MK2 inhibitors and their uses

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 TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 168,407, filed March 31, 2021, and U.S. Provisional Patent Application No. 63 / 318,118, filed March 9, 2022, which are incorporated by reference herein in their entireties. [Background technology]

[0002] Mitogen-activated protein kinases (MAPKs) are a conserved family of enzymes that relay and propagate external stimuli using phosphorylation cascades to generate coordinated cellular responses to the environment. MAPKs are proline-directed serine / threonine-specific protein kinases that regulate cellular activities such as gene expression, mitosis, differentiation, and cell survival / apoptosis. To date, four distinct classes of mammalian MAPKs have been identified: extracellular signaling kinases (ERKs 1 and 2), c-jun N-terminal kinase 1 (JNKs 1-3), p38 MAPKs (ρ38α, β, γ, and δ), and ERK5. MAPKs are activated by dual phosphorylation of Thr and Tyr residues within the TXY activation motif by coordinated dual-specificity MAPKKs, where X is Glu, Pro, and Gly in ERKs, JNKs, and p38 MAPKs, respectively. MAPKs are 60–70% identical to each other, yet differ in their activation loop sequences and sizes. The activation loop is adjacent to the enzyme active site, and its phosphorylation allows the enzyme to reposition active site residues into an optimal orientation for substrate binding and catalysis. Downstream substrates of MAPKs include mitogen-activated protein kinase-activated protein (MAPKAP) kinases and transcription factors, whose phosphorylation directly or indirectly regulates gene expression in several ways, including transcription, nuclear export, and mRNA stability and translation. Cellular consequences of MAPK activation include inflammation, apoptosis, differentiation, and proliferation.

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

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

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

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

[0007] The p38:MK2 complex is highly stable, with a Kd of 6 nM. The binding affinity of p38 for MK2 is driven by the C-terminal domain of MK2, which contains several positively charged amino acid residues. Crystallographic studies of the p38:MK2 complex have shown that the C-terminal region of MK2 wraps around p38a and binds to the negatively charged ED binding site. The tight binding of p38 to MK2 may result in a conformational change that provides an additional binding pocket for inhibitors that specifically rely on the p38:MK2 interaction. Together, these two studies suggest that selective p38 / MK2 axis blockade is achievable with small molecule inhibitors. Compared to conventional p38 MAPK inhibitors, these p38 / MK2 inhibitors should retain or enhance efficacy and exhibit improved safety profiles in animal models of disease or in human clinical settings.

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

[0009] Disclosed herein is 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. are independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently selected from the group consisting of one or more R Aa. is replaced by or two R on the same atom A together to form oxo, Each R Aa are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R 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 R on the same atom Aa together to form oxo, n is 0 to 4, R 1 and R 2 are independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heterocycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; or R 1 and R 2 together to form oxo, or or R 1 and R 2 together form a cycloalkyl or heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are optionally substituted with deuterium, halogen, —CN, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; X is -C(R 3 )2-, -NR 4 -, -O-, or -S-; Each R 3 are independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heterocycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; or two R 3 together to form oxo, R 4 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; R 5 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 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 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 heterocycloalkyl or heteroaryl; Each R B are independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently selected from the group consisting of one or more R Ba. is replaced by or two R on the same atom B together to form oxo, Each RBa are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -C(=O)C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R on the same atom Ba together to form oxo, m is 0 to 4; Ring C is a 5-membered heteroaryl; Each R C are independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a, -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -S(=O)(=NR b )R a , -SiR c R d OR b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (C1-C6 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 selected from the group consisting of one or more R Ca. is replaced by Each R Ca 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 R on the same atom Ca together to form oxo, p is 0 to 4; Each R aare 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 a Aryl and heteroaryl are independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Each R bare independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl , aryl, and heteroaryl are independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Each R c and R dare independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl , aryl, and heteroaryl are independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; or R c and R d together with the atoms to which they are attached form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; However, the compound is [ka] provided that it is not.

[0010] Disclosed herein are compounds of formula (I), or pharmaceutically acceptable salts, solvates, N-oxides, or stereoisomers thereof: [ka] During the ceremony, Ring A is phenyl or heteroaryl; Each R A. are independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently selected from the group consisting of one or more R Aa. is replaced by or two R on the same atom A together to form oxo, Each RAa are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -C(=O)C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R on the same atom Aa together to form oxo, n is 0 to 4, R 1 and R 2 are independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heterocycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; or R 1 and R 2 together to form oxo, or or R 1 and R 2 together form a cycloalkyl or heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are optionally substituted with deuterium, halogen, —CN, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; X is -C(R 3 )2-, -NR 4 -, -O-, or -S-; Each R 3 are independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heterocycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; or two R 3 together to form oxo, R 4 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 N or CR 5 and R 5 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 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 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Each R B 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 selected from the group consisting of one or more R Ba. is replaced by or two R on the same atom B together to form oxo, Each R Ba 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 R on the same atom Ba together to form oxo, m is 0 to 4; Ring C is heterocycloalkyl or heteroaryl; Each R C are independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -S(=O)(=NR b )R a , -SiR c R d OR b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -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 selected from the group consisting of one or more R Ca. is replaced by or two R on the same atom C together to form oxo, Each R Ca 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 R on the same atom Ca together to form oxo, p is 0 to 4; Each R a are independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, and a Aryl and heteroaryl are independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Each R bare independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl , aryl, and heteroaryl are independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Each R c and R dare independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl , aryl, and heteroaryl are independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; or R c and R d together with the atoms to which they are attached form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; however, [ka] but, [ka] provided that it is not.

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

[0012] Also disclosed herein are methods for treating a condition, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, wherein the condition is selected from the group consisting of an autoimmune disorder, a chronic inflammatory disorder, an acute inflammatory disorder, an autoinflammatory disorder, a fibrotic disorder, a metabolic disorder, an oncological disorder, and a cardiovascular or cerebrovascular disorder.

[0013] Also disclosed herein is a method of treating a p38 MAP kinase-mediated disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof.

[0014] Also disclosed herein is a method of treating an MK2-mediated disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof.

[0015] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. DETAILED DESCRIPTION OF THE INVENTION

[0016] definition In the following description, certain specific details are set forth to provide a thorough understanding of various embodiments. However, those skilled in the art will understand that the present invention may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring the description of the embodiments. Unless otherwise required by context, throughout this specification and the claims that follow, the word "comprise" and variations thereof, such as "comprises" or "comprising," should be interpreted in an open and inclusive sense, i.e., "including, but not limited to." Furthermore, the headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0017] References throughout this specification to "some embodiments" or "embodiments" mean that a particular feature, structure, or characteristic described in connection with an embodiment is included in at least one embodiment. Thus, the appearances of the phrase "in one embodiment" or "in an embodiment" in various places throughout this specification do not necessarily all refer to the same embodiment. Furthermore, particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. It should also be noted that the term "or" is generally used in its sense to include "and / or" unless the content clearly dictates otherwise.

[0018] As used herein, the following terms have the following meanings unless otherwise indicated.

[0019] "Oxo" refers to =O.

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

[0021] "Alkyl" refers to a straight or branched chain saturated hydrocarbon monoradical having 1 to about 10 carbon atoms, more preferably 1 to 6 carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl, and hexyl, as well as longer alkyl groups such as heptyl, octyl, and the like. Wherever it appears herein, a numerical range such as "C1-C6 alkyl" or "C1-6 alkyl" means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although this definition also encompasses occurrences of the term "alkyl" where no numerical range is specified. In some embodiments, alkyl is a C1- 10In some embodiments, the alkyl is a C alkyl. In some embodiments, the alkyl is a C alkyl. In some embodiments, the alkyl is a C alkyl. In some embodiments, the alkyl is a C alkyl. In some embodiments, the alkyl is a C alkyl. Unless stated otherwise specifically in the specification, an alkyl group can be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkyl is optionally substituted with oxo, halogen, —CN, —COOH, COOMe, —OH, —OMe, —NH, or —NO. In some embodiments, the alkyl is optionally substituted with halogen, —CN, —OH, or —OMe. In some embodiments, the alkyl is optionally substituted with halogen.

[0022] "Alkenyl" refers to a straight- or branched-chain hydrocarbon monoradical having one or more carbon-carbon double bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. This group may be in either the cis or trans conformation about the double bond and should be understood to include both isomers. Examples include, but are not limited to, ethenyl (-CH=CH), 1-propenyl (-CHCH=CH), isopropenyl [-C(CH=CH], butenyl, 1,3-butadienyl, and the like. Wherever it appears herein, a numerical range such as "C2-C6 alkenyl" or "C2-6 alkenyl" means that the alkenyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms; however, this definition also encompasses occurrences of the term "alkenyl" where no numerical range is specified. Unless specifically stated otherwise in this specification, an alkenyl group can be any It 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, alkenyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH, or -NO. In some embodiments, alkenyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, alkenyl is optionally substituted with halogen.

[0023] "Alkynyl" refers to a straight- or branched-chain hydrocarbon monoradical having one or more carbon-carbon triple bonds and having 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadinyl, and the like. Wherever it appears herein, a numerical range such as "C2-C6 alkynyl" or "C2-6 alkynyl" means that the alkynyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms; however, this definition also encompasses occurrences of the term "alkynyl" without a numerical range specified. Unless stated otherwise specifically in the specification, alkynyl groups can be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, alkynyl is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH, or -NO. In some embodiments, alkynyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, alkynyl is optionally substituted with halogen.

[0024] "Alkylene" refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group can be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an alkylene is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH, or -NO. In some embodiments, an alkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, an alkylene is optionally substituted with halogen.

[0025] "Alkoxy" means a group of the formula -OR a where R a is an alkyl radical as defined above. Unless stated otherwise specifically in the specification, an alkoxy group can be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an alkoxy is optionally substituted with halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, an 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. The aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused ring systems (when fused to a cycloalkyl or heterocycloalkyl ring, the aryl is attached through an aromatic ring atom) or bridged ring systems. In some embodiments, an aryl is a 6- to 10-membered aryl. In some embodiments, an aryl is a 6-membered aryl (phenyl). Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless stated otherwise specifically in the specification, aryl can be optionally substituted with, for example, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, aryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF, -OH, -OMe, -NH, or -NO. In some embodiments, aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF, -OH, or -OMe. In some embodiments, aryl is optionally substituted with halogen.

[0027] "Cycloalkyl" refers to a partially or fully saturated monocyclic or polycyclic carbocyclic ring, which can include fused ring systems (when fused to an aryl or heteroaryl ring, the cycloalkyl is attached through a non-aromatic ring atom) or bridged ring systems. In some embodiments, a cycloalkyl is fully saturated. Representative cycloalkyls include, but are not limited to, cycloalkyls containing 3 to 15 carbon atoms (C3 to C6). 15 Cycloalkyl or C3-C 15Cycloalkenyl), 3 to 10 carbon atoms (C3 to C 10 Cycloalkyl or C3-C 10Examples of cycloalkyl include cycloalkyls having 3 to 8 carbon atoms (C-C cycloalkyl or C-C cycloalkenyl), 3 to 6 carbon atoms (C-C cycloalkyl or C-C cycloalkenyl), 3 to 5 carbon atoms (C-C cycloalkyl or C-C cycloalkenyl), or 3 to 4 carbon atoms (C-C cycloalkyl or C-C cycloalkenyl). In some embodiments, a cycloalkyl is a 3 to 10-membered cycloalkyl or a 3 to 10-membered cycloalkenyl. In some embodiments, a cycloalkyl is a 3 to 6-membered cycloalkyl or a 3 to 6-membered cycloalkenyl. In some embodiments, a cycloalkyl is a 5 to 6-membered cycloalkyl or a 5 to 6-membered cycloalkenyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of polycyclic cycloalkyls include adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, as well as 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Examples of partially saturated cycloalkyls include cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless specifically stated otherwise in the specification, cycloalkyls are substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe.In some embodiments, the cycloalkyl is optionally substituted with halogen.

[0028] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, 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, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0030] "Hydroxyalkyl" refers to an alkyl radical, as defined above, substituted with one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl includes, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0031] "Aminoalkyl" refers to an alkyl radical, as defined above, substituted with one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyls include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

[0032] "Deuteroalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more deuteriums. In some embodiments, the alkyl is substituted with one deuterium. In some embodiments, the alkyl is substituted with one, two, or three deuteriums. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six deuteriums. Deuteroalkyls include, for example, CD3, CHD, CHD2, CH2CD3, CD2CD3, CHDCD3, CH2CH2D, or CH2CHD2. In some embodiments, the deuteroalkyl is CD3.

[0033] "Heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof. The heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In one aspect, the heteroalkyl is a C1-C6 heteroalkyl, where the heteroalkyl consists of 1 to 6 carbon atoms and one or more atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof, and the heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyls are, for example, -CHOCH, -CHCHOCH, -CHCHOCHCHOCH, -CH(CH)OCH, -CHNHCH, -CHN(CH), -CHCHNHCH, or -CHCHN(CH). Unless stated otherwise specifically in the specification, heteroalkyl is substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF, -OH, -OMe, -NH, or -NO. In some embodiments, heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF, -OH, or -OMe. In some embodiments, heteroalkyl is optionally substituted with halogen.

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

[0035] "Heteroaryl" refers to a 5-14 membered ring system radical containing 1-13 carbon atoms, 1-6 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. In some embodiments, a heteroaryl contains 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, a heteroaryl contains 1-3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, a heteroaryl contains 1-3 nitrogens. In some embodiments, a heteroaryl contains 1 or 2 nitrogens. In some embodiments, a heteroaryl contains 1 nitrogen. A heteroaryl can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused (when fused to a cycloalkyl or heterocycloalkyl ring, the heteroaryl is attached through an aromatic ring atom) or bridged ring systems, and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical can be optionally oxidized, and the nitrogen atom can be optionally quaternized. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl. In some embodiments, the heteroaryl is a 6-membered heteroaryl. In some embodiments, the heteroaryl is a 5-membered heteroaryl.Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzoyldolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzooxypyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, Zolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyranidyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, heteroaryl may be optionally substituted with, for example, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heteroaryl is optionally substituted with halogen, methyl, ethyl, —CN, —COOH, COOMe, —CF, —OH, —OMe, —NH, or —NO.In some embodiments, the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF, -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.

[0036] The term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances when the event or circumstance occurs and instances when the event or circumstance does not. For example, "optionally substituted alkyl" means either "alkyl" or "substituted alkyl" as defined above. Furthermore, optionally substituted groups can be unsubstituted (e.g., -CHCH), fully substituted (e.g., -CFCF), monosubstituted (e.g., -CHCHF), or substituted at any level between fully and monosubstituted (e.g., -CHCHF, -CHCF, -CFCH, -CFHCHF, etc.). Those of skill in the art will understand that with respect to any group containing one or more substituents, such groups are not intended to introduce any substitution or substitution pattern that is sterically impractical and / or synthetically infeasible (e.g., substituted alkyl includes optionally substituted cycloalkyl groups, which are defined to include a potentially infinite number of optionally substituted alkyl groups). Thus, any substituent described should generally be understood to have a maximum molecular weight of about 1,000 daltons, and more typically up to about 500 daltons.

