Pyridinone MK2 inhibitors and uses thereof

Abstract

Described herein are MK2 inhibitors and pharmaceutical compositions comprising the inhibitors.The compounds and compositions are useful for treating autoimmune disorders, chronic inflammatory disorders, acute inflammatory disorders, autoinflammatory disorders, fibrotic disorders, metabolic disorders, neoplastic disorders, and cardiovascular or cerebrovascular disorders.

Description

[Technical Field]

[0001] (cross reference) This application claims the benefit of U.S. Provisional Patent Application No. 63 / 220,322, filed July 9, 2021, and U.S. Provisional Patent Application No. 63 / 340,079, filed May 10, 2022, which are incorporated by reference herein in their entireties. [Background technology]

[0002] Mitogen-activated protein kinases (MAPKs) are a conserved family of enzymes that relay and propagate external stimuli using phosphorylation cascades 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 distinct classes of mammalian MAPKs have been identified: extracellular signaling kinases (ERKs 1 and 2), c-jun N-terminal kinase 1 (JNKs 1-3), p38 MAPKs (ρ38α, β, γ, and δ), and ERK5. MAPKs are activated by dual phosphorylation of Thr and Tyr residues within the TXY activation motif by coordinated dual-specificity MAPKKs, where X is Glu, Pro, and Gly in ERKs, JNKs, and p38 MAPKs, respectively. MAPKs are 60%–70% identical to each other, yet differ in their activation loop sequences and sizes. The activation loop is adjacent to the enzyme active site, and its phosphorylation allows the enzyme to reposition 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, whose phosphorylation directly or indirectly regulates gene expression in several ways, including transcription, nuclear export, and mRNA stability and translation. Cellular consequences of MAPK activation include inflammation, apoptosis, differentiation, and proliferation.

[0003] Distinct genes encode four p38 MAPKs in humans: ρ38α, β, γ, and δ. Significant amino acid sequence homology is observed among the four isoforms, with 60-75% overall sequence identity and >90% identity within the kinase domain. Tissue-selective expression is observed, with ρ38γ found primarily in skeletal muscle and ρ38δ found in the testis, pancreas, and small intestine. In contrast, p38a and β are more ubiquitously expressed.

[0004] p38 MAPK is the major isoform involved in immune and inflammatory responses. Therefore, its function is crucial 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 key inflammatory enzymes, such as COX2 and iNOS, which are major sources of eicosanoids and nitric oxide, respectively, at inflammatory sites. 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 direct or indirect phosphorylation of enzyme substrates, such as cytosolic phospholipase A2 and Cdc25 phosphatase, which are involved in the activation of cyclin-dependent protein kinase activity and cell cycle regulation. Thus, in addition to its role in inflammatory responses, p38 MAPK has other functions related to normal and abnormal cell growth and survival, as well as cellular function and homeostasis. MAPKAP kinases (MK2, MK-3, and PRAK) are selectively phosphorylated by p38 MAPK, whereas phosphorylation of MSK1 / 2, MNK1 / 2, and RSKb is catalyzed by both p38 MAPK and ERK.

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

[0007] The p38:MK2 complex is highly 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 p38a and binds to the negatively charged ED binding site. The tight binding of p38 to MK2 may result in a conformational change that provides an additional binding pocket for inhibitors that specifically rely on the p38:MK2 interaction. 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 in human clinical settings.

[0008] The role of p38 / MK2 in regulating inflammatory cytokines (TNFα, IL-Ιβ, IL-6) and enzymes involved in inflammation (COX-2, iNOS, and MMPs) makes it an attractive drug target. Several classical p38 MAPK inhibitors have been advanced into clinical trials. While some of these candidates have failed due to safety or other reasons, several 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, several IL-Ιβ-mediated diseases may be affected by p38 inhibitors based on the critical role of the p38 MAPK pathway in the biosynthesis and activity of this cytokine. These diseases include, among others, the cryopyrin-associated periodic disorders (CAPS), chronic gout, diabetes, Still's disease, and familial Mediterranean fever. Novel, safe, and effective p38 / MK2 inhibitors are needed. Summary of the Invention [Means for solving the problem]

[0009] A compound of formula (I) or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamer thereof [ka] (In the formula, Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Each R 10 are independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -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, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently selected from the group consisting of one or more R 10a is replaced by or two R on the same atom 10 together to form oxo, Each R 10a are independently deuterium, halogen, -CN, -NO2, -OH, -OR a, -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -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, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R on the same atom 10a together to form oxo, n is 1 to 4, R 1 and R 2 are independently hydrogen, deuterium, halogen, -CN, -NO2, -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, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; or R 1 and R 2 together to form oxo, or or R 1 and R 2 together form a cycloalkyl or heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are optionally substituted with 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 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; X is -C(R 3 )2-, -NR 4 -, -O-, or -S-; Each R 3 are independently hydrogen, deuterium, halogen, -CN, -NO2, -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, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; or two R's 3 together to form oxo, R 4 is hydrogen, -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, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; R 5 However, hydrogen, deuterium, halogens, -CN, -NO2, -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, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; R 6 However, hydrogen, deuterium, halogens, -CN, -NO2, -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, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; R 7 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Each R 11 are independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c Rd , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -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, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently selected from the group consisting of one or more R 11a is replaced by or two R on the same atom 11 together to form oxo, Each R 11a are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR bS(=O)2R a , -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, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R on the same atom 11a together to form oxo, m is 1 to 4; Ring C is an N-linked pyridinone, N-linked pyrimidinone, N-linked pyrazinone, N-linked pyridazinone, N-linked dihydroimidazolone, N-linked tetrahydropyrimidinone, N-linked piperazinone, or N-linked tetrahydropyridazinone; Each R 12 are independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -S(=O)(=NR b )R a , -SiR c R d OR b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -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, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently selected from one or more R 12a is replaced by Each R 12a are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -C(=O)C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R on the same atom 12a together to form oxo, p is 1 to 4; Each R a are independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl the alkyl, aryl, and heteroaryl are 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 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Each R bare independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl alkyl, aryl, and heteroaryl are 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 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Each R c and R dare independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl alkyl, aryl, and heteroaryl are 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 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Or R c and R d taken together with the atoms to which they are attached form a heterocycloalkyl 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 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Or R b and R ctaken together with the atoms to which they are attached form a heterocycloalkyl 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 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Or R a and R b taken together with the atoms to which they are attached form a heterocycloalkyl 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 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Or two R's b taken together with the atom to which they are attached form a heterocycloalkyl 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 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl).

[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 an autoimmune disorder, a chronic inflammatory disorder, an acute inflammatory disorder, an autoinflammatory disorder, a fibrotic disorder, a metabolic disorder, an oncological disorder, and a cardiovascular or cerebrovascular disorder.

[0012] Also disclosed herein is a method of treating a p38 MAP kinase-mediated disease in a subject in need thereof, 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 treating an MK2-mediated disease in a subject in need thereof, 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 in this specification are herein 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 [ka] (In the formula, Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Each R 10 are independently hydrogen, deuterium, halogen, -CN, -NO 2 , -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O) 2 R a , -S(=O) 2 NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O) 2 R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d 、C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently selected from one or more R 10a is replaced by or two R on the same atom 10 together to form oxo, Each R 10a are independently deuterium, halogen, -CN, -NO 2 , -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O) 2 R a , -S(=O) 2 NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O) 2 R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d 、C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C6 Alkenyl, C 2 ~C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R on the same atom 10a together to form oxo, n is 1 to 4, R 1 and R 2 are independently hydrogen, deuterium, halogen, -CN, -NO 2 , -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d 、C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 alkynyl, cycloalkyl, or heterocycloalkyl; or R 1 and R 2 together to form oxo, or or R 1 and R 2 taken together form a cycloalkyl or heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are optionally substituted with deuterium, halogen, —CN, —OH, —OCH 3 , -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -C(=O)CH 3 , -C(=O)OH, -C(=O)OCH 3 、C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, or C 1 ~C 6 is substituted with heteroalkyl; X is -C(R 3 ) 2 -, -NR 4 -, -O-, or -S-; Each R 3 are independently hydrogen, deuterium, halogen, -CN, -NO 2 , -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d 、C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 alkynyl, cycloalkyl, or heterocycloalkyl; or two R's 3 together to form oxo, R 4 is hydrogen, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d 、C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 alkynyl, cycloalkyl, or heterocycloalkyl; R 5 However, hydrogen, deuterium, halogens, -CN, -NO 2 , -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d 、C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 alkynyl, cycloalkyl, or heterocycloalkyl; R 6 However, hydrogen, deuterium, halogens, -CN, -NO 2 , -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d 、C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 alkynyl, cycloalkyl, or heterocycloalkyl; R 7 However, hydrogen, deuterium, halogens, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, or C 1 ~C 6 is a deuteroalkyl; Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Each R 11 are independently hydrogen, deuterium, halogen, -CN, -NO 2 , -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O) 2 R a , -S(=O) 2 NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O) 2 R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d 、C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently selected from one or more R 11a is replaced by or two R on the same atom 11 together to form oxo, Each R 11a are independently deuterium, halogen, -CN, -NO 2 , -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O) 2 R a , -S(=O) 2 NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O) 2 R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d 、C 1 ~C 6 Alkyl, C 1~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R on the same atom 11a together to form oxo, m is 1 to 4; Ring C is an N-linked pyridinone, N-linked pyrimidinone, N-linked pyrazinone, N-linked pyridazinone, N-linked dihydroimidazolone, N-linked tetrahydropyrimidinone, N-linked piperazinone, or N-linked tetrahydropyridazinone; Each R 12 are independently hydrogen, deuterium, halogen, -CN, -NO 2 , -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O) 2 R a , -S(=O) 2 NR c R d , -S(=O)(=NR b )R a , -SiR c R d OR b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O) 2 R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d 、C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 ~C 6 Alkylene (cycloalkyl), C 1 ~C 6 Alkylene (heterocycloalkyl), C 1 ~C 6 Alkylene (aryl), or C 1 ~C 6 alkylene(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently selected from one or more R 12a is replaced by Each R 12a are independently deuterium, halogen, -CN, -NO 2 , -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O) 2 R a , -S(=O) 2 NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NRb C(=O)R a , -NR b C(=O)OR b , -NR b S(=O) 2 R a , -C(=O)R a , -C(=O)C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -C(=O)C(=O)NR c R d 、C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R on the same atom 12a together to form oxo, p is 1 to 4; Each R a independently, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 ~C 6 Alkylene (cycloalkyl), C 1 ~C 6 Alkylene (heterocycloalkyl), C 1 ~C 6 Alkylene (aryl), or C 1 ~C 6 alkylene(heteroaryl), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently contains one or more of oxo, deuterium, halogen, —CN, —OH, —OCH 3 , -S(=O)CH 3 , -S(=O) 2 CH 3 , -S(=O) 2 NH 2 , -S(=O) 2 NHCH 3 , -S(=O) 2 N(CH 3 ) 2 , -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -C(=O)CH 3 , -C(=O)OH, -C(=O)OCH 3 、C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, or C 1 ~C 6 optionally substituted with heteroalkyl; Each R b are independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 ~C 6 Alkylene (cycloalkyl), C 1 ~C 6 Alkylene (heterocycloalkyl), C 1 ~C 6 Alkylene (aryl), or C 1 ~C 6 alkylene(heteroaryl), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently contains one or more of oxo, deuterium, halogen, —CN, —OH, —OCH 3 , -S(=O)CH 3 , -S(=O) 2 CH 3 , -S(=O) 2 NH 2 , -S(=O) 2 NHCH 3 , -S(=O) 2 N(CH 3 ) 2 , -NH 2 , -NHCH3 , -N(CH 3 ) 2 , -C(=O)CH 3 , -C(=O)OH, -C(=O)OCH 3 、C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, or C 1 ~C 6 optionally substituted with heteroalkyl; Each R c and R d are independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 ~C 6 Alkylene (cycloalkyl), C 1 ~C 6 Alkylene (heterocycloalkyl), C 1 ~C 6 Alkylene (aryl), or C 1 ~C 6 alkylene(heteroaryl), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently contains one or more of oxo, deuterium, halogen, —CN, —OH, —OCH 3 , -S(=O)CH 3 , -S(=O) 2 CH 3 , -S(=O) 2 NH 2 , -S(=O) 2 NHCH 3 , -S(=O) 2 N(CH 3 ) 2 , -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -C(=O)CH 3 , -C(=O)OH, -C(=O)OCH 3 、C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Hydroxyalkyl, C1 ~C 6 Aminoalkyl, or C 1 ~C 6 optionally substituted with heteroalkyl; Or R c and R d together with the atoms to which they are attached, can contain one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 , -S(=O)CH 3 , -S(=O) 2 CH 3 , -S(=O) 2 NH 2 , -S(=O) 2 NHCH 3 , -S(=O) 2 N(CH 3 ) 2 , -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -C(=O)CH 3 , -C(=O)OH, -C(=O)OCH 3 、C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, or C 1 ~C 6 forming a heterocycloalkyl optionally substituted with a heteroalkyl; Or R b and R c together with the atoms to which they are attached, can contain one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 , -S(=O)CH 3 , -S(=O) 2 CH 3 , -S(=O) 2 NH 2 , -S(=O) 2 NHCH 3 , -S(=O) 2 N(CH 3 ) 2 , -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -C(=O)CH 3 , -C(=O)OH, -C(=O)OCH 3 、C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, or C 1~C 6 forming a heterocycloalkyl optionally substituted with a heteroalkyl; Or R a and R b together with the atoms to which they are attached, can contain one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 , -S(=O)CH 3 , -S(=O) 2 CH 3 , -S(=O) 2 NH 2 , -S(=O) 2 NHCH 3 , -S(=O) 2 N(CH 3 ) 2 , -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -C(=O)CH 3 , -C(=O)OH, -C(=O)OCH 3 、C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, or C 1 ~C 6 forming a heterocycloalkyl optionally substituted with a heteroalkyl; Or two R's b together with the atoms to which they are attached, can contain one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 , -S(=O)CH 3 , -S(=O) 2 CH 3 , -S(=O) 2 NH 2 , -S(=O) 2 NHCH 3 , -S(=O) 2 N(CH 3 ) 2 , -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -C(=O)CH 3 , -C(=O)OH, -C(=O)OCH 3 、C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, or C 1 ~C 6 forming a heterocycloalkyl optionally substituted with a heteroalkyl). (Item 2) 2. The compound according to item 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamer thereof, wherein Ring C is an N-linked pyridinone, an N-linked pyrimidinone, an N-linked pyrazinone, or an N-linked pyridazinone. (Item 3) 2. The compound according to item 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamer thereof, wherein Ring C is an N-linked pyridinone. (Item 4) 2. The compound according to item 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamer thereof, wherein Ring C is an N-linked pyrimidinone. (Item 5) 2. The compound according to item 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamer thereof, wherein Ring C is an N-linked pyrazinone. (Item 6) 2. The compound according to item 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamer thereof, wherein Ring C is an N-linked pyridazinone. (Item 7) Ring C is

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

[0016] References throughout this specification to "some embodiments" or "embodiments" mean that a particular feature, structure, or characteristic described in connection with an embodiment is included in at least one embodiment. Thus, the appearances of the phrase "in one embodiment" or "in an embodiment" in various places throughout this specification do not necessarily all refer to the same embodiment. Furthermore, 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 its sense to include "and / or" unless the content clearly dictates otherwise.

