Pyridinone MK2 inhibitors and uses thereof

Abstract

To provide pyridinone MK2 inhibitors and uses thereof.SOLUTION: Described herein are MK2 inhibitors and pharmaceutical compositions comprising the inhibitors. The subject compounds and compositions are useful for the treatment of autoimmune disorders, chronic inflammatory disorders, acute inflammatory disorders, auto-inflammatory disorders, fibrotic disorders, metabolic disorders, neoplastic disorders, and cardiovascular or cerebrovascular disorders.SELECTED DRAWING: None

Description

Technical Field

[0001] (Cross - reference) This application claims the benefit of U.S. Provisional Patent Application No. 63 / 220,322, filed Jul. 9, 2021, and U.S. Provisional Patent Application No. 63 / 340,079, filed May 10, 2022, which are hereby incorporated by reference in their entirety.

Background Art

[0002] Mitogen - activated protein kinases (MAPKs) are a conserved family of enzymes that use phosphorylation cascades to relay and propagate external stimuli to generate coordinated cellular responses to the environment. MAPKs are proline - directed serine / threonine - specific protein kinases that regulate cellular activities such as gene expression, mitosis, differentiation, and cell survival / apoptosis. To date, four different classes of mammalian MAPKs have been identified: extracellular signal - regulated kinases (ERK1 and 2), c - jun N - terminal kinases 1 (JNK1 - 3), p38 MAPK (p38α, β, γ, and δ), and ERK5. MAPKs are activated by dual phosphorylation of Thr and Tyr residues within the TXY activation motif by a coordinated dual - specificity MAPKK, where X is Glu, Pro, and Gly in ERK, JNK, and p38 MAPK, respectively. MAPKs are 60% - 70% identical to each other, yet still differ in their activation - loop sequences and sizes. The activation loop is adjacent to the enzyme active site, and its phosphorylation enables the enzyme to re - position its active - site residues into an optimal orientation for substrate binding and catalysis. Downstream substrates of MAPKs include mitogen - activated protein - kinase - activated protein (MAPKAP) kinases and transcription factors, and their phosphorylation regulates gene expression at several points, including directly or indirectly, transcription, nuclear export, and mRNA stability and translation. Cellular consequences of MAPK activation include inflammation, apoptosis, differentiation, and proliferation.

[0003] Different genes encode four p38 MAPKs in humans: ρ38α, β, γ, and δ. Significant amino acid sequence homology is observed among the four isoforms, with overall sequence identity of 60 - 75% and >90% identity within the kinase domain. Tissue-selective expression is observed, with ρ38γ mainly found in skeletal muscle and ρ38δ found in the testis, pancreas, and small intestine. In contrast, p38α and β are more ubiquitously expressed.

[0004] p38 MAPK is a major isoform involved in immune and inflammatory responses. Thus, its function is important for the production and activity of multiple pro-inflammatory cytokines, including TNFα, IL-1, IL-6, and IL-8, in cells such as macrophages, monocytes, synoviocytes, and endothelial cells. p38 MAPK is also involved in the induction of important inflammatory enzymes such as COX2 and iNOS, which are the main sources of eicosanoids and nitric oxide at the site of inflammation, respectively. Furthermore, the p38 MAPK pathway regulates the expression of matrix metalloproteinases (MMPs) including MMP2, MMP9, and MMP13.

[0005] The use of selective and potent inhibitors has facilitated the discovery of several families of p38 MAPK substrates, including transcription factors, MAPKAP kinases, and other enzymes. p38 MAPK can directly phosphorylate several transcription factors such as myocyte-specific enhancer-binding factor 2C (MEF2C), CHOP, peroxisome proliferator-activated receptor (PPAR)α, PPARγ coactivator 1, and p53. These transcription factors are involved in cellular functions such as apoptosis, gluconeogenesis, and the synthesis of enzymes involved in fatty acid oxidation. p38 MAPK is also involved in the activation of cyclin-dependent protein kinase activity and cell cycle regulation. It is involved in the direct or indirect phosphorylation of enzyme substrates such as cytoplasmic phospholipase A2 and Cdc25 phosphatase that are involved in the node. Therefore, in addition to its role in the inflammatory response, p38 MAPK has other functions related to normal and abnormal cell growth and survival, as well as cell function and homeostasis. MAPKAP kinases (MK2, MK-3, and PRAK) are selectively phosphorylated by p38 MAPK, while the phosphorylation of MSK1 / 2, MNK1 / 2, and RSkb is catalyzed by both p38 MAPK and ERK.

[0006] When MK-2, MK-3, and PRAK are phosphorylated and activated by p38 MAPK, they share similar substrate specificities. All of these kinases can phosphorylate the small heat shock protein Hsp27. Studies have shown that PRAK- and MK3-deficient mice do not show any resistance to endotoxin shock or reduction in lipopolysaccharide (LPS)-induced cytokine production. In contrast, MK-2-deficient mice show resistance to endotoxin shock and impaired inflammatory responses, as well as a significant reduction in the production of cytokines such as TNFα, IFNγ, and IL-6. Therefore, the p38 / MK2 axis is important for mediating pro-inflammatory responses.

[0007] The p38:MK2 complex is very stable, with a Kd of 6 nM. The binding affinity of p38 for MK2 is driven by the C-terminal domain of MK2, which contains several positively charged amino acid residues. Crystallographic studies of the p38:MK2 complex have shown that the C-terminal region of MK2 wraps around p38α and binds to the negatively charged ED binding site. The strong binding of p38 to MK2 can result in a conformational change that provides an additional binding pocket for inhibitors that specifically depend on the p38:MK2 interaction. Taken together, these two studies suggest that selective p38 / MK2 axis blockade is achievable with small molecule inhibitors. Compared to conventional p38 MAPK inhibitors, these p38 / MK2 inhibitors should retain or enhance efficacy and exhibit improved safety profiles in animal models of disease or human clinical settings.

[0008] The role of p38 / MK2 in the regulation of inflammatory cytokines (TNFα, IL-1β, IL-6) and enzymes involved in inflammation (COX-2, iNOS, and MMP) makes it an attractive drug target. Some classical p38 MAPK inhibitors are being advanced in clinical trials. Some of these candidates have failed due to safety or other reasons, while some have reported clinical data in diseases such as rheumatoid arthritis, pain, Crohn's disease, acute coronary syndrome, multiple myeloma, and chronic obstructive pulmonary disease. In addition to these diseases, some IL-1β-mediated diseases can be affected by p38 inhibitors based on the important role of the p38 MAPK pathway in the biosynthesis and activity of this cytokine. These diseases include, among others, the family of cryopyrin-associated periodic syndromes (CAPS), chronic gout, diabetes, Still's disease, and familial Mediterranean fever. There is a need for new safe and effective p38 / MK2 inhibitors.

Summary of the Invention

Means for Solving the Problems

[0009] A compound of formula (I), or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamer thereof

Chemical Formula

[0010] Also disclosed herein are pharmaceutical compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamer thereof, and a pharmaceutically acceptable carrier.

[0011] Also disclosed herein are methods for treating a condition, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamer thereof, wherein the condition is selected from the group consisting of autoimmune disorders, chronic inflammatory disorders, acute inflammatory disorders, autoinflammatory disorders, fibrotic disorders, metabolic disorders, neoplastic disorders, and cardiovascular or cerebrovascular disorders.

[0012] Also disclosed herein is a method of doing so in a subject in need of treating a p38 MAP kinase-mediated disease, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamer thereof.

[0013] Also disclosed herein is a method of doing so in a subject in need of treating an MK2-mediated disease, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamer thereof.

[0014] Incorporation by reference All publications, patents, and patent applications mentioned herein are hereby incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. The present invention provides, for example, the following items. (Item 1) A compound of formula (I), or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamer thereof

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chem.

Chem.

Chem.

Chem.

Chem.

Chemical formula

Chemical formula

Mode for Carrying Out the Invention

[0015] Definitions In the following description, specific specific details are set forth in order to provide a thorough understanding of the various embodiments. However, those skilled in the art will understand that the present invention can be practiced without these details. In other instances, well-known structures are not shown in detail or described in order to avoid unnecessarily obscuring the description of the embodiments. Unless otherwise required by context, throughout the following specification and the entire scope of the claims, the word "comprise" and its variations, such as "comprises" and "comprising" ) shall be construed in an open and inclusive sense, i.e., "including but not limited to." Further, the headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0016] References to "some embodiments" or "embodiments" throughout this specification mean that particular features, structures, or characteristics described in connection with the embodiments are included in at least one embodiment. Thus, appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the content clearly dictates otherwise. Note also that the term "or" is generally used in the sense of "and / or" unless the content clearly dictates otherwise.

[0017] The following terms, when used in this specification, have the following meanings unless otherwise indicated.

[0018] "Oxo" refers to =O.

[0019] "Carboxyl" refers to -COOH.

[0020] "Alkyl" refers to a straight-chain or branched-chain saturated hydrocarbon monoradical having from 1 to about 10 carbon atoms, more preferably from 1 to 6 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups such as heptyl, octyl, etc., but are not limited thereto. Whenever it appears in this specification, numerical ranges such as "C1-C6 alkyl" or "C1-6 alkyl" mean that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, but this definition also encompasses the occurrence of the term "alkyl" where no numerical range is specified. In some embodiments, alkyl is C1- 10It is alkyl. In some embodiments, the alkyl is C1-6 alkyl. In some embodiments, the alkyl is C1-5 alkyl. In some embodiments, the alkyl is C1-4 alkyl. In some embodiments, the alkyl is C1-3 alkyl. Unless otherwise specified herein, the alkyl group may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl is optionally substituted with halogen.

[0021] "Alkenyl" refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon double bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. This group can be in either the cis or trans conformation with respect to the double bond(s) and should be understood to include both isomers. Examples include, but are not limited to, ethenyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3=CH2], butenyl, 1,3-butadienyl, etc. Whenever it appears in this specification, numerical ranges such as "C2-C6 alkenyl" or "C2-6 alkenyl" mean that the alkenyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, but this definition also encompasses the occurrence of the term "alkenyl" where no numerical range is specified. Unless otherwise specifically stated in this specification, the alkenyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkenyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, alkenyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, alkenyl is optionally substituted with halogen.

[0022] "Alkynyl" refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon triple bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadynyl, etc. Whenever it appears in this specification, numerical ranges such as "C2-C6 alkynyl" or "C2-6 alkynyl" mean that the alkynyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, but this definition also encompasses the occurrence of the term "alkynyl" where no numerical range is specified. Unless otherwise specifically stated herein, the alkynyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkynyl is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkynyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen.

[0023] "Alkylene" refers to a straight-chain or branched divalent hydrocarbon chain. Unless otherwise specifically stated herein, the alkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkylene is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen.

[0024] "Alkoxy" refers to a radical of the formula -OR a wherein R a is an alkyl radical as defined. Unless otherwise specifically stated herein, an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.

[0025] "Aryl" refers to a radical derived from a hydrocarbon ring system containing 6 to 30 carbon atoms and at least one aromatic ring. The aryl radical may be monocyclic, bicyclic, tricyclic or tetracyclic ring system, and may include a fused ring system (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded via an aromatic ring atom) or a bridged ring system. In some embodiments, the aryl is 6- to 10-membered aryl. In some embodiments, the aryl is 6-membered aryl (phenyl). Examples of aryl radicals include aryl radicals derived from hydrocarbon ring systems such as anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, preiadene, pyrene, and triphenylene, but this It is not limited thereto. Unless otherwise specified herein, aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, aryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, aryl is optionally substituted with halogen.

[0026] "Cycloalkyl" refers to a partially or fully saturated monocyclic or polycyclic carbocyclic ring which may include a fused ring system (when fused to an aryl ring or heteroaryl ring, cycloalkyl is bonded via a non-aromatic ring atom) or a bridged ring system. In some embodiments, cycloalkyl is fully saturated. Representative cycloalkyls include those having 3 to 15 carbon atoms (C3 - C 15 cycloalkyl or C3 - C 15 cycloalkenyl), 3 to 10 carbon atoms (C3 - C 10 cycloalkyl or C3 - C 10cycloalkyl having 3 to 8 carbon atoms (C3-C8 cycloalkyl or C3-C8 cycloalkenyl), 3 to 6 carbon atoms (C3-C6 cycloalkyl or C3-C6 cycloalkenyl), 3 to 5 carbon atoms (C3-C5 cycloalkyl or C3-C5 cycloalkenyl), or 3 to 4 carbon atoms (C3-C4 cycloalkyl or C3-C4 cycloalkenyl), but is not limited thereto. In some embodiments, the cycloalkyl is a 3- to 10-membered cycloalkyl or a 3- to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3- to 6-membered cycloalkyl or a 3- to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5- to 6-membered cycloalkyl or a 5- to 6-membered cycloalkenyl. Examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of polycyclic cycloalkyl include adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Examples of partially saturated cycloalkyl include cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless otherwise specified herein, the cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2.In some embodiments, the cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl is optionally substituted with halogen.

[0027] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo. In some embodiments, the halogen is fluoro or chloro. In some embodiments, the halogen is fluoro.

[0028] "Haloalkyl" refers to an alkyl radical as defined above substituted by one or more of the halo radicals defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. methyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0029] "Hydroxyalkyl" refers to an alkyl radical as defined above substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with 1, 2, or 3 hydroxyls. Examples of hydroxyalkyl include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0030] "Aminoalkyl" refers to an alkyl radical as defined above substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with 1, 2, or 3 amines. Examples of aminoalkyl include aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

[0031] "Deuterioalkyl" refers to an alkyl radical as defined above that is substituted by one or more deuteriums. In some embodiments, the alkyl is substituted with one deuterium. In some embodiments, the alkyl is substituted with 1, 2, or 3 deuteriums. In some embodiments, the alkyl is substituted with 1, 2, 3, 4, 5, or 6 deuteriums. Examples of deuterioalkyl include, for example, CD3, CH2D, CHD2, CH2CD3, CD2CD3, CHDCD3, CH2CH2D, or CH2CHD2. In some embodiments, the deuterioalkyl is CD3.

[0032] "Heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl are atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof. The heteroalkyl is bonded to the remainder of the molecule at a carbon atom of the heteroalkyl. In one embodiment, the heteroalkyl is a C1-C6 heteroalkyl, and the heteroalkyl is composed of 1 to 6 carbon atoms and one or more atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof, and the heteroalkyl is bonded to the remainder of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyls are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, or -CH2CH2N(CH3)2. Unless otherwise specifically stated herein, the heteroalkyl is optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.

[0033] "Heterocycloalkyl" refers to a 3- to 24-membered partially or fully saturated ring radical containing 2 to 23 carbon atoms and 1 to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl is nitrogen, oxygen, It contains 1 to 3 heteroatoms selected from the group consisting of nitrogen and sulfur. In some embodiments, the heterocycloalkyl contains 1 to 3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl contains 1 to 3 nitrogens. In some embodiments, the heterocycloalkyl contains 1 or 2 nitrogens. In some embodiments, the heterocycloalkyl contains 1 nitrogen. In some embodiments, the heterocycloalkyl contains 1 nitrogen and 1 oxygen. Unless otherwise specifically stated herein, the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, a fused ring system (when fused to an aryl ring or a heteroaryl ring, the heterocycloalkyl is bonded via a non-aromatic ring atom) or a bridged ring system may be included, and the nitrogen, carbon or sulfur atoms in the heterocycloalkyl radical may optionally be oxidized, and the nitrogen atoms may optionally be quaternized. Representative heterocycloalkyls include 2 to 15 carbon atoms (C2 - C 15 heterocycloalkyl or C2 - C 15 heterocycloalkenyl), 2 to 10 carbon atoms (C2 - C 10 heterocycloalkyl or C2 - C 10heterocycloalkyl having from 2 to 8 carbon atoms (C2-C8 heterocycloalkyl or C2-C8 heterocycloalkenyl), from 2 to 7 carbon atoms (C2-C7 heterocycloalkyl or C2-C7 heterocycloalkenyl), from 2 to 6 carbon atoms (C2-C6 heterocycloalkyl or C2-C7 heterocycloalkenyl), from 2 to 5 carbon atoms (C2-C5 heterocycloalkyl or C2-C5 heterocycloalkenyl), or from 2 to 4 carbon atoms (C2-C4 heterocycloalkyl or C2-C4 heterocycloalkenyl), but are not limited thereto. Examples of such heterocycloalkyl radicals include aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, and 2-oxo-1,3-dioxol-4-yl, but are not limited thereto. The term heterocycloalkyl also includes all cyclic forms of carbohydrates, including but not limited to monosaccharides, disaccharides, and oligosaccharides. Unless otherwise stated, heterocycloalkyl has from 2 to 10 carbons in the ring. When referring to the number of carbon atoms in heterocycloalkyl, it is understood that the number of carbon atoms in heterocycloalkyl is not the same as the total number of atoms (i.e., the backbone atoms of the heterocycloalkyl ring) that make up the heterocycloalkyl (including heteroatoms). In some embodiments, heterocycloalkyl is a 3- to 8-membered heterocycloalkyl.In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkenyl. Unless otherwise specifically stated herein, the heterocycloalkyl may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl. Haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc., and may be optionally substituted as described below. In some embodiments, the heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.

[0034] "Heteroaryl" refers to a 5- to 14-membered ring system radical containing 1 to 13 carbon atoms, 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. In some embodiments, heteroaryl contains 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, heteroaryl contains 1 to 3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, heteroaryl contains 1 to 3 nitrogens. In some embodiments, heteroaryl contains 1 or 2 nitrogens. In some embodiments, heteroaryl contains 1 nitrogen. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, and may include a fused ring system (when fused to a cycloalkyl or heterocycloalkyl ring, heteroaryl is bonded through an aromatic ring atom) or a bridged ring system. The nitrogen, carbon, or sulfur atoms in the heteroaryl radical may optionally be oxidized, and the nitrogen atoms may optionally be quaternized. In some embodiments, heteroaryl is 5- to 10-membered heteroaryl. In some embodiments, heteroaryl is 5- to 6-membered heteroaryl. In some embodiments, heteroaryl is 6-membered heteroaryl. In some embodiments, heteroaryl is 5-membered heteroaryl. Examples include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl , benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4 - benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2 - a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2 - oxoazepinyl, oxazolyl, oxiranyl, 1 - oxidopyridinyl, 1 - oxidopyrimidinyl, 1 - oxidopyranidinyl, 1 - oxidopyridazinyl, 1 - phenyl - 1H - pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl), but are not limited thereto. Unless otherwise specifically stated herein, heteroaryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, he teroaryl is optionally substituted with halogen.

[0035] The terms "optionally" or "optionally substituted" mean that the event or situation described thereafter may or may not occur, and that the description includes both the case where the event or situation occurs and the case where the event or situation does not occur. For example, "optionally substituted alkyl" means either "alkyl" or "substituted alkyl" as defined above. Further, a group that is optionally substituted may be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F), or substituted at any level between full substitution and monosubstitution (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.). One of ordinary skill in the art will understand that for any group containing one or more substituents, such groups are not intended to introduce any substitution or substitution pattern that is sterically unrealistic and / or synthetically infeasible (e.g., a substituted alkyl group is defined to contain an optionally substituted cycloalkyl group, which in turn contains an optionally substituted alkyl group, and could continue indefinitely). Thus, any substituents described are generally to be understood as having a maximum molecular weight of about 1,000 Daltons, more typically about 500 Daltons.

[0036] The term "one or more" when referring to an optionally substituted group means that the subject group is optionally substituted with 1, 2, 3, 4, or more substituents. In some embodiments, the subject group is optionally substituted with 1, 2, 3, or 4 substituents. In some embodiments, the subject group is optionally substituted with 1, 2, or 3 substituents. In some embodiments, the subject group is optionally substituted with 1 or 2 substituents. In some embodiments, the subject group is optionally substituted with 1 substituent. In some embodiments, the subject group is optionally substituted with 2 substituents.

[0037] "Effective amount" or "therapeutically effective amount" refers to the amount of a compound administered to a mammalian subject as a single dose or as part of a series of doses, which is effective to produce the desired therapeutic effect.

[0038] "Treatment" of an individual (e.g., a mammalian such as a human) or a cell is any type of intervention used in an attempt to alter the natural course of the individual or cell. In some embodiments, treatment includes administration of a pharmaceutical composition following the onset of a pathological event or contact with a pathogen, and includes stabilization (e.g., the condition does not worsen) or alleviation of the condition.

[0039] "Synergistic" or "showing synergy" refers to an effect of a combination that is greater than the sum of the effects of each component alone at the same dose.

[0040] As used herein, "disease or disorder associated with MK2" or alternatively "MK2-mediated disease or disorder" means any disease or other adverse condition in which MK2 or a variant thereof is known or suspected to play a role. As used herein, "disease or disorder associated with p38 MAP kinase" or "p38 MAP kinase-mediated disease or disorder" means any disease or other adverse condition in which p38 MAP kinase or a variant thereof is known or suspected to play a role. Compound

[0041] Compounds of formulas (I)-(Ia)-(Ij), or pharmaceutically acceptable salts, solvates, stereoisomers , or rotamers thereof, useful in the treatment of autoimmune disorders, chronic inflammatory disorders, acute inflammatory disorders, autoinflammatory disorders, fibrotic disorders, metabolic disorders, neoplastic disorders, or cardiovascular or cerebrovascular disorders are described herein.

[0042] Compounds of formula (I), or pharmaceutically acceptable salts, solvates, stereoisomers, or rotamers thereof

Chemical formula

[0043] Also disclosed herein are compounds of formula (Ia), or pharmaceutically acceptable salts, solvates, stereoisomers, or rotamers thereof:

Chemical formula

[0044] Also disclosed herein are compounds of formula (Ib), or pharmaceutically acceptable salts, solvates, stereoisomers, or rotamers thereof:

Chemical formula

[0045] Also disclosed herein are compounds of formula (Ic), or pharmaceutically acceptable salts, solvates, stereoisomers, or rotamers thereof:

Chemical formula

[0046] Also disclosed herein are compounds of formula (Id), or pharmaceutically acceptable salts, solvates, stereoisomers, or rotamers thereof:

Chemical formula

[0047] Also disclosed herein is a compound of formula (Ie), or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamer thereof:

Chem.

[0048] Also disclosed herein is a compound of formula (If), or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamer thereof:

Chem.

[0049] Also disclosed herein is a compound of formula (Ig), or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamer thereof:

Chem.

[0050] Also disclosed herein is a compound of formula (Ih), or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamer thereof:

Chem.

[0051] Also disclosed herein is a compound of formula (Ii), or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamer thereof:

Chem.

[0052] Also disclosed herein is a compound of formula (Ij), or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamer thereof:

Chem.

[0053] In some embodiments of the compounds of formula (I), (Ia)-(Ie), (Ig), or (Ii), ring A is heteroaryl. In some embodiments of the compounds of formula (I), (Ia)-(Ie), (Ig), or (Ii), ring A is 6-membered heteroaryl. In some embodiments of the compounds of formula (I), (Ia)-(Ie), (Ig), or (Ii), ring A is pyridyl. In some embodiments of the compounds of formula (I), (Ia)-(Ie), (Ig), or (Ii), ring A is phenyl.

[0054] In some embodiments of the compounds of formula (I), (Ia)-(Ij), each R 10 is independently hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl. In some embodiments of the compounds of formula (I), (Ia)-(Ij), each R 10 is independently hydrogen, halogen, or C1-C6 alkyl. In some embodiments of the compounds of formula (I), (Ia)-(Ij), each R 10 is independently hydrogen or halogen.

[0055] In some embodiments of the compounds of formula (I), (Ia)-(Ij), each R 10 is independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl. In some embodiments of the compounds of formula (I), (Ia)-(Ij), each R 10 is independently halogen or is C1-C6 alkyl. In some embodiments of the compounds of formula (I), (Ia)-(Ij), each R 10 is independently halogen.

[0056] In some embodiments of the compounds of formula (I), (Ia)-(Ie), (Ig), or (Ii), n is 1 or 2. In some embodiments of the compounds of formula (I), (Ia)-(Ie), (Ig), or (Ii), n is 2 or 3. In some embodiments of the compounds of formula (I), (Ia)-(Ie), (Ig), or (Ii), n is 1. In some embodiments of the compounds of formula (I), (Ia)-(Ie), (Ig), or (Ii), n is 2. In some embodiments of the compounds of formula (I), (Ia)-(Ie), (Ig), or (Ii), n is 3.

[0057] In some embodiments of the compounds of formula (I), (Ia)-(Ij), R 1 and R 2 are independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of the compounds of formula (I), (Ia)-(Ij), R 1 and R 2 are independently hydrogen, deuterium, halogen, or C1-C6 alkyl. In some embodiments of the compounds of formula (I), (Ia)-(Ij), R 1 and R 2 are hydrogen. In some embodiments of the compounds of formula (I), (Ia)-(Ij), R 1 and R 2 are deuterium.

[0058] In some embodiments of the compounds of formula (I), (Ia)-(Ij), X is -O-.

[0059] In some embodiments of the compounds of formula (I), (Ia)-(Ij), R 5 is hydrogen, deuterium, halogen, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl, or cycloalkyl. In some embodiments of the compounds of formula (I), (Ia)-(Ij), R 5is hydrogen, deuterium, halogen, -CN, or C1-C6 alkyl. In some embodiments of the compounds of formula (I), (Ia)-(Ij), R 5 is hydrogen. In some embodiments of the compounds of formula (I), (Ia)-(Ij), R 6 is hydrogen, deuterium, halogen, -CN, or C1-C6 alkyl.

[0060] In some embodiments of the compounds of formula (I), (Ia)-(Ij), R 6 is hydrogen, deuterium, halogen, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl, or cycloalkyl. In some embodiments of the compounds of formula (I), (Ia)-(Ij), R 6 is hydrogen, deuterium, halogen, -CN, or C1-C6 alkyl. In some embodiments of the compounds of formula (I), (Ia)-(Ij), R 6 is C1-C6 alkyl.

[0061] In some embodiments of the compounds of formula (I), (Ia)-(Ij), R 7 is hydrogen, deuterium, halogen, or C1-C6 haloalkyl. In some embodiments of the compounds of formula (I), (Ia)-(Ij), R 7 is hydrogen, deuterium, or halogen. In some embodiments of the compounds of formula (I), (Ia)-(Ij), R 7 is halogen. In some embodiments of the compounds of formula (I), (Ia)-(Ij), R 7 is chloro. In some embodiments of the compounds of formula (I), (Ia)-(Ij), R 7 is bromo. In some embodiments of the compounds of formula (I), (Ia)-(Ij), R 7 is -CHF2.

[0062] In some embodiments of the compounds of formula (I), (Ia) - (Ie), (Ig), or (Ih), ring B is phenyl or 6 - membered heteroaryl. In some embodiments of the compounds of formula (I), (Ia) - (Ie), (Ig), or (Ih), ring B is pyridinyl. In some embodiments of the compounds of formula (I), (Ia) - (Ie), (Ig), or (Ih), ring B is phenyl.

[0063] In some embodiments of the compounds of formula (I), (Ia) - (Ij), each R 11 is independently deuterium, halogen, - CN, - OH, - OR a , C1 - C6 alkyl, C1 - C6 haloalkyl, C1 - C6 deuteroalkyl, C1 - C6 hydroxyalkyl, C1 - C6 aminoalkyl, C1 - C6 heteroalkyl, C2 - C6 alkynyl, or cycloalkyl. In some embodiments of the compounds of formula (I), (Ia) - (Ij), each R 11 is independently C1 - C6 alkyl.

[0064] In some embodiments of the compounds of formula (I), (Ia) - (Ij), each R 11 is independently hydrogen, deuterium, halogen, - CN, - OH, - OR a , C1 - C6 alkyl, C1 - C6 haloalkyl, C1 - C6 deuteroalkyl, C1 - C6 hydroxyalkyl, C1 - C6 aminoalkyl, C1 - C6 heteroalkyl, C2 - C6 alkynyl, or cycloalkyl. In some embodiments of the compounds of formula (I), (Ia) - (Ij), each R 11 is independently hydrogen or C1 - C6 alkyl.

[0065] In some embodiments of the compounds of formula (I), (Ia) - (Ij), m is 1 or 2. In some embodiments of the compounds of formula (I), (Ia) - (Ij), m is 1 - 4. In some embodiments of the compounds of formula (I), (Ia) - (Ij), m is 2 - 4. In some embodiments of the compounds of formula (I), (Ia) - (Ij), m is 1. In some embodiments of the compounds of formula (I), (Ia) - (Ij), m is 2.

[0066] In some embodiments of the compounds of formula (I), (If), (Ig), ring C is N - linked pyridinone, N - linked pyrimidinone, N - linked pyrazinone, or N - linked pyridazinone. In some embodiments of the compounds of formula (I), (If), (Ig), ring C is N - linked pyridinone. In some embodiments of the compounds of formula (I), (If), (Ig), ring C is N - linked pyrimidinone. In some embodiments of the compounds of formula (I), (If), (Ig), ring C is N - linked pyrazinone. In some embodiments of the compounds of formula (I), (If), (Ig), ring C is N - linked pyridazinone.

[0067] In some embodiments of the compounds of formula (I), (If), (Ig), ring C is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0068] In some embodiments of the compounds of formula (I), (Ia)-(Ij), each R 12 is independently hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterioalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), and alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently substituted with one or more R 12a .

[0069] In some embodiments of the compounds of formula (I), (Ia)-(Ij), each R 12 is independently hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterioalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), or C1-C6 alkylene(heterocycloalkyl), and alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently substituted with one or more R 12a .

[0070] In some embodiments of the compounds of formula (I), (Ia)-(Ij), each R 12 is independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, heterocycloalkyl, C1-C6 alkylene(cycloalkyl), or C1-C6 alkylene(heterocycloalkyl), and the alkyl, cycloalkyl, and heterocycloalkyl are optionally and independently substituted with one or more R 12a .

[0071] In some embodiments of the compounds of formula (I), (Ia)-(Ij), each R 12 is independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, or heterocycloalkyl, and the alkyl, cycloalkyl, and heterocycloalkyl are optionally and independently substituted with one or more R 12a .