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

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

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

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

[0041] compound Described herein are compounds of Formulas (I)-(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, fibrotic disorders, metabolic disorders, oncological disorders, or cardiovascular or cerebrovascular disorders.

[0042] Disclosed herein are compounds of formula (I), or pharmaceutically acceptable salts, solvates, N-oxides, or stereoisomers thereof: [ka] During the ceremony, Ring A is phenyl or heteroaryl; Each R A. 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 selected from the group consisting of one or more R Aa. is replaced by or two R on the same atom A together to form oxo, Each R Aa 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 R on the same atom Aa together to form oxo, n is 0 to 4, R 1 and R 2 are independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heterocycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; or R 1 and R 2 together to form oxo, or or R 1 and R 2together form a cycloalkyl or heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are optionally substituted with deuterium, halogen, —CN, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; X is -C(R 3 )2-, -NR 4 -, -O-, or -S-; Each R 3 are independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heterocycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; or two R 3 together to form oxo, R 4 is hydrogen, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; Z is N or CR 5 and R 5 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 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 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Each R B 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 selected from the group consisting of one or more R Ba. is replaced by or two R on the same atom B together to form oxo, Each R Ba 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 R on the same atom Ba together to form oxo, m is 0 to 4; Ring C is heterocycloalkyl or heteroaryl; Each R C are independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -S(=O)(=NR b )R a , -SiR c R d OR b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (C1-C6 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 selected from the group consisting of one or more R Ca. is replaced by or two R on the same atom C together to form oxo, Each R Ca are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -C(=O)C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R on the same atom Ca together to form oxo, p is 0 to 4; Each R a are independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, and a Aryl and heteroaryl are independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Each R bare independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl , aryl, and heteroaryl are independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Each R c and R dare independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl , aryl, and heteroaryl are independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; or R c and R d together with the atoms to which they are attached form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; however, [ka] but, [ka] provided that it is not.

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

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

[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 compounds of Formula (I), R 1 and R 2 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 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 compounds of Formula (I), R 1 and R 2 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 is.

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

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

[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 compounds 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] is.

[0054] In some embodiments of the compounds of Formula (I), Ring C is a 5- or 6-membered heteroaryl. In some embodiments of the compounds of Formula (I), Ring C is 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 are independently hydrogen, deuterium, halogen, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of compounds of Formula (I), each R C are independently C1-C6 hydroxyalkyl.

[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] Also disclosed herein is 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 RA. are independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently selected from the group consisting of one or more R Aa. is replaced by or two R on the same atom A together to form oxo, Each R Aa are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a, -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -C(=O)C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R on the same atom Aa together to form oxo, n is 0 to 4, R 1 and R 2 are independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heterocycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; or R 1 and R 2together to form oxo, or or R 1 and R 2 together form a cycloalkyl or heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are optionally substituted with deuterium, halogen, —CN, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; X is -C(R 3 )2-, -NR 4 -, -O-, or -S-; Each R 3 are independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heterocycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; or two R 3 together to form oxo, R 4 is hydrogen, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; R 5are 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 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 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 heterocycloalkyl or heteroaryl; Each R B 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 selected from the group consisting of one or more R Ba. is replaced by or two R on the same atom B together to form oxo, Each R Ba 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 R on the same atom Ba together to form oxo, m is 0 to 4; Ring C is a 5-membered heteroaryl; Each R C are independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -S(=O)(=NR b )R a , -SiR c R d OR b , -NR c R d , -NR b C(=O)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 selected from the group consisting of one or more R Ca. is replaced by Each R Ca 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 R on the same atom Ca together to form oxo, p is 0 to 4; Each R a are independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 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 are independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Each R bare independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl , aryl, and heteroaryl are independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Each R c and R dare independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl , aryl, and heteroaryl are independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; or R c and R d together with the atoms to which they are attached form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; However, the compound is [ka] provided that it is not.

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

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

[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 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 is independently hydrogen, deuterium, halogen, or C1-C6 alkyl. In some embodiments of the compound of Formula (II), R 1 and R 2 is independently hydrogen or deuterium. In some embodiments of the compound of Formula (II), R 1 and R 2 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 represents hydrogen, deuterium, halogens, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl, or cycloalkyl. In some embodiments of compounds of formula (II), R 5 is hydrogen, deuterium, halogen, —CN, or C1-C6 alkyl.

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

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

[0067] In some embodiments of the compound of Formula (II), Ring B is a 6-membered heteroaryl. In some embodiments of the compound of Formula (II), Ring B is pyridinyl.

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

[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 are independently hydrogen, deuterium, halogen, -CN, -OH, -OR a, 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 are independently C1-C6 hydroxyalkyl.

[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] Also disclosed herein is a compound of formula (III), or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof: [ka] During the ceremony, Ring A is phenyl or heteroaryl; Each R A. 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 selected from the group consisting of one or more R Aa. is replaced by or two R on the same atom A together to form oxo, Each R Aa are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -C(=O)C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R on the same atom Aa together to form oxo, n is 0 to 4, R 1 and R 2 are independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heterocycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; or R 1 and R 2 together to form oxo, or or R 1 and R 2 together form a cycloalkyl or heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are optionally substituted with deuterium, halogen, —CN, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; X is -C(R 3 )2-, -NR 4 -, -O-, or -S-; Each R 3are 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 together to form oxo, R 4 is hydrogen, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; Ring D is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Each R D 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 selected from the group consisting of one or more R Da. is replaced by or two R on the same atom D together to form oxo, Each R Da are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)C(=O)R a , -C(=O)OR b , -C(=O)NR c R d, -C(=O)C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R on the same atom Da together to form oxo, q is 0 to 6; R 9 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 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 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 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 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 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently selected from the group consisting of one or more R 12a. is replaced by Each R 12a are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -C(=O)C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R on the same atom 12a together to form oxo, R 13 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 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 aare 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 are independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Each R bare independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl , aryl, and heteroaryl are independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Each R c and R dare independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl , aryl, and heteroaryl are independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; or R c and R d together with the atoms to which they are attached form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; however, [ka] but, [ka] provided that it is not.

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

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

[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 is independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl. In some embodiments of compounds of Formula (III), R 1 and R 2 is independently hydrogen, deuterium, halogen, or C1-C6 alkyl. In some embodiments of the compound of Formula (III), R 1 and R 2 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 are independently hydrogen, deuterium, halogen, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, or two R on the same atom D together form oxo. In some embodiments of the compound of Formula (III), each R D are independently hydrogen, deuterium, halogen, -CN, -OR a , C1-C6 alkyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, or two R on the same atom D together to form 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] is.

[0083] In some embodiments of the compound of Formula (III), R 9is hydrogen, deuterium, halogen, C1-C6 alkyl, or C1-C6 haloalkyl.

[0084] In some embodiments of the compound of Formula (III), R 10 is hydrogen, deuterium, halogen, C1-C6 alkyl, or C1-C6 haloalkyl.

[0085] In some embodiments of the compound of Formula (III), R 11 is hydrogen, deuterium, halogen, C1-C6 alkyl, or C1-C6 haloalkyl.

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

[0087] In some embodiments of the compound of Formula (III), R 13 is hydrogen, deuterium, halogen, or C1-C6 alkyl.

[0088] In some embodiments of the compound of Formula (III), R 14 is hydrogen, deuterium, halogen, or C1-C6 alkyl.

[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. 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 selected from the group consisting of one or more R Aa. is replaced by or two R on the same atom A together to form oxo, Each R Aa 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 R on the same atom Aa together to form oxo, n is 0 to 4, R 1 and R 2 are independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heterocycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; or R 1 and R 2 together to form oxo, or or R 1 and R2 together form a cycloalkyl or heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are optionally substituted with deuterium, halogen, —CN, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; X is -C(R 3 )2-, -NR 4 -, -O-, or -S-; Each R 3 are independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heterocycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; or two R 3 together to form oxo, R 4 is hydrogen, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; R 5 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 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 cycloalkyl, heterocycloalkyl, alkyl, or heteroaryl; Each R B 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 selected from the group consisting of one or more R Ba. is replaced by or two R on the same atom B together to form oxo, Each R Ba are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -C(=O)C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R on the same atom Ba together to form oxo, m is 0 to 4; R 12 , R 13 , and R 14 is defined in (a), (b), or (c) as follows: (a) R 12 is 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 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 selected from the group consisting of one or more R 12a. is replaced by Each R 12a are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -C(=O)C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R on the same atom 12a together to form oxo, R 13 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 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 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 is 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 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 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 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 is 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 aare 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 are independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Each R bare independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl , aryl, and heteroaryl are independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Each R c and R dare independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl , aryl, and heteroaryl are independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; or R c and R d together with the atoms to which they are attached form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl.

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

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

[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 is independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl. In some embodiments of compounds of Formula (IV), R 1 and R 2 is independently hydrogen, deuterium, halogen, or C1-C6 alkyl. In some embodiments of the compound of Formula (IV), R 1 and R 2 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 represents hydrogen, deuterium, halogens, -CN, -OH, -OR a, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl, or cycloalkyl. In some embodiments of compounds of formula (IV), R 5 is hydrogen, deuterium, halogen, —CN, or C1-C6 alkyl.

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

[0097] In some embodiments of the compound of Formula (IV), Ring B is a 6-membered heteroaryl. In some embodiments of the compound of Formula (IV), Ring B is pyridinyl.

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

[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 is deuterium, halogen, -CN, -OH, -OR a , -S(=O)2NR c R d , -S(=O)(=NR b )R a , -SiR c R d OR 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 selected from one or more R 12a is replaced by Each R 12a are independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, or two R on the same atom 12a together to form oxo, R 13 is hydrogen, deuterium, halogen, or C1-C6 alkyl, R 14 is hydrogen, deuterium, halogen, or C1-C6 alkyl.

[0101] In some embodiments of the compound of formula (IV), R 12 is -S(=O)(=NR b )R a , -SiR c R d OR 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 selected from one or more R 12a is replaced by Each R 12a are independently -OH, -NR c R d or C1-C6 haloalkyl, R 13 is hydrogen, R 14 is hydrogen.

[0102] In some embodiments of the compound of formula (IV), R 12 is C1-C6 hydroxyalkyl, R 13 is 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 is hydrogen, deuterium, halogen, or C1-C6 alkyl.

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

[0104] Also disclosed herein is a compound of formula (V), or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof: [ka] During the ceremony, Ring A is phenyl or heteroaryl; Each R A. are independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b, -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently selected from the group consisting of one or more R Aa. is replaced by or two R on the same atom A together to form oxo, Each R Aa are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -C(=O)C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R on the same atom Aa together to form oxo, n is 0 to 4, R 1 and R 2 are independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heterocycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; or R 1 and R 2 together to form oxo, or or R 1 and R 2 together form a cycloalkyl or heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are optionally substituted with deuterium, halogen, —CN, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; X is -C(R 3 )2-, -NR 4 -, -O-, or -S-; Each R 3are 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 together to form oxo, R 4 is hydrogen, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; R 5 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 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 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 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, pyrazinone, or pyridazinone; Each R B 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 selected from the group consisting of one or more R Ba. is replaced by or two R on the same atom B together to form oxo, Each R Ba 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 R on the same atom Ba together to form oxo, m is 0 to 4; Ring C is heterocycloalkyl or heteroaryl; Each R C are independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -S(=O)(=NR b )R a , -SiR c R d OR b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -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 selected from the group consisting of one or more R Ca. is replaced by or two R on the same atom C together to form oxo, Each R Ca 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 R on the same atom Ca together to form oxo, p is 0 to 4; Each R a are independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 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 are independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Each R bare independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl , aryl, and heteroaryl are independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Each R c and R dare independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl , aryl, and heteroaryl are independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; or R c and R d together with the atoms to which they are attached form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl.

[0105] In some embodiments of compounds of Formula (V), ring A is heteroaryl.

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

[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 compounds of Formula (V), R 1 and R 2 is independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl. In some embodiments of compounds of Formula (V), R 1 and R 2 is independently hydrogen, deuterium, halogen, or C1-C6 alkyl. In some embodiments of compounds of Formula (V), R 1 and R 2 is hydrogen.

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

[0112] In some embodiments of compounds of Formula (V), R 5 represents hydrogen, deuterium, halogens, -CN, -OH, -OR a, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl, or cycloalkyl. In some embodiments of compounds of formula (V), R 5 is hydrogen, deuterium, halogen, —CN, or C1-C6 alkyl.

[0113] In some embodiments of compounds of Formula (V), R 6 represents hydrogen, deuterium, halogens, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl, or cycloalkyl. In some embodiments of compounds of formula (V), R 6 is hydrogen, deuterium, halogen, —CN, or C1-C6 alkyl.

[0114] In some embodiments of compounds of Formula (V), R 7 represents hydrogen, deuterium, halogens, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl, or cycloalkyl. In some embodiments of compounds of formula (V), R 7 is hydrogen, deuterium, halogen, —CN, or C1-C6 alkyl.

[0115] In some embodiments of compounds of Formula (V), R 8 represents hydrogen, deuterium, halogens, -CN, -OH, -OR a, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl, or cycloalkyl. In some embodiments of a compound of Formula (V), is hydrogen, deuterium, halogen, —CN, or C1-C6 alkyl.

[0116] In some embodiments of the compound of Formula (V), Ring B is pyridinone. In some embodiments of the compound of Formula (V), Ring B is pyrimidinone. In some embodiments of the compound of Formula (V), Ring B is pyrazinone. In some embodiments of the compound of Formula (V), Ring B is pyridazinone.

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

[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] is.

[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 pyrimidinyl.

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

[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] Also disclosed herein is a compound of formula (VI), or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof: [ka] During the ceremony, Ring A is phenyl or heteroaryl; Each R A. are independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c Rd , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently selected from the group consisting of one or more R Aa. is replaced by or two R on the same atom A together to form oxo, Each R Aa 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 R on the same atom Aa together to form oxo, n is 0 to 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 is 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 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 together to form oxo, or or R 1 and R 2 together form a cycloalkyl or heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are optionally substituted with deuterium, halogen, —CN, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Each R 3 are independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heterocycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; or two R 3 together to form oxo, R 4 is hydrogen, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; 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 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 together to form oxo, or or R 1 and R 2 together form a cycloalkyl or heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are optionally substituted with deuterium, halogen, —CN, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Each R 3are 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 together to form oxo, R 4 is hydrogen, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; R 5 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 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 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 heterocycloalkyl or heteroaryl; Each R B 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 selected from the group consisting of one or more R Ba. is replaced by or two R on the same atom B together to form oxo, Each R Ba are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -C(=O)C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R on the same atom Ba together to form oxo, m is 0 to 4; Ring C is heterocycloalkyl or heteroaryl; Each R C are independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -S(=O)(=NR b )R a , -SiR c R d OR b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (C1-C6 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 selected from the group consisting of one or more R Ca. is replaced by or two R on the same atom C together to form oxo, Each R Ca are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -C(=O)C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R on the same atom Ca together to form oxo, p is 0 to 4; Each R a are independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 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 are independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Each R bare independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl , aryl, and heteroaryl are independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Each R c and R dare independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl , aryl, and heteroaryl are independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; or R c and R d together with the atoms to which they are attached form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; However, the compound is [ka] provided that it is not.

