-6-chloro- 3,6'-difluoro-[2,2'-bipyridine]-4-carboxylate (540 mg,1.8 mmol, 80 % yield) as a yellow solid. LC purity: 40.1% (UV at 254 nm); Mass calculated for C12H8F2N3O2[M+1]+, 300.1, found 300.1; Retention time: 0.743 min.

[0405] Step 3: To a solution of methyl 5'-amino-6-chloro-3,6'-difluoro-[2,2'-bipyridine]-4- carboxylate (1.0 eq, 446 mg, 1.6 mmol) and 2-ethoxy-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridine (1.0 eq, 500 mg, 1.6 mmol) in 1,4-Dioxane (6 mL) and Water (0.6 mL) were added Na2CO3 (3.0 eq, 531 mg, 5.0 mmol) and Pd(dppf)Cl2 (0.1 eq, 122 mg, 0.1 mmol). The resulting mixture was stirred at 80 °C for 2 h under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (2 x 100 mL) and the combined organic layers were washed with brine (1x30 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford crude product methyl 5-amino-6''-ethoxy-3',5'',6-trifluoro-[2,2':6',3''- terpyridine]-4'-carboxylate (600 mg,1.4 mmol, 89 % yield) as a light yellow solid used in the next step without further purification. LC purity: 82.1% (UV at 254 nm); Mass calculated for C19H15F3N4O3 [M+1]+, 405.1, found 405.1; Retention time: 0.935 min.

[0406] Step 4: To a stirred solution of methyl 5-amino-6''-ethoxy-3',5'',6-trifluoro- [2,2':6',3''-terpyridine]-4'-carboxylate (1.0 eq, 600 mg, 1.4 mmol) in THF (6 mL) and Water (2 mL) was added LiOH (3.00 eq, 107 mg, 4.45 mmol). The resulting mixture was stirred at 20 °C for 2 h. The resulting mixture was extracted with EtOAc (2 x 100mL) and the combined organic layers were washed with brine (1 x 30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford 5-amino-6''-ethoxy-3',5'',6-trifluoro-[2,2':6',3''- terpyridine]-4'-carboxylic acid (400 mg,1.0 mmol, 69% yield) as a light yellow solid used in the next step without further purification. LC purity: 76.0% (UV at 254 nm); Mass calculated for C18H13F3N4O3[M+1]+, 391.1, found 391.1; Retention time: 0.855 min.

[0407] Step 5: To a solution of 5-amino-6''-ethoxy-3',5'',6-trifluoro-[2,2':6',3''-terpyridine]- 4'-carboxylic acid (1.0 eq, 400 mg, 0.8 mmol) and tert-butyl 4-amino-2- azabicyclo[2.2.2]octane-2-carboxylate (1.0 eq, 182 mg, 0.8 mmol) in DMF (5 mL) were added DIEA (2.0 eq, 207 mg, 1.6 mmol) and HATU (2.0 eq, 610 mg, 1.6 mmol). The mixturewas stirred at ambient temperature overnight. The resulting mixture was quenched with water and extracted with EtOAc (2 x 100 mL) and the combined organic layers were washed with brine (1 x 30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified via reversed phase flash chromatography using a gradient of 70% to 100% ACN in water (with 10 mmol / L NH4HCO3) to afford tert-butyl 4-(5-amino-6''- ethoxy-3',5'',6-trifluoro-[2,2':6',3''-terpyridine]-4'-carboxamido)-2-azabicyclo[2.2.2]octane-2- carboxylate (363 mg, 0.9 mmol, 41% yield) as a yellow solid. LC purity: 35.8% (UV at 254 nm); Mass calculated for C30H33F3N6O4 [M+1]+, 599.3, found 599.3; Retention time: 0.992 min.

[0408] Step 6: To a solution of tert-butyl 4-(5-amino-6''-ethoxy-3',5'',6-trifluoro-[2,2':6',3''- terpyridine]-4'-carboxamido)-2-azabicyclo[2.2.2]octane-2-carboxylate (1.0 eq, 360 mg, 0.6 mmol) in DCM (4 mL) was added TFA (4 mL). The mixture was stirred at 20 °C for 1 h. The resulting mixture was concentrated in vacuo and the residue purified by reversed phase flash (NH4HCO3 / H2O) to afford 5-amino-N-(2-azabicyclo[2.2.2]octan-4-yl)-6''-ethoxy-3',5'',6- trifluoro-[2,2':6',3''-terpyridine]-4'-carboxamide (240 mg,0.4 mmol, 80% yield) as a yellow solid. LC purity: 87.1% (UV at 254 nm); Mass calculated for C25H25F3N6O2 [M+1]+, 499.2, found 499.2; Retention time: 0.601 min.

[0409] Step 7: To a solution of 5-amino-N-(2-azabicyclo[2.2.2]octan-4-yl)-6''-ethoxy- 3',5'',6-trifluoro-[2,2':6',3''-terpyridine]-4'-carboxamide (1.0 eq, 120 mg, 0.2 mmol) in MeOH (5mL) were added C2H4O (2.0 eq, 21 mg, 0.4 mmol) and AcOH (1.0 eq, 14 mg, 0.2 mmol), and the resulting mixture was stirred at ambient temperature for 20 min. NaBH3CN (1.0 eq, 16 mg, 0.2 mmol) was added to above mixture at 0 °C and the reaction was stirred at ambient temperature for 1 h. Upon completion, the reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine over 4 times, dried over anhydrous sodium sulfate, filtered, and concentrated vacuo. The residue was purified by prep-HPLC (UV 254nm / 220nm XBridge Prep OBD C18 Column, 30X150 mm, 5μm Water (10mmol / L NH4HCO3+0.05% NH3H2O) ACN 60 mL / min 33% B to 53% B in 8min 7.59). The pure fractions were concentrated and lyophilized to afford the title compound (34 mg, 0.0 mmol, 24% yield) as an off-white solid. LC purity: 99.7% (UV at 254 nm); Mass calculated for Calc’d for C27H29F3N6O2[M+1]+, 527.2, found 527.2; Retention time: 1.166 min.1H NMR (400 MHz, MeOD) δ 8.65 (d, J = 2.0 Hz, 1H), 8.57 (s, 1H), 8.26 (dd, J = 11.5, 2.1 Hz, 1H), 7.95 – 7.85 (m, 2H), 7.34 (dd, J = 10.8, 8.1 Hz, 1H), 4.55 – 4.51(m, 2H), 3.55 (s, 2H), 3.29 (s, 1H), 3.16 (d, J = 7.3 Hz, 2H), 2.34 – 2.25 (m, 4H), 1.97 (d, J = 12.7 Hz, 4H), 1.46 (t, J = 7.1 Hz, 3H), 1.32 (t, J = 7.2 Hz, 3H). Example 89.5-amino-6''-ethoxy-3',5'',6-trifluoro-N-(2-methyl-2-azabicyclo[2.2.2]octan- 4-yl)-[2,2':6',3''-terpyridine]-4'-carboxamide