[0072] In some embodiments of the compounds of formula (I), (Ia)-(Ij), each R 12 is independently hydrogen or C1-C6 hydroxyalkyl.

[0073] In some embodiments of the compounds of formula (I), (Ia)-(Ij), each R 12 is independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 Aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), wherein alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently substituted with one or more R 12a and are optionally and independently substituted.

[0074] In some embodiments of the compounds of formula (I), (Ia)-(Ij), each R 12 is independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), or C1-C6 alkylene(heterocycloalkyl), wherein alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently substituted with one or more R 12a and are optionally and independently substituted.

[0075] In some embodiments of the compounds of formula (I), (Ia)-(Ij), each R 12 is independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, heterocycloalkyl, C1-C6 alkylene(cycloalkyl), or C1-C6 alkylene(heterocycloalkyl), wherein alkyl, cycloalkyl, and heterocycloalkyl are optionally and independently substituted with one or more R 12a and are substituted.

[0076] In some embodiments of the compounds of formula (I), (Ia)-(Ij), each R 12is independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, or heterocycloalkyl, and the alkyl, cycloalkyl, and heterocycloalkyl are optionally and independently substituted with one or more R 12a s.

[0077] In some embodiments of the compounds of formula (I), (Ia)-(Ij), each R 12 is independently C1-C6 hydroxyalkyl.

[0078] In some embodiments of the compounds of formula (I), (Ia)-(Ij), each R 12a is independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl.

[0079] In some embodiments of the compounds of formula (I), (Ia)-(Ij), each R 12a is independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of the compounds of formula (I), (Ia)-(Ij), each R 12a is independently deuterium, halogen, -CN, -OH, -OR a , C1-C6 alkyl, or C1-C6 haloalkyl.

[0080] In some embodiments of the compounds of formula (I), (If), or (Ig), p is 1 or 2. In some embodiments of the compounds of formula (I), (If), or (Ig), p is from 1 to 3. In some embodiments of the compounds of formula (I), (If), or (Ig), p is 1. In some embodiments of the compounds of formula (I), (If), or (Ig) , p is 2.

[0081] In some embodiments of the compounds disclosed herein, each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl. In some embodiments of the compounds disclosed herein, each R ais independently C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl, and each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 dideuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl. In some embodiments of the compounds disclosed herein, each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of the compounds disclosed herein, each R a is independently C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, each R a is independently C1-C6 alkyl.

[0082] In some embodiments of the compounds disclosed herein, each R bis, independently, hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterioalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterioalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl. In some embodiments of the compounds disclosed herein, each R b is, independently, hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl, and each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterioalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl. In some embodiments of the compounds disclosed herein, each R b is, independently, hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of the compounds disclosed herein, each R b is, independently, hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, each R bis independently hydrogen or C1-C6 alkyl.

[0083] In some embodiments of the compounds disclosed herein, each R c and R d are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl. In some embodiments of the compounds disclosed herein, each R c and R d are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl, and each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl. In some embodiments of the compounds disclosed herein, each R c and R dis independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of the compounds disclosed herein, each R c and R d is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, each R c and R d is independently hydrogen, or C1-C6 alkyl.

[0084] In some embodiments of the compounds disclosed herein, R c and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 dideuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl.

[0085] In some embodiments of the compounds disclosed herein, each R 10 , R 11 , R 12 , R a , R b , R c , R d , R c and R d when combined together form a heterocycloalkyl, R a and R b when combined together form a heterocycloalkyl, R b and R c when combined together form a heterocycloalkyl which is independently substituted with 1, 2, 3, 4, or 5 substituents as defined herein. In some embodiments of the compounds disclosed herein, each R 10 , R 11 , R 12 , R a, R b , R c , R d , R c and R d the heterocycloalkyl formed when combined with R a and R b the heterocycloalkyl formed when combined with R b and R c the heterocycloalkyl formed when combined with R is independently substituted with 1, 2, 3, or 4 substituents as defined herein. In some embodiments of the compounds disclosed herein, each R 10 , R 11 , R 12 , R a , R b , R c , R d , R c and R d formed when combined the heterocycloalkyl formed when combined with R a and R b the heterocycloalkyl formed when combined with R b and R c the heterocycloalkyl formed when combined with R is independently substituted with 1, 2, or 3 substituents as defined herein. In some embodiments of the compounds disclosed herein, each R 10 , R 11 , R 12 , R a , R b , R c , R d , R c and R d the heterocycloalkyl formed when combined with R a and R b the heterocycloalkyl formed when combined with R b and R c the heterocycloalkyl formed when combined with R is independently substituted with 1 or 2 substituents as defined herein. In some embodiments of the compounds disclosed herein, each R 10 , R 11 , R 12, R a , R b , R c , R d , R c and R d The heterocycloalkyl formed when R a and R b are combined together, the heterocycloalkyl formed when R b and R c are combined together is independently substituted with one substituent as defined herein.

[0086] Any combination of the groups described above for the various variable parts is contemplated herein. Throughout this specification, those groups and substituents are selected by one of ordinary skill in the art to provide stable moieties and compounds.

[0087] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamer thereof, is selected from the following.

Table 1-1

Table 1-2

Table 1-3

Table 1-4

Table 1-5

Table 1-6

[0088] Note: All rotamers found in Table 1 were arbitrarily assigned.

[0089] In some embodiments, compound (I) is [Chemistry] [Chemistry] [Chemistry] or is selected from their pharmaceutically acceptable salts, solvates, stereoisomers, or rotamers. Further forms of the compounds disclosed herein Isomers / Stereoisomers

[0090] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds shown herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, as well as corresponding mixtures thereof. In some situations, the compounds described herein have one or more chiral centers, and each center exists in the R or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms, as well as corresponding mixtures thereof. In further embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers obtained from a single preparation step, combination, or interconversion are useful for the uses described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereomeric compounds, separating the diastereoisomers, and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereomers have different physical properties (e.g., melting point, boiling point, solubility, reactivity, etc.) and are separated by taking advantage of these differences. In some embodiments, the diastereomers are separated by chiral chromatography or, preferably, by separation / resolution techniques based on differences in solubility. In some embodiments, the optically pure enantiomers are then recovered from the resolving agent by any practical means that does not result in racemization.

[0091] In some embodiments, the compounds described herein exist as rotational isomers caused by the slow rotation of the N-C bond between the central pyridinone ring and ring B.

[0092] In some embodiments,

Chemical Structure

[0093] For example, [Chemical formula] exists as. Labeling compound

[0094] In some embodiments, the compounds described herein exist in isotopically labeled forms. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically labeled compounds as a pharmaceutical composition. Thus, in some embodiments, the compounds disclosed herein include isotopically labeled compounds, which are identical to those listed herein, except that one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, for example, 2 H, 3 H, 13 C, 14 C, l5 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl. The compounds described herein containing the aforementioned isotopes and / or other isotopes of other atoms, as well as their pharmaceutically acceptable salts, solvates, stereoisomers, or rotational isomers are within the scope of the present invention. Certain isotopically labeled compounds, for example, 3 H and 14 C, etc., incorporating radioactive isotopes are useful in drug and / or substrate tissue distribution assays. Tritiation, i.e., 3 H and carbon-14, i.e.,14 C isotopes are particularly preferred because of the ease of their preparation and detectability. Furthermore, substitution with heavy isotopes, such as deuterium, i.e., 2 H, etc., results in higher metabolic stability, for example, a longer in vivo half-life or a lower required dose, thus providing certain therapeutic advantages.

[0095] In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of a chromophore or fluorophore, a bioluminescent label, or a chemiluminescent label. Pharmaceutically acceptable salts

[0096] In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts as a pharmaceutical composition.

[0097] In some embodiments, the compounds described herein have an acidic or basic group and thus react with any of several inorganic or organic bases, as well as inorganic and organic acids, to form pharmaceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or of their solvates, stereoisomers, or rotamers, or by reacting the purified compound in free form with a suitable acid or base and isolating the salt thus formed.

[0098] Examples of pharmaceutically acceptable salts include salts prepared by reacting the compounds described herein with a mineral, organic acid, or inorganic base, such salts including acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyne-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogen phosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, γ-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodate, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogen phosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, undecanoate tosylate, and xylenesulfonate. Also included are salts formed by reacting the compounds described herein in their free base form with a pharmaceutically acceptable inorganic or organic acid.

[0099] Furthermore, the compounds described herein can be formed as pharmaceutically acceptable salts by reacting the compound in its free base form with a pharmaceutically acceptable inorganic or organic acid. can be prepared, and such acids include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, etc.; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-en-1-carboxylic acid, glucoheptonic acid, 4,4’-methylenebis-(3-hydroxy-2-en-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid, but are not limited thereto. In some embodiments, other acids such as oxalic acid, although not pharmaceutically acceptable per se, are used in the preparation of salts useful as intermediates in obtaining the compounds, solvates, stereoisomers, or rotamers disclosed herein and their pharmaceutically acceptable acid addition salts.

[0100] In some embodiments, the compounds described herein containing a free acid group react with appropriate bases such as hydroxides, carbonates, bicarbonates, sulfates, etc. of pharmaceutically acceptable metal cations, ammonia, or pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amines. Representative salts include alkali or alkaline earth salts such as lithium, sodium, potassium, calcium, and magnesium salts, and aluminum salts, etc. Specific examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1~4 alkyl)4, etc.

[0101] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the compounds described herein also include quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water-soluble or oil-soluble or dispersible products are obtained by such quaternization. Solvate

[0102] In some embodiments, the compounds described herein exist as solvates. The present invention provides methods of treating a disease by administering such solvates. The present invention further provides methods of treating a disease by administering such solvates as pharmaceutical compositions.

[0103] Solvates contain a solvent in either stoichiometric or non-stoichiometric amounts and, in some embodiments, are formed using pharmaceutically acceptable solvents such as water, ethanol, etc. When the solvent is water, a hydrate is formed, or when the solvent is an alcohol, an alcoholate is formed. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. For example, hydrates of the compounds described herein can be conveniently prepared from aqueous / organic solvent mixtures using organic solvents including, but not limited to, dioxane, tetrahydrofuran, or methanol. Further, the compounds provided herein can exist in unsolvated and solvated forms. Generally, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein. Tautomer

[0104] In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the scope of the formulas described herein. Tautomerism The body is a compound that can be interconverted by the movement of hydrogen atoms, involving the switching of single bonds and adjacent double bonds. In bond arrangements that allow for tautomerization, a chemical equilibrium of tautomers exists. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of tautomers depends on several factors including temperature, solvent, and pH. Therapeutic method

[0105] Compounds and compositions generally useful for inhibiting the kinase activity of one or more enzymes are described herein. Examples of kinases inhibited by the compounds and compositions described herein and for which the methods described herein are useful include p38 MAP kinase, MK2, or variants thereof.

[0106] Mitogen-activated protein kinase-activated protein kinase 2 ("MK2") is an enzyme encoded by the MAPKAPK2 gene in humans. This gene encodes a member of the Ser / Thr protein kinase family. This kinase is regulated through direct phosphorylation by p38 MAP kinase. Along with p38 MAP kinase, this kinase is known to be involved in many cellular processes including stress and inflammatory responses, nuclear export, regulation of gene expression, and cell proliferation. Heat shock protein HSP27 has been shown to be one of the substrates of this kinase in vivo. Two transcript variants encoding two different isoforms have been found for this gene.

[0107] MK2 is a multi-domain protein consisting of an N-terminal proline-rich domain, a catalytic domain, an auto-inhibitory domain, and a C-terminal nuclear export signal (NES) and nuclear localization signal (NLS). Two isoforms of human MK2 have been characterized. One isoform consists of 400 amino acids and the other consists of 370 residues, which is thought to be a splice variant lacking the C-terminal NLS. MK2 is located in the cell nucleus, and upon binding and phosphorylation by p38, the MK2 NES becomes functional and both kinases are co-transported from the nucleus to the cytoplasm. Interestingly, the transport of the MK2 / p38 complex does not require catalytically active MK2 as the active site mutant Asp207Ala is still transported to the cytoplasm. Phosphorylation of human MK2 by p38 on residues T222, S272, and T334 is thought to activate the enzyme by inducing a conformational change in the auto-inhibitory domain and thus exposing the active site for substrate binding. Mutations of two auto-inhibitory domain residues, W332A and K326E, in mouse MK2 show increased basal activity, and C-terminal deletion of the auto-inhibitory domain constitutively activates this domain, providing further evidence for the role of this domain in the inhibition of MK2 activity.

[0108] Diseases or disorders related to MK2 treated by the compounds disclosed herein include autoimmune disorders, chronic inflammatory disorders, acute inflammatory disorders, autoinflammatory disorders, fibrotic disorders, metabolic disorders, neoplastic disorders, and cardiovascular or cerebrovascular disorders.

[0109] In some embodiments, the MK2-mediated disease or disorder is an autoimmune disorder, a chronic and / or acute inflammatory disorder, and / or an autoinflammatory disorder. Exemplary autoimmune and / or inflammatory and / or autoinflammatory disorders include inflammatory bowel disease (e.g., ulcerative colitis or Crohn's disease), multiple sclerosis, psoriasis, arthritis, rheumatoid arthritis, osteoarthritis, juvenile arthritis, psoriatic arthritis, reactive arthritis, ankylosing spondylitis, cryopyrin-associated periodic syndrome, Muckle-Wells syndrome, familial cold autoinflammatory syndrome, neonatal-onset multisystem autoinflammatory disease, TNF receptor-associated periodic syndrome, acute and chronic pancreatitis, atherosclerosis, gout, ankylosing spondylitis, fibrotic disorders (e.g., liver fibrosis or idiopathic pulmonary fibrosis), nephrosis, sarcoidosis, scleroderma, anaphylaxis, diabetes (e.g., type 1 diabetes or type 2 diabetes), diabetic retinopathy, Still's disease, vasculitis, sarcoidosis, pulmonary inflammation, acute respiratory distress syndrome, wet and dry age-related macular degeneration, autoimmune hemolytic syndrome, autoimmune and inflammatory hepatitis, autoimmune neuropathy, autoimmune ovarian failure, autoimmune orchitis, autoimmune thrombocytopenia, silicone implant-associated autoimmune disease, Sjogren's syndrome, familial Mediterranean fever, systemic lupus erythematosus, vasculitis syndromes (e.g., temporal Takayasu's arteritis and giant cell arteritis, Behçet's disease or Wegener's granulomatosis), vitiligo, secondary hematological manifestations of autoimmune diseases (e.g., anemia), drug-induced autoimmunity, Hashimoto's thyroiditis, hypophysitis, idiopathic thrombocytopenic purpura, metal-induced autoimmunity, myasthenia gravis, pemphigus, autoimmune deafness (e.g., Meniere's disease), Goodpasture's syndrome, Graves' disease, HW-associated autoimmune syndrome, Guillain-Barré syndrome, Addison's disease, antiphospholipid syndrome, asthma, atopic dermatitis, celiac disease, Cushing's syndrome, dermatomyositis, idiopathic adrenal atrophy, idiopathic thrombocytopenia, Kawasaki disease, Eaton-Lambert syndrome, malignant anemia, hay fever, polyarteritis nodosa, primary biliary cirrhosis, primary sclerosing cholangitis, Raynaud's disease, Reiter's syndrome, relapsing polychondritis, Schmidt's syndrome, thyrotoxicosis, sepsis, septic shock, endotoxic shock, exotoxin-induced toxic shock syndrome, gram-negative sepsis, toxic shock syndrome, glomerulonephritis, peritonitis, interstitial cystitis, hyperoxia-induced inflammation, chronic obstructive pulmonary disease (COPD), vasculitis, graft-versus-host reaction (e.g., graft-versus-host disease), allogeneic transplantation These include rejection (e.g., acute allograft rejection or chronic allograft rejection), early transplant rejection (e.g., acute rejection), reperfusion injury, pain (e.g., acute pain, chronic pain, neuropathic pain, or fibromyalgia), chronic infection, meningitis, encephalitis, myocarditis, gingivitis, post-operative trauma, tissue injury, traumatic brain injury, enteritis, sinusitis, uveitis, eye inflammation, optic neuritis, gastric ulcer, esophagitis, peritonitis, periodontitis, dermatomyositis, gastritis, myositis, polymyalgia, pneumonia, and bronchitis.

[0110] In some embodiments, the MK2-mediated disease or disorder is a fibrotic disorder. Exemplary fibrotic disorders include systemic sclerosis / scleroderma, lupus nephritis, connective tissue disease, wound healing, surgical scarring, spinal cord injury, CNS scarring, acute lung injury, pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis or cystic fibrosis), chronic obstructive pulmonary disease, adult respiratory distress syndrome, acute lung injury, drug-induced lung injury, glomerulonephritis, chronic kidney disease (e.g., diabetic nephropathy), hypertensive nephropathy, gastrointestinal or bowel fibrosis, renal fibrosis, liver or biliary fibrosis, liver fibrosis (e.g., non-alcoholic steatohepatitis, hepatitis C, or hepatocellular carcinoma), cirrhosis (e.g., primary biliary cirrhosis or cirrhosis due to fatty liver disease (e.g., alcoholic and non-alcoholic steatosis)), radiation-induced fibrosis (e.g., in the head and neck, gastrointestinal, or lung), primary sclerosing cholangitis, restenosis, cardiac fibrosis (e.g., endomyocardial fibrosis or atrial fibrosis), ocular scarring, fibrosclerosis, fibrotic cancer, fibroma-like, fibroma, fibroadenoma, fibrosarcoma, transplant arteriopathy, keloid, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis, and nephrogenic systemic fibrosis.

[0111] In some embodiments, the MK2-mediated disease or disorder is a metabolic disorder. Exemplary metabolic disorders include obesity, steroid resistance, glucose intolerance, and metabolic syndrome.

[0112] In some embodiments, the MK2-mediated disease or disorder is a neoplastic disease or disorder. Exemplary neoplastic diseases or disorders include cancer. In some embodiments, exemplary neoplastic diseases or disorders include angiogenesis disorders, multiple myeloma, leukemia (e.g., acute lymphoblastic leukemia, acute and chronic myelogenous leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, or promyelocytic leukemia), lymphoma (e.g., B-cell lymphoma, T-cell lymphoma, mantle cell lymphoma, hairy cell lymphoma, Burkitt lymphoma, mast cell tumor, Hodgkin disease, or non-Hodgkin disease), myelodysplastic syndrome, fibrosarcoma, rhabdomyosarcoma; astrocytoma, neuroblastoma, glioma, and schwannoma; melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoctanthoma, thyroid follicular carcinoma, Kaposi sarcoma, melanoma, strange Sarcoma, rhabdomyosarcoma, metastatic and bone disorders, as well as bone cancer, oral / pharyngeal cancer, esophageal cancer, laryngeal cancer, gastric cancer, intestinal cancer, colon cancer, rectal cancer, lung cancer (e.g., non-small cell lung cancer or small cell lung cancer), liver cancer, pancreatic cancer, nerve cancer, brain cancer (e.g., glioma or glioblastoma multiforme), head and neck cancer, laryngopharyngeal cancer, ovarian cancer, uterine cancer, prostate cancer, testicular cancer, bladder cancer, kidney cancer, breast cancer, gallbladder cancer, cervical cancer, thyroid cancer, prostate cancer, and skin cancer.

[0113] In some embodiments, the MK2-mediated disorder is a cardiovascular disorder or a cerebrovascular disorder. Exemplary cardiovascular disorders include atherosclerosis, restenosis of atherosclerotic coronary arteries, acute coronary syndrome, myocardial infarction, cardiac allograft vasculopathy, and stroke. Exemplary cerebrovascular diseases include central nervous system disorders with an inflammatory or apoptotic component, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, spinal cord injury, neuronal ischemia, and peripheral neuropathy. Administration

[0114] In certain embodiments, the composition(s) containing the compound(s) described herein is administered for prophylactic and / or therapeutic treatment. In certain therapeutic uses, the composition is administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. The amount effective for this use depends on the severity and course of the disease or condition, the patient's medical history, health status, weight, and response to the drug, as well as the judgment of the treating physician. The therapeutically effective amount is optionally determined by methods including, but not limited to, dose escalation and / or dose range clinical trials.

[0115] In a prophylactic use, a composition containing the compounds described herein is administered to a patient who is susceptible to, or at risk of, developing a particular disease, disorder or condition. Such an amount is defined as a "prophylactically effective amount or dose". In this use, the exact amount also depends on the patient's health status, weight, etc. When used in a patient, the effective amount for this use depends on the severity and course of the disease, disorder or condition, the patient's medical history, the patient's health status and response to the drug, and the judgment of the treating physician. In one aspect, prophylactic treatment involves administering to a mammal that has previously experienced at least one symptom or risk factor of the disease being treated and is currently in remission, a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof, to prevent recurrence of symptoms of the disease or condition.

[0116] In certain embodiments where the patient's condition does not improve, at the discretion of the physician, the administration of the compound is continued long-term, i.e., over a long period including the entire lifespan of the patient, to improve or otherwise control or limit the symptoms of the patient's disease or condition.

[0117] In certain embodiments where the patient's condition improves, the dose of the drug being administered is temporarily reduced or temporarily discontinued for a specific period (i.e., a "drug holiday"). In a specific embodiment, the length of the drug holiday is from 2 days to 1 year, including, for example, by way of illustration only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, or more than 28 days. The dose reduction during the drug holiday is, by way of illustration only, from 10% to 100%, including, for example, by way of illustration only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.

[0118] If the patient's condition improves, a maintenance dose is administered as needed. Thereafter, in specific embodiments, the dosage or dosing frequency, or both, are reduced, depending on the symptoms, to a level at which the improved disease, disorder, or condition is maintained. However, in certain embodiments, the patient will require long-term, intermittent, or daily treatment upon any recurrence of symptoms.

[0119] The amount of a given agent corresponding to such amounts will vary depending on factors such as the particular compound, disease state and its severity, the identity of the subject or host in need of treatment (e.g., weight, gender), etc., but nevertheless is determined according to the particular circumstances surrounding the case, including, for example, the particular agent being administered, the route of administration, the condition being treated, and the subject or host being treated.

[0120] However, generally, dosages used in the treatment of adults typically range from 0.01 mg to 5000 mg per day. In one aspect, dosages used in the treatment of adults are from about 1 mg to about 1000 mg per day. In one embodiment, the desired dosage is conveniently presented as a single dose, or as divided doses administered simultaneously or at appropriate intervals, for example, as two, three, four, or more divided doses per day.

[0121] In one embodiment, a suitable daily dosage of the compounds described herein or a pharmaceutically acceptable salt thereof is about 0.01 to about 50 mg / kg of body weight. In some embodiments, the daily dosage or amount of the active substance in the dosage form is lower or higher than the ranges indicated herein, based on the number of variables regarding the individual treatment regimen. In various embodiments, the daily dosage and unit dosage are varied according to several variables including, but not limited to, the activity of the compound used, the disease or condition being treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the physician.

[0122] The toxicity and therapeutic efficacy of such treatment regimens are determined by methods including, but not limited to, LD 10 and ED90 It is determined by standard pharmaceutical procedures in cell culture or experimental animals, including the determination of 50 LD 50 and ED 50 The dose ratio between toxicity and therapeutic effect is the therapeutic index, expressed as the ratio between

[0123] In any of the foregoing aspects, in a further embodiment, an effective amount of the compound or a pharmaceutically acceptable salt thereof described herein is (a) administered systemically to a mammal, and / or (b) administered orally to a mammal, and / or (c) administered intravenously to a mammal, and / or (d) administered to a mammal by injection, and / or (e) administered topically to a mammal, and / or (f) administered non-systemically or topically to a mammal.

[0124] In any of the foregoing aspects, a further embodiment includes a single administration of an effective amount of the compound, including (i) the compound is administered once a day, or (ii) the compound is administered to the mammal multiple times over a period of one day.

[0125] In any of the foregoing aspects, further embodiments include multiple administrations of an effective amount of the compound, where (i) the compound is administered continuously or intermittently as a single dose, (ii) the time between multiple administrations is every 6 hours, (iii) the compound is administered to the mammal every 8 hours, (iv) the compound is administered to the subject every 12 hours, (v) the compound is administered to the subject every 24 hours, including further embodiments. In further or alternative embodiments, the method includes a drug-free period, during which the administration of the compound is temporarily interrupted or the dose of the compound administered is temporarily reduced, and at the end of the drug-free period, the administration of the compound is resumed. In one embodiment, the length of the drug-free period varies from 2 days to 1 year. Route of Administration

[0126] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal membrane, transdermal, vaginal, otic, nasal, and topical administration. Further, by way of mere example, parenteral administration includes intramuscular, subcutaneous, intravenous, intrathecal injection, as well as intracisternal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injection.

[0127] In certain embodiments, the compounds described herein are administered in a non-systemic but local manner, for example, in many cases, via direct injection of the compound into the organ in the form of a depot preparation or a sustained-release formulation. In a specific embodiment, the long-acting formulation is administered by implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. Further, in other embodiments, the drug is delivered in a targeted drug delivery system, for example, in liposomes coated with an organ-specific antibody. In such embodiments, the liposomes target the organ and are selectively taken up by the organ. In still other embodiments, the compounds described herein are provided in the form of an immediate-release formulation, a sustained-release formulation, or an intermediate-release formulation. In still other embodiments, the compounds described herein are administered locally. Pharmaceutical Composition / Formulation

[0128] The compounds described herein are administered in pharmaceutical compositions to a subject in need thereof, alone or in combination with a pharmaceutically acceptable carrier, excipient, or diluent, in accordance with standard pharmaceutical practice. In one embodiment, the compounds of the invention can be administered to animals. The compounds can be administered orally or parenterally, such as by intravenous, intramuscular, intraperitoneal, subcutaneous, rectal, and topical routes of administration.

[0129] In another aspect, provided herein is a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamer thereof, and at least one pharmaceutically acceptable excipient. The pharmaceutical composition is formulated by conventional methods using one or more pharmaceutically acceptable excipients that facilitate processing the active compound into a pharmaceutically usable preparation. The appropriate formulation depends on the selected route of administration. An overview of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995), Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975, Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980, and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), and such disclosures are incorporated herein by reference.

[0130] In some embodiments, pharmaceutically acceptable excipients are selected from carriers, binders, fillers, suspending agents, flavoring agents, sweetening agents, disintegrants, dispersants, surfactants, lubricants, coloring agents, diluents, solubilizing agents, moistening agents, plasticizers, stabilizers, permeation enhancers, wetting agents, defoaming agents, antioxidants, preservatives, and any combination thereof.

[0131] The pharmaceutical compositions described herein are administered to a subject by a suitable route of administration including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal routes. The pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, self-emulsifying dispersions, solid solutions, liposome dispersions, aerosols, solid oral dosage forms, powders, immediate release formulations, controlled release formulations, rapid melt formulations, tablets, capsules, pills, powders, dragees, effervescent formulations, lyophilized formulations, delayed release formulations, sustained release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.

[0132] Pharmaceutical compositions comprising a compound or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamer thereof described herein are merely exemplary and are prepared by conventional methods such as conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or compression processes.

[0133] A pharmaceutical composition for oral use is obtained by mixing one or more solid excipients with one or more compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients include, for example, fillers such as sugars including lactose, sucrose, mannitol, or sorbitol, cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methyl cellulose, microcrystalline cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, or others such as polyvinyl pyrrolidone (PVP or povidone) or calcium phosphate. If desired, disintegrants such as cross-linked sodium carboxymethyl starch, polyvinyl pyrrolidone, agar, or salts of alginic acid or sodium alginate are added. In some embodiments, dyes or pigments are added to the tablet or dragee coating for identification or to characterize different combinations of active compound dosages.

[0134] Pharmaceutical compositions for oral administration include push-fit capsules made of gelatin, and sealed soft capsules made of gelatin and plasticizers such as glycerol or sorbitol. Push-fit capsules contain the active ingredient in a mixture of a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally a stabilizer. In soft capsules, the active compound is dissolved or suspended in a suitable liquid (e.g., fatty oil, liquid paraffin, or liquid polyethylene glycol). In some embodiments, a stabilizer is added.

[0135] A pharmaceutical composition for parenteral use is formulated as an infusion or injection. In some embodiments, a pharmaceutical composition suitable for injection or infusion comprises a sterile aqueous solution, dispersion, or sterile powder comprising a compound described herein or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamer thereof. In some embodiments, the pharmaceutical composition comprises a liquid carrier. In some embodiments, the liquid carrier is a solvent or liquid dispersion medium comprising, for example, water, saline, ethanol, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol, etc.), vegetable oils, non-toxic glyceryl esters, and any combination thereof. In some embodiments, the pharmaceutical composition further comprises a preservative to prevent the growth of microorganisms. Combination

[0136] Disclosed herein is a method of treating an autoimmune disorder, chronic inflammatory disorder, acute inflammatory disorder, autoinflammatory disorder, fibrotic disorder, metabolic disorder, neoplastic disorder, or cardiovascular or cerebrovascular disorder by using a compound disclosed herein or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamer thereof in combination with an additional therapeutic agent.

[0137] In some embodiments, the additional therapeutic agent is selected from the group consisting of anti-inflammatory agents, anti-atherosclerotic agents, immunosuppressive agents, immunomodulatory agents, cytostatic agents, antiproliferative agents, angiogenesis inhibitors, kinase inhibitors, cytokine blockers, and inhibitors of cell adhesion molecules.

[0138] In some embodiments, the additional therapeutic agent is selected from the group consisting of NSAIDs, immunosuppressive agents, immunomodulatory agents, cytostatic agents, antiproliferative agents, angiogenesis inhibitors, biological agents, steroids, vitamin D3 analogs, retinoids, other kinase inhibitors, cytokine blockers, corticosteroids, and inhibitors of cell adhesion molecules. In some embodiments, the additional therapeutic agent is selected from the group consisting of torcetrapib, aspirin, niacin, HMG CoA reductase inhibitors (e.g., atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin), colesevelam, cholestyramine, colestipol, gemfibrozil, probucol, and clofibrate.