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

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

[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 is 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 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 together to form oxo, or or R 1 and R 2 together form a cycloalkyl or heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are optionally substituted with deuterium, halogen, —CN, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Each R 3 are independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heterocycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; or two R 3 together to form oxo, R 4 is hydrogen, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl.

[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 is halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; R 2 is hydrogen, deuterium, halogen, or C1-C6 alkyl, or R 1 and R 2 together form a cycloalkyl or heterocycloalkyl, Each R 3 are independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; R 4 is hydrogen or C1-C6 alkyl.

[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 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 together to form oxo, or or R 1 and R 2 together form a cycloalkyl or heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are optionally substituted with deuterium, halogen, —CN, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Each R 3 are independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)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 together to form oxo, R 4 is hydrogen, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl.

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

[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 are independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; or R 1 and R 2 together to form oxo, or or R 1 and R 2 together form a cycloalkyl or heterocycloalkyl, R 4 is hydrogen or C1-C6 alkyl.

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

[0133] In some embodiments of the compound of Formula (VI), R 6 represents hydrogen, deuterium, halogens, -CN, -OH, -OR a, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl, or cycloalkyl. In some embodiments of compounds of formula (VI), R 6 is hydrogen, deuterium, halogen, —CN, or C1-C6 alkyl.

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

[0135] In some embodiments of the compound of Formula (VI), Ring B is a 6-membered heteroaryl. In some embodiments of the compound of Formula (VI), Ring B is pyridinyl.

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

[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 pyrimidinyl.

[0139] In some embodiments of the compound of Formula (VI), each R C are independently hydrogen, deuterium, halogen, -CN, -OH, -OR a , 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 are independently C1-C6 hydroxyalkyl.

[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] Also disclosed herein is a compound of formula (VII), or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof: [ka] During the ceremony, Ring A is phenyl or heteroaryl; Each R A. 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 selected from the group consisting of one or more R Aa. is replaced by or two R on the same atom A together to form oxo, Each R Aa 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 R on the same atom Aa together to form oxo, n is 0 to 4, R 1 and R 2 are independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heterocycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; or R 1 and R 2 together to form oxo, or or R 1 and R 2together form a cycloalkyl or heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are optionally substituted with deuterium, halogen, —CN, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Ring B is pyridinyl, Each R B are independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently selected from the group consisting of one or more R Ba.is replaced by Each R Ba are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -C(=O)C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R on the same atom Ba together to form oxo, m is 0 to 3; Ring D is a bicyclic ring; Each R D are independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d, -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently selected from the group consisting of one or more R Da. is replaced by or two R on the same atom D together to form oxo, Each R Da 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 R on the same atom Da together to form oxo, q is 0 to 6; R 12 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 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 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently selected from the group consisting of one or more R 12a. is replaced by Each R 12a are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -C(=O)C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R on the same atom 12a together to form oxo, R 13 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 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 aare 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 are independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Each R bare independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl , aryl, and heteroaryl are independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Each R c and R dare independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl , aryl, and heteroaryl are independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; or R c and R d together with the atoms to which they are attached form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl.

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

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

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

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

[0147] In some embodiments of the compound of Formula (VII), each R D are independently hydrogen, deuterium, halogen, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl, or cycloalkyl, or two R on the same atom D together form oxo. In some embodiments of the compound of Formula (VII), each R D are independently hydrogen, deuterium, halogen, -CN, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkynyl, or cycloalkyl, or two R on the same atom D together to form 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] is.

[0150] In some embodiments of the compound of Formula (VII), each R B are independently deuterium, halogen, -CN, -OH, -OR a , 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 are independently deuterium, -CN, -OH, -OR a , 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 are independently C1 to C6 alkyl.

[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 represents hydrogen, deuterium, halogens, -CN, -OH, -OR a, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of compounds of formula (VII), R 12 is a C1-C6 hydroxyalkyl.

[0153] In some embodiments of the compound of Formula (VII), R 13 is hydrogen, deuterium, halogen, or C1-C6 alkyl.

[0154] In some embodiments of the compound of Formula (VII), R 14 is hydrogen, deuterium, halogen, or C1-C6 alkyl.

[0155] Also disclosed herein is a compound of formula (VIII), or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof: [ka] During the ceremony, Ring A is phenyl or heteroaryl; Each R A. 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 selected from the group consisting of one or more R Aa. is replaced by or two R on the same atom A together to form oxo, Each R Aa are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -C(=O)C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R on the same atom Aa together to form oxo, n is 0 to 4, R 1 and R 2 are independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heterocycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; or R 1 and R 2 together to form oxo, or or R 1 and R 2 together form a cycloalkyl or heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are optionally substituted with deuterium, halogen, —CN, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; X is -C(R 3 )2-, -NR 4 -, -O-, or -S-; Each R 3are 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 together to form oxo, R 4 is hydrogen, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; R 5 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 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 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 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Each R B are independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently selected from the group consisting of one or more R Ba. is replaced by or two R on the same atom B together to form oxo, Each R Ba are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -C(=O)C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R on the same atom Ba together to form oxo, m is 0 to 4; Ring E is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Each R E are independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -S(=O)(=NR b )R a , -SiR c R d OR b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (C1-C6 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 selected from the group consisting of one or more R Ea. is replaced by Each R Ea are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -C(=O)C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R on the same atom Ea together to form oxo, R 13 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 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 0 to 4; Each R aare 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 are independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Each R bare independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl , aryl, and heteroaryl are independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Each R c and R dare independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl , aryl, and heteroaryl are independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; or R c and R d together with the atoms to which they are attached form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl.

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

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

[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 is independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl. In some embodiments of compounds of Formula (VIII), R 1 and R 2 is independently hydrogen, deuterium, halogen, or C1-C6 alkyl. In some embodiments of the compound of Formula (VIII), R 1 and R 2 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 represents hydrogen, deuterium, halogens, -CN, -OH, -OR a, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl, or cycloalkyl. In some embodiments of compounds of formula (VIII), R 5 is hydrogen, deuterium, halogen, —CN, or C1-C6 alkyl.

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

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

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

[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 cycloalkyl.

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

[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 is hydrogen, deuterium, halogen, or C1-C6 alkyl.

[0171] In some embodiments of the compound of Formula (VIII), R 14 is hydrogen, deuterium, halogen, or C1-C6 alkyl.

[0172] In some embodiments of the compounds disclosed herein, each R a are independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently optionally comprises one or more of oxo, deuterium, halogen, —CN, —OH, —O and substituted with 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. In some embodiments of the compounds disclosed herein, each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl, and each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of the compounds disclosed herein, each R ais independently C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments, each R a is independently C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, each R a are independently C1 to C6 alkyl.

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

[0174] In some embodiments of the compounds disclosed herein, each R c and R dare independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently optionally contains one or more of oxo, deuterium, halogen, —CN, —OH, — OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl. In some embodiments of the compounds disclosed herein, each R c and R d 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 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 dis independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, each R c and R d are independently hydrogen or C1-C6 alkyl.

[0175] In some embodiments of the compounds disclosed herein, R c and R d together with the atoms to which they are attached form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl.

[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 taken together, the heterocycloalkyl formed is independently substituted with 1, 2, 3, or 4 substituents as defined herein. In some embodiments of the compounds disclosed herein, each R A , R B , R C , R D , R E , R 12 , R a , R b , R c , R d , and R c and R dtaken together, the heterocycloalkyl formed is independently substituted with 1, 2, or 3 substituents as defined herein. In some embodiments of the compounds disclosed herein, each 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 taken together, the heterocycloalkyl formed is independently substituted with 1 or 2 substituents as defined herein. In some embodiments of the compounds disclosed herein, each R 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 taken together form a heterocycloalkyl, which is independently substituted with one substituent, as defined herein.

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

[0178] In some embodiments, the compound disclosed herein, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, is one of the compounds 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] * The stereochemistry was arbitrarily assigned.

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

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

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

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

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

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

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

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

[0187] In some embodiments, the compounds described herein contain a bond with hindered rotation, such that two distinct rotamers or atropisomers can be isolated. In some embodiments, the atropisomers are [ka] where each A corresponds to the appropriate R group defined in each of formulas (I)-(VIII). In some embodiments, these atropisomers are separated and found to have different biological activities that may be advantageous. In some embodiments, the atropisomers are [ka] In some embodiments, the atropisomer is [ka] is.

[0188] labeled compound In some embodiments, the compounds described herein exist in their isotopically labeled form. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically labeled compounds, which are identical to those listed herein except for the fact that one or more atoms have been replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that can be incorporated into the compounds disclosed herein include, respectively: 2 H, 3 H, 13 C. 14 C. l5 N, 18 O. 17 O. 31 P, 32 P,35 S, 18 F, and 36 Included are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as Cl. Compounds described herein, and pharmaceutically acceptable salts, solvates, or stereoisomers thereof, that contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present invention. Certain isotopically labeled compounds, e.g., 3 H and 14 Those in which a radioactive isotope such as C is incorporated are useful in drug and / or substrate tissue distribution assays. 3 H and carbon-14, i.e., 14 C isotopes are particularly preferred for their ease of preparation and detectability. Additionally, deuterium, i.e., 2 Substitution with heavier isotopes such as H may afford certain therapeutic advantages due to greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.

[0189] pharmaceutically acceptable salts In some embodiments, the compounds described herein are present as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0190] In some embodiments, the compounds described herein possess acidic or basic groups and thus react with any of a number of inorganic or organic bases and inorganic and organic acids to form pharmaceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or solvates or stereoisomers thereof, or by separately reacting the purified compounds in free form with a suitable acid or base and isolating the salt thus formed.

[0191] Examples of pharmaceutically acceptable salts include salts prepared by reaction of the compounds described herein with inorganic, organic, or inorganic bases, such as acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyne-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, gamma-hydroxybutyrate, hydrochloride, Hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 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, suberate, sebacate, sulfonate, tartrate, thiocyanate, undecanoic acid tosylate, and xylenesulfonate.

[0192] Additionally, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; 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, 3-(4-hydroxybenzoyl)benzoic acid, and the like. Examples of suitable organic acids include benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid. In some embodiments, other acids, such as oxalic acid, although not themselves pharmaceutically acceptable, are used in the preparation of salts useful as intermediates in obtaining the compounds disclosed herein, their solvates, or stereoisomers, and their pharmaceutically acceptable acid addition salts.

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

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

[0195] solvate In some embodiments, the compounds described herein exist as solvates. The present invention provides methods of treating diseases by administering such solvates. The present invention further provides methods of treating diseases by administering such solvates as pharmaceutical compositions.

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

[0197] tautomers In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that can be interconverted by the migration of a hydrogen atom, accompanied by the switching of a single bond and an adjacent double bond. In bonding configurations where tautomerization is possible, a chemical equilibrium of tautomers exists. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH.

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

[0199] MAP kinase-activated protein kinase 2 ("MK2") is an enzyme encoded by the MAPKAPK2 gene in humans. This gene encodes a member of the Ser / Thr protein kinase family. This kinase is regulated through direct phosphorylation by p38 MAP kinase. Together with p38 MAP kinase, this kinase is known to be involved in many cellular processes, including stress and inflammatory responses, nuclear export, gene expression regulation, and cell proliferation. The heat shock protein HSP27 has been shown to be one of the substrates of this kinase in vivo. Two transcript variants encoding two different isoforms have been found for this gene.

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

[0201] MK2-associated diseases or disorders that may be treated by the compounds disclosed herein include autoimmune disorders, chronic inflammatory disorders, acute inflammatory disorders, autoinflammatory disorders, fibrotic disorders, metabolic disorders, oncological disorders, and cardiovascular or cerebrovascular disorders.

[0202] In some embodiments, the MK2-mediated disease or disorder is an autoimmune disorder, a chronic and / or acute inflammatory disorder, and / or an autoinflammatory disorder. Exemplary autoimmune and / or inflammatory and / or autoinflammatory disorders include inflammatory bowel disease (e.g., ulcerative colitis or Crohn's disease), multiple sclerosis, psoriasis, arthritis, rheumatoid arthritis, osteoarthritis, juvenile arthritis, psoriatic arthritis, reactive arthritis, ankylosing spondylitis, cryopyrin-associated periodic fever syndrome, Muckle-Wells syndrome, familial cold autoinflammatory syndrome, neonatal-onset multisystem autoinflammatory disease, TNF receptor-associated periodic syndrome, acute and chronic pancreatitis, atherosclerosis, gout, ankylosing spondylitis, fibrotic disorders (e.g., ...inflammatory bowel disease (e.g., inflammatory bowel disease (e.g., inflammatory bowel disease (e.g., inflammatory bowel disease (e.g., inflammatory bowel disease (e.g., inflammatory bowel disease (e.g., inflammatory bowel disease (e.g., inflammatory bowel disease (e. Hepatic fibrosis or idiopathic pulmonary fibrosis), nephropathy, sarcoidosis, scleroderma, anaphylaxis, diabetes (e.g., type 1 diabetes or type 2 diabetes), diabetic retinopathy, Still's disease, vasculitis, sarcoidosis, pulmonary inflammation, acute respiratory distress syndrome, wet and dry age-related macular degeneration, autoimmune hemolytic syndrome, autoimmune and inflammatory hepatitis, autoimmune neuropathy, autoimmune ovarian failure, autoimmune orchitis, autoimmune thrombocytopenia, silicone implant-associated autoimmune disease, Sjogren's syndrome, familial Mediterranean fever, systemic lupus erythematosus Death, vasculitis syndromes (e.g., temporal Takayasu arteritis and giant cell arteritis, Behcet's disease or Wegener's granulomatosis), vitiligo, secondary hematological signs of autoimmune disease (e.g., anemia), drug-induced autoimmunity, Hashimoto's thyroiditis, hypophysitis, idiopathic thrombocytopenic purpura, metal-induced autoimmunity, myasthenia gravis, pemphigus, autoimmune hearing loss (e.g., Meniere's disease), Goodpasture's syndrome, Graves' disease, HW-associated autoimmune syndrome, Guillain-Barré syndrome, Addison's disease, antiphospholipid syndrome, asthma, atopic dermatitis, celiac disease, Cushing's syndrome, dermatomyositis, idiopathic adrenal atrophy, idiopathic thrombocytopenia, Kawasaki disease, Eaton-Lambert syndrome, pernicious anemia, hay fever, polyarteritis nodosa, primary biliary cirrhosis, primary sclerosing cholangitis, Raynaud's disease, Reiter's syndrome, relapsing polychondritis, Schmidt's syndrome, thyrotoxicosis, sepsis, septic shock, endotoxic shock, exotoxin-induced toxic shock syndrome, gram-negative bacterial sepsis, toxic shock syndrome, glomerulonephritis, peritonitis, interstitial cystitis, hyperoxia-induced inflammation, chronic obstructive pulmonary disease (COPD), vasculitis,These include graft-versus-host reaction (e.g., graft-versus-host disease), allograft rejection (e.g., acute allograft rejection or chronic allograft rejection), early transplant rejection (e.g., acute rejection), reperfusion injury, pain (e.g., acute pain, chronic pain, neuropathic pain, or fibromyalgia), chronic infection, meningitis, encephalitis, myocarditis, gingivitis, post-operative trauma, tissue injury, traumatic brain injury, enteritis, sinusitis, uveitis, eye inflammation, optic neuritis, gastric ulcer, esophagitis, peritonitis, periodontitis, dermatomyositis, gastritis, myositis, polymyalgia, pneumonia, and bronchitis.