[0017] As used herein, the following terms have the following meanings unless otherwise indicated.

[0018] "Oxo" refers to =O.

[0019] "Carboxyl" refers to --COOH.

[0020] "Alkyl" refers to a straight- or branched-chain saturated hydrocarbon monoradical having 1 to about 10 carbon atoms, more preferably 1 to 6 carbon atoms. Examples include, but are not limited to, 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, as well as longer alkyl groups such as heptyl, octyl, and the like. Wherever it appears herein, a numerical range such as "C1-C6 alkyl" or "C1-6 alkyl" means 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, although this definition also encompasses occurrences of the term "alkyl" where no numerical range is specified. In some embodiments, alkyl is a C1- 10In some embodiments, the alkyl is an alkyl. In some embodiments, the alkyl is a C1-6 alkyl. In some embodiments, the alkyl is a C1-5 alkyl. In some embodiments, the alkyl is a C1-4 alkyl. In some embodiments, the alkyl is a C1-3 alkyl. Unless stated otherwise specifically in the specification, an alkyl group can 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- 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 about the double bond(s) and should be understood to include both isomers. Examples include, but are not limited to, ethenyl (-CH=CH), 1-propenyl (-CHCH=CH), isopropenyl [-C(CH=CH], butenyl, 1,3-butadienyl, and the like. Wherever it appears herein, a numerical range such as "C2-C6 alkenyl" or "C2-6 alkenyl" means that the alkenyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms; however, this definition also encompasses occurrences of the term "alkenyl" where no numerical range is specified. Unless specifically stated otherwise in this specification, an alkenyl group can be any group, including, for example, For example, alkenyl may be optionally substituted 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, —NH, or —NO. 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- or branched-chain hydrocarbon monoradical having one or more carbon-carbon triple bonds and having 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadinyl, and the like. Wherever it appears herein, a numerical range such as "C2-C6 alkynyl" or "C2-6 alkynyl" means that the alkynyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms; however, this definition also encompasses occurrences of the term "alkynyl" without a specified numerical range. Unless stated otherwise specifically in the specification, alkynyl groups may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, alkynyl is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH, or -NO. In some embodiments, alkynyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, alkynyl is optionally substituted with halogen.

[0023] "Alkylene" refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, alkylene groups can be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkylene is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH, or -NO. In some embodiments, alkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, alkylene is optionally substituted with halogen.

[0024] "Alkoxy" means a group of the formula -OR a refers to the radical of R a is an alkyl radical as defined above. Unless stated otherwise specifically in the specification, an alkoxy 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, an alkoxy is optionally substituted with halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH, or -NO. In some embodiments, an alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, an 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. Aryl radicals may be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems and may include fused ring systems (when fused to a cycloalkyl or heterocycloalkyl ring, the aryl is attached through an aromatic ring atom) or bridged ring systems. In some embodiments, an aryl is a 6- to 10-membered aryl. In some embodiments, an aryl is a 6-membered aryl (phenyl). Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless stated otherwise specifically in the specification, an aryl may be optionally substituted with, for example, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF, -OH, -OMe, -NH, or -NO. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF, -OH, or -OMe. In some embodiments, an aryl is optionally substituted with halogen.

[0026] "Cycloalkyl" refers to a partially or fully saturated monocyclic or polycyclic carbocyclic ring, which may include fused ring systems (when fused to an aryl or heteroaryl ring, the cycloalkyl is attached through a non-aromatic ring atom) or bridged ring systems. In some embodiments, a cycloalkyl is fully saturated. Representative cycloalkyls include those having 3 to 15 carbon atoms (C3 to C6). 15 Cycloalkyl or C3-C 15Cycloalkenyl), 3 to 10 carbon atoms (C3 to C 10 Cycloalkyl or C3-C 10Examples of cycloalkyls include, but are not limited to, cycloalkyls having 3 to 8 carbon atoms (C-C cycloalkyl or C-C cycloalkenyl), 3 to 6 carbon atoms (C-C cycloalkyl or C-C cycloalkenyl), 3 to 5 carbon atoms (C-C cycloalkyl or C-C cycloalkenyl), or 3 to 4 carbon atoms (C-C cycloalkyl or C-C cycloalkenyl). In some embodiments, a cycloalkyl is a 3- to 10-membered cycloalkyl or a 3- to 10-membered cycloalkenyl. In some embodiments, a cycloalkyl is a 3- to 6-membered cycloalkyl or a 3- to 6-membered cycloalkenyl. In some embodiments, a cycloalkyl is a 5- to 6-membered cycloalkyl or a 5- to 6-membered cycloalkenyl. Monocyclic cycloalkyls include, for example, 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 stated otherwise specifically in the specification, cycloalkyl is optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, —CN, —COOH, COOMe, —CF, —OH, —OMe, —NH, or —NO.In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF, -OH, or -OMe. In some embodiments, cycloalkyl is optionally substituted with halogen.

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

[0028] "Haloalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as 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.

[0029] "Hydroxyalkyl" refers to an alkyl radical, as defined above, substituted with one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl includes, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0030] "Aminoalkyl" refers to an alkyl radical, as defined above, substituted with one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyls include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

[0031] "Deuteroalkyl" refers to an alkyl radical, as defined above, that is substituted with one or more deuteriums. In some embodiments, the alkyl is substituted with one deuterium. In some embodiments, the alkyl is substituted with one, two, or three deuteriums. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six deuteriums. Deuteroalkyls include, for example, CD3, CHD, CHD2, CH2CD3, CD2CD3, CHDCD3, CH2CH2D, or CH2CHD2. In some embodiments, the deuteroalkyl is CD3.

[0032] "Heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or a combination thereof. The heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In one aspect, the heteroalkyl is a C1-C6 heteroalkyl, where the heteroalkyl consists 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 a combination thereof, and the heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyls are, for example, -CHOCH, -CHCHOCH, -CHCHOCHCHOCH, -CH(CH)OCH, -CHNHCH, -CHN(CH), -CHCHNHCH, or -CHCHN(CH). Unless stated otherwise specifically in the specification, a 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, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF, -OH, -OMe, -NH, or -NO. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF, -OH, or -OMe. In some embodiments, a 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, a heterocycloalkyl is fully saturated. In some embodiments, a heterocycloalkyl contains 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, a heterocycloalkyl contains 1 to 3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, a heterocycloalkyl contains 1 to 3 nitrogens. In some embodiments, a heterocycloalkyl contains 1 or 2 nitrogens. In some embodiments, a heterocycloalkyl contains 1 nitrogen. In some embodiments, a heterocycloalkyl contains 1 nitrogen and 1 oxygen. Unless stated otherwise specifically in the specification, a heterocycloalkyl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, and can include fused ring systems (when fused to an aryl or heteroaryl ring, the heterocycloalkyl is attached through a non-aromatic ring atom) or bridged ring systems, and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical can be optionally oxidized, and the nitrogen atom can be optionally quaternized. Representative heterocycloalkyls include those having 2 to 15 carbon atoms (C2 to C6). 15 Heterocycloalkyl or C2-C 15 heterocycloalkenyl), 2 to 10 carbon atoms (C2 to C 10 Heterocycloalkyl or C2-C 10heterocycloalkenyl), 2 to 8 carbon atoms (C2-C8 heterocycloalkyl or C2-C8 heterocycloalkenyl), 2 to 7 carbon atoms (C2-C7 heterocycloalkyl or C2-C7 heterocycloalkenyl), 2 to 6 carbon atoms (C2-C6 heterocycloalkyl or C2-C7 heterocycloalkenyl), 2 to 5 carbon atoms (C2-C5 heterocycloalkyl or C2-C5 heterocycloalkenyl), or 2 to 4 carbon atoms (C2-C4 heterocycloalkyl or C2-C4 heterocycloalkenyl). 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, and pyrrolidinyl. Examples of heterocycloalkyl include, but are not limited to, pyrazolidinyl, 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. The term heterocycloalkyl also includes all ring forms of carbohydrates, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. Unless otherwise specified, heterocycloalkyls have 2 to 10 carbons in the ring. When referring to the number of carbon atoms in a heterocycloalkyl, it is understood that the number of carbon atoms in the heterocycloalkyl is not the same as the total number (including heteroatoms) of atoms comprising the heterocycloalkyl (i.e., skeletal atoms of the heterocycloalkyl ring). In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkyl.In some embodiments, a heterocycloalkyl is a 3- to 7-membered heterocycloalkyl. In some embodiments, a heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, a heterocycloalkyl is a 4- to 6-membered heterocycloalkyl. In some embodiments, a heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. In some embodiments, a heterocycloalkyl is a 3- to 8-membered heterocycloalkenyl. In some embodiments, a heterocycloalkyl is a 3- to 7-membered heterocycloalkenyl. In some embodiments, a heterocycloalkyl is a 3- to 6-membered heterocycloalkenyl. In some embodiments, a heterocycloalkyl is a 4- to 6-membered heterocycloalkenyl. In some embodiments, a heterocycloalkyl is a 5- to 6-membered heterocycloalkenyl. Unless stated otherwise specifically in the specification, a heterocycloalkyl may be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF, -OH, -OMe, -NH, or -NO. In some embodiments, a heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF, -OH, or -OMe. In some embodiments, a heterocycloalkyl is optionally substituted with halogen.

[0034] "Heteroaryl" refers to a 5-14 membered ring system radical containing 1-13 carbon atoms, 1-6 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. In some embodiments, a heteroaryl contains 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, a heteroaryl contains 1-3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, a heteroaryl contains 1-3 nitrogens. In some embodiments, a heteroaryl contains 1 or 2 nitrogens. In some embodiments, a heteroaryl contains 1 nitrogen. A heteroaryl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system and can include fused (when fused to a cycloalkyl or heterocycloalkyl ring, the heteroaryl is attached through an aromatic ring atom) or bridged ring systems, and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical can be optionally oxidized, and the nitrogen atom can be optionally quaternized. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl. In some embodiments, the heteroaryl is a 6-membered heteroaryl. In some embodiments, the heteroaryl is a 5-membered heteroaryl.Examples include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzoindolyl, 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, isoi Examples include, but are not limited to, indolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyranidyl, 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). Unless stated otherwise specifically in the specification, a heteroaryl can be optionally substituted with, for example, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, a heteroaryl is optionally substituted with halogen, methyl, ethyl, —CN, —COOH, COOMe, —CF, —OH, —OMe, —NH, or —NO.In some embodiments, heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, heteroaryl is optionally substituted with halogen.

[0035] The term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances when the event or circumstance occurs and instances when the event or circumstance does not. For example, "optionally substituted alkyl" means either "alkyl" or "substituted alkyl" as defined above. Furthermore, an optionally substituted group may be unsubstituted (e.g., -CHCH), fully substituted (e.g., -CFCF), monosubstituted (e.g., -CHCHF), or substituted at any level between fully and monosubstituted (e.g., -CHCHF, -CHCF, -CFCH, -CFHCHF, etc.). Those of skill in the art will understand that with respect to any group containing one or more substituents, such groups are not intended to introduce any substitution or substitution pattern that is sterically impractical and / or synthetically unfeasible (e.g., a substituted alkyl may include an optionally substituted cycloalkyl group, which may continue indefinitely as defined to include an optionally substituted alkyl group). Thus, any substituent described should generally be understood to have a maximum molecular weight of up to about 1,000 daltons, more typically up to about 500 daltons.

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

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

[0038] "Treatment" of an individual (e.g., a mammal such as a human) or 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 of the condition (e.g., the condition does not worsen) or alleviation of the condition.

[0039] "Synergistic" or "synergizing" refers to an effect of the combination that is greater than the additive effect of each component alone at the same dose.

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

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

[0042] A compound of formula (I) or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamer thereof [ka] (In the formula, Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Each R 10 are independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -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, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently selected from the group consisting of one or more R 10a is replaced by or two R on the same atom 10 together to form oxo, Each R 10a are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -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, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R on the same atom 10atogether to form oxo, n is 1 to 4, R 1 and R 2 are independently hydrogen, deuterium, halogen, -CN, -NO2, -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, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; or R 1 and R 2 together to form oxo, or or R 1 and R 2 together form a cycloalkyl or heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are optionally substituted with 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 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; X is -C(R 3 )2-, -NR 4 -, -O-, or -S-; Each R 3 are independently hydrogen, deuterium, halogen, -CN, -NO2, -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, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; or two R's 3 together to form oxo, R 4 is hydrogen, -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, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; R 5 However, hydrogen, deuterium, halogens, -CN, -NO2, -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, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; R 6 However, hydrogen, deuterium, halogens, -CN, -NO2, -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, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; R 7 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Each R 11 are independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -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, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently selected from the group consisting of one or more R 11a is replaced by or two R on the same atom 11 together to form oxo, Each R 11a are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -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, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R on the same atom 11atogether to form oxo, m is 1 to 4; Ring C is an N-linked pyridinone, N-linked pyrimidinone, N-linked pyrazinone, N-linked pyridazinone, N-linked dihydroimidazolone, N-linked tetrahydropyrimidinone, N-linked piperazinone, or N-linked tetrahydropyridazinone; Each R 12 are independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -S(=O)(=NR b )R a , -SiR c R d OR b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -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, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently selected from one or more R 12a is replaced by Each R 12a are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -C(=O)C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R on the same atom 12a together to form oxo, p is 1 to 4; Each R a are independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl the alkyl, aryl, and heteroaryl are 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 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Each R bare independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl alkyl, aryl, and heteroaryl are 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 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Each R c and R dare independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl alkyl, aryl, and heteroaryl are 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 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Or R c and R d taken together with the atoms to which they are attached form a heterocycloalkyl 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 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Or R b and R ctaken together with the atoms to which they are attached form a heterocycloalkyl 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 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Or R a and R b taken together with the atoms to which they are attached form a heterocycloalkyl 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 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Or two R's b taken together with the atom to which they are attached form a heterocycloalkyl 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 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl).

[0043] Also disclosed herein are compounds of formula (Ia), or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamer thereof: [ka]

[0044] Also disclosed herein is a compound of formula (Ib), or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamer thereof: [ka]

[0045] Also disclosed herein is a compound of formula (Ic), or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamer thereof: [ka]

[0046] Also disclosed herein are compounds of formula (Id), or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamer thereof: [ka]

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

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

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

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

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

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

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

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

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

[0056] In some embodiments of a compound of Formula (I), (Ia)-(Ie), (Ig), or (Ii), n is 1 or 2. In some embodiments of a compound of Formula (I), (Ia)-(Ie), (Ig), or (Ii), n is 2 or 3. In some embodiments of a compound of Formula (I), (Ia)-(Ie), (Ig), or (Ii), n is 1. In some embodiments of a compound of Formula (I), (Ia)-(Ie), (Ig), or (Ii), n is 2. In some embodiments of a compound of Formula (I), (Ia)-(Ie), (Ig), or (Ii), n is 3.

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

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

[0059] In some embodiments of compounds of Formula (I), (Ia)-(Ij), R 5 represents hydrogen, deuterium, halogens, -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 compounds of Formula (I), (Ia)-(Ij), R 5 is hydrogen, deuterium, halogen, —CN, or C1-C6 alkyl. In some embodiments of compounds of Formula (I), (Ia)-(Ij), R 5 is hydrogen. In some embodiments of compounds of Formula (I), (Ia)-(Ij), R 6 is hydrogen, deuterium, halogen, —CN, or C1-C6 alkyl.

