CN117120430A

CN117120430A - MK2 inhibitors and uses thereof

Info

Publication number: CN117120430A
Application number: CN202280026830.4A
Authority: CN
Inventors: L·特佐斯; Q·董; S·W·卡尔多; R·L·霍夫曼
Original assignee: Xintra Co ltd
Current assignee: Xintra Co ltd
Priority date: 2021-03-31
Filing date: 2022-03-30
Publication date: 2023-11-24

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, auto-inflammatory disorders, fibrotic disorders, metabolic disorders, oncological disorders, and cardiovascular or cerebrovascular disorders.

Description

MK2 inhibitors and uses thereof

Cross reference

The present application claims the benefit of U.S. provisional application Ser. No. 63/168,407, filed on 3 months 31 in 2021, and U.S. provisional application Ser. No. 63/318118, filed on 3 months 9 in 2022, both of which are hereby incorporated by reference in their entireties.

Background

Mitogen-activated protein kinases (MAPKs) are a family of conserved enzymes that use a phosphorylation cascade to deliver and spread external stimuli to produce a coordinated cellular response to the environment. MAPK is a proline-directed serine/threonine-specific protein kinase that regulates cellular activities such as gene expression, mitosis, differentiation, and cell survival/apoptosis. To date, four different classes of mammalian MAPKs have been identified: extracellular signaling kinases (ERKs 1 and 2), c-jun N-terminal kinase 1 (JNK 1-3), p38 MAPK (ρ38α, β, γ, and δ), and ERK5.MAPK is activated by dual phosphorylation of Thr and Tyr residues within the TXY activation motif by a coordinated bispecific MAPKK, where X is Glu, pro and Gly in ERK, JNK and p38 MAPK, respectively. MAPKs are 60% -70% identical to each other, but differ in their activation loop sequence and size. The activation loop is adjacent to the enzyme active site and its phosphorylation allows the enzyme to relocate the active site residues to the optimal orientation for substrate binding and catalysis. Downstream substrates for MAPK include mitogen-activated protein kinase activated protein (MAPKAP) kinase and transcription factors whose phosphorylation directly or indirectly regulates gene expression at multiple points, including transcription, nuclear export, and mRNA stability and translation. Cellular consequences of MAPK activation include inflammation, apoptosis, differentiation, and proliferation.

Different genes in humans encode four p38 MAPKs: ρ38α, β, γ, and δ. Significant amino acid sequence homology was observed in the 4 isoforms, with overall sequence identity of 60% -75% and identity within the kinase domain >90%. Tissue selective expression was observed, with ρ38γ being present predominantly in skeletal muscle and ρ38δ being present predominantly in testis, pancreas and small intestine. In contrast, p38a and β expression is more prevalent.

p38 MAPK is the major isoform involved in immune and inflammatory responses. Thus, its function is critical for the production and activity of a variety of pro-inflammatory cytokines (including TNFa, IL-1, IL-6 and IL-8) in cells such as macrophages, monocytes, synovial cells and endothelial cells. p38 MAPK is also responsible for the induction of key inflammatory enzymes such as COX2 and iNOS, which are the major sources of eicosanoids and nitric oxide, respectively, at the site of inflammation. In addition, the p38 MAPK pathway regulates the expression of Matrix Metalloproteinases (MMPs), including MMP2, MMP9, and MMP 13.

The use of selective potent inhibitors has prompted the discovery of multiple families of p38 MAPK substrates, including transcription factors, MAPKAP kinases, and other enzymes. The p38 MAPK can directly phosphorylate a variety of transcription factors such as the muscle cell specific enhancer binding factor 2C (MEF 2C), CHOP, peroxisome proliferator-activated receptor (PPAR) a, PPARγ coactivator 1 and p53. These transcription factors are involved in cellular functions such as apoptosis, gluconeogenesis and 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 in the regulation of the cell cycle. Thus, in addition to its role in inflammatory responses, p38 MAPK has other functions associated with normal and abnormal cell growth and survival, as well as cell function and homeostasis. MAPKAP kinases (MK 2, MK-3 and PRAK) are selectively phosphorylated by p38 MAPK, whereas phosphorylation of MSK1/2, MNK1/2 and RSKb is catalysed by p38 MAPK and ERK.

MK-2, MK-3 and PRAK have similar substrate specificities once phosphorylated and activated by p38 MAPK. All of these kinases phosphorylate the small heat shock protein Hsp27. Studies have shown that PRAK-and MK 3-deficient mice do not exhibit any resistance to endotoxin shock or a reduction in Lipopolysaccharide (LPS) -induced cytokine production. In contrast, MK-2 deficient mice exhibit resistance to endotoxic shock and impaired inflammatory response, as well as significantly reduced production of cytokines such as TNFa, IFNy and IL-6. Thus, the p38/MK2 axis is important for mediating pro-inflammatory responses.

The MK2 complex is very stable with a Kd of 6nM. 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 MK2 complex indicate that the C-terminal region of MK2 encapsulates p38a and binds to the negatively charged ED binding site. Tight binding of p38 to MK2 may cause conformational changes, thereby providing additional binding pockets for inhibitors, which will depend inter alia on the p38: MK2 interaction. Taken together, these two studies indicate that selective p38/MK2 axis blocking can be achieved using small molecule inhibitors. These p38/MK2 inhibitors should retain or enhance efficacy compared to traditional p38MAPK inhibitors and exhibit improved safety profiles in animal disease models or in the human clinical environment.

The role of p38/MK2 in the regulation of inflammatory cytokines (TNFa, IL-I beta, IL-6) and enzymes responsible for inflammation (COX-2, iNOS and MMP) makes them attractive drug targets. Several classical p38 MAPK inhibitors have been tested in clinical trials. Some of these candidates have failed for safety or other reasons, but several report 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- β mediated diseases can be affected by p38 inhibitors based on the key role of the p38 MAPK pathway in the biosynthesis and activity of this cytokine. These diseases include Cryptothermal protein related periodic disorders (CAPS), chronic gout, diabetes, steve's disease, familial mediterranean fever, and the like.

Disclosure of Invention

Disclosed herein is a compound of formula (II), or a pharmaceutically acceptable salt, solvate, N-oxide or stereoisomer thereof:

wherein:

ring a is phenyl or heteroaryl;

each R ^A Independently hydrogen, deuterium, halogen, -CN, -NO ₂ 、-OH、-OR ^a 、-OC(＝O)R ^a 、-OC(＝O)OR ^b 、-OC(＝O)NR ^c R ^d 、-SH、-SR ^a 、-S(＝O)R ^a 、-S(＝O) ₂ R ^a 、-S(＝O) ₂ NR ^c R ^d 、-NR ^c R ^d 、-NR ^b C(＝O)NR ^c R ^d 、-NR ^b C(＝O)R ^a 、-NR ^b C(＝O)OR ^b 、-NR ^b S(＝O) ₂ R ^a 、-C(＝O)R ^a 、-C(＝O)OR ^b 、-C(＝O)NR ^c R ^d 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently substituted with one or more R ^Aa Substitution;

or two R's on the same atom ^A Together forming oxo;

each R ^Aa 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 ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

or two R's on the same atom ^Aa Together form oxygenSubstitution;

n is 0-4;

R ¹ and R is ² Independently hydrogen, deuterium, halogen, -CN, -NO ₂ 、-OH、-OR ^a 、-NR ^c R ^d 、-C(＝O)R ^a 、-C(＝O)OR ^b 、-C(＝O)NR ^c R ^d 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, cycloalkyl or heterocycloalkyl;

or R is ¹ And R is ² Together forming oxo;

or R is ¹ And R is ² Together forming cycloalkyl or heterocycloalkyl; wherein the cycloalkyl and heterocycloalkyl are optionally substituted with deuterium, halogen, -CN, -OH, -OCH ₃ 、-NH ₂ 、-NHCH ₃ 、-N(CH ₃ ) ₂ 、-C(＝O)CH ₃ 、-C(＝O)OH、-C(＝O)OCH ₃ 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl or C ₁ -C ₆ Heteroalkyl substitution;

X is-C (R) ³ ) ₂ -、-NR ⁴ -, -O-or-S-;

each R ³ Independently hydrogen, deuterium, halogen, -CN, -NO ₂ 、-OH、-OR ^a 、-NR ^c R ^d 、-C(＝O)R ^a 、-C(＝O)OR ^b 、-C(＝O)NR ^c R ^d 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, cycloalkyl or heterocycloalkyl;

or two R ³ Together forming oxo;

R ⁴ is hydrogen, -C (=O) R ^a 、-C(＝O)OR ^b 、-C(＝O)NR ^c R ^d 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, cycloalkyl or heterocycloalkyl;

R ⁵ is hydrogen, deuterium, halogen, -CN, -NO ₂ 、-OH、-OR ^a 、-NR ^c R ^d 、-C(＝O)R ^a 、-C(＝O)OR ^b 、-C(＝O)NR ^c R ^d 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, cycloalkyl or heterocycloalkyl;

R ⁶ is hydrogen, deuterium, halogen, -CN, -NO ₂ 、-OH、-OR ^a 、-NR ^c R ^d 、-C(＝O)R ^a 、-C(＝O)OR ^b 、-C(＝O)NR ^c R ^d 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, cycloalkyl or heterocycloalkyl;

R ⁷ is hydrogen, deuterium, halogen, -CN, -NO ₂ 、-OH、-OR ^a 、-NR ^c R ^d 、-C(＝O)R ^a 、-C(＝O)OR ^b 、-C(＝O)NR ^c R ^d 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, cycloalkyl or heterocycloalkyl;

ring B is heterocycloalkyl or heteroaryl;

each R ^B Independently hydrogen, deuterium, halogen, -CN, -NO ₂ 、-OH、-OR ^a 、-OC(＝O)R ^a 、-OC(＝O)OR ^b 、-OC(＝O)NR ^c R ^d 、-SH、-SR ^a 、-S(＝O)R ^a 、-S(＝O) ₂ R ^a 、-S(＝O) ₂ NR ^c R ^d 、-NR ^c R ^d 、-NR ^b C(＝O)NR ^c R ^d 、-NR ^b C(＝O)R ^a 、-NR ^b C(＝O)OR ^b 、-NR ^b S(＝O) ₂ R ^a 、-C(＝O)R ^a 、-C(＝O)OR ^b 、-C(＝O)NR ^c R ^d 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently substituted with one or more R ^Ba Substitution;

or two R's on the same atom ^B Together forming 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 ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

or two R's on the same atom ^Ba Together forming oxo;

m is 0-4;

ring C is a 5 membered heteroaryl;

each R ^C Independently hydrogen, deuterium, halogen, -CN, -NO ₂ 、-OH、-OR ^a 、-OC(＝O)R ^a 、-OC(＝O)OR ^b 、-OC(＝O)NR ^c R ^d 、-SH、-SR ^a 、-S(＝O)R ^a 、-S(＝O) ₂ R ^a 、-S(＝O) ₂ NR ^c R ^d 、-S(＝O)(＝NR ^b )R ^a 、-SiR ^c R ^d OR ^b 、-NR ^c R ^d 、-NR ^b C(＝O)NR ^c R ^d 、-NR ^b C(＝O)R ^a 、-NR ^b C(＝O)OR ^b 、-NR ^b S(＝O) ₂ R ^a 、-C(＝O)R ^a 、-C(＝O)OR ^b 、-C(＝O)NR ^c R ^d 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (C) ₁ -C ₆ 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 substituted with one or more R ^Ca Substitution;

each R ^Ca 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 ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

or two R's on the same atom ^Ca Together forming oxo;

p is 0-4;

each R ^a Independently C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁ -C ₆ Alkyl (cycloalkyl), C ₁ -C ₆ Alkyl (heterocycloalkyl), C ₁ -C ₆ Alkyl (aryl) or C ₁ -C ₆ Alkyl (heteroaryl); wherein each alkyl, alkenyl, alkynyl,Cycloalkyl, heterocycloalkyl, aryl and heteroaryl are independently optionally substituted with 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 Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl or C ₁ -C ₆ Heteroalkyl substitution;

each R ^b Independently hydrogen, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁ -C ₆ Alkyl (cycloalkyl), C ₁ -C ₆ Alkyl (heterocycloalkyl), C ₁ -C ₆ Alkyl (aryl) or C ₁ -C ₆ Alkyl (heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with 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 Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl or C ₁ -C ₆ Heteroalkyl substitution; and is also provided with