[0139] In some embodiments, the additional therapeutic agent is selected from the group consisting of corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs) (e.g., ibuprofen, naproxen, acetaminophen, aspirin, fenoprofen (Nalfon), flurbiprofen (Ansaid), ketoprofen, oxaprozin (Daypro), diclofenac sodium (Voltaren), diclofenac potassium (Cataflam), etodolac (Lodine), indomethacin (Indocin), ketorolac (Toradol), sulindac (Clinoril), tolmetin (Tolectin), meclofenamate (Meclomen), mefenamic acid (Ponstel), nabumetone (Relafen), piroxicam (Feldene), cox-2 inhibitors (e.g., celecoxib (Celebrex)), immunosuppressive agents (e.g., methotrexate (Rheumatrex), leflunomide (Arava), azathioprine (Imuran), cyclosporine (Neoral, Sandimmune), tacrolimus and cyclophosphamide (Cytoxan), CD20 blockers (rituximab), tumor necrosis factor (TNF) blockers (e.g., etanercept (Enbrel), infliximab (Remicade) and adalimumab (Humira)), abatacept (CTLA4-Ig) and interleukin 1 receptor antagonists (e.g., anakinra (Kineret), interleukin 6 inhibitors (e.g., Actemra), interleukin 17 inhibitors (e.g., AIN457), Janus kinase inhibitors (e.g., tasocitinib), syk inhibitors (e.g., R788), and chloroquine and its derivatives).

[0140] In some embodiments, the additional therapeutic agent is selected from the group consisting of an EGFR kinase inhibitor, a MEK inhibitor, a VEGFR inhibitor, an anti-VEGFR2 antibody, a KDR antibody, an AKT inhibitor, a PDK-1 inhibitor, a PI3K inhibitor, a c-kit / Kdr tyrosine kinase inhibitor, a Bcr-Abl tyrosine kinase inhibitor, a VEGFR2 inhibitor, a PDGFR-beta inhibitor, a KIT inhibitor, a Flt3 tyrosine kinase inhibitor, a PDGF receptor family inhibitor, a Flt3 tyrosine kinase inhibitor, a RET tyrosine kinase receptor family inhibitor, a VEGF-3 receptor antagonist, a Raf protein kinase family inhibitor, an angiogenesis inhibitor, an Erb2 inhibitor, an mTOR inhibitor, an IGF-1R antibody, an NFkB inhibitor, a proteasome inhibitor, a chemotherapeutic agent, and a glucose reducing agent.

[0141] In some embodiments, the additional therapeutic agent is administered concomitantly with the compounds disclosed herein. In some embodiments, the additional therapeutic agent and the compounds disclosed herein are administered sequentially. In some embodiments, the additional therapeutic agent is administered less frequently than the compounds disclosed herein. In some embodiments, the additional therapeutic agent is administered more frequently than the compounds disclosed herein. In some embodiments, the additional therapeutic agent is administered prior to the administration of the compounds disclosed herein. In some embodiments, the additional therapeutic agent is administered after the administration of the compounds disclosed herein. Examples Intermediate 1

Chemical Structure

[0142] A stirred solution of methyl 2-oxo-1H-pyridine-3-carboxylate (2 g, 13.060 mmol, 1.00 equiv) in THF (20 mL) was added dropwise with MeMgBr (32.65 mL, 65.300 mmol, 5.00 equiv) in THF at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. The reaction was quenched with saturated NH4Cl (aqueous solution) (40 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-(2-hydroxypropan-2-yl)-1H-pyridin-2-one (1.1 g, 54.98%) as a white solid. LC-MS: (ES + H, m / z): [M + H] + = 154.1. Intermediates 2 - 4

Chemical Structure

[0143] A solution of 3,5-difluoropyridine-2-carboxylic acid (50.00 g, 314.28 mmol, 1.00 equiv) in ethanol (200 mL) was cooled using an ice bath, and then SOCl2 (50 mL, 689.25 mmol, 2.20 equiv) was added dropwise at 0 °C. The resulting mixture was stirred at 60 °C for 3 h under a nitrogen atmosphere. The mixture was brought to room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography to give ethyl 3,5-difluoropicolinate (59 g, 100%) as a colorless liquid. LC-MS: (ES + H, m / z): [M + H] + = 188.1. Step 2: Preparation of (3,5-difluoropyridin-2-yl)methanol: To a stirred solution of ethyl 3,5-difluoropyridine-2-carboxylate (40.00 g, 213.74 mmol, 1.00 eq) in ethanol (300 mL), NaBH4 (20.22 g, 534.34 mmol, 2.50 eq) was added portionwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 30 minutes under a nitrogen atmosphere. The resulting mixture was further stirred at room temperature for 2 hours under a nitrogen atmosphere. The reaction was quenched with saturated NH4Cl (aqueous solution) at 0 °C. EtOH was removed under reduced pressure. The aqueous layer was basified to pH 10 with saturated Na2CO3 (aqueous solution, 300 mL), and then extracted with EtOAc (3 × 300 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum to give (3,5-difluoropyridin-2-yl)methanol (26.6 g, 85.76%) as a colorless liquid. LC-MS: (ES + H, m / z): [M + H] + = 146.1. Step 3: Preparation of 2-(chloromethyl)-3,5-difluoropyridine:

[0144] To a stirred solution of (3,5-difluoropyridin-2-yl)methanol (3 4.00 g, 234.31 mmol, 1.00 eq) in DCM (500 mL) was added DMF (160 mg), and then cooled using an ice-water bath. To the above mixture, SOCl2 (40 mL, 551.40 mmol, 2.35 eq) was added dropwise under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum to give 2-(chloromethyl)-3,5-difluoropyridine (34.75 g, 90.68%) as a yellowish-brown semi-solid. LC-MS: (ES + H, m / z): [M + H] + = 164.0. 1 1H NMR (400 MHz, chloroform-d) δ 8.35 (d, 1H), 7.28 (td, 1H), 4.73 (d, 2H). Intermediates 5 - 8

Chemical Structure

[0145] A solution of LiHMDS (3.16 L, 3.16 mol, 1.50 equiv., 1 M in THF) in THF (1000 mL) was treated with 2,2,6-trimethyl-1,3-dioxin-4-one (300 g, 2.11 mol, 1.00 equiv.) at -20 °C for 1 h under a nitrogen atmosphere, and then ZnEt2 (3.16 L, 3.16 mol, 1.50 equiv., 1 M in hexane) was added dropwise at -20 °C over 2 h. The resulting mixture was stirred at -20 °C for 30 min under a nitrogen atmosphere. To the above mixture, acetylimidazole (348.58 g, 3.16 mol, 1.50 equiv.) was added at -10 °C. The resulting mixture was stirred at room temperature overnight. The reaction was quenched by adding 1 L of water / THF (1:1) at -10 °C. The mixture was acidified to pH 1 - 2 with 2 M HCl (aqueous solution). The resulting mixture was extracted with EtOAc (3 × 5 L). The combined organic layers were washed with brine (3 × 5 L) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 2,2-dimethyl-6-(2-oxopropyl)-1,3-dioxin-4-one (200 g, 51.45%) as yellowish-brown crystals. LC-MS: (ES + H, m / z): [M + H] + = 185.0。 1 H NMR (400 MHz, DMSO-d6) δ 5.35 (s, 1H), 3.35 (s, 2H), 2.25 (s, 3H), 1.72 (d, 6H). Process 2: Preparation of 2'-bromo-4-hydroxy-5',6-dimethyl-[1,4'-bipyridin]-2-one:

[0146] 2,2-Dimethyl-6-(2-oxopropyl)-1,3-dioxin-4-one (22.16 g, 120.296 mmol, 1.5 equiv.) and 2-bromo-5-methylpyridin-4-amine (15 g, 80.197 mmol , A mixture (1.00 equivalent) was stirred at 90 °C for 2 h. To the above mixture, H2SO4 (7.87 g, 80.197 mmol, 1 equivalent) was added dropwise at room temperature under an air atmosphere. The resulting mixture was stirred at 90 °C for an additional 1 h. The resulting mixture was concentrated under reduced pressure. H2O (40 mL) was added to the resulting mixture, and the slurry was stirred for 10 min. The precipitated solid was collected by filtration, washed with Et2O (3 × 10 mL), and then dried under vacuum to give 2'-bromo-4-hydroxy-5',6-dimethyl-[1,4'-bipyridin]-2-one (22.7 g, crude) as a yellow solid. The resulting crude mixture was used directly in the next step without further purification. LC-MS: (ES + H, m / z): [M + H] + = 294.9 Step 3: 2'-Chloro-4-[(4-methoxyphenyl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one:

[0147] To a stirred mixture of 2'-bromo-4-hydroxy-5',6-dimethyl-[1,4'-bipyridin]-2-one (42.00 g, 142.307 mmol, 1 equivalent) and 2-(chloromethyl)-3,5-difluoropyridine (46.55 g, 284.614 mmol, 2 equivalents) in DMF (450 mL), K2CO3 (98.34 g, 711.535 mmol, 5.00 equivalents) and 18-crown-6 (3.76 g, 14.231 mmol, 0.10 equivalent) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 60 °C for 2 h under a nitrogen atmosphere. The desired product could be detected by LCMS. The reaction mixture was partitioned between EA (1000 mL) and water (500 mL). The organic layer was washed with water (500 mL) and brine (500 mL), and then dried over Na2SO4. The solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2'-bromo-4-[(3,5-difluoropyridin-2-yl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one (48.5 g, 80.72%) as a yellow oil. LC-MS: (ES + H, m / z): [M + H] + = 424.0 Step 4: Preparation of 2'-Bromo-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one:

[0148] To a stirred mixture of 2'-bromo-4-[(3,5-difluoropyridin-2-yl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one (12 g, 28.421 mmol, 1 equiv) and NCS (3.79 g, 28.421 mmol, 1 equiv) in 2-propanol (21 mL) was added dichloroacetic acid (1.2 mL, 2.870 mmol, 0.10 equiv) dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 60 °C for 2 h under a nitrogen atmosphere. The precipitated solid was collected by filtration and washed with 2-propanol to give 2'-bromo-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one (7.40 g, 57.02%) as a white solid. LC-MS: (ES + H, m / z): [M + H] + = 457.9. 1 H NMR (300 MHz, DMSO-d6) δ 8.60 (d, J = 2.4 Hz, 1H), 8.52 (s, 1H), 8.10 (ddd, J = 10.0, 8.9, 2.4 Hz, 1H), 7.81 (s, 1H), 6.80 (s, 1H), 5.48 (d, J = 2.0 Hz, 2H), 1.98 - 1.94 (m, 6H). Intermediates 9 - 11

Chemical Structure

[0149] A solution of 5-chloro-3-fluoropyridine-2-carboxylic acid (2.00 g, 11.39 mmol, 1.00 equiv) in EtOH (4 mL) was cooled using an ice bath, and then H2SO4 (2.00 mL) was added dropwise at 0 °C. The resulting mixture was stirred at 50 °C overnight under a nitrogen atmosphere. The mixture was brought to room temperature. The resulting mixture was diluted with H2O (10 mL). The mixture was basified to pH 9 with Na2CO3. The resulting mixture was extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give ethyl 5-chloro-3-fluoropyridine-2-carboxylate (2.10 g, 90.53%) as a yellow liquid. LC-MS: (ES+ H, m / z): [M + H] + = 204.1. Step 2: Preparation of (5-chloro-3-fluoropyridin-2-yl)methanol:

[0150] To a stirred solution of ethyl 5-chloro-3-fluoropyridine-2-carboxylate (2.10 g, 10.31 mmol, 1.00 equiv) in EtOH (4 mL), NaBH4 (0.98 g, 25.90 mmol, 2.51 equiv) was added portionwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 30 minutes under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for an additional 2 hours under a nitrogen atmosphere. The reaction was quenched with saturated NH4Cl (aqueous solution) at 0 °C. EtOH was removed under reduced pressure. The aqueous layer was basified to pH 10 with saturated Na2CO3 (aqueous solution) and then extracted with EA (3 × 100 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum to give (5-chloro-3-fluoropyridin-2-yl)methanol (1.50 g, 90.02%) as a yellow solid. LC-MS: (ES+ H, m / z): [M + H] + = 162.1. Step 3: Preparation of 5-chloro-2-(chloromethyl)-3-fluoropyridine:

[0151] To a stirred solution of (5-chloro-3-fluoropyridin-2-yl)methanol (1.45 g, 8.97 mmol, 1.00 eq) in DCM (2 mL) was added DMF (0.66 g, 8.97 mmol, 1.00 eq), and then the mixture was cooled using an ice-water bath. To the above mixture was added SOCl2 (1.00 mL, 13.78 mmol, 1.54 eq) dropwise under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum to give 5-chloro-2-(chloromethyl)-3-fluoropyridine (2.00 g, crude) as a yellowish-brown semi-solid. The crude product was used directly in the next step without further purification. LC-MS: (ES + H, m / z): [M + H]+ = 180.1. Intermediates 12 - 14

Chemical formula

[0152] A solution of 3-chloro-5-fluoropyridine-2-carboxylic acid (4.50 g, 25.63 mmol, 1.00 eq) in EtOH (100 mL) was cooled in an ice-water bath. To the above mixture was added SOCl2 (6.13 g, 51.53 mmol, 2.01 eq) dropwise at 0 °C over 3 min. The resulting mixture was stirred at room temperature for an additional 3 h. The mixture was brought to room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography to give ethyl 3-chloro-5-fluoropyridine-2-carboxylate (4.40 g, 84.29%) as a colorless liquid. LC-MS: (ES + H, m / z): [M + H] + = 203.9. Step 2: Preparation of (3-chloro-5-fluoropyridin-2-yl)methanol:

[0153] To a stirred solution of ethyl 3-chloro-5-fluoropyridine-2-carboxylate (2.10 g, 10.31 mmol, 1.00 eq) in EtOH (30 mL) was added NaBH4 (0.98 g, 25.90 mmol, 2.51 eq) portionwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 30 minutes under a nitrogen atmosphere. The resulting mixture was further stirred at room temperature for 2 hours under a nitrogen atmosphere. The reaction was quenched with saturated NH4Cl (aqueous solution) at 0 °C. The resulting mixture was concentrated under reduced pressure to remove EtOH and then extracted with EA (3 × 30 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum to give (3-chloro-5-fluoropyridin-2-yl)methanol (2 g, 95.24%) as a yellow oil. LC-MS: (ES + H, m / z): [M + H] + = 162.0. Step 3: Preparation of 3-chloro-2-(chloromethyl)-5-fluoropyridine:

[0154] To a stirred solution of (3-chloro-5-fluoropyridin-2-yl)methanol (2.10 g, 12.99 mmol, 1.00 eq) in DCM (30 mL) was added DMF (0.1 mL, 1.30 mmol, 0.10 eq) at 0 °C under a nitrogen atmosphere. SOCl2 (2.3 mL, 32.49 mmol, 2.50 eq) was added dropwise under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under vacuum to give 3-chloro-2-(chloromethyl)-5-fluoropyridine (2.00 g, crude) as a yellowish-brown oil. The crude product was used directly in the next step without further purification. LC-MS: (ES + H, m / z): [M + H] + = 179.90. Intermediates 15 - 18

Chemical Structure

[0155] To a stirred solution of ethyl 5-chloro-3-fluoropyridine-2-carboxylate (500.00 g, 2671.71 mmol, 1.00 equiv) in CD3OD (500 mL) and THF (1000 mL), sodium borohydride (111.84 g, 2671.71 mmol, 1.00 equiv) was added portionwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. The resulting mixture was quenched by adding D2O (200 mL) at 0 °C and stirred at 0 °C for 30 min. The mixture was diluted with EtOAc (2000 mL) and washed with water (2000 mL) and brine (2000 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give (3,5-difluoropyridin-2-yl)methane-d2-ol methanol (360.00 g, 91.5%) as a yellow oil. LC-MS: (ES+H, m / z): [M+H] + = 148.1. 1 H NMR (300 MHz, DMSO-d6) δ 8.44 (d, 1H), 7.88 (ddd, 1H), 5.37 (s, 1H). Step 2: Preparation of 2-(chloromethyl-d2)-3,5-difluoropyridine:

[0156] To a stirred solution of (3,5-difluoropyridin-2-yl)methane-d2-ol (300.00 g, 2039.13 mmol, 1.00 equiv) in DCM (1000 mL), DMF (14.91 g, 203.91 mmol, 0.10 equiv) and SOCl2 (606.44 g, 5097.84 mmol, 2.50 equiv) were added dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum to give 2-(chloromethyl-d2)-3,5-difluoropyridine (320.00 g, 94.7%) as a yellow oil, which was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + = 166.1. 1 H NMR (300 MHz, DMSO-d6) δ 8.48 (d, 1H), 8.04 - 7.93 (m, 1H). Step 3: Preparation of 2'-Bromo-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one:

[0157] To a stirred mixture of 2'-bromo-4-hydroxy-5',6-dimethyl-[1,4'-bipyridin]-2-one (100.00 g, 338.82 mmol, 1.00 equiv), 18-crown-6 (5.37 g, 3.00 mmol, 0.40 equiv), and K2CO3 (42.14 g, 304.94 mmol, 3.00 equiv) in DMF (200 mL) was added 2-(chloromethyl-d2)-3,5-difluoropyridine (27.75 g, 152.47 mmol, 1.50 equiv) at room temperature. The resulting mixture was stirred at 60 °C for 2.5 h under a nitrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with EtOAc (3 × 500 mL). The filtrate was diluted with EA (3000 mL). The resulting mixture was washed with brine (3 × 2000 mL) and water (5 × 2000 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by trituration with Et2O (3 × 250 mL) and dried under reduced pressure to give 2'-bromo-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one (90 g, 62.8%) as a white solid. LC-MS: (ES + H, m / z): [M + H] + = 424.0. 1 H NMR (300 MHz, DMSO-d6) δ 8.59 (d, 1H), 8.48 (s, 1H), 8.08 (ddd, 1H), 7.73 (s, 1H), 6.13 (dd, 1H), 6.03 (d, 1H), 1.97 (s, 3H), 1.85 (s, 3H). Step 4: Preparation of 2'-Bromo-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one:

[0158] To a stirred solution of 2'-bromo-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one (100.00 g, 235.71 mmol, 1.00 eq) and NCS (37.77 g, 282.85 mmol, 1.20 eq) in IPA (500 mL) was added dichloroacetic acid (3.04 g, 23.57 mmol, 0.10 eq) dropwise at room temperature. The resulting mixture was stirred at 60 °C for 1 h under a nitrogen atmosphere. The mixture was cooled to room temperature. The precipitated solid was collected by filtration and washed with cold IPA (4 x 30 mL) to give 2'-bromo-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one (60.00 g, 55.5%) as a white solid. LC-MS: (ES + H, m / z): [M + H] + = 458.0. 1 H NMR 300 MHz, DMSO-d6) δ 8.60 (d, 1H), 8.52 (s, 1H), 8.10 (ddd, 1H), 7.81 (s, 1H), 6.80 (d, 1H), 1.96 (s, 6H). Intermediate 19

Chemical Structure

[0159] To a stirred solution of methyl 3-oxo-4H-pyrazine-2-carboxylate (500 mg, 3.24 mmol, 1.00 eq) in THF (30 mL), bromo(methyl)magnesium (32 mL, 32.44 mmol, 10.00 eq) was added dropwise at -5 °C under a N2 atmosphere. The resulting mixture was stirred at room temperature for 2 h under a N2 atmosphere. The reaction was quenched by adding saturated NH4Cl (10 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give 3-(2-hydroxypropan-2-yl)-1H-pyrazin-2-one (350 mg, crude) as a yellow solid. LC-MS: (ES + H, m / z): [M + H]+ = 155.3. Intermediates 20 - 23 [Chemical Formula] Step 1: Preparation of ethyl 5-chloro-3-fluoropyridine-2-carboxylate:

[0160] To a stirred mixture of 2-bromo-5-chloro-3-fluoropyridine (50.00 g, 237.60 mmol, 1.00 eq) and Pd(dppf)Cl2 (8.69 g, 11.88 mmol, 0.05 eq) in EtOH (250 mL), NEt3 (72.13 g, 712.82 mmol, 3.00 eq) was added at room temperature. The resulting mixture was stirred at 80 °C for 6 h under a carbon monoxide atmosphere (50 atm). The mixture was warmed to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give ethyl 5-chloro-3-fluoropyridine-2-carboxylate (36.40 g, 75.24%) as a yellow-green liquid. LC-MS: (ES + H, m / z): [M + H] + = 204.2. 1 1H NMR (300 MHz, DMSO-d6) δ 8.63 (dd, 1H), 8.24 (dd, 1H), 4.36 (q, 2H), 1.32 (t, 3H). Step 2: Preparation of (5-chloro-3-fluoropyridin-2-yl)(2H2)methanol:

[0161] To a stirred solution of ethyl 5-chloro-3-fluoropyridine-2-carboxylate (42.00 g, 206.28 mmol, 1.00 eq) and CaCl2 (68.68 g, 618.85 mmol, 3.00 eq) in CD3OD (200 mL) and THF (400 mL), sodium borohydride (17.27 g, 412.57 mmol, 2.00 eq ) was added portionwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 3 h under a nitrogen atmosphere. The resulting mixture was diluted with EtOAc (500 mL). Celite (100 g) was added to the reaction solvent and the resulting mixture was stirred for 10 min. The resulting mixture was filtered and the filter cake was washed with EtOAc (3 × 1 L). The filtrate was quenched by adding D2O (35 mL) at 0 °C. Washed with brine (2 × 500 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. (5-Chloro-3-fluoropyridin-2-yl)(2H2) (23.60 g, 69.94%) was obtained as a white solid. LC-MS: (ES + H, m / z): [M + H] + = 164.2. 1 H NMR (300 MHz, DMSO-d6) δ 8.48 (dd, 1H), 8.06 (dd, 1H), 5.41 (s, 1H). Step 3: Preparation of 5-chloro-2-[chloro( 2 H2)methyl]-3-fluoropyridine:

[0162] To a stirred solution of (5-chloro-3-fluoropyridin-2-yl)(2H2)methanol (23.60 g, 144.28 mmol, 1.00 eq) and DMF (1.05 g, 14.42 mmol, 0.10 eq) in DCM (200 mL), SOCl2 (42.91 g, 360.70 mmol, 2.50 eq) was added dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum. 5-Chloro-2-[chloro(2H2)methyl]-3-fluoropyridine (26.30 g, 100%) was obtained as a brown oil. LC-MS: (ES + H, m / z): [M + H]+ = 182.1. 1 1H NMR (300 MHz, DMSO-d6) δ 8.53 (dd, 1H), 8.18 (dd, 1H). Step 4: Preparation of 2'-bromo-4-[(5-chloro-3-fluoropyridin-2-yl)(2H2)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one:

[0163] To a stirred mixture of 2'-bromo-4-hydroxy-5',6-dimethyl-[1,4'-bipyridin]-2-one (30.00 g, 101.64 mmol, 1.00 equiv), 5-chloro-2-[chloro(2H2)methyl]-3-fluoropyridine (27.75 g, 152.47 mmol, 1.50 equiv), 18-crown-6 (5.37 g, 20.33 mmol, 0.20 equiv) and K2CO3 (42.14 g, 304.94 mmol, 3.00 equiv) in DMF (200 mL) was added. The resulting mixture was stirred at 60 °C for 2.5 h under a nitrogen atmosphere. The mixture was warmed to room temperature. The resulting mixture was diluted with EA (2 L). The resulting mixture was washed with water (5 × 100 mL) and brine (500 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2'-bromo-4-[(5-chloro-3-fluoropyridin-2-yl)(2H2)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one (30.91 g, 69.00%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + = 440.1 / 442.1. 1 1H NMR (400 MHz, DMSO-d6) δ 8.60 (dd, 1H), 8.47 (s, 1H), 8.22 (dd, 1H), 7.72 (s, 1H), 6.13 (s, 1H), 6.01 (d, 1H), 1.96 (s, 3H), 1.85 (s, 3H). Step 5: Preparation of 2'-bromo-3-chloro-4-[(5-chloro-3-fluoropyridin-2-yl)(2H2)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one:

[0164] To a stirred solution of 2'-bromo-4-[((5-chloro-3-fluoropyridin-2-yl)(2H2)methoxy]-3',-5',6-dimethyl-[1,4'-bipyridin]-2-one (30.00 g, 68.07 mmol, 1.00 equiv) and NCS (10.91 g, 81.69 mmol, 1.20 equiv) in IPA (200 mL), dichloroacetic acid (0.88 g, 6.80 mmol, 0.10 equiv) was added dropwise at room temperature under an air atmosphere. The resulting mixture was stirred at 60 °C for 1 h under a nitrogen atmosphere. The mixture was cooled to 0 °C. The precipitated solid was collected by filtration and washed with IPA (3 × 20 mL). 2'-Bromo-3-chloro-4-[(5-chloro-3-fluoropyridin-2-yl)(2H2)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one (24.00 g, 74.20%) was obtained as a white solid. LC-MS: (ES + H, m / z): [M + H] + = 474.0 / 476.0. 1 H NMR (400 MHz, DMSO-d6) δ 8.60 (dd, 1H), 8.52 (s, 1H), 8.23 (dd, 1H), 7.80 (s, 1H), 6.78 (d, 1H), 1.97 (s, 3H), 1.96 (s, 3H). Intermediates 24 - 27

Chemical Structure

[0165] To a stirred mixture of 2,3-dichloro-5-fluoropyridine (50.00 g, 301.24 mmol, 1.00 eq) and Pd(dppf)Cl2 (4.41 g, 6.02 mmol, 0.02 eq) in EtOH (250 mL), Et3N (72.13 g, 712.82 mmol, 3.00 eq) was added dropwise at room temperature. The resulting mixture was stirred at 100 °C for 18 h under a carbon monoxide atmosphere (50 atm). The mixture was warmed to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford ethyl 3-chloro-5-fluoropyridine-2-carboxylate (33.00 g, 53.80%) as a colorless liquid. LC-MS: (ES + H, m / z): [M + H] + = 204.0. 1 1H NMR (400 MHz, DMSO-d6) δ 8.70 (d, 1H), 8.29 (dd, 1H), 4.42 (q, 2H), 1.36 (t, 3H). Step 2: Preparation of (3-chloro-5-fluoropyridin-2-yl)methan-d2-ol:

[0166] To a stirred solution of ethyl 3-chloro-5-fluoropyridine-2-carboxylate (84.00 g, 412.57 mmol, 1.00 eq) and CaCl2 (91.57 g, 825.14 mmol, 2.00 eq) in CD3OD (500 mL) and THF (500 mL), sodium borodeuteride (51.81 g, 1237.72 mmol, 3.00 eq) was added portionwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. The resulting mixture was diluted with EtOAc (500 mL). Celite (100 g) was added to the reaction solvent. The resulting mixture was filtered and the filter cake was washed with EtOAc (3 × 1 L). The filtrate was quenched by adding D2O (50 mL) at 0 °C and washed with brine (500 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford (3-chloro-5-fluoropyridin-2-yl)methan-d2-ol (46.00 g, 68.16%) as a colorless liquid. LC- MS: (ES + H, m / z): [M + H] += 164.0. 1 1H NMR (300 MHz, DMSO-d6) δ 8.53 (d, 1H), 8.01 (dd, 1H), 5.22 (br, 1H). Step 3: Preparation of 3-chloro-2-(chloromethyl-d2)-5-fluoropyridine:

[0167] To a stirred solution of (3-chloro-5-fluoropyridin-2-yl)methane-d2-ol (46.00 g, 281.22 mmol, 1.00 equiv) and DMF (2.18 mL, 28.12 mmol, 0.1 equiv) in DCM (200 mL) was added SOCl2 (40.80 mL, 562.45 mmol, 2.00 equiv) dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum to give 3-chloro-2-(chloromethyl-d2)-5-fluoropyridine (31.00 g, 60.56%) as a yellowish-brown liquid. LC-MS: (ES+H, m / z): [M+H] + = 182.0. 1 1H NMR (300 MHz, DMSO-d6) δ 8.59 (d, 1H), 8.16 (dd, 1H). Step 4: Preparation of 2'-bromo-4-((3-chloro-5-fluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one:

[0168] To a stirred mixture of 2'-bromo-4-hydroxy-5',6-dimethyl-[1,4'-bipyridin]-2-one (25.00 g, 84.70 mmol, 1.00 eq), 18-crown-6 (4.48 mg, 16.94 mmol, 0.2 eq) and K2CO3 (58.53 g, 423.53 mmol, 5.00 eq) in DMF (250 mL) was added 3-chloro-2-(chloromethyl-d2)-5-fluoropyridine (30.84 g, 169.41 mmol, 2.00 eq) at room temperature. The resulting mixture was stirred at 60 °C for 2 h under a nitrogen atmosphere. The mixture was warmed to room temperature. The resulting mixture was diluted with EA (2000 mL). The resulting mixture was washed with brine (5 × 500 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was obtained as a white solid of 2'-bromo-4-((3-chloro-5-fluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one (30.00 g, 56.26%). LC-MS: (ES + H, m / z): [M + H] + = 440.0。 1 H NMR (300 MHz, DMSO-d6) δ 8.67 (d, 1H), 8.48 (s, 1H), 8.23 (dd, 1H), 7.73 (s, 1H), 6.14 (dd, 1H), 6.01 (d, 1H), 1.97 (s, 3H), 1.86 (s, 3H). Step 5: Preparation of 2'-bromo-3-chloro-4-((3-chloro-5-fluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one:

[0169] To a stirred solution of 2'-bromo-4-((3-chloro-5-fluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one (30.00 g, 68.07 mmol, 1.00 eq) and NCS (11.82 g, 88.49 mmol, 1.30 eq) in IPA (300 mL) was added dichloroacetic acid (0.88 g, 6.80 mmol, 0.10 eq) dropwise at room temperature. The resulting mixture was stirred at 60 °C for 1 h under a nitrogen atmosphere. The mixture was cooled to room temperature. The precipitated solid was collected by filtration and washed with cold IPA (3 × 40 mL) to afford 2'-bromo-3-chloro-4-((3-chloro-5-fluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one (17.52 g, 54.17%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + = 476.05. 1 H NMR (300 MHz, DMSO-d6) δ 8.68 (d, 1H), 8.55 - 8.50 (m, 1H), 8.25 (dd, 1H), 7.81 (s, int e 1H), 6.77 (d, 1H), 1.97 (s, 3H), 1.95 (s, 3H). Example 1A, 1B

Chemical Structure

[0170] A stirred solution of 2'-bromo-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one (500 mg, 1.095 mmol, 1 equiv), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (311.49 mg, 2.190 mmol, 2 equiv) and CuI (417.04 mg, 2.190 mmol, 2.00 equiv) in dioxane (20 mL) was added K2CO3 (302.64 mg, 2.190 mmol, 2.00 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C overnight under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The reaction was quenched by adding saturated NH4Cl (aqueous solution) (50 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 25 mL). The combined organic layers were washed with brine (40 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2'-[3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one (250 mg, 43.17%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + = 529.1。 1 H NMR (300 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.60 (d, 1H), 8.64 - 8.00 (m, 1H), 7.86 (d, 1H), 7.79 (s, 1H), 7.69 (s, 1H), 6.81 (s, 1H), 6.43 (t, 1H), 5.48 (s, 2H), 5.23 (s, 1H), 2.08 (s, 3H), 2.01 (s, 3H), 1.47 (d, 6H). Process 2: Preparation of rel-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2’-[3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-5’,6-dimethyl-[1,4’-bipyridin]-2-one and rel-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2’-[3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-5’,6-dimethyl-[1,4’-bipyridin]-2-one:

[0171] 3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2’-[3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-5’,6-dimethyl-[1,4’-bipyridin]-2-one (250 mg, 0.473 mmol , 1 equivalent) was isolated by preparative HPLC to give rel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2’-[3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-5’,6-dimethyl-[1,4’-bipyridin]-2-one (Example 1A, 48.0 mg, purity 97.6%, ee = 100.0%) and rel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2’-[3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-5’,6-dimethyl-[1,4’-bipyridin]-2-one (Example 1B, 51.4 mg, purity 98.7%, ee = 99.6%) as white solids.

