MK2 inhibitors and their use

Abstract

Described herein are MK2 inhibitors and pharmaceutical compositions comprising the inhibitors.The subject 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 of related applications This application claims the interests of U.S. Provisional Patent Application No. 63 / 168,407, filed on 31 March 2021, and U.S. Provisional Patent Application No. 63 / 318,118, filed on 9 March 2022, which are incorporated herein by reference in their entirety. [Background technology]

[0002] Mitogen-activated protein kinases (MAPKs) are a conserved family of enzymes that use phosphorylation cascades to relay and propagate external stimuli to generate coordinated cellular responses to the environment. MAPKs are proline-directed serine / threonine-specific protein kinases that regulate cellular activities such as gene expression, mitosis, differentiation, and cell survival / apoptosis. To date, four distinct classes of mammalian MAPKs have been identified: extracellular signaling kinases (ERK1 and 2), c-jun N-terminal kinases 1 (JNK1-3), p38 MAPKs (ρ38α, β, γ, and δ), and ERK5. MAPKs are activated by the biphosphorylation of Thr and Tyr residues within the TXY activation motif by coordinated bispecific MAPKs, where X is Glu, Pro, and Gly in ERK, JNK, and p38 MAPKs, respectively. While MAPKs are 60-70% identical to one another, they still differ in their activation loop sequences and sizes. The activation loop is adjacent to the enzyme's active site, and its phosphorylation allows the enzyme to rearrange active site residues to an optimal orientation for substrate binding and catalysis. Downstream substrates of MAPK include mitogen-activated protein-kinase-activated protein (MAPKAP) kinases and transcription factors, and their 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] Different genes encode four p38 MAPKs in humans: ρ38α, β, γ, and δ. Significant amino acid sequence homology is observed among the four isoforms, with 60–75 whole sequence identity and >90% identity within the kinase domain. Tissue-selective expression is observed, with ρ38γ mainly found in skeletal muscle, and ρ38δ found in the testes, pancreas, and small intestine. In contrast, p38a and β are expressed more ubiquitously.

[0004] p38 MAPK is a major isoform involved in immune and inflammatory responses. Therefore, its function is crucial for the production and activity of several pro-inflammatory cytokines, including TNFα, IL-1, IL-6, and IL-8, in cells such as macrophages, monocytes, synovial cells, 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 at inflammatory sites, respectively. Furthermore, the p38 MAPK pathway regulates the expression of matrix metalloproteinases (MMPs), including MMP2, MMP9, and MMP13.

[0005] The use of selective and potent inhibitors 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 muscle cell-specific enhancer-binding factor 2C (MEF2C), CHOP, peroxisome proliferator-activated receptor (PPAR)a, 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 cytoplasmic phospholipase A2 and Cdc25 phosphatase, which are involved in the activation of cyclin-dependent protein kinase activity and cell cycle regulation. Therefore, 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, while the 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 show no tolerance to endotoxin shock or reduced lipopolysaccharide (LPS)-induced cytokine acidity. In contrast, MK-2-deficient mice exhibit tolerance to endotoxin shock and an impaired inflammatory response, as well as a significant reduction in the production of cytokines such as TNFα, IFNy, and IL-6. Therefore, the p38 / MK2 axis is crucial in mediating pro-inflammatory responses.

[0007] The p38:MK2 complex is highly stable, with a Kd of 6 nM. The binding affinity of p38 to 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 encapsulates p38a and binds to a negatively charged ED binding site. The strong binding of p38 to MK2 may result in conformational changes that provide further binding pockets for inhibitors specifically dependent on the p38:MK2 interaction. In summary, 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 characteristics in animal models of the disease or in human clinical settings.

[0008] The role of p38 / MK2 in regulating inflammatory cytokines (TNFα, IL-Iβ, IL-6) and enzymes involved in inflammation (COX-2, iNOS, and MMP) makes it an attractive drug target. Several classic p38 MAPK inhibitors have progressed to clinical trials. While some of these candidates have failed for 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-Iβ-mediated diseases may be affected by p38 inhibitors based on the crucial role of the p38 MAPK pathway in the biosynthesis and activity of this cytokine. These diseases include, among others, the family of cryopyrin-associated periodic disorders (CAPS), chronic gout, diabetes mellitus, Still's disease, and familial Mediterranean fever. [Overview of the Initiative] [Means for solving the problem]

[0009] Compounds of formula (II), or pharmaceutically acceptable salts, solvates, N-oxides, or stereoisomers thereof are disclosed herein. [ka] In the formula, ring A is phenyl or heteroaryl, each R A. is 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 , -NR c R d , -NR b , -NR a , -NR b , -NR b , -NR b , -NR a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 dideuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently substituted with one or more R Aa. or two R on the same atom are joined together to form oxo, A each R is independently deuterium, halogen, -CN, -NO2, -OH, -OR Aa , -OC(=O)R a , -OC(=O)OR a , -OC(=O)ORb -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 Rs on the same atom Aa They come together to form an oxo, n is between 0 and 4. R 1 and R 2 These 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 heterocycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, or R 1 and R 2 They come together to form an oxo, or R 1 and R 2 These combine to form a cycloalkyl or heterocycloalkyl group, and the cycloalkyl and heterocycloalkyl groups 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 These 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 heterocycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, or two R 3 They come together to form an oxo, R 4 This is hydrogen, -C(=O)R a , -C(=O)OR b -C(=O)NR c Rd is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 dideuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, R 5 is 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 is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 dideuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, R 6 is 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 is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 dideuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, R 7 is 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, Ring B is a heterocycloalkyl or heteroaryl ring. Each R B These 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 one or more R Ba. It is replaced by, or two Rs on the same atom B They come together to form an oxo, Each RBa These 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 Rs on the same atom Ba They come together to form an oxo, m is between 0 and 4. Ring C is a 5-membered heteroaryl, Each R C These 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 Ure 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 alkyl)cycloalkyl, (C1-C6 alkyl)heterocycloalkyl, (C1-C6 alkyl)aryl, or (C1-C6 alkyl)heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently one or more R Ca. It is replaced by, Each R Ca These 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 , -NRc 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 Rs on the same atom Ca They come together to form an oxo, p is between 0 and 4. Each R aThese 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 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, and The reel and heteroaryl are independently and 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 bThese are 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 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl aryl and heteroaryl are independently and 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 dThese are 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 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl aryl and heteroaryl are independently and 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 These, together with the atoms to which they bond, optionally form heterocycloalkyls 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. However, if the compound is [ka] This is conditional on the fact that it is not the case.

[0010] Compounds of formula (I), or pharmaceutically acceptable salts, solvates, N-oxides, or stereoisomers thereof are disclosed herein. [ka] During the ceremony, Ring A is phenyl or heteroaryl, Each R A. These 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 one or more R Aa. It is replaced by, or two Rs on the same atom A They come together to form an oxo, Each RAa These 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 Rs on the same atom Aa They come together to form an oxo, n is between 0 and 4. R 1 and R 2 These 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 heterocycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, or R 1 and R 2 They come together to form an oxo, or R 1 and R 2 These combine to form a cycloalkyl or heterocycloalkyl group, and the cycloalkyl and heterocycloalkyl groups 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 These 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 heterocycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, or two R 3 They come together to form an oxo, R 4 This is hydrogen, -C(=O)R a , -C(=O)OR b -C(=O)NR c Rd , 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, Z is either N or CR 5 And, R 5 These are 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 These are 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, Ring B is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring. Each R B These are independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c Rd -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 one or more R Ba. It is replaced by, or two Rs on the same atom B They come together to form an oxo, Each R Ba These 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 Rd , -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 Rs on the same atom Ba They come together to form an oxo, m is between 0 and 4. Ring C is a heterocycloalkyl or heteroaryl ring. Each R C These 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 Ure b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NRb 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 alkyl)cycloalkyl, (C1-C6 alkyl)heterocycloalkyl, (C1-C6 alkyl)aryl, or (C1-C6 alkyl)heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently one or more R Ca. It is replaced by, or two Rs on the same atom C They come together to form an oxo, Each R Ca These 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)ORb -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 Rs on the same atom Ca They come together to form an oxo, p is between 0 and 4. Each R a These 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 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, and The reel and heteroaryl are independently and 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 bThese are 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 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl aryl and heteroaryl are independently and 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 dThese are 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 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl aryl and heteroaryl are independently and 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 These, together with the atoms to which they bond, optionally form heterocycloalkyls 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. however, [ka] but, [ka] This is conditional on the fact that it is not the case.

[0011] Pharmaceutical compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, and a pharmaceutically acceptable carrier are also disclosed herein.

[0012] Methods for treating conditions are also disclosed herein, the methods comprising administering to a subject in need a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, the conditions being selected from the group consisting of autoimmune disorders, chronic inflammatory disorders, acute inflammatory disorders, autoinflammatory disorders, fibrous disorders, metabolic disorders, neoplastic disorders, and cardiovascular or cerebrovascular disorders.

[0013] p38 Methods for treating MAP kinase-mediated diseases in subjects requiring such treatment are also disclosed herein, the methods comprising administering a therapeutically effective amount of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, N-oxides, or stereoisomers thereof, to the subject.

[0014] Methods for treating MK2-mediated diseases in subjects requiring such treatment are also disclosed herein, the methods comprising administering a therapeutically effective amount of the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, N-oxides, or stereoisomers thereof, to the subject.

[0015] Built-in by reference All publications, patents, and patent applications referenced herein are incorporated by reference to the same extent as if each individual publication, patent, or patent application were specifically and individually indicated as being incorporated by reference. The present invention provides, for example, the following items: (Item 1) A compound of formula (II), or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, [ka] During the ceremony, Ring A is phenyl or heteroaryl, Each R A These independently produce hydrogen, deuterium, halogens, -CN, -NO2, -OH, and -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 the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently one or more R Aa. It is replaced by, or two Rs on the same atom A They come together to form an oxo, Each R Aa These independently produce deuterium, halogen, -CN, -NO2, -OH, and -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 Rs on the same atom Aa They come together to form an oxo, n is between 0 and 4, R 1 and R 2 These independently produce hydrogen, deuterium, halogens, -CN, -NO2, -OH, and -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 They come together to form an oxo, or R 1 and R 2 These combine to form a cycloalkyl or heterocycloalkyl group, and the cycloalkyl and heterocycloalkyl groups 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 These independently produce hydrogen, deuterium, halogens, -CN, -NO2, -OH, and -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 3 They come together to form an oxo, R 4 However, hydrogen, -C(=O)R a , -C(=O)OR b -C(=O)NR c Rd , 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 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, Ring B is a heterocycloalkyl or heteroaryl ring. Each R B These independently produce hydrogen, deuterium, halogens, -CN, -NO2, -OH, and -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 the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently one or more R Ba. It is replaced by, or two Rs on the same atom B They come together to form an oxo, Each R Ba These independently produce deuterium, halogen, -CN, -NO2, -OH, and -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 Rs on the same atom Ba They come together to form an oxo, m is between 0 and 4. The ring C is a 5-membered heteroaryl, Each R C These independently produce hydrogen, deuterium, halogens, -CN, -NO2, -OH, and -OR. a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c R d -SH, -SRa -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -S(=O)(=NR b )R a , -SiR c R d Ure 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 alkyl)cycloalkyl, (C1-C6 alkyl)heterocycloalkyl, (C1-C6 alkyl)aryl, or (C1-C6 alkyl)heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently one or more R Ca. It has been replaced with, Each R Ca These independently produce deuterium, halogen, -CN, -NO2, -OH, and -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 Rs on the same atom Ca They come together to form an oxo, p is between 0 and 4, Each R aThese 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 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, The aryl and heteroaryl compounds are independently and 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 compounds. Each R bThese are 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 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl The aryl and heteroaryl compounds are independently and 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 compounds. Each R c and R dThese are 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 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl aryl and heteroaryl are independently and 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 However, together with the atoms to which they bond, they optionally form heterocycloalkyls 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. However, if the above compound is [ka] A compound of formula (II), or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, provided that it is not [the other compound]. (Item 2) A compound as described in item 1, wherein ring A is a heteroaryl compound, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof. (Item 3) The compounds listed in item 1, wherein ring A is pyridyl, or any pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof. (Item 4) A compound as described in item 1, wherein ring A is phenyl, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof. (Item 5) Each R A A compound described in any one of items 1 to 4, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, in which a halogen is independently present. (Item 6) A compound described in any one of items 1 to 5, where n is 1 or 2, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof. (Item 7) R 1 and R 2 However, a compound described in any one of items 1 to 6, which is hydrogen or deuterium, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof. (Item 8) A compound described in any one of items 1 to 7, wherein X is -O-, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof. (Item 9) R 5 However, hydrogen, deuterium, halogens, -CN, -OH, -OR a A compound described in any one of items 1 to 8, which is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl, or cycloalkyl, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof. (Item 10) R 5A compound described in any one of items 1 to 9, which is hydrogen, deuterium, halogen, -CN, or C1-C6 alkyl, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof. (Item 11) R 6 However, hydrogen, deuterium, halogens, -CN, -OH, -OR a A compound described in any one of items 1 to 10, which is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl, or cycloalkyl, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof. (Item 12) R 6 A compound described in any one of items 1 to 11, wherein the compound is hydrogen, deuterium, halogen, -CN, or C1-C6 alkyl, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof. (Item 13) R 7 However, hydrogen, deuterium, halogens, -CN, -OH, -OR a A compound described in any one of items 1 to 12, which is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl, or cycloalkyl, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof. (Item 14) R 7 A compound described in any one of items 1 to 13, which is hydrogen, deuterium, halogen, -CN, or C1-C6 alkyl, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof. (Item 15) A compound described in any one of items 1 to 14, wherein ring B is pyridinyl, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof. (Item 16) Each RB These independently produce hydrogen, deuterium, halogens, -CN, -OH, and -OR a A compound described in any one of items 1 to 15, which is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl, or cycloalkyl, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof. (Item 17) Each R B A compound described in any one of items 1 to 16, wherein the element is independently a halogen or a C1-C6 alkyl, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof. (Item 18) Each R B A compound described in any one of items 1 to 17, wherein the elements are independently C1 to C6 alkyl, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof. (Item 19) A compound described in any one of items 1 to 18, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, wherein m is 1 or 2. (Item 20) A compound described in any one of items 1 to 19, wherein the C ring is thiazolyl, pyrazolyl, imidazolyl, oxazolyl, thiadiazole, or triazolyl, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof. (Item 21) A compound described in any one of items 1 to 20, wherein the carbon ring is thiazolyl, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof. (Item 22) A compound described in any one of items 1 to 20, wherein the carbon ring is pyrazolyl, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof. (Item 23) A compound described in any one of items 1 to 20, wherein the carbon ring is imidazolyl, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof. (Item 24) A compound described in any one of items 1 to 20, wherein ring C is thiadiazole, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof. (Item 25) A compound described in any one of items 1 to 20, wherein the carbon ring is triazolyl, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof. (Item 26) Each R C These independently produce hydrogen, deuterium, halogens, -CN, -OH, and -OR a A compound described in any one of items 1 to 25, which is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof. (Item 27) Each R C A compound described in any one of items 1 to 26, wherein each of the elements is independently a C1-C6 hydroxyalkyl group, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof. (Item 28) A compound described in any one of items 1 to 27, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, wherein p is 1 or 2. (Item 29) A compound of formula (I), or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, [ka] During the ceremony, Ring A is phenyl or heteroaryl, Each R A These independently produce hydrogen, deuterium, halogens, -CN, -NO2, -OH, and -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 the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently one or more R Aa. It is replaced by, or two Rs on the same atom A They come together to form an oxo, Each R Aa These independently produce deuterium, halogen, -CN, -NO2, -OH, and -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)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 Rs on the same atom Aa They come together to form an oxo, n is between 0 and 4, R 1 and R 2 These independently produce hydrogen, deuterium, halogens, -CN, -NO2, -OH, and -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 They come together to form an oxo, or R 1and R 2 These combine to form a cycloalkyl or heterocycloalkyl group, and the cycloalkyl and heterocycloalkyl groups 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 These independently produce hydrogen, deuterium, halogens, -CN, -NO2, -OH, and -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 3 They come together to form an oxo, R 4 However, 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, Z is N or CR 5 And, R 5However, 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, Ring B is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring. Each R B These independently produce hydrogen, deuterium, halogens, -CN, -NO2, -OH, and -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 bC(=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 the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently one or more R Ba. It is replaced by, or two Rs on the same atom B They come together to form an oxo, Each R Ba These independently produce deuterium, halogen, -CN, -NO2, -OH, and -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)NRc R d 、 -C(=O)C(=O)NR c R d 、 C1 - C6 alkyl, C1 - C6 haloalkyl, C1 - C6 dideuteroalkyl, C1 - C6 hydroxyalkyl, C1 - C6 aminoalkyl, C1 - C6 heteroalkyl, C2 - C6 alkenyl, C2 - C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or two Rs on the same atom Ba together form an oxo, m is 0 - 4, ring C is heterocycloalkyl or heteroaryl, each R C is 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 alkyl)cycloalkyl, (C1-C6 alkyl)heterocycloalkyl, (C1-C6 alkyl)aryl, or (C1-C6 alkyl)heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently one or more R Ca. It is replaced by, or two Rs on the same atom C They come together to form an oxo, Each R Ca These independently produce deuterium, halogen, -CN, -NO2, -OH, and -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 Rs on the same atom Ca They come together to form an oxo, p is between 0 and 4, Each R a These independently include 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, and C1-C6 alkyl (cycloalkyl). , C1~C6 alkyl (heterocycloalkyl), C1~C6 alkyl (aryl), or C1~C6 alkyl (heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and 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 bThese are 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 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl The aryl and heteroaryl compounds are independently and 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 compounds. Each R c and R dThese are 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 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl aryl and heteroaryl are independently and 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 However, together with the atoms to which they bond, they optionally form heterocycloalkyls 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. however, [ka] but, [ka] A compound of formula (I), or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, provided that it is not [a specific compound]. (Item 30) A compound as described in item 29, wherein ring A is a heteroaryl compound, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof. (Item 31) A compound as described in item 29, wherein ring A is pyridyl, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof. (Item 32) Each R A A compound described in any one of items 26-31, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, in which the halogen is independently present. (Item 33) A compound described in any one of items 26-32, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, where n is 1 or 2. (Item 34) R 1 and R 2 A compound described in any one of items 26-33, which is hydrogen or deuterium, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof. (Item 35) A compound described in any one of items 26-34, wherein X is -O-, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof. (Item 36) R 5 However, hydrogen, deuterium, halogens, -CN, -OH, -OR a A compound described in any one of items 26 to 35, which is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl, or cycloalkyl, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof. (Item 37) R 5A compound described in any one of items 26 to 36, wherein the compound is hydrogen, deuterium, halogen, -CN, or C1-C6 alkyl, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof. (Item 38) R 6 However, hydrogen, deuterium, halogens, -CN, -OH, -OR a Compounds described in any one of items 26 to 37, which are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl, or cycloalkyl, or pharmaceutically acceptable salts, solvates, N-oxides, or stereoisomers thereof. (Item 39) R 6 A compound described in any one of items 26 to 38, which is hydrogen, deuterium, halogen, -CN, or C1-C6 alkyl, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof. (Item 40) A compound described in any one of items 26 to 39, wherein ring B is a six-membered heteroaryl, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof. (Item 41) A compound described in any one of items 26-40, wherein ring B is pyridinyl, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof. (Item 42) Each R B These independently form deuterium, halogen, -CN, -OH, and -OR a A compound described in any one of items 26 to 41, which is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C2-C6 alkynyl, or cycloalkyl, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof. (Item 43) Each R BA compound described in any one of items 26 to 42, wherein the element is independently a halogen or a C1-C6 alkyl, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof. (Item 44) A compound described in any one of items 26-43, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, where m is 1 or 2. (Item 45) [ka] but, [ka] The compounds described in any one of items 26-39, or their pharmaceutically acceptable salts, solvates, N-oxides, or stereoisomers. (Item 46) [ka] but, [ka] The compounds described in any one of items 26-39 or 45, or their pharmaceutically acceptable salts, solvates, N-oxides, or stereoisomers. (Item 47) A compound described in any one of items 26 to 46, wherein the carbon ring is a five-membered or six-membered heteroaryl, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof. (Item 48) A compound described in any one of items 26-47, wherein the carbon ring is pyrimidinyl, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof. (Item 49) Each R C These independently produce hydrogen, deuterium, halogens, -CN, -OH, and -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 Hydro The compound according to any one of items 26 to 48, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, which is a xyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. (Item 50) Each R C The compound according to any one of items 26 to 49, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, wherein each R is independently a C1-C6 hydroxyalkyl. (Item 51) The compound according to any one of items 26 to 50, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, wherein p is 1 or 2. (Item 52) A compound selected from the compounds found in Table 1 or the specification, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof. (Item 53) A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of items 1 to 52, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, and a pharmaceutically acceptable addition agent. (Item 54) A method for treating a condition, comprising administering to a subject in need thereof a therapeutically effective amount of the compound according to any one of items 1 to 52, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, wherein the condition is selected from the group consisting of autoimmune disorders, chronic inflammatory disorders, acute inflammatory disorders, autoinflammatory disorders, fibrotic disorders, metabolic disorders, neoplastic disorders, and cardiovascular or cerebrovascular disorders. (Item 55) A method of doing so in a subject in need of treating a p38 MAP kinase-mediated disease, comprising administering to the subject a therapeutically effective amount of the compound according to any one of items 1 to 52, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof. (Item 56) A method for treating an MK2-mediated disease in a subject requiring treatment, comprising administering to the subject a therapeutically effective amount of a compound described in any one of items 1 to 52, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof. [Modes for carrying out the invention]

[0016] definition The following description includes certain specific details to provide a complete understanding of the various embodiments. However, those skilled in the art will understand that the invention can be carried out without these details. In other examples, well-known structures are not shown or described in detail to avoid unnecessarily obscuring the description of the embodiments. Unless otherwise required by context, the word “comprise” and its variations, e.g., “comprises,” i.e., “comprising,” throughout this specification and the subsequent claims should be interpreted in an open and comprehensive sense, i.e., “includes, but not limited.” Furthermore, the headings provided herein are for convenience only and do not constitute an interpretation of the scope or meaning of the claimed invention.