Each R ^c And R is ^d Independently hydrogen, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁ -C ₆ Alkyl (cycloalkyl), C ₁ -C ₆ Alkyl (heterocycloalkyl), C ₁ -C ₆ Alkyl (aryl) or C ₁ -C ₆ Alkyl (heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with 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 Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl or C ₁ -C ₆ Heteroalkyl substitution;

or R is ^c And R is ^d Together with the atoms to which they are attached form a moiety optionally substituted with 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 Deuterated alkaneRadical, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl or C ₁ -C ₆ Heteroalkyl-substituted heterocycloalkyl;

Provided that the compound is not

Disclosed herein is a compound of formula (I), or a pharmaceutically acceptable salt, solvate, N-oxide or stereoisomer thereof:

wherein:

ring a is phenyl or heteroaryl;

each R ^A Independently hydrogen, deuterium, halogen, -CN, -NO ₂ 、-OH、-OR ^a 、-OC(＝O)R ^a 、-OC(＝O)OR ^b 、-OC(＝O)NR ^c R ^d 、-SH、-SR ^a 、-S(＝O)R ^a 、-S(＝O) ₂ R ^a 、-S(＝O) ₂ NR ^c R ^d 、-NR ^c R ^d 、-NR ^b C(＝O)NR ^c R ^d 、-NR ^b C(＝O)R ^a 、-NR ^b C(＝O)OR ^b 、-NR ^b S(＝O) ₂ R ^a 、-C(＝O)R ^a 、-C(＝O)OR ^b 、-C(＝O)NR ^c R ^d 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein said alkyl, alkenyl, alkynyl,Cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally and independently substituted with one or more R ^Aa Substitution;

or two R's on the same atom ^A Together forming oxo;

or two R's on the same atom ^Aa Together forming oxo;

n is 0-4;

Or R is ¹ And R is ² Together forming oxo;

x is-C (R) ³ ) ₂ -、-NR ⁴ -, -O-or-S-;

or two R ³ Together forming oxo;

z is N or CR ⁵ ；

Ring B is cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

each R ^B Independently hydrogen, deuterium, halogen, -CN, -NO ₂ 、-OH、-OR ^a 、-OC(＝O)R ^a 、-OC(＝O)OR ^b 、-OC(＝O)NR ^c R ^d 、-SH、-SR ^a 、-S(＝O)R ^a 、-S(＝O) ₂ R ^a 、-S(＝O) ₂ NR ^c R ^d 、-NR ^c R ^d 、-NR ^b C(＝O)NR ^c R ^d 、-NR ^b C(＝O)R ^a 、-NR ^b C(＝O)OR ^b 、-NR ^b S(＝O) ₂ R ^a 、-C(＝O)R ^a 、-C(＝O)OR ^b 、-C(＝O)NR ^c R ^d 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl compoundsRadical, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently substituted with one or more R ^Ba Substitution;

or two R's on the same atom ^B Together forming oxo;

or two R's on the same atom ^Ba Together forming oxo;

m is 0-4;

ring C is heterocycloalkyl or heteroaryl;

or two R's on the same atom ^C Together forming oxo;

each R ^Ca 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 ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl group、C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

or two R's on the same atom ^Ca Together forming oxo;

p is 0-4;

each R ^a Independently C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁ -C ₆ Alkyl (cycloalkyl), C ₁ -C ₆ Alkyl (heterocycloalkyl), C ₁ -C ₆ Alkyl (aryl) or C ₁ -C ₆ Alkyl (heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with 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 Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl or C ₁ -C ₆ Heteroalkyl substitution;

or R is ^c And R is ^d Together with the atoms to which they are attached form a moiety optionally substituted with 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 Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl or C ₁ -C ₆ Heteroalkyl-substituted heterocycloalkyl;

provided that it isNot->

Also disclosed herein is a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, and a pharmaceutically acceptable carrier.

Also disclosed herein is a method of treating a condition 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, a oncological disorder, and a cardiovascular or cerebrovascular disorder.

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.

Also disclosed herein is a method of treating an MK 2-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.

Incorporated 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

Definition of the definition

In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, it will be understood by those skilled in the art 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. Throughout the specification and the claims which follow, unless the context requires otherwise, the word "comprise" and variations such as "comprises" and "comprising" will be interpreted in an open, inclusive sense, i.e. as "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.

Reference throughout this specification to "some embodiments" or "one embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrase "in one embodiment" or "in an embodiment" appearing in various places throughout the specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Furthermore, 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 employed in its sense including "and/or" unless the content clearly dictates otherwise.

As used herein, the following terms have the following meanings, unless otherwise indicated:

"oxo" means =o.

"carboxy" refers to-COOH.

"alkyl" refers to a straight or branched saturated hydrocarbon monovalent radical having from one to about ten carbon atoms, more preferably from one to six 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-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-dimethyl-1-butyl, 3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl and hexyl, and longer alkyl groups such as heptyl, octyl, and the like. Whenever appearing herein, a numerical range such as "C ₁ -C ₆ Alkyl "or" C _1-6 Alkyl "means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, but the present definition also covers the occurrence of the term" alkyl "where no numerical range is specified. In some embodiments, alkyl is C _1-10 An alkyl group. In some embodiments, alkyl is C ₁ - ₆ An alkyl group. In some embodiments, alkyl is C _1-5 An alkyl group. In some embodiments, alkyl is C _1-4 An alkyl group. In some embodiments, alkyl is C _1-3 An alkyl group. Unless specifically indicated otherwise in the specification, alkyl groups may be optionally substituted, for example by oxo, halogen, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH ₂ or-NO ₂ And (3) substitution. In some embodiments, alkyl is optionally substituted with halogen, -CN, -OH, or-OMe. In some embodiments, the alkyl group is optionally substituted with halo.

"alkenyl" refers to a straight or branched hydrocarbon monovalent radical having one or more carbon-carbon double bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. The group may be in cis or trans conformation with respect to the double bond and should be understood to include both isomers. Examples include, but are not limited to, vinyl (-ch=ch) ₂ ) 1-propenyl (-CH) ₂ CH＝CH ₂ ) Isopropenyl [ -C (CH) ₃ )＝CH ₂ ]Butenyl, 1, 3-butadienyl, and the like. Whenever appearing herein, a numerical range such as "C ₂ -C ₆ Alkenyl "or" C _2-6 Alkenyl "means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, but the present definition also covers the occurrence of the term" alkenyl "where no numerical range is specified. Unless specifically indicated otherwise in the specification, alkenyl groups may be optionally substituted, for example by oxo, halogen, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkenyl is optionally oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH ₂ or-NO ₂ And (3) substitution. In some embodiments, alkenyl is optionally substituted with halogen, -CN, -OH, or-OMe. In some embodiments, alkenyl is optionally substituted with halo.

"alkynyl" refers to a straight or branched hydrocarbon monovalent radical having one or more carbon-carbon triple bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1, 3-butadiynyl, and the like. Whenever appearing herein, a numerical range such as "C ₂ -C ₆ Alkynyl "or" C _2-6 Alkynyl "means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, but the present definition also covers the occurrence of the term" alkynyl "where no numerical range is specified. Unless specifically indicated otherwise in the specification, alkynyl groups may be optionally substituted, for example by oxo, halogen, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkynyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH ₂ or-NO ₂ And (3) substitution. In some embodiments, alkynyl is optionally substituted with halogen, -CN, -OH, or-OMe. In some embodiments, alkynyl is optionally substituted with halo.

"alkylene" means a straight or branched divalent hydrocarbon chain. Unless specifically indicated otherwise in the specification, alkylene groups may be optionally substituted, for example by oxo, halogen, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkylene is optionally oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH ₂ or-NO ₂ And (3) substitution. In some embodiments, the alkylene is optionally substituted with halogen, -CN, -OH, or-OMe. In some embodiments, the alkylene is optionally substituted with halo.

"alkoxy" means-OR _a Wherein R is a group of _a Is an alkyl group as defined. Unless otherwise specifically indicated in the specification, alkoxy groups may be optionally substituted, e.g., by oxo, halogen, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, carboxyl, carboxylate, aryl,Cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH ₂ or-NO ₂ And (3) substitution. In some embodiments, the alkoxy group is optionally substituted with halogen, -CN, -OH, or-OMe. In some embodiments, the alkoxy group is optionally substituted with halogen.

"aryl" refers to a group derived from a hydrocarbon ring system containing 6 to 30 carbon atoms and at least one aromatic ring. Aryl groups may be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which may include fused ring systems (when fused to a cycloalkyl or heterocycloalkyl ring, aryl groups are bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6 to 10 membered aryl. In some embodiments, the aryl is a 6 membered aryl (phenyl). Aryl groups include, but are not limited to, those derived from anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, Aryl groups of hydrocarbon ring systems of fluoranthene, fluorene, asymmetric bisindene, symmetric bisindene, indane, indene, naphthalene, phenalene, phenanthrene, pyrene, and triphenylene. Unless specifically indicated otherwise in the specification, aryl groups may be optionally substituted, for example by halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, aryl is optionally substituted with halo, methyl, ethyl, -CN, -COOH, -COOMe, -CF ₃ 、-OH、-OMe、-NH ₂ or-NO ₂ And (3) substitution. In some embodiments, aryl is optionally substituted with halo, methyl, ethyl, -CN, -CF ₃ -OH or-OMe substitution. In some embodiments, aryl is optionally substituted with halo.