[0410] Scheme 48

[0411] Step 1: To a solution of 5-amino-6''-ethoxy-3',5'',6-trifluoro-[2,2':6',3''-terpyridine]- 4'-carboxylic acid (preparation in Example 88, Step 4, 1.00 eq, 400 mg, 0.80 mmol) and tert- butyl 4-amino-2-azabicyclo[2.2.2]octane-2-carboxylate (1.0 eq, 182 mg, 0.8 mmol) in DMF (5 mL) were added DIEA (2.0 eq, 207 mg, 1.6 mmol) and HATU (2.0 eq, 610 mg, 1.6 mmol) at ambient temperature. The reaction was stirred at ambient temperature overnight. The reaction mixture was quenched with water and extracted with EA (2 x 100 mL). The combined organic layers were washed with brine (1x30 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The mixture was purified via reversed phase flash chromatography using a gradient of 70% to 100% ACN in water (with 10 mmol / L NH4HCO3) to afford semi-crude tert-butyl 4-(5-amino-6''-ethoxy-3',5'',6-trifluoro-[2,2':6',3''- terpyridine]-4'-carboxamido)-2-azabicyclo[2.2.2]octane-2-carboxylate as a yellow solid. LC purity: 35.8% (UV at 254 nm); Mass calculated for C30H33F3N6O4 [M+1]+, 599.3, found, 599.3; Retention time: 0.992 min.

[0412] Step 2: To a solution of tert-butyl 4-(5-amino-6''-ethoxy-3',5'',6-trifluoro-[2,2':6',3''- terpyridine]-4'-carboxamido)-2-azabicyclo[2.2.2]octane-2-carboxylate (1.0 eq, 360 mg, 0.6mmol) in DCM (4 mL) was added TFA (4 mL). The resulting mixture was stirred at ambient temperature for 1 h and concentrated in vacuo. The residue was purified via reverse phase flash chromatography (C18 silica gel) using a gradient of 60% to 80% ACN in water (with 10 mmol / L NH4HCO3) to afford 5-amino-N-(2-azabicyclo[2.2.2]octan-4-yl)-6''-ethoxy-3',5'',6- trifluoro-[2,2':6',3''-terpyridine]-4'-carboxamide (240 mg, 0.4 mmol, 80% yield) as a yellow solid. LC purity: 87.1% (UV at 254 nm); Mass calculated for C25H25F3N6O2 [M+1]+, 499.2, found 499.2; Retention time: 0.601 min.

[0413] Step 3: To a solution of 5-amino-N-(2-azabicyclo[2.2.2]octan-4-yl)-6''-ethoxy- 3',5'',6-trifluoro-[2,2':6',3''-terpyridine]-4'-carboxamide (1.0 eq, 100 mg, 0.2 mmol) in MeCN (3 mL) were added CH2O (2.0 eq, 12 mg, 0.4 mmol) and AcOH (3.0 eq, 36 mg, 0.6 mmol), and the resulting mixture was stirred at ambient temperature for 20 min. NaBH3CN (2.0 eq, 27 mg, 0.4 mmol) was added to above mixture at 0 °C and the reaction was stirred at ambient temperature for 1 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by prep-HPLC (UV 254nm / 220nm XBridge Prep OBD C18 Column, 30X150 mm, 5μm Water(10mmol / L NH4HCO3+0.05% NH3H2O) ACN 60 mL / min 33% B to 53% B in 8min 7.59). The pure fractions were concentrated and lyophilized to afford title compound (17 mg, 0.03 mmol, 16% yield) as an off-white solid. LC purity: 97.5% (UV at 254 nm); Mass calculated for C26H27F3N6O2 [M+1]+, 513.2, found 513.2; Retention time: 0.933 min.1H NMR (400 MHz, MeOD) δ 8.64 (d, J = 2.0 Hz, 1H), 8.26 (dd, J = 11.6, 2.0 Hz, 1H), 7.91 – 7.83 (m, 2H), 7.34 (dd, J = 10.8, 8.0 Hz, 1H), 4.53 (d, J = 7.0 Hz, 2H), 3.11 (d, J = 1.4 Hz, 2H), 2.63 (t, J = 2.7 Hz, 1H), 2.46 (s, 3H), 2.17 (d, J = 4.7 Hz, 4H), 2.03 – 1.89 (m, 2H), 1.79 – 1.67 (m, 2H), 1.46 (t, J = 7.0 Hz, 3H). Example 90.5-amino-6''-ethoxy-N-(2-ethyl-2-azabicyclo[2.2.2]octan-4-yl)-3',6-difluoro- [2,2':6',3''-terpyridine]-4'-carboxamide

[0414] Scheme 49

[0415] Step 1: To a solution of 2-ethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridine (1.0 eq, 249 mg, 1.0 mmol) and methyl 5'-amino-6-chloro-3,6'-difluoro-[2,2'- bipyridine]-4-carboxylate (preparation in Example 83, Step 2, 1.0 eq, 300 mg, 1.0 mmol) in 1,4-Dioxane (5 mL) and Water (0.5 mL) were added Na2CO3 (3.0 eq, 318 mg, 3.0 mmol) and Pd(dppf)Cl2(0.1 eq, 73 mg, 0.1 mmol). The mixture was stirred at 80 °C for 2 h under nitrogen atmosphere. The resulting mixture was extracted with EA (2 x 100 mL). The combined organic layers were washed with brine (1x30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo to afford crude product methyl 5- amino-6''-ethoxy-3',6-difluoro-[2,2':6',3''-terpyridine]-4'-carboxylate (250 mg, 0.6 mmol, 64% yield) as a light yellow solid which was used directly in the next step without further purification. LC purity: 77.6% (UV at 254 nm); Mass calculated for C19H16F2N4O3 [M+1]+, 387.1, found 387.1; Retention time: 0.888 min.