[0172] Example 1A: LC-MS: (ES + H, m / z): [M + H] + = 529.00. 1 H NMR (300 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.61 (d, 1H), 8.17 - 8.03 (m, 1H), 7.86 (m, 1H), 7.79 (s, 1H), 7.70 (m, 1H), 6.81 (m, 1H), 6.43 (t, 1H), 5.48 (d, 2H), 5.23 (s, 1H), 2.08 (s, 3H), 2.01 (s, 3H), 1.47 (S, 3H), 1.46 (S, 3H). 19 19F NMR (377 MHz, DMSO-d6) δ -120.16, -120.18, -122.36, -122.38. [a] D 25 = -171 (C = 1, MeOH).

[0173] Example 1B: LC-MS: (ES + H, m / z): [M + H] + = 529.10. 1 H 1H NMR (400 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.60 (d, 1H), 8.09 (m, 1H), 7.85 (m, 1H), 7.78 (s, 1H), 7.69 (m, 1H), 6.82 - 6.77 (m, 1H), 6.42 (t, 1H), 5.48 (d, 2H), 5.22 (s, 1H), 2.07 (s, 3H), 2.01 (s, 3H), 1.47 (S, 3H), 1.46 (S, 3H). 19 19F NMR (377 MHz, DMSO-d6) δ -120.16, -120.18, -122.35, -122.37. [a] D 25 = +174.8 (C = 1, MeOH). Examples 2A, 2B

Chemical formula

[0174] 1-(5-Bromo-2-methylphenyl)-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-6-methylpyridin-2-one (300 mg, 0.65 mmol, 1.00 equiv), 3-(2-hydroxypropan-2-yl)-1H-pyridin-2-one (200 mg, 1.31 mmol, 2.00 equiv), CuI (250.77 mg, 1.31 mmol, 2.00 equiv), and (1 (R,2R)-1-N,2-N-dimethylcyclohexane-1,2-diamine (187.29 mg, 1.31 mmol, 2.00 equiv) in a stirred mixture of 1,4-dioxane (5 mL) was added K2CO3 (181.98 mg, 1.31 mmol, 2.00 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 3 h under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The reaction was quenched by adding saturated NH4Cl (aqueous solution) (50 mL) at room temperature. The resulting mixture was extracted with EtOAc (2 × 25 mL). The combined organic layers were washed with brine (30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase combiflash chromatography to give 3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-1-{5-[3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-2-methylphenyl}-6-methylpyridin-2-one (140 mg, 40.28%) as a pale yellow solid. LC-MS: (ES + H, m / z): [M + H] + = 528.1. 1 H NMR (400 MHz, DMSO-d6) δ 8.59 (d, 1H), 8.12 - 8.06 (m, 1H), 7.66 - 7.64 (m, 1H), 7.63 - 7.60 (m, 1H), 7.54 (d, 1H), 7.48 - 7.44 (m, 1H), 7.37 (d, 1H), 6.77 - 6.72 (m, 1H), 6.39 - 6.34 (m, 1H), 5.46 (d, 2H), 5.29 (s, 1H), 2.03 (s, 3H), 2.16 (s, 3H), 1.46 (s, 6H). Step 5: Preparation of rel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-1-{5-[3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-2-methylphenyl}6-methylpyridin-2-one and rel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-1-{5-[3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-2-methylphenyl}6-methylpyridin-2-one:

[0175] The racemic mixture (140 mg) was isolated by preparative chiral HPLC to give rel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-1-{5-[3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-2-methylphenyl}6-methylpyridin-2-one (Example 2A: 68.7 mg, ee = 100.00%) as a pale yellow solid and rel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-1-{5-[3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-2-methylphenyl}6-methylpyridin-2-one (Example 2B: 38.8 mg, ee = 100.00%) as a pale yellow solid.

[0176] Example 2A: LC-MS: (ES + H, m / z): [M + H] + = 528.25. 1 H NMR (300 MHz, DMSO-d6) δ 8.60 (d, 1H), 8.15 - 8.05 (m, 1H), 7.70 - 7.60 (m, 2H), 7.55 (d, 1H), 7.49 - 7.44 (m, 1H), 7.38 (d, 1H), 6.75 (s, 1H), 6.40 - 6.34 (m, 1H), 5.47 (d, 2H), 5.30 (s, 1H), 2.03 (s, 3H), 2.16 (s, 3H), 1.47 (s, 3H), 1.46 (s, 3H). 19 F NMR (377 MHz, DMSO-d6) δ -120.15, -120.17, -122.39, -122.41.

[0177] Example 2B: LC-MS: (ES+H, m / z): [M+H] + =528.25 1 H NMR (300 MHz, DMSO-d6) δ 8.60 (d, 1H), 8.15 - 8.05 (m, 1H), 7.70 - 7.60 (m, 2H), 7.55 (d, 1H), 7.49 - 7.44 (m, 1H), 7.38 (d, 1H), 6.75 (s, 1H), 6.40 - 6.34 (m, 1H), 5.47 (d, 2H), 5.30 (s, 1H), 2.03 (s, 3H), 2.16 (s, 3H), 1.47 (s, 3H), 1.46 (s, 3H). 19 F NMR (377 MHz, DMSO-d6) δ -120.15, -120.17, -122.39, -122.41 Examples 3A, 3B

Chemical formula

[0178] To a stirred solution of imidazole (25.09 g, 368.60 mmol, 2.00 equivalents) in THF (200 mL), methoxyacetyl chloride (20.00 g, 184.30 mmol, 1.00 equivalent) was added dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 3 hours under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was filtered, and the filter cake was washed with THF (3 × 50 mL). The filtrate was concentrated under reduced pressure to give 1-(imidazol-1-yl)-2-methoxyethanone (16.00 g, 61.95%) as a yellow oil. 1 H NMR (300 MHz, Chloroform-d) δ 7.52 (t, 1H), 7.22 (d, 1H), 7.15 - 7.05 (m, 1H), 4.55 (s, 2H), 3.51 (s, 3H). Step 2: Preparation of 6-(3-methoxy-2-oxopropyl)-2,2-dimethyl-1,3-dioxin-4-one:

[0179] To a 1 L three-necked round-bottom flask, THF (50 mL) was added at room temperature, and then LiHMDS (56.98 mL, 1 M in THF, 56.98 mmol, 1.50 equiv) was added at -20 °C under a nitrogen atmosphere. To the above solution, 2,2,6-trimethyl-1,3-dioxin-4-one (5.40 g, 37.99 mmol, 1.00 equiv) was added dropwise at -20 °C under a nitrogen atmosphere. The resulting mixture was stirred at -20 °C for 1 h. To the above mixture, diethylzinc (56.98 mL, 56.98 mmol, 1.50 equiv) was added dropwise at -20 °C under a nitrogen atmosphere. The temperature of the reaction mixture was slowly raised to -10 °C and stirred for 10 min. Then, 1-(imidazol-1-yl)-2-methoxyethanone (7.99 g, 56.98 mmol, 1.50 equiv) was added to the above mixture at -10 °C under a nitrogen atmosphere. The resulting mixture was further stirred at room temperature for 2 h. The reaction was quenched by adding water (50 mL) at -20 °C. The mixture was acidified to pH 6 with HCl (aqueous solution). The resulting mixture was diluted with EtOAc (200 mL). The resulting mixture was washed with brine (200 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 6-(3-methoxy-2-oxopropyl)-2,2-dimethyl-1,3-dioxin-4-one (4.68 g, 57.51%) as a yellow liquid. LC-MS: (ES + H, m / z): [M + H] + = 215.1. 1 H NMR (300 MHz, DMSO-d6) δ 5.47 (s, 1H), 4.14 (s, 2H), 3.53 (s, 2H), 3.30 (s, 3H), 1.64 (s, 6H). Step 3: Preparation of 2'-chloro-4-hydroxy-6-(methoxymethyl)-5'-methyl-[1,4'-bipyridin]-2-one:

[0180] To a stirred solution of 6-(3-methoxy-2-oxopropyl)-2,2-dimethyl-1,3-dioxin-4-one (4.00 g, 18.67 mmol, 1.00 equiv) in 1,4-dioxane (40 mL) was added 2-chloro-5-methoxypyridin-4-amine (2.66 g, 18.67 mmol, 1.00 equiv) at room temperature under nitrogen. The resulting mixture was stirred at 90 °C for 3 h under a nitrogen atmosphere. To the resulting mixture was added H2SO4 (1.83 g, 18.67 mmol, 1.00 equiv) dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 1 h under a nitrogen atmosphere. The desired product could be detected. The mixture was allowed to cool to room temperature. H2O (3 mL) was added to the above mixture, followed by a large amount of ethyl ether, and then the mixture was stirred at room temperature for 15 min. The precipitated solid was collected by filtration and washed with diethyl ether. The filter cake was concentrated under reduced pressure to give 2'-chloro-4-hydroxy-6-(methoxymethyl)-5'-methyl-[1,4'-bipyridin]-2-one (400 mg, 7.63%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =281.2。 Step 4: Preparation of 2'-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-6-(methoxymethyl)-5'-methyl-[1,4'-bipyridin]-2-one:

[0181] To a stirred mixture of 2'-chloro-4-hydroxy-6-(methoxymethyl)-5'-methyl-[1,4'-bipyridin]-2-one (417 mg, 1.49 mmol, 1.00 equiv) and 2-(chloromethyl)-3,5-difluoropyridine (486 mg, 2.92 mmol, 2.00 equiv) in DMF (5 mL) were added K2CO3 (1.02 g, 7.43 mmol, 5.00 equiv) and 18-crown-6 (39 mg, 0.15 mmol, 0.10 equiv) under a nitrogen atmosphere at room temperature. The resulting mixture was stirred at 60 °C for 2 h under a nitrogen atmosphere. The resulting mixture was diluted with EtOAc (50 mL). The resulting mixture was washed with brine (50 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2'-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-6-(methoxymethyl)-5'-methyl-[1,4'-bipyridin]-2-one (468 mg, 77.25%) as a white solid. LC-MS: (ES + H, m / z): [M + H] + = 408.0. Step 5: Preparation of 2',3-dichloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-6-(methoxymethyl)-5'-methyl-[1,4'-bipyridin]-2-one:

[0182] To a stirred mixture of 2'-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-6-(methoxymethyl)-5'-methyl-[1,4'-bipyridin]-2-one (418 mg, 1.03 mmol, 1.00 equiv) and NCS (137 mg, 1.03 mmol, 1.00 equiv) in 2-propanol (2 mL) was added 2,2-dichloroacetic acid (0.01 mL, 0.10 mmol, 0.10 equiv) dropwise under a nitrogen atmosphere at room temperature. The resulting mixture was stirred at 60 °C for 2 h under a nitrogen atmosphere. The desired product could be detected by LCMS. The resulting mixture was diluted with EtOAc (50 mL). The obtained The resulting mixture was washed with NaHCO3 (50 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain 2′,3-dichloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-6-(methoxymethyl)-5′-methyl-[1,4′-bipyridin]-2-one (440 mg, 97.07%) as a white solid. LC-MS: (ES+H, m / z): [M+H]+ = 441.9. Step 6: Preparation of 3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2′-[3-(2-hydroxypropan-2-yl)-2-oxopropan-1-yl)-6-(methoxymethyl)-5′-methyl-[1,4′-bipyridin]-2-one:

[0183] To a stirred mixture of 2’,3-dichloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-,6-(methoxymethyl)-5’-methyl-[1,4’-bipyridin]-2-one (450 mg, 1.02 mmol, 1.00 equiv) and 3-(2-hydroxypropan-2-yl)-1H-pyridin-2-one (312 mg, 2.04 mmol, 2.00 equiv) in 1,4-dioxane (4 mL), K2CO3 (281 mg, 2.04 mmol, 2.00 equiv), CuI (388 mg, 2.04 mmol, 2.00 equiv), NaI (305 mg, 2.04 mmol, 2.00 equiv) and (1S,2S)-N1,N,2-N-dimethylcyclohexane-1,2-diamine (289 mg, 2.04 mmol, 2.00 equiv) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C overnight under a nitrogen atmosphere. The resulting mixture was diluted with EtOAc (50 mL). The resulting mixture was washed with water (3 × 50 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give a crude product (230 mg), which was purified by preparative HPLC to give 3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2’-[3-(2-hydroxypropan-2-yl)-2-oxopropan-1-yl)-6-(methoxymethyl)-5’-methyl-[1,4’-bipyridin]-2-one (130 mg, 22.86%) as a white solid. LC-MS: (ES + H, m / z): [M + H]+ = 559.2. Step 7: Preparation of rel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2’-[3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-6-(methoxymethyl)-5’-methyl-[1,4’-bipyridin]-2-one and rel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2’-[3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-6-(methoxymethyl)-5’-methyl-[1,4’-bipyridin]-2-one

[0184] The racemate (130 mg) was separated by preparative chiral HPLC to obtain Example 3A (47.1 mg, 99.1%, ee = 100%) as a white solid and Example 3B (45.1 mg, 99.1%, ee = 97.24%) as a white solid.

[0185] Example 3A: LC-MS: (ES + H, m / z): [M + H] + = 559.1. 1 H NMR (300 MHz, DMSO-d6) δ 8.65 (s, 1H), 8.60 (d, 1H), 8.14 - 8.06 (m, 1H), 7.87 - 7.82 (m, 1H), 7.79 (s, 1H), 7.72 - 7.67 (m, 1H), 6.87 (s, 1H), 6.42 (t, 1H), 5.53 (s, 2H), 5.23 (s, 1H), 4.12 - 3.95 (m, 2H), 3.07 (s, 3H), 2.06 (s, 3H), 1.47 (s, 6H). 19 F NMR (282 MHz, DMSO-d6) δ -120.09, -120.11, -122.31, -122.35.

[0186] Example 3B: LC-MS: (ES + H, m / z): [M + H] + = 559.1. 1 H NMR (300 MHz, DMSO-d6) δ 8.65 (s, 1H), 8.60 (d, 1 H), 8.14 - 8.06 (m, 1H), 7.87 - 7.82 (m, 1H), 7.79 (s, 1H), 7.72 - 7.67 (m, 1H), 6.87 (s, 1H), 6.42 (t, 1H), 5.53 (s, 3H), 5.23 (s, 1H), 4.12 - 3.95 (m, 2H), 3.07 (s, 3H), 2.06 (s, 3H), 1.47 (s, 6H). 19 F NMR (282 MHz, DMSO-d6) δ -120.09, -120.11, -122.31, -122.35. Examples 4A, 4B

Chemical Structure

[0187] To a stirred solution of 2'-bromo-4'-hydroxy-5',6-dimethyl-[1,4'-bipyridin]-2-one (1.00 g, 3.38 mmol, 1.00 eq) and 5-chloro-2-(chloromethyl)-3-fluoropyridine (914 mg, 5.08 mmol, 1.50 eq) in DMF (10 mL), 18-crown-6 (89 mg, 0.33 mmol, 0.10 eq) and K2CO3 (1.40 g, 10.16 mmol, 3.00 eq) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 60 °C overnight under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The reaction was poured into water (50 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (5 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2'-bromo-4-[(5-chloro-3-fluoropyridin-2-yl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one (1.30 g, 87.46%) as an off-white solid. LC-MS: (ES + H, m / z): [M + H] + = 439.9. Step 2: Preparation of 2'-bromo-3-chloro-4-[(5-chloro-3-fluoropyridin-2-yl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one:

[0188] To a stirred solution of 2’-bromo-4-[(5-chloro-3-fluoropyridin-2-yl)methoxy]-5’,6-dimethyl-[1,4’-bipyridin]-2-one (500 mg, 1.14 mmol, 1.00 equiv) and NCS (152 mg, 1.14 mmol, 1.00 equiv) in IPA (2.5 mL), dichloroacetic acid (14 mg, 0.11 mmol, 0.10 equiv) was added dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 60 °C for 2 h under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The precipitated solid was collected by filtration and washed with cold IPA (2 × 10 mL) to afford 2’-bromo-3-chloro-4-[(5-chloro-3-fluoropyridin-2-yl)methoxy]-5’,6-dimethyl-[1,4’-bipyridin]-2-one (440 mg, 81.59%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + = 473.9. Step 3: Preparation of 3-chloro-4-[(5-chloro-3-fluoropyridin-2-yl)methoxy]-2’-[3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-5’,6-dimethyl-[1,4’-bipyridin]-2-one:

[0189] 2'-Bromo-3-chloro-4-[(5-chloro-3-fluoropyridin-2-yl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one (440 mg, 0.93 mmol, 1.00 eq), 3-(2-hydroxypropan-2-yl)-1H-pyridin-2-one (285 mg, 1.86 mmol, 2.00 eq), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (264 mg, 1.86 mmol, 2.00 eq), CuI (44 mg, 0.23 mmol, 0.25 eq) and K2CO3 (257 mg, 1.86 mmol, 2.00 eq) in ultradry 1,4-dioxane (5 mL) were stirred at 100 °C for 3 h under a nitrogen atmosphere. The reaction mixture was poured into water (50 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (220 mg) was purified by preparative HPLC and the pure fractions were concentrated under reduced pressure to give 3-chloro-4-[(5-chloro-3-fluoropyridin-2-yl)methoxy]-2'-[3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one (145 mg, 28.59%) as an off-white solid. LC-MS: (ES + H, m / z): [M + H] + = 544.8. Step 4: Preparation of rel-3-chloro-4-[(5-chloro-3-fluoropyridin-2-yl)methoxy]-2'-[3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one and rel-3-chloro-4-[(5-chloro-3-fluoropyridin-2-yl)methoxy]-2'-[3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one

[0190] The racemate 3-chloro-4-[(5-chloro-3-fluoropyridin-2-yl)methoxy]-2’-[3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-5’,6-dimethyl-[1,4’-bipyridin]-2-one (190 mg) was separated by preparative chiral HPLC to obtain Example 4A (45.1 mg, purity 98.6%, ee = 100%) as an off-white solid and Example 4B (50.0 mg, purity 98.9%, ee = 100%) as an off-white solid.

[0191] Example 4A: LC-MS: (ES + H, m / z): [M + H] + = 545.10. 1 H NMR (400 MHz, DMSO-d6) δ 8.68 (d, 1H), 8.63 - 8.60 (m, 1H), 8.27 - 8.21 (m, 1H), 7.88 - 7.83 (m, 1H), 7.78 (s, 1H), 7.72 - 7.68 (m, 1H), 6.81 - 6.75 (m, 1H), 6.45 - 6.39 (m, 1H), 5.50 (d, 2H), 5.22 (s, 1H), 2.07 (s, 3H), 1.99 (s, 3H), 1.47 (s, 3H), 1.46 (s, 3H). 19 F NMR (377 MHz, DMSO-d6) δ -121.60.

[0192] Example 4B: LC-MS: (ES + H, m / z): [M + H] + = 545.10. 1 H NMR (400 MHz, DMSO-d6) δ 8.68 (d, 1H), 8.62 - 8.60 (m, 1H), 8.26 - 8.21 (m, 1H), 7.88 - 7.83 (m, 1H), 7.78 (s, 1H), 7.72 - 7.68 (m, 1H), 6.79 - 6.76 (m, 1H), 6.45 - 6.40 (m, 1H), 5.50 (d, 2H), 5.22 (s, 1H), 2.07 (s, 3H), 1.99 (s, 3H), 1.47 (s, 3H), 1.46 (s, 3H). 19 F NMR (377 MHz, DMSO-d6) δ -121.60. Examples 5A, 5B

Chem.

[0193] A mixture of 2'-bromo-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one (500 mg, 1.09 mmol, 1.00 equiv), 3-(2-hydroxypropan-2-yl)-1H-pyrazin-2-one (337 mg, 2.19 mmol, 2.00 equiv), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (311 mg, 2.19 mmol, 2.00 equiv), K2CO3 (302 mg, 2.19 mmol, 2.00 equiv), and CuI (417 mg, 2.19 mmol, 2.00 equiv) in 1,4-dioxane (5 mL) was stirred at 80 °C for 2 h under a nitrogen atmosphere. The resulting mixture was cooled to room temperature and poured into 10 mL of water. The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain a crude product, which was further purified by preparative HPLC to give 3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2'-[3-(2-hydroxypropan-2-yl)-2-oxopyrazin-1-yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one (160 mg, 27.58%) as a white solid. LC-MS: (ES + H, m / z): [M + H] + = 530.0。 Process 2: Preparation of rel-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(3-(2-hydroxypropan-2-yl)-2-oxopyrazin-1-yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one and rel-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(3-(2-hydroxypropan-2-yl)-2-oxopyrazin-1-yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one:

[0194] The racemate (160 mg) was separated by preparative chiral HPLC to give Example 5A (69.5 mg, purity 98.2%, ee = 100%) as a white solid and Example 5B (56.2 mg, purity 99.5%, ee = 100%) as a white solid.

[0195] Example 5A: LC-MS: (ES + H, m / z): [M + H] + = 530.2. 1 H NMR (400 MHz, DMSO-d6) δ 8.74 (s, 1H), 8.60 (d, 1H), 8.15 - 8.05 (m, 1H), 8.00 (d, 1H), 7.94 (s, 1H), 7.47 (d, 1H), 6.81 (s, 1H), 5.49 (d, 2H), 5.12 (s, 1H), 2.10 (s, 3H), 2.00 (s, 3H), 1.50 (s, 6H). 19 F NMR (377 MHz, DMSO-d6) δ -120.17, -120.19, -122.36, -122.38.

[0196] Example 5B: LC-MS: (ES + H, m / z): [M + H] + = 530.2. 1 H NMR (400 MHz, DMSO-d6) δ 8.74 (s, 1H), 8.60 (d, 1H), 8.13 - 8.06 (m, 1H), 8.00 (d, 1H), 7.94 (s, 1H), 7.47 (d, 1H), 6.81 (s, 1H), 5.49 (d, 2H), 5.12 (s, 1H), 2.10 (s, 3H), 2.00 (s, 3H), 1.50 (s, 6H). 1919F NMR (377 MHz, DMSO-d6) δ -120.17, -120.19, -122.36, -122.38. Example 6 [Chemical formula] Step 1: Preparation of ethyl 2-(3-chloro-6-oxopyridazin-1-yl)-2-methylpropanoate:

[0197] To a stirred solution of 6-chloro-2H-pyridazin-3-one (2.60 g, 19.91 mmol, 1.00 equiv) in DMF (50 mL), LiHMDS (19.92 mL, 1 mol / L in THF, 19.91 mmol, 1.00 equiv) was added dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. To the above mixture, α-bromoisobutyrate (7.77 g, 39.83 mmol, 2.00 equiv) was added dropwise at room temperature. The resulting mixture was stirred at 80 °C overnight. The mixture was allowed to cool to room temperature. The reaction was quenched with saturated NH4Cl (aqueous solution) at 0 °C. The mixture was acidified to pH 6 with CH3COOH. The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (5 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and the pure fractions were concentrated under vacuum to give ethyl 2-(3-chloro-6-oxopyridazin-1-yl)-2-methylpropanoate (800 mg, 16.41%) as a yellow liquid. 1 1H NMR (300 MHz, Chloroform-d) δ 7.21 (d, 1H), 6.87 (d, 1H), 4.18 (q, 2H), 1.67 (s, 6H), 1.22 (t, 3H). Steps 2-3: Preparation of ethyl 2-(3-{3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-5’,6-dimethyl-2-oxo-[1,4’-bipyridin]-2’-yl}-6-oxopyridazin-1-yl)-2-methylpropanoate:

[0198] Ethyl 2-(3-chloro-6-oxopyridazin-1-yl)-2-methylpropanoate (280 mg, 1.14 mmol, 1.00 equiv) and bis(pinacolato)diboron (581 mg, 2.28 mmol, 2.00 equiv) in 1,4-dioxane (5 mL) were added with XPhos (54 mg, 0.11 mmol, 0.10 equiv), Pd(AcO)2 (12 mg, 0.05 mmol, 0.05 equiv) and AcOK (336 mg, 3.43 mmol, 3.00 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 2 h under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was used directly in the next step without further purification. ) To the stirred mixture of the above, 2'-bromo-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one (439 mg, 0.96 mmol, 0.84 equiv), K2CO3 (474 mg, 3.43 mmol, 3.00 equiv) and Pd(dppf)Cl2CH2Cl2 (46 mg, 0.05 mmol, 0.05 equiv), and H2O (1 mL) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 2 h under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The reaction mixture was poured into water (100 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and the pure fractions were concentrated under vacuum to give the crude product (270 mg). The crude product (100 mg) was further purified by preparative HPLC and the pure fractions were concentrated under reduced pressure to give ethyl 2-(3-{3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-5',6-dimethyl-2-oxo-[1,4'-bipyridin]-2'-yl}-6-oxopyridazin-1-yl)-2-methylpropanoate (56.6 mg, 22.76%) as a white solid. LC-MS: (ES + H, m / z): [M + H]

[0199] = 586.1. + 11H NMR (300 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.61 (d, 1H), 8.38 (d, 1H), 8.17 - 8.04 (m, 2H), 7.13 (d, 1H), 6.82 (s, 1H), 5.49 (s, 2H), 4.08 (q, 2H), 2.06 (s, 3H), 1.98 (s, 3H), 1.68 (s, 3H), 1.67 (s, 3H), 1.13 (t, 3H). 19 19F NMR (282 MHz, DMSO-d6) δ -120.11, -120.14, -122.29, 122.32. Examples 7A, 7B

Chemical formula

[0200] To a stirred mixture of 2'-bromo-4-hydroxy-5',6-dimethyl-[1,4'-bipyridin]-2-one (3.00 g, 10.16 mmol, 1.00 equivalent) and 3-chloro-2-(chloromethyl)-5-fluoropyridine (3.64 g, 20.22 mmol, 1.99 equivalents) in DMF (0.79 mL, 10.16 mmol, 1.00 equivalent), K2CO3 (7.02 g, 50.82 mmol, 5.00 equivalents) and 18-crown-6 (8 06 mg, 3.04 mmol, 0.30 equivalent) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 60 °C for 1 hour under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with ethyl acetate (100 mL). The organic layer was washed with water (100 mL) and brine (100 mL), and then dried over Na2SO4. The solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2'-bromo-4-[(3-chloro-5-fluoropyridin-2-yl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one (2.00 g, 66.67%) as an off-white solid. LC-MS: (ES + H, m / z): [M + H] + = 439.9. Step 2: Preparation of 2'-Bromo-3-chloro-4-[(3-chloro-5-fluoropyridin-2-yl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one:

[0201] To a stirred mixture of 2'-Bromo-4-[(3-chloro-5-fluoropyridin-2-yl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one (2.00 g, 4.55 mmol, 1.00 eq) and dichloroacetic acid (0.06 mL, 0.45 mmol, 0.10 eq) in i-PrOH (10 mL) was added NCS (608 mg, 4.55 mmol, 1.00 eq) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 60 °C for 2 h under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The precipitated solid was collected by filtration and washed with cold IPA (2 x 5 mL) to give 2'-Bromo-3-chloro-4-[(3-chloro-5-fluoropyridin-2-yl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one (1.50 g, 75%) as a white solid. LC-MS: (ES + H, m / z): [M + H] + = 473.9。 Step 3: Preparation of 3-Chloro-4-[(3-chloro-5-fluoropyridin-2-yl)methoxy]-2'-[3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one:

[0202] A stirred solution of 2'-bromo-3-chloro-4-[(3-chloro-5-fluoropyridin-2-yl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one (750 mg, 1.58 mmol, 1.00 equiv), 3-(2-hydroxypropan-2-yl)-1H-pyridin-2-one (485.65 mg, 3.17 mmol, 2 equiv), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (450 mg, 3.17 mmol, 2.00 equiv) and CuI (603 mg, 3.17 mmol, 2.00 equiv) in dioxane (15 mL) was added with K2CO3 (438 mg, 3.17 mmol, 2.00 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C overnight under a nitrogen atmosphere. The resulting mixture was diluted with ethyl acetate (100 mL), then washed with water (2 × 50 mL) and brine (50 mL), and dried over anhydrous Na2SO4. After filtration, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-chloro-4-[(3-chloro-5-fluoropyridin-2-yl)methoxy]-2'-[3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one (600 mg, 80%) as a white solid. LC-MS: (ES + H, m / z): [M + H] + = 545.0。 Step 4: Preparation of rel-3-chloro-4-[(3-chloro-5-fluoropyridin-2-yl)methoxy]-2'-[3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one and rel-3-chloro-4-[(3-chloro-5-fluoropyridin-2-yl)methoxy]-2'-[3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one:

[0203] 3-chloro-4-[(3-chloro-5-fluoropyridin-2-yl)methoxy]-2 ’-[3-(2-Hydroxypropan-2-yl)-2-oxopyridin-1-yl]-5’,6-dimethyl-[1,4’-bipyridin]-2-one (190 mg) was separated by preparative chiral HPLC to give rel-3-chloro-4-[(3-chloro-5-fluoropyridin-2-yl)methoxy]-2’-[3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-5’,6-dimethyl-[1,4’-bipyridin]-2-one (Example 7A, 76.3 mg, purity 96.7%, ee = 100%) as an off-white solid, and rel-3-chloro-4-[(3-chloro-5-fluoropyridin-2-yl)methoxy]-2’-[3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-5’,6-dimethyl-[1,4’-bipyridin]-2-one (Example 7B, 67.2 mg, purity 98.4%, ee = 100%) as an off-white solid.