"cycloalkyl" refers to a partially or fully saturated monocyclic or polycyclic carbocycle which may include a fused ring system (cycloalkyl being bonded through a non-aromatic ring atom when fused to an aryl or heteroaryl ring) or a bridged ring system. In some embodiments, cycloalkyl groups are fully saturated. Representative cycloalkyl groups include, but are not limited to, having threeCycloalkyl of up to fifteen carbon atoms (C ₃ -C ₁₅ Cycloalkyl or C ₃ -C ₁₅ Cycloalkenyl), cycloalkyl having three to ten carbon atoms (C ₃ -C ₁₀ Cycloalkyl or C ₃ -C ₁₀ Cycloalkenyl), cycloalkyl having three to eight carbon atoms (C ₃ -C ₈ Cycloalkyl or C ₃ -C ₈ Cycloalkenyl), cycloalkyl having three to six carbon atoms (C ₃ -C ₆ Cycloalkyl or C ₃ -C ₆ Cycloalkenyl), cycloalkyl having three to five carbon atoms (C ₃ -C ₅ Cycloalkyl or C ₃ -C ₅ Cycloalkenyl) or cycloalkyl having three to four carbon atoms (C) ₃ -C ₄ Cycloalkyl or C ₃ -C ₄ Cycloalkenyl group). In some embodiments, cycloalkyl is 3-to 10-membered cycloalkyl or 3-to 10-membered cycloalkenyl. In some embodiments, cycloalkyl is 3-to 6-membered cycloalkyl or 3-to 6-membered cycloalkenyl. In some embodiments, cycloalkyl is 5-to 6-membered cycloalkyl or 5-to 6-membered cycloalkenyl. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups include, for example, adamantyl, norbornyl, decalinyl, bicyclo [3.3.0 ]]Octane, bicyclo [4.3.0 ]]Nonane, cis-decalin, trans-decalin, bicyclo [2.1.1]Hexane, bicyclo [2.2.1]Heptane, bicyclo [2.2.2]Octane, bicyclo [3.2.2]Nonane and bicyclo [3.3.2]Decane, and 7, 7-dimethyl-bicyclo [2.2.1]A heptyl group. Partially saturated cycloalkyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless specifically indicated otherwise in the specification, cycloalkyl groups may be optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxy, 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, -CF ₃ 、-OH、-OMe、-NH ₂ or-NO ₂ And (3) substitution. In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF ₃ -OH or-OMe substitution. In some casesIn embodiments, cycloalkyl is optionally substituted with halo.

"halo" or "halogen" refers to bromine, chlorine, fluorine, or iodine. In some embodiments, the halogen is fluorine or chlorine. In some embodiments, the halogen is fluorine.

"haloalkyl" refers to an alkyl group as defined above substituted with one or more halo groups as defined above, such as trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2-trifluoroethyl, 1, 2-difluoroethyl, 3-bromo-2-fluoropropyl, 1, 2-dibromoethyl and the like.

"hydroxyalkyl" refers to an alkyl group as defined above substituted with one or more hydroxyl groups. In some embodiments, the alkyl group is substituted with one hydroxy group. In some embodiments, the alkyl group is substituted with one, two, or three hydroxyl groups. Hydroxyalkyl groups include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl or hydroxypentyl. In some embodiments, the hydroxyalkyl group is hydroxymethyl.

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

"deuterated alkyl" refers to an alkyl group as defined above substituted with one or more deuterium. In some embodiments, the alkyl group is substituted with one deuterium. In some embodiments, the alkyl group is substituted with one, two, or three deuterium. In some embodiments, the alkyl group is substituted with one, two, three, four, five, or six deuterium. Deuterated alkyl groups include, for example, CD ₃ 、CH ₂ D、CHD ₂ 、CH ₂ CD ₃ 、CD ₂ CD ₃ 、CHDCD ₃ 、CH ₂ CH ₂ D or CH ₂ CHD ₂ . In some embodiments, the deuterated alkyl is CD ₃ 。

"heteroalkyl" refers to a compound wherein one or more backbone atoms of the alkyl are selected from atoms other than carbon (e.g., oxygen, nitrogen (e.g.,-NH-, -N (alkyl) -), sulfur, phosphorus, or a combination thereof). The heteroalkyl group is attached to the remainder of the molecule at a carbon atom of the heteroalkyl group. In one aspect, the heteroalkyl is C ₁ -C ₆ A heteroalkyl group, wherein the heteroalkyl group consists of 1 to 6 carbon atoms and one or more atoms other than carbon (e.g., oxygen, nitrogen (e.g., -NH-, -N (alkyl) -), sulfur, phosphorus, or a combination thereof), wherein the heteroalkyl group is attached to the remainder of the molecule at a carbon atom of the heteroalkyl group. Examples of such heteroalkyl groups are, for example, -CH ₂ OCH ₃ 、-CH ₂ CH ₂ OCH ₃ 、-CH ₂ CH ₂ OCH ₂ CH ₂ OCH ₃ 、-CH(CH ₃ )OCH ₃ 、-CH ₂ NHCH ₃ 、-CH ₂ N(CH ₃ ) ₂ 、-CH ₂ CH ₂ NHCH ₃ or-CH ₂ CH ₂ N(CH ₃ ) ₂ . Unless specifically indicated otherwise in the specification, heteroalkyl groups may be optionally substituted, e.g., with oxo, halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, heteroalkyl is optionally substituted with oxo, halo, methyl, ethyl, -CN, -CF ₃ 、-OH、-OMe、-NH ₂ or-NO ₂ And (3) substitution. In some embodiments, heteroalkyl is optionally substituted with oxo, halo, methyl, ethyl, -CN, -CF ₃ -OH or-OMe substitution. In some embodiments, the heteroalkyl is optionally substituted with halo.

"heterocycloalkyl" means a 3 to 24 membered partially or fully saturated cyclic group containing 2 to 23 carbon atoms and 1 to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus and sulfur. In some embodiments, the heterocycloalkyl group is fully saturated. In some embodiments, the heterocycloalkyl group comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl group comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl group comprises one to three nitrogens. In some embodiments, the heterocycloalkyl group contains one or two nitrogens. In some embodiments, the heterocycloalkyl group comprises one nitrogen. In some embodiments, the heterocycloalkyl group comprises one nitrogen and one oxygen. Unless specifically stated otherwise in the specification, heterocycloalkyl may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include a fused ring system (when fused to an aryl or heteroaryl ring, heterocycloalkyl is bonded through a non-aromatic ring atom) or a bridged ring system; and the nitrogen, carbon or sulfur atom in the heterocycloalkyl group may be optionally oxidized; the nitrogen atom may optionally be quaternized. Representative heterocycloalkyl groups include, but are not limited to, heterocycloalkyl groups having from two to fifteen carbon atoms (C ₂ -C ₁₅ Heterocycloalkyl or C ₂ -C ₁₅ Heterocycloalkenyl), heterocycloalkyl having two to ten carbon atoms (C) ₂ -C ₁₀ Heterocycloalkyl or C ₂ -C ₁₀ Heterocycloalkenyl), heterocycloalkyl having two to eight carbon atoms (C) ₂ -C ₈ Heterocycloalkyl or C ₂ -C ₈ Heterocycloalkenyl), heterocycloalkyl having two to seven carbon atoms (C) ₂ -C ₇ Heterocycloalkyl or C ₂ -C ₇ Heterocycloalkenyl), heterocycloalkyl having two to six carbon atoms (C) ₂ -C ₆ Heterocycloalkyl or C ₂ -C ₇ Heterocycloalkenyl), heterocycloalkyl having two to five carbon atoms (C) ₂ -C ₅ Heterocycloalkyl or C ₂ -C ₅ Heterocycloalkenyl) or heterocycloalkyl having two to four carbon atoms (C) ₂ -C ₄ Heterocycloalkyl or C ₂ -C ₄ Heterocycloalkenyl). Examples of such heterocycloalkyl groups include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl [1,3 ]]Dithianyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidinyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, 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 cyclic forms of carbohydrates including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. Unless otherwise indicated, heterocycloalkyl groups have 2 to 10 carbons in the ring. It is to be understood that when referring to the number of carbon atoms in the heterocycloalkyl group, the number of carbon atoms in the heterocycloalkyl group is different from the total number of atoms (including heteroatoms) constituting the heterocycloalkyl group (i.e., the backbone atoms of the heterocycloalkyl ring). In some embodiments, the heterocycloalkyl is a 3 to 8 membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3 to 7 membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3 to 6 membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4 to 6 membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5-to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-to 8-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3 to 7 membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3-to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4-to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5-to 6-membered heterocycloalkenyl. Unless specifically indicated otherwise in the specification, heterocycloalkyl groups may be optionally substituted as described below, for example by oxo, halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF ₃ 、-OH、-OMe、-NH ₂ or-NO ₂ And (3) substitution. In some embodiments, heterocycloalkyl is optionally substituted with halo, methyl, ethyl, -CN, -CF ₃ -OH or-OMe substitution. In some embodiments, the heterocycloalkyl group is optionally substituted with halo.

"heteroaryl" means a 5 to 14 membered ring system group comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus and sulfur, and at least one aromatic ring. In some embodiments, heteroaryl packagesContaining one to three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. In some embodiments, the heteroaryl group comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, heteroaryl groups comprise one to three nitrogens. In some embodiments, heteroaryl groups comprise one or two nitrogens. In some embodiments, the heteroaryl group comprises one nitrogen. Heteroaryl groups may be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which may include fused ring systems (heteroaryl groups are bonded through an aromatic ring atom when fused to a cycloalkyl or heterocycloalkyl ring) or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl group may optionally be oxidized; the nitrogen atom may optionally be quaternized. In some embodiments, the heteroaryl is a 5-to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5-to 6-membered heteroaryl. In some embodiments, the heteroaryl is a 6 membered heteroaryl. In some embodiments, the heteroaryl is a 5-membered heteroaryl. Examples include, but are not limited to, aza Group, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo [ b ]][1,4]Dioxepinyl, 1, 4-benzodioxanyl, benzonaphtofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothienyl), benzotriazole, benzo [4,6 ]]Imidazo [1,2-a]Pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxo-aza->Group, oxazolyl group, oxiranyl group, 1-pyridyl oxide group, 1-pyrimidyl oxide group, 1-pyrazinyl oxide group, 1-pyridazinyl oxide groupOxazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless specifically indicated otherwise in the specification, heteroaryl groups may be optionally substituted, for example by halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, heteroaryl is optionally substituted with halo, methyl, ethyl, -CN, -COOH, -COOMe, -CF ₃ 、-OH、-OMe、-NH ₂ or-NO ₂ And (3) substitution. In some embodiments, heteroaryl is optionally substituted with halo, methyl, ethyl, -CN, -CF ₃ -OH or-OMe substitution. In some embodiments, heteroaryl is optionally substituted with halo.

The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, "optionally substituted alkyl" refers to "alkyl" or "substituted alkyl" as defined above. In addition, the optionally substituted group may be unsubstituted (e.g., -CH ₂ CH ₃ ) Fully substituted (e.g. -CF) ₂ CF ₃ ) Monosubstituted (e.g. -CH ₂ CH ₂ F) Or substituted at any level between full substitution and single substitution (e.g., -CH ₂ CHF ₂ 、-CH ₂ CF ₃ 、-CF ₂ CH ₃ 、-CFHCHF ₂ Etc.). It will be understood by those skilled in the art that with respect to any group containing one or more substituents, such groups are not intended to introduce any substitution or pattern of substitution that is sterically impractical and/or synthetically infeasible (e.g., substituted alkyl groups include optionally substituted cycloalkyl groups, which in turn are defined to include optionally substituted alkyl groups, possibly unlimited). Because of Any substituents described herein are generally understood to have a maximum molecular weight of about 1,000 daltons, and more typically up to about 500 daltons.