[0416] Step 2: To a solution of methyl 5-amino-6''-ethoxy-3',6-difluoro-[2,2':6',3''- terpyridine]-4'-carboxylate (1.0 eq, 250 mg, 0.6 mmol) in THF (3 mL) and Water (1 mL) was added LiOH (3.0 eq, 47 mg, 1.9 mmol). The mixture was stirred at ambient temperature for 2 h. The resulting mixture was extracted with EA (2 x 100mL). The combined organic layers were washed with brine (1 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo to afford crude product 5-amino-6''-ethoxy-3',6-difluoro- [2,2':6',3''-terpyridine]-4'-carboxylic acid (300 mg,0.8 mmol, 83% yield) as a light yellow solid which was used directly in the next step without further purification. LC purity: 67.7% (UV at 254 nm); Mass calculated for C18H14F2N4O3 [M+1]+, 373.1, found 373.1; Retention time: 0.785 min.

[0417] Step 3: To a solution of 5-amino-6''-ethoxy-3',6-difluoro-[2,2':6',3''-terpyridine]-4'- carboxylic acid (1.0 eq, 300 mg, 0.8 mmol) and 2-methyl-2-azabicyclo[2.2.2]octan-4-amine (1.0 eq, 113 mg, 0.8 mmol) in DMF (6 mL) were added DIEA (2.0 eq, 208 mg, 1.6 mmol) and HATU (2.0 eq, 612 mg, 1.6 mmol). The mixture was stirred at ambient temperature for overnight. The resulting mixture was quenched with water and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (1 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo. The mixture was purified via reversed phase flash chromatography using a gradient of 70% to 100% ACN in water (with 10 mmol / L NH4HCO3) to afford tert-butyl 4-(5-amino-6''-ethoxy-3',6-difluoro- [2,2':6',3''-terpyridine]-4'-carboxamido)-2-azabicyclo[2.2.2]octane-2-carboxylate (200 mg, 0.3 mmol, 42% yield) as a yellow solid. LC purity: 46.8% (UV at 254 nm); Mass calculated for C30H34F2N6O4 [M+1]+, 581.3, found 581.3; Retention time: 0.947 min.

[0418] Step 4: To a stirred solution of tert-butyl 4-(5-amino-6''-ethoxy-3',6-difluoro- [2,2':6',3''-terpyridine]-4'-carboxamido)-2-azabicyclo[2.2.2]octane-2-carboxylate in DCM (2 mL) was added TFA (3 mL). The mixture was stirred at ambient temperature for 1 h. The resulting mixture was concentrated in vacuo. The residue was purified via reversed phase flash chromatography using a gradient of 40% to 60% ACN in water (with 10 mmol / L NH4HCO3) to afford 5-amino-N-(2-azabicyclo[2.2.2]octan-4-yl)-6''-ethoxy-3',6-difluoro- [2,2':6',3''-terpyridine]-4'-carboxamide (140 mg, 0.2 mmol, 84% yield) as a yellow solid. LC purity: 95.3% (UV at 254 nm); Mass calculated for C25H26F2N6O2 [M+1]+, 481.2, found 481.2; Retention time: 0.663 min.

[0419] Step 5: To a stirred solution of 5-amino-N-(2-azabicyclo[2.2.2]octan-4-yl)-6''- ethoxy-3',6-difluoro-[2,2':6',3''-terpyridine]-4'-carboxamide (1.0 eq, 140 mg, 0.2 mmol) in MeOH (5 mL) were added C2H4O (2.0 eq, 26 mg, 0.5 mmol) and AcOH (3.0 eq, 52 mg, 0.8 mmol), the resulting mixture was stirred at ambient temperature for 20 min. NaBH3CN (2.0 eq, 40 mg, 0.5 mmol) was added to above mixture at 0 °C and the reaction was stirred at ambient temperature for 1 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by prep-HPLC (Column: X- Select Prep OBD C18 Column, 30X150 mm, 5μm; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient (B%): 20% B to 45% B in 10 min; Wave Length: 254nm / 220nm nm; RT1(min): 7.83). The pure fractions were concentrated and lyophilized to afford title compound (19 mg,0.03 mmol, 13% yield) as an off-white solid. LCpurity: 99.3% (UV at 254 nm); Mass calculated for C27H30F2N6O2[M+1]+, 509.2, found 509.2; Retention time: 0.880 min.1H NMR (400 MHz, MeOD) δ 8.84 (dd, J = 2.6, 0.7 Hz, 1H), 8.41 (dd, J = 8.7, 2.6 Hz, 1H), 7.90 – 7.83 (m, 2H), 7.33 (dd, J = 10.8, 8.1 Hz, 1H), 6.90 (dd, J = 8.8, 0.7 Hz, 1H), 4.41 (d, J = 7.1 Hz, 2H), 3.12 (t, J = 1.4 Hz, 2H), 2.80 – 2.75 (m, 1H), 2.71 – 2.65 (m, 2H), 2.28 – 2.09 (m, 4H), 1.99 (td, J = 11.6, 3.6 Hz, 2H), 1.79 – 1.65 (m, 2H), 1.43 (t, J = 7.0 Hz, 3H), 1.16 (t, J = 7.2 Hz, 3H).-

[0420] Scheme 50

[0421] Step 1: To a solution of 6-(5-((2,4-dimethoxybenzyl)amino)-6-fluoropyrazin-2-yl)- 6'-ethoxy-5-fluoro-[2,3'-bipyridine]-4-carboxylic acid (preparation in Example 74, Step 2, 1.0 eq, 50 mg, 0.1 mmol), tert-butyl 4-amino-2-azabicyclo[2.2.2]octane-2-carboxylate (1.2 eq, 26 mg, 0.1 mmol) and DIEA (3.0 eq, 37 mg, 0.3 mmol) in DMF (5 mL) was added HATU (1.5 eq, 54 mg, 0.1 mmol). The resulting mixture was stirred at ambient temperature for 1 h. The reaction was quenched with water and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated in vacuo to afford crude product tert-butyl 4-(6-(5- ((2,4-dimethoxybenzyl)amino)-6-fluoropyrazin-2-yl)-6'-ethoxy-5-fluoro-[2,3'-bipyridine]-4- carboxamido)-2-azabicyclo[2.2.2]octane-2-carboxylate which was used in the next step directly without further purification. LC purity: 74 % (UV at 254 nm); Mass calculated for C38H43F2N7O6 [M+1]+, 732.8, found 732.4; Retention time: 1.072 min.