[0017] Throughout this specification, any reference to “several embodiments” or “embodiments” means that a particular feature, structure, or characteristic described in relation to an embodiment is included in at least one embodiment. Therefore, occurrences of the phrase “in one embodiment” or “in one embodiment” in various places throughout this specification do not necessarily all refer to the same embodiment. Furthermore, a particular feature, structure, or characteristic may be combined in any preferred manner in one or more embodiments. Also, as used herein and in the appended claims, the singular forms “a,” “an,” and “the” refer to multiple subjects unless the context clearly indicates otherwise. Furthermore, the term “or” is generally used to mean “and / or” unless the context clearly indicates otherwise.

[0018] The following terms, as used herein, have the meanings set forth below unless otherwise indicated.

[0019] "Oxo" refers to =O.

[0020] "Carboxyl" refers to the -COOH group.

[0021] "Alkyl" refers to a linear or branched saturated hydrocarbon monoradical having 1 to about 10 carbon atoms, more preferably 1 to 6 carbon atoms. Examples, but not limited to, include methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl, and hexyl, as well as longer alkyl groups such as heptyl and octyl. Wherever it appears herein, numerical ranges such as “C1-C6 alkyl” or “C1-6 alkyl” mean that an alkyl group may consist of one carbon atom, two carbon atoms, three carbon atoms, four carbon atoms, five carbon atoms, or six carbon atoms; however, this definition also includes instances of the term “alkyl” where no numerical range is specified. In some embodiments, alkyl is C1- 10It is an alkyl group. In some embodiments, the alkyl group is a C1-6 alkyl group. In some embodiments, the alkyl group is a C1-5 alkyl group. In some embodiments, the alkyl group is a C1-4 alkyl group. In some embodiments, the alkyl group is a C1-3 alkyl group. Unless otherwise specifically stated herein, the alkyl group may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkyl group is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl group is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl group is optionally substituted with halogen.

[0022] "Alkenyl" refers to a linear or branched hydrocarbon monoradical having one or more carbon-carbon double bonds and 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. This group can be in either a cis or trans conformation with respect to the double bond and should be understood to include both isomers. Examples, but not limited to, include ethenyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3=CH2)], butenyl, and 1,3-butadienyl. Whenever it appears herein, numerical ranges such as "C2-C6 alkenyl" or "C2-6 alkenyl" mean that the alkenyl group can consist of 2, 3, 4, 5, or 6 carbon atoms, but this definition also includes instances where the term "alkenyl" does not specify a numerical range. Unless otherwise specifically stated herein, the alkenyl group is arbitrary. The alkenyl may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkenyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkenyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with halogen.

[0023] "Alkynyl" refers to a linear or branched hydrocarbon monoradical having one or more carbon-carbon triple bonds and 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. Examples, but not limited to, include ethynyl, 2-propynyl, 2-butynyl, and 1,3-butazinyl. Whenever it appears herein, numerical ranges such as "C2-C6 alkynyl" or "C2-6 alkynyl" mean that the alkynyl group may consist of 2, 3, 4, 5, or 6 carbon atoms, but this definition also includes instances of the term "alkynyl" where no numerical range is specified. Unless otherwise specifically stated herein, the alkynyl group may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkynyl is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkynyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen.

[0024] "Alkylene" refers to a linear or branched divalent hydrocarbon chain. Unless otherwise specified herein, alkylene groups 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, alkylene is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, alkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, alkylene is optionally substituted with halogen.

[0025] "alkoxy" is the formula -OR a This refers to the radical of the expression, where R is located in the formula. a The alkoxy group is an alkyl radical as defined above. Unless otherwise specifically stated herein, the 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, the alkoxy is optionally substituted with halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.

[0026] "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 (where the aryl is bonded via aromatic ring atoms when fused with a cycloalkyl or heterocycloalkyl ring) or bridging ring systems. In some embodiments, the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl (phenyl). Examples of aryl radicals, but not limited to, include aryl radicals derived from the hydrocarbon ring systems of anthreene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluorantene, fluorene, as-indacene, s-indacene, indan, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless otherwise specifically stated herein, aryls may be substituted with, for example, halogens, aminos, nitriles, nitros, hydroxyls, alkyls, alkenyls, alkynyls, haloalkyls, alkoxys, carboxyls, carboxylates, aryls, cycloalkyls, heterocycloalkyls, heteroaryls, etc. In some embodiments, the aryl is optionally substituted with halogens, methyls, ethyls, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the aryl is optionally substituted with halogens, methyls, ethyls, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogens.

[0027] "Cycloalkyl" refers to a partially or fully saturated monocyclic or polycyclic carbocyclic ring, which may include fused ring systems (when fused with an aryl or heteroaryl ring, the cycloalkyl is bonded via non-aromatic ring atoms) or bridging ring systems. In some embodiments, the cycloalkyl is fully saturated. Typical cycloalkyls include, but are not limited to, those with 3 to 15 carbon atoms (C3 to C3). 15 Cycloalkyl or C3-C 15Cycloalkenyl), 3 to 10 carbon atoms (C3~C 10 Cycloalkyl or C3-C 10Examples of monocyclic cycloalkyls include cycloalkenyls, cycloalkyls (C3-C8 cycloalkyl or C3-C8 cycloalkenyl), cycloalkyls (C3-C6 cycloalkyl or C3-C6 cycloalkenyl), cycloalkyls (C3-C5 cycloalkyl or C3-C5 cycloalkenyl), or cycloalkyls having 3-4 carbon atoms (C3-C4 cycloalkyl or C3-C4 cycloalkenyl). In some embodiments, the cycloalkyl is a 3-10 membered cycloalkyl or a 3-10 membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3-6 membered cycloalkyl or a 3-6 membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5-6 membered cycloalkyl or a 5-6 membered cycloalkenyl. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of polycyclic cycloalkyls include adamantyl, norbornyl, dekalinyl, 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, as well as 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Examples of partially saturated cycloalkyls include cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless otherwise specified herein, cycloalkyls are substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, and heteroaryl compounds. In some embodiments, the cycloalkyl group is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2.In some embodiments, the cycloalkyl group is optionally substituted with a halogen.

[0028] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodine. In some embodiments, the halogen is fluoro or chloro. In some embodiments, the halogen is fluoro.

[0029] "Haloalkyl" refers to an alkyl radical as defined above that is substituted by one or more halo radicals as defined above, such as trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, and 1,2-dibromoethyl.

[0030] "Hydroxyalkyl" refers to an alkyl radical as defined above, which is 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. Examples of hydroxyalkyls include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0031] "Aminoalkyl" refers to an alkyl radical as defined above, which is 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. Examples of aminoalkyls include aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

[0032] "Duteroalkyl" refers to the alkyl radical as defined above, which is substituted with one or more deuterium atoms. In some embodiments, the alkyl is substituted with one deuterium atom. In some embodiments, the alkyl is substituted with one, two, or three deuterium atoms. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six deuterium atoms. Examples of deuteroalkyls include CD3, CH2D, CHD2, CH2CD3, CD2CD3, CHDCD3, CH2CH2D, or CH2CHD2. In some embodiments, the deuteroalkyl is CD3.

[0033] A "heteroalkyl" refers to an alkyl group in which one or more of the alkyl backbone atoms are atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or a combination thereof. In a heteroalkyl group, the carbon atoms of the heteroalkyl group are bonded to the rest of the molecule. In one embodiment, the heteroalkyl group is a C1-C6 heteroalkyl group, which consists of 1-6 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 carbon atoms of the heteroalkyl group are bonded to the rest of the molecule. Examples of such heteroalkyl groups are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, or -CH2CH2N(CH3)2. Unless otherwise specified herein, heteroalkyls are substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heteroalkyls are optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, heteroalkyls are optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, heteroalkyls are optionally substituted with halogens.

[0034] "Hypercycloalkyl" refers to a 3-24 membered moiety or fully saturated ring radical containing 2-23 carbon atoms and 1-8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl contains 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl contains 1-3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl contains 1-3 nitrogen atoms. In some embodiments, the heterocycloalkyl contains 1 or 2 nitrogen atoms. In some embodiments, the heterocycloalkyl contains 1 nitrogen atom. In some embodiments, the heterocycloalkyl contains 1 nitrogen atom and 1 oxygen atom. Unless otherwise specified herein, heterocycloalkyl radicals may be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which may include fused ring systems (where the heterocycloalkyl is bonded via a non-aromatic ring atom when fused with an aryl or heteroaryl ring) or bridging ring systems, and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may optionally be oxidized, and the nitrogen atom may optionally be quaternized. Typical heterocycloalkyls include, but are not limited to, heterocycloalkyls having 2 to 15 carbon atoms (C2-C2). 15 Heterocycloalkyl or C2-C 15 Heterocycloalkenyl), 2 to 10 carbon atoms (C2 to C 10 Heterocycloalkyl or C2-C 10Examples include heterocycloalkenyls, 2-8 carbon atoms (C2-C8 heterocycloalkyl or C2-C8 heterocycloalkenyl), 2-7 carbon atoms (C2-C7 heterocycloalkyl or C2-C7 heterocycloalkenyl), 2-6 carbon atoms (C2-C6 heterocycloalkyl or C2-C7 heterocycloalkenyl), 2-5 carbon atoms (C2-C5 heterocycloalkyl or C2-C5 heterocycloalkenyl), or 2-4 carbon atoms (C2-C4 heterocycloalkyl or C2-C4 heterocycloalkenyl). Examples of such heterocycloalkyl radicals include, but are not limited to, azilidinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, Examples include 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianil, 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 monosaccharides, disaccharides, and oligosaccharides, but is not limited to these. Unless otherwise stated, heterocycloalkyls have 2 to 10 carbon atoms in the ring. When referring to the number of carbon atoms in a heterocycloalkyl, it should be understood that the number of carbon atoms in a heterocycloalkyl is not the same as the total number of atoms constituting the heterocycloalkyl (including heteroatoms) (i.e., the skeletal atoms of the heterocycloalkyl ring). In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkyl.In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkenyl. Unless otherwise specifically stated herein, the heterocycloalkyl may be substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc., as described below. In some embodiments, the heterocycloalkyl group is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heterocycloalkyl group is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocycloalkyl group is optionally substituted with halogen.

[0035] A "heteroaryl" refers to a 5-14 membered ring radical comprising 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, the heteroaryl contains 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl contains 1-3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl contains 1-3 nitrogen atoms. In some embodiments, the heteroaryl contains 1 or 2 nitrogen atoms. In some embodiments, the heteroaryl contains 1 nitrogen atom. The heteroaryl may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, and may include a fused ring system (where the heteroaryl is bonded via aromatic ring atoms when fused with a cycloalkyl or heterocycloalkyl ring) or a bridging ring system, and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may optionally be oxidized, and the nitrogen atom may optionally be 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, though not limited to these, include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzoyldolyl, benzodioxolyl, benzofuranil, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanil, benzonaphthofuranil, benzoxazolyl, benzodioxolyl, benzodioxynil, benzooxypyranil, benzopyranonil, benzofuranil, benzofuranonil, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, sinnolinil, dibenzofuranil, dibenzothiophenyl, furanil, furanonil, isothiazolyl, imidazolyl, indazolyl, indolyl, inda Examples include zolyl, isoindolyl, indolinyl, isoindolyl, isoquinolyl, indolidinyl, isoxazolyl, naphthilidinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxyranil, 1-oxidepyridinyl, 1-oxidepyrimidinyl, 1-oxidepyranidyl, 1-oxidepyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxadinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridadinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless otherwise specifically stated herein, heteroaryls may be substituted with, for example, halogens, aminos, nitriles, nitros, hydroxyls, alkyls, alkenyls, alkynyls, haloalkyls, alkoxys, carboxyls, carboxylates, aryls, cycloalkyls, heterocycloalkyls, heteroaryls, etc. In some embodiments, the heteroaryl is optionally substituted with halogens, methyls, ethyls, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2.In some embodiments, the heteroaryl is optionally substituted with a halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with a halogen.

[0036] The terms “optional” or “optionally” mean that the event or situation described thereafter may or may not occur, and that the description includes both the cases in which such event or situation occurs and the cases in which it does not occur. For example, “optionally substituted alkyl” means either “alkyl” or “substituted alkyl” as defined above. Furthermore, an optionally substituted group may be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F), or substituted at any level between fully substituted and monosubstituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.). Those skilled in the art will understand that with respect to any group containing one or more substituents, such a group is not intended to introduce any substitution or substitution pattern that is sterically unrealistic and / or synthetically impossible (e.g., a substituted alkyl includes an optionally substituted cycloalkyl group, which is defined as potentially infinitely including optionally substituted alkyl groups). Therefore, any substituent described should be understood to have a maximum molecular weight of approximately 1,000 daltons, and more typically, up to approximately 500 daltons.

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

[0038] "Therapy" of an individual (e.g., a mammal such as a human) or a cell is any type of intervention used in an attempt to alter the natural processes of an individual or cell. In some embodiments, therapy includes the administration of a pharmaceutical composition following the onset of a pathological event or contact with a causative agent, and includes stabilization of the condition (e.g., preventing the condition from worsening) or alleviation of the condition.

[0039] "Synergistic effect" or "to have a synergistic effect" refers to a combined effect that is greater than the sum of the effects of each component individually at the same dose.

[0040] As used herein, “MK2-related disease or disorder” or alternatively “MK2-mediated disease or disorder” means any disease or other adverse condition in which MK2 or its variants are known or suspected to play a role. As used herein, “p38 MAP kinase-related disease or disorder” or “p38 MAP kinase-mediated disease or disorder” means any disease or other adverse condition in which p38 MAP kinase or its variants are known or suspected to play a role.

[0041] compound Compounds of formulas (I) to (VIII), or pharmaceutically acceptable salts, solvates, N-oxides, or stereoisomers thereof, that are useful in the treatment of autoimmune disorders, chronic inflammatory disorders, acute inflammatory disorders, autoinflammatory disorders, fibrous disorders, metabolic disorders, neoplastic disorders, or cardiovascular or cerebrovascular disorders, are described herein.

[0042] Compounds of formula (I), or pharmaceutically acceptable salts, solvates, N-oxides, or stereoisomers thereof are disclosed herein. [ka] During the ceremony, Ring A is phenyl or heteroaryl, Each R A. These are independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a -OC(=O)Ra , -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 one or more R Aa. It is replaced by, or two Rs on the same atom A They come together to form an oxo, Each R Aa These 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 cR 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 Rs on the same atom Aa They come together to form an oxo, n is between 0 and 4. R 1 and R 2 These 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 heterocycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, or R 1 and R 2 They come together to form an oxo, or R 1 and R 2These combine to form a cycloalkyl or heterocycloalkyl group, and the cycloalkyl and heterocycloalkyl groups 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 These 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 heterocycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, or two R 3 They come together to form an oxo, R 4 This 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, Z is either N or CR 5 And, R 5 These are hydrogen, deuterium, halogens, -CN, -NO2, -OH, -ORa , -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 These are 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, Ring B is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring. Each R B These 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 , -NRb 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 one or more R Ba. It is replaced by, or two Rs on the same atom B They come together to form an oxo, Each R Ba These 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)NRc 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 Rs on the same atom Ba They come together to form an oxo, m is between 0 and 4. Ring C is a heterocycloalkyl or heteroaryl ring. Each R C These 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 Ure 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 dC1-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 alkyl)cycloalkyl, (C1-C6 alkyl)heterocycloalkyl, (C1-C6 alkyl)aryl, or (C1-C6 alkyl)heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently one or more R Ca. It is replaced by, or two Rs on the same atom C They come together to form an oxo, Each R Ca These 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 Rs on the same atom Ca They come together to form an oxo, p is between 0 and 4. Each R a These 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 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, and The reel and heteroaryl are independently and 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 bThese are 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 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl aryl and heteroaryl are independently and 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 dThese are 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 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl aryl and heteroaryl are independently and 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 These, together with the atoms to which they bond, optionally form heterocycloalkyls 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. however, [ka] but, [ka] This is conditional on the fact that it is not the case.

[0043] In some embodiments of the compound of formula (I), ring A is a heteroaryl compound. In some embodiments of the compound of formula (I), ring A is a pyridyl compound. In some embodiments of the compound of formula (I), ring A is a phenyl compound.

[0044] In some embodiments of the compound of formula (I), each R A These are independently deuterium, halogen, -CN, -OH, and -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of the compound of formula (I), each R A R is independently a halogen or a C1-C6 alkyl. In some embodiments of the compound of formula (I), each R A It is a halogen independently.

[0045] In some embodiments of the compound of formula (I), n is 1 or 2. In some embodiments of the compound of formula (I), n is 1 to 3. In some embodiments of the compound of formula (I), n is 2. In some embodiments of the compound of formula (I), n is 1.

[0046] In some embodiments of the compound of formula (I), R 1 and R 2 R is independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of the compound of formula (I), R 1 and R 2 R is independently hydrogen, deuterium, halogen, or C1-C6 alkyl. In some embodiments of the compound of formula (I), R 1 and R 2 is hydrogen or deuterium. In some embodiments of the compound of formula (I), R 1 and R 2 It is hydrogen.

[0047] In some embodiments of the compound of formula (I), X is -O-. In some embodiments of the compound of formula (I), Z is N. In some embodiments of the compound of formula (I), Z is CR. 5 That is the case.

[0048] In some embodiments of the compound of formula (I), R 5 These are hydrogen, deuterium, halogens, -CN, -OH, and -OR a These are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl, or cycloalkyl. In some embodiments of the compound of formula (I), R 5 These are hydrogen, deuterium, halogen, -CN, or C1-C6 alkyl.

[0049] In some embodiments of the compound of formula (I), R 6 These are hydrogen, deuterium, halogens, -CN, -OH, and -OR a These are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl, or cycloalkyl. In some embodiments of the compound of formula (I), R 6 These are hydrogen, deuterium, halogen, -CN, or C1-C6 alkyl.

[0050] In some embodiments of the compound of formula (I), ring B is phenyl. In some embodiments of the compound of formula (I), ring B is a 5-membered heteroaryl. In some embodiments of the compound of formula (I), ring B is a 6-membered heteroaryl. In some embodiments of the compound of formula (I), ring B is pyridinyl. In some embodiments of the compound of formula (I), ring B is pyridinone.

[0051] In some embodiments of the compound of formula (I), each R B These are independently deuterium, halogen, -CN, -OH, and -ORa These are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C2-C6 alkynyl, or cycloalkyl. In some embodiments of the compound of formula (I), each R B These are independently deuterium, -CN, -OH, and -OR a These are C2-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C2-C6 alkynyl, or cycloalkyl. In some embodiments of the compound of formula (I), each R B These are independently halogens or C1-C6 alkyl groups.

[0052] In some embodiments of the compound of formula (I), m is 1 or 2. In some embodiments of the compound of formula (I), m is 1 to 4. In some embodiments of the compound of formula (I), m is 2 to 4. In some embodiments of the compound of formula (I), m is 1. In some embodiments of the compound of formula (I), m is 2.

[0053] In some embodiments of the compound of formula (I), [ka] teeth, [ka] In some embodiments of the compound of formula (I), [ka] teeth, [ka] In some embodiments of the compound of formula (I), [ka] teeth, [ka] That is the case.

[0054] In some embodiments of the compound of formula (I), ring C is a 5- or 6-membered heteroaryl. In some embodiments of the compound of formula (I), ring C is a pyrimidinyl.

[0055] In some embodiments of the compound of formula (I), ring C is thiazolyl, pyrazolyl, imidazolyl, oxazolyl, thiadiazole, or triazolyl. In some embodiments of the compound of formula (I), ring C is thiazolyl. In some embodiments of the compound of formula (I), ring C is pyrazolyl. In some embodiments of the compound of formula (I), ring C is imidazolyl. In some embodiments of the compound of formula (I), ring C is thiadiazole. In some embodiments of the compound of formula (I), ring C is triazolyl.