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

"treatment" of an individual (e.g., a mammal, such as a human) or cell is any type of intervention that is used to attempt to alter the natural course of the individual or cell. In some embodiments, the treatment comprises administering the pharmaceutical composition after initiating a pathological event or contacting with a pathogen, and comprises stabilizing the condition (e.g., the condition does not worsen) or alleviating the condition.

"synergistic" or "synergistically" means that the effect of the combination is greater than the sum of the effects of each component alone at the same dosage.

As used herein, "a disease or disorder associated with MK 2" or optionally "an MK 2-mediated disease or disorder" means any disease or other deleterious condition in which MK2 or a mutant thereof is known or suspected to play a role.

As used herein, "a disease or disorder associated with a p38 MAP kinase" or "a p38 MAP kinase-mediated disease or disorder" means any disease or other deleterious condition in which a p38 MAP kinase or mutant thereof is known or suspected to play a role.

Compounds of formula (I)

Described herein are compounds of formulae (I) - (VIII), or pharmaceutically acceptable salts, solvates, N-oxides, or stereoisomers thereof, which are useful in the treatment of autoimmune disorders, chronic inflammatory disorders, acute inflammatory disorders, auto-inflammatory disorders, fibrotic disorders, metabolic disorders, oncological disorders, or cardiovascular or cerebrovascular disorders.

wherein:

ring a is phenyl or heteroaryl;

or two R's on the same atom ^A Together forming oxo;

Or two R's on the same atom ^Aa Together forming oxo;

n is 0-4;

or R is ¹ And R is ² Together forming oxo;

x is-C (R) ³ ) ₂ -、-NR ⁴ -, -O-or-S-;

or two R ³ Together forming oxo;

z is N or CR ⁵ ；

ring B is cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

or two R's on the same atom ^B Together forming oxo;

or two R's on the same atom ^Ba Together forming oxo;

m is 0-4;

ring C is heterocycloalkyl or heteroaryl;

each R ^C Independently hydrogen, deuterium, halogen, -CN, -NO ₂ 、-OH、-OR ^a 、-OC(＝O)R ^a 、-OC(＝O)OR ^b 、-OC(＝O)NR ^c R ^d 、-SH、-SR ^a 、-S(＝O)R ^a 、-S(＝O) ₂ R ^a 、-S(＝O) ₂ NR ^c R ^d 、-S(＝O)(＝NR ^b )R ^a 、-SiR ^c R ^d OR ^b 、-NR ^c R ^d 、-NR ^b C(＝O)NR ^c R ^d 、-NR ^b C(＝O)R ^a 、-NR ^b C(＝O)OR ^b 、-NR ^b S(＝O) ₂ R ^a 、-C(＝O)R ^a 、-C(＝O)OR ^b 、-C(＝O)NR ^c R ^d 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (C) ₁ -C ₆ Alkyl) cycloalkyl, (C ₁ -C ₆ Alkyl) heterogeniesCycloalkyl, (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 substituted with one or more R ^Ca Substitution;

or two R's on the same atom ^C Together forming oxo;

or two R's on the same atom ^Ca Together forming oxo;

p is 0-4;

each R ^a Independently C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁ -C ₆ Alkyl (cycloalkyl)Radical, C ₁ -C ₆ Alkyl (heterocycloalkyl), C ₁ -C ₆ Alkyl (aryl) or C ₁ -C ₆ Alkyl (heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with 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 Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl or C ₁ -C ₆ Heteroalkyl substitution;

each R ^b Independently hydrogen, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁ -C ₆ Alkyl (cycloalkyl), C ₁ -C ₆ Alkyl (heterocycloalkyl), C ₁ -C ₆ Alkyl (aryl) or C ₁ -C ₆ Alkyl (heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with 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 group、C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl or C ₁ -C ₆ Heteroalkyl substitution; and is also provided with

provided that it isNot->

In some embodiments of the compounds of formula (I), ring a is heteroaryl. In some embodiments of the compounds of formula (I), ring a is pyridinyl. In some embodiments of the compounds of formula (I), ring a is phenyl.

In some embodiments of the compounds of formula (I), each R ^A Is independently deuterium, halogen, -CN, -OH, -OR ^a 、-NR ^c R ^d 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl or C ₁ -C ₆ Deuterated alkyl. In some embodiments of the compounds of formula (I), each R ^A Independently halogen or C ₁ -C ₆ An alkyl group. In some embodiments of the compounds of formula (I), each R ^A Independently halogen.

In some embodiments of the compounds of formula (I), n is 1 or 2. In some embodiments of the compounds of formula (I), n is 1-3. In some embodiments of the compounds of formula (I), n is 2. In some embodiments of the compounds of formula (I), n is 1.

In some embodiments of the compounds of formula (I), R ¹ And R is ² Independently hydrogen, deuterium, halogen, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl or C ₁ -C ₆ Deuterated alkyl.In some embodiments of the compounds of formula (I), R ¹ And R is ² Independently hydrogen, deuterium, halogen or C ₁ -C ₆ An alkyl group. In some embodiments of the compounds of formula (I), R ¹ And R is ² Hydrogen or deuterium. In some embodiments of the compounds of formula (I), R ¹ And R is ² Is hydrogen.

In some embodiments of the compounds of formula (I), X is-O-. In some embodiments of the compounds of formula (I), Z is N. In some embodiments of the compounds of formula (I), Z is CR ⁵ 。

In some embodiments of the compounds of formula (I), R ⁵ Is hydrogen, deuterium, halogen, -CN, -OH, -OR ^a 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkynyl or cycloalkyl. In some embodiments of the compounds of formula (I), R ⁵ Is hydrogen, deuterium, halogen, -CN or C ₁ -C ₆ An alkyl group.

In some embodiments of the compounds of formula (I), R ⁶ Is hydrogen, deuterium, halogen, -CN, -OH, -OR ^a 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkynyl or cycloalkyl. In some embodiments of the compounds of formula (I), R ⁶ Is hydrogen, deuterium, halogen, -CN or C ₁ -C ₆ An alkyl group.

In some embodiments of the compounds of formula (I), ring B is phenyl. In some embodiments of the compounds of formula (I), ring B is a 5 membered heteroaryl. In some embodiments of the compounds of formula (I), ring B is 6 membered heteroaryl. In some embodiments of the compounds of formula (I), ring B is pyridinyl. In some embodiments of the compounds of formula (I), ring B is pyridone.

In the formula(I) In some embodiments of the compounds, each R ^B Is independently deuterium, halogen, -CN, -OH, -OR ^a 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₂ -C ₆ Alkynyl or cycloalkyl. In some embodiments of the compounds of formula (I), each R ^B Is independently deuterium, -CN, -OH, -OR ^a 、C ₂ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₂ -C ₆ Alkynyl or cycloalkyl. In some embodiments of the compounds of formula (I), each R ^B Independently halogen or C ₁ -C ₆ An alkyl group.

In some embodiments of the compounds of formula (I), m is 1 or 2. In some embodiments of the compounds of formula (I), m is 1-4. In some embodiments of the compounds of formula (I), m is 2-4. In some embodiments of the compounds of formula (I), m is 1. In some embodiments of the compounds of formula (I), m is 2.

In some embodiments of the compounds of formula (I),is->

In some embodiments of the compounds of formula (I),is->/> In some embodiments of the compounds of formula (I), the compound is->Is->

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.

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

In some embodiments of the compounds of formula (I), each R ^C Independently hydrogen, deuterium, halogen, -CN, -OH, -OR ^a 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl or C ₁ -C ₆ A heteroalkyl group. In some embodiments of the compounds of formula (I), each R ^C Independently C ₁ -C ₆ Hydroxyalkyl groups.

In some embodiments of the compounds of formula (I), p is 1 or 2. In some embodiments of the compounds of formula (I), p is 1. In some embodiments of the compounds of formula (I), p is 2.

Also disclosed herein is a compound of formula (II), or a pharmaceutically acceptable salt, solvate, N-oxide or stereoisomer thereof:

wherein:

ring a is phenyl or heteroaryl;

or two R's on the same atom ^A Together forming oxo;

or two R's on the same atom ^Aa Together forming oxo;

n is 0-4;

or R is ¹ And R is ² Together forming oxo;

x is-C (R) ³ ) ₂ -、-NR ⁴ -, -O-or-S-;

or two R ³ Together forming oxo;

ring B is heterocycloalkyl or heteroaryl;

each R ^B Independently hydrogen, deuterium, halogen, -CN, -NO ₂ 、-OH、-OR ^a 、-OC(＝O)R ^a 、-OC(＝O)OR ^b 、-OC(＝O)NR ^c R ^d 、-SH、-SR ^a 、-S(＝O)R ^a 、-S(＝O) ₂ R ^a 、-S(＝O) ₂ NR ^c R ^d 、-NR ^c R ^d 、-NR ^b C(＝O)NR ^c R ^d 、-NR ^b C(＝O)R ^a 、-NR ^b C(＝O)OR ^b 、-NR ^b S(＝O) ₂ R ^a 、-C(＝O)R ^a 、-C(＝O)OR ^b 、-C(＝O)NR ^c R ^d 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, cycloalkyl, heterocycloalkyl, aryl orHeteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently substituted with one or more R ^Ba Substitution;

or two R's on the same atom ^B Together forming oxo;

or two R's on the same atom ^Ba Together forming oxo;

m is 0-4;

ring C is a 5 membered heteroaryl;

or two on the same atomR is a number of ^Ca Together forming oxo;

p is 0-4;

provided that the compound is not

In some embodiments of the compounds of formula (II), ring a is heteroaryl. In some embodiments of the compounds of formula (II), ring a is pyridinyl. In some embodiments of the compounds of formula (II), ring a is phenyl.

In some embodiments of the compounds of formula (II), each R ^A Is independently deuterium, halogen, -CN, -OH, -OR ^a 、-NR ^c R ^d 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl or C ₁ -C ₆ Deuterated alkyl. In some embodiments of the compounds of formula (II), each R ^A Independently halogen or C ₁ -C ₆ An alkyl group. In some embodiments of the compounds of formula (II), each R ^A Independently halogen.

In some embodiments of the compounds of formula (II), n is 1 or 2. In some embodiments of the compounds of formula (II), n is 1-3. In some embodiments of the compounds of formula (II), n is 2. In some embodiments of the compounds of formula (II), n is 1.

In some embodiments of the compounds of formula (II), R ¹ And R is ² Independently hydrogen, deuterium, halogen, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl or C ₁ -C ₆ Deuterated alkyl. In some embodiments of the compounds of formula (II), R ¹ And R is ² Independently hydrogen, deuterium, halogen or C ₁ -C ₆ An alkyl group. In some embodiments of the compounds of formula (II), R ¹ And R is ² Independently hydrogen or deuterium. In some embodiments of the compounds of formula (II), R ¹ And R is ² Is hydrogen.

In some embodiments of the compounds of formula (II), X is-O-.

In some embodiments of the compounds of formula (II), R ⁵ Is hydrogen, deuterium, halogen, -CN, -OH, -OR ^a 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkynyl or cycloalkyl. In some embodiments of the compounds of formula (II), R ⁵ Is hydrogen, deuterium, halogen, -CN or C ₁ -C ₆ An alkyl group.

In some embodiments of the compounds of formula (II), R ⁶ Is hydrogen, deuterium, halogen, -CN, -OH, -OR ^a 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkynyl or cycloalkyl. In some embodiments of the compounds of formula (II), R ⁶ Is hydrogen, deuterium, halogen, -CN or C ₁ -C ₆ An alkyl group.