[0422] Step 2: To a solution of tert-butyl 4-(6-(5-((2,4-dimethoxybenzyl)amino)-6- fluoropyrazin-2-yl)-6'-ethoxy-5-fluoro-[2,3'-bipyridine]-4-carboxamido)-2- azabicyclo[2.2.2]octane-2-carboxylate (1.0 eq, 50 mg, 0.1 mmol) in DCM (3 mL) was added TFA (1 mL). The mixture was stirred at ambient temperature for 1 h. The resulting solution was concentrated in vacuo. The residue was purified by Prep-HPLC (Column: xBridge Prep Shield RP185μm OBD 30X150mm; Mobile Phase A: Water (10mmol / L NH4HCO3), MobilePhase B: ACN'; Flow rate: 60 mL / min mL / min; Gradient (B%): isocratic 25-55B IN 10 MIN; Wave Length: 220 / 254 nm; RT1(min): 9.65). The pure fractions were concentrated and lyophilized to afford the title compound (25 mg, 0.1 mmol, 75 % yield) as a light-yellow solid. LC purity: 98 % (UV at 254 nm); Mass calculated for C24H25F2N7O2[M+1]+, 482.5, found 482.2; Retention time: 1.297 min.1H NMR (400 MHz, DMSO) δ 8.94 (d, J = 2.8 Hz, 1H), 8.70 (d, J = 4.6 Hz, 1H), 8.54 – 8.14 (m, 2H), 8.01 – 7.91 (m, 1H), 7.37 (s, 2H), 6.92 (d, J = 8.7 Hz, 1H), 4.43 – 4.34 (m, 2H), 3.11 (s, 2H), 2.68 (d, J = 5.1 Hz, 1H), 2.08 – 1.90 (m, 4H), 1.82 (s, 2H), 1.69 (d, J = 12.0 Hz, 4H), 1.36 (t, J = 7.0 Hz, 3H). Example 92.6-(5-amino-6-fluoropyrazin-2-yl)-6'-ethoxy-N-(2-(ethyl-d5)-2- azabicyclo[2.2.2]octan-4-yl)-5-fluoro-[2,3'-bipyridine]-4-carboxamide

[0423] Scheme 51

[0424] Step 1: To a solution of 6-(5-((2,4-dimethoxybenzyl)amino)-6-fluoropyrazin-2-yl)- 6'-ethoxy-5-fluoro-[2,3'-bipyridine]-4-carboxylic acid (preparation in Example 74, Step 2, 1.0 eq, 220 mg, 0.4 mmol) and tert-butyl 4-amino-2-azabicyclo[2.2.2]octane-2-carboxylate (1.5 eq, 152 mg, 0.6 mmol) in DMF (5 mL) were added HATU (1.5 eq, 255 mg, 0.6 mmol) and DIEA (3.0 eq, 173 mg, 1.3 mmol). The mixture was purified via reversed phase flash chromatography directly using a gradient of 50% to 70% ACN in water (with 10 mmol / L NH4HCO3) to afford tert-butyl 4-(6-(5-((2,4-dimethoxybenzyl)amino)-6-fluoropyrazin-2-yl)- 6'-ethoxy-5-fluoro-[2,3'-bipyridine]-4-carboxamido)-2-azabicyclo[2.2.2]octane-2-carboxylate (200 mg, 0.2 mmol, 63% yield) as a yellow solid. LC purity: 42 % (UV at 254 nm); Mass calculated for C38H43F2N7O6[M+1]+, 732.3, found 732.3; Retention time: 1.129 min.

[0425] Step 2: To a solution of tert-butyl 4-(6-(5-((2,4-dimethoxybenzyl)amino)-6- fluoropyrazin-2-yl)-6'-ethoxy-5-fluoro-[2,3'-bipyridine]-4-carboxamido)-2- azabicyclo[2.2.2]octane-2-carboxylate (1.0 eq, 200 mg, 0.2 mmol) in 1,4-Dioxane (3 mL) was added HCl (3 mL), and the resulting mixture was stirred at ambient temperature for 1 h. The mixture was concentrated in vacuo to afford crude product N-(2-azabicyclo[2.2.2]octan- 4-yl)-6-(5-((2,4-dimethoxybenzyl)amino)-6-fluoropyrazin-2-yl)-6'-ethoxy-5-fluoro-[2,3'- bipyridine]-4-carboxamide (150 mg, 0.2 mmol, 87% yield) which used directly in the next step without further purification. LC purity: 75 % (UV at 254 nm); Mass calculated for C33H35F2N7O4 [M+1]+, 632.3, found, 632.2; Retention time: 0.643 min.

[0426] Step 3: To a solution of N-(2-azabicyclo[2.2.2]octan-4-yl)-6-(5-((2,4- dimethoxybenzyl)amino)-6-fluoropyrazin-2-yl)-6'-ethoxy-5-fluoro-[2,3'-bipyridine]-4- carboxamide (1.0 eq, 150 mg, 0.2 mmol) and 1-iodoethane-1,1,2,2,2-d5 (2.0 eq, 81 mg, 0.5 mmol) in Acetonitrile (3 mL) was added DIEA (3.0 eq, 97 mg, 0.7 mmol), the mixture was stirred at 80 °C for 4 h. The mixture was concentrated in vacuo, and the residue was purified by Prep-HPLC to afford 6-(5-((2,4-dimethoxybenzyl)amino)-6-fluoropyrazin-2-yl)-6'-ethoxy- N-(2-(ethyl-d5)-2-azabicyclo[2.2.2]octan-4-yl)-5-fluoro-[2,3'-bipyridine]-4-carboxamide (70 mg, 0.1 mmol, 44% yield) as a white solid. LC purity: 41% (UV at 254 nm); Mass calculated for C35H34D5F2N7O4[M+1]+, 665.3, found 665.3; Retention time: 0.942 min.