[0203] In some embodiments, the MK2-mediated disease or disorder is a fibrotic disorder. Exemplary fibrotic disorders include systemic sclerosis / scleroderma, lupus nephritis, connective tissue diseases, wound healing, surgical scarring, spinal cord injury, CNS scarring, acute lung injury, pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis or cystic fibrosis), chronic obstructive pulmonary disease, adult respiratory distress syndrome, acute lung injury, drug-induced lung injury, glomerulonephritis, chronic kidney disease (e.g., diabetic nephropathy), hypertensive nephropathy, gastrointestinal or gastrointestinal fibrosis, renal fibrosis, liver or biliary fibrosis, liver fibrosis (e.g., nonalcoholic steatohepatitis, hepatitis C, or hepatocellular carcinoma), and the like. ), cirrhosis (e.g., primary biliary cirrhosis or cirrhosis due to fatty liver disease (e.g., alcoholic and non-alcoholic steatosis)), radiation-induced fibrosis (e.g., head and neck, gastrointestinal, or pulmonary), primary sclerosing cholangitis, restenosis, cardiac fibrosis (e.g., endomyocardial fibrosis or atrial fibrosis), ocular scarring, fibrosclerosis, fibrocarcinoma, fibroids, fibromas, fibroadenomas, fibrosarcomas, transplant arterial lesions, keloids, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis, and nephrogenic systemic fibrosis.

[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 syndrome.

[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 lymphocytic leukemia, acute and chronic myeloid leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, or promyelocytic leukemia), lymphoma (e.g., B-cell lymphoma, T-cell lymphoma, mantle cell lymphoma, hairy cell lymphoma, Burkitt's lymphoma, mast cell tumor, Hodgkin's disease, or non-Hodgkin's disease), myelodysplastic syndrome, fibrosarcoma, rhabdomyosarcoma; astrocytoma, neuroblastoma, glioma, and schwannoma; melanoma, seminoma, teratocarcinoma, osteosarcoma, psoriasis pigmentosa, and the like. Cancers of the bone include thyroid cancer, ...

[0206] In some embodiments, the MK2-mediated disorder is a cardiovascular disorder or cerebrovascular disorder.Exemplary cardiovascular disorders include atherosclerosis, atherosclerotic coronary restenosis, acute coronary syndrome, myocardial infarction, cardiac allograft vasculopathy, and stroke.Exemplary cerebrovascular diseases include central nervous system disorders with inflammatory or apoptotic components, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, spinal cord injury, neuronal ischemia, and peripheral neuropathy.

[0207] dosage In certain embodiments, compositions comprising the compounds described herein are administered for prophylactic and / or therapeutic treatment. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially halt at least one symptom of the disease or condition. Amounts effective for this use will depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drug, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, dose escalation and / or dose ranging clinical trials.

[0208] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder, or condition. Such an amount is defined to be a "prophylactically effective amount or dose." For this use, the precise amount will also depend on the patient's health, weight, and the like. When used in a patient, the effective amount for this use will depend on the severity and course of the disease, disorder, or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician. In one aspect, prophylactic treatment involves administering a pharmaceutical composition containing a compound described herein, or a pharmaceutically acceptable salt thereof, to a mammal that has previously experienced at least one symptom or risk factor of the disease being treated and is currently in remission, to prevent the recurrence of symptoms of the disease or condition.

[0209] In certain embodiments where the patient's condition does not improve, at the physician's discretion, administration of the compound is administered chronically, i.e., for an extended period of time, including the entire lifespan of the patient, to ameliorate or otherwise control or limit the symptoms of the patient's disease or condition.

[0210] In certain embodiments where the patient's condition improves, the dose of the administered drug is temporarily reduced or temporarily stopped for a certain period of time (i.e., a "drug holiday"). In certain embodiments, the length of the drug holiday is between 2 days and 1 year, including, by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, or more than 28 days. Dose reductions during drug holidays are, by way of example only, 10% to 100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.

[0211] Once improvement of the patient's condition occurs, a maintenance dose is administered if necessary. Thereafter, in certain embodiments, the dosage or frequency of administration, or both, is reduced, depending on the effect of symptoms, to a level at which the improved disease, disorder, or condition is maintained. In certain embodiments, however, the patient requires intermittent or daily treatment on a long-term basis upon any recurrence of symptoms.

[0212] The amount of a given agent that corresponds to such an amount will vary depending on factors such as the particular compound, the disease state and its severity, the identity (e.g., weight, sex) of the subject or host requiring treatment, but will nevertheless be determined according to the particular circumstances surrounding the case, including, for example, the particular agent being administered, the route of administration, the condition being treated, and the subject or host being treated.

[0213] In general, however, doses used for adult treatment typically range from 0.01 mg to 5000 mg per day. In one aspect, doses used for adult treatment are from about 1 mg to about 1000 mg per day. In one embodiment, the desired dose is conveniently presented as a single dose or as divided doses administered simultaneously or at appropriate intervals, for example, as two, three, four, or more subdoses per day.

[0214] In one embodiment, a suitable daily dosage for a compound described herein or a pharmaceutically acceptable salt thereof is about 0.01 to about 50 mg / kg body weight. In some embodiments, the amount of active agent in a daily dosage or dosage form is lower or higher than the ranges set forth herein, depending on several variables related to the individual treatment regimen. In various embodiments, the daily dosage and unit dosage amount will vary depending on several variables, including, but not limited to, the activity of the compound used, the disease or condition being treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the physician.

[0215] The toxicity and therapeutic efficacy of such treatment regimens are discussed in detail below. 10 and ED 90 The dose ratio between toxic and therapeutic effects is the therapeutic index, and is known as the LD. 50 and ED 50 In certain embodiments, data obtained from cell culture assays and animal studies are used in formulating therapeutically effective daily dose ranges and / or therapeutically effective unit doses for use in mammals, including humans. In some embodiments, the daily dose of the compounds described herein is sufficient to achieve an ED with minimal toxicity. 50 In certain embodiments, the daily dosage range and / or unit dosage amount varies within this range depending upon the dosage form employed and the route of administration utilized.

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

[0217] In any of the foregoing aspects, further embodiments include a single administration of an effective amount of the compound, including further embodiments where (i) the compound is administered once daily, or (ii) the compound is administered multiple times over a daily period to the mammal.

[0218] In any of the foregoing aspects, further embodiments include multiple administrations of an effective amount of the compound, including further embodiments in which (i) the compound is administered continuously or intermittently as a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the compound is administered to the mammal every 8 hours; (iv) the compound is administered to the subject every 12 hours; or (v) the compound is administered to the subject every 24 hours. In further or alternative embodiments, the method includes a drug holiday, during which administration of the compound is temporarily suspended or the dose of the administered compound is temporarily reduced, and at the end of the drug holiday, administration of the compound is resumed. In one embodiment, the length of the drug holiday ranges from two days to one year.

[0219] Administration route Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. Further, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injection, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injection.

[0220] In certain embodiments, the compounds described herein are administered in a local rather than systemic manner, for example, via injection of the compound directly into an organ, often in a depot or sustained-release preparation. 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, in a liposome coated with an organ-specific antibody. In such embodiments, the liposome targets the organ and is selectively taken up by the organ. In still other embodiments, the compounds described herein are provided in the form of a rapid-release formulation, a sustained-release formulation, or an intermediate-release formulation. In still other embodiments, the compounds described herein are administered locally.

[0221] Pharmaceutical Compositions / Formulations The compounds described herein can be administered to a subject in need thereof in a pharmaceutical composition, either alone or in combination with a pharmaceutically acceptable carrier, excipient, or diluent, according to standard pharmaceutical practice. In one embodiment, the compounds of the present invention can be administered to animals. The compounds can be administered orally or parenterally, including intravenous, intramuscular, intraperitoneal, subcutaneous, rectal, and topical routes of administration.

[0222] In another aspect, provided herein is a pharmaceutical composition comprising the compound described herein or its pharmaceutically acceptable salt, solvate, N-oxide or stereoisomer and at least one pharmaceutically acceptable excipient.The pharmaceutical composition is formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate the processing of the active compound into a preparation that can be used pharmaceutically.Appropriate formulation depends on the selected route of administration. Summary summaries of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed. (Easton, Pa.: Mack Publishing Company, 1995), Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975, Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980, and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), the disclosures of which are incorporated herein by reference.

[0223] In some aspects, the pharmaceutically acceptable excipient is selected from a carrier, a binder, a filler, a suspending agent, a flavoring agent, a sweetening agent, a disintegrating agent, a dispersing agent, a surfactant, a lubricant, a coloring agent, a diluent, a solubilizing agent, a moistening agent, a plasticizer, a stabilizer, a penetration enhancer, a wetting agent, an antifoaming agent, an antioxidant, a preservative, and any combination thereof.

[0224] The pharmaceutical compositions described herein are administered to a subject by any suitable route of administration, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal routes. Pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid oral dosage forms, powders, immediate-release formulations, controlled-release formulations, fast-melt formulations, tablets, capsules, pills, powders, dragees, effervescent formulations, lyophilized formulations, delayed-release formulations, extended-release formulations, pulsatile-release formulations, multiparticulate formulations, and combined immediate- and controlled-release formulations.

[0225] Pharmaceutical compositions comprising a compound described herein or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof are manufactured in a conventional manner, for example, by way of example only, conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or compressing processes.

[0226] Pharmaceutical compositions for oral use can be prepared by mixing one or more solid excipients with one or more compounds described herein, optionally grinding the resulting mixture, and then processing the granulated mixture to obtain tablets or dragee cores, if desired, with the addition of suitable additives.Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others, such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate.If desired, disintegrants such as cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or its salts (e.g., sodium alginate) can be added. In some embodiments, dyestuffs or pigments are added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

[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. Push-fit capsules contain the 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 soft capsules, the active compound is dissolved or suspended in a suitable liquid such as fatty oils, liquid paraffin, or liquid polyethylene glycol. In some embodiments, stabilizers are added.

[0228] Pharmaceutical compositions for parenteral use are formulated as infusions or injections. In some embodiments, pharmaceutical compositions suitable for injection or infusion comprise a sterile aqueous solution or dispersion, or a sterile powder, containing a compound described herein, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof. In some embodiments, the pharmaceutical composition comprises a liquid carrier. In some embodiments, the liquid carrier is a solvent or liquid dispersion medium, including, for example, water, saline, ethanol, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol, etc.), vegetable oils, non-toxic glyceryl esters, and any combination thereof. In some embodiments, the pharmaceutical composition further comprises a preservative to prevent the growth of microorganisms.

[0229] combination Disclosed herein are methods of treating an autoimmune disorder, a chronic inflammatory disorder, an acute inflammatory disorder, an autoinflammatory disorder, a fibrotic disorder, a metabolic disorder, an oncological disorder, or a cardiovascular or cerebrovascular disorder using a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, in combination with an additional therapeutic agent.

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

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

[0232] In some embodiments, the additional therapeutic agent is a corticosteroid, a nonsteroidal anti-inflammatory drug (NSAID) (e.g., ibuprofen, naproxen, acetaminophen, aspirin, fenoprofen (Nalfon), flurbiprofen (Ansaid), ketoprofen, oxaprozin (Daypro), diclofenac sodium (Voltaren), diclofenac potassium (Cataflam), etodolac (Lodine), indomethacin (Indocin), ketorolac (Toradol), sulindac (Clinoril), tolmetin (Tolectin), meclofenamate (Meclomen), mefenamic acid (Ponstel), nabumetone (Relafen), piroxicam (Feldene), a cox-2 inhibitor (e.g., celecoxib (Celebrex)), an immunosuppressant (e.g., For example, methotrexate (Rheumatrex), leflunomide (Arava), azathioprine (Imuran), cyclosporine (Neoral, Sandimmune), tacrolimus and cyclophosphamide (Cytoxan), CD20 blockers (rituximab), tumor necrosis factor (TNF) blockers (e.g., etanercept (Enbrel), infliximab (Remicade), and adalimumab (Humira)), abatacept (CTLA4-Ig) and interleukin-1 receptor antagonists (e.g., anakinra (Kineret)), interleukin-6 inhibitors (e.g., Actemra), interleukin-17 inhibitors (e.g., AIN457), Janus kinase inhibitors (e.g., tasocitinib), syk inhibitors (e.g., R788), and chloroquine and its derivatives.

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

[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 prior to administration of the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered after administration of the compound disclosed herein. [Example]

[0235] Intermediates 1, 2, and 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 equiv) in ethanol (200 mL) was cooled using an ice bath, followed by the dropwise addition of SOCl (50 mL, 689.25 mmol, 2.20 equiv) at 0° C. The resulting mixture was stirred at 60° C. for 3 hours under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to reach room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography to give ethyl 3,5-difluoropicolinate (59 g, 100%) as a colorless liquid. LC-MS: (ES+H, m / z): [M+H] + =188.1.

[0237] Step 2: Preparation of (3,5-difluoropyridin-2-yl)methanol: To a stirred solution of ethyl 3,5-difluoropyridine-2-carboxylate (40.00 g, 213.74 mmol, 1.00 equiv) in ethanol (300 mL) was added NaBH (20.22 g, 534.34 mmol, 2.50 equiv) portionwise at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at 0° C. for 30 minutes under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for an additional 2 hours. The reaction was monitored by LCMS. The reaction was quenched with saturated NH Cl (aq) at 0° C. EtOH was removed under reduced pressure. The aqueous layer was basified to pH 10 with saturated Na CO (aq, 300 mL) and subsequently extracted with EtOAc (3×300 mL). The combined organic layers were washed with brine and dried over anhydrous Na SO . After filtration, the filtrate was concentrated in vacuo to give (3,5-difluoropyridin-2-yl)methanol (26.6 g, 85.76%) as a colorless liquid. LC-MS: (ES+H, m / z): [M+H] + =146.1.