In some embodiments of the compounds of formula (II), R ⁷ Is hydrogen, deuterium, halogen, -CN, -OH, -OR ^a 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkynyl or cycloalkyl. In some embodiments of the compounds of formula (II), R ⁷ Is hydrogen, deuterium, halogen, -CN or C ₁ -C ₆ An alkyl group.

In some embodiments of the compounds of formula (II), ring B is 6 membered heteroaryl. In some embodiments of the compounds of formula (II), ring B is pyridinyl.

In some embodiments of the compounds of formula (II), each R ^B Independently hydrogen, deuterium, halogen, -CN, -OH, -OR ^a 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkynyl or cycloalkyl. In some embodiments of the compounds of formula (II), each R ^B Independently halogen or C ₁ -C ₆ An alkyl group. In some embodiments of the compounds of formula (II), each R ^B Independently C ₁ -C ₆ An alkyl group.

In some embodiments of the compounds of formula (II), m is 1 or 2. In some embodiments of the compounds of formula (II), m is 1-4. In some embodiments of the compounds of formula (II), m is 2-4. In some embodiments of the compounds of formula (II), m is 1. In some embodiments of the compounds of formula (II), m is 2.

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

In some embodiments of the compounds of formula (II), each R ^C Independently hydrogen, deuterium, halogen, -CN, -OH, -OR ^a 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl or C ₁ -C ₆ A heteroalkyl group. In some embodiments of the compounds of formula (II), each R ^C Independently C ₁ -C ₆ Hydroxyalkyl groups.

In some embodiments of the compounds of formula (II), p is 1 or 2. In some embodiments of the compounds of formula (II), p is 1-3. In some embodiments of the compounds of formula (II), p is 1. In some embodiments of the compounds of formula (II), p is 2.

Also disclosed herein is a compound of formula (III):

wherein:

ring a is phenyl or heteroaryl;

or two R's on the same atom ^A Together forming oxo;

or two R's on the same atom ^Aa Together forming oxo;

n is 0-4;

or R is ¹ And R is ² Together forming oxo;

x is-C (R) ³ ) ₂ -、-NR ⁴ -, -O-or-S-;

or two R ³ Together forming oxo;

R ⁴ is hydrogen, -C (=O) R ^a 、-C(＝O)OR ^b 、-C(＝O)NR ^c R ^d 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl group、C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, cycloalkyl or heterocycloalkyl;

ring D is cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

each R ^D Independently hydrogen, deuterium, halogen, -CN, -NO ₂ 、-OH、-OR ^a 、-OC(＝O)R ^a 、-OC(＝O)OR ^b 、-OC(＝O)NR ^c R ^d 、-SH、-SR ^a 、-S(＝O)R ^a 、-S(＝O) ₂ R ^a 、-S(＝O) ₂ NR ^c R ^d 、-NR ^c R ^d 、-NR ^b C(＝O)NR ^c R ^d 、-NR ^b C(＝O)R ^a 、-NR ^b C(＝O)OR ^b 、-NR ^b S(＝O) ₂ R ^a 、-C(＝O)R ^a 、-C(＝O)OR ^b 、-C(＝O)NR ^c R ^d 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently substituted with one or more R ^Da Substitution;

or two R's on the same atom ^D Together forming oxo;

each R ^Da 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 ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

or two R's on the same atom ^Da Together forming oxo;

q is 0-6;

R ⁹ is hydrogen, deuterium, halogen, -CN, -NO ₂ 、-OH、-OR ^a 、-NR ^c R ^d 、-C(＝O)R ^a 、-C(＝O)OR ^b 、-C(＝O)NR ^c R ^d 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, cycloalkyl or heterocycloalkyl;

R ¹⁰ is hydrogen, deuterium, halogen, -CN, -NO ₂ 、-OH、-OR ^a 、-NR ^c R ^d 、-C(＝O)R ^a 、-C(＝O)OR ^b 、-C(＝O)NR ^c R ^d 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, cycloalkyl or heterocycloalkyl;

R ¹¹ is hydrogen, deuterium, halogen, -CN, -NO ₂ 、-OH、-OR ^a 、-NR ^c R ^d 、-C(＝O)R ^a 、-C(＝O)OR ^b 、-C(＝O)NR ^c R ^d 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, cycloalkyl or heterocycloalkyl;

R ¹² is hydrogen, deuterium, halogen, -CN, -NO ₂ 、-OH、-OR ^a 、-OC(＝O)R ^a 、-OC(＝O)OR ^b 、-OC(＝O)NR ^c R ^d 、-SH、-SR ^a 、-S(＝O)R ^a 、-S(＝O) ₂ R ^a 、-S(＝O) ₂ NR ^c R ^d 、-S(＝O)(＝NR ^b )R ^a 、-SiR ^c R ^d OR ^b 、-NR ^c R ^d 、-NR ^b C(＝O)NR ^c R ^d 、-NR ^b C(＝O)R ^a 、-NR ^b C(＝O)OR ^b 、-NR ^b S(＝O) ₂ R ^a 、-C(＝O)R ^a 、-C(＝O)OR ^b 、-C(＝O)NR ^c R ^d 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (C) ₁ -C ₆ 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 substituted with one or more R ^12a Substitution;

each R ^12a 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 ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

or two R's on the same atom ^12a Together forming oxo;

R ¹³ is hydrogen, deuterium, halogen, -CN, -NO ₂ 、-OH、-OR ^a 、-NR ^c R ^d 、-C(＝O)R ^a 、-C(＝O)OR ^b 、-C(＝O)NR ^c R ^d 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, cycloalkyl or heterocycloalkyl;

R ¹⁴ is hydrogen, deuterium, halogen, -CN, -NO ₂ 、-OH、-OR ^a 、-NR ^c R ^d 、-C(＝O)R ^a 、-C(＝O)OR ^b 、-C(＝O)NR ^c R ^d 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, cycloalkyl or heterocycloalkyl;

each R ^b Independently hydrogen, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁ -C ₆ Alkyl (cycloalkyl), C ₁ -C ₆ Alkyl (heterocycloalkyl), C ₁ -C ₆ Alkyl (aryl) or C ₁ -C ₆ Alkyl (heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionallyIs substituted with 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 Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl or C ₁ -C ₆ Heteroalkyl substitution; and is also provided with

provided that it isNot->

In some embodiments of the compounds of formula (III), ring a is heteroaryl. In some embodiments of the compounds of formula (III), ring a is pyridinyl. In some embodiments of the compounds of formula (III), ring a is phenyl.

In some embodiments of the compounds of formula (III), each R ^A Is independently deuterium, halogen, -CN, -OH, -OR ^a 、-NR ^c R ^d 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl or C ₁ -C ₆ Deuterated alkyl. In some embodiments of the compounds of formula (III), each R ^A Independently halogen or C ₁ -C ₆ An alkyl group. In some embodiments of the compounds of formula (III), each R ^A Independently halogen.

In some embodiments of the compounds of formula (III), n is 1 or 2. In some embodiments of the compounds of formula (III), n is 1-3. In some embodiments of the compounds of formula (III), n is 2. In some embodiments of the compounds of formula (III), n is 1.

In some embodiments of the compounds of formula (III), R ¹ And R is ² Independently hydrogen, deuterium, halogen, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl or C ₁ -C ₆ Deuterated alkyl. In some embodiments of the compounds of formula (III), R ¹ And R is ² Independently hydrogen, deuterium, halogen or C ₁ -C ₆ An alkyl group. In some embodiments of the compounds of formula (III), R ¹ And R is ² Is hydrogen.

In some embodiments of the compounds of formula (III), X is-O-.

In some embodiments of the compounds of formula (III), ring D is phenyl. In some embodiments of the compounds of formula (III), ring D is pyridinyl.

In some embodiments of the compounds of formula (III), each R ^D Independently hydrogen, deuterium, halogen, -CN, -OH, -OR ^a 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkynyl, cycloalkyl or heterocycloalkyl; or two R's on the same atom ^D Together forming oxo. In some embodiments of the compounds of formula (III), each R ^D Independently hydrogen, deuterium, halogen, -CN, -OR ^a 、C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkynyl, cycloalkyl or heterocycloalkyl; or two R's on the same atom ^D Together forming oxo.

In some embodiments of the compounds of formula (III), q is 1-4. In some embodiments of the compounds of formula (III), q is 1-3. In some embodiments of the compounds of formula (III), q is 2-4.

In some embodiments of the compounds of formula (III)，Is->

In some embodiments of the compounds of formula (III), R ⁹ Is hydrogen, deuterium, halogen, C ₁ -C ₆ Alkyl or C ₁ -C ₆ A haloalkyl group.

In some embodiments of the compounds of formula (III), R ¹⁰ Is hydrogen, deuterium, halogen, C ₁ -C ₆ Alkyl or C ₁ -C ₆ A haloalkyl group.

In some embodiments of the compounds of formula (III), R ¹¹ Is hydrogen, deuterium, halogen, C ₁ -C ₆ Alkyl or C ₁ -C ₆ A haloalkyl group.

In some embodiments of the compounds of formula (III), R ¹² Is hydrogen, deuterium, halogen, -CN, -OH, -OR ^a 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl or C ₁ -C ₆ A heteroalkyl group. In some embodiments of the compounds of formula (III), R ¹² Is C ₁ -C ₆ Hydroxyalkyl groups.

In some embodiments of the compounds of formula (III), R ¹³ Is hydrogen, deuterium, halogen or C ₁ -C ₆ An alkyl group.

In some embodiments of the compounds of formula (III), R ¹⁴ Is hydrogen, deuterium, halogen or C ₁ -C ₆ An alkyl group.