[0060] In some embodiments of compounds of Formula (I), (Ia)-(Ij), R 6 represents hydrogen, deuterium, halogens, -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 compounds of Formula (I), (Ia)-(Ij), R 6 is hydrogen, deuterium, halogen, —CN, or C1-C6 alkyl. In some embodiments of compounds of Formula (I), (Ia)-(Ij), R 6 is a C1-C6 alkyl.

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

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

[0063] In some embodiments of compounds of Formula (I), (Ia)-(Ij), each R 11 are 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 compounds of Formula (I), (Ia)-(Ij), each R 11 are independently C1 to C6 alkyl.

[0064] In some embodiments of compounds of Formula (I), (Ia)-(Ij), each R 11 are 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 compounds of Formula (I), (Ia)-(Ij), each R 11 are independently hydrogen or C1-C6 alkyl.

[0065] In some embodiments of a compound of Formula (I), (Ia)-(Ij), m is 1 or 2. In some embodiments of a compound of Formula (I), (Ia)-(Ij), m is 1 to 4. In some embodiments of a compound of Formula (I), (Ia)-(Ij), m is 2 to 4. In some embodiments of a compound of Formula (I), (Ia)-(Ij), m is 1. In some embodiments of a compound of Formula (I), (Ia)-(Ij), m is 2.

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

[0067] In some embodiments of compounds of Formula (I), (If), (Ig), Ring C is [ka] In some embodiments of compounds of Formula (I), (If), (Ig), Ring C is: [ka] In some embodiments of compounds of Formula (I), (If), (Ig), Ring C is: [ka] In some embodiments of compounds of Formula (I), (If), (Ig), Ring C is: [ka] In some embodiments of compounds of Formula (I), (If), (Ig), Ring C is: [ka] is.

[0068] In some embodiments of compounds of Formula (I), (Ia)-(Ij), each R 12 are independently hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c Rd , -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, 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 each independently selected from the group consisting of one or more R 12a are optionally and independently substituted with

[0069] In some embodiments of compounds of Formula (I), (Ia)-(Ij), each R 12 are independently hydrogen, 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, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), or C1-C6 alkylene(heterocycloalkyl), and alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently selected from the group consisting of one or more R 12a are optionally and independently substituted with

[0070] In some embodiments of compounds of Formula (I), (Ia)-(Ij), each R 12 are 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 alkyl, cycloalkyl, and heterocycloalkyl are optionally and independently selected from one or more R 12ais replaced by .

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

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

[0073] In some embodiments of compounds of Formula (I), (Ia)-(Ij), each R 12 are 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, 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 each independently selected from the group consisting of one or more R 12a are optionally and independently substituted with

[0074] In some embodiments of compounds of Formula (I), (Ia)-(Ij), each R 12 are independently deuterium, halogen, -CN, -OH, -OR a , -NR c Rd , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, 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 each independently selected from the group consisting of one or more R 12a are optionally and independently substituted with

[0075] In some embodiments of compounds of Formula (I), (Ia)-(Ij), each R 12 are independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, heterocycloalkyl, C1-C6 alkylene(cycloalkyl), or C1-C6 alkylene(heterocycloalkyl), and alkyl, cycloalkyl, and heterocycloalkyl are optionally and independently selected from one or more R 12a is replaced by .

[0076] In some embodiments of compounds of Formula (I), (Ia)-(Ij), each R 12 are independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, or heterocycloalkyl, and alkyl, cycloalkyl, and heterocycloalkyl are optionally and independently selected from the group consisting of one or more R 12a is replaced by .

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

[0078] In some embodiments of compounds of Formula (I), (Ia)-(Ij), each R 12a are 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 compounds of Formula (I), (Ia)-(Ij), each R 12a are 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 compounds of Formula (I), (Ia)-(Ij), each R 12a are independently deuterium, halogen, -CN, -OH, -OR a , C1 to C6 alkyl, or C1 to C6 haloalkyl.

[0080] In some embodiments of a compound of Formula (I), (If), or (Ig), p is 1 or 2. In some embodiments of a compound of Formula (I), (If), or (Ig), p is 1 to 3. In some embodiments of a compound of Formula (I), (If), or (Ig), p is 1. In some embodiments of a compound of Formula (I), (If), or (Ig), p is 2.

[0081] In some embodiments of the compounds disclosed herein, each R aare independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently contains one or more of oxo, deuterium, halogen, —CN, —OH, —OCH3, — and optionally substituted with 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 deuteroalkyl, 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, 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 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or 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 to C6 alkyl.

[0082] In some embodiments of the compounds disclosed herein, each R b are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently contains one or more of 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 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl. In some embodiments of the compounds disclosed herein, each R b 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 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or 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 bis independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, each R b are 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 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently contains one or more of 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 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl. In some embodiments of the compounds disclosed herein, each R c and R dare 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 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of the compounds disclosed herein, each R c and R d is 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 are independently hydrogen or C1-C6 alkyl.

[0084] In some embodiments of the compounds disclosed herein, R c and R d together with the atoms 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 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl.

[0085] In some embodiments of the compounds disclosed herein, each R 10 , R11 , R 12 , R a , R b , R c , R d , R c and R d heterocycloalkyl formed when R and a and R b heterocycloalkyl formed when R and b and R c and taken together, the heterocycloalkyl formed 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 heterocycloalkyl formed when R and a and R b heterocycloalkyl formed when R and b and R c and taken together, the heterocycloalkyl formed 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 heterocycloalkyl formed when R and a and R b heterocycloalkyl formed when R and b and R c and taken together, the heterocycloalkyl formed is independently substituted with 1, 2, or 3 substituents as defined herein. In some embodiments of the compounds disclosed herein, each R10 , R 11 , R 12 , R a , R b , R c , R d , R c and R d heterocycloalkyl formed when R and a and R b heterocycloalkyl formed when R and b and R c and taken together, the heterocycloalkyl formed 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 heterocycloalkyl formed when R and a and R b heterocycloalkyl formed when R and b and R c The heterocycloalkyl formed when taken together is independently substituted with one substituent as defined herein.

[0086] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, such groups and substituents are chosen 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: [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 assigned arbitrarily.

[0089] In some embodiments, Compound (I) is [ka] [ka] [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamer thereof. 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 possess one or more double bonds. The compounds described herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, as well as their corresponding mixtures. In some circumstances, the compounds described herein possess one or more chiral centers, with each center existing in either the R or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms, as well as their corresponding mixtures. 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 applications 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, diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation / resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomers are then recovered, along with the resolving agent, by any practical means that does not result in racemization.

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

[0092] In some embodiments, [ka] It exists as.

[0093] for example, [ka] It exists as. labeled compound

[0094] In some embodiments, the compounds described herein exist in their isotopically labeled form. 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 pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically labeled compounds that are identical to those listed herein, except for the fact that one or more atoms have been replaced by an atom having an atomic mass or mass number different from that 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 Compounds described herein, and pharmaceutically acceptable salts, solvates, stereoisomers, or rotamers thereof, that contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present invention. Certain isotopically labeled compounds, e.g., 3 H and 14 Those in which a radioactive isotope such as 3C is incorporated are useful in drug and / or substrate tissue distribution assays. 3 H and carbon-14, i.e. 14C isotopes are particularly preferred for their ease of preparation and detectability. Additionally, heavy isotopes such as deuterium, i.e., 2 Substitutions such as H may confer particular therapeutic advantages due to greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.

[0095] In some embodiments, the compounds described herein are labeled by other means, including but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels. pharmaceutically acceptable salts

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

[0097] In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and 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 solvates, stereoisomers, or rotamers thereof, or by separately reacting the purified compounds in free form with the appropriate acid or base and isolating the salt thus formed.

[0098] Examples of pharmaceutically acceptable salts include salts prepared by reaction of the compounds described herein with a mineral, organic acid, or inorganic base, such as 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, gamma-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate 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, tosylate undeconate, and xylenesulfonate.

[0099] Additionally, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; 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-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-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. In some embodiments, other acids, such as oxalic acid, while not themselves pharmaceutically acceptable, are used in the preparation of salts useful as intermediates in obtaining the compounds disclosed herein, their solvates, stereoisomers, or rotamers, and their pharmaceutically acceptable acid addition salts.

[0100] In some embodiments, compounds described herein containing free acid groups are reacted with a suitable base, such as a hydroxide, carbonate, bicarbonate, or sulfate salt of a pharmaceutically acceptable metal cation, ammonia, or a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include alkali or alkaline earth salts, such as lithium, sodium, potassium, calcium, and magnesium, as well as aluminum salts. Specific examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1~4 alkyl)4.

[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 the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water- 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 diseases by administering such solvates. The present invention further provides methods of treating diseases by administering such solvates as pharmaceutical compositions.

[0103] Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent and, in some embodiments, are formed using pharmaceutically acceptable solvents such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. 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. Furthermore, the compounds provided herein can exist in unsolvated and solvated forms. In general, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein. tautomers

[0104] In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that can be interconverted by the migration of a hydrogen atom, accompanied by the switching of a single bond and an adjacent double bond. In bonding configurations where tautomerization is possible, 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. Treatment method

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

[0106] MAP 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. Together with p38 MAP kinase, this kinase is known to be involved in many cellular processes, including stress and inflammatory responses, nuclear export, gene expression regulation, and cell proliferation. The 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 multidomain protein consisting of an N-terminal proline-rich domain, a catalytic domain, an autoinhibitory 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, while the other isoform consists of 370 residues and is thought to be a splice variant lacking the C-terminal NLS. MK2 is located in the nucleus of cells, and upon binding and phosphorylation by p38, the MK2 NES becomes functional and both kinases are co-exported from the nucleus to the cytoplasm. Interestingly, export of the MK2 / p38 complex does not require catalytically active MK2, as the active site mutant Asp207Ala is still exported 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 autoinhibitory domain, thus exposing the active site for substrate binding. Mutation of two autoinhibitory domain residues, W332A and K326E, in mouse MK2 showed increased basal activity, and C-terminal deletion of the autoinhibitory domain rendered this domain constitutively active, providing further evidence for the role of this domain in inhibiting MK2 activity.

[0108] MK2-associated diseases or disorders that may be treated by the compounds disclosed herein include autoimmune disorders, chronic inflammatory disorders, acute inflammatory disorders, autoinflammatory disorders, fibrotic disorders, metabolic disorders, oncological 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 fever 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., ...inflammatory bowel disease (e.g., inflammatory bowel disease (e.g., inflammatory bowel disease (e.g., inflammatory bowel disease (e.g., inflammatory bowel disease (e.g., inflammatory bowel disease (e.g., inflammatory bowel disease (e.g., inflammatory bowel disease (e. Hepatic fibrosis or idiopathic pulmonary fibrosis), nephropathy, 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 Death, vasculitis syndromes (e.g., temporal Takayasu arteritis and giant cell arteritis, Behcet's disease or Wegener's granulomatosis), vitiligo, secondary hematological signs of autoimmune disease (e.g., anemia), drug-induced autoimmunity, Hashimoto's thyroiditis, hypophysitis, idiopathic thrombocytopenic purpura, metal-induced autoimmunity, myasthenia gravis, pemphigus, autoimmune hearing loss (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, pernicious 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 bacterial sepsis, toxic shock syndrome, glomerulonephritis, peritonitis, interstitial cystitis, hyperoxia-induced inflammation, chronic obstructive pulmonary disease (COPD), vasculitis,These include graft-versus-host reaction (e.g., graft-versus-host disease), allograft 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 diseases, 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 gastrointestinal fibrosis, renal fibrosis, liver or biliary fibrosis, liver fibrosis (e.g., nonalcoholic steatohepatitis, hepatitis C, or hepatocellular carcinoma), and the like. ), 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., head and neck, gastrointestinal, or pulmonary), primary sclerosing cholangitis, restenosis, cardiac fibrosis (e.g., endomyocardial fibrosis or atrial fibrosis), ocular scarring, fibrosclerosis, fibrocarcinoma, fibroids, fibromas, fibroadenomas, fibrosarcomas, transplant arterial lesions, keloids, 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, impaired glucose tolerance, 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 angiogenic disorders, multiple myeloma, leukemia (e.g., acute lymphocytic leukemia, acute and chronic myeloid 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's lymphoma, mast cell tumor, Hodgkin's disease, or non-Hodgkin's disease), myelodysplastic syndrome, fibrosarcoma, rhabdomyosarcoma; astrocytoma, neuroblastoma, glioma, and schwannoma; melanoma, seminoma, teratocarcinoma, osteosarcoma, psoriasis pigmentosa, and the like. Cancers of the bone include thyroid cancer, ...

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

[0114] In certain embodiments, compositions containing a compound(s) described herein are administered for prophylactic and / or therapeutic treatments. In certain therapeutic applications, the compositions are 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 symptom of the disease or condition. Amounts effective for this use will depend on the severity and course of the disease or condition, previous medications, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, dose escalation and / or dose ranging clinical trials.

[0115] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder, or condition. Such an amount is defined as a "prophylactically effective amount or dose." For this use, the precise amount will also depend on the patient's health, weight, and the like. When used in a patient, the effective amount for this use will depend on the severity and course of the disease, disorder, or condition, previous medications, the patient's health status and response to the drugs, and the judgment of the treating physician. In one aspect, prophylactic treatment involves administering a pharmaceutical composition containing a compound described herein, or a pharmaceutically acceptable salt thereof, to a mammal that has previously experienced at least one symptom or risk factor of the disease being treated and is now in remission, to prevent the recurrence of symptoms of the disease or condition.

[0116] In certain embodiments in which the patient's condition does not improve, at the physician's discretion, administration of the compound is administered chronically, i.e., for an extended period of time, including the entire lifespan of the patient, to ameliorate 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 administered drug is temporarily reduced or temporarily stopped for a specified period of time (i.e., a "drug holiday"). In specific embodiments, the length of the drug holiday is between 2 days and 1 year, including, by way of example 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 example only, between 10% and 100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.

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

[0119] The amount of a given agent that corresponds to such an amount will vary depending on factors such as the particular compound, the disease state and its severity, the identity (e.g., weight, sex) of the subject or host requiring treatment, but will nevertheless be 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] In general, however, doses used for adult treatment typically range from 0.01 mg to 5000 mg per day. In one aspect, doses used for adult treatment are from about 1 mg to about 1000 mg per day. In one embodiment, the desired dose 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 for a compound 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 active agent in a dosage form is lower or higher than the ranges set forth herein, based on a number of variables related to the particular treatment regimen. In various embodiments, the daily dosage and unit dosage amount will vary depending on 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 include, but are not limited to, LD 10 and ED 90 The dose ratio between toxic and therapeutic effects is the therapeutic index, and the LD 50 and ED 50 In certain embodiments, data obtained from cell culture assays and animal studies are used in formulating therapeutically effective daily dose ranges and / or therapeutically effective unit doses for use in mammals, including humans. In some embodiments, the daily dosage of the compounds described herein is such that the ED 50 In certain embodiments, the daily dosage range and / or unit dosage amount varies within this range depending on the dosage form employed and the route of administration utilized.

[0123] In any of the foregoing aspects, in further embodiments, an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, 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 by injection to a mammal, 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, further embodiments include a single administration of an effective amount of the compound, including further embodiments where (i) the compound is administered once daily, or (ii) the compound is administered multiple times over a daily period to the mammal.