[0204] Example 7A: LC-MS: (ES + H, m / z): [M + H] + = 545.0. 1 1H NMR (300 MHz, DMSO-d6) δ 8.72 - 8.65 (m, 2H), 8.25 (dd, 1H), 7.86 (dd, 1H), 7.79 (s, 1H), 7.70 (dd, 1H), 6.77 (s, 1H), 6.43 (t, 1H), 5.50 (s, 2H), 5.23 (s, 1H), 2.08 (s, 3H), 2.00 (s, 3H), 1.48 (s, 3H), 1.47 (s, 3H). 19 19F NMR (282 MHz, DMSO-d6) δ -124.21.

[0205] Example 7B: LC-MS: (ES + H, m / z): [M + H] + = 545.0. 1 1H NMR (300 MHz, DMSO-d6) δ 8.72 - 8.64 (m, 2H), 8.25 (dd, 1H), 7.86 (dd, 1H), 7.79 (s, 1H), 7.70 (dd, 1H), 6.77 (s, 1H), 6.43 (t, 1H), 5.50 (s, 2H), 5.24 (s, 1H), 2.08 (s, 3H), 2.00 (s, 3H), 1.48 (s, 3H), 1.47 (s, 3H).19 19F NMR (282 MHz, DMSO-d6) δ -124.19. Examples 8A, 8B [Chemical Formula] Step 1: Preparation of 3-(3,6-dihydro-2H-pyran-4-yl)-1H-pyridin-2-one

[0206] To a stirred mixture of 3-bromo-1H-pyridin-2-one (5.00 g, 28.73 mmol, 1.00 equiv) and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (18.11 g, 86.20 mmol, 3.00 equiv) in dioxane (150 mL) and H 2 O (30 mL), Ac OK (8.46 g, 86.20 mmol, 3.00 equiv), Pd(dppf)Cl2 (4.21 g, 5.74 mmol, 0.20 equiv) were added and the resulting mixture was stirred at 110 °C overnight under a nitrogen atmosphere. The reaction was cooled to room atmosphere. The resulting mixture was filtered and the filter cake was washed with EtOAc (3 × 100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-(3,6-dihydro-2H-pyran-4-yl)-1H-pyridin-2-one (2.60 g, 51.0%) as a yellow solid. LC-MS: (ES + H, m / z): [M + H] + = 177.9. Step 2: Preparation of 3-(oxan-4-yl)-1H-pyridin-2-one:

[0207] A mixture of 3-(3,6-dihydro-2H-pyran-4-yl)-1H-pyridin-2-one (2.00 g, 11.28 mmol, 1.00 eq) and Pd / C (158 mg, 1.12 mmol, 0.10 eq) in MeOH (100 mL) was stirred at room temperature for 3 h under a hydrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with MeOH (3 × 50 mL). The filtrate was concentrated under reduced pressure. Thereby, 3-(oxan-4-yl)-1H-pyridin-2-one (1.80 g, 88.9%) was obtained as a yellow solid. LC-MS: (ES + H, m / z): [M + H] + = 180.2. Step 3: Preparation of 3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-5’,6-dimethyl-2’-[3-(oxan-4-yl)-2-oxopyridin-1-yl]-[1,4’-bipyridin]-2-one:

[0208] A solution of 3-(oxan-4-yl)-1H-pyridin-2-one (500 mg, 2.79 mmol, 2.00 equiv) and 2'-bromo-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one (637 mg, 1.39 mmol, 1.00 equiv) in dioxane (15 mL) was added with CuI (531 mg, 2.79 mmol, 2.00 equiv), N1,N2-dimethylcyclohexane-1,2-diamine (396 mg, 2.79 mmol, 2.00 equiv) and K2CO3 (386 mg, 2.79 mmol, 2.00 equiv). The resulting mixture was stirred at 80 °C for 3 h under a nitrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with EtOAc (3 × 10 mL). The filtrate was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (60 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC. Thereby, 3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-5',6-dimethyl-2'-[3-(oxan-4-yl)-2-oxopyridin-1-yl]-[1,4'-bipyridin]-2-one (547 mg, 70.6%) was obtained as a white solid. LC-MS: (ES + H, m / z): [M + H] + = 555.1。 Step 4: Preparation of rel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-5',6-dimethyl-2'-[3-(oxan-4-yl)-2-oxopyridin-1-yl]-[1,4'-bipyridin]-2-one and rel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-5',6-dimethyl-2'-[3-(oxan-4-yl)-2-oxopyridin-1-yl]-[1,4'-bipyridin]-2-one

[0209] 3-Chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-5’,6-dimethyl-2’-[3-(oxan-4-yl)-2-oxopyridin-1-yl]-[1,4’-bipyridin]-2-one (260 mg) was separated by preparative chiral HPLC to give Example 8A (68.5 mg, purity 98.5%, ee = 100.0%) and Example 8B (56.6 mg, purity 99.2%, ee = 100.0%) as white solids.

[0210] Example 8A: LC-MS: (ES + H, m / z): [M + H]+ = 555.05. 1 H NMR (300 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.61 (d, 1H), 8.13 - 8.10 (m, 1H), 7.86 (dd, 1H), 7.80 (s, 1H), 7.40 - 7.34 (m, 1H), 6.81 (s, 1H), 6.39 (t, 1H), 5.49 (d, 2H), 3.94 (d, 2H), 3.47 - 3.37 (m, 2H), 2.99 - 2.92 (m, 1H), 2.08 (s, 3H), 2.02 (s, 3H), 1.69 - 1.81 (m, 2H), 1.62 - 1.52 (m, 2H). 19 F NMR (282 MHz, DMSO-d6) δ -120.16, -120.19, -122.36, -122.38.

[0211] Example 8B: LC-MS: (ES + H, m / z): [M + H] + = 555.00. 1 H NMR (300 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.60 (d, 1H), 8.13 - 8.06 (m, 1H), 7.87 (dd, 1H), 7.80 (s, 1H), 7.38 - 7.36 (m, 1H), 6.81 (s, 1H), 6.39 (t, 1H), 5.49 (d, 2H), 3.94 (d, 2H), 3.51 - 3.33 (m, 2H), 2.95 (t, 1H), 2.08 (s, 3H), 2.01 (s, 3H), 1.82 - 1.39 (m, 4H). 19 F NMR (282 MHz, DMSO-d6) δ -120.16, -120.19, -122.36, -122.38. Examples 9A, 9B

Chem.

[0212] To a stirred solution of ethyl 3-oxo-2H-pyridazine-4-carboxylate (1.00 g, 5.94 mmol, 1.00 equiv) in THF (10 mL) was added CH3MgBr (19.80 mL, 3 M in 2-MeTHF, 59.40 mmol, 10.00 equiv) dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 2 h under a nitrogen atmosphere. The reaction was quenched with saturated NH4Cl (aqueous solution) at 0 °C. The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. The filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LC-MS: (ES + H, m / z): [M + H] + = 155.3. Step 2: Preparation of bis(3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2’-[5-(2-hydroxypropan-2-yl)-6-oxopyridazin-1-yl]-5’,6-dimethyl-[1,4’-bipyridin]-2-one):

[0213] 4-(2-Hydroxypropan-2-yl)-2H-pyridin in dioxane (20 mL) A mixture of Dazin-3-one (1.00 g, 6.49 mmol, 1.00 equiv), 2'-bromo-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one (3.26 g, 7.12 mmol, 1.10 equiv), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (0.92 g, 6.48 mmol, 1.00 equiv), CuI (1.24 g, 6.48 mmol, 1.00 equiv) and K2CO3 (1.80 g, 12.98 mmol, 2.00 equiv) was added at room temperature. The mixture was heated at 80 °C for 3 h. The mixture was cooled to room temperature. The resulting mixture was diluted with water (100 mL). It was then extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2'-[5-(2-hydroxypropan-2-yl)-6-oxopyridazin-1-yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one (0.68 g, 19.78%) as a white solid. LC-MS: (ES + H, m / z): [M + H]+ = 529.9. 1 H NMR (400 MHz, Chloroform-d) δ 8.68 (s, 1H), 8.40 (d, 1H), 8.00 (d, 1H), 7.55 (s, 1H), 7.36 - 7.27 (m, 1H), 7.25 (d, 1H), 6.41 (d, 1H), 5.41 (d, 2H), 5.14 - 4.43 (m, 1H), 2.19 (s, 3H), 2.07 (s, 3H), 1.60 (s, 3H), 1.59 (s, 3H). Process 3: Preparation of rel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2'-[5-(2-hydroxypropan-2-yl)-6-oxopyridazin-1-yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one and rel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2'-[5-(2-hydroxypropan-2-yl)-6-oxopyridazin-1-yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one:

[0214] The racemic mixture (150 mg) was isolated by preparative chiral HPLC to give rel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2'-[5-(2-hydroxypropan-2-yl)-6-oxopyridazin-1-yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one (Example 9A: 45.9 mg, ee = 100%) as an off-white solid and rel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2'-[5-(2-hydroxypropan-2-yl)-6-oxopyridazin-1-yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one (Example 9B: 50.8 mg, ee = 99.32%).

[0215] Example 9A: LC-MS: (ES + H, m / z): [M + H] + = 530.0。 1 1H NMR (300 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.60 (d, 1H), 8.15 - 8.08 (m, 1H), 8.07 (d, 1H), 7.69 (s, 1H), 7.59 (d, 1H), 6.81 (d, 1H), 5.48 (d, 2H), 5.40 (s, 1H), 2.09 (s, 3H), 1.98 (s, 3H), 1.50 (s, 3H), 1.49 (s, 3H). 19 19F NMR (282 MHz, DMSO-d6) δ -120.15, -120.18, -122.35, -122.37.

[0216] Example 9B: LC-MS: (ES + H, m / z): [M + H] += 530.0。 1 1H NMR (300 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.60 (d, 1H), 8.15 - 8.08 (m, 1H), 8.07 (d, 1H), 7.69 (s, 1H), 7.59 (d, 1H), 6.81 (d, 1H), 5.48 (d, 2H), 5.40 (s, 1H), 2.09 (s, 3H), 1.98 (s, 3H), 1.50 (s, 3H), 1.49 (s, 3H). 19 19F NMR (282 MHz, DMSO-d6) δ -120.15 , -120.18, -122.35, -122.37。 Example 10A, 10B

Chem.

[0217] To a stirred solution of methyl 4-oxo-3H-pyrimidine-5-carboxylate (3.00 g, 19.46 mmol, 1.00 equiv) in THF (200 mL), MeMgBr (64 mL, 3 M in 2-MeTHF, 194.65 mmol, 10.00 equiv) was added dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 1 h under a nitrogen atmosphere. The reaction was quenched by adding saturated NH4Cl (aqueous solution) (100 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. Thereby, 5-(2-hydroxypropan-2-yl)-3H-pyrimidin-4-one (1.50 g, 49.99%) was obtained as a white solid. The crude product was used directly in the next step without further purification. LC-MS: (ES + H, m / z): [M + H] + = 155.3。 Step 2: Preparation of 3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2'-[5-(2-hydroxypropan-2-yl)-6-oxopyrimidin-1-yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one:

[0218] To a stirred solution of methyl 5-(2-hydroxypropan-2-yl)-3H-pyrimidin-4-one (337 mg, 2.19 mmol, 2.00 equiv) and 2'-bromo-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one (500 mg, 1.09 mmol, 1.00 equiv) in dioxane (20 mL), CuI (417 mg, 2.19 mmol, 2.00 equiv), K2CO3 (302 mg, 2.19 mmol, 2.00 equiv), and (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (311 mg, 2.19 mmol, 2.00 equiv) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C overnight under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was filtered and the filter cake was washed with EtOAc (3 × 20 mL). The resulting mixture was poured into water (100 mL) and extracted with EtOAc (100 mL). The combined organic layers were washed with brine (200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC. Thereby, 3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2'-[5-(2-hydroxypropan-2-yl)-6-oxopyrimidin-1-yl] -5',6-dimethyl-[1,4'-bipyridin]-2-one (130 mg, 22.41%) was obtained as a white solid. LC-MS: (ES + H, m / z): [M + H] + = 530.2. Step 3: Preparation of rel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2'-[5-(2-hydroxypropan-2-yl)-6-oxopyrimidin-1-yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one and rel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2'-[5-(2-hydroxypropan-2-yl)-6-oxopyrimidin-1-yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one:

[0219] 3-Chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2'-[5-(2-hydroxypropan-2-yl)-6-oxopyrimidin-1-yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one (260 mg) was separated by preparative chiral HPLC to give Example 10A (93.1 mg, purity 99.2%, ee = 100%) and Example 10B (73.9 mg, purity 99.6%, ee = 100%) as white solids.

[0220] Example 10A: LC-MS: (ES + H, m / z): [M + H] + = 530.05. 1 H NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.61 (s, 1H) 8.59 (d, 1H), 8.14 (s, 1H), 8.09 - 8.06 (m, 1H), 7.79 (s, 1H), 6.81 (s, 1H), 5.49 (d, 2H), 5.22 (s, 1H), 2.10 (s, 3H), 2.00 (s, 3H), 1.48 (s, 3H), 1.47 (s, 3H). 19 F NMR (377 MHz, DMSO-d6) δ -120.16, -120.18, -122.34, -122.36.

[0221] Example 10B: LC-MS: (ES + H, m / z): [M + H] + = 530.05. 1 H NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.61 (s, 1H) 8.59 (d, 1H), 8.14 (s, 1H), 8.09 - 8.06 (m, 1H), 7.80 (s, 1H), 6.81 (s, 1H), 5.49 (d, 2H), 5.23 (s, 1H), 2.10 (s, 3H), 2.00 (s, 3H), 1.48 (s, 3H), 1.47 (s, 3H). 19 F NMR (377 MHz, DMSO-d6) δ -120.15, -120.17, -122.33, -122.35. Examples 11A, 11B

Chemical Structure

[0222] To a stirred mixture of methyl 2-(2-chloropyridin-3-yl)acetate (5.00 g, 26.93 mmol, 1.00 equiv) in THF (50 mL) was added LiHMDS (80.81 mL, 1 M in THF, 80.81 mmol, 3.00 equiv) dropwise at -78 °C under a nitrogen atmosphere. The resulting mixture was stirred at -78 °C for 30 minutes under a nitrogen atmosphere. MeI (11.47 g, 80.81 mmol, 3.00 equiv) was added dropwise to the above solution at -78 °C under a nitrogen atmosphere. The resulting mixture was stirred at -78 °C for 1 hour under a nitrogen atmosphere. The desired product could be detected by LCMS. The mixture was warmed to room temperature. The reaction was quenched with saturated NH4Cl (aqueous solution) (500 mL) at room temperature. The resulting mixture was extracted with CH2Cl2 (3 × 500 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give methyl 2-(2-chloropyridin-3-yl)-2-methylpropanoate (5.7 g, crude) as a colorless oil. LC-MS: (ES+H, m / z): [M+H] + = 214.1. Step 2: Preparation of methyl 2-(2-methoxypyridin-3-yl)-2-methylpropanoate:

[0223] To a mixture of methyl 2-(2-chloropyridin-3-yl)-2-methylpropanoate (3.00 g, 14.04 mmol, 1.00 equiv), Cs2CO3 (6.86 g, 21.06 mmol, 1.50 equiv), t-BuXPhos (0.36 g, 0.84 mmol, 0.06 equiv) and MeOH (20.00 mL, 493.97 mmol, 35.18 equiv) in toluene (20.00 mL), Pd(OAc)2 (0.19 g, 0.84 mmol, 0.06 equiv) was added at room temperature. The resulting mixture was stirred at 80 °C overnight under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The reaction mixture was poured into water (400 mL) and extracted with EtOAc (3 × 400 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give methyl 2-(2-methoxypyridin-3-yl)-2-methylpropanoate (2.40 g, crude) as a white solid. LC-MS: (ES+H, m / z): [M+H] + = 210.2. Step 3: Preparation of methyl 2-methyl-2-(2-oxo-1H-pyridin-3-yl)propanoate:

[0224] To a stirred solution of methyl 2-(2-methoxypyridin-3-yl)-2-methylpropanoate (2.00 g, 9.55 mmol, 1.00 equiv) in MeCN (50 mL), TMSI (7.65 g, 38.23 mmol, 4.00 equiv) was added at room temperature. The resulting mixture was stirred at 50 °C for 2 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 2-methyl-2-(2-oxo-1H-pyridin-3-yl)propanoate (800 mg, 42.87%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + = 196.1. 1 H NMR (300 MHz, Chloroform-d) δ 7.44 (dd, 1H), 7.38 (dd, 1H), 6.33 (t, 1H), 3.66 (s, 3H), 1.52 (s, 6H). Step 4: Preparation of methyl 2-(1-{3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-5’,6-dimethyl-2-oxo-[1,4’-bipyridin]-2’-yl}-2-oxopyridin-3-yl)-2-methylpropanoate:

[0225] A mixture of methyl 2-methyl-2-(2-oxo-1H-pyridin-3-yl)propanoate (0.85 g, 4.38 mmol, 1.00 equiv), K2CO3 (1.21 g, 8.76 mmol, 2.00 equiv), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (0.25 g, 1.75 mmol, 0.40 equiv) and 2’-bromo-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-5’,6-dimethyl-[1,4’-bipyridin]-2-one (2.00 g, 4.38 mmol, 1.00 equiv) in 1,4-dioxane (30.00 mL) was added with CuI (0.17 g, 0.87 mmol, 0.20 equiv) at room temperature. The resulting mixture was stirred at 80 °C for 2 h under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The reaction was poured into water (300 mL) and extracted with EtOAc (3 × 300 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 2-(1-{3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-5’,6-dimethyl-2-oxo-[1,4’-bipyridin]-2’-yl}-2-oxopyridin-3-yl)-2-methylpropanoate (1.40 g, 55.99%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + = 571.1。 11H NMR (400 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.60 (d, 1H), 8.14 - 8.05 (m, 1H), 7.97 - 7.90 (m, 1H), 7.77 (s, 1H), 7.55 - 7.48 (m, 1H), 6.80 (s, 1H), 6.43 (t, 1H), 5.54 - 5.44 (m, 2H), 3.49 (s, 3H), 2.07 (s, 3H), 1.99 (s, 3H), 1.42 (s, 3H), 1.40 (s, 3H). Step 5: Preparation of 3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2'-[3-(1-hydroxy-2-methylpropan-2-yl)-2-oxopyridin-1-yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one:

[0226] To a stirred solution of methyl 2-(1-{3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-5',6-dimethyl-2-oxo-[1,4'-bipyridin]-2'-yl}-2-oxopyridin-3-yl)-2-methylpropanoate (900 mg, 1.57 mmol, 1.00 equiv) in THF (12.00 mL) was added LiAlH4 (0.63 mL, 2.5 M in THF, 1.57 mmol, 1.00 equiv) dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 1 h under a nitrogen atmosphere. The reaction was quenched with 15% aqueous sodium hydroxide at 0 °C. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC to give 3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2'-[3-(1-hydroxy-2-methylpropan-2-yl)-2-oxopyridin-1-yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one (110 mg, 12.85%) as a white solid. LC-MS: (ES + H, m / z): [M + H] + = 543.3. Step 6: Preparation of rel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2’-[3-(1-hydroxy-2-methylpropan-2-yl)-2-oxopyridin-1-yl]-5’,6-dimethyl-[1,4’-bipyridin]-2-one and rel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2’-[3-(1-hydroxy-2-methylpropan-2-yl)-2-oxopyridin-1-yl]-5’,6-dimethyl-[1,4’-bipyridin]-2-one

[0227] The racemic 3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2’-[3-(1-hydroxy-2-methylpropan-2-yl)-2-oxopyridin-1-yl]-5’,6-dimethyl-[1,4’-bipyridin]-2-one (110 mg, 0.20 mmol) was separated by preparative chiral HPLC to give rel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2’-[3-(1-hydroxy-2-methylpropan-2-yl)-2-oxopyridin-1-yl]-5’,6-dimethyl-[1,4’-bipyridin]-2-one (Example 11A, 33.7 mg, ee = 100.00%) as a white solid and rel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2’-[3-(1-hydroxy-2-methylpropan-2-yl)-2-oxopyridin-1-yl]-5’,6-dimethyl-[1,4’-bipyridin]-2-one (Example 11B, 31.5 mg, ee = 100.00%) as a white solid.

[0228] Example 11A: LC-MS: (ES+H, m / z): [M+H] + = 543.3. 1 H NMR (300 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.61 (d, 1H), 8.15 - 8.05 (m, 1H), 7.86 - 7.80 (m, 1H), 7.75 (s, 1H), 7.43 - 7.35 (m, 1H), 6.81 (s, 1H), 6.35 (t, 1H), 5.53 - 5.44 (m, 2H), 4.49 (t, 1H), 3.74 - 3.56 (m, 2H), 2.08 (s, 3H), 2.02 (s, 3H), 1.23 (s, 3H), 1.23 (s, 3H). 19 19F NMR (377 MHz, DMSO-d6) δ -120.15, -120.18, -122.35, -122.37.

[0229] Example 11B: LC-MS: (ES + H, m / z): [M + H] + = 543.3. 1 H 1H NMR (300 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.61 (d, 1H), 8.15 - 8.05 (m, 1H), 7.88 - 7.80 (m, 1H), 7.75 (s, 1H), 7.44 - 7.34 (m, 1H), 6.81 (s, 1H), 6.35 (t, 1H), 5.53 - 5.44 (m, 2H), 4.49 (t, 1H), 3.73 - 3.55 (m, 2H), 2.08 (s, 3H), 2.02 (s, 3H), 1.23 (s, 3H), 1.23 (s, 3H). 19 19F NMR (377 MHz, DMSO-d6) δ -120.15, -120.18, -122.35, -122.37. Examples 12A, 12B

Chemical formula

[0230] To a stirred solution of 3-iodo-2-methoxypyridine (5.00 g, 21.27 mmol, 1.00 eq) in toluene (100.00 mL), i-PrMgCl (2.84 g, 27.65 mmol, 1.30 eq) was added dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 0.5 h under a nitrogen atmosphere. To the above mixture, cyclobutanone (2.24 g, 31.91 mmol, 1.50 eq) was added dropwise at 0 °C. The resulting mixture was stirred at 0 °C for an additional 1 h. The reaction was quenched with water at 0 °C. The resulting mixture was extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 1-(2-methoxypyridin-3-yl)cyclobutan-1-ol (1.75 g, 45.90%) as a yellow oil. LC-MS: (ES+H, m / z): [M+H] + = 180.1. 1 H NMR (400 MHz, DMSO-d6) δ 8.08 - 8.02 (m, 1H), 7.68 - 7.63 (m, 1H), 6.97 - 6.92 (m, 1H), 5.20 (s, 1H), 3.88 (s, 3H), 2.61 - 2.48 (m, 2H), 2.22 - 2.13 (m, 2H), 2.02 - 1.93 (m, 1H), 1.67 - 1.54 (m, 1H). Step 2: Preparation of 3-(1-hydroxycyclobutyl)-1H-pyridin-2-one:

[0231] A mixture of 1-(2-methoxypyrimidin-3-yl)cyclobutan-1-ol (400 mg, 2.23 mmol, 1.00 equiv) in DMF (10.00 mL) was added with (ethylsulfanyl)sodium (1877 mg, 22.32 mmol, 10.00 equiv) at room temperature. The resulting mixture was stirred at 100 °C overnight under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The mixture was neutralized to pH 7 with AcOH. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-(1-hydroxycyclobutyl)-1H-pyridin-2-one (200 mg, 54.25%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + = 166.1. 1 H NMR (400 MHz, DMSO-d6) δ 11.76 (s, 1H), 7.49 (dd, 1H), 7.32 (dd, 1H), 6.24 (t, 1H), 5.81 - 5.55 (m, 1H), 2.48 - 2.41 (m, 2H), 2.13 - 2.02 (m, 2H), 1.93 - 1.81 (m, 1H), 1.65 - 1.53 (m, 1H). Step 3: Preparation of 3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2’-[3-(1-hydroxycyclobutyl)-2-oxopyridin-1-yl]-5’,6-dimethyl-[1,4’-bipyridin]-2-one:

[0232] A mixture of 3-(1-hydroxycyclobutyl)-1H-pyridin-2-one (173 mg, 1.05 mmol, 1.20 equiv), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (49 mg, 0.35 mmol, 0.40 equiv), K2CO3 (242 mg, 1.75 mmol, 2.00 equiv) and 2'-bromo-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one (400 mg, 0.87 mmol, 1.00 equiv) in 1,4-dioxane (8.00 mL) was added with CuI (33 mg, 0.17 mmol, 0.20 equiv) at room temperature. The resulting mixture was stirred at 80 °C for 2 h under a nitrogen atmosphere. The reaction was poured into water (150 mL) and extracted with EtOAc (3 × 150 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography to give 3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2'-[3-(1-hydroxycyclobutyl)-2-oxopyridin-1-yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one (280 mg, 59.09%) as a white solid. LC-MS: (ES + H, m / z): [M + H] + = 541.1。 Step 3: Preparation of rel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2'-[3-(1-hydroxycyclobutyl)-2-oxopyridin-1-yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one and rel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2'-[3-(1-hydroxycyclobutyl)-2-oxopyridin-1-yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one

[0233] The racemate 3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2’-[3-(1-hydroxycyclobutyl)-2-oxopyridin-1-yl]-5’,6-dimethyl-[1,4’-bipyridin]-2-one (280 mg, 0.51 mmol) was separated by preparative chiral HPLC to obtain rel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2’-[3-(1-hydroxycyclobutyl)-2-oxopyridin-1-yl]-5’,6-dimethyl-[1,4’-bipyridin]-2-one (Example 12A, 100.8 mg, ee = 100.00%) as a white solid and rel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2’-[3-(1-hydroxycyclobutyl)-2-oxopyridin-1-yl]-5’,6-dimethyl-[1,4’-bipyridin]-2-one (Example 12B, 103.2 mg, ee = 99.32%) as a white solid.

[0234] Example 12A: LC-MS: (ES + H, m / z): [M + H] + = 541.2. 1 H NMR (400 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.60 (d, 1H), 8.15 - 8.05 (m, 1H), 7.95 - 7.90 (m, 1H), 7.84 (s, 1H), 7.59 (dd, 1H), 6.81 (s, 1H), 6.44 (t, 1H), 5.48 (s, 2H), 5.31 (s, 1H), 2.64 - 2.54 (m, 2H), 2.13 - 2.09 (m, 1H), 2.08 (s, 3H), 2.07 - 2.03 (m, 1H), 2.01 (s, 3H), 1.98 - 1.85 (m, 1H), 1.72 - 1.59 (m, 1H). 19 F NMR (377 MHz, DMSO-d6) δ -120.15, -120.17, -122.34, -122.36.

[0235] Example 12B: LC-MS: (ES + H, m / z): [M + H] + = 541.2. 1 H NMR (400 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.60 (d, 1H), 8.14 - 8.06 (m, 1H), 7.95 - 7.89 (m, 1H), 7.84 (s, 1H), 7.62 - 7.56 (m, 1H), 6.81 (s, 1H), 6.43 (t, 1H), 5.48 (s, 2H), 5.31 (s, 1H), 2.64 - 2.54 (m, 2H), 2.12 - 2.09 (m, 1H), 2.08 (s, 3H), 2.07 - 2.03 (m, 1H), 2.01 (s, 3H), 1.98 - 1.84 (m, 1H), 1.72 - 1.57 (m, 1H). 19 F NMR (377 MHz, DMSO-d6) δ -120.16, -120.18, -122.34, -122.36. Examples 13A, 13B

Chemical Structure

[0236] To a stirred solution of methyl 6-oxo-1H-pyridine-3-carboxylate (1.00 g, 6.53 mmol, 1.00 equiv) in THF (50 mL) was added MeMgBr (21.77 mL, 3 M in 2-MeTHF, 65.30 mmol, 10.00 equiv) dropwise at -10 °C. The resulting mixture was stirred at room temperature for an additional 1 hour. The reaction was monitored by LCMS. The reaction was quenched by adding saturated NH4Cl (aqueous solution) (150 mL) at 0 °C. The resulting mixture was extracted with EtOAc (4 × 300 mL). The combined organic layers were washed with brine (400 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give 5-(2-hydroxypropan-2-yl)-1H-pyridin-2-one (580 mg, 57.98%) as a white solid. LC-MS: (ES + H, m / z): [M + H] + = 154.3. Step 2: Preparation of 3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2'-[5-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one:

[0237] To a solution of 5-(2-hydroxypropan-2-yl)-1H-pyridin-2-one (537 mg, 3.50 mmol, 2.00 eq) and 2'-bromo-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one (800 mg, 1.75 mmol, 1.00 eq) in 1,4-dioxane (6 mL), K2CO3 (484 mg, 3.50 mmol, 2.00 eq), CuI (667 mg, 3.50 mmol, 2.00 eq), and (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (498 mg, 3.50 mmol, 2.00 eq) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 3 h under a nitrogen atmosphere. The residue was diluted with H2O (50 mL) and the mixture was extracted with EtOAc (2 × 100 mL). The combined organic phases were washed with brine (100 mL) and dried over Na2SO4. The crude product was purified by preparative HPLC to give 3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2'-[5-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one (130 mg, 14.03%) as a white solid. LC-MS: (ES + H, m / z): [M + H] + = 529.05. 1 H NMR (400 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.60 (d, 1H), 8.13 - 8.05 (m, 1H), 7.93 (d, 1H), 7.85 (s, 1H), 7.70 - 7.65 (m, 1H), 6.81 (s, 1H), 6.51 (d, 1H), 5.50 (d, 2H), 5.18 (s, 1H), 2.09 (s, 3H), 2.02 (s, 3H), 1.41 (s, 3H), 1.40 (s, 3H). Step 3: Preparation of (3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2'-[5-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one) and (3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2'-[5-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one):

[0238] (3-Chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2'-[5-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one) (130 mg, 0.233 mmol, 1.00 eq) was separated by preparative chiral HPLC to give Example 13A (43.9 mg, purity 98.2%, ee = 100%) as a white solid and Example 13B (33.6 mg, purity 98.3%, ee = 100%) as a white solid.