A compound of formula (IV) or a pharmaceutically acceptable salt, solvate, N-oxide or stereoisomer thereof:

wherein:

ring a is phenyl or heteroaryl;

or two R's on the same atom ^A Together forming oxo;

or two R's on the same atom ^Aa Together forming oxo;

n is 0-4;

or R is ¹ And R is ² Together forming oxo;

or R is ¹ And R is ² Together forming cycloalkyl or heterocycloalkyl; wherein the cycloalkyl and heterocycloalkyl are optionally substituted with deuterium, halogen, -CN, -OH, -OCH ₃ 、-NH ₂ 、-NHCH ₃ 、-N(CH ₃ ) ₂ 、-C(＝O)CH ₃ 、-C(＝O)OH、-C(＝O)OCH ₃ 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl、C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl or C ₁ -C ₆ Heteroalkyl substitution;

x is-C (R) ³ ) ₂ -、-NR ⁴ -, -O-or-S-;

or two R ³ Together forming oxo;

R ⁶ is hydrogen, deuterium, halogen, -CN,-NO ₂ 、-OH、-OR ^a 、-NR ^c R ^d 、-C(＝O)R ^a 、-C(＝O)OR ^b 、-C(＝O)NR ^c R ^d 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, cycloalkyl or heterocycloalkyl;

ring B is cycloalkyl, heterocycloalkyl, alkyl or heteroaryl;

or two R's on the same atom ^B Together forming oxo;

or two R's on the same atom ^Ba Together forming oxo;

m is 0-4;

R ¹² 、R ¹³ and R is ¹⁴ The definition in (a), (b) or (c) is as follows:

(a)

R ¹² is deuterium, halogen, -CN, -NO ₂ 、-OH、-OR ^a 、-OC(＝O)R ^a 、-OC(＝O)OR ^b 、-OC(＝O)NR ^c R ^d 、-SH、-SR ^a 、-S(＝O)R ^a 、-S(＝O) ₂ R ^a 、-S(＝O) ₂ NR ^c R ^d 、-S(＝O)(＝NR ^b )R ^a 、-SiR ^c R ^d OR ^b 、-NR ^c R ^d 、-NR ^b C(＝O)NR ^c R ^d 、-NR ^b C(＝O)R ^a 、-NR ^b C(＝O)OR ^b 、-NR ^b S(＝O) ₂ R ^a 、-C(＝O)R ^a 、-C(＝O)OR ^b 、-C(＝O)NR ^c R ^d 、C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Dihydroxyalkyl, C ₁ -C ₆ Aminoalkyl radical,C ₁ -C ₆ Hydroxy heteroalkyl, C ₂ -C ₆ Alkenyl, 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 substituted with one or more R ^12a Substitution;

or two R's on the same atom ^12a Together forming oxo;

R ¹³ is hydrogen, deuterium, halogen, -CN, -NO ₂ 、-OH、-OR ^a 、-NR ^c R ^d 、-C(＝O)R ^a 、-C(＝O)OR ^b 、-C(＝O)NR ^c R ^d 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl group,C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, cycloalkyl or heterocycloalkyl;

or alternatively

(b)

R ¹² Is hydrogen, deuterium, halogen, -CN, -NO ₂ 、-OH、-OR ^a 、-NR ^c R ^d 、-C(＝O)R ^a 、-C(＝O)OR ^b 、-C(＝O)NR ^c R ^d 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, cycloalkyl or heterocycloalkyl;

R ¹³ is deuterium, halogen, -CN, -NO ₂ 、-OH、-OR ^a 、-NR ^c R ^d 、-C(＝O)R ^a 、-C(＝O)OR ^b 、-C(＝O)NR ^c R ^d 、C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, cycloalkyl or heterocycloalkyl;

or alternatively

(c)

R ¹⁴ Is deuterium, halogen, -CN, -NO ₂ 、-OH、-OR ^a 、-NR ^c R ^d 、-C(＝O)R ^a 、-C(＝O)OR ^b 、-C(＝O)NR ^c R ^d 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, cycloalkyl or heterocycloalkyl;

each R ^b Independently hydrogen, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, C ₁ -C ₆ Alkyl (cycloalkyl), C ₁ -C ₆ Alkyl (heterocycloalkyl), C ₁ -C ₆ Alkyl (aryl) or C ₁ -C ₆ Alkyl (heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with 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 Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl or C ₁ -C ₆ Heteroalkyl substitution; and is also provided with

or R is ^c And R is ^d Together with the atoms to which they are attached form a moiety optionally substituted with 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 Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl or C ₁ -C ₆ Heteroalkyl-substituted heterocycloalkyl.

In some embodiments of the compounds of formula (IV), ring a is heteroaryl. In some embodiments of the compounds of formula (IV), ring a is pyridinyl. In some embodiments of the compounds of formula (IV), ring a is phenyl.

In some embodiments of the compounds of formula (IV), each R ^A Is independently deuterium, halogen, -CN, -OH, -OR ^a 、-NR ^c R ^d 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl or C ₁ -C ₆ Deuterated alkyl. In some embodiments of the compounds of formula (IV), each R ^A Independently halogen or C ₁ -C ₆ An alkyl group. In some embodiments of the compounds of formula (IV), each R ^A Independently halogen.

In some embodiments of the compounds of formula (IV), n is 1 or 2. In some embodiments of the compounds of formula (IV), n is 1-3. In some embodiments of the compounds of formula (IV), n is 2. In some embodiments of the compounds of formula (IV), n is 1.

In some embodiments of the compounds of formula (IV), R ¹ And R is ² Independently hydrogen, deuterium, halogen, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl or C ₁ -C ₆ Deuterated alkyl. In some embodiments of the compounds of formula (IV), R ¹ And R is ² Independently hydrogen, deuterium, halogen or C ₁ -C ₆ An alkyl group. In some embodiments of the compounds of formula (IV), R ¹ And R is ² Is hydrogen.

In some embodiments of the compounds of formula (IV), X is-O-.

In some embodiments of the compounds of formula (IV), R ⁵ Is hydrogen, deuterium, halogen, -CN, -OH, -OR ^a 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkynyl or cycloalkyl. In some embodiments of the compounds of formula (IV), R ⁵ Is hydrogen, deuterium, halogen, -CN or C ₁ -C ₆ An alkyl group.

In some embodiments of the compounds of formula (IV), R ⁶ Is hydrogen, deuterium, halogen, -CN, -OH, -OR ^a 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkynyl or cycloalkyl. In some embodiments of the compounds of formula (IV), R ⁶ Is hydrogen, deuterium, halogen, -CN or C ₁ -C ₆ An alkyl group.

In some embodiments of the compounds of formula (IV), ring B is 6 membered heteroaryl. In some embodiments of the compounds of formula (IV), ring B is pyridinyl.

In some embodiments of the compounds of formula (IV), each R ^B Independently hydrogen, deuterium, or halogenElement, -CN, -OH, -OR ^a 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkynyl or cycloalkyl. In some embodiments of the compounds of formula (IV), each R ^B Independently hydrogen, deuterium, halogen, -CN, -OR ^a 、C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkynyl or cycloalkyl. In some embodiments of the compounds of formula (IV), each R ^B Independently C ₁ -C ₆ An alkyl group.

In some embodiments of the compounds of formula (IV), m is 1 or 2. In some embodiments of the compounds of formula (IV), m is 1-4. In some embodiments of the compounds of formula (IV), m is 2-4. In some embodiments of the compounds of formula (IV), m is 1. In some embodiments of the compounds of formula (IV), m is 2.

In some embodiments of the compounds of formula (IV):

R ¹² is deuterium, halogen, -CN, -OH, -OR ^a 、-S(＝O) ₂ NR ^c R ^d 、-S(＝O)(＝NR ^b )R ^a 、-SiR ^c R ^d OR ^b 、-NR ^b S(＝O) ₂ R ^a 、C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Dihydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Hydroxy heteroalkyl, C ₂ -C ₆ Alkynyl, cycloalkyl, heterocycloalkyl, (C) ₁ -C ₆ Alkyl) cycloalkyl or (C) ₁ -C ₆ Alkyl) heterocycloalkyl; wherein the alkyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally and independently substituted with one or more R ^12a Substitution;

each R ^12a Is independently deuterium, halogen, -CN, -OH, -OR ^a 、-NR ^c R ^d 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl or C ₁ -C ₆ A heteroalkyl group; or two R's on the same atom ^12a Together forming oxo;

R ¹³ is hydrogen, deuterium, halogen or C ₁ -C ₆ An alkyl group; and is also provided with

R ¹⁴ Is hydrogen, deuterium, halogen or C ₁ -C ₆ An alkyl group.

In some embodiments of the compounds of formula (IV):

R ¹² is-S (=o) (=nr ^b )R ^a 、-SiR ^c R ^d OR ^b 、-NR ^b S(＝O) ₂ R ^a 、C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Dihydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Hydroxy heteroalkyl, C ₂ -C ₆ Alkynyl, cycloalkyl, heterocycloalkyl or (C) ₁ -C ₆ Alkyl) cycloalkyl; wherein the alkyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally and independently substituted with one or more R ^12a Substitution;

each R ^12a Is independently-OH, -NR ^c R ^d Or C ₁ -C ₆ A haloalkyl group;

R ¹³ is hydrogen; and is also provided with

R ¹⁴ Is hydrogen.

In some embodiments of the compounds of formula (IV):

R ¹² Is C ₁ -C ₆ A hydroxyalkyl group;

R ¹³ is deuterium, halogen, -CN, -OH, -OR ^a 、-NR ^c R ^d 、C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkynyl, cycloalkyl or heterocycloalkyl; and is also provided with

R ¹⁴ Is hydrogen, deuterium, halogen or C ₁ -C ₆ An alkyl group.

In some embodiments of the compounds of formula (IV):

R ¹² is C ₁ -C ₆ A hydroxyalkyl group;

R ¹⁴ Is deuterium, halogen, -CN, -OH, -OR ^a 、-NR ^c R ^d 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkynyl, cycloalkyl or heterocycloalkyl.

Also disclosed herein is a compound of formula (V), or a pharmaceutically acceptable salt, solvate, N-oxide or stereoisomer thereof:

wherein:

ring a is phenyl or heteroaryl;

each R ^A Independently hydrogen, deuterium, halogen, -CN, -NO ₂ 、-OH、-OR ^a 、-OC(＝O)R ^a 、-OC(＝O)OR ^b 、-OC(＝O)NR ^c R ^d 、-SH、-SR ^a 、-S(＝O)R ^a 、-S(＝O) ₂ R ^a 、-S(＝O) ₂ NR ^c R ^d 、-NR ^c R ^d 、-NR ^b C(＝O)NR ^c R ^d 、-NR ^b C(＝O)R ^a 、-NR ^b C(＝O)OR ^b 、-NR ^b S(＝O) ₂ R ^a 、-C(＝O)R ^a 、-C(＝O)OR ^b 、-C(＝O)NR ^c R ^d 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl group、C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently substituted with one or more R ^Aa Substitution;

or two R's on the same atom ^A Together forming oxo;

or two R's on the same atom ^Aa Together forming oxo;

n is 0-4;

or R is ¹ And R is ² Together forming oxo;

x is-C (R) ³ ) ₂ -、-NR ⁴ -, -O-or-S-;

or two R ³ Together forming oxo;

R ⁸ is hydrogen, deuterium, halogen, -CN, -NO ₂ 、-OH、-OR ^a 、-NR ^c R ^d 、-C(＝O)R ^a 、-C(＝O)OR ^b 、-C(＝O)NR ^c R ^d 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, cycloalkyl or heterocycloalkyl;

ring B is pyridone, pyrimidinone, pyrazinone or pyridazinone;

or two R's on the same atom ^B Together forming oxo;

or two R's on the same atom ^Ba Together forming oxo;

m is 0-4;

ring C is heterocycloalkyl or heteroaryl;

or two R's on the same atom ^C Together forming oxo;

Or two R's on the same atom ^Ca Together forming oxo;

p is 0-4;

In some embodiments of the compounds of formula (V), ring a is heteroaryl.

In some embodiments of the compounds of formula (V), ring a is pyridinyl.

In some embodiments of the compounds of formula (V), ring a is phenyl.

In some embodiments of the compounds of formula (V), each R ^A Is independently deuterium, halogen, -CN, -OH, -OR ^a 、-NR ^c R ^d 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl or C ₁ -C ₆ Deuterated alkyl. In some embodiments of the compounds of formula (V), each R ^A Independently halogen or C ₁ -C ₆ An alkyl group. In some embodiments of the compounds of formula (V), each R ^A Independently halogen.

In some embodiments of the compounds of formula (V), n is 1 or 2. In some embodiments of the compounds of formula (V), n is 1-3. In some embodiments of the compounds of formula (V), n is 2. In some embodiments of the compounds of formula (V), n is 1.