[0125] In any of the foregoing aspects, further embodiments include multiple administrations of an effective amount of the compound, including further embodiments 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, or (v) the compound is administered to the subject every 24 hours. In further or alternative embodiments, the method includes a drug holiday, during which administration of the compound is temporarily suspended or the dose of the administered compound is temporarily reduced, and at the end of the drug holiday, administration of the compound is resumed. In one embodiment, the length of the drug holiday ranges from two days to one year. Route of administration

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

[0127] In certain embodiments, the compounds described herein are administered in a local rather than systemic manner, for example, via direct injection of the compound into an organ, often in a depot or sustained-release preparation. In specific embodiments, long-acting formulations are administered by implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. Furthermore, in other embodiments, the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with an organ-specific antibody. In such embodiments, the liposome targets the organ and is 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 Compositions / Formulations

[0128] The compounds described herein are administered to a subject in need thereof, in accordance with standard pharmaceutical practice, either alone or in a pharmaceutical composition in combination with a pharmaceutically acceptable carrier, excipient, or diluent. In one embodiment, the compounds of the present invention can be administered to animals. The compounds can be administered orally or parenterally, including 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. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate the processing of the active compound into a pharmaceutically usable preparation. The appropriate formulation depends on the selected route of administration. Summary summaries 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, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), the disclosures of which are incorporated herein by reference.

[0130] In some embodiments, the pharmaceutically acceptable excipient is selected from carriers, binders, fillers, suspending agents, flavoring agents, sweetening agents, disintegrating agents, dispersing agents, surfactants, lubricants, coloring agents, diluents, solubilizers, moistening agents, plasticizers, stabilizers, penetration enhancers, wetting agents, antifoaming 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 of administration. Pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid oral dosage forms, powders, immediate-release formulations, controlled-release formulations, fast-melt formulations, tablets, capsules, pills, powders, dragees, effervescent formulations, lyophilized formulations, delayed-release formulations, sustained-release formulations, pulsatile-release formulations, multiparticulate formulations, and combined immediate- and controlled-release formulations.

[0132] Pharmaceutical compositions comprising a compound described herein or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamer thereof are prepared by conventional means, including, by way of example only, conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or compressing processes.

[0133] Pharmaceutical compositions for oral use can be prepared by mixing one or more solid excipients with one or more compounds described herein, optionally grinding the resulting mixture, and optionally adding suitable additives to obtain tablets or dragee cores, followed by processing the resulting granules. 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, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, or others, such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. Optionally, disintegrants such as cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate, are added. In some embodiments, dyes or pigments are added to tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

[0134] Orally administered pharmaceutical compositions include push-fit capsules made of gelatin and soft sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Push-fit capsules contain the active ingredient in a mixture of fillers such as lactose, binders such as starch, and / or lubricants such as talc or magnesium stearate, and optional stabilizers. In soft capsules, the active compound is dissolved or suspended in a suitable liquid (e.g., fatty oils, liquid paraffin, or liquid polyethylene glycol). In some embodiments, stabilizers are added.

[0135] Pharmaceutical compositions for parenteral use are formulated as infusions or injections. In some embodiments, pharmaceutical compositions suitable for injection or infusion comprise a sterile aqueous solution or dispersion, or a sterile powder, containing 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, including, 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 are methods of treating an autoimmune disorder, a chronic inflammatory disorder, an acute inflammatory disorder, an autoinflammatory disorder, a fibrotic disorder, a metabolic disorder, an oncological disorder, or a cardiovascular or cerebrovascular disorder 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, immunosuppressants, 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 an NSAID, an immunosuppressant, an immunomodulator, a cytostatic, an antiproliferative, an antiangiogenic agent, a biologic agent, a steroid, a vitamin D3 analog, a retinoid, another kinase inhibitor, a cytokine blocker, a corticosteroid, and an inhibitor of a cell adhesion molecule. In some embodiments, the additional therapeutic agent is selected from the group consisting of torcetrapib, aspirin, niacin, an HMG CoA reductase inhibitor (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 a corticosteroid, a nonsteroidal anti-inflammatory drug (NSAID) (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), a cox-2 inhibitor (e.g., celecoxib (Celebrex)), an immunosuppressant (e.g., For example, 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, an Flt3 tyrosine kinase inhibitor, a PDGF receptor family inhibitor, an 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 proteosome inhibitor, a chemotherapeutic agent, and a glucose reducing agent.

[0141] In some embodiments, the additional therapeutic agent is administered simultaneously with the compound disclosed herein. In some embodiments, the additional therapeutic agent and the compound disclosed herein are administered sequentially. In some embodiments, the additional therapeutic agent is administered less frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered more frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered before administration of the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered after administration of the compound disclosed herein. Example Intermediate 1 [ka] Step 1: Preparation of 3-(2-hydroxypropan-2-yl)-1H-pyridin-2-one:

[0142] To 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 MeMgBr (32.65 mL, 65.300 mmol, 5.00 equiv) in THF dropwise at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. The reaction was quenched with saturated NH4Cl(aq) (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 [ka] Step 1: Preparation of ethyl 3,5-difluoropicolinate:

[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, followed by the dropwise addition of SOCl (50 mL, 689.25 mmol, 2.20 equiv.) at 0° C. The resulting mixture was stirred at 60° C. for 3 hours under a nitrogen atmosphere. The mixture was allowed to reach 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 equiv) in ethanol (300 mL) was added NaBH (20.22 g, 534.34 mmol, 2.50 equiv) 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 NH Cl (aq) at 0° C. EtOH was removed under reduced pressure. The aqueous layer was basified to pH 10 with saturated Na CO (aq, 300 mL) and subsequently extracted with EtOAc (3×300 mL). The combined organic layers were washed with brine and dried over anhydrous Na SO . After filtration, the filtrate was concentrated in vacuo 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 (34.00 g, 234.31 mmol, 1.00 equiv.) in DCM (500 mL) was added DMF (160 mg) and then cooled using an ice-water bath. To the above mixture, SOCl (40 mL, 551.40 mmol, 2.35 equiv.) was added dropwise under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated under vacuum to give 2-(chloromethyl)-3,5-difluoropyridine (34.75 g, 90.68%) as a tan semi-solid. LC-MS: (ES+H, m / z): [M+H] + =164.0. 1 H NMR (400 MHz, chloroform-d) δ 8.35 (d, 1H), 7.28 (td, 1H), 4.73 (d, 2H). Intermediates 5-8 [ka] Step 1: Preparation of 2,2-dimethyl-6-(2-oxopropyl)-1,3-dioxin-4-one:

[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.) under a nitrogen atmosphere at −20° C. for 1 hour, followed by the dropwise addition of ZnEt (3.16 L, 3.16 mol, 1.50 equiv., 1 M in hexanes) over 2 hours at −20° C. The resulting mixture was stirred at −20° C. for 30 minutes 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 further 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 2M HCl (aq). The resulting mixture was extracted with EtOAc (3 x 5 L). The combined organic layers were washed with brine (3 x 5 L) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2,2-dimethyl-6-(2-oxopropyl)-1,3-dioxin-4-one (200 g, 51.45%) as tan crystals. LC-MS: (ES+H, m / z): [M+H] + =185.0. 1 H NMR (400MHz, DMSO-d6) δ 5.35 (s, 1H), 3.35 (s, 2H), 2.25 (s, 3H), 1.72 (d, 6H). Step 2: Preparation of 2'-bromo-4-hydroxy-5',6-dimethyl-[1,4'-bipyridin]-2-one:

[0146] A mixture of 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, 1.00 equiv) in 1,4-dioxane (200 mL) was stirred at 90 °C for 2 h. To the above mixture, H SO (7.87 g, 80.197 mmol, 1 equiv) 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. To the resulting mixture, HO (40 mL) was added, and the slurry was stirred for 10 min. The precipitated solid was collected by filtration, washed with EtO (3 x 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 equiv.) and 2-(chloromethyl)-3,5-difluoropyridine (46.55 g, 284.614 mmol, 2 equiv.) in DMF (450 mL), KCO (98.34 g, 711.535 mmol, 5.00 equiv.) and 18-crown-6 (3.76 g, 14.231 mmol, 0.10 equiv.) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 60 °C under a nitrogen atmosphere for 2 h. 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), 2,2-dichloroacetic acid (1.2 mL, 2.870 mmol, 0.10 equiv.) was added dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 60°C under a nitrogen atmosphere for 2 hours. 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(300MHz,DMSO-d6)δ 8.60(d,J=2.4Hz,1H),8.52(s,1H),8.10(ddd,J=10.0,8.9,2.4Hz,1H),7.81(s,1H),6.80(s,1H),5.48(d,J=2.0Hz,2H),1.98-1.94(m,6H). Intermediates 9-11 [ka] Step 1: Preparation of ethyl 5-chloro-3-fluoropyridine-2-carboxylate:

[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, followed by dropwise addition of H2SO4 (2.00 mL) at 0 °C. The resulting mixture was stirred overnight at 50 °C under a nitrogen atmosphere. The mixture was allowed to reach 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) was added NaBH (0.98 g, 25.90 mmol, 2.51 equiv) portionwise at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at 0° C. for 30 min under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for an additional 2 h. The reaction was quenched with saturated NH Cl (aq) at 0° C. EtOH was removed under reduced pressure. The aqueous layer was basified to pH 10 with saturated Na CO (aq) and subsequently extracted with EA (3×100 mL). The combined organic layers were washed with brine and dried over anhydrous Na SO . After filtration, the filtrate was concentrated in vacuo 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 equiv.) in DCM (2 mL) was added DMF (0.66 g, 8.97 mmol, 1.00 equiv.) and then cooled using an ice-water bath. To the above mixture, SOCl (1.00 mL, 13.78 mmol, 1.54 equiv.) was added dropwise under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated in vacuo to give 5-chloro-2-(chloromethyl)-3-fluoropyridine (2.00 g, crude) as a tan 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 [ka] Step 1: Preparation of ethyl 3-chloro-5-fluoropyridine-2-carboxylate:

[0152] A solution of 3-chloro-5-fluoropyridine-2-carboxylic acid (4.50 g, 25.63 mmol, 1.00 equiv.) in EtOH (100 mL) was cooled in an ice bath. To the above mixture, SOCl (6.13 g, 51.53 mmol, 2.01 equiv.) was added dropwise over 3 minutes at 0° C. The resulting mixture was stirred at room temperature for an additional 3 hours. The mixture was allowed to reach 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 equiv) in EtOH (30 mL) was added NaBH (0.98 g, 25.90 mmol, 2.51 equiv) portionwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 30 min under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for an additional 2 h under a nitrogen atmosphere. The reaction was quenched with saturated NH Cl (aq) 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 Na SO . After filtration, the filtrate was concentrated in vacuo 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 equiv.) in DCM (30 mL) was added DMF (0.1 mL, 1.30 mmol, 0.10 equiv.) under a nitrogen atmosphere at 0° C. SOCl (2.3 mL, 32.49 mmol, 2.50 equiv.) was added dropwise under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated in vacuo to give 3-chloro-2-(chloromethyl)-5-fluoropyridine (2.00 g, crude) as a tan 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 [ka] Step 1: Preparation of (3,5-difluoropyridin-2-yl)methan-d2-ol:

[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) was added sodium borohydride (111.84 g, 2671.71 mmol, 1.00 equiv.) in a nitrogen atmosphere at 0° C. in portions. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The resulting mixture was quenched by the addition of DO (200 mL) at 0° C. and stirred at 0° C. for 30 minutes. 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)methan-d2-olmethanol (360.00 g, 91.5%) as a yellow oil. LC-MS: (ES+H, m / z): [M+H] + =148.1. 1 H NMR (300MHz, 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)methan-d2-ol (300.00 g, 2039.13 mmol, 1.00 equiv.) in DCM (1000 mL) was added DMF (14.91 g, 203.91 mmol, 0.10 equiv.) and SOCl2 (606.44 g, 5097.84 mmol, 2.50 equiv.) dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 h. The resulting mixture was concentrated in vacuo 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 (300MHz, 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 under a nitrogen atmosphere for 2.5 h. 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 x 2000 mL) and water (5 x 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 x 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(300MHz,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 equiv.) and NCS (37.77 g, 282.85 mmol, 1.20 equiv.) in IPA (500 mL) was added 2,2-dichloroacetic acid (3.04 g, 23.57 mmol, 0.10 equiv.) dropwise at room temperature. The resulting mixture was stirred at 60°C under a nitrogen atmosphere for 1 hour. The mixture was allowed to cool to room temperature. The precipitated solid was collected by filtration and washed with cold IPA (4x30 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 300MHz, 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 [ka] Step 1: Preparation of 3-(2-hydroxypropan-2-yl)-1H-pyrazin-2-one:

[0159] To a stirred solution of methyl 3-oxo-4H-pyrazine-2-carboxylate (500 mg, 3.24 mmol, 1.00 equiv) in THF (30 mL) was added bromo(methyl)magnesium (32 mL, 32.44 mmol, 10.00 equiv) dropwise at −5° C. under a N atmosphere. The resulting mixture was stirred at room temperature for 2 h under a N atmosphere. The reaction was quenched by adding saturated NH Cl (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 Na SO . 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 [ka] 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 equiv.) and Pd(dppf)Cl (8.69 g, 11.88 mmol, 0.05 equiv.) in EtOH (250 mL) was added NEt (72.13 g, 712.82 mmol, 3.00 equiv.) at room temperature. The resulting mixture was stirred at 80 °C under a carbon monoxide atmosphere (50 atm) for 6 hours. The mixture was allowed to warm 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 H NMR (300MHz, 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 equiv.) and CaCl (68.68 g, 618.85 mmol, 3.00 equiv.) in CD3OD (200 mL) and THF (400 mL) was added sodium borodeuteride (17.27 g, 412.57 mmol, 2.00 equiv.) in a nitrogen atmosphere at 0 °C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. The resulting mixture was diluted with EtOAc (500 mL). Diatomaceous earth (100 g) was added to the reaction mixture, and the resulting mixture was stirred for 10 minutes. The resulting mixture was filtered, and the filter cake was washed with EtOAc (3 × 1 L). The filtrate was quenched by adding DO (35 mL) at 0 °C. The mixture was washed with brine (2 × 500 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give (5-chloro-3-fluoropyridin-2-yl)(2H2) (23.60 g, 69.94%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =164.2. 1 H NMR (300MHz, DMSO-d6) δ 8.48 (dd, 1H), 8.06 (dd, 1H), 5.41 (s, 1H). Step 3: 5-chloro-2-[chloro( 2 H2) Preparation of [methyl]-3-fluoropyridine:

[0162] To a stirred solution of (5-chloro-3-fluoropyridin-2-yl)(2H)methanol (23.60 g, 144.28 mmol, 1.00 equiv.) and DMF (1.05 g, 14.42 mmol, 0.10 equiv.) in DCM (200 mL), SOCl (42.91 g, 360.70 mmol, 2.50 equiv.) was added dropwise at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated in vacuo. 5-chloro-2-[chloro(2H)methyl]-3-fluoropyridine (26.30 g, 100%) was obtained as a brown oil. LC-MS: (ES+H, m / z): [M+H] +=182.1. 1 H NMR (300MHz, 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(2H)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 under a nitrogen atmosphere for 2.5 h. The mixture was allowed to warm 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 H NMR(400MHz,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) was added 2,2-dichloroacetic acid (0.88 g, 6.80 mmol, 0.10 equiv.) dropwise under air at room temperature. The resulting mixture was stirred at 60° C. under a nitrogen atmosphere for 1 hour. 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 (400MHz, 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 [ka] Step 1: Preparation of ethyl 3-chloro-5-fluoropyridine-2-carboxylate:

[0165] To a stirred mixture of 2,3-dichloro-5-fluoropyridine (50.00 g, 301.24 mmol, 1.00 equiv.) and Pd(dppf)Cl (4.41 g, 6.02 mmol, 0.02 equiv.) in EtOH (250 mL), EtN (72.13 g, 712.82 mmol, 3.00 equiv.) was added dropwise at room temperature. The resulting mixture was stirred at 100° C. under a carbon monoxide atmosphere (50 atm) for 18 hours. The mixture was allowed to warm to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 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 H NMR (400MHz, 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 equiv.) and CaCl (91.57 g, 825.14 mmol, 2.00 equiv.) in CD3OD (500 mL) and THF (500 mL) was added sodium borodeuteride (51.81 g, 1237.72 mmol, 3.00 equiv.) in a nitrogen atmosphere at 0 °C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The resulting mixture was diluted with EtOAc (500 mL). Diatomaceous earth (100 g) was added to the reaction mixture. The resulting mixture was filtered, and the filter cake was washed with EtOAc (3 × 1 L). The filtrate was quenched at 0 °C by the addition of DO (50 mL) and washed with brine (500 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give (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 H NMR (300MHz, 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)methan-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 under a nitrogen atmosphere for 2 h. The resulting mixture was concentrated in vacuo to give 3-chloro-2-(chloromethyl-d2)-5-fluoropyridine (31.00 g, 60.56%) as a tan liquid. LC-MS: (ES+H, m / z): [M+H] + =182.0. 1 H NMR (300MHz, 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 equiv.), 18-crown-6 (4.48 mg, 16.94 mmol, 0.2 equiv.), and K2CO3 (58.53 g, 423.53 mmol, 5.00 equiv.) in DMF (250 mL) was added 3-chloro-2-(chloromethyl-d2)-5-fluoropyridine (30.84 g, 169.41 mmol, 2.00 equiv.) at room temperature. The resulting mixture was stirred at 60 °C under a nitrogen atmosphere for 2 h. The mixture was allowed to warm 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 to give 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%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =440.0. 1 H NMR(300MHz,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 equiv.) and NCS (11.82 g, 88.49 mmol, 1.30 equiv.) in IPA (300 mL) was added 2,2-dichloroacetic acid (0.88 g, 6.80 mmol, 0.10 equiv.) dropwise at room temperature. The resulting mixture was stirred at 60°C under a nitrogen atmosphere for 1 hour. The mixture was allowed to cool to room temperature. The precipitated solid was collected by filtration and washed with cold IPA (3×40 mL) to give 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(300MHz,DMSO-d6)δ 8.68(d,1H),8.55-8.50(m,1H),8.25(dd,1H),7.81(s,inte1H),6.77(d,1H),1.97(s,3H),1.95(s,3H). Examples 1A and 1B [ka] Step 1: Preparation of 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:

[0170] To 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 equiv.) in dioxane (20 mL), K2CO3 (302.64 mg, 2.190 mmol, 2 equiv.) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C under a nitrogen atmosphere overnight. The mixture was allowed to cool to room temperature. The reaction was quenched by adding saturated NH4Cl (aq.) (50 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 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(300MHz,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),6.8 1(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). Step 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 equiv.) 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] -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%) were obtained as white solids.

[0172] Example 1A: LC-MS: (ES+H, m / z): [M+H] + =529.00. 1 H NMR(300MHz,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,1 H),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). 19F NMR(377MHz,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 NMR(400MHz,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,1 H),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 F NMR(377MHz,DMSO-d6)δ-120.16,-120.18,-122.35,-122.37.[a] D 25 =+174.8(C=1,MeOH). Examples 2A and 2B [ka] Step 1: Preparation of 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:

[0174] To a stirred mixture of 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 (1R,2R)-1-N,2-N-dimethylcyclohexane-1,2-diamine (187.29 mg, 1.31 mmol, 2.00 equiv.) in 1,4-dioxane (5 mL) was added KCO (181.98 mg, 1.31 mmol, 2.00 equiv.) under a nitrogen atmosphere at room temperature. The resulting mixture was stirred at 80° C. for 3 hours under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The reaction was quenched by adding saturated NH4Cl(aq) (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(400MHz,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(300MHz,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(377MHz,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(300MHz,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(377MHz,DMSO-d6)δ-120.15,-120.17,-122.39,-122.41. Examples 3A and 3B [ka] Step 1: Preparation of 1-(imidazol-1-yl)-2-methoxyethanone:

[0178] To a stirred solution of imidazole (25.09 g, 368.60 mmol, 2.00 equiv) in THF (200 mL) was added methoxyacetyl chloride (20.00 g, 184.30 mmol, 1.00 equiv) dropwise under a nitrogen atmosphere at 0° C. The resulting mixture was stirred at 0° C. under a nitrogen atmosphere for 3 hours. 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 (300MHz, Chloroform-d) δ7.52(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 was added THF (50 mL) at room temperature, followed by LiHMDS (56.98 mL, 1 M in THF, 56.98 mmol, 1.50 equiv) at −20° C. under a nitrogen atmosphere. To the above solution was added 2,2,6-trimethyl-1,3-dioxin-4-one (5.40 g, 37.99 mmol, 1.00 equiv) dropwise at −20° C. under a nitrogen atmosphere. The resulting mixture was stirred at −20° C. for 1 hour. To the above mixture was added diethylzinc (56.98 mL, 56.98 mmol, 1.50 equiv) dropwise at −20° C. under a nitrogen atmosphere. The temperature of the reaction was slowly raised to −10° C. and stirred for 10 minutes. 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 stirred at room temperature for another 2 hours. The reaction was quenched by adding water (50 mL) at −20° C. The mixture was acidified to pH 6 with HCl (aq.). 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 NaSO. 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 (300MHz, 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. under a nitrogen atmosphere for 3 hours. To the resulting mixture was added HSO (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. under a nitrogen atmosphere for 1 hour. The desired product could be detected. The mixture was allowed to cool to room temperature. HO (3 mL) was added to the above mixture, followed by a large amount of ethyl ether, and then stirred at room temperature for 15 minutes. 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) was added K2CO3 (1.02 g, 7.43 mmol, 5.00 equiv.) and 18-crown-6 (39 mg, 0.15 mmol, 0.10 equiv.) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 60 °C under a nitrogen atmosphere for 2 h. 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), 2,2-dichloroacetic acid (0.01 mL, 0.10 mmol, 0.10 equiv.) was added dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 60 °C under a nitrogen atmosphere for 2 hours. The desired product could be detected by LCMS. The resulting mixture was diluted with EtOAc (50 mL). The resulting mixture was washed with NaHCO (50 mL). The organic layer was dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give 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] 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). To a stirred mixture of (1S,2S)-N1,N,2-N-dimethylcyclohexane-1,2-diamine (289 mg, 2.04 mmol, 2.00 equiv.) was added 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.) under a nitrogen atmosphere at room temperature. The resulting mixture was stirred overnight at 100 °C 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 obtain crude product (230 mg), which was purified by preparative HPLC to obtain 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 give 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(300MHz,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(282MHz,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(300MHz,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,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(282MHz,DMSO-d6)δ-120.09,-120.11,-122.31,-122.35. Examples 4A and 4B [ka] Step 1: Preparation of 2'-bromo-4-[(5-chloro-3-fluoropyridin-2-yl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one:

[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 equiv.) and 5-chloro-2-(chloromethyl)-3-fluoropyridine (914 mg, 5.08 mmol, 1.50 equiv.) in DMF (10 mL) was added 18-crown-6 (89 mg, 0.33 mmol, 0.10 equiv.) and K2CO3 (1.40 g, 10.16 mmol, 3.00 equiv.) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 60 °C 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) was added 2,2-dichloroacetic acid (14 mg, 0.11 mmol, 0.10 equiv.) dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 60°C under a nitrogen atmosphere for 2 hours. The mixture was allowed to cool to room temperature. The precipitated solid was collected by filtration and washed with cold IPA (2 x 10 mL) to give 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] A mixture of 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 equiv.), 3-(2-hydroxypropan-2-yl)-1H-pyridin-2-one (285 mg, 1.86 mmol, 2.00 equiv.), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (264 mg, 1.86 mmol, 2.00 equiv.), CuI (44 mg, 0.23 mmol, 0.25 equiv.), and K2CO3 (257 mg, 1.86 mmol, 2.00 equiv.) in ultra-dry 1,4-dioxane (5 mL) was stirred at 100 °C under a nitrogen atmosphere for 3 h. The reaction was poured into water (50 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous NaSO. 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] Racemic 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 give 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(400MHz,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(377MHz,DMSO-d6)δ-121.60.

[0192] Example 4B: LC-MS: (ES+H,m / z):[M+H] + =545.10. 1 H NMR(400MHz,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(377MHz,DMSO-d6)δ-121.60. Examples 5A and 5B [ka] Step 1: Preparation of 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:

[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 under a nitrogen atmosphere for 2 h. The resulting mixture was cooled to room temperature and poured into 10 mL of water. The resulting mixture was extracted with EtOAc (3 x 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 give the 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. Step 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, 98.2% purity, ee=100%) as a white solid and Example 5B (56.2 mg, 99.5% purity, ee=100%) as a white solid.

[0195] Example 5A: LC-MS: (ES+H,m / z):[M+H] + =530.2. 1 H NMR(400MHz,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,1 H),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 (377MHz, 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(400MHz,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,1 H),6.81(s,1H),5.49(d,2H),5.12(s,1H),2.10(s,3H),2.00(s,3H),1.50(s,6H). 19F NMR (377MHz, DMSO-d6) δ-120.17,-120.19,-122.36,-122.38. Example 6 [ka] 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) was added LiHMDS (19.92 mL, 1 mol / L in THF, 19.91 mmol, 1.00 equiv.) 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 was added α-bromoisobutyrate (7.77 g, 39.83 mmol, 2.00 equiv.) 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 (aq.) 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 in vacuo to give ethyl 2-(3-chloro-6-oxopyridazin-1-yl)-2-methylpropanoate (800 mg, 16.41%) as a yellow liquid. 1 H NMR (300MHz, Chloroform-d) δ 7.21 (d, 1H), 6.87 (d, 1H), 4.18 (q, 2H), 1.67 (s, 6H), 1.22 (t, 3H). Step 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] To a stirred mixture of 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), XPhos (54 mg, 0.11 mmol, 0.10 equiv.), Pd(AcO) (12 mg, 0.05 mmol, 0.05 equiv.), and AcOK (336 mg, 3.43 mmol, 3.00 equiv.) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 2 hours. The mixture was allowed to cool to room temperature. The resulting mixture was used directly in the next step without further purification.

[0199] To the above mixture, 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), Pd(dppf)Cl2CH2Cl2 (46 mg, 0.05 mmol, 0.05 equiv), and HO (1 mL) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 2 hours. 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] + =586.1. 1H NMR(300MHz,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),5.4 9(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 F NMR(282MHz,DMSO-d6)δ-120.11,-120.14,-122.29,122.32. Examples 7A and 7B [ka] Step 1: Preparation of 2'-bromo-4-[(3-chloro-5-fluoropyridin-2-yl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one:

[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 equiv.) and 3-chloro-2-(chloromethyl)-5-fluoropyridine (3.64 g, 20.22 mmol, 1.99 equiv.) in DMF (0.79 mL, 10.16 mmol, 1.00 equiv.), KCO (7.02 g, 50.82 mmol, 5.00 equiv.) and 18-crown-6 (806 mg, 3.04 mmol, 0.30 equiv.) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 60 °C under a nitrogen atmosphere for 1 hour. 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), 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 equiv.) and 2,2-dichloroacetic acid (0.06 mL, 0.45 mmol, 0.10 equiv.) in i-PrOH (10 mL), NCS (608 mg, 4.55 mmol, 1.00 equiv.) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 60°C under a nitrogen atmosphere for 2 hours. The mixture was allowed to cool to room temperature. The precipitated solid was collected by filtration and washed with cold IPA (2x5 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] To 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 K2CO3 (438 mg, 3.17 mmol, 2.00 equiv.) under a nitrogen atmosphere at room temperature. 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 NaSO. 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 4-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 H NMR(300MHz,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 F NMR(282MHz,DMSO-d6)δ-124.21.

[0205] Example 7B: LC-MS: (ES+H,m / z):[M+H] + =545.0. 1H NMR(300MHz,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 F NMR(282MHz,DMSO-d6)δ-124.19. Examples 8A and 8B [ka] Step 1: Preparation of 3-(3,6-dihydro-2H-pyran-4-yl)-1H-pyridin-2-one

[0206] Dioxane (150 mL) and H 2 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 2H-O (30 mL), AcOK (8.46 g, 86.20 mmol, 3.00 equiv.) and Pd(dppf)Cl (4.21 g, 5.74 mmol, 0.20 equiv.) were added, and the resulting mixture was stirred overnight at 110 °C under a nitrogen atmosphere. The reaction was allowed to cool to room temperature. 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 equiv.) and Pd / C (158 mg, 1.12 mmol, 0.10 equiv.) in MeOH (100 mL) was stirred under a hydrogen atmosphere at room temperature for 3 hours. The resulting mixture was filtered, and the filter cake was washed with MeOH (3×50 mL). The filtrate was concentrated under reduced pressure. This afforded 3-(oxan-4-yl)-1H-pyridin-2-one (1.80 g, 88.9%) 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] To 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 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.) and the resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 3 h. 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 NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC. This afforded 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%) 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, =99.2% purity, ee=100.0%) as white solids.

[0210] Example 8A: LC-MS: (ES+H, m / z): [M+H]+ = 555.05. 1 H NMR(300MHz,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(282MHz,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(300MHz,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(282MHz,DMSO-d6)δ-120.16,-120.19,-122.36,-122.38. Examples 9A and 9B [ka] Step 1: Preparation of 4-(2-hydroxypropan-2-yl)-2H-pyridazin-3-one:

[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 CHMgBr (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 NHCl (aq.) 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 NaSO. 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] To a mixture of 4-(2-hydroxypropan-2-yl)-2H-pyridazin-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.) in dioxane (20 mL) was added at room temperature. The mixture was heated at 80 °C for 3 h. The mixture was allowed to cool 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 NaSO. 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(400MHz,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). Step 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 H NMR(300MHz,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),6.8 1(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 F NMR(282MHz,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 H NMR(300MHz,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),6.8 1(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 F NMR(282MHz,DMSO-d6)δ-120.15,-120.18,-122.35,-122.37. Examples 10A and 10B [ka] Step 1: Preparation of 5-(2-hydroxypropan-2-yl)-3H-pyrimidin-4-one:

[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) was added MeMgBr (64 mL, 3 M in 2-MeTHF, 194.65 mmol, 10.00 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 by adding saturated NH4Cl(aq.) (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. This afforded 5-(2-hydroxypropan-2-yl)-3H-pyrimidin-4-one (1.50 g, 49.99%) 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.), KCO (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. This afforded 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%) 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(400MHz,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),6.8 1(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(377MHz,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(400MHz,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),6.8 1(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(377MHz,DMSO-d6)δ-120.15,-120.17,-122.33,-122.35. Examples 11A and 11B [ka] Step 1: Preparation of methyl 2-(2-chloropyridin-3-yl)-2-methylpropanoate:

[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 under a nitrogen atmosphere at −78° C. 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 allowed to warm to room temperature. The reaction was quenched with saturated NH4Cl(aq) (500 mL) at room temperature. The resulting mixture was extracted with CHCl (3×500 mL). The combined organic layers were dried over anhydrous NaSO. 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.), CsCO (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) (0.19 g, 0.84 mmol, 0.06 equiv.) was added at room temperature. The resulting mixture was stirred at 80 °C under a nitrogen atmosphere overnight. 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 NaSO. 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) was added TMSI (7.65 g, 38.23 mmol, 4.00 equiv.) at room temperature. The resulting mixture was stirred at 50° C. under a nitrogen atmosphere for 2 hours. 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 (300MHz, 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] To a mixture of methyl 2-methyl-2-(2-oxo-1H-pyridin-3-yl)propanoate (0.85 g, 4.38 mmol, 1.00 equiv.), KCO (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), CuI (0.17 g, 0.87 mmol, 0.20 equiv.) was added at room temperature. The resulting mixture was stirred at 80° C. for 2 hours 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. 1 H NMR(400MHz,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 LiAlH (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 hour under a nitrogen atmosphere. The reaction was quenched with 15% sodium hydroxide (aq) 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] 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] [1,4'-bipyridin-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(300MHz,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),6.3 5(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 F NMR(377MHz,DMSO-d6)δ-120.15,-120.18,-122.35,-122.37.