[0239] Example 13A: LC-MS: (ES + H, m / z): [M + H] + = 529.0. 1 H NMR (300 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.60 (d, 1H), 8.14 - 8.05 (m, 1H), 7.90 (d, 1H), 7.84 (s, 1H), 7.70 - 7.64 (m, 1H), 6.81 (s, 1H), 6.50 (d, 1H), 5.49 (d, 2H), 5.17 (s, 1H), 2.08 (s, 3H), 2.01 (s, 3H), 1.41 (s, 3H), 1.40 (s, 3H). 19 F NMR (282 MHz, DMSO-d6) δ -120.15, -120.17, -122.35, -122.38.

[0240] Example 13B: LC-MS: (ES + H, m / z): [M + H] + = 529.0. 1 H NMR (300 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.60 (d, 1H), 8.14 - 8.05 (m, 1H), 7.90 (d, 1H), 7.84 (s, 1H), 7.70 - 7.64 (m, 1H), 6.81 (s, 1H), 6.50 (d, 1H), 5.49 (d, 2H), 5.17 (s, 1H), 2.08 (s, 3H), 2.01 (s, 3H), 1.41 (s, 3H), 1.40 (s, 3H). 19 F NMR (282 MHz, DMSO-d6) δ -120.15, -120.17, -122.35, -122.3 8. Examples 14A, 14B, 14C, 14D

Chem.

[0241] To a stirred solution of 3-iodo-2-methoxypyridine (4.00 g, 17.02 mmol, 1.00 equiv) in toluene (100 mL) was added i-PrMgCl (11.06 mL, 2 M in THF, 22.12 mmol, 1.30 equiv) dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 30 minutes under a nitrogen atmosphere. To the above mixture was added cyclopropyl methyl ketone (2.15 g, 25.55 mmol, 1.50 equiv) dropwise at 0 °C over 20 minutes. The resulting mixture was stirred at 0 °C for an additional 1 hour. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (2 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase combiflash chromatography to give 1-cyclopropyl-1-(2-methoxypyridin-3-yl)ethanol (751 mg, 22.83%) as a yellow oil. LC-MS: (ES + H, m / z): [M + H] + = 194.1. 11H NMR (300 MHz, DMSO-d6) δ 8.02 (dd, 1H), 7.81 (dd, 1H), 6.95 (dd, 1H), 4.65 (s, 1H), 3.89 (s, 3H), 1.66 - 1.56 (m, 1H), 1.54 (s, 3H), 0.58 - 0.41 (m, 1H), 0.35 - 0.12 (m, 2H), 0.11 - 0.04 (m, 1H). Step 2: Preparation of the product 3-(1-cyclopropyl-1-hydroxyethyl)-1H-pyridin-2-one:

[0242] A mixture of 1-cyclopropyl-1-(2-methoxypyridin-3-yl)ethanol (1.14 g, 5.88 mmol, 1.00 equivalent) and sodium (ethylsulfanyl) (4.95 g, 58.84 mmol, 10.0 equivalents) in DMF (20 mL) was stirred at 100 °C for 3 h under a nitrogen atmosphere. The mixture was allowed to come to room temperature. The resulting mixture was diluted with water (100 mL). The mixture was acidified to pH = 4 - 5 with concentrated HCl. The resulting mixture was extracted with CHCl3:IPA = 3:1 (3 × 100 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-(1-cyclopropyl-1-hydroxyethyl)-1H-pyridin-2-one (1.40 g ) as a yellow oil. The crude product was used directly in the next step without further purification. LC-MS: (ES + H, m / z): [M + H] + = 180.0. 1 1H NMR (300 MHz, DMSO-d6) δ 12.07 - 11.10 (m, 1H), 7.52 (dd, 1H), 7.29 (dd, 1H), 6.23 (t, 1H), 5.56 (s, 1H), 1.54 - 1.46 (m, 1H), 1.44 (s, 3H), 0.50 - 0.30 (m, 1H), 0.34 - 0.20 (m, 2H), 0.20 - 0.07 (m, 1H). Step 3: Preparation of 3-chloro-2'-[3-(1-cyclopropyl-1-hydroxyethyl)-2-oxopyridin-1-yl]-4-[(3,5-difluoropyridin-2-yl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one:

[0243] A mixture of 3-(1-cyclopropyl-1-hydroxyethyl)-1H-pyridin-2-one (1.30 g, 7.25 mmol, 1.50 equiv), 2'-bromo-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one (2.21 g, 4.83 mmol, 1.00 equiv), K2CO3 (1.34 g, 9.67 mmol, 2.00 equiv), CuI (1.84 g, 9.67 mmol, 2.00 equiv) and (1R,2R)-1-N,2-N-dimethylcyclohexane-1,2-diamine (1.38 g, 9.67 mmol, 2.00 equiv) in 1,4-dioxane (10 mL) was stirred at 80 °C for 2 h. The mixture was cooled to room temperature. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with brine (150 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-chloro-2'-[3-(1-cyclopropyl-1-hydroxyethyl)-2-oxopyridin-1-yl]-4-[(3,5-difluoropyridin-2-yl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one (0.79 g, 29.40%) as a white solid. LC-MS: (ES + H, m / z): [M + H] + = 555.0。 1 1H NMR (400 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.60 (d, 1H), 8.15 - 8.03 (m, 1H), 7.86 (dd, 1H), 7.79 (d, 1H), 7.70 - 7.61 (m, 1H), 6.80 (t, 1H), 6.43 (t, 1H), 5.48 (d, 2H), 4.94 (d, 1H), 2.08 (s, 3H), 2.00 (s, 3H), 1.72 - 1.62 (m, 1H), 1.53 (d, 3H), 0.52 - 0.43 (m, 1H), 0.30 - 0.21 (m, 2H), 0.16 - 0.05 (m, 1H). Procedure for the preparation of 4:rel-3-chloro-2’-[3-(1-cyclopropyl-1-hydroxyethyl)-2-oxopyridin-1-yl]-4-[(3,5-difluoropyridin-2-yl)methoxy]-5’,6-dimethyl-[1,4’-bipyridin]-2-one, rel-3-chloro-2’-[3-(1-cyclopropyl-1-hydroxyethyl)-2-oxopyridin-1-yl]-4-[(3,5-difluoropyridin-2-yl)methoxy]-5’,6-dimethyl-[1,4’-bipyridin]-2-one, rel-3-chloro-2’-[3-(1-cyclopropyl-1-hydroxyethyl)-2-oxopyridin-1-yl]-4-[(3,5-difluoropyridin-2-yl)methoxy]-5’,6-dimethyl-[1,4’-bipyridin]-2-one, and rel-3-chloro-2’-[3-(1-cyclopropyl-1-hydroxyethyl)-2-oxopyridin-1-yl]-4-[(3,5-difluoropyridin-2-yl)methoxy]-5’,6-dimethyl-[1,4’-bipyridin]-2-one:

[0244] The rac-mixture (570 mg) was separated by preparative chiral HPLC to give a mixture of Example 14A and Example 14B (270 mg), rel-3-chloro-2’-[3-(1-cyclopropyl-1-hydroxyethyl)-2-oxopyridin-1-yl]-4-[(3,5-difluoropyridin-2-yl)methoxy]-5’,6-dimethyl-[1,4’-bipyridin]-2-one (Example 14C, 100.1 mg, purity 97.8%, de = 100 %) as an off-white solid, and rel-3-chloro-2’-[3-(1-cyclopropyl-1-hydroxyethyl)-2-oxopyridin-1-yl]-4-[(3,5-difluoropyridin-2-yl)methoxy]-5’,6-dimethyl-[1,4’-bipyridin]-2-one (Example 14D, 84.0 mg, purity 97.0%, de = 98.2%).

[0245] The mixture (270 mg) of Example 14A and Example 14B was further separated by preparative chiral HPLC to obtain rel-3-chloro-2'-[3-(1-cyclopropyl-1-hydroxyethyl)-2-oxopyridin-1-yl]-4-[(3,5-difluoropyridin-2-yl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one (Example 14A, 104.2 mg, purity 97.5%, de = 100%) as an off-white solid, and rel-3-chloro-2'-[3-(1-cyclopropyl-1-hydroxyethyl)-2-oxopyridin-1-yl]-4-[(3,5-difluoropyridin-2-yl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one (Example 14B, 116.2 mg, purity 96.6%, de = 100%).

[0246] Example 14A: LC-MS: (ES + H, m / z): [M + H] + = 555.00. 1 H NMR (300 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.60 (d, 1H), 8.16 - 8.04 (m, 1H), 7.87 (dd, 1H), 7.80 (s, 1H), 7.66 (dd, 1H), 6.80 (s, 1H), 6.43 (t, 1H), 5.48 (d, 2H), 4.96 (s, 1H), 2.08 (s, 3H), 2.01 (s, 3H), 1.73 - 1.61 (m, 1H), 1.53 (s, 3H), 0.54 - 0.42 (m, 1H), 0.32 - 0.19 (m, 2H), 0.18 - 0.07 (m, 1H). 19 F NMR (282 MHz, DMSO-d6) δ -120.16, -120.18, -122.35, -122.37.

[0247] Example 14B: LC-MS: (ES + H, m / z): [M + H] + = 555.00. 11H NMR (300 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.60 (d, 1H), 8.16 - 8.03 (m, 1H), 7.87 (dd, 1H), 7.80 (s, 1H), 7.66 (dd, 1H), 6.80 (s, 1H), 6.43 (t, 1H), 5.48 (d, 2H), 4.96 (s, 1H), 2.08 (s, 3H), 2.01 (s, 3H), 1.73 - 1.61 (m, 1H), 1.53 (s, 3H), 0.53 - 0.43 (m, 1H), 0.32 - 0.20 (m, 2H), 0.18 - 0.06 (m, 1H). 19 F NMR (282 MHz, DMSO-d6) δ -120.16, -120.18, -122.35, -122.37.

[0248] Example 14C: LC-MS: (ES + H, m / z): [M + H] + = 555.00. 1 1H NMR (300 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.61 (d, 1H), 8.17 - 8.03 (m, 1H), 7.87 (dd, 1H), 7.79 (s, 1H), 7.66 (dd, 1H), 6.81 (s, 1H), 6.43 (t, 1H), 5.48 (d, 2H), 4.94 (s, 1H), 2.08 (s, 3H), 2.01 (s, 3H), 1.72 - 1.62 (m, 1H), 1.54 (s, 3H), 0.54 - 0.44 (m, 1H), 0.30 - 0.21 (m, 2H), 0.16 - 0.05 (m, 1H). 19 F NMR (282 MHz, DMSO-d6) δ -120.16, -120.18, -122.35, -122.37.

[0249] Example 14D: LC-MS: (ES + H, m / z): [M + H] + = 554.95. 1 1H NMR (300 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.60 (d, 1H), 8.16 - 8.03 (m, 1H), 7.87 (dd, 1H), 7.80 (s, 1H), 7.66 (dd, 1H), 6.80 (s, 1H), 6.43 (t, 1H), 5. 48 (d, 2H), 4.96 (s, 1H), 2.08 (s, 3H), 2.01 (s, 3H), 1.73 - 1.62 (m, 1H), 1.53 (s, 3H), 0.52 - 0.42 (m, 1H), 0.31 - 0.21 (m, 2H), 0.17 - 0.07 (m, 1H). 19 F NMR (282 MHz, DMSO - d6) δ - 120.16, - 120.18, - 122.35, - 122.37. Example 15A, 15B

Chemical formula

[0250] To a stirred mixture of 3 - bromo - 2 - methoxy - 4 - methylpyridine (2.00 g, 9.89 mmol, 1.00 equiv) in MeOH (5 mL), Pd(dppf)Cl2 (0.72 g, 0.99 mmol, 0.10 equiv) and DIEA (3.84 g, 29.69 mmol, 3.00 equiv) were added at room temperature under an atmosphere of carbon monoxide (20 atm). The resulting mixture was stirred at 110 °C for 24 h. The reaction was poured into water at room temperature. The aqueous layer was extracted with CH2Cl2 (3 × 20 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 2 - methoxy - 4 - methylpyridine - 3 - carboxylate (480 mg, 26.76%) as a yellow oil. LC - MS: (ES + H, m / z): [M + H] + = 181.9. 1 1H NMR (300 MHz, DMSO - d6) δ 8.12 (d, 1H), 6.97 - 6.92 (m, 1H), 3.85 (s, 3H), 3.83 (s, 3H), 2.23 (s, 3H). Step 2: Preparation of methyl 2 - oxo - 1H - pyridine - 3 - carboxylate:

[0251] To a stirred solution of methyl 2-methoxy-4-methylpyridine-3-carboxylate (710 mg, 3.91 mmol, 1.00 equiv) in MeCN, TMSI (1.57 g, 7.83 mmol, 2.00 equiv) was added dropwise at room temperature. The resulting mixture was stirred at 50 °C for an additional 4 h. The reaction was poured into water at room temperature. The aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford methyl 2-oxo-1H-pyridine-3-carboxylate (540 mg, 89.99%) as a yellow solid. LC-MS: (ES + H, m / z): [M + H] + = 168.1. 1 H NMR (400 MHz, DMSO-d6) δ 11.80 (s, 1H), 7.36 (d, 1H), 6.10 (d, 1H), 3.75 (s, 3H), 2.10 (s, 3H). Step 3: Preparation of 3-(2-hydroxypropan-2-yl)-4-methyl-1H-pyridin-2-one:

[0252] To a stirred solution of methyl 4-methyl-2-oxo-1H-pyridine-3-carboxylate (440 mg, 2.63 mmol, 1.00 equiv) in THF (5 mL), 1 M bromo(methyl)magnesium in THF (26 mL, 26.32 mmol, 10.00 equiv) was added dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C for an additional 2 h. The reaction was quenched with saturated NH4Cl (aqueous solution) at 0 °C. The aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford 3-(2-hydroxypropan-2-yl)-4-methyl-1H-pyridin-2-one (300 mg, 68.16%) as a white solid. LC-MS: (ES + H, m / z): [M + H] + = 168.3. 11H NMR (300 MHz, DMSO-d6) δ 11.68 (s, 1H), 7.42 (s, 1H), 7.20 (d, 1H), 6.08 (d, 1H), 2.31 (s, 3H), 1.47 (s, 6H). Step 4: Preparation of 3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2'-[3-(2-hydroxypropan-2-yl)-4-methyl-2-oxopyridin-1-yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one:

[0253] To a stirred mixture of 3-(2-hydroxypropan-2-yl)-4-methyl-1H-pyridin-2-one (300 mg, 1.79 mmol, 1.50 equiv) and (2E)-3-{3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-6-methyl-2-oxopyridin-1-yl}pent-2-ene-1-carboximidoyl bromide (534 mg, 1.19 mmol, 1.00 equiv) in 1,4-dioxane (8 mL), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (68 mg, 0.47 mmol, 0.40 equiv), K2CO3 (330 mg, 2.39 mmol, 2.00 equiv) and CuI (45 mg, 0.23 mmol, 0.20 equiv) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for an additional 2 h. The reaction was poured into water at room temperature. The aqueous layer was extracted with EtOAc (4 × 30 mL). The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC to give 3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2'-[3-(2-hydroxypropan-2-yl)-4-methyl-2-oxopyridin-1-yl]-5',6-dimethyl-[1,4'-bipyridin]-4--2-one (380 mg, 58.51%) as a white solid. LC-MS: (ES + H, m / z): [M + 2 + H] + = 545.2. Procedure 5: Preparation of rel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2’-[3-(2-hydroxypropan-2-yl)-4-methyl-2-oxopyridin-1-yl]-5’,6-dimethyl-[1,4’-bipyridin]-2-one and rel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2’-[3-(2-hydroxypropan-2-yl)-4-methyl-2-oxopyridin-1-yl]-5’,6-dimethyl-[1,4’-bipyridin]-2-one: The racemate (300 mg) was separated by preparative chiral HPLC to give Example 15A (130.3 mg, purity 97.7%, ee = 100%) as a white solid and Example 15B (130.0 mg, purity 98.3%, ee = 100%) as a white solid.

[0254] Example 15A: LC-MS: (ES + H, m / z): [M + H] + = 543.0. 1 H NMR (400 MHz, DMSO-d6) δ 8.66 (s, 1H), 8.60 (d, 1H), 8.11 - 8.06 (m, 1H), 7.77 - 7.71 (m, 2H), 6.80 (s, 1H), 6.21 (d, 1H), 5.89 (s, 1H), 5.48 (d, 2H), 2.45 (s, 3H), 2.07 (s, 3H), 1.99 (s, 3H), 1.54 (s, 3H), 1.53 (s, 3H). 19 F NMR (377 MHz, DMSO-d6) δ -120.16, -120.18, -122.36, -122.38.

[0255] Example 15B: LC-MS: (ES + H, m / z): [M + H] + = 543.1. 1 H NMR (400 MHz, DMSO-d6) δ 8.66 (s, 1H), 8.60 (d, 1H), 8.11 - 8.06 (m, 1H), 7.77 - 7.71 (m, 2H), 6.80 (s, 1H), 6.21 (d, 1H), 5.89 (s, 1H), 5.48 (d, 2H), 2.45 (s, 3H), 2.07 (s, 3H), 1.99 (s, 3H), 1.54 (s, 3H), 1.53 (s, 3H). 19 19F NMR (377 MHz, DMSO-d6) δ -120.16, -120.18, -122.35, -122.37. Examples 16A, 16B [Chemical formula] Step 1: Preparation of 5'-bromo-4-hydroxy-2',6-dimethyl-[1,3'-bipyridin]-2-one:

[0256] A solution of 5-bromo-2-methylpyridin-3-amine (10.00 g, 53.46 mmol, 1.00 equivalent) and 2,2-dimethyl-6-(2-oxopropyl)-1,3-dioxin-4-one (19.70 g, 106.92 mmol, 2.00 equivalents) in 1,4-dioxane (100 mL) was stirred at 80 °C for 2 hours under a nitrogen atmosphere. To the above mixture, H2SO4 (3.99 mL, 74.85 mmol, 1.40 equivalents) was added dropwise at 0 °C. The resulting mixture was stirred at 80 °C for an additional 2 hours under a nitrogen atmosphere. The mixture was brought to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in water (50 mL) and Et2O (100 mL). The precipitated solid was collected by filtration and washed with Et2O (3 × 10 mL) to obtain 5'-bromo-4-hydroxy-2',6-dimethyl-[1,3'-bipyridin]-2-one (15.00 g, 95.06%) as a white solid. LC-MS: (ES + H, m / z): [M + H] + = 294.9. Step 2: Preparation of 5'-bromo-4-[(3,5-difluoropyridin-2-yl)methoxy]-2',6-dimethyl-[1,3'-bipyridin]-2-one:

[0257] A stirred mixture of 5'-bromo-4-hydroxy-2',6-dimethyl-[1,3'-bipyridin]-2-one (3.00 g, 10.16 mmol, 1.00 equiv) and 2-(chloromethyl)-3,5-difluoropyridine (3.32 g, 20.33 mmol, 2.00 equiv) in DMF (70 mL) was added with 18-crown-6 (0.81 g, 3.06 mmol, 0.30 equiv) and K2CO3 (7.02 g, 50.79 mmol, 5.00 equiv) at r.t. The resulting mixture was stirred at 60 °C for 3 h under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was filtered, and the filter cake was washed with DCM (3 × 50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5'-bromo-4-[(3,5-difluoropyridin-2-yl)methoxy]-2',6-dimethyl-[1,3'-bipyridin]-2-one (1.90 g, 44.27%) as a pale yellow solid. LC-MS: (ES + H, m / z): [M + H] + = 422.0. Step 3: Preparation of 5'-bromo-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2',6-dimethyl-[1,3'-bipyridin]-2-one:

[0258] To a stirred solution of 5'-bromo-4-[(3,5-difluoropyridin-2-yl)methoxy]-2',6-dimethyl-[1,3'-bipyridin]-2-one (1.70 g, 4.02 mmol, 1.00 equiv) and NCS (537 mg, 4.02 mmol, 1.00 equiv) in i-PrOH (9 mL) was added 2,2-dichloroacetic acid (51 mg, 0.40 mmol, 0.10 equiv) dropwise at room temperature. The resulting mixture was stirred at 60 °C for 2 h under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The precipitated solid was collected by filtration and washed with hexane (3 × 10 mL). Thereby, 5'-bromo-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2',6-dimethyl-[1,3'-bipyridin]-2-one (880 mg, 47.86%) was obtained as a white solid. LC-MS: (ES + H, m / z): [M + H] +=457.9。 Step 4: Preparation of 5’-{3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-6-methyl-2-oxopyridin-1-yl}-3-(2-hydroxypropan-2-yl)-6’-methyl-[1,3’-bipyridin]-2-one:

[0259] To a stirred mixture of 5’-bromo-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2’,6-dimethyl-[1,3’-bipyridin]-2-one (700 mg, 1.53 mmol, 1.00 equiv) and 3-(2-hydroxypropan-2-yl)-1H-pyridin-2-one (469 mg, 3.06 mmol, 2.00 equiv) in 1,4-dioxane (14 mL) were added CuI (58 mg, 0.30 mmol, 0.20 equiv), K2CO3 (423 mg, 3.06 mmol, 2.00 equiv), and N1,N2-dimethylcyclohexane-1,2-diamine (87 mg, 0.61 mmol, 0.40 equiv). The resulting mixture was stirred at 90 °C for 3 h under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was filtered and the filter cake was washed with EtOAc (3 × 15 mL). The filtrate was poured into water (60 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (80 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was isolated by preparative HPLC to give 5’-{3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-6-methyl-2-oxopyridin-1-yl}-3-(2-hydroxypropan-2-yl)-6’-methyl-[1,3’-bipyridin]-2-one (303 mg, 37.3%) as a white solid. LC-MS: (ES + H, m / z): [M + H] + =529.3。 Process 5: Preparation of rel-5’-{3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-6-methyl-2-oxopyridin-1-yl}-3-(2-hydroxypropan-2-yl)-6’-methyl-[1,3’-bipyridin]-2-one and rel-5’-{3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-6-methyl-2-oxopyridin-1-yl}-3-(2-hydroxypropan-2-yl)-6’-methyl-[1,3’-bipyridin]-2-one:

[0260] 5’-{3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-6-methyl-2-oxopyridin-1-yl}-3-(2-hydroxypropan-2-yl)-6’-methyl-[1,3’-bipyridin]-2-one (290 mg) was separated by preparative chiral HPLC to give Example 16A (90.1 mg, purity 97.1%, ee = 100.0%) and Example 16B (66.3 mg, purity 98.6%, ee = 100.0%) as white solids.

[0261] Example 16A: LC-MS: (ES + H, m / z): [M + H] + = 529.0. 1 H NMR (300 MHz, DMSO-d6) δ 8.67 (d, 1H), 8.60 (d, 1H), 8.15 - 8.05 (m, 1H), 8.02 (d, 1H), 7.76 - 7.65 (m, 2H), 6.80 (s, 1H), 6.42 (t, 1H), 5.49 (d, 2H), 5.25 (s, 1H), 2.26 (s, 3H), 2.01 (s, 3H), 1.47 (s, 3H), 1.46 (s, 3H). 19 F NMR (282 MHz, DMSO-d6) δ -120.13, -120.16, -122.34, -122.37.

[0262] Example 16B: LC-MS: (ES + H, m / z): [M + H] + = 529.0. 1 H NMR (300 MHz, DMSO-d6) δ 8.67 (d, 1H), 8.60 (d, 1H), 8.16 - 8.05 (m, 1H), 8.02 (d, 1H), 7.77 - 7.66 (m, 2H), 6.81 (s, 1H), 6.42 (t, 1H), 5.49 (d, 2H), 5.26 (s, 1H), 2.26 (s, 3H), 2.01 (s, 3H), 1.47 (s, 3H), 1.46 (s, 3H). 19 F NMR (282 MHz, DMSO-d6) δ -120.13, -120.15, -122.33, -122.36. Examples 17A, 17B

Chemical Structure

[0263] To a stirred solution of 3-bromo-1H-pyridin-2-one (6.00 g, 34.48 mmol, 1.00 equiv) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (23.18 g, 137.93 mmol, 4.00 equiv) in 1,4-dioxane (60 mL) and H2O (10 mL), K2CO3 (9.53 g, 68.96 mmol, 2.00 equiv) and Pd(dppf)Cl2 (3.78 g, 5.17 mmol, 0.15 equiv) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 2 h. The reaction mixture was poured into water, and the aqueous layer was extracted with EtOAc (3 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-(prop-1-en-2-yl)-1H-pyridin-2-one (1.2 g, 11.1%, purity 50%) as a yellow solid. LC-MS: (ES + H, m / z): [M + H]+ = 135.9. Step 2: Preparation of 3-(prop-1-en-2-yl)-1H-pyridin-2-one:

[0264] To a stirred mixture of 3-(prop-1-en-2-yl)-1H-pyridin-2-one (1.00 g) in DCM (10 mL), TFA (10 mL) and SiH(Et)3 (5 mL) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 24 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure to give 3-(prop-1-en-2-yl) -1H-pyridin-2-one (2.00 g, crude). The crude product was used directly in the next step without further purification. LC-MS: (ES + H, m / z): [M + H]+ = 138.1. Step 3: Preparation of 3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2'-(3-isopropyl-2-oxopyridin-1-yl)-5',6-dimethyl-[1,4'-bipyridin]-2-one:

[0265] To a stirred mixture of 3-isopropyl-1H-pyridin-2-one (600 mg, 4.38 mmol, 2.00 equiv) and 2'-bromo-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one (1.00 g, 2.19 mmol, 1.00 equiv) in 1,4-dioxane (6 mL), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (624 mg, 4.38 mmol, 2.00 equiv), CuI (835 mg, 4.38 mmol, 2.00 equiv) and K2CO3 (597 mg, 4.38 mmol, 2.00 equiv) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 2 h. The mixture was cooled to room temperature. The reaction mixture was poured into water (30 mL), and the aqueous layer was extracted with EtOAc (3 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the crude product, which was further purified by preparative HPLC to give 3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2'-(3-isopropyl-2-oxopyridin-1-yl)-5',6-dimethyl-[1,4'-bipyridin]-2-one (220 mg, 69.4%) as a white solid. LC-MS: (ES + H, m / z): [M + H] + = 513.2. Step 4: Preparation of rel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2'-(3-isopropyl-2-oxopyridin-1-yl)-5',6-dimethyl-[1,4'-bipyridin]-2-one and rel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2'-(3-isopropyl-2-oxopyridin-1-yl)-5',6-dimethyl-[1,4'-bipyridin]-2-one:

[0266] The racemate (180 mg) was separated by preparative chiral HPLC to give Example 17A (63.2 mg, purity 99.7%, ee = 100%) and Example 17B (62.0 mg, purity 96.3%, ee = 100%) as white solids.

[0267] Example 17A: LC-MS: (ES + H, m / z): [M + H] + = 513.1. 1 H NMR (300 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.60 (d, 1H), 8.12 - 8.06 (m, 1H), 7.84 - 7.81 (m, 2H), 7.38 - 7.36 (m, 1H), 6.81 (s, 1H), 6.40 - 6.35 (m, 1H), 5.49 (d, 2H), 3.09 - 3.00 (m, 1H), 2.07 (s, 3H), 2.01 (s, 3H), 1.16 - 1.13 (m, 6H). 19 F NMR (282 MHz, DMSO-d6) δ -120.16, -120.18, -122.36, -122.38.