In some embodiments of the compounds of formula (V), R ¹ And R is ² Independently hydrogen, deuterium, halogen, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl or C ₁ -C ₆ Deuterated alkyl. In some embodiments of the compounds of formula (V), R ¹ And R is ² Independently hydrogen, deuterium, halogen or C ₁ -C ₆ An alkyl group. In some embodiments of the compounds of formula (V), R ¹ And R is ² Is hydrogen.

In some embodiments of the compounds of formula (V), X is-O-.

In some embodiments of the compounds of formula (V), R ⁵ Is hydrogen, deuterium, halogen, -CN, -OH, -OR ^a 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkynyl or cycloalkyl. In some embodiments of the compounds of formula (V), R ⁵ Is hydrogen, deuterium, halogen, -CN or C ₁ -C ₆ An alkyl group.

In some embodiments of the compounds of formula (V), R ⁶ Is hydrogen, deuterium, halogen, -CN, -OH, -OR ^a 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkynyl or cycloalkyl. In some embodiments of the compounds of formula (V), R ⁶ Is hydrogen, deuterium, halogen, -CN or C ₁ -C ₆ An alkyl group.

In some embodiments of the compounds of formula (V), R ⁷ Is hydrogen, deuterium, halogen, -CN, -OH, -OR ^a 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkynyl or cycloalkyl. In some embodiments of the compounds of formula (V), R ⁷ Is hydrogen, deuterium, halogen, -CN or C ₁ -C ₆ An alkyl group.

In some embodiments of the compounds of formula (V), R ⁸ Is hydrogen, deuterium, halogen, -CN, -OH, -OR ^a 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkynyl or cycloalkyl. In some embodiments of the compounds of formula (V) are hydrogen, deuterium, halogen, -CN or C ₁ -C ₆ An alkyl group.

In some embodiments of the compounds of formula (V), ring B is pyridone. In some embodiments of the compounds of formula (V), ring B is pyrimidinone. In some embodiments of the compounds of formula (V), ring B is pyrazinone. In some embodiments of the compounds of formula (V), ring B is pyridazinone.

In some embodiments of the compounds of formula (V), each R ^B Independently hydrogen, deuterium, halogen, -CN, -OH, -OR ^a 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkynyl or cycloalkyl. In some embodiments of the compounds of formula (V), each R ^B Independently C ₁ -C ₆ An alkyl group.

In some embodiments of the compounds of formula (V),is->

In some embodiments of the compounds of formula (V), ring C is a 5 or 6 membered heteroaryl. In some embodiments of the compounds of formula (V), ring C is pyrimidinyl.

In some embodiments of the compounds of formula (V)Each R is ^C Independently hydrogen, deuterium, halogen, -CN, -OH, -OR ^a 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl or C ₁ -C ₆ A heteroalkyl group. In some embodiments of the compounds of formula (V), each R ^C Independently C ₁ -C ₆ Hydroxyalkyl groups.

In some embodiments of the compounds of formula (V), p is 1 or 2. In some embodiments of the compounds of formula (V), p is 1-3. In some embodiments of the compounds of formula (V), p is 1. In some embodiments of the compounds of formula (V), p is 2.

Also disclosed herein is a compound of formula (VI), or a pharmaceutically acceptable salt, solvate, N-oxide or stereoisomer thereof:

wherein:

ring a is phenyl or heteroaryl;

or two R's on the same atom ^A Together forming oxo;

or two R's on the same atom ^Aa Together forming oxo;

n is 0-4;

x and Y are defined as follows in (a) or (b):

(a)

x is-C (R) ³ ) ₂ -、-NR ⁴ -, -O-or-S-;

y is-CR ¹ R ² -；

R ¹ Is halogen, -CN, -NO ₂ 、-OH、-OR ^a 、-NR ^c R ^d 、-C(＝O)R ^a 、-C(＝O)OR ^b 、-C(＝O)NR ^c R ^d 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, cycloalkyl or heterocycloalkyl;

R ² is hydrogen, deuterium, halogen, -CN, -NO ₂ 、-OH、-OR ^a 、-NR ^c R ^d 、-C(＝O)R ^a 、-C(＝O)OR ^b 、-C(＝O)NR ^c R ^d 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, cycloalkyl or heterocycloalkyl;

or R is ¹ And R is ² Together forming oxo;

or two R ³ Together forming oxo; and is also provided with

or (b)

X is-C (R) ³ ) ₂ -、-NR ⁴ -or-S-;

y is-CR ¹ R ² -、-NR ⁴ -, -O-or-S-;

or R is ¹ And R is ² Together forming oxo;

or two R ³ Together forming oxo; and is also provided with

ring B is heterocycloalkyl or heteroaryl;

or two R's on the same atom ^B Together forming oxo;

Or two R's on the same atom ^Ba Together forming oxo;

m is 0-4;

ring C is heterocycloalkyl or heteroaryl;

or two R's on the same atom ^C Together forming oxo;

or two R's on the same atom ^Ca Together forming oxo;

p is 0-4;

provided that the compound is not:

in some embodiments of the compounds of formula (VI), ring a is heteroaryl. In some embodiments of the compounds of formula (VI), ring a is pyridinyl. In some embodiments of the compounds of formula (VI), ring a is phenyl.

In some embodiments of the compounds of formula (VI), each R ^A Is independently deuterium, halogen, -CN, -OH, -OR ^a 、-NR ^c R ^d 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl or C ₁ -C ₆ Deuterated alkyl. In some embodiments of the compounds of formula (VI), each R ^A Independently halogen or C ₁ -C ₆ An alkyl group. In some embodiments of the compounds of formula (VI), each R ^A Independently halogen.

In some embodiments of the compounds of formula (VI), n is 1 or 2. In some embodiments of the compounds of formula (VI), n is 1-3. In some embodiments of the compounds of formula (VI), n is 2. In some embodiments of the compounds of formula (VI), n is 1.

In some embodiments of the compounds of formula (VI):

x is-C (R) ³ ) ₂ -、-NR ⁴ -, -O-or-S-;

y is-CR ¹ R ² -；

or R is ¹ And R is ² Together forming oxo;

or two R ³ Together forming oxo; and is also provided with

R ⁴ Is hydrogen, -C (=O) R ^a 、-C(＝O)OR ^b 、-C(＝O)NR ^c R ^d 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, cycloalkyl or heterocycloalkyl.

In some embodiments of the compounds of formula (VI):

x is-C (R) ³ ) ₂ -、-NR ⁴ -, -O-or-S-;

y is-CR ¹ R ² -；

R ¹ Is halogen, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl or C ₁ -C ₆ Deuterated alkyl;

R ² is hydrogen, deuterium, halogen or C ₁ -C ₆ An alkyl group;

or R is ¹ And R is ² Together forming cycloalkyl or heterocycloalkyl;

each R ³ Independently hydrogen, deuterium, halogen, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl or C ₁ -C ₆ Deuterated alkyl;

R ⁴ is hydrogen or C ₁ -C ₆ An alkyl group.

In some embodiments of the compounds of formula (VI):

x is-C (R) ³ ) ₂ -、-NR ⁴ -or-S-;

y is-CR ¹ R ² -、-NR ⁴ -, -O-or-S-;

or R is ¹ And R is ² Together forming oxo;

each R ³ Independently hydrogen, deuterium, or halogen、-CN、-NO ₂ 、-OH、-OR ^a 、-NR ^c R ^d 、-C(＝O)R ^a 、-C(＝O)OR ^b 、-C(＝O)NR ^c R ^d 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, cycloalkyl or heterocycloalkyl;

or two R ³ Together forming oxo; and is also provided with

In some embodiments of the compounds of formula (VI):

x is-C (R) ³ ) ₂ -；

Y is-CR ¹ R ² -、-NR ⁴ -, -O-or-S-;

R ¹ and R is ² Independently hydrogen, deuterium, halogen, -OH, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl or C ₁ -C ₆ Deuterated alkyl;

or R is ¹ And R is ² Together forming oxo;

or R is ¹ And R is ² Together forming cycloalkyl or heterocycloalkyl;

each R ³ Independently hydrogen, deuterium, halogen, -OH, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl or C ₁ -C ₆ Deuterated alkyl;

or two R ³ Together formOxo; and is also provided with

R ⁴ Is hydrogen or C ₁ -C ₆ An alkyl group.

In some embodiments of the compounds of formula (VI):

x is-NR ⁴ -or-S-;

y is-CR ¹ R ² -；

R ¹ And R is ² Independently hydrogen, deuterium, halogen, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl or C ₁ -C ₆ Deuterated alkyl;

or R is ¹ And R is ² Together forming oxo;

or R is ¹ And R is ² Together forming cycloalkyl or heterocycloalkyl; and is also provided with

R ⁴ Is hydrogen or C ₁ -C ₆ An alkyl group.

In some embodiments of the compounds of formula (VI), R ⁵ Is hydrogen, deuterium, halogen, -CN, -OH, -OR ^a 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkynyl or cycloalkyl. In some embodiments of the compounds of formula (VI), R ⁵ Is hydrogen, deuterium, halogen, -CN or C ₁ -C ₆ An alkyl group.

In some embodiments of the compounds of formula (VI), R ⁶ Is hydrogen, deuterium, halogen, -CN, -OH, -OR ^a 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkynyl or cycloalkyl. In some embodiments of the compounds of formula (VI), R ⁶ Is hydrogen, deuterium, halogen, -CN or C ₁ -C ₆ An alkyl group.

In some embodiments of the compounds of formula (VI)In the scheme, R ⁷ Is hydrogen, deuterium, halogen, -CN, -OH, -OR ^a 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkynyl or cycloalkyl. In some embodiments of the compounds of formula (VI), R ⁷ Is hydrogen, deuterium, halogen, -CN or C ₁ -C ₆ An alkyl group.

In some embodiments of the compounds of formula (VI), ring B is 6 membered heteroaryl. In some embodiments of the compounds of formula (VI), ring B is pyridinyl.

In some embodiments of the compounds of formula (VI), each R ^B Independently hydrogen, deuterium, halogen, -CN, -OH, -OR ^a 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkynyl or cycloalkyl. In some embodiments of the compounds of formula (VI), each R ^B Independently C ₁ -C ₆ An alkyl group.

In some embodiments of the compounds of formula (VI), m is 1 or 2. In some embodiments of the compounds of formula (VI), m is 1-4. In some embodiments of the compounds of formula (VI), m is 2-4. In some embodiments of the compounds of formula (VI), m is 1. In some embodiments of the compounds of formula (VI), m is 2.

In some embodiments of the compounds of formula (VI), ring C is a 5 or 6 membered heteroaryl. In some embodiments of the compounds of formula (VI), ring C is pyrimidinyl.

In some embodiments of the compounds of formula (VI), each R ^C Independently hydrogen, deuterium, halogen, -CN, -OH, -OR ^a 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl or C ₁ -C ₆ A heteroalkyl group. In some embodiments of the compounds of formula (VI), each R ^C Independently C ₁ -C ₆ Hydroxyalkyl groups.

In some embodiments of the compounds of formula (VI), p is 1 or 2. In some embodiments of the compounds of formula (VI), p is 1-3. In some embodiments of the compounds of formula (VI), p is 1. In some embodiments of the compounds of formula (VI), p is 2.