[0056] In some embodiments of the compound of formula (I), each R C These are independently hydrogen, deuterium, halogen, -CN, -OH, and -OR a These are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of the compound of formula (I), each R C These are independently C1-C6 hydroxyalkyl groups.

[0057] In some embodiments of the compound of formula (I), p is 1 or 2. In some embodiments of the compound of formula (I), p is 1. In some embodiments of the compound of formula (I), p is 2.

[0058] Compounds of formula (II), or their pharmaceutically acceptable salts, solvates, N-oxides, or stereoisomers are also disclosed herein. [ka] During the ceremony, Ring A is phenyl or heteroaryl, Each RA. These 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 one or more R Aa. It is replaced by, or two Rs on the same atom A They come together to form an oxo, Each R Aa These 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 Rs on the same atom Aa They come together to form an oxo, n is between 0 and 4. R 1 and R 2 These 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 heterocycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, or R 1 and R 2They come together to form an oxo, or R 1 and R 2 These combine to form a cycloalkyl or heterocycloalkyl group, and the cycloalkyl and heterocycloalkyl groups 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 These 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 heterocycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, or two R 3 They come together to form an oxo, R 4 This 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 5These are 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 These are 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 These are 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, Ring B is a heterocycloalkyl or heteroaryl ring. Each R B These are independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa -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 one or more R Ba. It is replaced by, or two Rs on the same atom B They come together to form an oxo, Each R Ba These 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 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)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 Rs on the same atom Ba They come together to form an oxo, m is between 0 and 4. Ring C is a 5-membered heteroaryl, Each R C These 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 Ure b , -NR c R d , -NR b C(=O)NRc 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 alkyl)cycloalkyl, (C1-C6 alkyl)heterocycloalkyl, (C1-C6 alkyl)aryl, or (C1-C6 alkyl)heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently one or more R Ca. It is replaced by, Each R Ca These 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)Ra , -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 Rs on the same atom Ca They come together to form an oxo, p is between 0 and 4. Each R a These 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 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, Aryls and heteroaryls are independently and 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 bThese are 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 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl aryl and heteroaryl are independently and 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 dThese are 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 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl aryl and heteroaryl are independently and 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 These, together with the atoms to which they bond, optionally form heterocycloalkyls 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. However, if the compound is [ka] This is conditional on the fact that it is not the case.

[0059] In some embodiments of the compound of formula (II), ring A is a heteroaryl compound. In some embodiments of the compound of formula (II), ring A is a pyridyl compound. In some embodiments of the compound of formula (II), ring A is a phenyl compound.

[0060] In some embodiments of the compound of formula (II), each R A These are independently deuterium, halogen, -CN, -OH, and -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of the compound of formula (II), each R A R is independently a halogen or a C1-C6 alkyl. In some embodiments of the compound of formula (II), each R A It is a halogen independently.

[0061] In some embodiments of the compound of formula (II), n is 1 or 2. In some embodiments of the compound of formula (II), n is 1 to 3. In some embodiments of the compound of formula (II), n is 2. In some embodiments of the compound of formula (II), n is 1.

[0062] In some embodiments of the compound of formula (II), R 1 and R 2 R is independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of the compound of formula (II), R 1 and R 2 R is independently hydrogen, deuterium, halogen, or C1-C6 alkyl. In some embodiments of the compound of formula (II), R 1 and R 2 R is independently hydrogen or deuterium. In some embodiments of the compound of formula (II), R 1 and R 2 It is hydrogen.

[0063] In some embodiments of the compound of formula (II), X is -O-.

[0064] In some embodiments of the compound of formula (II), R 5 These are hydrogen, deuterium, halogens, -CN, -OH, and -OR a These are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl, or cycloalkyl. In some embodiments of the compound of formula (II), R 5 These are hydrogen, deuterium, halogen, -CN, or C1-C6 alkyl.

[0065] In some embodiments of the compound of formula (II), R 6 These are hydrogen, deuterium, halogens, -CN, -OH, and -OR a These are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl, or cycloalkyl. In some embodiments of the compound of formula (II), R 6 These are hydrogen, deuterium, halogen, -CN, or C1-C6 alkyl.

[0066] In some embodiments of the compound of formula (II), R 7 These are hydrogen, deuterium, halogens, -CN, -OH, and -OR a These are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl, or cycloalkyl. In some embodiments of the compound of formula (II), R 7 These are hydrogen, deuterium, halogen, -CN, or C1-C6 alkyl.

[0067] In some embodiments of the compound of formula (II), ring B is a six-membered heteroaryl. In some embodiments of the compound of formula (II), ring B is a pyridinyl.

[0068] In some embodiments of the compound of formula (II), each R B These are independently hydrogen, deuterium, halogen, -CN, -OH, and -OR a These are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl, or cycloalkyl. In some embodiments of the compound of formula (II), each R B R is independently a halogen or a C1-C6 alkyl. In some embodiments of the compound of formula (II), each R B These are independently C1-C6 alkyl groups.

[0069] In some embodiments of the compound of formula (II), m is 1 or 2. In some embodiments of the compound of formula (II), m is 1 to 4. In some embodiments of the compound of formula (II), m is 2 to 4. In some embodiments of the compound of formula (II), m is 1. In some embodiments of the compound of formula (II), m is 2.

[0070] In some embodiments of the compound of formula (II), ring C is thiazolyl, pyrazolyl, imidazolyl, oxazolyl, thiadiazole, or triazolyl. In some embodiments of the compound of formula (II), ring C is thiazolyl. In some embodiments of the compound of formula (II), ring C is pyrazolyl. In some embodiments of the compound of formula (II), ring C is imidazolyl. In some embodiments of the compound of formula (II), ring C is thiadiazole. In some embodiments of the compound of formula (II), ring C is triazolyl.

[0071] In some embodiments of the compound of formula (II), each R C These are independently hydrogen, deuterium, halogen, -CN, -OH, and -OR aThese are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of the compound of formula (II), each R C These are independently C1-C6 hydroxyalkyl groups.

[0072] In some embodiments of the compound of formula (II), p is 1 or 2. In some embodiments of the compound of formula (II), p is 1 to 3. In some embodiments of the compound of formula (II), p is 1. In some embodiments of the compound of formula (II), p is 2.

[0073] Compounds of formula (III), or their pharmaceutically acceptable salts, solvates, N-oxides, or stereoisomers are also disclosed herein. [ka] During the ceremony, Ring A is phenyl or heteroaryl, Each R A. These 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)ORb -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 one or more R Aa. It is replaced by, or two Rs on the same atom A They come together to form an oxo, Each R Aa These 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 Rs on the same atom Aa They come together to form an oxo, n is between 0 and 4. R 1 and R 2 These 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 heterocycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, or R 1 and R 2 They come together to form an oxo, or R 1 and R 2 These combine to form a cycloalkyl or heterocycloalkyl group, and the cycloalkyl and heterocycloalkyl groups 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 3These 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 heterocycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, or two R 3 They come together to form an oxo, R 4 This 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, Ring D is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring. Each R D These 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)Ra , -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 one or more R Da. It is replaced by, or two Rs on the same atom D They come together to form an oxo, Each R Da These 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 Rs on the same atom Da They come together to form an oxo, q is between 0 and 6. R 9 These are 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 10 These are 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 11 These are 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 12 These are hydrogen, deuterium, halogens, -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 Ure 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 dC1-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 alkyl)cycloalkyl, (C1-C6 alkyl)heterocycloalkyl, (C1-C6 alkyl)aryl, or (C1-C6 alkyl)heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently one or more R 12a. It is replaced by, Each R 12a These 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 Rs on the same atom 12a They come together to form an oxo, R 13 These are 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 14 These are 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, Each R aThese 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 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, Aryls and heteroaryls are independently and 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 bThese are 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 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl aryl and heteroaryl are independently and 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 dThese are 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 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl aryl and heteroaryl are independently and 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 These, together with the atoms to which they bond, optionally form heterocycloalkyls 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. however, [ka] but, [ka] This is conditional on the fact that it is not the case.

[0074] In some embodiments of the compound of formula (III), ring A is a heteroaryl compound. In some embodiments of the compound of formula (III), ring A is a pyridyl compound. In some embodiments of the compound of formula (III), ring A is a phenyl compound.

[0075] In some embodiments of the compound of formula (III), each R A These are independently deuterium, halogen, -CN, -OH, and -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of the compound of formula (III), each R A R is independently a halogen or a C1-C6 alkyl. In some embodiments of the compound of formula (III), each R A It is a halogen independently.

[0076] In some embodiments of the compound of formula (III), n is 1 or 2. In some embodiments of the compound of formula (III), n is 1 to 3. In some embodiments of the compound of formula (III), n is 2. In some embodiments of the compound of formula (III), n is 1.

[0077] In some embodiments of the compound of formula (III), R 1 and R 2 R is independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl. In some embodiments of the compound of formula (III), R 1 and R 2 R is independently hydrogen, deuterium, halogen, or C1-C6 alkyl. In some embodiments of the compound of formula (III), R 1 and R 2 It is hydrogen.

[0078] In some embodiments of the compound of formula (III), X is -O-.

[0079] In some embodiments of the compound of formula (III), ring D is phenyl. In some embodiments of the compound of formula (III), ring D is pyridinyl.

[0080] In some embodiments of the compound of formula (III), each R D These are independently hydrogen, deuterium, halogen, -CN, -OH, and -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, or two R on the same atom D These combine to form an oxo. In some embodiments of the compound of formula (III), each R D These are independently hydrogen, deuterium, halogen, -CN, and -OR. a , C1-C6 alkyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, or two R on the same atom D These come together to form an oxo.

[0081] In some embodiments of the compound of formula (III), q is 1 to 4. In some embodiments of the compound of formula (III), q is 1 to 3. In some embodiments of the compound of formula (III), q is 2 to 4.

[0082] In some embodiments of the compound of formula (III), [ka] [ka] That is the case.

[0083] In some embodiments of the compound of formula (III), R 9These are hydrogen, deuterium, halogens, C1-C6 alkyl groups, or C1-C6 haloalkyl groups.

[0084] In some embodiments of the compound of formula (III), R 10 These are hydrogen, deuterium, halogens, C1-C6 alkyl groups, or C1-C6 haloalkyl groups.

[0085] In some embodiments of the compound of formula (III), R 11 These are hydrogen, deuterium, halogens, C1-C6 alkyl groups, or C1-C6 haloalkyl groups.

[0086] In some embodiments of the compound of formula (III), R 12 These are hydrogen, deuterium, halogens, -CN, -OH, and -OR a These are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of the compound of formula (III), R 12 These are C1-C6 hydroxyalkyl groups.

[0087] In some embodiments of the compound of formula (III), R 13 These are hydrogen, deuterium, halogens, or C1-C6 alkyl groups.

[0088] In some embodiments of the compound of formula (III), R 14 These are hydrogen, deuterium, halogens, or C1-C6 alkyl groups.

[0089] A compound of formula (IV), or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, [ka] During the ceremony, Ring A is phenyl or heteroaryl, Each R A. These are independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa -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 one or more R Aa. It is replaced by, or two Rs on the same atom A They come together to form an oxo, Each R Aa These 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 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)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 Rs on the same atom Aa They come together to form an oxo, n is between 0 and 4. R 1 and R 2 These 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 heterocycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, or R 1 and R 2 They come together to form an oxo, or R 1 and R2 These combine to form a cycloalkyl or heterocycloalkyl group, and the cycloalkyl and heterocycloalkyl groups 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 These 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 heterocycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, or two R 3 They come together to form an oxo, R 4 This 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 These are hydrogen, deuterium, halogens, -CN, -NO2, -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, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, R 6 These are 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, Ring B is a cycloalkyl, heterocycloalkyl, alkyl, or heteroaryl ring. Each R B These 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 , -NRb 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 one or more R Ba. It is replaced by, or two Rs on the same atom B They come together to form an oxo, Each R Ba These 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 Rs on the same atom Ba They come together to form an oxo, m is between 0 and 4. R 12 , R 13 , and R 14 It is defined in (a), (b), or (c) as follows: (a) R 12 These are 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 Ure 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 dC1-C6 haloalkyl, C1-C6 dihydroxyalkyl, C1-C6 aminoalkyl, C1-C6 hydroxyheteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (C1-C6 alkyl)cycloalkyl, (C1-C6 alkyl)heterocycloalkyl, (C1-C6 alkyl)aryl, or (C1-C6 alkyl)heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently one or more R 12a. It is replaced by, Each R 12a These 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 Rs on the same atom 12a They come together to form an oxo, R 13 These are 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 14 These are 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, or (b) R 12 These are hydrogen, deuterium, halogens, -CN, -NO2, -OH, -OR a , -NR c R d -C(=O)R a , -C(=O)OR b -C(=O)NRc 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 13 These are 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 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, R 14 These are 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, or (c) R 12 These are 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 13 These are 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 14 These are 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, Each R aThese 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 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, Aryls and heteroaryls are independently and 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 bThese are 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 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl aryl and heteroaryl are independently and 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 dThese are 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 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl aryl and heteroaryl are independently and 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 These, together with the atoms to which they bond, form heterocycloalkyls that are 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.

[0090] In some embodiments of the compound of formula (IV), ring A is a heteroaryl compound. In some embodiments of the compound of formula (IV), ring A is a pyridyl compound. In some embodiments of the compound of formula (IV), ring A is a phenyl compound.

[0091] In some embodiments of the compound of formula (IV), each R A These are independently deuterium, halogen, -CN, -OH, and -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of the compound of formula (IV), each R A R is independently a halogen or a C1-C6 alkyl. In some embodiments of the compound of formula (IV), each R A It is a halogen independently.

[0092] In some embodiments of the compound of formula (IV), n is 1 or 2. In some embodiments of the compound of formula (IV), n is 1 to 3. In some embodiments of the compound of formula (IV), n is 2. In some embodiments of the compound of formula (IV), n is 1.

[0093] In some embodiments of the compound of formula (IV), R 1 and R 2 R is independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl. In some embodiments of the compound of formula (IV), R 1 and R 2 R is independently hydrogen, deuterium, halogen, or C1-C6 alkyl. In some embodiments of the compound of formula (IV), R 1 and R 2 It is hydrogen.

[0094] In some embodiments of the compound of formula (IV), X is -O-.

[0095] In some embodiments of the compound of formula (IV), R 5 These are hydrogen, deuterium, halogens, -CN, -OH, and -OR aThese are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl, or cycloalkyl. In some embodiments of the compound of formula (IV), R 5 These are hydrogen, deuterium, halogen, -CN, or C1-C6 alkyl.

[0096] In some embodiments of the compound of formula (IV), R 6 These are hydrogen, deuterium, halogens, -CN, -OH, and -OR a These are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl, or cycloalkyl. In some embodiments of the compound of formula (IV), R 6 These are hydrogen, deuterium, halogen, -CN, or C1-C6 alkyl.

[0097] In some embodiments of the compound of formula (IV), ring B is a six-membered heteroaryl. In some embodiments of the compound of formula (IV), ring B is a pyridinyl.

[0098] In some embodiments of the compound of formula (IV), each R B These are independently hydrogen, deuterium, halogen, -CN, -OH, and -OR a These are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl, or cycloalkyl. In some embodiments of the compound of formula (IV), each R B These are independently hydrogen, deuterium, halogen, -CN, and -OR. a , C1-C6 alkyl, C2-C6 alkynyl, or cycloalkyl. In some embodiments of the compound of formula (IV), each R B These are independently C1-C6 alkyl groups.

[0099] In some embodiments of the compound of formula (IV), m is 1 or 2. In some embodiments of the compound of formula (IV), m is 1 to 4. In some embodiments of the compound of formula (IV), m is 2 to 4. In some embodiments of the compound of formula (IV), m is 1. In some embodiments of the compound of formula (IV), m is 2.

[0100] In some embodiments of the compound of formula (IV), R 12 These are deuterium, halogen, -CN, -OH, -OR a -S(=O)2NR c R d -S(=O)(=NR b )R a , -SiR c R d Ure b , -NR b S(=O)2R a , C1-C6 haloalkyl, C1-C6 dihydroxyalkyl, C1-C6 aminoalkyl, C1-C6 hydroxyheteroalkyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, (C1-C6 alkyl)cycloalkyl, or (C1-C6 alkyl)heterocycloalkyl, wherein alkyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally and independently one or more R 12a It has been replaced with, Each R 12a These are independently deuterium, halogen, -CN, -OH, and -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, or two R on the same atom 12a They come together to form an oxo, R 13 These are hydrogen, deuterium, halogen, or C1-C6 alkyl. R 14 These are hydrogen, deuterium, halogens, or C1-C6 alkyl groups.

[0101] In some embodiments of the compound of formula (IV), R 12 -S(=O)(=NR b )R a , -SiR c R d Ure b , -NR b S(=O)2R a , C1-C6 haloalkyl, C1-C6 dihydroxyalkyl, C1-C6 aminoalkyl, C1-C6 hydroxyheteroalkyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, or (C1-C6 alkyl)cycloalkyl, wherein alkyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally and independently one or more R 12a It has been replaced with, Each R 12a These are independently -OH and -NR c R d or C1-C6 haloalkyl, R 13 It is hydrogen, R 14 It is hydrogen.

[0102] In some embodiments of the compound of formula (IV), R 12 These are C1-C6 hydroxyalkyl groups, R 13 These are deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, R 14 These are hydrogen, deuterium, halogens, or C1-C6 alkyl groups.

[0103] In some embodiments of the compound of formula (IV), R12 These are C1-C6 hydroxyalkyl groups, R 13 These are hydrogen, deuterium, halogen, or C1-C6 alkyl. R 14 These are deuterium, halogen, -CN, -OH, -OR a , -NR c R d These are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl.

[0104] Compounds of formula (V), or their pharmaceutically acceptable salts, solvates, N-oxides, or stereoisomers are also disclosed herein. [ka] During the ceremony, Ring A is phenyl or heteroaryl, Each R A. These 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 one or more R Aa. It is replaced by, or two Rs on the same atom A They come together to form an oxo, Each R Aa These 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 Rs on the same atom Aa They come together to form an oxo, n is between 0 and 4. R 1 and R 2 These 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 heterocycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, or R 1 and R 2 They come together to form an oxo, or R 1 and R 2 These combine to form a cycloalkyl or heterocycloalkyl group, and the cycloalkyl and heterocycloalkyl groups 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 3These 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 heterocycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, or two R 3 They come together to form an oxo, R 4 This 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 These are 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 These are 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 These are 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 8 These are 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, Ring B is pyridinone, pyrimidinone, pyrazinonone, or pyridazinone. Each R B These are independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c Rd -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 one or more R Ba. It has been replaced with, or two Rs on the same atom B They come together to form an oxo, Each R Ba These 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 Rd , -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 Rs on the same atom Ba They come together to form an oxo, m is between 0 and 4. Ring C is a heterocycloalkyl or heteroaryl ring. Each R C These 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 Ure b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NRb 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 alkyl)cycloalkyl, (C1-C6 alkyl)heterocycloalkyl, (C1-C6 alkyl)aryl, or (C1-C6 alkyl)heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently one or more R Ca. It is replaced by, or two Rs on the same atom C They come together to form an oxo, Each R Ca These 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)ORb -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 Rs on the same atom Ca They come together to form an oxo, p is between 0 and 4. Each R a These 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 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, Aryls and heteroaryls are independently and 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 bThese are 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 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl aryl and heteroaryl are independently and 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 dThese are 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 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl aryl and heteroaryl are independently and 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 These, together with the atoms to which they bond, form heterocycloalkyls that are 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.

[0105] In some embodiments of the compound of formula (V), ring A is a heteroaryl compound.

[0106] In some embodiments of the compound of formula (V), ring A is pyridyl.

[0107] In some embodiments of the compound of formula (V), ring A is phenyl.

[0108] In some embodiments of the compound of formula (V), each R A These are independently deuterium, halogen, -CN, -OH, and -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of the compound of formula (V), each R A R is independently a halogen or a C1-C6 alkyl. In some embodiments of the compound of formula (V), each R A It is a halogen independently.

[0109] In some embodiments of the compound of formula (V), n is 1 or 2. In some embodiments of the compound of formula (V), n is 1 to 3. In some embodiments of the compound of formula (V), n is 2. In some embodiments of the compound of formula (V), n is 1.

[0110] In some embodiments of the compound of formula (V), R 1 and R 2 R is independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl. In some embodiments of the compound of formula (V), R 1 and R 2 R is independently hydrogen, deuterium, halogen, or C1-C6 alkyl. In some embodiments of the compound of formula (V), R 1 and R 2 It is hydrogen.

[0111] In some embodiments of the compound of formula (V), X is -O-.

[0112] In some embodiments of the compound of formula (V), R 5 These are hydrogen, deuterium, halogens, -CN, -OH, and -OR aThese are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl, or cycloalkyl. In some embodiments of the compound of formula (V), R 5 These are hydrogen, deuterium, halogen, -CN, or C1-C6 alkyl.