[0268] Example 17B: LC-MS: (ES + H, m / z): [M + H] + = 512.95. 1 H NMR (300 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.60 (d, 1H), 8.13 - 8.06 (m, 1H), 7.84 - 7.81 (m, 2H), 7.38 - 7.36 (m, 1H), 6.80 (s, 1H), 6.40 - 6.35 (m, 1H), 5.49 (d, 2H), 3.09 - 3.00 (m, 1H), 2.07 (s, 3H), 2.01 (s, 3H), 1.16 - 1.13 (m, 6H). 19 F NMR (282 MHz, DMSO-d6) δ -120.16, -120.18, -122.36, -122.38. Examples 18A, 18B

Chemical formula

[0269] A stirred solution of 2'-bromo-3-chloro-4-[(3,5-difluoropyridin-2-yl)(2H2)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one (25.00 g, 54.50 mmol, 1.00 equiv), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (3.10 g, 21.79 mmol, 0.40 equiv), K2CO3 (15.07 g, 109.00 mmol, 2.00 equiv) and CuI (2.08 g, 10.90 mmol, 0.20 equiv) in dioxane (210 mL) was added 3-(2-hydroxypropan-2-yl)-1H-pyridin-2-one (26.72 g, 174.43 mmol, 2.00 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 3 h under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was filtered and the filter cake was washed with ethyl acetate (3 × 100 mL). The filtrate was diluted with ethyl acetate (2 L) and washed with water (10% NH3, 3 × 1 L). The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the crude product (23.88 g) as a pale yellow solid, which was further purified by recrystallization from ACN. The material was dissolved in ACN at 80 °C and then cooled to room temperature for 2 h and maintained at 4 °C overnight. The precipitated solid was collected by filtration and washed with cold ACN (4 × 20 mL) to give 3-chloro-4-((3,5-difluoropyridin-2-yl)(2H2)methoxy]-2'-[3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-5',6'-dimethyl-[1,4-bipyridin]-2-one (18.21 g, yield 62.8%, purity 97.2%) as a white solid. LC-MS: (ES + H, m / z): [M + H] + = 531.1。 1 H NMR (300 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.60 (d, 1H), 8.09 (ddd, 1H), 7.86 (dd, 1H), 7.80 (s, 1H), 7.70 (dd, 1H), 6.81 (d, 1H), 6.43 (t, 1H), 5.24 (s, 1H), 2.08 (s, 3H), 2.01 (s, 3H), 1.48 (s, 3H), 1.47 (s, 3H). Step 2: Preparation of rel-3”-chloro-4”-((3,5-difluoropyridin-2-yl)methoxy-d2)-3-(2-hydroxypropan-2-yl)-5’,6”-dimethyl-2H,2’’H-[1,2’:4’,1”-terpyridine]-2,2”-dione (Example 18A):

[0270] The racemate (65.00 g) was separated by preparative chiral-SFC. The pure fractions were concentrated under reduced pressure to obtain a solid, which was redissolved in ACN and then concentrated to dryness. The product was suspended in water (120 mL) at 50 °C for 30 minutes, then brought to room temperature and held at 4 °C for 20 minutes, and the precipitated solid was collected to give rel-3”-chloro-4”-((3,5-difluoropyridin-2-yl)methoxy-d2)-3-(2-hydroxypropan-2-yl)-5’,6”-dimethyl-2H,2’’H-[1,2’:4’,1”-terpyridine]-2,2”-dione (Example 18A: 29.42 g, purity 98.4%, deuterium purity 97.8%, ee = 100%) as a white solid, and Example 18B (approx. 30.40 g).

[0271] 30 g of isomer 2 (Example 18B) in dioxane (200 mL) was heated at 100 °C for 24 hours, and the resulting mixture was concentrated to obtain a racemate (approx. 30 g), which was combined with another 6 g from the previous mother liquor and then further separated by preparative-chiral-SFC. The pure fractions were concentrated under reduced pressure to obtain a solid, which was redissolved in ACN and then concentrated to dryness to give rel-3”-chloro-4”-((3,5-difluoropyridin-2-yl)methoxy-d2)-3-(2-hydroxypropan-2-yl)-5’,6”-dimethyl-2H,2’’H-[1,2’:4’,1”-terpyridine]-2,2”-dione (Example 18A: 15.10 g, purity 99.2%, deuterium purity 97.8%) as a white solid, and Example 18B (approx. 15.40 g, white solid).

[0272] Two batches of Example 18A were combined (44.52 g), and then a co-solvent of IPA and water (440 mL, V IPA / V H2OIt was suspended in (1:6), the slurry was stirred at room temperature for 30 minutes, then seeds were added, and the resulting mixture was stirred for an additional 48 hours, then stored at 4 °C for 30 minutes. The precipitated solid was collected and dried to obtain rel-3”-chloro-4”-((3,5-difluoropyridin-2-yl)methoxy-d2)-3-(2-hydroxypropan-2-yl)-5’,6”-dimethyl-2H,2’’H-[1,2’:4’,1’’-terpyridine]-2,2’’-dione (Example 18A: 41.62 g, purity 99.3%, deuterium purity 97.9%, ee = 100%).

[0273] Example 18A: LC-MS: (ES+H, m / z): [M+H] + =531.15. 1 H NMR (300 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.61 (d, 1H), 8.16 - 8.03 (m, 1H), 7.86 (dd, 2.1 Hz, 1H), 7.80 (s, 1H), 7.70 (dd, 1H), 6.81 (s, 1H), 6.43 (t, 1H), 5.24 (s, 1H), 2.08 (s, 3H), 2.01 (s, 3H), 1.47 (d, 6H). 19 F NMR (282 MHz, DMSO-d6) δ -120.22, -120.24, -122.28, -122.31. Examples 19A, 19B

Chemical Structure

[0274] A mixture of 2'-bromo-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one (25.00 g, 54.50 mmol, 1.00 eq), 3-(2-hydroxypropan-2-yl)-1H-pyrazin-2-one (25.21 g, 163.51 mmol, 3.00 eq), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (1.55 g, 10.90 mmol, 0.20 eq), K2CO3 (15.07 g, 109.00 mmol, 2.00 eq), and CuI (1.04 g, 5.45 mmol, 0.10 eq) was stirred at 80 °C for 2 h under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with EtOAc (500 mL). The resulting mixture was washed with water (10% NH3·H2O, 5 × 300 mL). The combined organic layers were washed with brine (500 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and the pure fractions were concentrated under reduced pressure to give the crude product (21.5 g) as a yellow solid. The crude product was recrystallized from ACN (150 mL) to give 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2'-(3-(2-hydroxypropan-2-yl)-2-oxopyridin-1(2H)-yl)-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one (16.50 g, 56.91%) as a pale yellow solid. LC-MS: (ES+H, m / z): [M+H] + = 532.3. Step 2: Preparation of rel-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2'-(3-(2-hydroxypropan-2-yl)-2-oxopyridin-1(2H)-yl)-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one and rel-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2'-(3-(2-hydroxypropan-2-yl)-2-oxopyridin-1(2H)-yl)-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one:

[0275] The racemate (80.00 g) was separated by preparative chiral-SFC. The pure fractions were concentrated under reduced pressure to obtain the crude product and Example 19B (about 35.00 g). The crude product was redissolved in ACN and then concentrated to dryness. The solid was suspended in water (150 mL), stirred at 50 °C for 30 minutes, then brought to room temperature, and the precipitated solid was collected and dried to obtain Example 19A as a pale yellow solid (33.60 g, purity 98.2%, deuterium purity 98.1%, ee = 99.8%).

[0276] 35 g of isomer 2 (Example 19B) in dioxane (200 mL) was heated at 100 °C for 24 hours. The resulting mixture was concentrated to obtain the racemate (about 35 g), which was then further separated by preparative chiral-SFC. The pure fractions were concentrated under reduced pressure to obtain a solid, which was redissolved in ACN and then concentrated to dryness to obtain rel-3”-chloro-4”-((3,5-difluoropyridin-2-yl)methoxy-d2)-3-(2-hydroxypropan-2-yl)-5’,6”-dimethyl-2H,2’’H-[1,2’:4’,1”-terpyridine]-2,2”-dione (Example 19A: 16.1 g, purity 98.0%, deuterium purity 97.7%, ee = 100.0%) as a white solid and Example 19B (about 15.20 g, yellow solid).

[0277] Two batches of Example 19A were combined (49.51 g). The product was redissolved in ACN and then concentrated to dryness. The product was suspended in water (150 mL), stirred at 50 °C for 30 minutes, then brought to room temperature, and the precipitated solid was collected to obtain (Example 19A: purity 98.0%, deuterium purity 97.7%, ee = 100.0%) as a pale yellow solid.

[0278] Example 19A: LC-MS: (ES + H, m / z): [M + H] + = 532.25. 11H NMR (400 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.60 (d, 1H), 8.13 - 8.07 (m, 1H), 8.00 (d, 1H), 7.94 (s, 1H), 7.48 (d, 1H), 6.82 (d, 1H), 5.13 (s, 1H), 2.11 (s, 3H), 2.01 (s, 3H), 1.51 (s, 6H). 19 19F NMR (377 MHz, DMSO-d6) δ -120.25, -120.27, -122.32, -122.34.

[0279] Example 19B: LC-MS: (ES + H, m / z): [M + H]+ = 532.3. 1 H 1H NMR (400 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.60 (d, 1H), 8.13 - 8.07 (m, 1H), 8.00 (d, 1H), 7.94 (s, 1H), 7.48 (d, 1H), 6.82 (d, 1H), 5.13 (s, 1H), 2.11 (s, 3H), 2.01 (s, 3H), 1.51 (s, 6H). 19F NMR (377 MHz, DMSO-d6) δ -120.25, -120.27, -122.32, -122.34. Examples 20A, 20B

Chem.

[0280] A mixture of 2'-bromo-3-chloro-4-[(5-chloro-3-fluoropyridin-2-yl)(2H2)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one (15.00 g, 31.57 mmol, 1.00 eq), 3-(2-hydroxypropan-2-yl)-1H-pyrazin-2-one (9.73 g, 63.14 mmol, 2.00 eq), K2CO3 (8.73 g, 63.14 mmol, 2.00 eq), CuI (1.20 g, 6.31 mmol, 0.20 eq) and (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (1.80 g, 12.62 mmol, 0.40 eq) was stirred at 80 °C for 2 h under a nitrogen atmosphere. The mixture was warmed to room temperature. The resulting mixture was diluted with ethyl acetate (1500 mL) and washed with water 10% NH3 (3 × 500 mL). The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the crude product (13 g) as a white solid. The crude product was recrystallized from DCM (20 mL) and ACN (40 mL) to give 3-chloro-4-[(5-chloro-3-fluoropyridin-2-yl)(2H2)methoxy]-2'-[3-(2-hydroxypropan-2-yl)-2-oxopyrazin-1-yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one (9.26 g, 53.49%) as a white solid. LC-MS: (ES + H, m / z): [M + H] + = 548.2。 1 H NMR (400 MHz, DMSO-d6) δ 8.74 (s, 1H), 8.61 (dd, 1H), 8.24 (dd, 1H), 8.00 (d, 1H), 7.94 (s, 1H), 7.47 (d, 1H), 6.79 (d, 1H), 5.12 (s, 1H), 2.10 (s, 3H), 2.00 (s, 3H), 1.50 (s, 6H). Process 2: Preparation of rel-3-chloro-4-((5-chloro-3-fluoropyridin-2-yl)methoxy-d2)-2'-(3-(2-hydroxypropan-2-yl)-2-oxopyrazin-1(2H)-yl)-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one and rel-3-chloro-4-((5-chloro-3-fluoropyridin-2-yl)methoxy-d2)-2'-(3-(2-hydroxypropan-2-yl)-2-oxopyrazin-1(2H)-yl)-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one:

[0281] The racemate (9.20 g) was separated by preparative chiral SFC to give rel-3-chloro-4-((5-chloro-3-fluoropyridin-2-yl)methoxy-d2)-2'-(3-(2-hydroxypropan-2-yl)-2-oxopyrazin-1(2H)-yl)-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one (Example 20A: 3.47 g, purity 98.6%, deuterium purity 96.5%, ee = 100%) as a white solid, and rel-3-chloro-4-((5-chloro-3-fluoropyridin-2-yl)methoxy-d2)-2'-(3-(2-hydroxypropan-2-yl)-2-oxopyrazin-1(2H)-yl)-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one (Example 20B: 3.55 g, purity 97.2%, deuterium purity 96.3%, ee = 100%) as a white solid.

[0282] Example 20A: LC-MS: (ES + H, m / z): [M + H] + = 548.1. 1 H NMR (400 MHz, DMSO-d6) δ 8.74 (s, 1H), 8.61 (dd, 1H), 8.24 (dd, 1H), 8.00 (d, 1H), 7.94 (s, 1H), 7.47 (d, 1H), 6.79 (s, 1H), 5.12 (s, 1H), 2.10 (s, 3H), 2.00 (s, 3H), 1.51 (s, 6H). 19 F NMR (377 MHz, DMSO-d6) δ -121.68.

[0283] Example 20B: LC-MS: (ES + H, m / z): [M + H] + = 548.0 1 H NMR (400 MHz, DMSO-d6) δ 8.74 (s, 1H), 8.61 (dd, 1H), 8.24 (dd, 1H), 8.00 (d, 1H), 7.95 (s, 1H), 7.47 (d, 1H), 6.79 (s, 1H), 5.13 (s, 1H), 2.10 (s, 3H), 2.00 (s, 3H), 1.51 (s, 6H). 19 F NMR (377 MHz, DMSO-d6) δ -121.68 Examples 21A, 21B

Chemical formula

[0284] A mixture of 2'-bromo-3-chloro-4-[(5-chloro-3-fluoropyridin-2-yl)(2H2)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one (1.00 g, 2.10 mmol, 1.00 eq), 3-(2-hydroxypropan-2-yl)-1H-pyridin-2-one (0.64 g, 4.21 mmol, 2.00 eq), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (0.20 g, 1.05 mmol, 1.00 eq), K2CO3 (0.58 g, 4.21 mmol, 2.00 eq), and CuI (0.30 g, 2.10 mmol, 0.50 eq) was stirred at 80 °C for 2 h under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with EtOAc (20 mL). The resulting mixture was washed with water (10% NH3·H2O, 3 × 20 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC to give 3-chloro-4-[(5-chloro-3-fluoropyridin-2-yl)(2H2)methoxy]-2'-[3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one (680 mg, 58.6%) as a white solid. LC-MS: (ES + H, m / z): [M + H] + = 547.1. Step 2: Preparation of rel-3-chloro-4-[(5-chloro-3-fluoropyridin-2-yl)(2H2)methoxy]-2'-[3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one and rel-3-chloro-4-[(5-chloro-3-fluoropyridin-2-yl)(2H2)methoxy]-2'-[3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one pyrazol-1-yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one:

[0285] The racemate (680 mg) was separated by preparative-SFC to obtain Example 21A (103.8 mg, purity 98.1%, deuterium purity 97.6%, ee = 100.0%) and Example 21B (75.4 mg, purity 95.3%, deuterium purity 97.0%, ee = 100.0%) as white solids.

[0286] Example 21A: LC-MS: (ES + H, m / z): [M + H] + = 547.2. 1 H NMR (300 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.61 (s, 1H), 8.30 - 8.20 (m, 1H), 7.91 - 7.82 (m, 1H), 7.79 (s, 1H), 7.75 - 7.66 (m, 1H), 6.78 (s, 1H), 6.43 (t, 1H), 5.24 (s, 1H), 2.08 (s, 3H), 2.00 (s, 3H), 1.47 (s, 3H), 1.46 (s, 3H). 19 F NMR (282 MHz, DMSO-d6) δ -121.66.

[0287] Example 21B: LC-MS: (ES + H, m / z): [M + H] + = 547.3. 1 H NMR (300 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.61 (d, 1H), 8.32 - 8.19 (m, 1H), 7.91 - 7.82 (m, 1H), 7.79 (s, 1H), 7.75 - 7.66 (m, 1H), 6.78 (s, 1H), 6.43 (t, 1H), 5.23 (s, 1H), 2.08 (s, 3H), 2.00 (s, 3H), 1.47 (s, 3H), 1.46 (s, 3H). 19 F NMR (282 MHz, DMSO-d6) δ -121.67. Examples 22A, 22B

Chemical formula

[0288] A mixture of 2'-bromo-3-chloro-4-((3-chloro-5-fluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one (16.00 g, 33.67 mmol, 1 equiv), 3-(2-hydroxypropan-2-yl)-1H-pyrazin-2-one (454.26 mg, 2.94 mmol, 2.00 equiv), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (83.83 mg, 0.58 mmol, 0.40 equiv), CuI (0.80 g, 4.20 mmol, 0.20 equiv), and K2CO3 (407.22 mg, 2.94 mmol, 2.00 equiv) in 1,4-dioxane (100 mL) was stirred at 80 °C for 2 h under a nitrogen atmosphere. The mixture was warmed to room temperature. The resulting mixture was diluted with ethyl acetate (1000 mL) and washed with water (10% NH3, 3 × 500 mL). The organic layer was concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give the crude product (9.8 g). The crude product was recrystallized from ACN (50 mL) to give 3-chloro-4-((3-chloro-5-fluoropyridin-2-yl)methoxy-d2)-2'-(3-(2-hydroxypropan-2-yl)-2-oxopyrazin-1(2H)-yl)-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one (8.4 g, 43.67%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + = 548.0. 1 H NMR (400 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.68 (d, 1H), 8.25 (dd, 1H), 8.00 (d, 1H), 7.95 (s, 1H), 7.47 (d, 1H), 6.78 (d, 1H), 5.13 (s, 1H), 2.10 (s, 3H), 2.00 (s, 3H), 1.51 (s, 6H). Process 2: Preparation of rel-3-chloro-4-((3-chloro-5-fluoropyridin-2-yl)methoxy-d2)-2'-(3-(2-hydroxypropan-2-yl)-2-oxopyrazin-1(2H)-yl)-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one and 3-chloro-4-((3-chloro-5-fluoropyridin-2-yl)methoxy-d2)-2'-(3-(2-hydroxypropan-2-yl)-2-oxopyrazin-1(2H)-yl)-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one:

[0289] The racemate (8.40 g) was separated by preparative-chiral-SFC to give Example 22A (3.23 g, purity 98.2%, ee = 100%, [a] 25 D (c = 1.075, MeOH): -136.93)) as a white solid, and Example 22B (3.13 g, purity 95.0%, ee = 100%, [a] 25 D (c = 1.075, MeOH): +127.53) as a white solid.

[0290] Example 22A: LC-MS: (ES + H, m / z): [M + H] + = 548.2. 1 H NMR (300 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.68 (d, 1H), 8.25 (dd, 1H), 8.00 (d, 1H), 7.95 (s, 1H), 7.48 (d, 1H), 6.79 (s, 1H), 5.13 (s, 1H), 2.11 (s, 3H), 2.00 (s, 3H), 1.51 (s, 6H). 19 F NMR (282 MHz, DMSO-d6) δ -124.18, -124.20.

[0291] Example 22B: LC-MS: (ES + H, m / z): [M + H] + = 548.2. 1 H NMR (300 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.68 (d, 1H), 8.25 (dd, 1H), 8.00 (d, 1H), 7.96 (s, 1H), 7.48 (d, 1H), 6.79 (s, 1H), 5.13 (s, 1H), 2.11 (s, 3H), 2.00 (s, 3H), 1.51 (s, 6H). 19 19F NMR (282 MHz, DMSO-d6) δ -124.18, -124.20. Examples 23A, 23B [Chemical formula] Step 1: Preparation of 4’-{3-chloro-4-[(3-chloro-5-fluoropyridin-2-yl)(2H2)methoxy]-6-methyl-2-oxopyridin-1-yl}-3-(2-hydroxypropan-2-yl)-5’-methyl-[1,2’-bipyridin]-2-one:

[0292] A mixture of 2'-bromo-3-chloro-4-[(3-chloro-5-fluoropyridin-2-yl)(2H2)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one (600 mg, 1.26 mmol, 1.00 equiv), 3-(2-hydroxypropan-2-yl)-1H-pyridin-2-one (386 mg, 2.52 mmol, 2.00 equiv), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (71 mg, 0.50 mmol, 0.40 equiv), K2CO3 (349 mg, 2.52 mmol, 2.00 equiv), and CuI (48 mg, 0.25 mmol, 0.20 equiv) was stirred at 80 °C for 2 h under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with EtOAc (20 mL). The resulting mixture was washed with water (10% NH3·H2O, 3 × 20 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (550 mg) was isolated by preparative HPLC to give 4'-{3-chloro-4-[(3-chloro-5-fluoropyridin-2-yl)(2H2)methoxy]-6-methyl-2-oxopyridin-1-yl}-3-(2-hydroxypropan-2-yl)-5'-methyl-[1,2'-bipyridin]-2-one (550 mg, 79.57%) as a white solid. LC-MS: (ES+ H, m / z): [M + H] + = 547.0。 Step 2: Preparation of rel-4'-{3-chloro-4-[(3-chloro-5-fluoropyridin-2-yl)(2H2)methoxy]-6-methyl-2-oxopyridin-1-yl}-3-(2-hydroxypropan-2-yl)-5'-methyl-[1,2'-bipyridin]-2-one and rel-4'-{3-chloro-4-[(3-chloro-5-fluoropyridin-2-yl)(2H2)methoxy]-6-methyl-2-oxopyridin-1-yl}-3-(2-hydroxypropan-2-yl)-5'-methyl-[1,2'-bipyridin]-2-one:

[0293] The racemate (500 mg) was separated by preparative-SFC to obtain Example 23A (192.8 mg, purity 98.4%, deuterium purity 95.9%, ee = 100.0%) as a white solid and Example 23B (201.8 mg, purity 98.4%, deuterium purity 96.0%, ee = 100.0%) as a white solid.

[0294] Example 23A: LC-MS: (ES + H, m / z): [M + H] + = 547.00. 1 H NMR (400 MHz, DMSO-d6) δ 8.70 - 8.64 (m, 2H), 8.25 (dd, 1H), 7.86 (dd, 1H), 7.79 (s, 1H), 7.70 (dd, 1H), 6.77 (s, 1H), 6.42 (t, 1H), 5.22 (s, 1H), 2.08 (s, 3H), 2.00 (s, 3H), 1.47 (s, 3H), 1.46 (s, 3H). 19 F NMR (282 MHz, DMSO-d6) δ -124.16.

[0295] Example 23B: LC-MS: (ES + H, m / z): [M + H]+ = 547.05. 1 H NMR (400 MHz, DMSO-d6) δ 8.71 - 8.65 (m, 2H), 8.25 (dd, 1H), 7.86 (dd, 1H), 7.79 (s, 1H), 7.70 (dd, 1H), 6.77 (s, 1H), 6.42 (t, 1H), 5.23 (s, 1H), 2.08 (s, 3H), 2.00 (s, 3H), 1.47 (s, 3H), 1.46 (s, 3H). 19 F NMR (282 MHz, DMSO-d6) δ -124.16. Examples 24A, 24B

Chemical formula

[0296] A mixture of 2'-bromo-4-hydroxy-5',6-dimethyl-[1,4'-bipyridin]-2-one (1.32 g, 4.40 mmol, 1.00 equiv), 3-chloro-2-(chloromethyl)-5-fluoropyridine (2.43 g, 13.21 mmol, 3.00 equiv), 18-crown-6 (349 mg, 1.32 mmol, 0.30 equiv), and K2CO3 (3.71 g, 26.43 mmol, 6.00 equiv) in DMF (8 mL) was stirred at 60 °C for 1 h under a nitrogen atmosphere. The resulting mixture was diluted with ethyl acetate (300 mL) and washed with 3 × 100 mL of H2O. The residue was concentrated under reduced pressure and purified by silica gel column chromatography to give 2'-bromo-4-[(3-chloro-5-fluoropyridin-2-yl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one (1.30 g, 66.2%) as a yellow oil. LC-MS: (ES+ H, m / z): [M + H] + = 440.1。 1 H NMR (400 MHz, DMSO-d6) δ 8.68 - 8.65 (m, 1H), 8.48 (s, 1H), 8.25 - 8.20 (m, 1H), 7.74 (s, 1H), 6.16 - 6.12 (m, 1H), 6.02 (d, 1H), 5.26 (s, 2H), 1.97 (s, 3H), 1.86 (s, 3H). Step 2: Preparation of 2'-bromo-3-chloro-4-[(3-chloro-5-fluoropyridin-2-yl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one:

[0297] 2'-Bromo-4-[(3-chloro-5-fluoropyridin-2-yl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one (1.10 g, 2.50 mmol, 1.00 equiv), NCS (401 mg, 3.01 mmol, 1.20 equiv), 2,2-dichloroacetic acid (323 mg, 2.50 mmol, 1.00 equiv) were added to IPA (5 mL) at room temperature. The resulting mixture was stirred at 60 °C for 2 h under a nitrogen atmosphere. The mixture was brought to room temperature. The resulting mixture was filtered and the filter cake was washed with IPA (3 × 5 mL). The filtrate was concentrated under reduced pressure. Thereby, 2'-bromo-3-chloro-4-[(3-chloro-5-fluoropyridin-2-yl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one (810 mg, 68.2%) was obtained as a white solid. LC-MS: (ES + H, m / z): [M + H] + = 474.0。 1 H NMR (400 MHz, DMSO-d6) δ 8.67 (d, 1H), 8.52 (s, 1H), 8.25 (dd, 1H), 7.81 (s, 1H), 6.76 (s, 1H), 5.48 (d, 2H), 1.96 (s, 3H), 1.94 (s, 3H). Step 3: Preparation of 3-chloro-4-[(3-chloro-5-fluoropyridin-2-yl)methoxy]-2'-[3-(2-hydroxypropan-2-yl)-2-oxopyrazin-1- yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one:

[0298] A mixture of 2'-bromo-3-chloro-4-[(3-chloro-5-fluoropyridin-2-yl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one (725 mg, 1.53 mmol, 1.00 eq), 3-(2-hydroxypropan-2-yl)-1H-pyrazin-2-one (708 mg, 4.59 mmol, 3.00 eq), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (87 mg, 0.61 mmol, 0.40 eq), CuI (58 mg, 0.30 mmol, 0.20 eq), and K2CO3 (423 mg, 3.06 mmol, 2.00 eq) was stirred at 80 °C for 3 h under a nitrogen atmosphere. The resulting mixture was diluted with ethyl acetate (150 mL) and washed with 3 × 50 mL of 10% NH3·H2O. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain a crude product, which was further purified by preparative-HPLC. Thereby, 3-chloro-4-[(3-chloro-5-fluoropyridin-2-yl)methoxy]-2'-[3-(2-hydroxypropan-2-yl)-2-oxopyrazin-1-yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one (140 mg, 16.7%) was obtained as a white solid. LC-MS: (ES + H, m / z): [M + H] + = 546.2。 Step 4: Preparation of rel-3-chloro-4-[(3-chloro-5-fluoropyridin-2-yl)methoxy]-2'-[3-(2-hydroxypropan-2-yl)-2-oxopyrazin-1-yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one and rel-3-chloro-4-[(3-chloro-5-fluoropyridin-2-yl)methoxy]-2'-[3-(2-hydroxypropan-2-yl)-2-oxopyrazin-1-yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one:

[0299] 3-Chloro-4-[(3-chloro-5-fluoropyridin-2-yl)methoxy]-2'-[3-(2-hydroxypropan-2-yl)-2-oxopyrazin-1-yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one (140 mg) was separated by preparative-chiral-HPLC to give Example 24A (57.6 mg, purity 99.7%, ee = 100%) and Example 24B (42.6 mg, purity 99.6%, ee = 100.0%) as white solids.

[0300] Example 24A: LC-MS: (ES + H, m / z): [M + H] + = 546.00. 1 H NMR (300 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.68 (d, 1H), 8.26 (dd, 1H), 8.00 (d, 1H), 7.95 (s, 1H), 7.48 (d, 1H), 6.79 (s, 1H), 5.51 (s, 2H), 5.13 (s, 1H), 2.10 (s, 3H), 2.00 (s, 3H), 1.51 (s, 6H). 19 F NMR (282 MHz, DMSO-d6) δ -124.24.