[0238] Step 3: Preparation of 2-(chloromethyl)-3,5-difluoropyridine: To a stirred solution of (3,5-difluoropyridin-2-yl)methanol (34.00 g, 234.31 mmol, 1.00 equiv.) in DCM (500 mL) was added DMF (160 mg) and then cooled using an ice-water bath. To the above mixture, SOCl (40 mL, 551.40 mmol, 2.35 equiv.) was added dropwise under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under vacuum to give 2-(chloromethyl)-3,5-difluoropyridine (34.75 g, 90.68%) as a tan semi-solid. LC-MS: (ES+H, m / z): [M+H] + =164.0. 1 H NMR (400 MHz, chloroform-d) δ 8.35 (d, 1H), 7.28 (td, 1H), 4.73 (d, 2H). Intermediates 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 equiv., 1 M in THF) in THF (1000 mL) was treated with 2,2,6-trimethyl-1,3-dioxin-4-one (300 g, 2.11 mol, 1.00 equiv.) under a nitrogen atmosphere at −20° C. for 1 hour, followed by the dropwise addition of ZnEt (3.16 L, 3.16 mol, 1.50 equiv., 1 M in hexanes) over 2 hours at −20° C. The resulting mixture was stirred at −20° C. for 30 minutes under a nitrogen atmosphere. To the above mixture was added acetylimidazole (348.58 g, 3.16 mol, 1.50 equiv.) at −10° C. The resulting mixture was further stirred at room temperature overnight. The reaction was monitored by LCMS. 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 (aq). The resulting mixture was extracted with EtOAc (3 x 5 L). The combined organic layers were washed with brine (3 x 5 L) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2,2-dimethyl-6-(2-oxopropyl)-1,3-dioxin-4-one (200 g, 51.45%) as a tan 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'-bipyridin]-2-one: A solution of 2,2-dimethyl-6-(2-oxopropyl)-1,3-dioxin-4-one (200.00 g, 1.08 mol, 1.00 equiv) and 2-chloro-5-methylpyridin-4-amine (154.83 g, 1.08 mol, 1.00 equiv) 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 LCMS. To the above mixture was added HSO (60 mL, 1.12 mol, 1.05 equiv) dropwise. The resulting mixture was stirred at 90° C. for an additional 1 hour. The mixture was allowed to cool to room temperature. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. To the resulting mixture was added HO (1000 mL) and stirred for 30 minutes. The precipitated solid was collected by filtration and washed with EtO (3 x 50 mL). This gave 2'-chloro-4-hydroxy-5',6-dimethyl-[1,4'-bipyridin]-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-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one: To a stirred mixture of 2'-chloro-4-hydroxy-5',6-dimethyl-[1,4'-bipyridin]-2-one (20.00 g, 79.78 mmol, 1.00 equiv), 2-(chloromethyl)-3,5-difluoropyridine (15.66 g, 95.74 mmol, 1.20 equiv), K2CO3 (33.08 g, 239.35 mmol, 3.00 equiv), and 18-crown-6 (2.11 g, 7.98 mmol, 0.10 equiv) in DMF (50 mL). The resulting mixture was stirred at 60 °C under a nitrogen atmosphere for 3 h. The reaction was monitored by LCMS. 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 give 2'-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-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-difluoropyridin-2-yl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one: To a stirred solution of 2'-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one (1.00 g, 2.65 mmol, 1.00 equiv.) and NCS (0.37 g, 2.78 mmol, 1.05 equiv.) in ACN (25 mL) was added 2,2-dichloroacetic acid (0.17 g, 1.32 mmol, 0.50 equiv.) dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 60°C under a nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The resulting mixture was diluted with ethyl acetate (300 mL). The resulting mixture was washed with 2 x 100 mL of water and brine (100 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and the pure fractions were concentrated under reduced pressure to give 2',3-dichloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one (901 mg, 82.57%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H] + =411.9. Intermediates 8-10 [ka]

[0243] Step 1: Preparation of 2'-bromo-4-hydroxy-5',6-dimethyl-[1,4'-bipyridin]-2-one: A mixture of 2,2-dimethyl-6-(2-oxopropyl)-1,3-dioxin-4-one (22.16 g, 120.296 mmol, 1.5 equiv) and 2-bromo-5-methylpyridin-4-amine (15 g, 80.197 mmol, 1.00 equiv) in 1,4-dioxane (200 mL) was stirred at 90° C. for 2 hours. To the above mixture, HSO (7.87 g, 80.197 mmol, 1 equiv) was added dropwise at room temperature under an air atmosphere. The resulting mixture was stirred at 90° C. for an additional 1 hour. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. To the resulting mixture, HO (40 mL) was added, and the slurry was stirred for 10 minutes. The precipitated solid was collected by filtration, washed with EtO (3 x 10 mL), and then dried under vacuum to give 2'-bromo-4-hydroxy-5',6-dimethyl-[1,4'-bipyridin]-2-one (22.7 g, crude) as a yellow solid. The crude resulting mixture 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'-bipyridin]-2-one: To a stirred mixture of 2'-bromo-4-hydroxy-5',6-dimethyl-[1,4'-bipyridin]-2-one (42.00 g, 142.307 mmol, 1 equiv.) and 2-(chloromethyl)-3,5-difluoropyridine (46.55 g, 284.614 mmol, 2 equiv.) in DMF (450 mL), K2CO3 (98.34 g, 711.535 mmol, 5.00 equiv.) and 18-crown-6 (3.76 g, 14.231 mmol, 0.10 equiv.) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 60 °C under a nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The desired product could be detected by LCMS. The reaction mixture was partitioned between EA (1000 mL) and water (500 mL). The organic layer was washed with water (500 mL) and brine (500 mL), then dried over Na2SO4. The solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2'-bromo-4-[(3,5-difluoropyridin-2-yl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one (48.5 g, 80.72%) as a yellow oil. LC-MS: (ES+H, m / z): [M+H] + =424.0.

[0245] Step 3: Preparation of 2'-bromo-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one: To a stirred mixture of 2'-bromo-4-[(3,5-difluoropyridin-2-yl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one (12 g, 28.421 mmol, 1 equiv.) and NCS (3.79 g, 28.421 mmol, 1 equiv.) in 2-propanol (21 mL), 2,2-dichloroacetic acid (1.2 mL, 2.870 mmol, 0.10 equiv.) was added dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 60°C for 2 hours under a nitrogen atmosphere. The reaction was monitored by LCMS. The desired product could be detected by LCMS. The precipitated solid was collected by filtration and washed with 2-propanol to give 2'-bromo-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one (7.40 g, 57.02%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + = 457.9. 1 H NMR (300MHz, DMSO-d6)δ 8.60 (d, J = 2.4Hz, 1H), 8.52 (s, 1H), 8.10 (ddd, J = 10.0, 8.9, 2.4Hz, 1H), 7.81 (s, 1H), 6.80 (s, 1H), 5.48 (d, J = 2.0Hz, 2H), 1.98 - 1.94 (m, 6H). Intermediates 11-16 [ka]

[0246] Step 1: 2'-chloro-4-[(4-methoxyphenyl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one: To a solution of 2'-chloro-4-hydroxy-5',6-dimethyl-[1,4'-bipyridin]-2-one (85.00 g, 339.08 mmol, 1.00 equiv) in DMF (300 mL) was added 4-methoxybenzyl chloride (159.31 g, 1017.23 mmol, 3.00 equiv), KCO (187.45 g, 1356.31 mmol, 4.00 equiv), and 18-crown-6 (4.48 g, 16.95 mmol, 0.05 equiv). The mixture was heated at 60 °C for 3 h. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The reaction mixture was partitioned between EA (1000 mL) and water (500 mL). The organic layer was washed with water (500 mL) and brine (500 mL), then dried over Na2SO4. The solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2'-chloro-4-[(4-methoxyphenyl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one (24 g, 19.09%) as an off-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'-bipyridin]-2-one: To a stirred solution of 2'-chloro-4-[(4-methoxyphenyl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one (24.00 g, 64.72 mmol, 1.00 equiv) and tributyl(1-ethoxyethenyl)stannane (28.05 g, 77.67 mmol, 1.20 equiv) in dioxane (200 mL) was added Pd(PPh3)2Cl2 (2.27 g, 3.23 mmol, 0.05 equiv). The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 10 h. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was filtered, and the filter cake was washed with 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'-bipyridin]-2-one (32 g) 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'-bipyridin]-2-one: To a stirred solution of 2'-(1-ethoxyethenyl)-4-[(4-methoxyphenyl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one (32 g, 78.72 mmol, 1.00 equiv) in THF (200 mL) was added concentrated HCl (20 mL) dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The mixture was basified to pH 10 with saturated aqueous NaCO at 0 °C. The resulting mixture was extracted with EA (2 × 100 mL). The combined organic layers were washed with saturated aqueous NaCl (200 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2'-acetyl-4-[(4-methoxyphenyl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one (20 g, 81.63%, two steps) as an off-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'-bipyridin]-2-one: To a stirred mixture of 2'-acetyl-4-[(4-methoxyphenyl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one (19.00 g, 50.21 mmol, 1.00 equiv.) and NCS (7.44 g, 55.72 mmol, 1.10 equiv.) in i-PrOH (100.00 mL) was added 2,2-dichloroacetic acid (0.39 g, 3.02 mmol, 0.06 equiv.) at room temperature. The mixture was stirred at 60°C under a nitrogen atmosphere for 5 hours. The reaction was monitored by LCMS. The mixture was allowed to cool 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). To the above mixture, TFA (100 mL) was added at 0°C. The resulting mixture was stirred at room temperature for an additional 2 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with EtO (50 mL). This gave 2'-acetyl-3-chloro-4-hydroxy-5',6-dimethyl-[1,4'-bipyridin]-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-difluoropyridin-2-yl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one: A mixture of 2'-acetyl-3-chloro-4-hydroxy-5',6-dimethyl-[1,4'-bipyridin]-2-one, TFA salt (14.00 g, 34.42 mmol, 1.00 equiv.), KCO (14.27 g, 103.25 mmol, 3.00 equiv.), 18-crown-6 (0.91 g, 3.44 mmol, 0.10 equiv.), and 2-(chloromethyl)-3,5-difluoropyridine (8.44 g, 51.60 mmol, 1.50 equiv.) in DMF (100.00 mL) was stirred at 60 °C under a nitrogen atmosphere for 10 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2'-acetyl-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one (11 g, 52.38%, two steps) as an off-white solid. LC-MS: (ES+H, m / z): [M+H] + =420.0.

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

[0252] Step 1: Preparation of N-(2-chloro-5-methylpyridin-4-yl)-2,2,2-trifluoroacetamide: To a stirred solution of 2-chloro-5-methylpyridin-4-amine (5.00 g, 35.07 mmol, 1.00 equiv) and trifluoroacetic anhydride (14.73 g, 70.13 mmol, 2.00 equiv) in DCM (100 mL) was added TEA (14.19 g, 140.26 mmol, 4.00 equiv) dropwise at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere overnight. The reaction was monitored by LCMS. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (3×100 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give N-(2-chloro-5-methylpyridin-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-methylpyridin-4-yl)-2,2,2-trifluoroacetamide: To a stirred solution of N-(2-chloro-5-methylpyridin-4-yl)-2,2,2-trifluoroacetamide (7.50 g, 31.44 mmol, 1.00 equiv.) and tributyl(1-ethoxyethenyl)stannane (34.06 g, 94.30 mmol, 3.00 equiv.) in dioxane (100 mL), palladium chloride; bis(triphenylphosphine) (1.10 g, 1.57 mmol, 0.05 equiv.) was added portionwise 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 LCMS. The mixture was allowed to cool 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-methylpyridin-2-yl)ethanone: To a stirred solution of N-[2-(1-ethoxyethenyl)-5-methylpyridin-4-yl]-2,2,2-trifluoroacetamide (11 g, 40.11 mmol, 1.00 equiv) in THF (120 mL) was added concentrated HCl (10 mL) dropwise at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS. The resulting mixture was diluted with water (200 mL). The resulting mixture was washed with EtO (8 × 200 mL). The aqueous layer was basified to pH 8 with saturated NaHCO (aq). The resulting mixture was extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (3 × 200 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 1-(4-amino-5-methylpyridin-2-yl)ethanone (4.00 g, 84.62%, two 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-methylpyridin-2-yl)ethanone: To a stirred solution of 1-(4-amino-5-methylpyridin-2-yl)ethanone (4.00 g, 26.64 mmol, 1.00 equiv) and triiodomethane (31.46 g, 79.90 mmol, 3.00 equiv) in THF (50 mL) was added tert-butyl nitrite (5.49 g, 53.27 mmol, 2.00 equiv) dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80° C. under a nitrogen atmosphere for 3 hours. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine (3×200 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 1-(4-iodo-5-methylpyridin-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-methylpyridin-2-yl)pyrimidin-2-yl]propan-2-ol: A mixture of 1-(4-iodo-5-methylpyridin-2-yl)ethanone (2.00 g, 7.66 mmol, 1.00 equiv) in DMF-DMA (20 mL) was stirred at 100° C. for 4 hours under a nitrogen atmosphere. The reaction was monitored by LCMS. 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). To the above mixture, 2-hydroxy-2-methylpropanimidamide (1.17 g, 11.49 mmol, 1.50 equiv) was added portionwise under a nitrogen atmosphere. The resulting mixture was stirred at 100° C. for an additional 1.5 hours under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (150 mL). The resulting mixture was extracted with EtOAc (3×150 mL). The combined organic layers were washed with brine (3×150 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2-[4-(4-iodo-5-methylpyridin-2-yl)pyrimidin-2-yl]propan-2-ol (2.07 g, 76.07%) as an off-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)pyridin-2-yl]pyrimidin-2-yl}propan-2-ol: To a stirred solution of 2-[4-(4-iodo-5-methylpyridin-2-yl)pyrimidin-2-yl]propan-2-ol (200 mg, 0.56 mmol, 1.00 equiv.) and bis(pinacolato)diboron (357 mg, 1.41 mmol, 2.50 equiv.) in dioxane (5 mL), Pd(dppf)Cl (16 mg, 0.03 mmol, 0.05 equiv.) and KOAc (221 mg, 2.25 mmol, 4.00 equiv.) were added portionwise 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 LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (25 mL). The resulting mixture was extracted with EtOAc (3×25 mL). The combined organic layers were washed with brine (3×25 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2-{4-[5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]pyrimidin-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-difluoropyridin-2-yl)methoxy]-3',6-dimethyl-2'-(trimethylstannyl)-[1,4'-bipyridin]-2-one: To a stirred solution of 2',3-dichloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-3',6-dimethyl-[1,4'-bipyridin]-2-one (1.00 g, 2.42 mmol, 1.00 equiv.), SnMe (6.36 g, 19.40 mmol, 8.00 equiv.) in 1,4-dioxane (20 mL), Pd(PPh)Cl (681 mg, 0.97 mmol, 0.40 equiv.) and AsPh (0.29 g, 0.97 mmol, 0.40 equiv.) were added. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 12 h. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with EA (200 mL). The combined organic layers were washed with KF (aq.) (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-bromopyridin-2-yl)-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one: To a stirred solution of 3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-5',6-dimethyl-2'-(trimethylstannyl)-[1,4'-bipyridin]-2-one (2.00 g, 3.70 mmol, 1.00 equiv.) and 2,6-dibromopyridine (2.63 g, 11.10 mmol, 3.00 equiv.) in 1,4-dioxane (20 mL), Pd(PPh3)2Cl2 (0.52 g, 0.74 mmol, 0.20 equiv.) was added, and the resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2'-(6-bromopyridin-2-yl)-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-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'-bipyridin]-2-one: To a stirred mixture of 2'-chloro-4-[(4-methoxyphenyl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one (5 g, 13.483 mmol, 1 equiv.) and 2,2-dichloroacetic acid (0.17 mL, 1.348 mmol, 0.1 equiv.) in i-PrOH (20.00 mL, 261.705 mmol, 19.41 equiv.), NCS (1.80 g, 13.483 mmol, 1 equiv.) was added 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 LCMS. The mixture was allowed to cool to room temperature. This afforded 2',3-dichloro-4-[(4-methoxyphenyl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-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'-bipyridin]-2-one: To a stirred solution of 2',3-dichloro-4-[(4-methoxyphenyl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one (5 g, 12.33 mmol, 1.00 equiv.) and dibutyl(1-ethoxyethenyl)propylstannane (12.85 g, 37.01 mmol, 3.00 equiv.) in 1,4-dioxane (55 mL), Pd(PPh3)2Cl2 (0.26 g, 0.37 mmol, 0.03 equiv.) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 120 °C under a nitrogen atmosphere for 3 hours. The reaction was monitored by LCMS. 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'-bipyridin]-2-one To a stirred mixture of 3-chloro-2'-(1-ethoxyethenyl)-4-[(4-methoxyphenyl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one (4.00 g, 9.07 mmol, 1.00 equiv) in THF (200 mL) was added HCl (4 mL) 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 LCMS. The resulting mixture was diluted with EtOAc (200 mL). The resulting mixture was washed with 2 x 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 give 2'-acetyl-3-chloro-4-[(4-methoxyphenyl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-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'-bipyridin]-2-one: A stirred mixture of 2'-acetyl-3-chloro-4-[(4-methoxyphenyl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one (2.90 g, 7.02 mmol, 1.00 equiv.) in DMF-DMA (25 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 100°C under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to give 3-chloro-2'-[(2E)-3-(dimethylamino)prop-2-enoyl]-4-[(4-methoxyphenyl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-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)pyrimidin-4-yl]-4-[(4-methoxyphenyl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one: To a stirred mixture of 3-chloro-2'-[(2E)-3-(dimethylamino)prop-2-enoyl]-4-[(4-methoxyphenyl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one (3.30 g, 7.05 mmol, 1.00 equiv.) and K2CO3 (2.92 g, 21.15 mmol, 3.00 equiv.) in IPA (33 mL) was added 2-hydroxy-2-methylpropanimidamide hydrochloride (1.95 g, 14.10 mmol, 2.00 equiv.) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The resulting mixture was diluted with EtOAc (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)pyrimidin-4-yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one: To a stirred solution of 3-chloro-2'-[2-(2-hydroxypropan-2-yl)pyrimidin-4-yl]-4-[(4-methoxyphenyl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one (3.70 g, 7.29 mmol, 1.00 equiv) in CHCl (50 mL) was added TFA (15 mL) 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 LCMS. The resulting mixture was diluted with EtOAc (200 mL). The resulting mixture was washed with 2 x 200 ml brine. The organic layer was dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-chloro-4-hydroxy-2'-[2-(2-hydroxypropan-2-yl)pyrimidin-4-yl]-5',6-dimethyl-[1,4'-bipyridin]-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). Intermediates 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 equiv) in EtOH (6.00 L) was added EtN (140.00 g, 1383.50 mmol, 2.00 equiv) and Pd(dppf)Cl (10.00 g, 13.66 mmol, 0.05 equiv) in a pressure tank. The mixture was purged with nitrogen for 2 minutes and then pressurized to 50 atmospheres with carbon monoxide at 100 °C for 12 hours. The reaction mixture was cooled to room temperature. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 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 equiv.) in MeCN (1.00 L) was added TMSI (262 mL, 1833.36 mmol, 4.00 equiv.) dropwise over 1 hour at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 50° C. The desired product could be detected by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was redissolved in DCM (500 mL) and then concentrated under reduced pressure. The above process was repeated three times. The residue was purified by trituration with hexane (800 mL). The resulting mixture was concentrated under reduced pressure. This gave 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 equiv.) in DCE (1.20 L) was added POCl3 (73 mL, 785.00 mmol, 4.00 equiv.) dropwise over 2 h at 0 °C under a nitrogen atmosphere. The resulting mixture was further stirred at 50 °C overnight. The desired product could be detected by LCMS. The mixture was allowed to cool to room temperature. The reaction was quenched by adding water / ice (600 mL) at 0 °C. The mixture was basified to pH 7-8 with saturated Na2CO3 (aq.). The resulting mixture was extracted with CHCl2 (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 give 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'-bipyridin]-2-one: To a solution of 2'-bromo-4-hydroxy-5',6-dimethyl-[1,4'-bipyridin]-2-one (7.00 g, 23.72 mmol, 1.00 equiv) in DMF (50 mL) was added PMBCl (11.14 g, 71.15 mmol, 3.00 equiv), K2CO3 (13.11 g, 94.872 mmol, 4.00 equiv), and 18-crown-6 (310 mg, 1.19 mmol, 0.05 equiv). The mixture was stirred at 60 °C for 3 h. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The reaction mixture was partitioned between 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 give 2'-bromo-4-[(4-methoxyphenyl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one (5.5 g, 55.84%) as an off-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'-bipyridin]-2-one: To a stirred mixture of 2'-bromo-4-[(4-methoxyphenyl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one (5.50 g, 13.24 mmol, 1.00 equiv.) and NCS (1.95 g, 14.57 mmol, 1.10 equiv.) in IPA (20 mL) was added 2,2-dichloroacetic acid (100 mg, 0.80 mmol, 0.06 equiv.) at room temperature. The mixture was stirred at 60°C under a nitrogen atmosphere for 3 hours. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The precipitated solid was collected by filtration to give 2'-bromo-3-chloro-4-[(4-methoxyphenyl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-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). Intermediates 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 equiv) in EtOH (100 mL) was cooled in an ice bath. To the above mixture, SOCl (6.13 g, 51.53 mmol, 2.01 equiv) was added dropwise over 3 minutes at 0 °C. The resulting mixture was stirred at room temperature for another 3 hours. The reaction was monitored by LCMS. The mixture was allowed to reach room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography to give ethyl 3-chloro-5-fluoropyridine-2-carboxylate (4.40 g, 84.29%) as a colorless liquid. LC-MS: (ES+H, m / z): [M+H] + =203.9.