[0113] In some embodiments of the compound of formula (V), R 6 These are hydrogen, deuterium, halogens, -CN, -OH, and -OR a These are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl, or cycloalkyl. In some embodiments of the compound of formula (V), R 6 These are hydrogen, deuterium, halogen, -CN, or C1-C6 alkyl.

[0114] In some embodiments of the compound of formula (V), R 7 These are hydrogen, deuterium, halogens, -CN, -OH, and -OR a These are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl, or cycloalkyl. In some embodiments of the compound of formula (V), R 7 These are hydrogen, deuterium, halogen, -CN, or C1-C6 alkyl.

[0115] In some embodiments of the compound of formula (V), R 8 These are hydrogen, deuterium, halogens, -CN, -OH, and -OR aThese are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl, or cycloalkyl. In some embodiments of the compound of formula (V), it is hydrogen, deuterium, halogen, -CN, or C1-C6 alkyl.

[0116] In some embodiments of the compound of formula (V), ring B is a pyridinone. In some embodiments of the compound of formula (V), ring B is a pyrimidinone. In some embodiments of the compound of formula (V), ring B is a pyrazinonone. In some embodiments of the compound of formula (V), ring B is a pyridadinone.

[0117] In some embodiments of the compound of formula (V), each R B These are independently hydrogen, deuterium, halogen, -CN, -OH, and -OR a These are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl, or cycloalkyl. In some embodiments of the compound of formula (V), each R B These are independently C1-C6 alkyl groups.

[0118] In some embodiments of the compound of formula (IV), m is 1 or 2. In some embodiments of the compound of formula (IV), m is 1 to 4. In some embodiments of the compound of formula (IV), m is 2 to 4. In some embodiments of the compound of formula (IV), m is 1. In some embodiments of the compound of formula (IV), m is 2.

[0119] In some embodiments of the compound of formula (V), [ka] teeth, [ka] That is the case.

[0120] In some embodiments of the compound of formula (V), ring C is a 5- or 6-membered heteroaryl. In some embodiments of the compound of formula (V), ring C is a pyrimidinyl.

[0121] In some embodiments of the compound of formula (V), each R C These are independently hydrogen, deuterium, halogen, -CN, -OH, and -OR a These are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of the compound of formula (V), each R C These are independently C1-C6 hydroxyalkyl groups.

[0122] In some embodiments of the compound of formula (V), p is 1 or 2. In some embodiments of the compound of formula (V), p is 1 to 3. In some embodiments of the compound of formula (V), p is 1. In some embodiments of the compound of formula (V), p is 2.

[0123] Compounds of formula (VI), or their pharmaceutically acceptable salts, solvates, N-oxides, or stereoisomers are also disclosed herein. [ka] During the ceremony, Ring A is phenyl or heteroaryl, Each R A. These 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 one or more R Aa. It is replaced by, or two Rs on the same atom A They come together to form an oxo, Each R Aa These 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)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 Rs on the same atom Aa They come together to form an oxo, n is between 0 and 4. X and Y are defined in (a) or (b) as follows: (a) X is -C(R 3 )2-, -NR 4 -, -O-, or -S- Y is -CR 1 R 2 -and, R 1 These are 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, R 2 These are hydrogen, deuterium, halogens, -CN, -NO2, -OH, -OR a , -NR c R d -C(=O)R a , -C(=O)ORb -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 They come together to form an oxo, or R 1 and R 2 These combine to form a cycloalkyl or heterocycloalkyl group, and the cycloalkyl and heterocycloalkyl groups 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. Each R 3 These 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 heterocycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, or two R 3 They come together to form an oxo, R 4 This 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, or (b) X is -C(R 3 )2-, -NR 4 -, or -S-, Y is -CR 1 R 2 -, -NR 4 -, -O-, or -S- R 1 and R 2 These 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 heterocycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, or R 1 and R 2 They come together to form an oxo, or R 1 and R 2 These combine to form a cycloalkyl or heterocycloalkyl group, and the cycloalkyl and heterocycloalkyl groups 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. Each R 3These 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 heterocycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, or two R 3 They come together to form an oxo, R 4 This 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 These are 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 These are 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 These are 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, Ring B is a heterocycloalkyl or heteroaryl ring. Each R B These 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)Ra , -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 one or more R Ba. It has been replaced with, or two Rs on the same atom B They come together to form an oxo, Each R Ba These 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 Rs on the same atom Ba They come together to form an oxo, m is between 0 and 4. Ring C is a heterocycloalkyl or heteroaryl ring. Each R C These 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 Ure 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 dC1-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 alkyl)cycloalkyl, (C1-C6 alkyl)heterocycloalkyl, (C1-C6 alkyl)aryl, or (C1-C6 alkyl)heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently one or more R Ca. It is replaced by, or two Rs on the same atom C They come together to form an oxo, Each R Ca These 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 Rs on the same atom Ca They come together to form an oxo, p is between 0 and 4. Each R a These 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 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, Aryls and heteroaryls are independently and 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 bThese are 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 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl aryl and heteroaryl are independently and 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 dThese are 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 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl aryl and heteroaryl are independently and 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 These, together with the atoms to which they bond, optionally form heterocycloalkyls 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. However, if the compound is [ka] This is conditional on the fact that it is not the case.

[0124] In some embodiments of the compound of formula (VI), ring A is a heteroaryl compound. In some embodiments of the compound of formula (VI), ring A is a pyridyl compound. In some embodiments of the compound of formula (VI), ring A is a phenyl compound.

[0125] In some embodiments of the compound of formula (VI), each R A These are independently deuterium, halogen, -CN, -OH, and -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of the compound of formula (VI), each R A R is independently a halogen or a C1-C6 alkyl. In some embodiments of the compound of formula (VI), each R A It is a halogen independently.

[0126] In some embodiments of the compound of formula (VI), n is 1 or 2. In some embodiments of the compound of formula (VI), n is 1 to 3. In some embodiments of the compound of formula (VI), n is 2. In some embodiments of the compound of formula (VI), n is 1.

[0127] In some embodiments of the compound of formula (VI), X is -C(R 3 )2-, -NR 4 -, -O-, or -S- Y is -CR 1 R 2 -and, R 1 These are 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, R 2 These are 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, or R 1 and R 2 They come together to form an oxo, or R 1 and R 2 These combine to form a cycloalkyl or heterocycloalkyl group, and the cycloalkyl and heterocycloalkyl groups 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. Each R 3 These 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 heterocycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, or two R 3 They come together to form an oxo, R 4 This is hydrogen, -C(=O)R a , -C(=O)OR b -C(=O)NR c R d These are 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.

[0128] In some embodiments of the compound of formula (VI), X is -C(R 3 )2-, -NR 4 -, -O-, or -S- Y is -CR 1 R 2 -and, R 1 These are halogens, C1-C6 alkyls, C1-C6 haloalkyls, or C1-C6 deuteroalkyls. R 2 These are hydrogen, deuterium, halogen, or C1-C6 alkyl. or R 1 and R 2 These come together to form a cycloalkyl or heterocycloalkyl group. Each R 3 These are independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. R 4 This is either hydrogen or a C1-C6 alkyl group.

[0129] In some embodiments of the compound of formula (VI), X is -C(R 3 )2-, -NR 4 -, or -S-, Y is -CR 1 R 2 -, -NR 4 -, -O-, or -S- R 1 and R 2 These 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 heterocycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, or R 1 and R 2 They come together to form an oxo, or R 1 and R 2 These combine to form a cycloalkyl or heterocycloalkyl group, and the cycloalkyl and heterocycloalkyl groups 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. Each R 3 These are independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a , -NR c R d -C(=O)R a , -C(=O)OR b -C(=O)NRc R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heterocycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, or two R 3 They come together to form an oxo, R 4 This is hydrogen, -C(=O)R a , -C(=O)OR b -C(=O)NR c R d These are 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.

[0130] In some embodiments of the compound of formula (VI), X is -C(R 3 )2-, Y is -CR 1 R 2 -, -NR 4 -, -O-, or -S- R 1 and R 2 These are independently hydrogen, deuterium, halogen, -OH, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. or R 1 and R 2 They come together to form an oxo, or R 1 and R 2 These come together to form a cycloalkyl or heterocycloalkyl group. Each R 3 These are independently hydrogen, deuterium, halogen, -OH, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. or two R 3They come together to form an oxo, R 4 This is either hydrogen or a C1-C6 alkyl group.

[0131] In some embodiments of the compound of formula (VI), X is -NR 4 -or -S-, Y is -CR 1 R 2 -and, R 1 and R 2 These are independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. or R 1 and R 2 They come together to form an oxo, or R 1 and R 2 These come together to form a cycloalkyl or heterocycloalkyl group. R 4 This is either hydrogen or a C1-C6 alkyl group.

[0132] In some embodiments of the compound of formula (VI), R 5 These are hydrogen, deuterium, halogens, -CN, -OH, and -OR a These are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl, or cycloalkyl. In some embodiments of the compound of formula (VI), R 5 These are hydrogen, deuterium, halogen, -CN, or C1-C6 alkyl.

[0133] In some embodiments of the compound of formula (VI), R 6 These are hydrogen, deuterium, halogens, -CN, -OH, and -OR aThese are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl, or cycloalkyl. In some embodiments of the compound of formula (VI), R 6 These are hydrogen, deuterium, halogen, -CN, or C1-C6 alkyl.

[0134] In some embodiments of the compound of formula (VI), R 7 These are hydrogen, deuterium, halogens, -CN, -OH, and -OR a These are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl, or cycloalkyl. In some embodiments of the compound of formula (VI), R 7 These are hydrogen, deuterium, halogen, -CN, or C1-C6 alkyl.

[0135] In some embodiments of the compound of formula (VI), ring B is a six-membered heteroaryl. In some embodiments of the compound of formula (VI), ring B is a pyridinyl.

[0136] In some embodiments of the compound of formula (VI), each R B These are independently hydrogen, deuterium, halogen, -CN, -OH, and -OR a These are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl, or cycloalkyl. In some embodiments of the compound of formula (VI), each R B These are independently C1-C6 alkyl groups.

[0137] In some embodiments of the compound of formula (VI), m is 1 or 2. In some embodiments of the compound of formula (VI), m is 1 to 4. In some embodiments of the compound of formula (VI), m is 2 to 4. In some embodiments of the compound of formula (VI), m is 1. In some embodiments of the compound of formula (VI), m is 2.

[0138] In some embodiments of the compound of formula (VI), ring C is a 5- or 6-membered heteroaryl. In some embodiments of the compound of formula (VI), ring C is a pyrimidinyl.

[0139] In some embodiments of the compound of formula (VI), each R C These are independently hydrogen, deuterium, halogen, -CN, -OH, and -OR a These are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of the compound of formula (VI), each R C These are independently C1-C6 hydroxyalkyl groups.

[0140] In some embodiments of the compound of formula (VI), p is 1 or 2. In some embodiments of the compound of formula (VI), p is 1 to 3. In some embodiments of the compound of formula (VI), p is 1. In some embodiments of the compound of formula (VI), p is 2.

[0141] Compounds of formula (VII), or their pharmaceutically acceptable salts, solvates, N-oxides, or stereoisomers are also disclosed herein. [ka] During the ceremony, Ring A is phenyl or heteroaryl, Each R A. These are independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a -OC(=O)Ra , -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 one or more R Aa. It is replaced by, or two Rs on the same atom A They come together to form an oxo, Each R Aa These 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 cR 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 Rs on the same atom Aa They come together to form an oxo, n is between 0 and 4. R 1 and R 2 These 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 heterocycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, or R 1 and R 2 They come together to form an oxo, or R 1 and R 2These combine to form a cycloalkyl or heterocycloalkyl group, and the cycloalkyl and heterocycloalkyl groups 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. Ring B is pyridinyl, Each R B These 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 one or more R Ba.It has been replaced with, Each R Ba These 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 Rs on the same atom Ba They come together to form an oxo, m is between 0 and 3. Ring D is a biring ring, Each R D These 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 one or more R Da. It is replaced by, or two Rs on the same atom D They come together to form an oxo, Each R Da These 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 , -NRb 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 Rs on the same atom Da They come together to form an oxo, q is between 0 and 6. R 12 These are hydrogen, deuterium, halogens, -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 Ure 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 alkyl)cycloalkyl, (C1-C6 alkyl)heterocycloalkyl, (C1-C6 alkyl)aryl, or (C1-C6 alkyl)heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently one or more R 12a. It has been replaced with, Each R 12a These 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 Rs on the same atom 12a They come together to form an oxo, R 13 These are 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 14 These are 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, Each R aThese 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 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, Aryls and heteroaryls are independently and 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 bThese are 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 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl aryl and heteroaryl are independently and 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 dThese are 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 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl aryl and heteroaryl are independently and 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 These, together with the atoms to which they bond, form heterocycloalkyls that are 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.

[0142] In some embodiments of the compound of formula (VII), ring A is a heteroaryl compound. In some embodiments of the compound of formula (VII), ring A is a pyridyl compound. In some embodiments of the compound of formula (VII), ring A is a phenyl compound.

[0143] In some embodiments of the compound of formula (VII), each R A These are independently deuterium, halogen, -CN, -OH, and -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of the compound of formula (I), each R A R is independently a halogen or a C1-C6 alkyl. In some embodiments of the compound of formula (VII), each R A It is a halogen independently.

[0144] In some embodiments of the compound of formula (VII), n is 1 or 2. In some embodiments of the compound of formula (VII), n is 1 to 3. In some embodiments of the compound of formula (VII), n is 2. In some embodiments of the compound of formula (VII), n is 1.

[0145] In some embodiments of the compound of formula (VII), R 1 and R 2 R is independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl. In some embodiments of the compound of formula (VII), R 1 and R 2 R is independently hydrogen, deuterium, halogen, or C1-C6 alkyl. In some embodiments of the compound of formula (VII), R 1 and R 2 It is hydrogen.

[0146] In some embodiments of the compound of formula (VII), ring D is a 6-12 membered bicyclic ring comprising 1 to 4 heteroatoms optionally selected from the group consisting of O, S, N, P, or B. In some embodiments of the compound of formula (VII), ring D is a 6-12 membered bicyclic ring comprising 1 to 4 heteroatoms optionally selected from the group consisting of O, S, or N. In some embodiments of the compound of formula (VII), ring D is a 6-12 membered bicyclic ring comprising 1 to 4 heteroatoms optionally selected from the group consisting of O and N. In some embodiments of the compound of formula (VII), ring D is a 6-12 membered bicyclic ring comprising 1 to 4 heteroatoms optionally selected from the group consisting of O and N. In some embodiments of the compound of formula (VII), ring D is a 6-12 membered bicyclic ring comprising 1 to 3 heteroatoms optionally selected from the group consisting of O and N. In some embodiments of the compound of formula (VII), ring D is a 6- to 10-membered bicyclic ring containing 1-3 heteroatoms that are N.

[0147] In some embodiments of the compound of formula (VII), each R D These are independently hydrogen, deuterium, halogen, -CN, -OH, and -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, or two R on the same atom D These combine to form an oxo. In some embodiments of the compound of formula (VII), each R D These are independently hydrogen, deuterium, halogen, -CN, and -OR. a , C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkynyl, or cycloalkyl, or two R on the same atom D These come together to form an oxo.

[0148] In some embodiments of the compound of formula (VII), q is 1 to 4. In some embodiments of the compound of formula (VII), q is 1 to 3. In some embodiments of the compound of formula (VII), q is 2 to 4.

[0149] In some embodiments of the compound of formula (VII), [ka] [ka] That is the case.

[0150] In some embodiments of the compound of formula (VII), each R B These are independently deuterium, halogen, -CN, -OH, and -OR a These are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C2-C6 alkynyl, or cycloalkyl. In some embodiments of the compound of formula (VII), each R B These are independently deuterium, -CN, -OH, and -OR a These are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C2-C6 alkynyl, or cycloalkyl. In some embodiments of the compound of formula (VII), each R B These are independently C1-C6 alkyl groups.

[0151] In some embodiments of the compound of formula (VII), m is 1 or 2. In some embodiments of the compound of formula (VII), m is 1. In some embodiments of the compound of formula (VII), m is 2.

[0152] In some embodiments of the compound of formula (VII), R 12 These are hydrogen, deuterium, halogens, -CN, -OH, and -OR aThese are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of the compound of formula (VII), R 12 These are C1-C6 hydroxyalkyl groups.

[0153] In some embodiments of the compound of formula (VII), R 13 These are hydrogen, deuterium, halogens, or C1-C6 alkyl groups.

[0154] In some embodiments of the compound of formula (VII), R 14 These are hydrogen, deuterium, halogens, or C1-C6 alkyl groups.

[0155] Compounds of formula (VIII), or their pharmaceutically acceptable salts, solvates, N-oxides, or stereoisomers are also disclosed herein. [ka] During the ceremony, Ring A is phenyl or heteroaryl, Each R A. These 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)2Ra -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 one or more R Aa. It is replaced by, or two Rs on the same atom A They come together to form an oxo, Each R Aa These 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 Rs on the same atom Aa They come together to form an oxo, n is between 0 and 4. R 1 and R 2 These 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 heterocycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, or R 1 and R 2 They come together to form an oxo, or R 1 and R 2 These combine to form a cycloalkyl or heterocycloalkyl group, and the cycloalkyl and heterocycloalkyl groups 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 3These 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 heterocycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, or two R 3 They come together to form an oxo, R 4 This 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 These are 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 These are 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 These are 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, Ring B is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring. Each R B These 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 one or more R Ba. It is replaced by, or two Rs on the same atom B They come together to form an oxo, Each R Ba These 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 Rs on the same atom Ba They come together to form an oxo, m is between 0 and 4. Ring E is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring. Each R E These 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 Ure 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 dC1-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 alkyl)cycloalkyl, (C1-C6 alkyl)heterocycloalkyl, (C1-C6 alkyl)aryl, or (C1-C6 alkyl)heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently one or more R Ea. It has been replaced with, Each R Ea These 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 Rs on the same atom Ea They come together to form an oxo, R 13 These are 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 14 These are 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, p is between 0 and 4. Each R aThese 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 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, Aryls and heteroaryls are independently and 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 bThese are 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 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl aryl and heteroaryl are independently and 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 dThese are 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 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl aryl and heteroaryl are independently and 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 These, together with the atoms to which they bond, form heterocycloalkyls that are 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.

[0156] In some embodiments of the compound of formula (VIII), ring A is a heteroaryl compound. In some embodiments of the compound of formula (VIII), ring A is a pyridyl compound. In some embodiments of the compound of formula (VIII), ring A is a phenyl compound.

[0157] In some embodiments of the compound of formula (VIII), each R A These are independently deuterium, halogen, -CN, -OH, and -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of the compound of formula (VIII), each R A R is independently a halogen or a C1-C6 alkyl. In some embodiments of the compound of formula (VIII), each R A It is a halogen independently.

[0158] In some embodiments of the compound of formula (VIII), n is 1 or 2. In some embodiments of the compound of formula (VIII), n is 1 to 3. In some embodiments of the compound of formula (VIII), n is 2. In some embodiments of the compound of formula (VIII), n is 1.

[0159] In some embodiments of the compound of formula (VIII), R 1 and R 2 R is independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl. In some embodiments of the compound of formula (VIII), R 1 and R 2 R is independently hydrogen, deuterium, halogen, or C1-C6 alkyl. In some embodiments of the compound of formula (VIII), R 1 and R 2 It is hydrogen.

[0160] In some embodiments of the compound of formula (VIII), X is -O-.

[0161] In some embodiments of the compound of formula (VIII), R 5 These are hydrogen, deuterium, halogens, -CN, -OH, and -OR aThese are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl, or cycloalkyl. In some embodiments of the compound of formula (VIII), R 5 These are hydrogen, deuterium, halogen, -CN, or C1-C6 alkyl.

[0162] In some embodiments of the compound of formula (VIII), R 6 These are hydrogen, deuterium, halogens, -CN, -OH, and -OR a These are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl, or cycloalkyl. In some embodiments of the compound of formula (VIII), R 6 These are hydrogen, deuterium, halogen, -CN, or C1-C6 alkyl.

[0163] In some embodiments of the compound of formula (VIII), R 7 These are hydrogen, deuterium, halogens, -CN, -OH, and -OR a These are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl, or cycloalkyl. In some embodiments of the compound of formula (VIII), R 7 These are hydrogen, deuterium, halogen, -CN, or C1-C6 alkyl.

[0164] In some embodiments of the compound of formula (VIII), ring B is a 6-membered heteroaryl. In some embodiments of the compound of formula (VIII), ring B is a pyridinyl.

[0165] In some embodiments of the compound of formula (VIII), each R B These are independently hydrogen, deuterium, halogen, -CN, -OH, and -OR aThese are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl, or cycloalkyl. In some embodiments of the compound of formula (VIII), each R B These are independently C1-C6 alkyl groups.

[0166] In some embodiments of the compound of formula (VIII), m is 1 or 2. In some embodiments of the compound of formula (VIII), m is 1 to 4. In some embodiments of the compound of formula (VIII), m is 2 to 4. In some embodiments of the compound of formula (VIII), m is 1. In some embodiments of the compound of formula (VIII), m is 2.