[0229] Example 11B: LC-MS: (ES+H,m / z):[M+H] + =543.3. 1H NMR(300MHz,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),6.3 5(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 F NMR(377MHz,DMSO-d6)δ-120.15,-120.18,-122.35,-122.37. Examples 12A and 12B [ka] Step 1: Preparation of 1-(2-methoxypyridin-3-yl)cyclobutan-1-ol:

[0230] To a stirred solution of 3-iodo-2-methoxypyridine (5.00 g, 21.27 mmol, 1.00 equiv) in toluene (100.00 mL) was added i-PrMgCl (2.84 g, 27.65 mmol, 1.30 equiv) 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 was added cyclobutanone (2.24 g, 31.91 mmol, 1.50 equiv) 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. 1H NMR(400MHz,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,3 H),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] To 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 (ethylsulfanyl)sodium (1877 mg, 22.32 mmol, 10.00 equiv.) at room temperature. The resulting mixture was stirred overnight at 100° C. 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(400MHz,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] To 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), CuI (33 mg, 0.17 mmol, 0.20 equiv.) was added at room temperature. The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 2 hours. The reaction mixture was poured into water (150 mL) and extracted with EtOAc (3×150 mL). The combined organic layers were dried over anhydrous NaSO. 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] Racemic 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 give rel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2'-[3-(1-hydroxycyclobutyl)-2-oxopyridin-1-yl] 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(400MHz,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 (377MHz, DMSO-d6) δ-120.15,-120.17,-122.34,-122.36.

[0235] Example 12B: LC-MS: (ES+H,m / z):[M+H] + =541.2. 1H NMR(400MHz,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(377MHz,DMSO-d6)δ-120.16,-120.18,-122.34,-122.36. Examples 13A and 13B [ka] Step 1: Preparation of 5-(2-hydroxypropan-2-yl)-1H-pyridin-2-one:

[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 for an additional 1 h at room temperature. The reaction was monitored by LCMS. The reaction was quenched by adding saturated NH4Cl(aq) (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 equiv.) 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 equiv.) in 1,4-dioxane (6 mL), KCO (484 mg, 3.50 mmol, 2.00 equiv.), CuI (667 mg, 3.50 mmol, 2.00 equiv.), and (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (498 mg, 3.50 mmol, 2.00 equiv.) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80° C. under a nitrogen atmosphere for 3 hours. The residue was diluted with HO (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 NaSO. 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(400MHz,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 rel-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 rel-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 equiv) was separated by preparative chiral HPLC to give Example 13A (43.9 mg, 98.2% purity, ee=100%) as a white solid and Example 13B (33.6 mg, 98.3% purity, ee=100%) as a white solid.

[0239] Example 13A: LC-MS: (ES+H,m / z):[M+H] + =529.0. 1 H NMR(300MHz,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 (282MHz, DMSO-d6) δ-120.15,-120.17,-122.35,-122.38.

[0240] Example 13B: LC-MS: (ES+H,m / z):[M+H] + =529.0. 1H NMR(300MHz,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 (282MHz, DMSO-d6) δ-120.15,-120.17,-122.35,-122.38. Examples 14A, 14B, 14C, 14D [ka] Step 1: Preparation of 1-cyclopropyl-1-(2-methoxypyridin-3-yl)ethanol:

[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, cyclopropyl methyl ketone (2.15 g, 25.55 mmol, 1.50 equiv) was added dropwise over 20 minutes at 0° C. 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 NaSO. 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. 1H NMR(300MHz,DMSO-d6)δ 8.02(dd,1H),7.81(dd,1H),6.95(dd,1H),4.65(s,1H),3.89(s,3H),1.6 6-1.56(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 equiv.) and (ethylsulfanyl)sodium (4.95 g, 58.84 mmol, 10.0 equiv.) in DMF (20 mL) was stirred at 100 °C for 3 h under a nitrogen atmosphere. The mixture was allowed to reach room temperature. The resulting mixture was diluted with water (100 mL). The mixture was acidified with concentrated HCl to pH 4-5. 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 H NMR(300MHz,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.), KCO (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 allowed to cool to room temperature. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 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 H NMR(400MHz,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). Step 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, Preparation of 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 mg). 1 mg, 97.8% purity, de=100%) was obtained as an off-white solid as 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, 97.0% purity, de=98.2%).

[0245] The mixture of Example 14A and Example 14B (270 mg) was further separated by preparative chiral HPLC to give 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%) were obtained.

[0246] Example 14A: LC-MS: (ES+H, m / z): [M+H] + =555.00. 1 H NMR(300MHz,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 (282MHz, 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 19F 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 19F 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. 1H NMR(300MHz,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 (282MHz, DMSO-d6) δ-120.16,-120.18,-122.35,-122.37. Examples 15A and 15B [ka] Step 1: Preparation of methyl 2-methoxy-4-methylpyridine-3-carboxylate:

[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)Cl (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 a carbon monoxide (20 atm) atmosphere. The resulting mixture was stirred at 110 °C for 24 h. The reaction mixture was poured into water at room temperature. The aqueous layer was extracted with CHCl (3 × 20 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous NaSO. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford 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 H NMR (300MHz, 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 hours. 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 NaSO. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 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 (400MHz, 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) was added 1 M bromo(methyl)magnesium in THF (26 mL, 26.32 mmol, 10.00 equiv) 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 NH Cl (aq) 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 Na SO . 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. 1 H NMR (300MHz, 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] 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-enecarbonimidoylbromide in 1,4-dioxane (8 mL) To a stirred mixture of bromide (534 mg, 1.19 mmol, 1.00 equiv.), (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. Step 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, 97.7% purity, ee=100%) as a white solid and Example 15B (130.0 mg, 98.3% purity, ee=100%) as a white solid.

[0254] Example 15A: LC-MS: (ES+H,m / z):[M+H] + =543.0. 1 H NMR(400MHz,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 (377MHz, 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(400MHz,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). 19F NMR (377MHz, DMSO-d6) δ -120.16, -120.18, -122.35, -122.37. Examples 16A and 16B [ka] 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 equiv) and 2,2-dimethyl-6-(2-oxopropyl)-1,3-dioxin-4-one (19.70 g, 106.92 mmol, 2.00 equiv) in 1,4-dioxane (100 mL) was stirred at 80° C. for 2 hours under a nitrogen atmosphere. To the above mixture, HSO (3.99 mL, 74.85 mmol, 1.40 equiv) 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 allowed to reach room temperature. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in water (50 mL) and EtO (100 mL). The precipitated solid was collected by filtration and washed with EtO (3 × 10 mL) to give 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] To 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 18-crown-6 (0.81 g, 3.06 mmol, 0.30 equiv.) and KCO (7.02 g, 50.79 mmol, 5.00 equiv.) at rt. The resulting mixture was stirred at 60 °C under a nitrogen atmosphere for 3 hours. 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 under a nitrogen atmosphere for 2 hours. The mixture was allowed to cool to room temperature. The precipitated solid was collected by filtration and washed with hexane (3 x 10 mL). This gave 5'-bromo-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2',6-dimethyl-[1,3'-bipyridin]-2-one (880 mg, 47.86%) 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), CuI (58 mg, 0.30 mmol, 0.20 equiv.), KCO (423 mg, 3.06 mmol, 2.00 equiv.), and N1,N2-dimethylcyclohexane-1,2-diamine (87 mg, 0.61 mmol, 0.40 equiv.) were added. The resulting mixture was stirred at 90 °C under a nitrogen atmosphere for 3 h. 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. Step 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(300MHz,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(282MHz,DMSO-d6)δ-120.13,-120.16,-122.34,-122.37.

[0262] Example 16B: LC-MS: (ES+H,m / z):[M+H] + =529.0. 1H NMR(300MHz,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(282MHz,DMSO-d6)δ-120.13,-120.15,-122.33,-122.36. Examples 17A and 17B [ka] Step 1: Preparation of 3-(prop-1-en-2-yl)-1H-pyridin-2-one:

[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 HO (10 mL), KCO (9.53 g, 68.96 mmol, 2.00 equiv.) and Pd(dppf)Cl (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 NaSO. 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) was added TFA (10 mL) and SiH(Et) (5 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 24 hours. 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 NaSO. 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, 99.7% purity, ee=100%) and Example 17B (62.0 mg, 96.3% purity, ee=100%) as white solids.

[0267] Example 17A: LC-MS: (ES+H,m / z):[M+H] + =513.1. 1 H NMR(300MHz,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(282MHz,DMSO-d6)δ-120.16,-120.18,-122.36,-122.38.

[0268] Example 17B: LC-MS: (ES+H,m / z):[M+H] + =512.95. 1H NMR(300MHz,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(282MHz,DMSO-d6)δ-120.16,-120.18,-122.36,-122.38. Examples 18A and 18B [ka] Step 1: Preparation of 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:

[0269] 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. To a stirred solution of 3-(2-hydroxypropan-2-yl)-1H-pyridin-2-one (26.72 g, 174.43 mmol, 2.00 equiv.), K2CO3 (15.07 g, 109.00 mmol, 2.00 equiv.), and CuI (2.08 g, 10.90 mmol, 0.20 equiv.) 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 under a nitrogen atmosphere for 3 hours. 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, then cooled to room temperature for 2 h and kept 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)(2H)methoxy]-2'-[3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-5',6'-dimethyl-[1,4-bipyridin]-2-one (18.21 g, 62.8% yield, 97.2% purity) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =531.1. 1 H NMR(300MHz,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),6.8 1(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. Pure fractions were concentrated under reduced pressure to give 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 min, then brought to room temperature and held at 4° C. for 20 min, 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, 98.4% purity, 97.8% deuterium purity, ee=100%) as a white solid, and Example 18B (approximately 30.40 g).

[0271] 30 g of Isomer 2 (Example 18B) in dioxane (200 mL) was heated at 100° C. for 24 h, and the resulting mixture was concentrated to give the racemate (approximately 30 g), which was combined with another 6 g from the previous mother liquor and then further separated by preparative chiral SFC. Pure fractions were concentrated under reduced pressure to give 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, 99.2% purity, 97.8% deuterium purity) as a white solid, and Example 18B (approximately 15.40 g, white solid).

[0272] The two batches of Example 18A were combined (44.52 g) and then added to a co-solvent of IPA and water (440 mL, V IPA / V H2O=1,2':4',1''-terpyridine]-2,2''-dione (Example 18A: 41.62 g, 99.3% purity, 97.9% deuterium purity, ee=100%).

[0273] Example 18A: LC-MS: (ES+H,m / z):[M+H] + =531.15. 1 H NMR(300MHz,DMSO-d6)δ 8.69(s,1H),8.61(d,1H),8.16-8.03(m,1H),7.86(dd,2.1Hz,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(282MHz,DMSO-d6)δ-120.22,-120.24,-122.28,-122.31. Examples 19A and 19B [ka] Step 1: Preparation of 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:

[0274] 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 equiv.), 3-(2-hydroxypropan-2-yl)-1H-pyrazin-2-one (25.21 g, 163 A mixture of (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (1.55 g, 10.90 mmol, 0.20 equiv.), K2CO3 (15.07 g, 109.00 mmol, 2.00 equiv.), and CuI (1.04 g, 5.45 mmol, 0.10 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 (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 give the crude product and Example 19B (approximately 35.00 g). The crude product was redissolved in ACN and then concentrated to dryness. The solid was suspended in water (150 mL) and stirred at 50° C. for 30 minutes, then allowed to reach room temperature. The precipitated solid was collected and dried to give Example 19A as a pale yellow solid (33.60 g, 98.2% purity, 98.1% deuterium purity, ee=99.8%).

[0276] 35 g of Isomer 2 (Example 19B) in dioxane (200 mL) was heated at 100° C. for 24 h, and the resulting mixture was concentrated to give the racemate (approximately 35 g), which was then further separated by preparative chiral SFC. Pure fractions were concentrated under reduced pressure to give 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 19A: 16.1 g, 98.0% purity, 97.7% deuterium purity, ee=100.0%) as a white solid, and Example 19B (approximately 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) and stirred at 50° C. for 30 minutes, then cooled to room temperature. The precipitated solid was collected to give 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. 1H NMR(400MHz,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),7.4 8(d,1H),6.82(d,1H),5.13(s,1H),2.11(s,3H),2.01(s,3H),1.51(s,6H). 19 F NMR(377MHz,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 NMR(400MHz,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),7.4 8(d,1H),6.82(d,1H),5.13(s,1H),2.11(s,3H),2.01(s,3H),1.51(s,6H). 19F NMR (377MHz, DMSO-d6) δ-120.25,-120.27,-122.32,-122.34. Examples 20A and 20B [ka] Step 1: Preparation of 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:

[0280] 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 equiv.), 3-(2-hydroxypropan-2-yl)-1H-pyrazin-2-one (9.73 g, 6 A mixture of (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (1.80 g, 12.62 mmol, 0.40 equiv.), K2CO3 (8.73 g, 63.14 mmol, 2.00 equiv.), CuI (1.20 g, 6.31 mmol, 0.20 equiv.), and (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (1.80 g, 12.62 mmol, 0.40 equiv.) was stirred at 80 °C for 2 h under a nitrogen atmosphere. The mixture was allowed to warm to room temperature. The resulting mixture was diluted with ethyl acetate (1500 mL) and washed with 10% NH3 in water (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(400MHz,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). Step 2: Preparation of rel-3-chloro-4-((5-chloro-3-fluoropyridin-2-yl)methoxy-d2)-2'-(3-(2-hydroxypropan-2-yl)-2-oxopyrazin-l(2H)-yl)-5',6-dimethyl-2H-[l,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-l(2H)-yl)-5',6-dimethyl-2H-[l,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, 98.6% purity, 96.5% deuterium purity, 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, 97.2% purity, 96.3% deuterium purity, ee=100%) as a white solid.

[0282] Example 20A: LC-MS: (ES+H,m / z):[M+H] + =548.1. 1 H NMR(400MHz,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 (377MHz, DMSO-d6) δ-121.68.