[0427] Step 4: To a solution of 6-(5-((2,4-dimethoxybenzyl)amino)-6-fluoropyrazin-2-yl)- 6'-ethoxy-N-(2-(ethyl-d5)-2-azabicyclo[2.2.2]octan-4-yl)-5-fluoro-[2,3'-bipyridine]-4- carboxamide (1.0 eq, 60 mg, 0.1 mmol) in DCM (3 mL) was added TFA (3 mL). The mixture was stirred at ambient temperature for 2 h. The resulting mixture was concentrated in vacuo. The residue was purified by prep HPLC (Column: XBridge Prep OBD C18 Column, 30X150 mm, 5μm; Mobile Phase A: Water (10mmol / L NH4HCO3+0.05% NH3H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient (B%): 27 % B to 47 % B in 8min; Wave Length: 254nm / 220nm nm; RT1(min): 6.28). The pure fractions were concentrated and lyophilized to afford title compound (23 mg, 0.04 mmol, 47% yield) as a white solid. LC purity: 98 % (UV at 254 nm); Mass calculated for C26H24D5F2N7O2[M+1]+, 515.3, found 515.3; Retention time: 1.271 min.1H NMR (400 MHz, DMSO) δ 8.95 (d, J = 2.6 Hz, 1H), 8.70 (d, J = 4.6 Hz, 1H), 8.47 (dd, J = 8.7, 2.6 Hz, 1H), 8.25 (s, 1H), 7.95 (d, J = 3.7 Hz, 1H), 7.37 (s, 2H), 6.92 (d, J = 8.7 Hz, 1H), 4.39 (d, J = 7.0 Hz, 2H), 2.89 (s, 2H), 2.56 (s, 1H), 2.01 – 1.81 (m, 6H), 1.54 – 1.52 (m, 2H), 1.36 (t, J = 7.0 Hz, 3H).Example 93.6-(5-amino-6-fluoropyrazin-2-yl)-N-(2-ethyl-2-azabicyclo[2.2.2]octan-4-yl)- 5-fluoro-6'-(trifluoromethoxy)-[2,3'-bipyridine]-4-carboxamide

[0428] Scheme 52

[0429] Step 1: To a solution of 2-ethyl-2-azabicyclo[2.2.2]octan-4-amine (1.1 eq, 466 mg, 3.0 mmol), 6-chloro-2-(5-((2,4-dimethoxybenzyl)amino)-6-fluoropyrazin-2-yl)-3- fluoroisonicotinic acid (1.0 eq, 1.2 g, 2.8 mmol) in DMF (15 mL) were added DIEA (5.0 eq, 1.8 g, 13.7 mmol) and HATU (2.0 eq, 2088 mg, 5.5 mmol). The mixture was stirred at ambient temperature for 2 h. The resulting solution was diluted with ethyl acetate (50 mL x 3), filtered and concentrated in vacuo. The residue was purified by reversed phase flash chromatography using a gradient of 50% to 80% ACN in water (with 5mM NH4HCO3) to afford 6-chloro-2-(5-((2,4-dimethoxybenzyl)amino)-6-fluoropyrazin-2-yl)-N-(2-ethyl-2- azabicyclo[2.2.2]octan-4-yl)-3-fluoroisonicotinamide (850 mg,1.48 mmol, 54% yield) as a light yellow solid. LC purity: 90% (UV at 254 nm); Mass calculated for C28H31ClF2N6O3[M+1]+573.2, found 573.2; Retention time: 1.135 min.

[0430] Step 2: To a solution of 6-chloro-2-(5-((2,4-dimethoxybenzyl)amino)-6- fluoropyrazin-2-yl)-N-(2-ethyl-2-azabicyclo[2.2.2]octan-4-yl)-3-fluoroisonicotinamide (1.0 eq, 80 mg, 0.1 mmol) and (6-(trifluoromethoxy)pyridin-3-yl)boronic acid (1.5 eq, 43 mg, 0.2 mmol) in 1,4-Dioxane (10 mL) and Water (1 mL) were added Pd(PPh3)4 (0.1 eq, 16 mg, 0.01 mmol) and Na2CO3(3.0 eq, 44 mg, 0.4 mmol). The resulting mixture was stirred at 80 °C for 1 h under nitrogen atmosphere. The reaction was then concentrated in vacuo and the residuewas purified by reversed-phase flash chromatography using a gradient of 30% to 80% ACN in water (with 0.1% FA) to afford 6-(5-((2,4-dimethoxybenzyl)amino)-6-fluoropyrazin-2-yl)- N-(2-ethyl-2-azabicyclo[2.2.2]octan-4-yl)-5-fluoro-6'-(trifluoromethoxy)-[2,3'-bipyridine]-4- carboxamide (80 mg, 0.1 mmol, 81% yield) as a yellow solid. LC purity: 90 % (UV at 254 nm); Mass calculated for C34H34F5N7O4 [M+1]+, 700.3, found 700.3. Retention time: 1.300 min.

[0431] Step 3: To a solution of 6-(5-((2,4-dimethoxybenzyl)amino)-6-fluoropyrazin-2-yl)- N-(2-ethyl-2-azabicyclo[2.2.2]octan-4-yl)-5-fluoro-6'-(trifluoromethoxy)-[2,3'-bipyridine]-4- carboxamide (1.0 eq, 80 mg, 0.1 mmol) in DCM (2 mL) was added TFA (2 mL) and the mixture was stirred at ambient temperature for 2 h. The resulting mixture was concentrated in vacuo. The residue was dissolved in MeCN and treated with 1 mL ammonium hydroxide at 0 ℃ and stirred for 30 min and concentrated in vacuo. The residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30X150 mm, 5μm; Mobile Phase A: Water (10 mmol / L NH4HCO3+0.05% NH3H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 33 % B to 53 % B in 8min; Wave Length: 254nm / 220nm; RT1(min): 7.19). Pure fractions were evaporated to afford the title compound (36 mg, 0.1 mmol, 56 % yield) was a yellow solid. LC purity: 97 % (UV at 254 nm); Mass calculated for C25H24F5N7O2[M+1]+, 550.2, found 550.2. Retention time: 8.551 min.1H NMR (400 MHz, DMSO) δ 9.15 (d, J = 2.5 Hz, 1H), 8.82 – 8.72 (m, 2H), 8.29 (s, 1H), 8.11 (d, J = 3.7 Hz, 1H), 7.47 – 7.36 (m, 3H), 2.89 (s, 2H), 2.56 – 2.51 (m, 2H), 2.48 (s, 1H), 2.03 – 1.83 (m, 6H), 1.54 (t, J = 11.5 Hz, 2H), 0.99 (t, J = 7.1 Hz, 3H). Example 94.6-(5-amino-6-fluoropyrazin-2-yl)-6'-(difluoromethoxy)-N-(2-ethyl-2- azabicyclo[2.2.2]octan-4-yl)-5-fluoro-[2,3'-bipyridine]-4-carboxamide