[0167] In some embodiments of the compound of formula (VIII), ring E is a cycloalkyl group.

[0168] In some embodiments of the compound of formula (VIII), each R E These are independently hydrogen, deuterium, halogen, -CN, -OH, and -OR a These are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of the compound of formula (VIII), each R E These are independently -OH or C1-C6 alkyl groups.

[0169] In some embodiments of the compound of formula (VIII), p is 1 or 2. In some embodiments of the compound of formula (VIII), p is 1 or 3. In some embodiments of the compound of formula (VIII), p is 1. In some embodiments of the compound of formula (VIII), p is 2.

[0170] In some embodiments of the compound of formula (VIII), R 13 These are hydrogen, deuterium, halogens, or C1-C6 alkyl groups.

[0171] In some embodiments of the compound of formula (VIII), R 14 These are hydrogen, deuterium, halogens, or C1-C6 alkyl groups.

[0172] In some embodiments of the compounds disclosed herein, each R a Each alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is independently a 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 is independently optionally a oxo, deuterium, halogen, -CN, -OH, or -O CH3, -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 are substituted. In some embodiments of the compounds disclosed herein, each R a R is independently a 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 aR is independently a C1-C6 alkyl, a C1-C6 haloalkyl, a cycloalkyl, or a heterocycloalkyl. In some embodiments, each R a R is independently a C1-C6 alkyl or a C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, each R a These are independently C1-C6 alkyl groups.

[0173] In some embodiments of the compounds disclosed herein, each R b Each alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl element is 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 element is independently and optionally 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, C1-C6 heteroalkyl. In some embodiments of the compounds disclosed herein, each R bR is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl, and each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of the compounds disclosed herein, each R b R is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments, each R b R is independently hydrogen, a C1-C6 alkyl group, or a C1-C6 haloalkyl group. In some embodiments of the compounds disclosed herein, each R b These are independently hydrogen or a C1-C6 alkyl group.

[0174] In some embodiments of the compounds disclosed herein, each R c and R dEach alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl element is 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 element is independently and optionally 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, C1-C6 heteroalkyl. In some embodiments of the compounds disclosed herein, each R c and R d R is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl, and each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 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 R 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 dR is independently hydrogen, a C1-C6 alkyl group, or a C1-C6 haloalkyl group. In some embodiments of the compounds disclosed herein, each R c and R d These are independently hydrogen or a C1-C6 alkyl group.

[0175] In some embodiments of the compounds disclosed herein, R c and R d These, together with the atoms to which they are bonded, form heterocycloalkyls 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.

[0176] In some embodiments of the compounds disclosed herein, each R A , R B , R C , R D , R E , R 12 , R a , R b , R c , R d , and R c and R d The heterocycloalkyl groups formed when these groups are combined are independently substituted with 1, 2, 3, or 4 substituents as defined herein. In some embodiments of the compounds disclosed herein, each R A , R B , R C , R D , R E , R 12 , R a , R b , R c , R d , and R c and R dThe heterocycloalkyl groups formed when these groups are combined are independently substituted with one, two, or three substituents as defined herein. In some embodiments of the compounds disclosed herein, each R A , R B , R C , R D , R E , R 12 , R a , R b , R c , R d , and R c and R d The heterocycloalkyl groups formed when these groups are combined are independently substituted with one or two substituents as defined herein. In some embodiments of the compounds disclosed herein, each R A , R B , R C , R D , R E , R 12 , R a , R b , R c , R d , and R c and R d The heterocycloalkyl groups formed when these groups are combined are independently substituted with a single substituent as defined herein.

[0177] Any combination of the groups described above for various variables is contemplated herein. Throughout this specification, the groups and their substituents are selected by those skilled in the art to provide stable moieties and compounds.

[0178] In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, N-oxides, or stereoisomers, are one of the compounds listed in Table 1. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] * Stereochemistry was assigned arbitrarily.

[0179] In some embodiments, the compound of formula (I) is [ka] Alternatively, a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof may be selected.

[0180] In some embodiments, the compound of formula (II) is [ka] Alternatively, a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof may be selected.

[0181] In some embodiments, the compound of formula (III) is [ka] [ka] Alternatively, a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof may be selected.

[0182] In some embodiments, the compound of formula (IV) is [ka] Alternatively, a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof may be selected.

[0183] In some embodiments, the compound of formula (V) is [ka] Alternatively, a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof may be selected.

[0184] In some embodiments, the compound of formula (VI) is [ka] Alternatively, a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof may be selected.

[0185] In some embodiments, the compound of formula (VII) is [ka] Alternatively, a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof may be selected.

[0186] Further forms of the compounds disclosed herein Isomers / stereoisomers In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds shown herein include all cis, trans, syn, anti, entgegen(E), and zusammen(Z) isomers, as well as their corresponding mixtures. In some situations, the compounds described herein have one or more chiral centers, each center existing in either an R or S configuration. The compounds described herein include all diastereomer, enantiomer, and epimer 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 compounds with an optically active resolving agent to form a pair of diastereoisomer compounds, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereomers have different physical properties (e.g., melting point, boiling point, solubility, reactivity, etc.) and are separated by utilizing these differences. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably by separation / resolution techniques based on differences in solubility. In some embodiments, the optically pure enantiomers are then recovered together with a resolving agent by any practical means that does not result in racemization.

[0187] In some embodiments, the compounds described herein include a rotationally hindered bond so that two distinct rotational or atropisomers can be isolated. In some embodiments, the atropisomer is [ka] Here, each A corresponds to the appropriate R group defined in each of formulas (I) to (VIII). In some embodiments, these atrop isomers are separated and found to have different biological activities that may be advantageous. In some embodiments, the atrop isomers are [ka] In some embodiments, the atrop isomer is [ka] That is the case.

[0188] labeled compound In some embodiments, the compounds described herein exist in their isotopically labeled forms. In some embodiments, the methods disclosed herein include methods for treating a disease by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods for treating a disease by administering such isotopically labeled compounds as a pharmaceutical composition. Thus, in some embodiments, the compounds disclosed herein include isotopically labeled compounds, which are identical to those enumerated herein, except that one or more atoms are replaced by atoms having atomic masses or mass numbers different from those commonly found in nature. Examples of isotopes that may be incorporated into the compounds disclosed herein include, 2 H, 3 H, 13 C, 14 C, l5 N, 18 O, 17 O, 31 P, 32 P,35 S, 18 F, and 36 Examples include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as Cl. Compounds described herein, including the aforementioned isotopes and / or other isotopes of other atoms, as well as their pharmaceutically acceptable salts, solvates, or stereoisomers, are within the scope of the present invention. Certain isotope-labeled compounds, for example, 3 H and 14 The incorporation of radioactive isotopes such as 13C is useful in drug and / or substrate tissue distribution assays. Tritiation, i.e., 3 H and carbon-14, that is, 14 14C isotopes are particularly preferred due to their ease of preparation and detectability. Furthermore, deuterium, i.e., 2 Substitution with heavier isotopes, such as 1H, can produce certain therapeutic benefits resulting from greater metabolic stability, such as increased half-life in vivo or reduced dosage requirements.

[0189] Pharmaceutically acceptable salts In some embodiments, the compounds described herein exist as pharmaceutically acceptable salts thereof. In some embodiments, the methods disclosed herein include methods for treating a disease by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods for treating a disease by administering such pharmaceutically acceptable salts as a pharmaceutical composition.

[0190] In some embodiments, the compounds described herein have an acidic or basic group and therefore react with several inorganic or organic bases, as well as either inorganic or 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 their solvates or stereoisomers, or by reacting the purified compound in its free form separately with a suitable acid or base and isolating the salt thus formed.

[0191] Examples of pharmaceutically acceptable salts include salts prepared by the reaction of the compounds described herein with inorganic substances, organic or inorganic bases, such salts include acetates, acrylates, adipicates, alginates, aspartates, benzoates, benzenesulfons, bisulfates, bisulfites, bromides, butyrates, butyn-1,4-dioate, camphorates, camphor sulfons, capronates, caprylates, chlorobenzoates, chlorides, citrates, cyclopentanepropionates, decanoates, diglucons, dihydrogen phosphates, dinitrobenzoates, dodecyl sulfates, ethanesulfons, formates, fumarates, glucoheptanoates, glycerophosphates, glycolates, hemisulfates, heptanoates, hexanoates, hexyn-1,6-dioate, hydroxybenzoates, γ-hydroxybutyrates, hydrochlorides, Examples include hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogen phosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmitate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propionate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberinate, sebacinate, sulfonate, tartrate, thiocyanate, undecanoate tosylate, and xylenesulfonate.

[0192] Furthermore, the compounds described herein may be prepared as pharmaceutically acceptable salts formed by reacting the compounds in their free base form with pharmaceutically acceptable inorganic or organic acids, which include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and metaphosphoric acid; as well 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, and 3-(4-hydroxybenzoyl)benzoic acid. Examples of organic acids include fusiform acid, cinnamic acid, mandelic acid, aryl sulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]octa-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 sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid. In some embodiments, other acids such as oxalic acid are used in the preparation of salts that are useful as intermediates in obtaining the compounds disclosed herein, their solvates, or stereoisomers and their pharmaceutically acceptable acid addition salts, although they are not pharmaceutically acceptable in themselves.

[0193] In some embodiments, compounds described herein containing a free acid group react with a suitable base such as a pharmaceutically acceptable metal cation hydroxide, carbonate, bicarbonate, or sulfate, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Typical salts include alkali or alkaline earth salts such as lithium, sodium, potassium, calcium, and magnesium, as well as aluminum salts. Exemplary examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, and N2. + (C 1-4 Examples include alkyl(4) and others.

[0194] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, and piperazine. It should be understood that the compounds described herein also involve quaternization of any basic nitrogen-containing group they contain. In some embodiments, water-soluble, oil-soluble, or dispersible products are obtained by such quaternization.

[0195] solvate In some embodiments, the compounds described herein exist as solvates. The present invention provides a method for treating a disease by administering such solvates. The present invention further provides a method for treating a disease by administering such solvates as a pharmaceutical composition.

[0196] Solvates are formed using either stoichiometric or non-stoichiometric amounts of a solvent, and in some embodiments, using pharmaceutically acceptable solvents such as water or ethanol. When the solvent is water, a hydrate is formed, or when the solvent is alcohol, an alcoholate is formed. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. Furthermore, the compounds provided herein may exist in both solvated and unsolvated forms. Generally, the solvated form is considered equivalent to the unsolvated form for the purposes of the compounds and methods provided herein.

[0197] Tautomers In some circumstances, compounds exist as tautomers. The compounds described herein include all possible tautomers within the range of formulas described herein. Tautomers are compounds that can be interconverted by the movement of hydrogen atoms, involving the switching of single bonds and adjacent double bonds. In bond configurations where tautomerization is possible, a chemical equilibrium of tautomers exists. All tautomer forms of the compounds disclosed herein are intended. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH.

[0198] Treatment method Compounds and compositions generally useful for inhibiting the kinase activity of one or more enzymes are described herein. Examples of kinases inhibited by the compounds and compositions described herein and for which the methods described herein are useful include p38 MAP kinase, MK2, or their variants.

[0199] MAP kinase-activated protein kinase 2 ("MK2") is an enzyme encoded in humans by the MAPKAPK2 gene. This gene encodes a member of the Ser / Thr protein kinase family. This kinase is regulated via 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 transcriptional variants encoding two different isoforms have been found for this gene.

[0200] MK2 is a multi-domain protein consisting of an N-terminal proline-rich domain, a catalytic domain, an autoinhibitory domain, and C-terminal nuclear export signaling (NES) and nuclear localization signaling (NLS). Two isoforms of human MK2 have been characterized. One isoform consists of 400 amino acids, while the other consists of 370 residues and is thought to be a splice variant lacking the C-terminal NLS. MK2 is located in the cell nucleus, and upon binding and phosphorylation by p38, the MK2 NES becomes functional, and both kinases are co-transported from the nucleus to the cytoplasm. Interestingly, the transport of the MK2 / p38 complex does not require catalytically active MK2, as the active site mutant Asp207Ala is still transported to the cytoplasm. Phosphorylation of human MK2 by p38 at residues T222, S272, and T334 is thought to induce conformational changes in the autoinhibitory domain and thus activate the enzyme by exposing the active site for substrate binding. Mutations in two autoinhibitory domain residues, W332A and K326E, in mouse MK2 resulted in increased basal activity, and C-terminal deletion of the autoinhibitory domain constitutively activated this domain, providing further evidence for the role of this domain in inhibiting MK2 activity.

[0201] Diseases or disorders related to MK2 that are treated with the compounds disclosed herein include autoimmune disorders, chronic inflammatory disorders, acute inflammatory disorders, autoinflammatory disorders, fibrotic disorders, metabolic disorders, neoplastic disorders, and cardiovascular or cerebrovascular disorders.

[0202] In some embodiments, MK2-mediated diseases or disorders are autoimmune disorders, chronic and / or acute inflammatory disorders, and / or autoinflammatory disorders. 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 syndromes, Macklewells syndrome, familial cold autoinflammatory syndrome, neonatal onset multi-organ autoinflammatory disease, TNF receptor-associated periodic syndromes, acute and chronic pancreatitis, atherosclerosis, gout, ankylosing spondylitis, fibrous disorders (e.g.) For example, hepatic fibrosis or idiopathic pulmonary fibrosis), nephropathy, sarcoidosis, scleroderma, anaphylaxis, diabetes (e.g., type 1 or type 2 diabetes), diabetic retinopathy, Still's disease, vasculitis, sarcoidosis, pneumonia, acute respiratory distress syndrome, exudative and atrophic age-related macular degeneration, autoimmune hemolytic syndrome, autoimmune and inflammatory hepatitis, autoimmune neuropathy, autoimmune ovarian failure, autoimmune orchitis, autoimmune thrombocytopenia, silicone implant-related autoimmune disease, Sjögren's syndrome, familial Mediterranean fever, systemic lupus erythematosus Death, vasculitis syndromes (e.g., temporal-Takayasu arteritis and giant cell arteritis, Behçet's disease or Wegener's granulomatosis), vitiligo, secondary hematological signs of autoimmune diseases (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 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 syndrome, thyrotoxicosis, sepsis, septic shock, endotoxin shock, exotoxin-induced toxic shock syndrome, gram-negative bacterial sepsis, toxic shock syndrome, glomerulonephritis, peritonitis, interstitial cystitis, oxygen-overload-induced inflammation, chronic obstructive pulmonary disease (COPD), vasculitis,These include graft-versus-host reactions (e.g., graft-versus-host disease), allograft rejection (e.g., acute or chronic allograft rejection), early rejection (e.g., acute rejection), reperfusion injury, pain (e.g., acute pain, chronic pain, neuropathic pain, or fibromyalgia), chronic infections, meningitis, encephalitis, myocarditis, gingivitis, postoperative trauma, tissue injury, traumatic brain injury, enteritis, sinusitis, uveitis, ocular inflammation, optic neuritis, gastric ulcers, esophagitis, peritonitis, periodontitis, dermatomyositis, gastritis, myositis, polymyalgia, pneumonia, and bronchitis.

[0203] In some embodiments, the MK2-mediated disease or disorder is a fibrotic disorder. Exemplary fibrotic disorders include systemic scleroderma / scleroderma, lupus nephritis, connective tissue disease, wound healing, surgical scarring, spinal cord injury, CNS scarring, acute lung injury, pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis or cystic fibrosis), chronic obstructive pulmonary disease, adult respiratory distress syndrome, acute lung injury, drug-induced lung injury, glomerulonephritis, chronic kidney disease (e.g., diabetic nephropathy), hypertensive nephropathy, gastrointestinal or gastrointestinal fibrosis, renal fibrosis, hepatic or biliary fibrosis, hepatic fibrosis (e.g., non-alcoholic steatohepatitis, hepatitis C, or hepatocellular carcinoma). Examples include cirrhosis (e.g., primary biliary cirrhosis or cirrhosis due to fatty liver disease (e.g., alcoholic and non-alcoholic steatohepatitis)), radiation-induced fibrosis (e.g., head and neck, gastrointestinal tract, or lung), primary sclerosing cholangitis, restenosis, cardiac fibrosis (e.g., endocardial myocardial fibrosis or atrial fibrosis), ocular scarring, fibrosclerosis, fibrous carcinoma, fibroid, fibroma, fibroadenoma, fibrosarcoma, transplanted artery lesions, keloids, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive mass fibrosis, and nephrogenic systemic fibrosis.

[0204] In some embodiments, the MK2-mediated disease or condition is a metabolic disorder. Exemplary metabolic disorders include obesity, steroid resistance, impaired glucose tolerance, and metabolic syndromes.

[0205] In some embodiments, the MK2-mediated disease or condition 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 lymphoblastic 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 lymphoma, mast cell tumor, Hodgkin's disease, or non-Hodgkin's disease), myelodysplastic syndromes, fibrosarcoma, rhabdomyosarcoma; astrocytoma, neuroblastoma, glioma, and schwannoma; melanoma, seminomas, teratoma, osteosarcoma, and pigmented xyloplasma. This includes skin diseases, keratoacanthoma, follicular thyroid carcinoma, Kaposi's sarcoma, melanoma, teratoma, rhabdomyosarcoma, metastatic and bone disorders, as well as bone cancer, oral / pharyngeal cancer, esophageal cancer, laryngeal cancer, gastric cancer, intestinal cancer, colon cancer, rectal cancer, lung cancer (e.g., non-small cell lung cancer or small cell lung cancer), liver cancer, pancreatic cancer, nerve cancer, brain cancer (e.g., glioma or glioblastoma multiforme), head and neck cancer, throat cancer, ovarian cancer, uterine cancer, prostate cancer, testicular cancer, bladder cancer, kidney cancer, breast cancer, gallbladder cancer, cervical cancer, thyroid cancer, prostate cancer, and skin cancer.

[0206] In some embodiments, MK2-mediated disorders are cardiovascular or cerebrovascular disorders. Exemplary cardiovascular disorders include atherosclerosis, atherosclerotic restenosis of the coronary arteries, acute coronary syndrome, myocardial infarction, allograft vascular vascular disease, and stroke. Exemplary cerebrovascular disorders 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.

[0207] dosage In certain embodiments, compositions comprising the compounds described herein are administered for prophylactic and / or therapeutic purposes. In certain therapeutic uses, the composition is administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially cessate at least one symptom of the disease or condition. The effective dose for this use depends on the severity and course of the disease or condition, previous therapies, the patient's health status, weight, and response to the drug, as well as the judgment of the treating physician. The therapeutically effective dose may be determined by methods including, but not limited to, dose escalation and / or dose-range clinical trials, at the discretion of the physician.

[0208] In prophylactic use, compositions comprising the compounds described herein are administered to patients who are susceptible to, or otherwise at risk of, a particular disease, disorder, or condition. Such amounts are defined as “an effective prophylactic dose or amount.” In this use, the exact amount also depends on the patient’s health, weight, etc. When used in a patient, the effective dose for this use depends on the severity and course of the disease, disorder, or condition, previous therapies, the patient’s health and response to the drug, and the judgment of the treating physician. In one embodiment, prophylactic treatment involves administering a pharmaceutical composition comprising the compounds 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 currently in remission, in order to prevent recurrence of symptoms of the disease or condition.

[0209] In certain embodiments where the patient's condition does not improve, the compound may, at the physician's discretion, be administered chronically, i.e., over a long period including the patient's entire lifespan, to improve, or otherwise control or limit, the symptoms of the patient's disease or condition.

[0210] In certain embodiments where the patient's condition improves, the dose of the administered drug is temporarily reduced or temporarily suspended for a certain period of time (i.e., a “drug-free period”). In certain embodiments, the length of the drug-free period is from 2 days to 1 year, and includes, in just a few examples, 2, 3, 4, 5, 6, 7, 10, 12, 15, 20, 28, or more than 28 days. The dose reduction during the drug-free period is from 10% to 100%, in just a few examples, and includes, in just a few examples, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.

[0211] Once the patient's condition improves, a maintenance dose is administered as needed. Subsequently, in certain embodiments, the dose, frequency, or both are reduced to a level that maintains the improved disease, disorder, or condition, depending on the effect on the symptoms. However, in certain embodiments, the patient requires long-term, intermittent or daily treatment upon any relapse of symptoms.

[0212] The amount of a given drug corresponding to such a quantity varies depending on factors such as the specific compound, the disease state and its severity, and the identity of the subject or host requiring treatment (e.g., weight, sex), but nevertheless, it is determined according to the specific circumstances surrounding the case, including, for example, the specific drug being administered, the route of administration, the condition being treated, and the subject or host being treated.

[0213] However, generally, the dose used for treating adults is typically in the range of 0.01 mg to 5000 mg per day. In one embodiment, the dose used for treating adults is approximately 1 mg to 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 subdoses per day.