[0283] Example 20B: LC-MS: (ES+H,m / z):[M+H] + =548.0. 1 H NMR(400MHz,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 (377MHz, DMSO-d6) δ-121.68. Examples 21A and 21B [ka] Step 1: Preparation of 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:

[0284] 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 equiv.), 3-(2-hydroxypropan-2-yl)-1H-pyridin-2-one (0.64 g, 4 A mixture of (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (0.20 g, 1.05 mmol, 1.00 equiv.), K2CO3 (0.58 g, 4.21 mmol, 2.00 equiv.), and CuI (0.30 g, 2.10 mmol, 0.50 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-[(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 give Example 21A (103.8 mg, 98.1% purity, 97.6% deuterium purity, ee=100.0%) and Example 21B (75.4 mg, 95.3% purity, 97.0% deuterium purity, ee=100.0%) as white solids.

[0286] Example 21A: LC-MS: (ES+H,m / z):[M+H] + =547.2. 1 H NMR(300MHz,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 (282MHz, DMSO-d6) δ-121.66.

[0287] Example 21B: LC-MS: (ES+H,m / z):[M+H] + =547.3. 1 H NMR(300MHz,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(282MHz,DMSO-d6)δ-121.67. Examples 22A and 22B [ka] Step 1: Preparation of 3-chloro-4-((3-chloro-5-fluoropyridin-2-yl)methoxy-d2)-2'-(3-(2-hydroxypropan-2-yl)-2-oxopyridin-1(2H)-yl)-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one:

[0288] 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.) in 1,4-dioxane (100 mL); CuI A mixture of (0.80 g, 4.20 mmol, 0.20 equiv) and K2CO3 (407.22 mg, 2.94 mmol, 2.00 equiv) was stirred at 80 °C for 2 h under a nitrogen atmosphere. The mixture was allowed to warm to room temperature. The resulting mixture was diluted with ethyl acetate (1000 mL) and washed with 10% NH3 in water (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(400MHz,DMSO-d6)δ8.75(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). Step 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) was obtained as a white solid.

[0290] Example 22A: LC-MS: (ES+H,m / z):[M+H] + =548.2. 1 H NMR(300MHz,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(282MHz,DMSO-d6)δ-124.18,-124.20.

[0291] Example 22B: LC-MS: (ES+H,m / z):[M+H] + =548.2. 1H NMR(300MHz,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 F NMR(282MHz,DMSO-d6)δ-124.18,-124.20. Examples 23A and 23B [ka] 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)(2H)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) in dioxane (6 mL) was stirred at 80 °C under a nitrogen atmosphere for 2 h. 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 give Example 23A (192.8 mg, 98.4% purity, 95.9% deuterium purity, ee=100.0%) as a white solid and Example 23B (201.8 mg, 98.4% purity, 96.0% deuterium purity, ee=100.0%) as a white solid.

[0294] Example 23A: LC-MS: (ES+H,m / z):[M+H] + =547.00. 1 H NMR(400MHz,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(282MHz,DMSO-d6)δ-124.16.

[0295] Example 23B: LC-MS: (ES+H, m / z): [M+H]+=547.05. 1 H NMR(400MHz,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(282MHz,DMSO-d6)δ-124.16. Examples 24A and 24B [ka] Step 1: Preparation of 2'-bromo-4-[(3-chloro-5-fluoropyridin-2-yl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one:

[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 KCO (3.71 g, 26.43 mmol, 6.00 equiv) in DMF (8 mL) was stirred at 60 °C under a nitrogen atmosphere for 1 h. The resulting mixture was diluted with ethyl acetate (300 mL) and washed with 3 × 100 mL of HO. 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(400MHz,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 equivalents), NCS (401 mg, 3.01 mmol, 1.20 equivalents), and 2,2-dichloroacetic acid (323 mg, 2.50 mmol, 1.00 equivalents) were added to IPA (5 mL) at room temperature. The resulting mixture was stirred at 60°C under a nitrogen atmosphere for 2 hours. The mixture was allowed to cool to room temperature. The resulting mixture was filtered, and the filter cake was washed with IPA (3 x 5 mL). The filtrate was concentrated under reduced pressure. This gave 2'-bromo-3-chloro-4-[(3-chloro-5-fluoropyridin-2-yl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one (810 mg, 68.2%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =474.0. 1 H NMR(400MHz,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 equiv), 3-(2-hydroxypropan-2-yl)-1H-pyrazin-2-one (708 mg, 4.59 mmol, 3.00 equiv), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (87 mg, 0.61 mmol, 0.40 equiv), CuI (58 mg, 0.30 mmol, 0.20 equiv), and K2CO3 (423 mg, 3.06 mmol, 2.00 equiv) in dioxane (5 mL) was stirred at 80 °C under a nitrogen atmosphere for 3 h. 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 give the crude product, which was further purified by preparative HPLC. This afforded 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%) 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(300MHz,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(282MHz,DMSO-d6)δ-124.24.

[0301] Example 24B: LC-MS: (ES+H,m / z):[M+H] + =546.00. 1 H NMR(300MHz,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(282MHz,DMSO-d6)δ-124.24. Examples 25A and 25B [ka] Step 1: Preparation of 2-chloro-4-iodo-5-methylpyridine:

[0302] To 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 tBuONO (21.7 g, 210.39 mmol, 1.5 equiv.) dropwise at 0° C. under a nitrogen atmosphere. The mixture was stirred at room temperature for 1 h. The mixture was then stirred at 50° C. under a nitrogen atmosphere for an additional 3 h. The mixture was allowed to cool 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 (400MHz, 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.), KCO (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 (aq.) (3 × 500 mL) and dried over anhydrous NaSO. 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. 1H NMR (400MHz, 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) was added methyl-3-chloro-3-oxopropanoate (1040.85 mg, 7.624 mmol, 2 equiv) 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 NaHCO (aq) (10 mL) at room temperature. The resulting mixture was poured into water (50 mL). The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were quenched with saturated NaCl (aq) (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 NMR (400MHz, 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. under a nitrogen atmosphere for 4 hours. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated in vacuo. 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, KCO (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 under a nitrogen atmosphere for 3 hours. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated in vacuo. 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), 2,2-dichloroacetic acid (22 mg, 0.17 mmol, 0.10 equiv.) was added dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 60° C. under a nitrogen atmosphere for 2 hours. The mixture was allowed to cool to room temperature. The precipitated solid was collected by filtration and washed with i-PrOH (3 x 5 mL) to give 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] 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. To a stirred solution of 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.) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 24 h. 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 give 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 H NMR(400MHz,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 F NMR(400MHz,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 H NMR(400MHz,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 F NMR(400MHz,DMSO-d6)δ-120.38,-120.40,-123.01,-123.03. Examples 26A and 26B [ka] Step 1: Preparation of ethyl 4-fluoro-2-methoxypyridine-3-carboxylate:

[0312] To a stirred mixture of 4-fluoro-2-methoxypyridine-3-carboxylic acid (1.00 g, 5.84 mmol, 1.00 equiv.) in DMF (20 mL) was added iodoethane (1.37 g, 8.76 mmol, 1.50 equiv.) and K2CO3 (1.62 g, 11.68 mmol, 2.00 equiv.) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 50 °C under a nitrogen atmosphere for 2 hours. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with EtOAc (100 mL). The resulting mixture was washed with HO (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 equiv.) in MeCN (15 mL) was added TMSI (3.62 g, 18.07 mmol, 4.00 equiv.) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. 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] To a stirred solution of ethyl 4-fluoro-2-oxo-1H-pyridine-3-carboxylate (700 mg, 3.78 mmol, 1.00 equiv.) in THF (70.00 mL) was added MeMgBr (3.7 mL, 3 M in 2-methyl-THF, 11.34 mmol, 3.00 equiv.) dropwise at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at 0° C. for 1 hour under a nitrogen atmosphere. The reaction was quenched by adding saturated NH4Cl(aq.) (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 afforded 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)(2H)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one (500 mg, 1.09 mmol, 1.00 equiv.) and 4-fluoro-3-(2-hydroxypropan-2-yl)-1H-pyridin-2-one (373 mg, 2.180 mmol, 2.00 equiv.) in dioxane (10 mL), CuI (41 mg, 0.21 mmol, 0.20 equiv.), (1R,2R)-1-N,2-N-dimethylcyclohexane-1,2-diamine (62 mg, 0.43 mmol, 0.40 equiv.), and KCO (301 mg, 2.18 mmol, 2.00 equiv.) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. The resulting mixture was diluted with EtOAc (50 mL). The combined organic layers were washed with brine (2 x 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 give 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(300MHz,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 (282MHz, 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(300MHz,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 (282MHz, DMSO-d6) δ -91.28, -120.25, -120.27, -122.32, -122.35. Examples 27A and 27B [ka] Steps 1 and 2: Preparation of methyl 2-{[(2,2-dimethoxyethyl)carbamoyl]amino}-2-methylpropanoate:

[0319] To a stirred mixture of 3-methoxy-2,2-dimethyl-3-oxopropanoic acid (2.00 g, 13.68 mmol, 1.00 equiv.) and EtN (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 minutes under a nitrogen atmosphere. The resulting mixture was stirred at 90 °C for an additional 2 hours 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 hours. The reaction was poured into saturated NaHCO (aq.) (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 NaSO. 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. under a nitrogen atmosphere for 1 hour. 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. 1H NMR (300MHz, 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) was added LiAlH (247 mg, 6.51 mmol, 2.00 equiv) portionwise at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 30 minutes. 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 NaSO. 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 H NMR (300MHz, 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) in dioxane (5 mL) was stirred at 80 °C under a nitrogen atmosphere for 2 h. 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, 98.1% purity, ee=100.0%) as a white solid and Example 27B (82.9 mg, 99.7% purity, ee=99.5%) as a white solid.

[0324] Example 27A: LC-MS: (ES+H,m / z):[M+H] + =532.2. 1 H NMR(400MHz,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(377MHz,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(400MHz,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(377MHz,DMSO-d6)δ-120.20,-120.22,-122.42,-122.44. Examples 28A and 28B [ka] Step 1: Preparation of ethyl 3-fluoro-5-methylpyridine-2-carboxylate:

[0326] To a stirred mixture of 2-bromo-3-fluoro-5-methylpyridine (4.00 g, 21.05 mmol, 1.00 equiv.) and Pd(dppf)Cl (1.54 g, 2.10 mmol, 0.10 equiv.) in EtOH (40 mL) was added EtN (25.56 g, 252.61 mmol, 3.00 equiv.) dropwise at room temperature. The resulting mixture was stirred at 80 °C under a carbon monoxide atmosphere (50 atm) for 18 hours. The mixture was allowed to warm to room temperature. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with CHCl (200 mL) and washed with 3 × 100 mL of HO. 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 H NMR (300MHz, 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) was added sodium borodeuteride (1.86 g, 49.13 mmol, 3.00 equiv.) portionwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 h. The filtrate was quenched by adding DO (4 mL) at 0 °C. The resulting mixture was diluted with ethyl acetate (300 mL) and washed with 3 × 100 mL of HO. 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. 1H NMR (300MHz, 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)(2H)methanol (2.40 g, 16.76 mmol, 1.00 equiv.) and DMF (0.1 mL, 1.67 mmol, 0.10 equiv.) in DCM (24 mL) was added SOCl (2.6 mL, 36.88 mmol, 2.20 equiv.) dropwise under a nitrogen atmosphere at 0° C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated in vacuo to give 2-[chloro(2H)methyl]-3-fluoro-5-methylpyridine (3.30 g, crude) as a tan liquid. LC-MS: (ES+H, m / z): [M+H] + =162.1. 1 H NMR (300MHz, 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(2H)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 under a nitrogen atmosphere for 2 h. The mixture was allowed to warm 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(300MHz,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)(2H)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 2,2-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 under a nitrogen atmosphere for 1 hour. The mixture was allowed to cool to 4°C. The precipitated solid was collected by filtration and washed with IPA (3 x 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(300MHz,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)(2H)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one (380 mg, 0.83 mmol, 1.00 equiv), 3-(2-hydroxypropan-2-yl)-1H-pyrazin-2-one (386 mg, 2.50 mmol, 3.00 equiv), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (47 mg, 0.33 mmol, 0.40 equiv), CuI (31 mg, 0.16 mmol, 0.20 equiv), and K2CO3 (230 mg, 1.67 mmol, 2.00 equiv) in 1,4-dioxane (3 mL) was stirred at 80 °C under a nitrogen atmosphere for 2 h. The mixture was allowed to warm to room temperature. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (10% NH3, 3 x 50 mL). The organic layer was concentrated under reduced pressure to give the 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(300MHz,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,1 H),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, 99.6% purity, ee=100%) as a white solid and Example 28B (26.7 mg, 99.7% purity, ee=100%) as a white solid.

[0333] Example 28A: LC-MS: (ES+H,m / z):[M+H] + =528.20. 1 H NMR(300MHz,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,1 H),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(282MHz,DMSO-d6)δ-126.30.

[0334] Example 28B: LC-MS: (ES+H,m / z):[M+H] + =528.20. 1 H NMR(300MHz,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,1 H),6.83(s,1H),5.13(s,1H),2.38(s,3H),2.10(s,3H),2.00(s,3H),1.51(s,6H). 19F NMR(282MHz,DMSO-d6)δ-126.30. Biological Examples: 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) into pGEX-4T1 (GE) for overexpression of these kinases with an N-terminal GST tag. Growing the host in TB medium yielded approximately 0.8 OD 600 Protein expression was performed in E. coli BL21 by inducing protein expression with 0.5 mM IPTG at 100°C and then incubating the culture at 18°C ​​for 14–20 hours. 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 three passages. Cell lysates were 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 extensive washing of the column 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 approximately 1 mg / mL and stored at -80°C. Biochemical assays

[0336] This study evaluates the inhibitory potency of compounds of the present invention on the p38 / MK2 pathway versus the p38 / PRAK pathway. More specifically, the compound concentration that inhibited half-maximal activation of MK2 or PRAK by p38 (IC 50 ) were determined. MK2 activation studies were set up without or with a 10-point 1:3 dilution series of compounds of the present invention at a top dose of 1 or 10 μM, and PRAK activation studies were set up without or with a 10-point 1:3 dilution series of compounds of the present invention at a top dose of 300 μM. MK2 and PRAK activities were determined by the phosphorylation level of HSP27 peptide conjugated with FITC.

[0337] A typical assay was performed in a 20 μL volume containing 60 pM active p38α (Carna, catalog no. 04-152), 10 μM ATP, 1 μM FITC-HSP27 peptide (Sangon, catalog no. P22354), and 1 nM inactive MK2 or PRAK in 1× reaction buffer (20 mM HEPES, pH 7.5, 10 mM MgCl2, 1 mM DTT, 0.01% Triton X-100, 0.01% BSA). After incubating the reaction mixture with various concentrations of compounds of the present invention (200 nL) for 2 hours, 60 μL of 1× IMAP solution mixture (Molecular Devices, catalog no. 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] Signals were then normalized to vehicle control and fitted with Xfit to obtain IC 50 The selectivity of MK2 for PRAK was calculated as selectivity = IC of PRAK. 50 / MK2 IC 50 was calculated by the method.