[0301] Example 24B: LC-MS: (ES + H, m / z): [M + H] + = 546.00. 1 H NMR (300 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.68 (d, 1H), 8.26 (dd, 1H), 8.00 (d, 1H), 7.95 (s, 1H), 7.48 (d, 1H), 6.79 (s, 1H), 5.51 (s, 2H), 5.13 (s, 1H), 2.10 (s, 3H), 2.00 (s, 3H), 1.51 (s, 6H). 19 F NMR (282 MHz, DMSO-d6) δ -124.24. Examples 25A, 25B

Chemical Structure

[0302] A stirred solution of 2-chloro-5-methylpyridin-4-amine (20 g, 140.26 mmol, 1.00 equiv) and triiodomethane (82.84 g, 210.39 mmol, 1.5 equiv) in THF (200 mL) was added dropwise with tBuONO (21.7 g, 210.39 mmol, 1.5 equiv) at 0 °C under a nitrogen atmosphere. The mixture was stirred at room temperature for 1 h. The mixture was further stirred at 50 °C for 3 h under a nitrogen atmosphere. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2-chloro-4-iodo-5-methylpyridine (29 g, 81.57%) as a yellow solid. LC-MS: (ES + H, m / z): [M + H] + = 253.9. 1 H NMR (400 MHz, DMSO-d6) δ 8.26 (s, 1H), 8.01 (s, 1H), 2.33 (s, 3H). Step 2: Preparation of N-(2-chloro-5-methylpyridin-4-yl)-acetimidamide:

[0303] A mixture of 2-chloro-4-iodo-5-methylpyridine (29 g, 114.412 mmol, 1.00 equiv), acetimidamide hydrochloride (32.27 g, 343.236 mmol, 3 equiv), K2CO3 (55.34 g, 400.442 mmol, 3.5 equiv), and CuI (43.58 g, 228.82 mmol, 2 equiv) in DMF (70 mL) was stirred at 80 °C overnight under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with EtOAc (1000 mL). The organic layer was washed with saturated NaCl (aqueous solution) (3 × 500 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give N-(2-chloro-5-methylpyridin-4-yl)-acetimidamide (3 g, 14.28%) as a brown solid. LC-MS: (ES + H, m / z): [M + H] + = 184.0. 1 H NMR (400 MHz, DMSO-d6) δ 8.03 (s, 1H), 6.68 ( s, 1H), 6.66 - 6.03 (m, 2H), 1.97 (s, 3H), 1.86 (s, 3H). Step 3: Preparation of methyl (E)-3-((1-((2-chloro-5-methylpyridin-4-yl)amino)ethylidene)amino)-3-oxopropanoate:

[0304] To a stirred solution of N-(2-chloro-5-methylpyridin-4-yl)-acetimidamide (700 mg, 3.812 mmol, 1.00 equiv) and 4-methylmorpholine (771.10 mg, 7.624 mmol, 2 equiv) in DCM (10 mL), methyl-3-chloro-3-oxopropanoate (1040.85 mg, 7.624 mmol, 2 equiv) was added dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with saturated NaHCO3 (aqueous solution) (10 mL) at room temperature. The resulting mixture was poured into water (50 mL). The resulting mixture was also extracted with EtOAc (3 × 50 mL). The combined organic layers were quenched with saturated NaCl (aqueous solution) (50 mL) and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl (E)-3-((1-((2-chloro-5-methylpyridin-4-yl)amino)ethylidene)amino)-3-oxopropanoate (470 mg, 43.46%) as a brown solid. LC-MS: (ES + H, m / z): [M + H] + = 283.8. 1 H 1H NMR (400 MHz, DMSO-d6) δ 10.68 (s, 1H), 8.14 (s, 1H), 6.85 (s, 1H), 3.63 (s, 3H), 3.61 (s, 2H), 2.05 (s, 3H), 1.99 (s, 3H). Step 4: Preparation of 3-(2-chloro-5-methylpyridin-4-yl)-6-hydroxy-2-methylpyrimidin-4(3H)-one:

[0305] To a stirred solution of (E)-3-((1-((2-chloro-5-methylpyridin-4-yl)amino)ethylidene)amino)-3-oxopropanoate (2.8 g, 9.869 mmol, 1.00 equiv) in dioxane (20 mL), DBU (4.51 g, 29.607 mmol, 3 equiv) was added dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 4 h under a nitrogen atmosphere. The mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography to give 3-(2-chloro-5-methylpyridin-4-yl)-6-hydroxy-2-methylpyrimidin-4(3H)-one (2.1 g, 84.55%) as a brown solid. LC-MS: (ES + H, m / z): [M + H] + = 252.0. Step 5: Preparation of 3-(2-chloro-5-methylpyridin-4-yl)-6-[(3,5-difluoropyridin-2-yl)methoxy]-2-methylpyrimidin-4-one:

[0306] To a stirred mixture of 3-(2-chloro-5-methylpyridin-4-yl)-6-hydroxy-2-methylpyrimidin-4-one (3.80 g, 15.10 mmol, 1.00 equiv) and 2-(chloromethyl)-3,5-difluoropyridine (2.96 g, 18.12 mmol, 1.20 equiv) in DMF, K2CO3 (6.26 g, 45.30 mmol, 3.00 equiv) and 18-crown-6 (399 mg, 1.51 mmol, 0.10 equiv) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 60 °C for 3 h under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography to give 3-(2-chloro-5-methylpyridin-4-yl)-6-[(3,5-difluoropyridin-2-yl)methoxy]-2-methylpyrimidin-4-one (650 mg, 11.3%) as a yellow solid. LC-MS: (ES + H, m / z): [M + H] + = 379.0. Step 6: Preparation of 5-chloro-3-(2-chloro-5-methylpyridin-4-yl)-6-[(3,5-difluoropyridin-2-yl)methoxy]-2-methylpyrimidin-4-one:

[0307] To a stirred solution of 3-(2-chloro-5-methylpyridin-4-yl)-6-[(3,5-difluoropyridin-2-yl)methoxy]-2-methylpyrimidin-4-one (650 mg, 1.72 mmol, 1.00 equiv) and NCS (275 mg, 2.06 mmol, 1.20 equiv) in i-PrOH (2 mL) was added dichloroacetic acid (22 mg, 0.17 mmol, 0.10 equiv) dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 60 °C for 2 h under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The precipitated solid was collected by filtration and washed with i-PrOH (3 × 5 mL) to afford 5-chloro-3-(2-chloro-5-methylpyridin-4-yl)-6-[(3,5-difluoropyridin-2-yl)methoxy]-2-methylpyrimidin-4-one (310 mg, 43.7%) as a white solid. LC-MS: (ES + H, m / z): [M + H] + = 414.9. Step 7: Preparation of 4’-{5-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2-methyl-6-oxopyrimidin-1-yl}-3-(2-hydroxypropan-2-yl)-5’-methyl-[1,2’-bipyridin]-2-one:

[0308] To a stirred solution of 5-chloro-3-(2-chloro-5-methylpyridin-4-yl)-6-[(3,5-difluoropyridin-2-yl)methoxy]-2-methylpyrimidin-4-one (297 mg, 0.72 mmol, 1.00 equiv) and 3-(2-hydroxypropan-2-yl)-1H-pyridin-2-one (330 mg, 2.16 mmol, 3.00 equiv) in 1,4-dioxane (10 mL) were added CuI (137 mg, 0.72 mmol, 1.00 equiv), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (205 mg, 1.44 mmol, 2.00 equiv), NaI (215 mg, 1.44 mmol, 2.00 equiv) and K2CO3 (298 mg, 2.16 mmol, 3.00 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 24 h under a nitrogen atmosphere. The resulting mixture was diluted with EtOAc (50 mL). The resulting mixture was washed with 5% NH3.H2O (3 × 50 mL). The combined organic layers were washed with brine (50 mL) and then dried over Na2SO4. The solution was concentrated under reduced pressure. The residue was purified by preparative HPLC. This gave 4’-{5-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2-methyl-6-oxopyrimidin-1-yl}-3-(2-hydroxypropan-2-yl)-5’-methyl-[1,2’-bipyridin]-2-one (55 mg, 14.4%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + = 530.1. Step 8: Preparation of rel-4’-{5-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2-methyl-6-oxopyrimidin-1-yl}-3-(2-hydroxypropan-2-yl)-5’-methyl-[1,2’-bipyridin]-2-one and rel-4’-{5-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2-methyl-6-oxopyrimidin-1-yl}-3-(2-hydroxypropan-2-yl)-5’-methyl-[1,2’-bipyridin]-2-one:

[0309] 4’-{5-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2-methyl-6-oxopyrimidin-1-yl}-3-(2-hydroxypropan-2-yl)-5’-methyl-[1,2’-bipyridin]-2-one (55 mg) was separated by preparative-chiral-HPLC to obtain Example 25A (23.5 mg, purity 99.1%, ee = 100%) and Example 25B (19.6 mg, purity 98.7%, ee = 98.7%) as white solids.

[0310] Example 25A: LC-MS: (ES + H, m / z): [M + H] + = 530.10. 1 1H NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.57 (d, 1H), 8.08 - 8.02 (m, 1H), 7.98 (s, 1H), 7.85 (d, 1H), 7.70 (d, 1H), 6.43 (t, 1H), 5.63 - 5.59 (m, 2H) , 5.22 (s, 1H), 2.15 (s, 3H), 2.12 (s, 3H), 1.47 (s, 3H), 1.46 (s, 3H). 19 19F NMR (400 MHz, DMSO-d6) δ -120.38, -120.40, -123.00, -123.03.

[0311] Example 25B: LC-MS: (ES + H, m / z): [M + H] + = 530.10. 1 1H NMR (400 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.57 (d, 1H), 8.08 - 8.02 (m, 1H), 7.97 (s, 1H), 7.85 (d, 1H), 7.70 (d, 1H), 6.43 (t, 1H), 5.63 - 5.59 (m, 2H), 5.21 (s, 1H), 2.15 (s, 3H), 2.12 (s, 3H), 1.47 (s, 3H), 1.46 (s, 3H). 19 19F NMR (400 MHz, DMSO-d6) δ -120.38, -120.40, -123.01, -123.03. Examples 26A, 26B

Chemical formula

[0312] To a stirred mixture of 4-Fluoro-2-methoxypyridine-3-carboxylic acid (1.00 g, 5.84 mmol, 1.00 eq) in DMF (20 mL), iodoethane (1.37 g, 8.76 mmol, 1.50 eq) and K2CO3 (1.62 g, 11.68 mmol, 2.00 eq) were added under a nitrogen atmosphere at room temperature. The resulting mixture was stirred at 50 °C for 2 h under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with EtOAc (100 mL). The resulting mixture was washed with H2O (5 × 60 mL), then brine (100 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give ethyl 4-fluoro-2-methoxypyridine-3-carboxylate (1.00 g, crude) as a yellow solid. LC-MS: (ES + H, m / z): [M + H] + = 200.3 Step 2: Preparation of Ethyl 4-Fluoro-2-oxo-1H-pyridine-3-carboxylate:

[0313] To a stirred solution of ethyl 4-fluoro-2-methoxypyridine-3-carboxylate (900 mg, 4.51 mmol, 1.00 eq) in MeCN (15 mL), TMSI (3.62 g, 18.07 mmol, 4.00 eq) was added under a nitrogen atmosphere at room temperature. The resulting mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give ethyl 4-fluoro-2-oxo-1H-pyridine-3-carboxylate (800 mg, 95.6%) as a yellow solid. LC-MS: (ES + H, m / z): [M + H] + = 186.3。 Step 3: Preparation of 4-Fluoro-3-(2-hydroxypropan-2-yl)-1H-pyridin-2-one:

[0314] Ethyl 4-fluoro-2-oxo-1H-pyridine-3 in THF (70.00 mL) To a stirred solution of -carboxylate (700 mg, 3.78 mmol, 1.00 equiv), MeMgBr (3.7 mL, 3 M in 2-methyl-THF, 11.34 mmol, 3.00 equiv) was added dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 1 h under a nitrogen atmosphere. The reaction was quenched by adding saturated NH4Cl (aqueous solution) (20 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 × 100 mL). After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography. This gave 4-fluoro-3-(2-hydroxypropan-2-yl)-1H-pyridin-2-one (400 mg, 61.8%) as a white solid. LC-MS: (ES + H, m / z): [M + H] + = 172.3. Step 4: Preparation of 3-chloro-4-[(3,5-difluoropyridin-2-yl)(2H2)methoxy]-2’-[4-fluoro-3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-5’,6-dimethyl-[1,4’-bipyridin]-2-one:

[0315] To a stirred mixture of 2'-bromo-3-chloro-4-[(3,5-difluoropyridin-2-yl)(2H2)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one (500 mg, 1.09 mmol, 1.00 eq) and 4-fluoro-3-(2-hydroxypropan-2-yl)-1H-pyridin-2-one (373 mg, 2.180 mmol, 2.00 eq) in dioxane (10 mL), CuI (41 mg, 0.21 mmol, 0.20 eq), (1R,2R)-1-N,2-N-dimethylcyclohexane-1,2-diamine (62 mg, 0.43 mmol, 0.40 eq), and K2CO3 (301 mg, 2.18 mmol, 2.00 eq) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 3 h under a nitrogen atmosphere. The resulting mixture was diluted with EtOAc (50 mL). The combined organic layers were washed with brine (2 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC to give 3-chloro-4-[(3,5-difluoropyridin-2-yl)(2H2)methoxy]-2'-[4-fluoro-3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one (280 mg, 46.7%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + = 549.2. Step 5: Preparation of rel-3-chloro-4-[(3,5-difluoropyridin-2-yl)(2H2)methoxy]-2'-[4-fluoro-3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one and rel-3-chloro-4-[(3,5-difluoropyridin-2-yl)(2H2)methoxy]-2'-[4-fluoro-3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one

[0316] 3-Chloro-4-[(3,5-difluoropyridin-2-yl)(2H2)methoxy]-2’-[4-fluoro-3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-5’,6-dimethyl-[1,4’-bipyridin]-2-one (200 mg) was separated by preparative-chiral-HPLC to obtain Example 26A (80.6 mg, purity 99.4%, deuterium purity 97.3%, ee = 100%) and Example 26B (82.5 mg, purity 97.7%, deuterium purity 97.1%, ee = 99%) as white solids.

[0317] Example 26A: LC-MS: (ES + H, m / z): [M + H] + = 549.05. 1 H NMR (300 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.61 (d, 1H), 8.17 - 8.03 (m, 2H), 7.81 (s, 1H), 6.81 (d, 1H), 6.56 - 6.53 (m, 1H), 6.41 (s, 1H), 2.09 (s, 3H) , 2.03 (s, 3H), 1.52 (s, 3H), 1.50 (s, 3H). 19 F NMR (282 MHz, DMSO-d6) δ -91.28, -120.25, -120.27, -122.32, -122.35.

[0318] Example 26B: LC-MS: (ES + H, m / z): [M + H] + = 549.1. 1 H NMR (300 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.61 (d, 1H), 8.17 - 8.03 (m, 2H), 7.81 (s, 1H), 6.81 (d, 1H), 6.56 - 6.53 (m, 1H), 6.41 (s, 1H), 2.09 (s, 3H), 2.03 (s, 3H), 1.51 (s, 3H), 1.50 (s, 3H). 19 F NMR (282 MHz, DMSO-d6) δ -91.28, -120.25, -120.27, -122.32, -122.35. Examples 27A, 27B

Chemical formula

[0319] To a stirred mixture of 3-methoxy-2,2-dimethyl-3-oxopropanoic acid (2.00 g, 13.68 mmol, 1.00 equiv) and Et3N (1.52 g, 15.05 mmol, 1.10 equiv) in DME (20 mL) was added DPPA (4.14 g, 15.05 mmol, 1.10 equiv) dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 30 min under a nitrogen atmosphere. The resulting mixture was stirred at 90 °C for an additional 2 h under a nitrogen atmosphere. To the above mixture was added 2,2-dimethoxyethanamine (2.88 g, 27.37 mmol, 2.00 equiv) at room temperature. The resulting mixture was stirred at room temperature for an additional 2 h. The reaction mixture was poured into saturated NaHCO3 (aqueous solution) (20 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give methyl 2-{[(2,2-dimethoxyethyl)carbamoyl]amino}-2-methylpropanoate (2.20 g, crude) as a colorless liquid. LC-MS: (ES + H, m / z): [M + H] + = 249.1. Step 3: Preparation of methyl 2-methyl-2-(2-oxo-3H-imidazol-1-yl)propanoate:

[0320] To a stirred mixture of methyl 2-{[(2,2-dimethoxyethyl)carbamoyl]amino}-2-methylpropanoate (2.20 g, 8.86 mmol, 1.00 equiv) in THF (5 mL) was added TFA (2.5 mL) dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 70 °C for 1 h under a nitrogen atmosphere. The residue was purified by reverse-phase flash chromatography to give methyl 2-methyl-2-(2-oxo-3H-imidazol-1-yl)propanoate (1.00 g, 39.67%) as a white solid. LC-MS: (ES + H, m / z): [M + H] += 185.1. 1 1H NMR (300 MHz, DMSO-d6) δ 9.96 (s, 1H), 6.54 (dd, 1H), 6.35 (t, 1H), 3.59 (s, 3H), 1.52 (s, 6H). Step 4: Preparation of 1-(1-hydroxy-2-methylpropan-2-yl)-3H-imidazol-2-one:

[0321] To a stirred mixture of methyl 2-methyl-2-(2-oxo-3H-imidazol-1-yl)propanoate (600 mg, 3.25 mmol, 1.00 equiv) in THF (6 mL), LiAlH4 (247 mg, 6.51 mmol, 2.00 equiv) was added portionwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 30 min under a nitrogen atmosphere. The reaction was quenched with water at 0 °C. The resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give 1-(1-hydroxy-2-methylpropan-2-yl)-3H-imidazol-2-one (360 mg, crude) as a white solid. 1 1H NMR (300 MHz, DMSO-d6) δ 9.97 (s, 1H), 6.50 (dd, 1H), 6.35 (t, 1H), 5.28 (t, 1H), 3.68 (d, 2H), 1.42 (s, 6H). Step 5: Preparation of 3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2’-[3-(1-hydroxy-2-methylpropan-2-yl)-2-oxoimidazol-1-yl]-5’,6-dimethyl-[1,4’-bipyridin]-2-one:

[0322] A mixture of 2'-bromo-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one (500 mg, 1.09 mmol, 1.00 equiv), 1-(1-hydroxy-2-methylpropan-2-yl)-3H-imidazol-2-one (342 mg, 2.19 mmol, 2.00 equiv), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (62 mg, 0.43 mmol, 0.40 equiv), K2CO3 (302 mg, 2.19 mmol, 2.00 equiv), and CuI (41 mg, 0.21 mmol, 0.20 equiv) was stirred at 80 °C for 2 h under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with EtOAc (20 mL). The resulting mixture was washed with water (10% NH3·H2O, 3 × 20 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC to give 3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2'-[3-(1-hydroxy-2-methylpropan-2-yl)-2-oxoimidazol-1-yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one (305 mg, 52.37%) as a white solid. LC-MS: (ES+ H, m / z): [M + H] + = 532.25。 Step 6: Preparation of rel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2'-[3-(1-hydroxy-2-methylpropan-2-yl)-2-oxoimidazol-1-yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one and rel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2'-[3-(1-hydroxy-2-methylpropan-2-yl)-2-oxoimidazol-1-yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one:

[0323] The racemate (300 mg) was separated by preparative-chiral-SFC to give Example 27A( (91.3 mg, purity 98.1%, ee = 100.0%) was obtained as a white solid, and Example 27B (82.9 mg, purity 99.7%, ee = 99.5%) was obtained as a white solid.

[0324] Example 27A: LC-MS: (ES + H, m / z): [M + H] + = 532.2. 1 H NMR (400 MHz, DMSO-d6) δ 8.60 (d, 1H), 8.52 (s, 1H), 8.20 (s, 1H), 8.14 - 8.01 (m, 1H), 7.30 (d, 1H), 6.80 (s, 1H), 6.79 (d, 1H), 5.49 (d, 2H), 4.99 (t, 1H), 3.77 - 3.61 (m, 2H), 1.99 (s, 3H), 1.98 (s, 3H), 1.43 (s, 6H). 19 F NMR (377 MHz, DMSO-d6) δ -120.20, -120.22, -122.42, -122.44.

[0325] Example 27B: LC-MS: (ES + H, m / z): [M + H]+ = 532.1. 1 H NMR (400 MHz, DMSO-d6) δ 8.60 (d, 1H), 8.52 (s, 1H), 8.20 (s, 1H), 8.14 - 8.05 (m, 1H), 7.30 (d, 1H), 6.80 (s, 1H), 6.79 (d, 1H), 5.49 (d, 2H), 4.99 (t, 1H), 3.79 - 3.57 (m, 2H), 1.99 (s, 3H), 1.99 (s, 3H), 1.43 (s, 6H). 19 F NMR (377 MHz, DMSO-d6) δ -120.20, -120.22, -122.42, -122.44. Examples 28A, 28B

Chemical formula

[0326] To a stirred mixture of 2-bromo-3-fluoro-5-methylpyridine (4.00 g, 21.05 mmol, 1.00 equiv) and Pd(dppf)Cl2 (1.54 g, 2.10 mmol, 0.10 equiv) in EtOH (40 mL), Et3N (25.56 g, 252.61 mmol, 3.00 equiv) was added dropwise at room temperature. The resulting mixture was stirred at 80 °C for 18 h under a carbon monoxide atmosphere (50 atm). The mixture was warmed to room temperature. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with CH2Cl2 (200 mL) and washed with 3 × 100 mL of H2O. The residue was purified by silica gel column chromatography to give ethyl 3-fluoro-5-methylpyridine-2-carboxylate (3.10 g, 80.39%) as a white solid. LC-MS: (ES + H, m / z): [M + H] + = 184.1. 1 1H NMR (300 MHz, DMSO-d6) δ 8.35 (d, 1H), 7.71 - 7.68 (m, 1H), 4.37 - 4.30 (m, 2H), 2.37 (s, 3H), 1.30 (t, 3H). Step 2: Preparation of (3-fluoro-5-methylpyridin-2-yl)(2H2)methanol:

[0327] To a stirred mixture of ethyl 3-fluoro-5-methylpyridine-2-carboxylate (3.00 g, 16.37 mmol, 1.00 equiv) in CD3OD (10 mL) and THF (20 mL), sodium borodeuteride (1.86 g, 49.13 mmol, 3.00 equiv) was added portionwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. The filtrate was quenched by adding D2O (4 mL) at 0 °C. The resulting mixture was diluted with ethyl acetate (300 mL) and washed with 3 × 100 mL of H2O. The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. (3-Fluoro-5-methylpyridin-2-yl)(2H2)methanol (2.4 g, crude) was obtained as a yellow liquid. LC-MS: (ES + H, m / z): [M + H] + = 144.3. 11H NMR (300 MHz, DMSO-d6) δ 8.23 (d, 1H), 7.55 - 7.50 (m, 1H), 5.20 (s, 1H), 2.32 (s, 3H). Step 3: Preparation of 2-chloro(2H2)methyl-3-fluoro-5-methylpyridine:

[0328] To a stirred mixture of (3-fluoro-5-methylpyridin-2-yl)(2H2)methanol (2.40 g, 16.76 mmol, 1.00 eq) and DMF (0.1 mL, 1.67 mmol, 0.10 eq) in DCM (24 mL), SOCl2 (2.6 mL, 36.88 mmol, 2.20 eq) was added dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum to afford 2-chloro(2H2)methyl-3-fluoro-5-methylpyridine (3.30 g, crude) as a yellowish brown liquid. LC-MS: (ES + H, m / z): [M + H] + = 162.1. 1 1H NMR (300 MHz, DMSO-d6) δ 8.29 (d, 1H), 7.69 - 7.64 (m, 1H), 2.35 (s, 3H). Step 4: Preparation of 2'-bromo-4-[(3-fluoro-5-methylpyridin-2-yl)(2H2)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one:

[0329] A mixture of 2'-bromo-4-hydroxy-5',6-dimethyl-[1,4'-bipyridin]-2-one (2.57 g, 8.72 mmol, 1.00 equiv), 2-[chloro(2H2)methyl]-3-fluoro-5-methylpyridine (3.10 g, 19.18 mmol, 2.20 equiv), 18-crown-6 (691 mg, 2.61 mmol, 0.30 equiv), and K2CO3 (7.23 g, 52.31 mmol, 6.00 equiv) in DMF (25 mL) was stirred at 60 °C for 2 h under a nitrogen atmosphere. The mixture was warmed to room temperature. The resulting mixture was diluted with ethyl acetate (200 mL). The resulting mixture was washed with brine (3 × 100 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2'-bromo-4-[(3-fluoro-5-methylpyridin-2-yl)(2H2)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one (2.30 g, 62.76%) as a white solid. LC-MS: (ES + H, m / z): [M + H] + = 420.1。 1 H NMR (300 MHz, DMSO-d6) δ 8.48 (s, 1H), 8.34 (d, 1H), 7.73 (s, 1H), 7.70 - 7.67 (m, 1H), 6.12 (d, 1H), 6.02 (d, 1H), 2.37 (s, 3H), 1.96 (s, 3H), 1.85 (s, 3H). Step 5: Preparation of 2'-bromo-3-chloro-4-[(3-fluoro-5-methylpyridin-2-yl)(2H2)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one:

[0330] To a stirred solution of 2'-bromo-4-[(3-fluoro-5-methylpyridin-2-yl)(2H2)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one (600 mg, 1.42 mmol, 1.00 equiv) and NCS (190 mg, 1.42 mmol, 1.00 equiv) in IPA (6 mL) was added dichloroacetic acid (18 mg, 0.14 mmol, 0.10 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 60 °C for 1 h under a nitrogen atmosphere. The mixture was cooled to 4 °C. The precipitated solid was collected by filtration and washed with IPA (3 × 40 mL). 2'-Bromo-3-chloro-4-[(3-fluoro-5-methylpyridin-2-yl)(2H2)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one (380 mg, 58.54%) was obtained as a white solid. LC-MS: (ES+H, m / z): [M+H] + = 455.90. 1 H NMR (300 MHz, DMSO-d6) δ 8.52 (s, 1H), 8.36 (d, 1H), 7.82 (s, 1H), 7.73 - 7.69 (m, 1H), 6.82 (s, 1H), 2.38 (s, 3H), 1.96 (s, 6H). Step 6: Preparation of 3-chloro-4-[(3-fluoro-5-methylpyridin-2-yl)(2H2)methoxy]-2'-[3-(2-hydroxypropan-2-yl)-2-oxopyrazin-1-yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one:

[0331] A mixture of 2'-bromo-3-chloro-4-[(3-fluoro-5-methylpyridin-2-yl)(2H2)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one (380 mg, 0.83 mmol, 1.00 eq), 3-(2-hydroxypropan-2-yl)-1H-pyrazin-2-one (386 mg, 2.50 mmol, 3.00 eq), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (47 mg, 0.33 mmol, 0.40 eq), CuI (31 mg, 0.16 mmol, 0.20 eq), and K2CO3 (230 mg, 1.67 mmol, 2.00 eq) in 1,4-dioxane (3 mL) was stirred at 80 °C for 2 h under a nitrogen atmosphere. The mixture was warmed to room temperature. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (10% NH3, 3 × 50 mL). The organic layer was concentrated under reduced pressure to give a crude product, which was further purified by preparative HPLC. This afforded 3-chloro-4-[(3-fluoro-5-methylpyridin-2-yl)(2H2)methoxy]-2'-[3-(2-hydroxypropan-2-yl)-2-oxopyrazin-1-yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one (107 mg, 24.25%) as a white solid. LC-MS: (ES + H, m / z): [M + H] + = 528.20. 1 H NMR (300 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.36 (d, 1H), 8.00 (d, 1H), 7.95 (s, 1H), 7.73 - 7.69 (m, 1H), 7.47 (d, 1H), 6.83 (s, 1H), 5.12 (s, 1H), 2.39 (s, 3H), 2.10 (s, 3H), 2.01 (s, 3H), 1.51 (s, 6H). Step 7: Preparation of rel-3-chloro-4-[(3-fluoro-5-methylpyridin-2-yl)(2H2)methoxy]-2’-[3-(2-hydroxypropan-2-yl)-2-oxopyrazin-1-yl]-5’,6-dimethyl-[1,4’-bipyridin]-2-one and rel-3-chloro-4-[(3-fluoro-5-methylpyridin-2-yl)(2H2)methoxy]-2’-[3-(2-hydroxypropan-2-yl)-2-oxopyrazin-1-yl]-5’,6-dimethyl-[1,4’-bipyridin]-2-one:

[0332] The racemate (102 mg) was separated by preparative chiral HPLC to give Example 28A (35.4 mg, purity 99.6%, ee = 100%) as a white solid and Example 28B (26.7 mg, purity 99.7%, ee = 100%) as a white solid.

[0333] Example 28A: LC-MS: (ES + H, m / z): [M + H] + = 528.20. 1 H NMR (300 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.36 (d, 1H), 8.00 (d, 1H), 7.95 (s, 1H), 7.73 - 7.69 (m, 1H), 7.47 (d, 1H), 6.83 (s, 1H), 5.13 (s, 1H), 2.38 (s, 3H), 2.10 (s, 3H), 2.00 (s, 3H), 1.51 (s, 6H). 19 F NMR (282 MHz, DMSO-d6) δ -126.30.

[0334] Example 28B: LC-MS: (ES + H, m / z): [M + H] + = 528.20. 1 H NMR (300 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.36 (d, 1H), 8.00 (d, 1H), 7.95 (s, 1H), 7.73 - 7.69 (m, 1H), 7.47 (d, 1H), 6.83 (s, 1H), 5.13 (s, 1H), 2.38 (s, 3H), 2.10 (s, 3H), 2.00 (s, 3H), 1.51 (s, 6H). 1919F NMR (282 MHz, DMSO-d6) δ -126.30. Biological Example: Protein Expression and Purification

[0335] Expression vectors for recombinant MK2 and PRAK kinases were constructed by cloning the codon-optimized sequences of MK2 (Uniprot ID P49137, amino acid fragment F46-H400), or PRAK (Uniprot ID Q8IW41, amino acid fragment M1-Q471) for overexpression of these kinases with an N-terminal GST tag into pGEX-4T1 (GE). The host was grown in TB medium, induction of protein expression with 0.5 mM IPTG at about 0.8 OD 600 and subsequent incubation of the culture at 18 °C for 14 - 20 h to perform protein expression in E. coli BL21. The harvested cells were resuspended in 100 mL of lysis buffer (50 mM Tris-HCl, pH 8.0, 500 mM NaCl, 1 mM DTT, 5% glycerol, and 1 mM PMSF) per gram of wet cell mass and homogenized at 4 °C in a microfluidizer (ATS, Suzhou, China) at 14,000 psi pressure for 3 passes. The cell lysate was clarified by centrifugation, and the supernatant containing the GST fusion protein was purified by affinity chromatography using a GSH-Sepharose (GE) gravity flow column pre-equilibrated in buffer A (50 mM Tris-HCl, pH 8.0, 500 mM NaCl, 1 mM DTT, and 5% glycerol). After washing the column thoroughly with buffer A, the bound GST protein was eluted with buffer B (50 mM Tris, pH 8.0, 500 mM NaCl, 1 mM DTT, 5% glycerol, 10 mM glutathione), followed by size exclusion purification on a Superdex 200 column equilibrated in buffer A. The purified protein was concentrated to about 1 mg / mL and stored at -80 °C. Biochemical Assay

[0336] This study evaluates the inhibitory efficacy of the compounds of the present invention against the p38 / MK2 pathway versus the p38 / PRAK pathway. More specifically, the compound concentration (IC 50 ) that inhibits half of the maximum activation of MK2 or PRAK by p38 was determined. The MK2 activation study was set up with or without a 1:3 dilution of a series of 10 points of the compounds of the present invention at a maximum dose of 1 or 10 μM, and the PRAK activation study was set up with or without a 1:3 dilution of a series of 10 points of the compounds of the present invention at a maximum dose of 300 μM. MK2 and PRAK activities were determined by the phosphorylation level of the HSP27 peptide conjugated to FITC.

[0337] A typical assay was performed in a volume of 20 μL containing 60 pM of active p38α (Carna, catalog number 04-152), 10 μM of ATP, 1 μM of FITC-HSP27 peptide (Sangon, catalog number P22354), and 1 nM of inactive MK2, or PRAK in 1X reaction buffer (20 mM HEPES, pH 7.5, 10 mM MgCl2, 1 mM DTT, 0.01% Triton X-100, 0.01% BSA). The re action mixture was incubated for 2 hours with various concentrations of the compounds of the present invention (200 nL), then 60 μL of 1X IMAP solution mixture (Molecular Devices, catalog number R8127) was added to the reaction mixture and incubated for an additional 30 minutes. The signal was then read by a Synergy(™) Neo2 Multi-Mode Microplate Reader with filter settings (Ex / Em = 485 nm / FITC FP-P pol 528 nm and FITC FP-S pol 528 nm).

[0338] The signal was then normalized to the vehicle control and fit with Xfit to generate the IC 50 . The selectivity of MK2 for PRAK was calculated by the formula selectivity = IC 50 of PRAK / IC 50 of MK2.

[0339] Data from the above assay are found in Table 2. [Table 2-1] [Table 2-2]

Claims

【Claim 1】 The invention described in the specification.

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