[0432] Scheme 52

[0433] The title compound (35 mg) was prepared in a 39 % overall yield as a yellow solid, following a procedure analogous to that described in Example 93 (Step 2 to Step 3). Prep-HPLC conditions: Column: XBridge Prep OBD C18 Column, 30X150 mm, 5μm; Mobile Phase A: Water (10mmol / L NH4HCO3+0.05% NH3H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B %): 31 % B to 51 % B in 8min; Wave Length: 254 nm / 220 nm; RT1 (min): 6.55. LC purity: 97 % (UV at 254 nm); Mass calculated for C25H25F4N7O2[M+1]+, 532.3, found 532.3. Retention time: 9.039 min.1H NMR (400 MHz, DMSO) δ 9.05 (d, J = 2.5 Hz, 1H), 8.76 – 8.66 (m, 2H), 8.28 (s, 1H), 8.07 (d, J = 3.7 Hz, 1H), 7.80 (s, 1H), 7.40 (s, 2H), 7.23 (d, J = 8.7 Hz, 1H), 2.89 (s, 2H), 2.56 – 2.51 (m, 2H), 2.48 (s, 1H), 2.05 – 1.81 (m, 6H), 1.59 – 1.47 (m, 2H), 0.99 (t, J = 7.2 Hz, 3H). Example 95.6-(5-amino-6-fluoropyrazin-2-yl)-N-(2-ethyl-2-azabicyclo[2.2.2]octan-4-yl)- 5-fluoro-6'-methoxy-[2,3'-bipyridine]-4-carboxamide

[0434] Scheme 53

[0435] The title compound (27 mg) was prepared in a 38 % overall yield as an off- white solid, following a procedure analogous to that described in Example 93 (Step 2 to Step 3). Prep-HPLC conditions: Column: XBridge Prep OBD C18 Column, 30X150 mm, 5μm; Mobile Phase A: Water (10mmol / L NH4HCO3+0.05 % NH3H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient (B %): 23 % B to 43 % B in 8min; Wave Length: 254 nm / 220 nm; RT1(min): 7.19. LC purity: 97 % (UV at 254 nm); Mass calculated for C25H27F2N7O2[M+1]+, 496.3, found 496.3. Retention time: 7.023 min.1H NMR (400 MHz, DMSO) δ 8.97 (d, J = 2.5 Hz, 1H), 8.70 (d, J = 4.6 Hz, 1H), 8.48 (dd, J = 8.7, 2.6 Hz, 1H), 8.26 (s, 1H), 7.96 (d, J = 3.8 Hz, 1H), 7.37 (s, 2H), 6.95 (d, J = 8.7 Hz, 1H), 3.93 (s, 3H), 2.89 (s, 2H), 2.59 – 2.54 (m, 2H), 2.47 (s, 1H), 1.94 – 1.89 (m, 6H), 1.53 (t, J = 11.5 Hz, 2H), 0.99 (t, J = 7.1 Hz, 3H). Example 96.6-(5-amino-6-fluoropyrazin-2-yl)-6'-(ethoxy-2,2,2-d3)-N-(2-ethyl-2- azabicyclo[2.2.2]octan-4-yl)-5-fluoro-[2,3'-bipyridine]-4-carboxamide

[0436] Scheme 54

[0437] Step 1: To a solution of acetic-d3 acid-d (1.0 eq, 5.00 g, 78 mmol) in THF (50 mL) was added LAH (1.2 eq, 47 mL, 94 mmol) at 0 ℃. The reaction was stirred for 1 h. The resulting mixture was quenched with sodium sulfate decahydrate and filtered. The filter cake was washed with THF, and the filtrate was dried over anhydrous Na₂SO₄ and filtered to afford a solution of ethan-2,2,2-d3-1-ol (0.6 eq, 0.8 g, 17 mmol) in THF (50 mL), which was used directly in next step without further purification. LC purity: NA (UV at 254 nm); Mass calculated for C2H3D3O [M+1]+NA, found NA; Retention time: NA.

[0438] Step 2: To a solution of 5-bromo-2-fluoropyridine (1.0 eq, 5.0 g, 28.4 mmol) and ethan-2,2,2-d3-1-ol (0.6 eq, 0.8 g, 17 mmol) in THF (50 mL) was added t-BuOK (1.8 eq, 5.7 g, 51.1 mmol). The reaction was stirred at ambient temperature for 12 h. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water, dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified via silica gel chromatography using a gradient of 0 to 30% EtOAc in PE to afford 5-bromo-2-(ethoxy- 2,2,2-d3)pyridine (2.2 g, 10.0 mmol, 35% yield) as a colorless oil. LC purity: 93% (UV at 254 nm); Mass calculated for C7H5D3BrNO [M+1]+205.1, found 205.1; Retention time: 1.039 min.

[0439] Step 3: To a solution of 5-bromo-2-(ethoxy-2,2,2-d3)pyridine (1.0 eq, 500 mg, 2.4 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (2.0 eq, 1238 mg, 4.9 mmol) in 1,4-dioxane (10 mL) were added KOAc (2.0 eq, 478 mg, 4.9 mmol) and Pd(dppf)Cl2(0.1 eq, 199 mg, 0.2 mmol). The reaction was stirred at 80 °C for 12 h under nitrogen atmosphere. The resulting mixture was filtered, and the filtrate was used directly in the next step without further purification. LC purity: 76 % (UV at 254 nm); Mass calculated for C13H17D3BNO3[M+1]+253.2, found 253.2; Retention time: 0.924 min.