[0214] In one embodiment, an appropriate daily dose for the compounds described herein or their pharmaceutically acceptable salts is about 0.01 to about 50 mg / kg body weight. In some embodiments, the daily dose or the amount of active substance in the dosage form may be lower or higher than the range shown herein, based on several variables relating to the individual treatment regimen. In various embodiments, the daily dose and unit dose may be modified 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 physician's judgment.

[0215] The toxicity and therapeutic efficacy of such treatment regimens are as follows: 10 and ED 90 This is determined by standard pharmaceutical procedures in cell cultures or experimental animals, including but not limited to the determination of the LD50. The dose-to-toxicity ratio is the therapeutic index, and LD50 is the dose-to-toxicity ratio. 50 and ED 50 It is expressed as a ratio between [value] and [value]. In certain embodiments, data obtained from cell culture assays and animal studies are used when formulating therapeutically effective daily dose ranges and / or therapeutically effective unit doses for use in mammals, including humans. In some embodiments, the daily dose of the compounds described herein is an ED with minimal toxicity. 50 It is within the range of circulating concentrations, including [the specified substance]. In certain embodiments, the daily dose range and / or unit dose vary within this range depending on the dosage form used and the route of administration utilized.

[0216] In any of the embodiments described above, in further embodiments, an effective amount of the compound described herein, or a pharmaceutically acceptable salt thereof, is administered (a) systemically to a mammal and / or (b) orally to a mammal and / or (c) intravenously to a mammal and / or (d) by injection to a mammal and / or (e) topically to a mammal and / or (f) non-systemically or topically to a mammal.

[0217] In any of the embodiments described above, further embodiments include a single dose of an effective amount of the compound, wherein (i) the compound is administered once daily, or (ii) the compound is administered to a mammal multiple times over a period of one day.

[0218] In any of the embodiments described above, further embodiments include administering multiple doses of an effective amount of the compound, wherein (i) the compound is administered as a single dose, either continuously or intermittently; (ii) the interval between doses is every 6 hours; (iii) the compound is administered to a mammal every 8 hours; (iv) the compound is administered to a subject every 12 hours; or (v) the compound is administered to a subject every 24 hours. In further or alternative embodiments, the method includes a drug-free period, during which the administration of the compound is temporarily interrupted or the dose of the compound being administered is temporarily reduced, and the administration of the compound is resumed at the end of the drug-free period. In one embodiment, the length of the drug-free period varies from 2 days to 1 year.

[0219] Route of administration Preferred routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transmucosal, transdermal, vaginal, ocular, nasal, and topical administration. Furthermore, as just one example, parenteral delivery includes intramuscular, subcutaneous, intravenous, intrathecal injection, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injection.

[0220] In certain embodiments, the compounds described herein are administered topically rather than systemically, for example, often by direct injection of the compound into an organ, such as a depot preparation or a sustained-release formulation. In certain 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, by liposomes coated with organ-specific antibodies. In such embodiments, the liposomes target an organ and are selectively taken up by the organ. In yet another embodiment, the compounds described herein are provided in the form of a rapid-release formulation, a sustained-release formulation, or an intermediate-release formulation. In yet another embodiment, the compounds described herein are administered topically.

[0221] Pharmaceutical composition / formulation The compounds described herein are administered to subjects requiring them, either alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, in pharmaceutical compositions according to standard pharmaceutical practice. In one embodiment, the compounds of the present invention may be administered to animals. The compounds may be administered orally or parenterally, including intravenous, intramuscular, intraperitoneal, subcutaneous, rectal, and topical administration routes.

[0222] In another embodiment, a compound described herein, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, and at least one pharmaceutically acceptable addition A pharmaceutical composition comprising an agent is provided herein. The pharmaceutical composition comprises one or more pharmaceutically acceptable agents that facilitate the processing of the active compound into a preparation that can be used pharmaceutically. additionThe formulations are prepared in a conventional manner using the agent. The appropriate formulation depends on the chosen route of administration. Outlines 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), and such disclosures are incorporated herein by reference.

[0223] In some embodiments, pharmaceutically acceptable addition The agents are selected from carriers, binders, fillers, suspending agents, flavoring agents, sweeteners, disintegrants, dispersants, surfactants, lubricants, colorants, diluents, solubilizers, moistening agents, plasticizers, stabilizers, penetration enhancers, wetting agents, defoaming agents, antioxidants, preservatives, and any combination thereof.

[0224] The pharmaceutical compositions described herein are administered to a subject by an appropriate route of administration, including but not limited to oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal routes. The pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, self-emulsifying dispersions, solid solutions, liposome dispersions, aerosols, solid oral dosage forms, powders, immediate-release formulations, controlled-release formulations, rapid-release formulations, tablets, capsules, pills, powders, sugar-coated tablets, effervescent formulations, lyophilized formulations, delayed-release formulations, extended-release formulations, pulsed-release formulations, multi-particle formulations, and mixed immediate and controlled-release formulations.

[0225] Pharmaceutical compositions comprising the compounds described herein or their pharmaceutically acceptable salts, solvates, N-oxides, or stereoisomers are prepared in a conventional manner, for example, by conventional mixing, dissolution, granulation, sugar-coating, levigating, emulsification, encapsulation, encapsulation, or compression processes.

[0226] Pharmaceutical compositions for oral use are obtained by mixing one or more solid excipients with one or more compounds described herein, optionally grinding the resulting mixture, and processing the granular mixture after adding suitable adjuvants if desired, to obtain tablets or sugar-coated tablet cores. Suitable excipients include, for example, fillers such as sugars containing lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, microcrystalline cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose; or others such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If desired, disintegrants such as cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or its salts (e.g., sodium alginate) may be added. In some embodiments, dyes or pigments are added to the tablet or sugar-coated tablet coating for identification purposes or to characterize different combinations of active compound dosages.

[0227] Orally administered pharmaceutical compositions include push-fit capsules made of gelatin, and sealed soft capsules made of gelatin and a plasticizer such as glycerol or sorbitol. The push-fit capsules contain an active ingredient mixed with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally a stabilizer. In the soft capsules, the active compound is dissolved or suspended in a suitable liquid such as fatty oil, liquid paraffin, or liquid polyethylene glycol. In some embodiments, a stabilizer is added.

[0228] Pharmaceutical compositions for parenteral use are formulated as infusions or injections. In some embodiments, pharmaceutical compositions suitable for injection or infusion include sterile aqueous solutions or dispersions or sterile powders containing compounds described herein or their pharmaceutically acceptable salts, solvates, N-oxides, or stereoisomers. In some embodiments, the pharmaceutical composition includes a liquid carrier. In some embodiments, the liquid carrier is a solvent or liquid dispersion medium including, for example, water, saline solution, 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 includes preservatives to prevent microbial growth.

[0229] combination Methods for treating autoimmune disorders, chronic inflammatory disorders, acute inflammatory disorders, autoinflammatory disorders, fibrous disorders, metabolic disorders, neoplastic disorders, or cardiovascular or cerebrovascular disorders by using the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, N-oxides, or stereoisomers, in combination with additional therapeutic agents are disclosed herein.

[0230] In some embodiments, additional therapeutic agents are selected from the group consisting of anti-inflammatory agents, anti-atherosclerotic agents, immunosuppressants, immunomodulators, cell proliferation inhibitors, antiproliferative agents, angiogenesis inhibitors, kinase inhibitors, cytokine blockers, and inhibitors of cell adhesion molecules.

[0231] In some embodiments, further therapeutic agents are selected from the group consisting of NSAIDs, immunosuppressants, immunomodulators, cell proliferation inhibitors, antiproliferative agents, angiogenesis inhibitors, biological agents, steroids, vitamin D3 analogs, retinoids, other kinase inhibitors, cytokine blockers, corticosteroids, and inhibitors of cell adhesion molecules. In some embodiments, additional therapeutic agents are selected from the group consisting of torcetrapib, aspirin, niacin, HMG CoA reductase inhibitors (e.g., atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin), coleseveram, cholestyramine, colestipol, gemfibrozil, probucol, and clofibrate.

[0232] In some embodiments, additional therapeutic agents include corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., ibuprofen, naproxen, acetaminophen, aspirin, fenoprofen (Nalfon), flurbiprofen (Ansaid), ketoprofen, oxaprozin (Daypro), diclofenac sodium (Voltaren), diclofenac potassium (Cataflam), etodolac (Lodine), indomethacin (Indocin), ketorolac (Toradol), sulindac (Clinoril), tolmetin (Tolectin), meclofenamete (Meclomen), mefenamic acid (Ponstel), nabumetone (Relafen), piroxicam (Feldene), cox-2 inhibitors (e.g., celecoxib (Celebrex)), immunosuppressants (e.g., For example, the following are selected from the group consisting of 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), 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.

[0233] In some embodiments, additional therapeutic agents are selected from the group consisting of EGFR kinase inhibitors, MEK inhibitors, VEGFR inhibitors, anti-VEGFR2 antibodies, KDR antibodies, AKT inhibitors, PDK-1 inhibitors, PI3K inhibitors, c-kit / Kdr tyrosine kinase inhibitors, Bcr-Abl tyrosine kinase inhibitors, VEGFR2 inhibitors, PDGFR-beta inhibitors, KIT inhibitors, Flt3 tyrosine kinase inhibitors, PDGF receptor family inhibitors, Flt3 tyrosine kinase inhibitors, RET tyrosine kinase receptor family inhibitors, VEGF-3 receptor antagonists, Raf protein kinase family inhibitors, angiogenesis inhibitors, Erb2 inhibitors, mTOR inhibitors, IGF-1R antibodies, NFκB inhibitors, proteosome inhibitors, chemotherapeutic agents, and glucose reducing agents.

[0234] 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 the administration of the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered after the administration of the compound disclosed herein. [Examples]

[0235] Intermediates 1, 2, 3 [ka]

[0236] Step 1: Preparation of ethyl 3,5-difluoropicolinate: A solution of 3,5-difluoropyridine-2-carboxylic acid (50.00 g, 314.28 mmol, 1.00 equivalent) in ethanol (200 mL) was cooled using an ice bath, and then SOCl2 (50 mL, 689.25 mmol, 2.20 equivalents) was added dropwise at 0°C. The resulting mixture was stirred at 60°C for 3 hours under a nitrogen atmosphere. The reaction was monitored by LC-MS. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography to obtain ethyl 3,5-difluoropicolinate (59 g, 100%) as a colorless liquid. LC-MS: (ES+H, m / z): [M+H] + =188.1.

[0237] Step 2: Preparation of (3,5-difluoropyridine-2-yl)methanol: To a stirred solution of ethyl 3,5-difluoropyridine-2-carboxylate (40.00 g, 213.74 mmol, 1.00 equivalent) in ethanol (300 mL), NaBH4 (20.22 g, 534.34 mmol, 2.50 equivalent) was gradually added 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 a further 2 hours under a nitrogen atmosphere. The reaction was monitored by LC-MS. The reaction was quenched at 0°C with saturated NH4Cl (aqueous solution). EtOH was removed under reduced pressure. The aqueous layer was basicized to pH 10 with saturated Na2CO3 (aqueous solution, 300 mL), and subsequently extracted with ELISA (3 × 300 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum to obtain (3,5-difluoropyridine-2-yl)methanol (26.6 g, 85.76%) as a colorless liquid. LC-MS: (ES+H, m / z): [M+H] + =146.1.

[0238] Step 3: Preparation of 2-(chloromethyl)-3,5-difluoropyridine: A stirred solution of (3,5-difluoropyridine-2-yl)methanol (34.00 g, 234.31 mmol, 1.00 equivalent) in DCM (500 mL) was mixed with DMF (160 mg), and then cooled using an ice bath. SOCl2 (40 mL, 551.40 mmol, 2.35 equivalents) was added dropwise to the mixture under a nitrogen atmosphere. The resulting mixture was stirred under a nitrogen atmosphere at room temperature for 2 hours. The reaction was monitored by LC-MS. The resulting mixture was concentrated under vacuum to obtain 2-(chloromethyl)-3,5-difluoropyridine (34.75 g, 90.68%) as a yellowish-brown semi-solid. LC-MS: (ES+H, m / z): [M+H] + =164.0. 1 ¹H NMR (400 MHz, chloroform-d) δ 8.35 (d, 1H), 7.28 (td, 1H), 4.73 (d, 2H). Intermediate 4-7 [ka]

[0239] Step 1: Preparation of 2,2-dimethyl-6-(2-oxopropyl)-1,3-dioxin-4-one: A solution of LiHMDS (3.16 L, 3.16 mol, 1.50 equivalents, 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 equivalent) under a nitrogen atmosphere at -20°C for 1 hour, followed by the dropwise addition of ZnEt2 (3.16 L, 3.16 mol, 1.50 equivalents, 1 M in hexane) over 2 hours at -20°C. The resulting mixture was stirred under a nitrogen atmosphere at -20°C for 30 minutes. Acetylimidazole (348.58 g, 3.16 mol, 1.50 equivalents) was added to the mixture at -10°C. The resulting mixture was stirred further overnight at room temperature. The reaction was monitored by LC-MS. The reaction was quenched by adding 1 L of water / THF (1:1) at -10°C. The mixture was acidified to pH 1-2 with 2 M HCl (aqueous solution). The resulting mixture was extracted with Depositphotos (3 × 5 L). The combined organic layers were washed with brine (3 × 5 L) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 2,2-dimethyl-6-(2-oxopropyl)-1,3-dioxin-4-one (200 g, 51.45%) as a yellowish-brown solid. 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).

[0240] Step 2: Preparation of 2'-chloro-4-hydroxy-5',6-dimethyl-[1,4'-bipyridine]-2-one: A solution of 2,2-dimethyl-6-(2-oxopropyl)-1,3-dioxin-4-one (200.00 g, 1.08 mol, 1.00 equivalent) and 2-chloro-5-methylpyridine-4-amine (154.83 g, 1.08 mol, 1.00 equivalent) in dioxane (2000 mL) was stirred at 90°C for 3.5 hours under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The reaction was monitored by LC-MS. H2SO4 (60 mL, 1.12 mol, 1.05 equivalent) was added dropwise to the above mixture. The resulting mixture was stirred at 90°C for a further 1 hour. The mixture was allowed to cool to room temperature. The reaction was monitored by LC-MS. The resulting mixture was concentrated under reduced pressure. H2O (1000 mL) was added to the resulting mixture and stirred for 30 minutes. The precipitated solid was collected by filtration and washed with Et2O (3 × 50 mL). This yielded 2'-chloro-4-hydroxy-5',6-dimethyl-[1,4'-bipyridine]-2-one (150 g, 55.11%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H] + =251.0. 1 H NMR (300MHz, DMSO-d6)δ 10.82 (s, 1H), 8.48 (s, 1H), 7.57 (s, 1H), 5.98 (d, 1H), 5.58 (d, 1H), 1.97 (s, 3H), 1.84 (s, 3H).

[0241] Step 3: Preparation of 2'-chloro-4-((3,5-difluoropyridine-2-yl)methoxy)-5',6-dimethyl-2H-[1,4'-bipyridine]-2-one: A stirred mixture of 2'-chloro-4-hydroxy-5',6-dimethyl-[1,4'-bipyridine]-2-one (20.00 g, 79.78 mmol, 1.00 equivalent), 2-(chloromethyl)-3,5-difluoropyridine (15.66 g, 95.74 mmol, 1.20 equivalent), K2CO3 (33.08 g, 239.35 mmol, 3.00 equivalent), and 18-crown-6 (2.11 g, 7.98 mmol, 0.10 equivalent) was added to DMF (50 mL). The resulting mixture was stirred at 60°C for 3 hours under a nitrogen atmosphere. The reaction was monitored by LC-MS. The residue was dissolved in EA (1500 mL). The organic layer was washed with water (3 × 400 mL). The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 2'-chloro-4-[(3,5-difluoropyridine-2-yl)methoxy]-5',6-dimethyl-[1,4'-bipyridine]-2-one (23 g, 76.3%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H] + =378.0. 1 H NMR (400MHz, DMSO-d6)δ 8.59 (s, 1H), 8.49 (s, 1H), 8.13 - 8.01 (m, 1H), 7.61 (s, 1H), 6.13 (d, 1H), 6.03 (d, 1H), 5.25 (s, 2H), 1.99 (s, 3H), 1.85 (s, 3H).

[0242] Step 4: Preparation of 2',3-dichloro-4-[(3,5-difluoropyridine-2-yl)methoxy]-5',6-dimethyl-[1,4'-bipyridine]-2-one: 2,2-dichloroacetic acid (0.17 g, 1.32 mmol, 0.50 equivalent) was added dropwise to a stirred solution of 2'-chloro-4-[(3,5-difluoropyridine-2-yl)methoxy]-5',6-dimethyl-[1,4'-bipyridine]-2-one (1.00 g, 2.65 mmol, 1.00 equivalent) and NCS (0.37 g, 2.78 mmol, 1.05 equivalent) in ACN (25 mL) under a nitrogen atmosphere at room temperature. The resulting mixture was stirred under a nitrogen atmosphere at 60°C for 2 hours. The reaction was monitored by LC-MS. The resulting mixture was diluted with ethyl acetate (300 mL). The resulting mixture was washed with 2 × 100 mL of water and 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, and the pure fraction was concentrated under reduced pressure to obtain 2',3-dichloro-4-[(3,5-difluoropyridine-2-yl)methoxy]-5',6-dimethyl-[1,4'-bipyridine]-2-one (901 mg, 82.57%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H] + =411.9. Intermediate 8-10 [ka]

[0243] Step 1: Preparation of 2'-bromo-4-hydroxy-5',6-dimethyl-[1,4'-bipyridine]-2-one: A mixture of 2,2-dimethyl-6-(2-oxopropyl)-1,3-dioxin-4-one (22.16 g, 120.296 mmol, 1.5 equivalents) and 2-bromo-5-methylpyridine-4-amine (15 g, 80.197 mmol, 1.00 equivalent) in 1,4-dioxane (200 mL) was stirred at 90°C for 2 hours. H2SO4 (7.87 g, 80.197 mmol, 1 equivalent) was added dropwise to the mixture at room temperature under an air atmosphere. The resulting mixture was stirred at 90°C for a further 1 hour. The reaction was monitored by LC-MS. The resulting mixture was concentrated under reduced pressure. H2O (40 mL) was added to the resulting mixture, and the slurry was stirred for 10 minutes. The precipitated solid was collected by filtration, washed with Et2O (3 × 10 mL), and then dried under vacuum to obtain 2'-bromo-4-hydroxy-5',6-dimethyl-[1,4'-bipyridine]-2-one (22.7 g, crude) as a yellow solid. The crude mixture obtained was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =294.9.

[0244] Step 2: 2'-Chloro-4-[(4-methoxyphenyl)methoxy]-5',6-dimethyl-[1,4'-bipyridine]-2-one: To a stirred mixture of 2'-bromo-4-hydroxy-5',6-dimethyl-[1,4'-bipyridine]-2-one (42.00 g, 142.307 mmol, 1 equivalent) and 2-(chloromethyl)-3,5-difluoropyridine (46.55 g, 284.614 mmol, 2 equivalents) in DMF (450 mL), K2CO3 (98.34 g, 711.535 mmol, 5.00 equivalents) and 18-crown-6 (3.76 g, 14.231 mmol, 0.10 equivalents) were added under a nitrogen atmosphere at room temperature. The resulting mixture was stirred under a nitrogen atmosphere at 60°C for 2 hours. The reaction was monitored by LC-MS. The desired product could be detected by LC-MS. The reaction mixture was partitioned into 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 obtain 2'-bromo-4-[(3,5-difluoropyridine-2-yl)methoxy]-5',6-dimethyl-[1,4'-bipyridine]-2-one (48.5 g, 80.72%) as a yellow oil. LC-MS: (ES+H, m / z): [M+H] + =424.0.

[0245] Step 3: Preparation of 2'-bromo-3-chloro-4-[(3,5-difluoropyridine-2-yl)methoxy]-5',6-dimethyl-[1,4'-bipyridine]-2-one: To a stirred mixture of 2'-bromo-4-[(3,5-difluoropyridine-2-yl)methoxy]-5',6-dimethyl-[1,4'-bipyridine]-2-one (12 g, 28.421 mmol, 1 equivalent) and NCS (3.79 g, 28.421 mmol, 1 equivalent) in 2-propanol (21 mL), 2,2-dichloroacetic acid (1.2 mL, 2.870 mmol, 0.10 equivalent) was added dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 60°C for 2 hours under a nitrogen atmosphere. The reaction was monitored by LC-MS. The desired product can be detected by LC-MS. The precipitated solid was collected by filtration and washed with 2-propanol to obtain 2'-bromo-3-chloro-4-[(3,5-difluoropyridine-2-yl)methoxy]-5',6-dimethyl-[1,4'-bipyridine]-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). Intermediate 11-16 [ka]

[0246] Step 1: 2'-Chloro-4-[(4-methoxyphenyl)methoxy]-5',6-dimethyl-[1,4'-bipyridine]-2-one: To a solution of 2'-chloro-4-hydroxy-5',6-dimethyl-[1,4'-bipyridine]-2-one (85.00 g, 339.08 mmol, 1.00 equivalent) in DMF (300 mL), 4-methoxybenzyl chloride (159.31 g, 1017.23 mmol, 3.00 equivalent), K2CO3 (187.45 g, 1356.31 mmol, 4.00 equivalent), and 18-crown-6 (4.48 g, 16.95 mmol, 0.05 equivalent) were added. The mixture was heated at 60°C for 3 hours. The reaction was monitored by LC-MS. The mixture was cooled to room temperature. The reaction mixture was partitioned into 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 obtain 2'-chloro-4-[(4-methoxyphenyl)methoxy]-5',6-dimethyl-[1,4'-bipyridine]-2-one (24 g, 19.09%) as a grayish-white solid. LC-MS: (ES+H, m / z): [M+H] + =371.0.