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

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

[0274] Step 1: Preparation of 2-bromo-3,5-dimethyl-4-nitropyridine: To a stirred solution of 3,5-dimethyl-4-nitropyridin-1-ol (5.00 g, 29.38 mmol, 1.00 equiv) in DCE (100 mL) was added POBr (12.64 g, 44.07 mmol, 1.50 equiv) dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 60 °C for 2 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to reach room temperature. The residue was basified to pH 10 with saturated NaCO (aq) at 0 °C. The reaction was poured into water (100 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 300 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford 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 H 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-dimethylpyridin-4-amine: A mixture of 2-bromo-3,5-dimethyl-4-nitropyridine (5.40 g, 23.37 mmol, 1.00 equiv), Fe (2.61 g, 46.74 mmol, 5.00 equiv), and CaCl (12.97 g, 116.86 mmol, 5.00 equiv) in EtOH (60 mL) was stirred at 90 °C for 3 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to reach 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 EtOAc (500 mL). The EtOAc layer was washed with saturated NaCO (aq) (2 × 300 mL). The organic layer was dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. 2-Bromo-3,5-dimethylpyridin-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'-bipyridin]-2-one: A solution of 2-bromo-3,5-dimethylpyridin-4-amine (2.30 g, 11.43 mmol, 1.00 equiv) and 2,2-dimethyl-6-(2-oxopropyl)-1,3-dioxin-4-one (2.11 g, 11.43 mmol, 1.00 equiv) in dioxane (15 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 LCMS. To the above mixture was added HSO (1.12 g, 11.43 mmol, 1.00 equiv) dropwise at 0° C. The resulting mixture was stirred at 90° C. for an additional 1 hour. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography to give 2'-bromo-4-hydroxy-3',5',6-trimethyl-[1,4'-bipyridin]-2-one (1.70 g, 62.46%) as a tan oil. LC-MS: (ES+H, m / z): [M+H] + =309.2 / 311.2. 1 H 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-difluoropyridin-2-yl)methoxy]-3',5',6-trimethyl-[1,4'-bipyridin]-2-one: A mixture of 2'-bromo-4-hydroxy-3',5',6-trimethyl-[1,4'-bipyridin]-2-one (1.70 g, 5.49 mmol, 1.00 equiv.), 2-(chloromethyl)-3,5-difluoropyridine (1.35 g, 8.24 mmol, 1.50 equiv.), 18-crown-6 (0.15 g, 0.55 mmol, 0.10 equiv.), and K2CO3 (3.04 g, 21.99 mmol, 4.00 equiv.) in DMF (15 mL) was stirred at 60 °C for 4 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool 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 give 2'-bromo-4-[(3,5-difluoropyridin-2-yl)methoxy]-3',5',6-trimethyl-[1,4'-bipyridin]-2-one (1.60 g, 66.70%) as a yellow-green solid. LC-MS: (ES+H, m / z): [M+H] + =436.2 / 438.2. 1 H NMR (400MHz, DMSO-d6)δ 8.60 (d, 1H), 8.34 (s, 1H), 8.14 - 8.02 (m, 1H), 6.20 (d, 1H), 6.08 (d, 1H), 5.26 (d, 2H), 2.04 (s, 3H), 1.95 (s, 3H), 1.81 (s, 3H). Intermediates 42-56 [ka]

[0278] Step 1: Preparation of 2-chloro-3-fluoro-5-iodopyridin-4-amine: To a stirred solution of 2-chloro-3-fluoropyridin-4-amine (5.00 g, 34.11 mmol, 1.00 equiv.) in CH3CN (150 mL), NIS (9.21 g, 40.94 mmol, 1.20 equiv.) and 4-methylbenzene-1-sulfonic acid hydrate (0.32 g, 1.70 mmol, 0.05 equiv.) were added portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 70 °C under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (300 mL). The resulting mixture was extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with brine (3 × 150 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give 2-chloro-3-fluoro-5-iodopyridin-4-amine (9.00 g, 96.82%) as a brown solid. LC-MS: (ES+H, m / z): [M+H] + =272.9. 1 H NMR (300MHz, DMSO-d6)δ 8.10 (s, 1H), 6.69 (s, 2H).

[0279] Step 2: Preparation of 2-chloro-3-fluoro-5-methylpyridin-4-amine: To a stirred mixture of 2-chloro-3-fluoro-5-iodopyridin-4-amine (9.00 g, 33.03 mmol, 1.00 equiv.) and methylboronic acid (3.95 g, 66.06 mmol, 2.00 equiv.) in toluene (200 mL) and HO (20 mL), CsCO (16.14 g, 49.55 mmol, 1.50 equiv.), PCy (0.46 g, 1.65 mmol, 0.05 equiv.), and Pd(OAc) (0.37 g, 1.65 mmol, 0.05 equiv.) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere overnight. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (500 mL). The resulting mixture was extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine (3×200 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and the filtrate was concentrated under reduced pressure to give 2-chloro-3-fluoro-5-methylpyridin-4-amine (3.50 g, 65.98%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H] + =161.00. 1 H NMR (300 MHz, chloroform-d) δ 7.75 (s, 1H), 4.36 (s, 2H), 2.15 (s, 3H).

[0280] Step 3: Preparation of 2'-chloro-3'-fluoro-4-hydroxy-5',6-dimethyl-[1,4'-bipyridin]-2-one: To a stirred solution of 2-chloro-3-fluoro-5-methylpyridin-4-amine (3.00 g, 18.68 mmol, 1.00 equiv) in 1,4-dioxane (100 mL) was added 2,2-dimethyl-6-(2-oxopropyl)-1,3-dioxin-4-one (6.88 g, 37.36 mmol, 2.00 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90° C. for 2 hours under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. To the above mixture was added HSO (1.83 g, 18.68 mmol, 1.00 equiv) dropwise at room temperature. The resulting mixture was stirred at 90° C. for an additional 2 hours. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with water (200 mL). The solid was collected by filtration and further purified by trituration with hexane (200 mL) to give 2'-chloro-3'-fluoro-4-hydroxy-5',6-dimethyl-[1,4'-bipyridin]-2-one (3.00 g, 59.77%) as a brown solid. LC-MS: (ES+ H, m / z): [M+H] + =269.1. 1 H NMR (300MHz, DMSO-d6)δ 11.03 (s, 1H), 8.42 (s, 1H), 6.05 (d, 1H), 5.61 (d, 1H), 2.06 (s, 3H), 1.89 (s, 3H).

[0281] Step 4: Preparation of 2'-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-3'-fluoro-5',6-dimethyl-[1,4'-bipyridin]-2-one: To a stirred mixture of 2'-chloro-3'-fluoro-4-hydroxy-5',6-dimethyl-[1,4'-bipyridin]-2-one (2.00 g, 7.44 mmol, 1.00 equiv.) and 2-(chloromethyl)-3,5-difluoropyridine (1.83 g, 11.16 mmol, 1.50 equiv.) in DMF (60 mL), CsCO (7.28 g, 22.33 mmol, 3.00 equiv.) and 18-crown-6 (196.7 mg, 0.74 mmol, 0.10 equiv.) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 70 °C under a nitrogen atmosphere overnight. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (150 mL). The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (3×100 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and the filtrate was concentrated under reduced pressure to give 2′-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-3′-fluoro-5′,6-dimethyl-[1,4′-bipyridin]-2-one (2.00 g, 67.89%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H] + =396.1. 1 H NMR (300MHz, DMSO-d6)δ 8.60 (d, 1H), 8.44 (s, 1H), 8.12 - 8.04 (m, 1H), 6.22 (d, 1H), 6.09 (d, 1H), 5.27 (d, 2H), 2.08 (s, 3H), 1.92 (s, 3H).

[0282] Step 5: Preparation of 3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-3'-fluoro-5',6-dimethyl-2'-(trimethylstannyl)-[1,4'-bipyridin]-2-one: To a stirred solution of 2',3-dichloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-3'-fluoro-5',6-dimethyl-[1,4'-bipyridin]-2-one (500 mg, 1.16 mmol, 1.00 equiv.) and SnMe (761.56 mg, 2.32 mmol, 2.00 equiv.) in dioxane (8 mL), Pd(PPh)Cl (163.15 mg, 0.23 mmol, 0.20 equiv.) and AsPh (71.18 mg, 0.23 mmol, 0.20 equiv.) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =560.0. Intermediates 47-48 [ka]

[0283] Step 1: Preparation of (3,5-difluoropyridin-2-yl)methan-d2-ol: To a stirred solution of ethyl 5-chloro-3-fluoropyridine-2-carboxylate (500.00 g, 2671.71 mmol, 1.00 equiv.) in CD3OD (500 mL) and THF (1000 mL) was added NaBD4 (111.84 g, 2671.71 mmol, 1.00 equiv.) portionwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The resulting mixture was quenched by adding DO (200 mL) at 0 °C and stirred at 0 °C for 30 min. The mixture was diluted with EtOAc (2000 mL) and washed with water (2000 mL) and brine (2000 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give (3,5-difluoropyridin-2-yl)methan-d2-olmethanol (360.00 g, 91.5%) as a yellow oil. LC-MS: (ES+H, m / z): [M+H] + =148.1.1 H NMR (300MHz, DMSO-d6)δ 8.44 (d, 1H), 7.88 (ddd, 1H), 5.37 (s, 1H).