[0440] The title compound (16 mg) was prepared in a 21 % overall yield as a white solid, following a procedure analogous to that described in Example 92 (Step 2 to Step 3). Prep- HPLC conditions: Column: Kinetex EVO C18 Column, 30X150mm, 5 um; Mobile Phase A: Water (10 mmol / L NH4HCO3+0.05 % NH3H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 25 % B to 50 % B in 8 min; Wavelength: 254 nm / 220 nm; RT1 (min): 8.63. LC purity: 98 % (UV at 254 nm); Mass calculated for C26H26D3F2N7O2 [M+1]+513.2, found 513.2; Retention time: 2.539 min.1H NMR (400 MHz, DMSO) δ 8.95 (d, J = 2.5 Hz, 1H), 8.70 (d, J = 4.7 Hz, 1H), 8.47 (dd, J = 8.7, 2.5 Hz, 1H), 8.25 (s, 1H), 7.96 (d, J = 3.8 Hz, 1H), 7.37 (s, 2H), 6.92 (d, J = 8.7 Hz, 1H), 4.37 (s, 2H), 2.89 (s, 2H), 2.56 (s, 1H), 2.48 (d, J = 7.1 Hz, 1H), 2.32 (s, 1H), 1.96-1.81 (m, 6H), 1.54 (t, J = 11.5 Hz, 2H), 1.00 (t, J = 7.1 Hz, 3H). Example 97.6-(5-amino-6-fluoropyrazin-2-yl)-N-(2-ethyl-2-azabicyclo[2.2.2]octan-4-yl)- 5-fluoro-6'-(2,2,2-trifluoroethoxy)-[2,3'-bipyridine]-4-carboxamide

[0441] Scheme 55

[0442] The title compound (28 mg) was prepared in a 21% overall yield as a white solid, following a procedure analogous to that described in Example 93 (Step 2 to Step 3). Prep- HPLC conditions: Column: Kinetex EVO C18 Column, 30X150mm, 5um; Mobile Phase A: Water (10mmol / L NH4HCO3+0.05 % NH3H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 35 % B to 50 % B in 8min; Wave Length: 254nm / 220nm; RT1(min): 8.67. LC purity: 98% (UV at 254 nm); Mass calculated for C26H26F5N7O2 [M+1]+564.2, found 564.1; Retention time: 0.694 min.1H NMR (400 MHz, DMSO) δ 8.99 (d, J = 2.4 Hz, 1H), 8.71 (d, J = 4.6 Hz, 1H), 8.59 (dd, J = 8.7, 2.5 Hz, 1H), 8.27 (s, 1H), 8.01 (d, J = 3.7 Hz, 1H), 7.38 (s, 2H), 7.13 (d, J = 8.7 Hz, 1H), 5.14 – 5.03 (m, 2H), 2.89 (s, 2H), 2.56 (s, 1H), 2.48 (d, J = 7.1 Hz, 1H), 2.04 – 1.81 (m, 7H), 1.59 – 1.48 (m, 2H), 1.03 – 0.95 (m, 3H). Example 98.6-(5-amino-6-fluoropyrazin-2-yl)-N-(2-cyclopropyl-2- azabicyclo[2.2.2]octan-4-yl)-6'-ethoxy-5-fluoro-[2,3'-bipyridine]-4-carboxamide

[0443] Scheme 56

[0444] Step 1: To a solution of 6-(5-((2,4-dimethoxybenzyl)amino)-6-fluoropyrazin-2-yl)- 6'-ethoxy-5-fluoro-[2,3'-bipyridine]-4-carboxylic acid (1.0 eq, 3.0 g, 5.7 mmol) (see Example 74, step 2 for preparation details) in DCM (20 mL) was added TFA (6 mL) and the mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated in vacuo. The residue was purified via reversed-phase flash chromatography using a gradient of 50 % to 90 % ACN in water (with 0.1% FA) to afford 6-(5-amino-6-fluoropyrazin-2-yl)-6'-ethoxy- 5-fluoro-[2,3'-bipyridine]-4-carboxylic acid (1.70 g, 4.55 mmol, 79% yield) as a white solid. LC purity: 88% (UV at 254 nm); Mass calculated for C17H13F2N5O3 [M+1]+, 374.1, found 374.1; Retention: 0.888.

[0445] Step 2: To a solution of cyclopropylboronic acid (2.0 eq, 66 mg, 0.7 mmol) and benzyl N-(2-azabicyclo[2.2.2]octan-4-yl)carbamate (1.0 eq, 100 mg, 0.3 mmol) in DCE (2 mL) were added Cu(OAc)2 (1.0 eq, 70 mg, 0.3 mmol), Bipy (1.0 eq, 60 mg, 0.3 mmol) and Na2CO3 (1.0 eq, 41 mg, 0.3 mmol). The mixture was stirred at 70 °C for overnight under air atmosphere. The solid was filtered out, washed with DCM, and the filtrate was concentrated in vacuo. The residue was purified by reversed phase chromatography using a gradient of 20% to 50% ACN in water (with 5mmol NH4HCO3) to afford benzyl (2-cyclopropyl-2- azabicyclo[2.2.2]octan-4-yl)carbamate (65 mg,0.2 mmol, 56% yield) as a colorless oil. LC purity: NA (UV at 254 nm); Mass calculated for C18H24N2O2 [M+1]+, 301.2, found 301.2; Retention: 0.613.

[0446] Step 3: A mixture of benzyl (2-cyclopropyl-2-azabicyclo[2.2.2]octan-4- yl)carbamate (1.0 eq, 60 mg, 0.2 mmol) in TFA (2.0 mL) was stirred at 60 °C for 2 h. Thesolvent was removed in vacuo. The resulting crude product was used directly in the next step without further purification. LC purity: NA (UV at 254 nm); Mass calculated for C10H18N2 [M+1]+, 167.1, found 167.1; Retention: 0.374.

[0447] Step 4: To a solution of 6-(5-amino-6-fluoropyrazin-2-yl)-6'-ethoxy-5-fluoro-[2,3'- bipyridine]-4-carboxylic acid (1.1 eq, 99 mg, 0.2 mmol) and 2-cyclopropyl-2- azabicyclo[2.2.2]octan-4-amine (1.0 eq, 40 mg, 0.24 mmol) in ACN (3.0 mL) were added NMI (4.0 eq, 79 mg, 0.9 mmol) and TCFH (2.0 eq, 135 mg, 0.4 mmol). The mixture was stirred at ambient temperature for 3 h. The reaction mixture was filtered and concentrated in v...