[0247] Step 2: Preparation of 2'-(1-ethoxyethenyl)-4-[(4-methoxyphenyl)methoxy]-5',6-dimethyl-[1,4'-bipyridine]-2-one: Pd(PPh3)2Cl2 (2.27 g, 3.23 mmol, 0.05 equivalent) was added to a stirred solution of 2'-chloro-4-[(4-methoxyphenyl)methoxy]-5',6-dimethyl-[1,4'-bipyridine]-2-one (24.00 g, 64.72 mmol, 1.00 equivalent) and tributyl(1-ethoxyethenyl) stannane (28.05 g, 77.67 mmol, 1.20 equivalent) in dioxane (200 mL). The resulting mixture was stirred at 100 °C for 10 hours under a nitrogen atmosphere. The reaction was monitored by LC-MS. The mixture was cooled to room temperature. The resulting mixture was filtered, and the filter cake was washed with EA (100 mL). The filtrate was concentrated under reduced pressure. The crude product 2'-(1-ethoxyethenyl)-4-[(4-methoxyphenyl)methoxy]-5',6-dimethyl-[1,4'-bipyridine]-2-one (32g) was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + = 407.1.

[0248] Step 3: Preparation of 2'-acetyl-4-[(4-methoxyphenyl)methoxy]-5',6-dimethyl-[1,4'-bipyridine]-2-one: To a stirred solution of 2'-(1-ethoxyethenyl)-4-[(4-methoxyphenyl)methoxy]-5',6-dimethyl-[1,4'-bipyridine]-2-one (32 g, 78.72 mmol, 1.00 equivalent) in THF (200 mL), concentrated HCl (20 mL) 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 reaction was monitored by LC-MS. The mixture was basicized to pH 10 with saturated Na2CO3 aqueous solution at 0°C. The resulting mixture was extracted with EA (2 × 100 mL). The combined organic layers were washed with saturated NaCl aqueous solution (200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 2'-acetyl-4-[(4-methoxyphenyl)methoxy]-5',6-dimethyl-[1,4'-bipyridine]-2-one (20 g, 81.63%, 2 steps) as a grayish-white solid. LC-MS: (ES+H, m / z): [M+H] + =379.1.

[0249] Step 4: Preparation of 2'-acetyl-3-chloro-4-hydroxy-5',6-dimethyl-[1,4'-bipyridine]-2-one: 2,2-Dichloroacetic acid (0.39 g, 3.02 mmol, 0.06 equivalents) was added at room temperature to a stirred mixture of 2'-acetyl-4-[(4-methoxyphenyl)methoxy]-5',6-dimethyl-[1,4'-bipyridine]-2-one (19.00 g, 50.21 mmol, 1.00 equivalent) and NCS (7.44 g, 55.72 mmol, 1.10 equivalent) in i-PrOH (100.00 mL). The mixture was then stirred at 60°C for 5 hours under a nitrogen atmosphere. The reaction was monitored by LC-MS. The mixture was cooled to room temperature. The precipitated solid was collected by filtration and washed with cold i-PrOH (10 mL). The resulting solid was dissolved in DCM (100 mL). TFA (100 mL) was added to the above mixture at 0°C. The resulting mixture was stirred at room temperature for a further 2 hours. The reaction was monitored by LC-MS. The resulting mixture was concentrated under reduced pressure. The residue was purified by grinding with Et2O (50 mL). This yielded 2'-acetyl-3-chloro-4-hydroxy-5',6-dimethyl-[1,4'-bipyridine]-2-one (14 g, crude, TFA salt) as a pale yellow solid. LC-MS: (ES+H, m / z): [M+H] + =293.0.

[0250] Step 5: Preparation of 2'-acetyl-3-chloro-4-[(3,5-difluoropyridine-2-yl)methoxy]-5',6-dimethyl-[1,4'-bipyridine]-2-one: A mixture of 2'-acetyl-3-chloro-4-hydroxy-5',6-dimethyl-[1,4'-bipyridine]-2-one, TFA salt (14.00 g, 34.42 mmol, 1.00 equivalent), K2CO3 (14.27 g, 103.25 mmol, 3.00 equivalent), 18-crown-6 (0.91 g, 3.44 mmol, 0.10 equivalent), and 2-(chloromethyl)-3,5-difluoropyridine (8.44 g, 51.60 mmol, 1.50 equivalent) in DMF (100.00 mL) was stirred at 60°C for 10 hours under a nitrogen atmosphere. The reaction was monitored by LC-MS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 2'-acetyl-3-chloro-4-[(3,5-difluoropyridine-2-yl)methoxy]-5',6-dimethyl-[1,4'-bipyridine]-2-one (11 g, 52.38%, 2 steps) as a grayish-white solid. LC-MS: (ES+H, m / z): [M+H] + =420.0.

[0251] Step 6: Preparation of 3-chloro-4-[(3,5-difluoropyridine-2-yl)methoxy]-2'-[(2E)-3-(dimethylamino)prop-2-enoyl]-5',6-dimethyl-[1,4'-bipyridine]-2-one: A solution of 2'-acetyl-3-chloro-4-[(3,5-difluoropyridine-2-yl)methoxy]-5',6-dimethyl-[1,4'-bipyridine]-2-one (11.00 g, 26.20 mmol, 1.00 equivalent) in DMF-DMA (50 mL) was stirred at 100°C for 12 hours under a nitrogen atmosphere. The reaction was monitored by LC-MS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. Intermediate 17-22 [ka]

[0252] Step 1: Preparation of N-(2-chloro-5-methylpyridine-4-yl)-2,2,2-trifluoroacetamide: To a stirred solution of 2-chloro-5-methylpyridine-4-amine (5.00 g, 35.07 mmol, 1.00 equivalent) and anhydrous trifluoroacetic acid (14.73 g, 70.13 mmol, 2.00 equivalent) in DCM (100 mL), TEA (14.19 g, 140.26 mmol, 4.00 equivalent) was added dropwise at 0°C under a nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was monitored by LC-MS. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with RINKAN (3 × 100 mL). The combined organic layers were washed with brine (3 × 100 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain N-(2-chloro-5-methylpyridine-4-yl)-2,2,2-trifluoroacetamide (7.60 g, 90.69%) as a pale yellow solid. LC-MS: (ES+H, m / z): [M+H] + =239.1.

[0253] Step 2: Preparation of N-(2-(1-ethoxyvinyl)-5-methylpyridine-4-yl)-2,2,2-trifluoroacetamide: To a stirred solution of N-(2-chloro-5-methylpyridine-4-yl)-2,2,2-trifluoroacetamide (7.50 g, 31.44 mmol, 1.00 equivalent) and tributyl(1-ethoxyethenyl) stannane (34.06 g, 94.30 mmol, 3.00 equivalent) in dioxane (100 mL), palladium chloride; bis(triphenylphosphine) (1.10 g, 1.57 mmol, 0.05 equivalent) was gradually added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 120 °C under a nitrogen atmosphere. The reaction was monitored by LC-MS. The mixture was cooled to room temperature. The resulting mixture was filtered, and the filter cake was washed with EA (100 mL). 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] + =275.0.

[0254] Step 3: Preparation of 1-(4-amino-5-methylpyridine-2-yl)ethanol: To a stirred solution of N-[2-(1-ethoxyethenyl)-5-methylpyridine-4-yl]-2,2,2-trifluoroacetamide (11 g, 40.11 mmol, 1.00 equivalent) in THF (120 mL), concentrated HCl (10 mL) was added dropwise at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The reaction was monitored by LC-MS. The resulting mixture was diluted with water (200 mL). The resulting mixture was washed with Et₂O (8 × 200 mL). The aqueous layer was basicized to pH 8 with saturated NaHCO₃ (aqueous solution). The resulting mixture was extracted with ELISA (3 × 200 mL). The combined organic layers were washed with brine (3 × 200 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1-(4-amino-5-methylpyridine-2-yl)ethanone (4.00 g, 84.62%, 2 steps) as a brown solid. LC-MS: (ES+H, m / z): [M+H] + =151.1. 1 H NMR (300MHz, DMSO-d6)δ 8.02 (s, 1H), 7.16 (s, 1H), 6.07 (s, 2H), 2.52 (s, 3H), 2.07 (s, 3H).

[0255] Step 4: Preparation of 1-(4-iodo-5-methylpyridine-2-yl)ethanone: To a stirred solution of 1-(4-amino-5-methylpyridine-2-yl)ethanone (4.00 g, 26.64 mmol, 1.00 equivalent) and triiodomethane (31.46 g, 79.90 mmol, 3.00 equivalent) in THF (50 mL), tert-butyl nitrite (5.49 g, 53.27 mmol, 2.00 equivalent) was added dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80°C for 3 hours under a nitrogen atmosphere. The reaction was monitored by LC-MS. The mixture was cooled to room temperature. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with siRNA (3 × 200 mL). The combined organic layers were washed with brine (3 × 200 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1-(4-iodo-5-methylpyridine-2-yl)ethanone (2.1 g, 30.20%) as a brown solid. LC-MS: (ES+H, m / z): [M+H] + =261.9. 1 H NMR (400MHz, DMSO-d6)δ 8.54 (s, 1H), 8.27 (s, 1H), 2.60 (s, 3H), 2.42 (s, 3H).

[0256] Step 5: Preparation of 2-[4-(4-iodo-5-methylpyridine-2-yl)pyrimidine-2-yl]propan-2-ol: A mixture of 1-(4-iodo-5-methylpyridine-2-yl)ethanone (2.00 g, 7.66 mmol, 1.00 equivalent) in DMF-DMA (20 mL) was stirred at 100°C for 4 hours under a nitrogen atmosphere. The reaction was monitored by LC-MS. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was diluted with DMF (20 mL). 2-hydroxy-2-methylpropanimidoamide (1.17 g, 11.49 mmol, 1.50 equivalent) was gradually added to the above mixture under a nitrogen atmosphere. The resulting mixture was stirred at 100°C for a further 1.5 hours under a nitrogen atmosphere. The reaction was monitored by LC-MS. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (150 mL). The resulting mixture was extracted with ELISA (3 × 150 mL). The combined organic layers were washed with brine (3 × 150 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 2-[4-(4-iodo-5-methylpyridine-2-yl)pyrimidine-2-yl]propan-2-ol (2.07 g, 76.07%) as a grayish-white solid. LC-MS: (ES+H, m / z): [M+H] + =355.9. 1 H NMR (300MHz, DMSO-d6)δ 9.09 (s, 1H), 8.93 (d, 1H), 8.58 (s, 1H), 8.17 (d, 1H), 5.31 (s, 1H), 2.44 (s, 3H), 1.56 (s, 6H).

[0257] Step 6: Preparation of 2-{4-[5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl]pyrimidine-2-yl}propan-2-ol: To a stirred solution of 2-[4-(4-iodo-5-methylpyridine-2-yl)pyrimidine-2-yl]propan-2-ol (200 mg, 0.56 mmol, 1.00 equivalent) and bis(pinacolate)diborone (357 mg, 1.41 mmol, 2.50 equivalents) in dioxane (5 mL), Pd(dppf)Cl2 (16 mg, 0.03 mmol, 0.05 equivalent) and KOAc (221 mg, 2.25 mmol, 4.00 equivalent) were gradually added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 120 °C under a nitrogen atmosphere. The reaction was monitored by LC-MS. The mixture was cooled to room temperature. The resulting mixture was diluted with water (25 mL). The resulting mixture was extracted with Â(3 × 25 mL). The combined organic layers were washed with brine (3 × 25 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 2-{4-[5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl]pyrimidine-2-yl}propan-2-ol (150 mg, 74.99%) as a brown solid. LC-MS: (ES+H, m / z): [M+H] + = 274.1 (mass signal of boric acid). 1 H NMR (300MHz, DMSO-d6)δ 8.92 (d, 1H), 8.62-8.66 (m, 2H), 8.19 (d, 1H), 5.19 (s, 1H), 2.53 (s, 3H), 1.57 (s, 6H), 1.36 (s, 12H). Intermediate 24 [ka]

[0258] Step 1: Preparation of 3-chloro-4-[(3,5-difluoropyridine-2-yl)methoxy]-3',6-dimethyl-2'-(trimethylstannyl)-[1,4'-bipyridine]-2-one: To a stirred solution of 2',3-dichloro-4-[(3,5-difluoropyridine-2-yl)methoxy]-3',6-dimethyl-[1,4'-bipyridine]-2-one (1.00 g, 2.42 mmol, 1.00 equivalent) and Sn2Me6 (6.36 g, 19.40 mmol, 8.00 equivalent) in 1,4-dioxane (20 mL), Pd(PPh3)2Cl2 (681 mg, 0.97 mmol, 0.40 equivalent) and AsPh3 (0.29 g, 0.97 mmol, 0.40 equivalent) were added. The resulting mixture was stirred at 100°C for 12 hours under a nitrogen atmosphere. The reaction was monitored by LC-MS. The mixture was cooled to room temperature. The resulting mixture was diluted with EA (200 mL). The combined organic layers were washed with KF (aqueous solution) (3 × 100 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (1.78 g) was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + = 542.3.

[0259] Step 2: Preparation of 2'-(6-bromopyridine-2-yl)-3-chloro-4-[(3,5-difluoropyridine-2-yl)methoxy]-5',6-dimethyl-[1,4'-bipyridine]-2-one: To a stirred solution of 3-chloro-4-[(3,5-difluoropyridine-2-yl)methoxy]-5',6-dimethyl-2'-(trimethylstannyl)-[1,4'-bipyridine]-2-one (2.00 g, 3.70 mmol, 1.00 equivalent) and 2,6-dibromopyridine (2.63 g, 11.10 mmol, 3.00 equivalent) in 1,4-dioxane (20 mL), Pd(PPh3)2Cl2 (0.52 g, 0.74 mmol, 0.20 equivalent) was added, and the resulting mixture was stirred at 80°C for 2 hours under a nitrogen atmosphere. The reaction was monitored by LC-MS. The mixture was cooled to room temperature. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with ELISA (3 × 100 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 2'-(6-bromopyridine-2-yl)-3-chloro-4-[(3,5-difluoropyridine-2-yl)methoxy]-5',6-dimethyl-[1,4'-bipyridine]-2-one (670 mg, 33.9%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H] + =535.1. 1 H NMR (300MHz, DMSO-d6)δ 8.82 (s, 1H), 8.61 (d, J = 2.4Hz, 1H), 8.42 (dd, J = 7.7, 0.9Hz, 1H), 8.16-8.04 (m, 2H), 7.95 (t, J = 7.8Hz, 1H), 7.74 (dd, J = 7.9, 0.9Hz, 1H), 6.81 (s, 1H), 5.49 (d, J = 2.0Hz, 2H), 2.09 (s, 3H), 1.98 (s, 3H). 19 F NMR (282MHz, DMSO-d6)δ -120.14, -120.17, -122.36, -122.39. Intermediate 25-30 [ka]

[0260] Step 1: Preparation of 2',3-dichloro-4-[(4-methoxyphenyl)methoxy]-5',6-dimethyl-[1,4'-bipyridine]-2-one: To a stirred mixture of 2'-chloro-4-[(4-methoxyphenyl)methoxy]-5',6-dimethyl-[1,4'-bipyridine]-2-one (5 g, 13.483 mmol, 1 equivalent) and 2,2-dichloroacetic acid (0.17 mL, 1.348 mmol, 0.1 equivalent) in i-PrOH (20.00 mL, 261.705 mmol, 19.41 equivalents), NCS (1.80 g, 13.483 mmol, 1 equivalent) was added under a nitrogen atmosphere at room temperature. The resulting mixture was stirred under a nitrogen atmosphere at 60°C for 2 hours. The reaction was monitored by LC-MS. The mixture was cooled to room temperature. This yielded 2',3-dichloro-4-[(4-methoxyphenyl)methoxy]-5',6-dimethyl-[1,4'-bipyridine]-2-one (4.9 g, 90%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H] + =405.1.

[0261] Step 2: 3-Chloro-2'-(1-ethoxyethenyl)-4-[(4-methoxyphenyl)methoxy]-5',6-dimethyl-[1,4'-bipyridine]-2-one: To a stirred solution of 2',3-dichloro-4-[(4-methoxyphenyl)methoxy]-5',6-dimethyl-[1,4'-bipyridine]-2-one (5 g, 12.33 mmol, 1.00 equivalent) and dibutyl(1-ethoxyethenyl)propylstanane (12.85 g, 37.01 mmol, 3.00 equivalent) in 1,4-dioxane (55 mL), Pd(PPh3)2Cl2 (0.26 g, 0.37 mmol, 0.03 equivalent) was added under a nitrogen atmosphere at room temperature. The resulting mixture was stirred under a nitrogen atmosphere at 120 °C for 3 hours. The reaction was monitored by LC-MS. The resulting mixture 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] + = 441.1.

[0262] Step 3: 2'-Acetyl-3-chloro-4-[(4-methoxyphenyl)methoxy]-5',6-dimethyl-[1,4'-bipyridine]-2-one To a stirred mixture of 3-chloro-2'-(1-ethoxyethenyl)-4-[(4-methoxyphenyl)methoxy]-5',6-dimethyl-[1,4'-bipyridine]-2-one (4.00 g, 9.07 mmol, 1.00 equivalent) in THF (200 mL), HCl (4 mL) was added dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The reaction was monitored by LC-MS. The resulting mixture was diluted with ELISA (200 mL). The resulting mixture was washed with 2 × 200 mL of brine. 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 obtain 2'-acetyl-3-chloro-4-[(4-methoxyphenyl)methoxy]-5',6-dimethyl-[1,4'-bipyridine]-2-one (2.90 g, 77.43%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H] + =413.1. 1 H NMR (300MHz, DMSO-d6)δ 8.83 (s, 1H), 7.88 (s, 1H), 7.48 - 7.40 (m, 2H), 7.07 - 6.95 (m, 2H), 6.79 - 6.73 (m, 1H), 5.27 (s, 2H), 3.79 (s, 3H), 2.67 (s, 3H), 2.09 (s, 3H), 1.92 (s, 3H).

[0263] Step 4: 3-Chloro-2'-[(2E)-3-(dimethylamino)prop-2-enoyl]-4-[(4-methoxyphenyl)methoxy]-5',6-dimethyl-[1,4'-bipyridine]-2-one: A stirred mixture of 2'-acetyl-3-chloro-4-[(4-methoxyphenyl)methoxy]-5',6-dimethyl-[1,4'-bipyridine]-2-one (2.90 g, 7.02 mmol, 1.00 equivalent) in DMF-DMA (25 mL) at room temperature was prepared under a nitrogen atmosphere. The resulting mixture was stirred overnight at 100°C under a nitrogen atmosphere. The reaction was monitored by LC-MS. The resulting mixture was concentrated under reduced pressure to obtain 3-chloro-2'-[(2E)-3-(dimethylamino)prop-2-enoyl]-4-[(4-methoxyphenyl)methoxy]-5',6-dimethyl-[1,4'-bipyridine]-2-one (3.26 g, 99.18%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H] + = 470.1.

[0264] Step 5: 3-Chloro-2'-[2-(2-hydroxypropan-2-yl)pyrimidine-4-yl]-4-[(4-methoxyphenyl)methoxy]-5',6-dimethyl-[1,4'-bipyridine]-2-one: 3-chloro-2'-[(2E)-3-(dimethylamino)prop-2-enoyl]-4-[(4-methoxyphenyl)methoxy]-5',6-dimethyl-[1,4'-bipyridine]-2-one (3.30 g, 7.05 mmol, 1.00 equivalent) and K2CO3 (2.92 g, 21.15 mmol, 3.00 equivalent) were stirred in IPA (33 mL). 2-hydroxy-2-methylpropanimidohydrochloride (1.95 g, 14.10 mmol, 2.00 equivalent) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80°C for 2 hours under a nitrogen atmosphere. The reaction was monitored by LC-MS. The resulting mixture was diluted with ELISA (200 mL). The resulting mixture was washed with 2 × 200 ml brine. The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture 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] + =507.0.