[0284] Step 2: Preparation of 2-(chloromethyl-d2)-3,5-difluoropyridine: To a stirred solution of (3,5-difluoropyridin-2-yl)methan-d2-ol (300.00 g, 2039.13 mmol, 1.00 equiv.) in DCM (1000 mL) was added DMF (14.91 g, 203.91 mmol, 0.10 equiv.) and SOCl2 (606.44 g, 5097.84 mmol, 2.50 equiv.) dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated in vacuo to give 2-(chloromethyl-d2)-3,5-difluoropyridine (320.00 g, 94.7%) as a yellow oil, which was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =166.1. 1 H NMR (300MHz, DMSO-d6)δ 8.48 (d, 1H), 8.04 - 7.93 (m, 1H). Intermediates 49-53 [ka]

[0285] Step 1: Preparation of 2'-chloro-4-[(3,5-difluoropyridin-2-yl)(2H2)methoxy]-3'-fluoro-5',6-dimethyl-[1,4'-bipyridin]-2-one: To a stirred mixture of 2'-chloro-3'-fluoro-4-hydroxy-5',6-dimethyl-[1,4'-bipyridin]-2-one (1.70 g, 6.32 mmol, 1.00 equiv.) and 2-[chloro(2H)methyl]-3,5-difluoropyridine (1.57 g, 9.49 mmol, 1.50 equiv.) in DMF (60 mL), CsCO (6.18 g, 18.98 mmol, 3.00 equiv.) and 18-crown-6 (0.17 g, 0.63 mmol, 0.10 equiv.) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 70 °C under a nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (150 mL). The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (3×100 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and the filtrate was concentrated under reduced pressure to give 2′-chloro-4-[(3,5-difluoropyridin-2-yl)(2H)methoxy]-3′-fluoro-5′,6-dimethyl-[1,4′-bipyridin]-2-one (1.40 g, 55.62%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H] + =398.1.

[0286] Step 2: Preparation of 2',3-dichloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-3'-fluoro-5',6-dimethyl-[1,4'-bipyridin]-2-one: To a stirred solution of 2'-chloro-4-[(3,5-difluoropyridin-2-yl)(2H)methoxy]-3'-fluoro-5',6-dimethyl-[1,4'-bipyridin]-2-one (1.40 g, 3.52 mmol, 1.00 equiv.) and NCS (0.61 g, 4.57 mmol, 1.30 equiv.) in i-PrOH, dichloroacetic acid (0.05 g, 0.35 mmol, 0.10 equiv.) was added dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 60°C under a nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 x 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and the filtrate was concentrated under reduced pressure to give 2',3-dichloro-4-[(3,5-difluoropyridin-2-yl)(2H2)methoxy]-3'-fluoro-5',6-dimethyl-[1,4'-bipyridin]-2-one (1.2 g, 78.88%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H] + =432.0. 1 H NMR (400MHz, DMSO-d6)δ 8.59 (d, 1H), 8.43 (d, 1H), 8.12 - 8.03 (m, 1H), 6.21 (s, 1H), 6.08 (d, 1H), 2.07 (s, 3H), 1.91 (s, 3H).

[0287] Step 3: 3-chloro-4-[(3,5-difluoropyridin-2-yl)(2H2)methoxy]-2'-(1-ethoxyethenyl)-3'-fluoro-5',6-dimethyl-[1,4'-bipyridin]-2-one: To a stirred solution of 2',3-dichloro-4-[(3,5-difluoropyridin-2-yl)(2H)methoxy]-3'-fluoro-5',6-dimethyl-[1,4'-bipyridin]-2-one (1.20 g, 2.77 mmol, 1.00 equiv.) and tributyl(1-ethoxyethenyl)stannane (2.01 g, 5.55 mmol, 2.00 equiv.) in 24.00 mL of dioxane, Pd(PPh3)2Cl2 (0.10 g, 0.14 mmol, 0.05 equiv.) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 120 °C under a nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The desired product could be detected by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + = 468.1.

[0288] Step 4: Preparation of 2'-acetyl-3-chloro-4-[(3,5-difluoropyridin-2-yl)(2H2)methoxy]-3'-fluoro-5',6-dimethyl-[1,4'-bipyridin]-2-one: The above mixture was diluted with 1,4-dioxane (80 mL), and then HCl (0.94 g, 25.65 mmol, 10.00 equiv.) was added dropwise at 0 °C. The resulting mixture was stirred at room temperature for another 30 minutes. The desired product could be detected by LCMS. The mixture was basified to pH 8 with saturated NaHCO (aq.). The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (3 × 10 mL) and dried over anhydrous NaSO. After filtration, the residue was purified by silica gel column chromatography, and the filtrate was concentrated under reduced pressure to give 2'-acetyl-3-chloro-4-[(3,5-difluoropyridin-2-yl)(2H)methoxy]-3'-fluoro-5',6-dimethyl-[1,4'-bipyridin]-2-one (880 mg, 78.01%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H] + = 440.20.

[0289] Step 5: Preparation of 3-chloro-4-[(3,5-difluoropyridin-2-yl)(2H)methoxy]-2'-[(2E)-3-(dimethylamino)prop-2-enoyl]-3'-fluoro-5',6-dimethyl-[1,4'-bipyridin]-2-one: A solution of 2'-acetyl-3-chloro-4-[(3,5-difluoropyridin-2-yl)(2H)methoxy]-3'-fluoro-5',6-dimethyl-[1,4'-bipyridin]-2-one (880 mg, 2.00 mmol, 1.00 equiv.) in DMF-DMA (6 mL) was stirred at 100 °C under a nitrogen atmosphere for 2 hours. The desired product could be detected by LCMS. The mixture was allowed to cool to room temperature. The precipitated solid was collected by filtration and washed with hexane (3 × 2 mL). This gave 3-chloro-4-[(3,5-difluoropyridin-2-yl)(2H)methoxy]-2'-[(2E)-3-(dimethylamino)prop-2-enoyl]-3'-fluoro-5',6-dimethyl-[1,4'-bipyridin]-2-one (760 mg, 76.75%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H] + = 495.1. Intermediates 54-55 [ka]

[0290] Step 1: Preparation of 2'-bromo-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one: To a stirred mixture of 2'-bromo-4-hydroxy-5',6-dimethyl-[1,4'-bipyridin]-2-one (100.00 g, 338.82 mmol, 1.00 equiv.), 18-crown-6 (5.37 g, 3.00 mmol, 0.40 equiv.), and K2CO3 (42.14 g, 304.94 mmol, 3.00 equiv.) in DMF (200 mL) was added 2-(chloromethyl-d2)-3,5-difluoropyridine (27.75 g, 152.47 mmol, 1.50 equiv.) at room temperature. The resulting mixture was stirred at 60 °C under a nitrogen atmosphere for 2.5 h. The reaction was monitored by LCMS. The resulting mixture was filtered, and the filter cake was washed with EtOAc (3 × 500 mL). The filtrate was diluted with EA (3000 mL). The resulting mixture was washed with brine (3×2000 mL) and water (5×2000 mL). The organic layer was dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by trituration with EtO (3×250 mL) and dried under reduced pressure to give 2′-bromo-4-((3,5-difluoropyridin-2-yl)methoxy-d)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one (90 g, 62.8%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =424.0. 1 H NMR (300MHz, DMSO-d6)δ 8.59 (d, 1H), 8.48 (s, 1H), 8.08 (ddd, 1H), 7.73 (s, 1H), 6.13 (dd, 1H), 6.03 (d, 1H), 1.97 (s,3H), 1.85 (s, 3H).

[0291] Step 2: Preparation of 2'-bromo-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one: To a stirred solution of 2'-bromo-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one (100.00 g, 235.71 mmol, 1.00 equiv) and NCS (37.77 g, 282.85 mmol, 1.20 equiv) in IPA (500 mL) was added 2,2-dichloroacetic acid (3.04 g, 23.57 mmol, 0.10 equiv) dropwise at room temperature. The resulting mixture was stirred at 60°C under a nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The precipitated solid was collected by filtration and washed with cold IPA (4x30 mL) to give 2'-bromo-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one (60.00 g, 55.5%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =458.0. 1 H NMR 300MHz, DMSO-d6)δ 8.60 (d, 1H), 8.52 (s, 1H), 8.10 (ddd, 1H), 7.81 (s, 1H), 6.80 (d, 1H), 1.96 (s, 6H). Intermediates 56-57 [ka]

[0292] Step 1: Preparation of 2-(6-bromopyridin-2-yl)propan-2-ol: To a stirred solution of 2,6-dibromo-pyridine (25.00 g, 105.53 mmol, 1.00 equiv) in toluene (50 mL) was added n-BuLi (46.43 mL, 116.08 mmol, 1.10 equiv, 2.5 M in THF) dropwise at −50° C. under a nitrogen atmosphere. The resulting mixture was stirred at −50° C. for 30 minutes under a nitrogen atmosphere. To the above mixture was added acetone (9.19 g, 158.29 mmol, 1.5 equiv) dropwise over 10 minutes at −50° C. The resulting mixture was stirred at −50° C. for an additional 1 hour. The reaction was monitored by LCMS. The reaction was quenched with saturated NH4Cl (aq) at −10° C. The resulting mixture was extracted with EtOAc (3×300 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2-(6-bromopyridin-2-yl)propan-2-ol (15.80 g, 69.29%) as a colorless liquid. LC-MS: (ES+H, m / z): [M+H] + =216.2 / 218.2. 1 H NMR (400MHz, DMSO-d6)δ 7.73 (t, 1H), 7.68 (dd, 1H), 7.46 (dd, 1H), 5.33 (s, 1H), 1.43 (s, 6H).

[0293] Step 2: Preparation of 2-bromo-6-(2-hydroxypropan-2-yl)pyridin-1-ium-1-olate: To a stirred solution of 2-(6-bromopyridin-2-yl)propan-2-ol (5.00 g, 23.14 mmol, 1.00 equiv.) in DCM (50 mL) was added m-CPBA (11.98 g, 69.42 mmol, 3.00 equiv.) portionwise at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at 50° C. for 24 hours under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to reach room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2-bromo-6-(2-hydroxypropan-2-yl)pyridin-1-ium-1-olate (3.70 g, 68.90%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =232.3 / 234.3. 1 H NMR (300MHz, DMSO-d6)δ 7.91 (dd, 1H), 7.69 (dd, 1H), 7.33 (t, 1H), 6.70 - 6.04 (m, 1H), 1.58 (s, 6H). Example 1 [ka]

[0294] Step 1: Preparation of 2-(5-bromo-2-chloro-3-fluorophenoxymethyl)-3,5-difluoropyridine: A mixture of 5-bromo-2-chloro-1,3-difluorobenzene (6.00 g, 26.38 mmol, 1.00 equiv.), (3,5-difluoropyridin-2-yl)methanol (3.83 g, 26.38 mmol, 1.00 equiv.), 18-crown-6 (0.70 g, 2.64 mmol, 0.10 equiv.), and KCO (10.94 g, 79.15 mmol, 3.00 equiv.) in DMF (100 mL) was stirred overnight at 80 °C under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and pure fractions were concentrated under reduced pressure to give 2-(5-bromo-2-chloro-3-fluorophenoxymethyl)-3,5-difluoropyridine (3.00 g, 32%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =351.9 / 353.9. 1 H NMR (400MHz, DMSO-d6)δ 8.58 (d, 1H), 8.07 (td, 1H), 7.49 (t, 1H), 7.42 (dd, 1H), 5.41 (d, 2H).

[0295] Step 2: Preparation of 2-(2-chloro-3-fluoro-5-methylphenoxymethyl)-3,5-difluoropyridine: A mixture of 2-(5-bromo-2-chloro-3-fluorophenoxymethyl)-3,5-difluoropyridine (3.00 g, 8.51 mmol, 1.00 equiv.), methylboronic acid (0.76 g, 12.77 mmol, 1.50 equiv.), Pd(dppf)Cl (313 mg, 0.43 mmol, 0.05 equiv.), and KCO (3.53 g, 25.53 mmol, 3.00 equiv.) in dioxane:HO = 10:1 (100 mL) was stirred overnight at 80 °C under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and the pure fractions were concentrated under reduced pressure to give 2-(2-chloro-3-fluoro-5-methylphenoxymethyl)-3,5-difluoropyridine (1.90 g, 77%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =288.1. 1 H NMR (400MHz, DMSO-d6)δ 8.57 (d, 1H), 8.08 - 8.03 (m, 1H), 7.06 (s, 1H), 6.88 (dd, 1H), 5.30 (d, 2H), 2.32 (s, 3H).

[0296] Step 3: Preparation of 2-(4-bromo-2-chloro-3-fluoro-5-methylphenoxymethyl)-3,5-difluoropyridine: A mixture of 2-(2-chloro-3-fluoro-5-methylphenoxymethyl)-3,5-difluoropyridine (1.30 g, 4.52 mmol, 1.00 equiv.) and NBS (804 mg, 4.52 mmol, 1.00 equiv.) in MeCN was stirred overnight at 80° C. under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and the pure fractions were concentrated under reduced pressure to give 2-(4-bromo-2-chloro-3-fluoro-5-methylphenoxymethyl)-3,5-difluoropyridine (1.50 g, 91%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =365.9 / 367.9. 1H NMR (400MHz, DMSO-d6)δ 8.57 (d, 1H), 8.09-8.04 (m, 1H), 7.32 (d, 1H), 5.36 (d, 2H), 2.39 (s, 3H).

[0297] Step 4: Preparation of 3-{5-chloro-4-[(2,4-difluorophenyl)methoxy]-2-methyl-6-oxopyrimidin-1-yl}-N-methoxy-N,4-dimethylbenzamide: A mixture of 2-{4-[5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]pyrimidin-2-yl}propan-2-ol (50 mg, 0.18 mmol, 1.00 equiv.), 2-(4-bromo-2-chloro-3-fluoro-5-methylphenoxymethyl)-3,5-difluoropyridine (62 mg, 0.17 mmol, 1.20 equiv.), Pd(dppf)Cl (10 mg, 0.01 mmol, 0.10 equiv.), and CsCO (138 mg, 0.42 mmol, 3.00 equiv.) in dioxane:HO = 20:1 (1 mL) was stirred at 100 °C under a nitrogen atmosphere for 3 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC to give 2-[4-(4-{3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2-fluoro-6-methylphenyl}-5-methylpyridin-2-yl)pyrimidin-2-yl]propan-2-ol (50 mg, crude) as an off-white solid. The crude product (50 mg) was purified by preparative HPLC, and the pure fractions were concentrated and lyophilized to give 2-[4-(4-{3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2-fluoro-6-methylphenyl}-5-methylpyridin-2-yl)pyrimidin-2-yl]propan-2-ol (13 mg, 13%) as an off-white solid. LC-MS: (ES+H, m / z): [M+H] + =515.15. 1H NMR (400MHz, DMSO-d6)δ 8.95 (d, 1H), 8.78 (s, 1H), 8.61 (d, 1H), 8.53 (s, 1H), 8.24 (d, 1H), 8.10 (td, 1H), 7.33 (s, 1H), 5.42 (s, 2H), 5.23 (s, 1H), 2.13 (s, 3H), 2.06 (s, 3H), 1.52 (s, 6H). 19 F NMR (377MHz, DMSO)δ -115.32, -120.15, -122.47. Example 2 [ka]

[0298] Step 1: Preparation of 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2'-(trimethylstannyl)-2H-[1,4'-bipyridin]-2-one: To a mixture of 2',3-dichloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one (500 mg, 1.21 mmol, 1.00 equiv.) and hexamethyldistannane (477 mg, 1.46 mmol, 1.20 equiv.) in dioxane (10 mL), Pd(PPh3)2Cl2 (170 mg, 0.24 mmol, 0.20 equiv.) and AsPh3 (74 mg, 0.24 mmol, 0.20 equiv.) were added at room temperature under nitrogen. The mixture was stirred overnight at 80°C under a nitrogen atmosphere. The reaction was monitored by LCMS. The desired product could be detected by LCMS. The mixture was used directly in the next step. LC-MS: (ES+H, m / z): [M+H] + =542.1.