Claims

Attorney Docket No.: 064105-501001WO WHAT IS CLAIMED IS:

1. A compound of Formula II:or pharmaceutically acceptable salt thereof, wherein R1is a C3-C8cycloalkyl, heterocyclyl, C6-C10aryl, or heteroaryl, which are each substituted by 0, 1, 2, or 3 R1a; R2is a C3-C8 cycloalkyl, heterocyclyl, C6-C10 aryl, or heteroaryl, which are each substituted by 0, 1, 2, or 3 R2a; R3is -(C0-C3 alkylene)(nitrogen-containing heterocyclyl), which is substituted by 0, 1, 2, or 3 R3a; X1is C-X1aor N; X2is C-X2aor N; X1aand X2ais independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 aminoalkyl, C1-C6 sulfonylalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, halogen, or -CN; Y2is -C(O)NH- or -NHC(O)-; each R1a, R2a, and R3ais independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1- C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, C3-C6cycloalkyl, heterocyclyl, C6-C10 aryl, heteroaryl, halogen, -OR1b, -NR1cR1d, -CN, -C(O)R1b, -C(O)NR1cR1d, -OC(O)NR1cR1d, -N(R1b)C(O)NR1cR1d, or -S(O)2NR1cR1d; and each R1b, R1c, and R1dis independently H, C1-C6alkyl, C1-C6haloalkyl, –(C0-C3alkylene)(C3-C8cycloalkyl), –(C0-C3alkylene)(heterocyclyl), –(C0-C3alkylene)(C6-C10 aryl), or –(C0-C3 alkylene)(heteroaryl).

2. A compound of Formula I:or pharmaceutically acceptable salt thereof,Attorney Docket No.: 064105-501001WO wherein R1is a C3-C8 cycloalkyl, heterocyclyl, C6-C10 aryl, or heteroaryl, which are each substituted by 0, 1, 2, or 3 R1a; R2is a C3-C8cycloalkyl, heterocyclyl, C6-C10aryl, or heteroaryl, which are each substituted by 0, 1, 2, or 3 R2a; R3is -(C0-C3 alkylene)(C3-C8 cycloalkyl), -(C0-C3 alkylene)(heterocyclyl), -(C0-C3 alkylene)(C6-C10aryl), or -(C0-C3alkylene)(heteroaryl), which are each substituted by 0, 1, 2, or 3 R3a; X1is C-X1aor N; X2is C-X2aor N; X1aand X2ais independently H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6 aminoalkyl, C1-C6 sulfonylalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, halogen, or -CN; Y1is -S(O)NH-, -S(O)2NH-, -S(O)(=NRY)NH-, -NHS(O)-, -NHS(O)2-, or - NHS(O)(=NRY)-; RYis H or C1-C6 alkyl; each R1a, R2a, and R3ais independently C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1- C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, C3-C6cycloalkyl, heterocyclyl, C6-C10 aryl, heteroaryl, halogen, -OR1b, -NR1cR1d, -CN, -C(O)R1b, -C(O)NR1cR1d, -OC(O)NR1cR1d, -N(R1b)C(O)NR1cR1d, or -S(O)2NR1cR1d; and each R1b, R1c, and R1dis independently H, C1-C6alkyl, C1-C6haloalkyl, –(C0-C3alkylene)(C3-C8 cycloalkyl), –(C0-C3 alkylene)(heterocyclyl), –(C0-C3 alkylene)(C6-C10 aryl), or –(C0-C3 alkylene)(heteroaryl).

3. The compound of claim 1, wherein Y2is -C(O)NH-.

4. The compound of claim 2, wherein Y1is -S(O)2NH-.

5. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 4, wherein, unless otherwise indicated, the heteroaryl in each instance is 5- to 10-membered ring having 1, 2, 3, or 4 heteroatoms selected from N, O, and S; and the heterocyclyl in each instance is 3- to 12-membered ring having 1, 2, 3, or 4 heteroatoms selected from N, O, and S.Attorney Docket No.: 064105-501001WO 6. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 5, wherein X1is C-F.

7. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 5, wherein X1is CH.

8. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 5, wherein X1is N.

9. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 8, wherein X2is N.

10. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 9, wherein R1is heterocyclyl or heteroaryl, which are each substituted by 0, 1, 2, or 3 R1a.

11. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 9, wherein R1is a 4- to 7-membered heterocyclyl or 5- to 6-membered heteroaryl, which are each substituted by 0, 1, 2, or 3 R1a.

12. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 9, wherein R1is a 5- to 6-membered heteroaryl, which is substituted by 0, 1, 2, or 3 R1a.

13. The compound or pharmaceutically acceptable salt thereof of claim 12, wherein R1is a pyrazolyl, pyridyl, or pyrimidyl, which are each substituted by 0, 1, 2, or 3 R1a.

14. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 13, wherein each R1ais independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, halogen, -OR1b, -NR1cR1d, or -CN; and each R1b, R1c, and R1dis independently H and C1-C6alkyl.

15. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 9, wherein R1isAttorney Docket No.: 064105-501001WO.

16. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 14, wherein R2is phenyl or pyridyl, which are each substituted by 0, 1, 2, or 3 R2a.

17. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 16, wherein each R2ais independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6haloalkoxy, C3-C6cycloalkyl, halogen, -OR1b, -NR1cR1d, or -CN.

18. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 17, wherein R2isAttorney Docket No.: 064105-501001WO19. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 18, wherein R3is heterocyclyl, substituted by 0, 1, 2, or 3 R3a.

20. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 19, wherein R3is piperidinyl, substituted by 0, 1, 2, or 3 R3a.

21. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 20, wherein each R3ais independently C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, halogen, -CN, -C(O)R1b, or -C(O)NR1cR1d.

22. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 18, wherein R3is ,23. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 22, wherein the compound is any one shown in Table 1.Attorney Docket No.: 064105-501001WO 24. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 23, and a pharmaceutically acceptable excipient.

25. A method of inhibiting binding between SLC15A4 and TASL in an immune cell, comprising administering to the immune cell an effective amount of a compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 23, or a pharmaceutical composition of claim 24.

26. The method of claim 25, wherein the immune cell is a B-cell, neutrophil, dendritic cell, or monocyte.

27. A method of treating an autoimmune disorder or an inflammatory condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 23, or a pharmaceutical composition of claim 24.

28. The method of claim 27, wherein the autoimmune disorder comprises systemic lupus erythematosus (SLE).

29. The method of claim 27, wherein the inflammatory condition comprises inflammatory bowel disease.

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