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

Claims

1. A compound of formula (I) or a pharma- ceutically acceptable salt, solvate, stereoisomer, or rotamer thereof 【Chemistry 60】 (In the formula, Ring A is heteroaryl; Each R １０ are independently deuterium, halogen, -CN, -NO ２ , -OH, -OR ａ , -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SH, -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ N.R. ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C(=O)OR ｂ , -NR ｂ S (=O) ２ R ａ , -C(=O)R ａ , -C(=O)OR ｂ , -C(=O)NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Deuteroalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently selected from one or more R １０ａ or replaced by Or two R on the same atom １０ together to form oxo, Each R １０ａ are independently deuterium, halogen, -CN, -NO ２ , -OH, -OR ａ , -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SH, -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ N.R. ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C(=O)OR ｂ , -NR ｂ S (=O) ２ R ａ , -C(=O)R ａ , -C(=O)OR ｂ , -C(=O)NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Deuteroalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Or two R on the same atom １０ａ together to form oxo, n is 2; R １ and R ２ are independently hydrogen, deuterium, halogen, -CN, -NO ２ , -OH, -OR ａ , -NR ｃ R ｄ , -C(=O)R ａ , -C(=O)OR ｂ , -C(=O)NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Deuteroalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ alkynyl, cycloalkyl, or heterocycloalkyl; Or R １ and R ２ together to form oxo, or Or R １ and R ２ taken together form a cycloalkyl or heterocycloalkyl, the cycloalkyl and heterocycloalkyl optionally being selected from the group consisting of deuterium, halogen, —CN, —OH, —OCH ３ , -NH ２ , -NHCH ３ , -N(CH ３ ) ２ , -C(=O)CH ３ , -C(=O)OH, -C(=O)OCH ３ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Deuteroalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, or C １ ~C ６ is substituted with heteroalkyl; X is -C(R ３ ) ２ --, --NR ４ -, -O-, or -S-; Each R ３ are independently hydrogen, deuterium, halogen, -CN, -NO ２ , -OH, -OR ａ , -NR ｃ R ｄ , -C(=O)R ａ , -C(=O)OR ｂ , -C(=O)NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Deuteroalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ alkynyl, cycloalkyl, or heterocycloalkyl; Or two R's ３ together to form oxo, R ４ is hydrogen, -C(=O)R ａ , -C(=O)OR ｂ , -C(=O)NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Deuteroalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ alkynyl, cycloalkyl, or heterocycloalkyl; R ５ Hydrogen, deuterium, halogens, -CN, -NO ２ , -OH, -OR ａ , -NR ｃ R ｄ , -C(=O)R ａ , -C(=O)OR ｂ , -C(=O)NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Deuteroalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ alkynyl, cycloalkyl, or heterocycloalkyl; R ６ Hydrogen, deuterium, halogens, -CN, -NO ２ , -OH, -OR ａ , -NR ｃ R ｄ , -C(=O)R ａ , -C(=O)OR ｂ , -C(=O)NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Deuteroalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ alkynyl, cycloalkyl, or heterocycloalkyl; R ７ But hydrogen, deuterium, halogens, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, or C １ ~C ６ is a deuteroalkyl; Ring B is heteroaryl; Each R １１ are independently deuterium, halogen, -CN, -NO ２ , -OH, -OR ａ , -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SH, -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ N.R. ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C(=O)OR ｂ , -NR ｂ S (=O) ２ R ａ , -C(=O)R ａ , -C(=O)OR ｂ , -C(=O)NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Deuteroalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently selected from one or more R １１ａ is replaced by Or two R on the same atom １１ together to form oxo, Each R １１ａ are independently deuterium, halogen, -CN, -NO ２ , -OH, -OR ａ , -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SH, -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ N.R. ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C(=O)OR ｂ , -NR ｂ S (=O) ２ R ａ , -C(=O)R ａ , -C(=O)OR ｂ , -C(=O)NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Deuteroalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Or two R on the same atom １１ａ together to form oxo, m is 1, Ring C is an N-linked pyridinone, an N-linked pyrimidinone, an N-linked pyrazinone, or an N-linked pyridazinone; Each R １２ are independently deuterium, halogen, -CN, -NO ２ , -OH, -OR ａ , -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SH, -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ N.R. ｃ R ｄ , -S(=O)(=NR ｂ ) R ａ , -SiR ｃ R ｄ OR ｂ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C(=O)OR ｂ , -NR ｂ S (=O) ２ R ａ , -C(=O)R ａ , -C(=O)OR ｂ , -C(=O)NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Deuteroalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ ~C ６ Alkylene (cycloalkyl), C １ ~C ６ Alkylene (heterocycloalkyl), C １ ~C ６ Alkylene (aryl), or C １ ~C ６ alkylene(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently selected from one or more R １２ａ is replaced by Each R １２ａ are independently deuterium, halogen, -CN, -NO ２ , -OH, -OR ａ , -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SH, -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ N.R. ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C(=O)OR ｂ , -NR ｂ S (=O) ２ R ａ , -C(=O)R ａ , -C(=O)C(=O)R ａ , -C(=O)OR ｂ , -C(=O)NR ｃ R ｄ , -C(=O)C(=O)NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Deuteroalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Or two R on the same atom １２ａ together to form oxo, p is 1 or 2; Each R ａ became independent and C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Deuteroalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ ~C ６ Alkylene (cycloalkyl), C １ ~C ６ Alkylene (heterocycloalkyl), C １ ~C ６ Alkylene (aryl), or C １ ~C ６ alkylene(heteroaryl), where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently represents one or more of oxo, deuterium, halogen, —CN, —OH, —OCH ３ , -S(=O)CH ３ , -S(=O) ２ CH ３ , -S(=O) ２ N.H. ２ , -S(=O) ２ N.H.C.H. ３ , -S(=O) ２ N (CH ３ ) ２ , -NH ２ , -NHCH ３ , -N(CH ３ ) ２ , -C(=O)CH ３ , -C(=O)OH, -C(=O)OCH ３ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Deuteroalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, or C １ ~C ６ is optionally substituted with heteroalkyl; Each R ｂ are independently hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Deuteroalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ ~C ６ Alkylene (cycloalkyl), C １ ~C ６ Alkylene (heterocycloalkyl), C １ ~C ６ Alkylene (aryl), or C １ ~C ６ alkylene(heteroaryl), where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently represents one or more of oxo, deuterium, halogen, —CN, —OH, —OCH ３ , -S(=O)CH ３ , -S(=O) ２ CH ３ , -S(=O) ２ N.H. ２ , -S(=O) ２ N.H.C.H. ３ , -S(=O) ２ N (CH ３ ) ２ , -NH ２ , -NHCH ３ , -N(CH ３ ) ２ , -C(=O)CH ３ , -C(=O)OH, -C(=O)OCH ３ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Deuteroalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, or C １ ~C ６ is optionally substituted with heteroalkyl; Each R ｃ and R ｄ are independently hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Deuteroalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ ~C ６ Alkylene (cycloalkyl), C １ ~C ６ Alkylene (heterocycloalkyl), C １ ~C ６ Alkylene (aryl), or C １ ~C ６ alkylene(heteroaryl), where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently represents one or more of oxo, deuterium, halogen, —CN, —OH, —OCH ３ , -S(=O)CH ３ , -S(=O) ２ CH ３ , -S(=O) ２ N.H. ２ , -S(=O) ２ N.H.C.H. ３ , -S(=O) ２ N (CH ３ ) ２ , -NH ２ , -NHCH ３ , -N(CH ３ ) ２ , -C(=O)CH ３ , -C(=O)OH, -C(=O)OCH ３ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Deuteroalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, or C １ ~C ６ is optionally substituted with heteroalkyl; Or, R ｃ and R ｄ may be, together with the atom to which they are attached, one or more of oxo, deuterium, halogen, -CN, -OH, -OCH ３ , -S(=O)CH ３ , -S(=O) ２ CH ３ , -S(=O) ２ N.H. ２ , -S(=O) ２ N.H.C.H. ３ , -S(=O) ２ N (CH ３ ) ２ , -NH ２ , -NHCH ３ , -N(CH ３ ) ２ , -C(=O)CH ３ , -C(=O)OH, -C(=O)OCH ３ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Deuteroalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, or C １ ~C ６ forming a heterocycloalkyl optionally substituted with a heteroalkyl; Or, R ｂ and R ｃ may be, together with the atom to which they are attached, one or more of oxo, deuterium, halogen, -CN, -OH, -OCH ３ , -S(=O)CH ３ , -S(=O) ２ CH ３ , -S(=O) ２ N.H. ２ , -S(=O) ２ N.H.C.H. ３ , -S(=O) ２ N (CH ３ ) ２ , -NH ２ , -NHCH ３ , -N(CH ３ ) ２ , -C(=O)CH ３ , -C(=O)OH, -C(=O)OCH ３ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Deuteroalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, or C １ ~C ６ forming a heterocycloalkyl optionally substituted with a heteroalkyl; Or, R ａ and R ｂ may be, together with the atom to which they are attached, one or more of oxo, deuterium, halogen, -CN, -OH, -OCH ３ , -S(=O)CH ３ , -S(=O) ２ CH ３ , -S(=O) ２ N.H. ２ , -S(=O) ２ N.H.C.H. ３ , -S(=O) ２ N (CH ３ ) ２ , -NH ２ , -NHCH ３ , -N(CH ３ ) ２ , -C(=O)CH ３ , -C(=O)OH, -C(=O)OCH ３ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Deuteroalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, or C １ ~C ６ forming a heterocycloalkyl optionally substituted with a heteroalkyl; Or, two R ｂ may be, together with the atom to which they are attached, one or more of oxo, deuterium, halogen, -CN, -OH, -OCH ３ , -S(=O)CH ３ , -S(=O) ２ CH ３ , -S(=O) ２ N.H. ２ , -S(=O) ２ N.H.C.H. ３ , -S(=O) ２ N (CH ３ ) ２ , -NH ２ , -NHCH ３ , -N(CH ３ ) ２ , -C(=O)CH ３ , -C(=O)OH, -C(=O)OCH ３ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Deuteroalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, or C １ ~C ６ forming a heterocycloalkyl optionally substituted with a heteroalkyl.

2. 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, stereoisomer, or rotamer thereof, wherein Ring C is an N-linked pyridinone.

3. 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, stereoisomer, or rotamer thereof, wherein Ring C is an N-linked pyrimidinone.

4. 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, stereoisomer, or rotamer thereof, wherein Ring C is an N-linked pyrazinone.

5. 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, stereoisomer, or rotamer thereof, wherein Ring C is an N-linked pyridazinone.

6. Ring C is 【Chemistry 61】 2. The compound of claim 1, wherein:

7. 7. The compound of any one of claims 1 to 6, or a pharma- ceutically acceptable salt, solvate, stereoisomer, or rotamer thereof, wherein Ring A is pyridyl.

8. Each R １０ 10. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, stereoisomer, or rotamer thereof, wherein:

9. R １ and R ２ 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, stereoisomer, or rotamer thereof, wherein: is hydrogen.

10. R １ and R ２ 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, stereoisomer, or rotamer thereof, wherein: is deuterium.

11. 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, stereoisomer, or rotamer thereof, wherein X is -O-.

12. R ５ is hydrogen, deuterium, halogen, -CN, or C １ ~C ６ 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, stereoisomer, or rotamer thereof, wherein R is an alkyl group.

13. R ５ 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, stereoisomer, or rotamer thereof, wherein is hydrogen.

14. R ６ is hydrogen, deuterium, halogen, -CN, or C １ ~C ６ 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, stereoisomer, or rotamer thereof, wherein R is an alkyl group.

15. R ６ C １ ~C ６ 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R is an alkyl group;

16. R ７ 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, stereoisomer, or rotamer thereof, wherein is hydrogen, deuterium, or a halogen.

17. R ７ 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, stereoisomer, or rotamer thereof, wherein is halogen.

18. 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, stereoisomer, or rotamer thereof, wherein Ring B is a 6-membered heteroaryl.

19. 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, stereoisomer, or rotamer thereof, wherein Ring B is pyridinyl.

20. Each R １１ are independently deuterium, halogen, -CN, -OH, -OR ａ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Deuteroalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, stereoisomer, or rotamer thereof, which is alkynyl, or cycloalkyl.

21. Each R １１ But independently, C １ ~C ６ 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, stereoisomer, or rotamer thereof, wherein R is an alkyl group.

22. Each R １２ are 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 , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Deuteroalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ ~C ６ Alkylene (cycloalkyl), C １ ~C ６ Alkylene (heterocycloalkyl), C １ ~C ６ Alkylene (aryl), or C １ ~C ６ alkylene(heteroaryl), wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently one or more R １２ａ 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, stereoisomer, or rotamer thereof, optionally and independently substituted with:

23. Each R １２ are independently deuterium, halogen, -CN, -OH, -OR ａ , -NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Deuteroalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ ~C ６ Alkylene (cycloalkyl), or C １ ~C ６ alkylene (heterocycloalkyl), wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently one or more R １２ａ 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, stereoisomer, or rotamer thereof, optionally and independently substituted with:

24. Each R １２ are independently deuterium, halogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, cycloalkyl, heterocycloalkyl, C １ ~C ６ Alkylene (cycloalkyl), or C １ ~C ６ alkylene(heterocycloalkyl), wherein the alkyl, cycloalkyl, and heterocycloalkyl are each independently one or more R １２ａ 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, stereoisomer, or rotamer thereof, optionally and independently substituted with:

25. Each R １２ are independently deuterium, halogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ hydroxyalkyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, cycloalkyl, and heterocycloalkyl are each independently selected from one or more R １２ａ 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, stereoisomer, or rotamer thereof, optionally and independently substituted with:

26. Each R １２ But independently, C １ ~C ６ 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, stereoisomer, or rotamer thereof, which is hydroxyalkyl.

27. Each R １２ａ are 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 , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Deuteroalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, stereoisomer, or rotamer thereof, which is heteroalkyl, cycloalkyl, or heterocycloalkyl.

28. Each R １２ａ are independently deuterium, halogen, -CN, -OH, -OR ａ , -NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Deuteroalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, or C １ ~C ６ 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, stereoisomer, or rotamer thereof, which is heteroalkyl.

29. Each R ａ are independently deuterium, halogen, -CN, -OH, -OR ａ , C １ ~C ６ Alkyl, or C １ ~C ６ 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, stereoisomer, or rotamer thereof, which is haloalkyl.

30. 【Catalog 71】 【Chemical Formula 72】 【Chemical 73】 【Chemical 74】 【Chemistry 75】 【Chemical 76】 【Chemical Formula 77】 【Chemical 78】 2. The compound of claim 1 , or a pharma- ceutically acceptable salt, solvate, stereoisomer, or rotamer thereof, selected from:

31. 13. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1, or a pharma- ceutically acceptable salt, solvate, stereoisomer, or rotamer thereof, and a pharma- ceutically acceptable excipient.

32. 11. A composition for treating a condition comprising the compound of claim 1 or a pharma- ceutically acceptable salt, solvate, stereoisomer, or rotamer thereof, wherein the condition is selected from the group consisting of an autoimmune disorder, a chronic inflammatory disorder, an acute inflammatory disorder, an autoinflammatory disorder, a fibrotic disorder, a metabolic disorder, a neoplastic disorder, and a cardiovascular or cerebrovascular disorder.

33. 13. A composition for treating a p38 MAP kinase mediated disease in a subject in need thereof, comprising a compound of claim 1 or a pharma- ceutically acceptable salt, solvate, stereoisomer, or rotamer thereof.

34. A composition for treating an MK2-mediated disease in a subject in need thereof, comprising a compound of claim 1 or a pharma- ceutically acceptable salt, solvate, stereoisomer, or rotamer thereof.

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