[0299] Step 2: Preparation of ethyl 2-{3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-5',6-dimethyl-2-oxo-[1,4'-bipyridin]-2'-yl}-1,3-thiazole-4-carboxylate: To the final step of the reaction mixture, ethyl 2-bromo-1,3-thiazole-4-carboxylate (432.59 mg, 1.833 mmol, 1.50 equiv.) and Pd(PPh3)2Cl2 (170 mg, 0.24 mmol, 0.20 equiv.) were added at room temperature under nitrogen. The mixture was stirred overnight at 80°C under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was first purified by silica gel column chromatography to give the crude product (210 mg). The crude product (210 mg) was further purified by preparative HPLC, and the pure fractions were concentrated to give ethyl 2-{3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-5',6-dimethyl-2-oxo-[1,4'-bipyridin]-2'-yl}-1,3-thiazole-4-carboxylate (160 mg, 24.74%, two steps) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =533.1.

[0300] Step 3: Preparation of 3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2'-[4-(2-hydroxypropan-2-yl)-1,3-thiazol-2-yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one: To a mixture of ethyl 2-{3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-5',6-dimethyl-2-oxo-[1,4'-bipyridin]-2'-yl}-1,3-thiazole-4-carboxylate (100 mg, 0.19 mmol, 1.00 equiv.) in THF (5 mL) was added CHMgBr (0.6 mL, 0.56 mmol, 3.00 equiv.) dropwise under nitrogen at 0°C. The mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. The reaction was monitored by LCMS. The reaction was quenched with MeOH (1 mL). The resulting mixture was concentrated under reduced pressure. The residue was directly purified by preparative HPLC, and the pure fractions were concentrated and lyophilized to give 3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2'-[4-(2-hydroxypropan-2-yl)-1,3-thiazol-2-yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one (20.3 mg, 21%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =518.8. 1 H NMR (400MHz, DMSO-d6)δ 8.72 (s, 1H), 8.61 (d, 1H), 8.10 (ddd, 1H), 8.01 (s, 1H), 7.54 (s, 1H), 6.81 (s, 1H), 5.49 (s, 2H), 5.23 (s, 1H), 2.05 (s, 3H), 1.99 (s, 3H), 1.50 (s, 6H). 19 F NMR (377MHz, DMSO)δ -120.15, -122.34. Example 3 and Example 3A and Example 3B [ka]

[0301] Step 1: Preparation of methyl 1-(benzyloxy)cyclopropane-1-carboxylate: A solution of methyl 1-hydroxycyclopropane-1-carboxylate (3.00 g, 25.84 mmol, 1.00 equiv) in DMF (20 mL) was treated with NaH (0.93 g, 38.75 mmol, 1.50 equiv, 60 wt%) under a nitrogen atmosphere at 0° C. for 30 minutes, followed by the dropwise addition of benzyl bromide (8.84 g, 51.67 mmol, 2.00 equiv) at 0° C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS and TLC. The reaction was quenched by adding water / ice (150 mL) at 0° C. The resulting mixture was extracted with EtOAc (3×150 mL). The combined organic layers were washed with brine (1×150 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 1-(benzyloxy)cyclopropane-1-carboxylate (3.20 g, 60%) as a colorless oil. 1 H NMR (300MHz, DMSO-d6)δ 7.47 - 7.23 (m, 5H), 4.60 (s, 2H), 3.69 (s, 3H), 1.37 - 1.16 (m, 4H).

[0302] Step 2: Preparation of 1-(benzyloxy)cyclopropane-1-carboximidamide hydrochloride: To a stirred mixture of NH4Cl (2.50 g, 46.74 mmol, 9.64 equiv) in toluene (20 mL, 188.00 mmol, 38.77 equiv) was added trimethylaluminum (19.25 mL, 534.09 mmol, 110.15 equiv) dropwise at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 30 minutes under a nitrogen atmosphere. To the above mixture was added methyl 1-(benzyloxy)cyclopropane-1-carboxylate (1.00 g, 4.85 mmol, 1.00 equiv) in toluene (10 mL) dropwise over 10 minutes at room temperature. The resulting mixture was further stirred at 80°C overnight. The reaction was monitored by LCMS. The reaction was quenched by adding MeOH (10 mL) at 0°C. The resulting mixture was filtered, and the filter cake was washed with EtOH (5 x 20 mL). The filtrate was concentrated under reduced pressure to give 1-(benzyloxy)cyclopropane-1-carboximidamide hydrochloride (1.00 g, 91%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =191.1. 1 H NMR (300MHz, DMSO-d6)δ 8.85 (d, 4H), 7.56 - 7.23 (m, 5H), 4.57 (s, 2H), 1.48 (s, 4H).

[0303] Step 3: Preparation of 2'-{2-[1-(benzyloxy)cyclopropyl]pyrimidin-4-yl}-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one: A solution of 2'-acetyl-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one (200 mg, 0.48 mmol, 1.00 equiv.) in DMF-DMA (5 mL) was stirred overnight at 100°C under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum. To the above mixture was added 1-(benzyloxy)cyclopropane-1-carboximidamide hydrochloride (324 mg, 1.43 mmol, 3.00 equiv.) and K2CO3 (395 mg, 2.86 mmol, 6 equiv.) in IPA (5 mL). The resulting mixture was further stirred overnight at 100°C. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA=1:3) to give 2'-{2-[1-(benzyloxy)cyclopropyl]pyrimidin-4-yl}-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one (185 mg, 65%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =602.2.

[0304] Step 4: Preparation of 3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2'-[2-(1-hydroxycyclopropyl)pyrimidin-4-yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one: A mixture of 2'-{2-[1-(benzyloxy)cyclopropyl]pyrimidin-4-yl}-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one (150 mg, 0.25 mmol, 1.00 equiv.) and AlCl (199 mg, 1.49 mmol, 6.00 equiv.) in toluene (10 mL) was stirred at room temperature under a nitrogen atmosphere for 4 hours. The reaction was monitored by LCMS. The resulting mixture was filtered, and the filter cake was washed with DCM:MeOH = 5:1 (3 × 10 mL). The filtrate was concentrated under reduced pressure. The crude product (100 mg) was purified by preparative HPLC, and the pure fractions were concentrated and lyophilized to give 3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2'-[2-(1-hydroxycyclopropyl)pyrimidin-4-yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one (26.3 mg, 21%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =511.85. 1 H NMR (400MHz, DMSO-d6)δ 8.91 - 8.84 (m, 2H), 8.61 (d, 1H), 8.57 (s, 1H), 8.18 - 8.07 (m, 2H), 6.84 (s, 1H), 6.05 (s, 1H), 5.50 (d, 2H), 2.11 (s, 3H), 1.98 (s, 3H), 1.43 - 1.31 (m, 2H), 1.21-1.18 (m, 2H). 19 F NMR (377MHz, DMSO)δ -120.14 -122.34.

[0305] Step 5: Preparation of rel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2'-[2-(1-hydroxycyclopropyl)pyrimidin-4-yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one and rel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2'-[2-(1-hydroxycyclopropyl)pyrimidin-4-yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one: 3-Chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2'-[2-(1-hydroxycyclopropyl)pyrimidin-4-yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one (30 mg, 0.059 mmol, 1.00 equiv) was isolated by preparative chiral HPLC. Pure fractions were concentrated and lyophilized to give rel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2'-[2-(1-hydroxycyclopropyl)pyrimidin-4-yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one (isomer 1, 13.6 mg, ee%=100%) as a white solid and rel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2'-[2-(1-hydroxycyclopropyl)pyrimidin-4-yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one (isomer 2, 11.8 mg, ee%=99.8%) as a white solid.

[0306] Example 3A (Isomer 1): LC-MS: (ES+H, m / z): [M+H] + =511.80. 1 H NMR (400MHz, DMSO-d6)δ 8.90 - 8.83 (m, 2H), 8.61 (d, 1H), 8.57 (s, 1H), 8.15 (d, 1H), 8.11 (td, 1H), 6.85 (s, 1H), 6.05 (s, 1H), 5.50 (d, 2H), 2.11 (s, 3H), 1.98 (s, 3H), 1.43 - 1.30 (m, 2H), 1.18 (d, 2H). 19 F NMR (377MHz, DMSO)δ -120.14, -122.35.

[0307] Example 3B (Isomer 2): LC-MS: (ES+H, m / z): [M+H] + =511.80. 1H NMR (400MHz, DMSO-d6)δ 8.90 - 8.83 (m, 2H), 8.61 (d, 1H), 8.57 (s, 1H), 8.15 (d, 1H), 8.11 (td, 1H), 6.85 (s, 1H), 6.05 (s, 1H), 5.50 (d, 2H), 2.11 (s, 3H), 1.98 (s, 3H), 1.43 - 1.30 (m, 2H), 1.18 (d, 2H). 19 F NMR (377MHz, DMSO)δ -120.13, -122.35. Examples 4, 4A, and 4B [ka]

[0308] Step 1: Preparation of 3-hydroxy-2,2-dimethylpropanimidamide hydrochloride: To a stirred mixture of NH4Cl (9.15 g, 171.02 mmol, 5.00 equiv.) in toluene (40 mL) was added AlMe3 (85.51 mL, 2 M in toluene, 171.02 mmol, 5.00 equiv.) dropwise at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at 0°C for 10 minutes under a nitrogen atmosphere, and then at room temperature until gas evolution ceased. To the above mixture was added dropwise a solution of ethyl 3-hydroxy-2,2-dimethylpropanoate (5.00 g, 34.20 mmol, 1.00 equiv.) in toluene at room temperature. The resulting mixture was further stirred at 80°C overnight. The reaction was monitored by LCMS. The reaction was quenched by adding MeOH (30 mL) at 0°C. The resulting mixture was filtered, and the filter cake was washed with MeOH (500 mL). The filtrate was concentrated under reduced pressure. The residue was dissolved in EtOH (30 mL). The resulting mixture was filtered, and the filter cake was washed with EtOH (15 mL). The filtrate was concentrated under reduced pressure to give 3-hydroxy-2,2-dimethylpropanimidamide hydrochloride (4 g, crude) as a white solid. 1H NMR (400MHz, DMSO-d6)δ 9.04 (s, 2H), 8.62 (s, 2H), 5.43 (t, 1H), 3.48 (d, 2H), 1.18 (s, 6H).

[0309] Step 2: Preparation of 3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2'-[2-(1-hydroxy-2-methylpropan-2-yl)pyrimidin-4-yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one: A solution of 2'-acetyl-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-5',6-dimethyl-[1,4'-bipyridin]-2-one (450 mg, 0.95 mmol, 1.00 equiv.) in DMF-DMA (6 mL) was stirred overnight at 100°C under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was allowed to warm to room temperature and concentrated under reduced pressure. The crude product (550 mg) was used directly in the next step without further purification. To a solution of the above crude product in IPA (20 mL) were added 3-hydroxy-2,2-dimethylpropanimidamide, HCl salt (1.80 g, crude 2, 11.58 mmol, 10.00 equiv.), and KCO (1.60 g, 11.58 mmol, 10.00 equiv.), and the mixture was then stirred overnight at 80°C under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was allowed to reach room temperature and diluted with EtOAc (100 mL). The combined organic layers were washed with brine (3 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2'-[2-(1-hydroxy-2-methylpropan-2-yl)pyrimidin-4-yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one (450 mg, 73.59%) as an off-white solid. LC-MS: (ES+H, m / z): [M+H] + =528.25. 1H NMR (300MHz, DMSO-d6)δ 8.93 (d, 1H), 8.86 (s, 1H), 8.62 (d, 1H), 8.36 (s, 1H), 8.17 (d, 1H), 8.11 (ddd, 1H), 6.84 (s, 1H), 5.50 (d, 2H), 4.56 (t, 1H), 3.73 (d, 2H), 2.10 (s, 3H), 1.98 (s, 3H), 1.35 (s, 6H). 19 F NMR (377MHz, DMSO)δ-120.11, -120.14, -122.31, -122.336.

[0310] Step 3: Preparation of rel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2'-[2-(1-hydroxy-2-methylpropan-2-yl)pyrimidin-4-yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one and rel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2'-[2-(1-hydroxy-2-methylpropan-2-yl)pyrimidin-4-yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one: Racemic 3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2'-[2-(1-hydroxy-2-methylpropan-2-yl)pyrimidin-4-yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one (65 mg) was separated by preparative chiral HPLC to give rel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2'-[2-(1-hydroxy-2-methylpropan-2-yl)pyrimidin-4-yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one. [Rimidin-4-yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one (Example 4A, 18 mg, ee%=99.5%) and rel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2'-[2-(1-hydroxy-2-methylpropan-2-yl)pyrimidin-4-yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one (Example 4B, 23 mg, ee%=99.4%) were obtained as white solids.

[0311] Example 4A: LC-MS: (ES+H, m / z): [M+H] + = 528.2. 1 H NMR (400MHz, DMSO-d6)δ 8.92 (d, 1H), 8.85 (s, 1H), 8.61 (d, 1H), 8.35 (s, 1H), 8.16 (d, 1H), 8.12 - 8.05 (m, 1H), 6.83 (s, 1H), 5.49 (d, 2H), 4.59 (t, 1H), 3.73 (d, 2H), 2.10 (s, 3H), 1.98 (s, 3H), 1.34 (s, 6H). 19 F NMR (377MHz, DMSO)δ -120.06, -120.08, -122.20, -122.22.

[0312] Example 4B: LC-MS: (ES+H, m / z): [M+H] + = 528.2. 1 H NMR (400MHz, DMSO-d6)δ 8.92 (d, 1H), 8.85 (s, 1H), 8.60 (d, 1H), 8.34 (s, 1H), 8.16 (d, 1H), 8.10 - 8.03 (m, 1H), 6.82 (s, 1H), 5.48 (d, 2H), 4.62 (t, 1H), 3.72 (d, 2H), 2.09 (s, 3H), 1.97 (s, 3H), 1.33 (s, 6H). 19 F NMR (377MHz, DMSO)δ -120.03, -120.05, -122.11, -122.13. Examples 5, 5A, 5B [ka]

[0313] Step 1: Preparation of 2-(4-{3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-5′,6-dimethyl-2-oxo-[1,4′-bipyridin]-2′-yl}pyrimidin-2-yl)-2-methylpropanal: To a stirred mixture of Dess-Martin (422 mg, 1.00 mmol, 1.50 equiv) in DCM (10 mL) was added a solution of 3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2'-[2-(1-hydroxy-2-methylpropan-2-yl)pyrimidin-4-yl]-5',6-dimethyl-[1,4'-bipyridin]-2-one (350 mg, 0.66 mmol, 1.00 equiv) in DCM (5 mL) dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. The reaction was monitored by LCMS. The solvent was removed under reduced pressure. The resulting mixture was diluted with EtOAc (100 mL). The resulting mixture was washed with 3 x 100 mL of a saturated solution of NaHCO3. The combined organic layers were washed with brine (1 x 100 mL) and dried over anhy...

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, 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 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​​​​​​​​​​​​​​​​​​​​​​ 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 Is it 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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