[0265] Step 6: 3-Chloro-4-hydroxy-2'-[2-(2-hydroxypropan-2-yl)pyrimidine-4-yl]-5',6-dimethyl-[1,4'-bipyridine]-2-one: To a stirred solution of 3-chloro-2'-[2-(2-hydroxypropan-2-yl)pyrimidine-4-yl]-4-[(4-methoxyphenyl)methoxy]-5',6-dimethyl-[1,4'-bipyridine]-2-one (3.70 g, 7.29 mmol, 1.00 equivalent) in CH2Cl2 (50 mL), TFA (15 mL) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The reaction was monitored by LC-MS. The resulting mixture was diluted with ELISA (200 mL). The resulting mixture was washed with 2 × 200 ml brine. 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 obtain 3-chloro-4-hydroxy-2'-[2-(2-hydroxypropan-2-yl)pyrimidine-4-yl]-5',6-dimethyl-[1,4'-bipyridine]-2-one (2.50 g, 88.55%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H] + =387.1. 1 H NMR (400MHz, DMSO-d6)δ 11.62 (br, 1H), 8.97 (d, 1H), 8.84 (s, 1H), 8.64 (s, 1H), 8.24 (d, 1H), 6.22 (d, 1H), 5.76 (s, 1H), 2.10 (s, 3H), 1.88 (s, 3H), 1.53 (s, 6H). Intermediate 31-33 [ka]

[0266] Step 1: Preparation of ethyl 4-methoxypyrimidine-2-carboxylate: To a stirred solution of 2-chloro-4-methoxypyrimidine (100.00 g, 691.75 mmol, 1.00 equivalent) in EtOH (6.00 L), Et3N (140.00 g, 1383.50 mmol, 2.00 equivalent) and Pd(dppf)Cl2 (10.00 g, 13.66 mmol, 0.05 equivalent) were added in a pressure tank. The mixture was purged with nitrogen for 2 minutes and then pressurized to 50 atm using carbon monoxide at 100°C for 12 hours. The reaction mixture was cooled to room temperature. The reaction was monitored by LC-MS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain ethyl 4-methoxypyrimidine-2-carboxylate (123.50 g, 98.00%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H] + = 183.0. 1 H NMR (300MHz, DMSO-d6)δ 8.66 (d, 1H), 7.16 (d, 1H), 4.36 (q, 2H), 3.98 (s, 3H), 1.34 (t, 3H).

[0267] Step 2: Preparation of ethyl 4-hydroxypyrimidine-2-carboxylate: To a stirred solution of ethyl 4-methoxypyrimidine-2-carboxylate (83.50 g, 458.34 mmol, 1.00 equivalent) in MeCN (1.00 L), TMSI (262 mL, 1833.36 mmol, 4.00 equivalent) was added dropwise at room temperature over 1 hour under a nitrogen atmosphere. The resulting mixture was stirred overnight at 50°C. The desired product could be detected by LC-MS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was dissolved again in DCM (500 mL) and then concentrated under reduced pressure. The above steps were repeated three times. The residue was purified by grinding with hexane (800 mL). The resulting mixture was concentrated under reduced pressure. This yielded ethyl 4-hydroxypyrimidine-2-carboxylate (33.00 g, 42.82%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H] + = 169.1. 1H NMR (300MHz, DMSO-d6)δ 8.14 (d, 1H), 6.60 (d, 1H), 4.34 (q, 2H), 1.32 (t, 3H).

[0268] Step 3: Preparation of ethyl 4-chloropyrimidine-2-carboxylate: To a stirred mixture of ethyl 4-hydroxypyrimidine-2-carboxylate (33.00 g, 196.25 mmol, 1.00 equivalent) in DCE (1.20 L), POCl3 (73 mL, 785.00 mmol, 4.00 equivalent) was added dropwise over 2 hours at 0°C under a nitrogen atmosphere. The resulting mixture was stirred further overnight at 50°C. The desired product could be detected by LC-MS. The mixture was cooled to room temperature. The reaction was quenched by adding water / ice (600 mL) at 0°C. The mixture was basicized to pH 7-8 with saturated Na2CO3 (aqueous solution). The resulting mixture was extracted with CH2Cl2 (3 × 800 mL). The combined organic layers were washed with brine (2 × 800 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain ethyl 4-chloropyrimidine-2-carboxylate (20.00 g, 54.61%) as a yellow oil. LC-MS: (ES+H, m / z): [M+H] + = 187.0. 1 H NMR (400MHz, DMSO-d6)δ 8.98 (d, 1H), 7.97 (d, 1H), 4.40 (q, 2H), 1.34 (t, 3H). Intermediate 34 [ka]

[0269] Step 1: Preparation of 2'-bromo-4-[(4-methoxyphenyl)methoxy]-5',6-dimethyl-[1,4'-bipyridine]-2-one: To a solution of 2'-bromo-4-hydroxy-5',6-dimethyl-[1,4'-bipyridine]-2-one (7.00 g, 23.72 mmol, 1.00 equivalent) in DMF (50 mL), PMBCl (11.14 g, 71.15 mmol, 3.00 equivalent), K2CO3 (13.11 g, 94.872 mmol, 4.00 equivalent), and 18-crown-6 (310 mg, 1.19 mmol, 0.05 equivalent) were added. The mixture was stirred at 60°C for 3 hours. The reaction was monitored by LC-MS. The mixture was cooled to room temperature. The reaction mixture was partitioned into EA (500 mL) and water (200 mL). The organic layer was washed with water (200 mL) and brine (200 mL), and then dried over Na2SO4. The solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 2'-bromo-4-[(4-methoxyphenyl)methoxy]-5',6-dimethyl-[1,4'-bipyridine]-2-one (5.5 g, 55.84%) as a grayish-white solid. LC-MS: (ES+H, m / z): [M+H] + =415.0 / 417.0. 1 H NMR (300MHz, DMSO-d6)δ 8.48 (s, 1H), 7.71 (s, 1H), 7.44 - 7.35 (m, 2H), 7.03 - 6.92 (m, 2H), 6.12 (dd, 1H), 5.93 (d, 1H), 5.04 (s, 2H), 3.78 (s, 3H), 1.96(s, 3H), 1.85 (s, 3H).

[0270] Step 2: Preparation of 2'-bromo-3-chloro-4-[(4-methoxyphenyl)methoxy]-5',6-dimethyl-[1,4'-bipyridine]-2-one: 2,2-dichloroacetic acid (100 mg, 0.80 mmol, 0.06 equivalents) was added at room temperature to a stirred mixture of 2'-bromo-4-[(4-methoxyphenyl)methoxy]-5',6-dimethyl-[1,4'-bipyridine]-2-one (5.50 g, 13.24 mmol, 1.00 equivalent) and NCS (1.95 g, 14.57 mmol, 1.10 equivalent) in IPA (20 mL). The mixture was stirred at 60 °C for 3 hours under a nitrogen atmosphere. The reaction was monitored by LC-MS. The mixture was cooled to room temperature. The precipitated solid was collected by filtration to obtain 2'-bromo-3-chloro-4-[(4-methoxyphenyl)methoxy]-5',6-dimethyl-[1,4'-bipyridine]-2-one (3 g, 50.37%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =451.1. 1 H NMR (400MHz, DMSO-d6)δ 8.51 (s, 1H), 7.79 (s, 1H), 7.47 - 7.39 (m, 2H), 7.04 - 6.96 (m, 2H), 6.76 (s, 1H), 5.26 (s, 2H), 3.78 (s, 3H), 1.95 (s, 3H), 1.95 (s, 3H). Intermediate 35-37 [ka]

[0271] Step 1: Preparation of ethyl 3-chloro-5-fluoropyridine-2-carboxylate: A solution of 3-chloro-5-fluoropyridine-2-carboxylic acid (4.50 g, 25.63 mmol, 1.00 equivalent) in EtOH (100 mL) was cooled in an ice bath. SOCl2 (6.13 g, 51.53 mmol, 2.01 equivalents) was added dropwise to the mixture over 3 minutes at 0°C. The resulting mixture was stirred at room temperature for a further 3 hours. The reaction was monitored by LC-MS. 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 obtain 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.

[0272] Step 2: Preparation of (3-chloro-5-fluoropyridine-2-yl)methanol: To a stirred solution of ethyl 3-chloro-5-fluoropyridine-2-carboxylate (2.10 g, 10.31 mmol, 1.00 equivalent) in EtOH (30 mL), NaBH4 (0.98 g, 25.90 mmol, 2.51 equivalents) was gradually added at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at 0°C under a nitrogen atmosphere for 30 minutes. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for a further 2 hours. The reaction was monitored by LC-MS. The reaction was quenched at 0°C with saturated NH4Cl (aqueous solution). The resulting mixture was concentrated under reduced pressure to remove EtOH, and then extracted with EA (3 × 30 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum to obtain (3-chloro-5-fluoropyridine-2-yl)methanol (2 g, 95.24%) as a yellow oil. LC-MS: (ES+H, m / z): [M+H] + =162.0.

[0273] Step 3: Preparation of 3-chloro-2-(chloromethyl)-5-fluoropyridine: To a stirred solution of (3-chloro-5-fluoropyridine-2-yl)methanol (2.10 g, 12.99 mmol, 1.00 equivalent) in DCM (30 mL), DMF (0.1 mL, 1.30 mmol, 0.10 equivalent) was added under a nitrogen atmosphere at 0°C. SOCl2 (2.3 mL, 32.49 mmol, 2.50 equivalent) was added dropwise under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 hours. The reaction was monitored by LC-MS. The resulting mixture was concentrated under vacuum to obtain 3-chloro-2-(chloromethyl)-5-fluoropyridine (2.00 g, crude) as a yellowish-brown oil. The crude product was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =179.90. Intermediate 38-41 [ka]

[0274] Step 1: Preparation of 2-bromo-3,5-dimethyl-4-nitropyridine: To a stirred solution of 3,5-dimethyl-4-nitropyridine-1-ol (5.00 g, 29.38 mmol, 1.00 equivalent) in DCE (100 mL), POBr3 (12.64 g, 44.07 mmol, 1.50 equivalent) was added dropwise at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at 60°C for 2 hours under a nitrogen atmosphere. The reaction was monitored by LC-MS. The mixture was allowed to cool to room temperature. The residue was basicized to pH 10 with saturated Na2CO3 (aqueous solution) at 0°C. The reaction was poured into water (100 mL) at room temperature. The resulting mixture was extracted with RINKAN (3 × 300 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 2-bromo-3,5-dimethyl-4-nitropyridine (5.40 g, 39.77%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + = 231.1 / 233. 1 ¹H NMR (400 MHz, chloroform-d) δ 8.24 (s, 1H), 2.35 (s, 3H), 2.25 (s, 3H).

[0275] Step 2: Preparation of 2-bromo-3,5-dimethylpyridine-4-amine: A mixture of 2-bromo-3,5-dimethyl-4-nitropyridine (5.40 g, 23.37 mmol, 1.00 equivalent), Fe (2.61 g, 46.74 mmol, 5.00 equivalent), and CaCl2 (12.97 g, 116.86 mmol, 5.00 equivalent) in EtOH (60 mL) was stirred at 90°C for 3 hours under a nitrogen atmosphere. The reaction was monitored by LC-MS. The mixture was allowed to cool to room temperature. The resulting mixture was filtered, and the filter cake was washed with ethanol (500 mL). The filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (500 mL). The ethyl acetate layer was washed with saturated Na2CO3 (aqueous solution) (2 × 300 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. 2-bromo-3,5-dimethylpyridine-4-amine (4.60 g, 97.89%) is obtained as a white solid. LC-MS: (ES+H, m / z): [M+H] + =201.0 / 203.0. 1 H NMR (400MHz, DMSO-d6)δ 7.57 (s, 1H), 5.90 (s, 2H), 2.14 (s, 3H), 1.99 (s, 3H).

[0276] Step 3: Preparation of 2'-bromo-4-hydroxy-3',5',6-trimethyl-[1,4'-bipyridine]-2-one: A solution of 2-bromo-3,5-dimethylpyridine-4-amine (2.30 g, 11.43 mmol, 1.00 equivalent) and 2,2-dimethyl-6-(2-oxopropyl)-1,3-dioxin-4-one (2.11 g, 11.43 mmol, 1.00 equivalent) in dioxane (15 mL) was stirred at 90°C for 3.5 hours under a nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was monitored by LC-MS. H2SO4 (1.12 g, 11.43 mmol, 1.00 equivalent) was added dropwise to the above mixture at 0°C. The resulting mixture was stirred for a further 1 hour at 90°C. The reaction was monitored by LC-MS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography to obtain 2'-bromo-4-hydroxy-3',5',6-trimethyl-[1,4'-bipyridine]-2-one (1.70 g, 62.46%) as a yellowish-brown oil. LC-MS: (ES+H, m / z): [M+H] + =309.2 / 311.2. 1 ¹H NMR (400 MHz, chloroform-d)δ 8.25 (s, 1H), 7.69 - 7.57 (m, 1H), 6.14 (d, 1H), 6.06 (d, 1H), 2.13 (s, 3H), 2.02 (s, 3H), 1.85 (s, 3H).

[0277] Step 4: Preparation of 2'-bromo-4-[(3,5-difluoropyridine-2-yl)methoxy]-3',5',6-trimethyl-[1,4'-bipyridine]-2-one: A mixture of 2'-bromo-4-hydroxy-3',5',6-trimethyl-[1,4'-bipyridine]-2-one (1.70 g, 5.49 mmol, 1.00 equivalent), 2-(chloromethyl)-3,5-difluoropyridine (1.35 g, 8.24 mmol, 1.50 equivalent), 18-crown-6 (0.15 g, 0.55 mmol, 0.10 equivalent), and K2CO3 (3.04 g, 21.99 mmol, 4.00 equivalent) in DMF (15 mL) was stirred at 60°C for 4 hours under a nitrogen atmosphere. The reaction was monitored by LC-MS. The mixture was cooled to room temperature. The residue was dissolved in EA (400 mL). The mixture was washed with water (3 × 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 2'-bromo-4-[(3,5-difluoropyridine-2-yl)methoxy]-3',5',6-trimethyl-[1,4'-bipyridine]-2-one (1.60 g, 66.70%) as a yellowish-green solid. LC-MS: (ES+H, m / z): [M+H] + =...

Claims

1. A compound of formula (II), or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, 【Chemistry 127】 During the ceremony, Ring A is a heteroaryl ring, Each R Ａ They are halogens independently, n is between 1 and 4, R １ and R ２ These are independently hydrogen or deuterium, X is -O-, R ５ However, hydrogen, deuterium, halogen, or C １ ~C ６ It is alkyl, R ６ is hydrogen, deuterium, a halogen, or C １ to C ６ alkyl, and R ７ However, hydrogen, deuterium, halogen, or C １ ~C ６ It is alkyl, Ring B is a heteroaryl ring, Each R Ｂ These independently produce hydrogen, deuterium, halogens, -CN, and -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 Alkenil, C ２ ~C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently one or more R Ｂａ． It is replaced by, or two R on the same atom Ｂ They come together to form an oxo, Each R Ｂａ is 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 , -NR ｃ R ｄ , -NR ｂ , -NR ａ , -NR ｂ , -NR ｂ , -NR ｂ , -NR 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 dideuteroalkyl, C １ ~C ６ hydroxyalkyl, C １ ~C ６ aminoalkyl, C １ ~C ６ heteroalkyl, C ２ ~C ６ alkenyl, C ２ ~C ６ is alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or or two R on the same atom Ｂａ They come together to form an oxo, m is between 0 and 4. Ring C is a 5-membered heteroaryl, Each R Ｃ These independently produce hydrogen, deuterium, halogens, -CN, and -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 Alkenil, C ２ ~C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (C １ ~C ６ (Alkyl)cycloalkyl, (C １ ~C ６ (Alkyl) Heterocycloalkyl, (C １ ~C ６ Alkyl)aryl, or (C １ ~C ６ Alkyl)heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently one or more R Ｃａ． It has been replaced with, Each R Ｃａ These independently produce deuterium, halogen, -CN, and -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)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 Alkenil, C ２ ~C ６ It is an alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. or two Rs on the same atom Ｃａ They come together to form an oxo, p is 1 to 4, Each R 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 Alkenil, C ２ ~C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ ~C ６ Alkyl (cycloalkyl), C １ ~C ６ Alkyl (heterocycloalkyl), C １ ~C ６ Alkyl (aryl), or C １ ~C ６ The alkyl (heteroaryl) is an alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group can be independently and optionally selected to contain one or more oxo, deuterium, halogen, -CN, -OH, and -OCH2. 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 It is substituted with a heteroalkyl group. Each R ｂ 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 Alkenil, C ２ ~C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ ~C ６ Alkyl (cycloalkyl), C １ ~C ６ Alkyl (heterocycloalkyl), C １ ~C ６ Alkyl (aryl), or C １ ~C ６ The alkyl (heteroaryl) is an alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group can be independently and optionally selected to contain one or more oxo, deuterium, halogen, -CN, -OH, and -OCH2. 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 It is substituted with a heteroalkyl group. Each R ｃ and R ｄ 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 Alkenil, C ２ ~C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ ~C ６ Alkyl (cycloalkyl), C １ ~C ６ Alkyl (heterocycloalkyl), C １ ~C ６ Alkyl (aryl), or C １ ~C ６ The alkyl (heteroaryl) is an alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group can be independently and optionally selected to contain one or more oxo, deuterium, halogen, -CN, -OH, and -OCH2. 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 It is substituted with a heteroalkyl group, or R ｃ and R ｄ However, together with the atoms they bond to, they can optionally form 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 It forms heterocycloalkyl groups substituted with heteroalkyl groups, However, if the above compound is 【Chemistry 128】 A compound of formula (II), or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, provided that it is not [the other compound].

2. The compound according to claim 1, wherein ring A is pyridyl, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof.

3. A compound according to claim 1 or claim 2, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, wherein n is 1 or 2.

4. A compound according to any one of claims 1 to 3, wherein ring B is pyridinyl, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof.

5. Each R Ｂ These independently produce hydrogen, deuterium, halogen, -CN, -OH, and -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 A compound according to any one of claims 1 to 4, which is an alkynyl or cycloalkyl compound, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof.

6. Each R Ｂ Independently, halogen or C １ ~C ６ A compound according to any one of claims 1 to 5, which is alkyl, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof.

7. Each R Ｂ C １ ~C ６ A compound according to any one of claims 1 to 6, which is alkyl, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof.

8. A compound according to any one of claims 1 to 7, wherein m is 1 or 2, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof.

9. A compound according to any one of claims 1 to 8, wherein ring C is thiazolyl, pyrazolyl, imidazolyl, oxazolyl, thiadiazole, or triazolyl, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof.

10. A compound according to any one of claims 1 to 9, wherein the ring C is thiazolyl, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof.

11. A compound according to any one of claims 1 to 9, wherein the ring C is pyrazolyl, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof.

12. A compound according to any one of claims 1 to 9, wherein the ring C is imidazolyl, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof.

13. A compound according to any one of claims 1 to 9, wherein ring C is thiadiazole, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof.

14. A compound according to any one of claims 1 to 9, wherein the ring C is triazolyl, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof.

15. Each R Ｃ These independently produce hydrogen, deuterium, halogen, -CN, -OH, and -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, or C １ ~C ６ A compound according to any one of claims 1 to 14, which is a heteroalkyl compound, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof.

16. Each R Ｃ C １ ~C ６ A compound according to any one of claims 1 to 15, which is a hydroxyalkyl compound, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof.

17. A compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, wherein p is 1 or 2.

18. The following: 【Chemistry 18-9】 【Chemistry 18-10】 【Chemistry 18-11】 【Chemistry 18-12】 [Chemistry 18-13] [Chemistry 18-14] 【Chemistry 18-15】 [Chemistry 18-16] [Chemistry 18-17] 【Chemistry 18-18】 [Chemistry 18-19] [Chemistry 18-20] A compound selected from the above, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof.

19. The following: [Chemistry 19-20] [Chemistry 19-21] [Chemistry 19-22] A compound selected from the above, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof.

20. The compound is 【Chemistry 20】 The compound according to claim 19, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof.

21. The compound is 【Chemistry 21】 The compound according to claim 19.

22. The compound is 【Chemistry 22】 The compound according to claim 19, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof.

23. The compound is 【Chemistry 23】 The compound according to claim 19.

24. The compound is 【Chemistry 24】 The compound according to claim 19, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof.

25. The compound is 【Chemistry 25】 The compound according to claim 19.

26. The compound is 【Chemistry 26】 The compound according to claim 19, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof.

27. ​​The compound is 【Chemistry 27】 The compound according to claim 19.

28. The compound is 【Chemistry 28】 The compound according to claim 19, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof.

29. The compound is 【Chemistry 29】 The compound according to claim 19.

30. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, and a pharmaceutically acceptable additive.

31. A composition for treating a condition in a subject requiring treatment of a condition, comprising a compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, wherein the condition is selected from the group consisting of autoimmune disorders, chronic inflammatory disorders, acute inflammatory disorders, autoinflammatory disorders, fibrotic disorders, metabolic disorders, neoplastic disorders, and cardiovascular or cerebrovascular disorders.

32. p38 A composition for treating a MAP kinase-mediated disease in a subject requiring treatment, comprising a compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof.

33. A composition for treating MK2-mediated diseases in subjects requiring treatment, comprising a compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof.

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