Also disclosed herein is a compound of formula (VII):

wherein:

ring a is phenyl or heteroaryl;

or two R's on the same atom ^A Together forming oxo;

or two R's on the same atom ^Aa Together forming oxo;

n is 0-4;

or R is ¹ And R is ² Together forming oxo;

ring B is pyridinyl;

or two R's on the same atom ^Ba Together forming oxo;

m is 0-3;

ring D is a bicyclic ring;

each R ^D Independently hydrogen, deuterium, halogen, -CN, -NO ₂ 、-OH、-OR ^a 、-OC(＝O)R ^a 、-OC(＝O)OR ^b 、-OC(＝O)NR ^c R ^d 、-SH、-SR ^a 、-S(＝O)R ^a 、-S(＝O) ₂ R ^a 、-S(＝O) ₂ NR ^c R ^d 、-NR ^c R ^d 、-NR ^b C(＝O)NR ^c R ^d 、-NR ^b C(＝O)R ^a 、-NR ^b C(＝O)OR ^b 、-NR ^b S(＝O) ₂ R ^a 、-C(＝O)R ^a 、-C(＝O)OR ^b 、-C(＝O)NR ^c R ^d 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently substituted with one or more R ^Da Substitution;

or two R's on the same atom ^D Together forming oxo;

or two R's on the same atom ^Da Together forming oxo;

q is 0-6;

or two R's on the same atom ^12a Together forming oxo;

Each R ^c And R is ^d Independently hydrogen, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl group,C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁ -C ₆ Alkyl (cycloalkyl), C ₁ -C ₆ Alkyl (heterocycloalkyl), C ₁ -C ₆ Alkyl (aryl) or C ₁ -C ₆ Alkyl (heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with 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 Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl or C ₁ -C ₆ Heteroalkyl substitution;

In some embodiments of the compounds of formula (VII), ring a is heteroaryl. In some embodiments of the compounds of formula (VII), ring a is pyridinyl. In some embodiments of the compounds of formula (VII), ring a is phenyl.

In some embodiments of the compounds of formula (VII), each R ^A Is independently deuterium, halogen, -CN, -OH, -OR ^a 、-NR ^c R ^d 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl or C ₁ -C ₆ Deuterated alkyl. In some embodiments of the compounds of formula (I), each R ^A Independently halogen or C ₁ -C ₆ An alkyl group. In some embodiments of the compounds of formula (VII), each R ^A Independently halogen.

In some embodiments of the compounds of formula (VII), n is 1 or 2. In some embodiments of the compounds of formula (VII), n is 1-3. In some embodiments of the compounds of formula (VII), n is 2. In some embodiments of the compounds of formula (VII), n is 1.

In some embodiments of the compounds of formula (VII), R ¹ And R is ² Independently hydrogen, deuterium, halogen, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl or C ₁ -C ₆ Deuterated alkyl. In some embodiments of the compounds of formula (VII), R ¹ And R is ² Independently hydrogen, deuterium, halogen or C ₁ -C ₆ An alkyl group. In some embodiments of the compounds of formula (VII), R ¹ And R is ² Is hydrogen.

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

In some embodiments of the compounds of formula (VII), each R ^D Independently hydrogen, deuterium, halogen, -CN, -OH, -OR ^a 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkynyl or cycloalkyl; or two R's on the same atom ^D Together forming oxo. In some embodiments of the compounds of formula (VII), each R ^D Independently hydrogen, deuterium, halogen, -CN, -OR ^a 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₂ -C ₆ Alkynyl or cycloalkyl; or two R's on the same atom ^D Together forming oxo.

In some embodiments of the compounds of formula (VII), q is 1-4. In some embodiments of the compounds of formula (VII), q is 1-3. In some embodiments of the compounds of formula (VII), q is 2-4.

In some embodiments of the compounds of formula (VII),for (I)>

In some embodiments of the compounds of formula (VII), each R ^B Is independently deuterium, halogen, -CN, -OH, -OR ^a 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₂ -C ₆ Alkynyl or cycloalkyl. In some embodiments of the compounds of formula (VII), each R ^B Is independently deuterium, -CN, -OH, -OR ^a 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₂ -C ₆ Alkynyl or cycloalkyl. In some embodiments of the compounds of formula (VII), each R ^B Independently C ₁ -C ₆ An alkyl group.

In some embodiments of the compounds of formula (VII), m is 1 or 2. In some embodiments of the compounds of formula (VII), m is 1. In some embodiments of the compounds of formula (VII), m is 2.

In some embodiments of the compounds of formula (VII), R ¹² Is hydrogen, deuterium, halogen, -CN, -OH, -OR ^a 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl or C ₁ -C ₆ A heteroalkyl group. In some embodiments of the compounds of formula (VII), R ¹² Is C ₁ -C ₆ Hydroxyalkyl groups.

In some embodiments of the compounds of formula (VII), R ¹³ Is hydrogen, deuterium, halogen or C ₁ -C ₆ An alkyl group.

In some embodiments of the compounds of formula (VII), R ¹⁴ Is hydrogen, deuterium, halogen or C ₁ -C ₆ An alkyl group.

Also disclosed herein is a compound of formula (VIII):

wherein:

ring a is phenyl or heteroaryl;

or two R's on the same atom ^A Together forming oxo;

or two R's on the same atom ^Aa Together forming oxo;

n is 0-4;

or R is ¹ And R is ² Together forming oxo;

x is-C (R) ³ ) ₂ -、-NR ⁴ -, -O-or-S-;

each R ³ Independently hydrogen, deuterium, halogen, -CN, -NO ₂ 、-OH、-OR ^a 、-NR ^c R ^d 、-C(＝O)R ^a 、-C(＝O)OR ^b 、-C(＝O)NR ^c R ^d 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl radical,C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, cycloalkyl or heterocycloalkyl;

or two R ³ Together forming oxo;

ring B is cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

or two R's on the same atom ^B Together forming oxo;

or two R's on the same atom ^Ba Together forming oxo;

m is 0-4;

ring E is cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

each R ^E Independently hydrogen, deuterium, halogen, -CN, -NO ₂ 、-OH、-OR ^a 、-OC(＝O)R ^a 、-OC(＝O)OR ^b 、-OC(＝O)NR ^c R ^d 、-SH、-SR ^a 、-S(＝O)R ^a 、-S(＝O) ₂ R ^a 、-S(＝O) ₂ NR ^c R ^d 、-S(＝O)(＝NR ^b )R ^a 、-SiR ^c R ^d OR ^b 、-NR ^c R ^d 、-NR ^b C(＝O)NR ^c R ^d 、-NR ^b C(＝O)R ^a 、-NR ^b C(＝O)OR ^b 、-NR ^b S(＝O) ₂ R ^a 、-C(＝O)R ^a 、-C(＝O)OR ^b 、-C(＝O)NR ^c R ^d 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, cycloalkylHeterocyclyl, 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 substituted with one or more R ^Ea Substitution;

each R ^Ea 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 ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

or two R's on the same atom ^Ea Together forming oxo;

p is 0-4;

Each R ^c And R is ^d Independently hydrogen, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁ -C ₆ Alkyl (cycloalkyl), C ₁ -C ₆ Alkyl (heterocycloalkyl), C ₁ -C ₆ Alkyl (aryl) or C ₁ -C ₆ Alkyl (heteroaryl); each of which is provided withIndependently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH, or an alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group 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 Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl or C ₁ -C ₆ Heteroalkyl substitution;

In some embodiments of the compounds of formula (VIII), ring a is heteroaryl. In some embodiments of the compounds of formula (VIII), ring a is pyridinyl. In some embodiments of the compounds of formula (VIII), ring a is phenyl.

In some embodiments of the compounds of formula (VIII), each R ^A Is independently deuterium, halogen, -CN, -OH, -OR ^a 、-NR ^c R ^d 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl or C ₁ -C ₆ Deuterated alkyl. In some embodiments of the compounds of formula (VIII), each R ^A Independently halogen or C ₁ -C ₆ An alkyl group. In some embodiments of the compounds of formula (VIII), each R ^A Independently halogen.

In some embodiments of the compounds of formula (VIII), n is 1 or 2. In some embodiments of the compounds of formula (VIII), n is 1-3. In some embodiments of the compounds of formula (VIII), n is 2. In some embodiments of the compounds of formula (VIII), n is 1.

In some embodiments of the compounds of formula (VIII), R ¹ And R is ² Independently hydrogen, deuterium, halogen, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl or C ₁ -C ₆ Deuterated alkyl. In some embodiments of the compounds of formula (VIII), R ¹ And R is ² Independently hydrogen, deuterium, halogen or C ₁ -C ₆ An alkyl group. In some embodiments of the compounds of formula (VIII), R ¹ And R is ² Is hydrogen.

In some embodiments of the compounds of formula (VIII), X is-O-.

In some embodiments of the compounds of formula (VIII), R ⁵ Is hydrogen, deuterium, halogen, -CN, -OH, -OR ^a 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkynyl or cycloalkyl. In some embodiments of the compounds of formula (VIII), R ⁵ Is hydrogen, deuterium, halogen, -CN or C ₁ -C ₆ An alkyl group.

In some embodiments of the compounds of formula (VIII), R ⁶ Is hydrogen, deuterium, halogen, -CN, -OH, -OR ^a 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkynyl or cycloalkyl. In some embodiments of the compounds of formula (VIII), R ⁶ Is hydrogen, deuterium, halogen, -CN or C ₁ -C ₆ An alkyl group.

In some embodiments of the compounds of formula (VIII), R ⁷ Is hydrogen, deuterium, halogen, -CN, -OH, -OR ^a 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkynyl or cycloalkyl. In some embodiments of the compounds of formula (VIII), R ⁷ Is hydrogen, deuterium, halogen, -CN or C ₁ -C ₆ An alkyl group.

In some embodiments of the compounds of formula (VIII), ring B is 6 membered heteroaryl. In some embodiments of the compounds of formula (VIII), ring B is pyridinyl.

In some embodiments of the compounds of formula (VIII), each R ^B Independently hydrogen, deuterium, halogen, -CN, -OH, -OR ^a 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkynyl or cycloalkyl. In some embodiments of the compounds of formula (VIII), each R ^B Independently C ₁ -C ₆ An alkyl group.

In some embodiments of the compounds of formula (VIII), m is 1 or 2. In some embodiments of the compounds of formula (VIII), m is 1-4. In some embodiments of the compounds of formula (VIII), m is 2-4. In some embodiments of the compounds of formula (VIII), m is 1. In some embodiments of the compounds of formula (VIII), m is 2.

In some embodiments of the compounds of formula (VIII), ring E is cycloalkyl.

In some embodiments of the compounds of formula (VIII), each R ^E Independently hydrogen, deuterium, halogen, -CN, -OH、-OR ^a 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl or C ₁ -C ₆ A heteroalkyl group. In some embodiments of the compounds of formula (VIII), each R ^E independently-OH or C ₁ -C ₆ An alkyl group.

In some embodiments of the compounds of formula (VIII), p is 1 or 2. In some embodiments of the compounds of formula (VIII), p is 1 or 3. In some embodiments of the compounds of formula (VIII), p is 1. In some embodiments of the compounds of formula (VIII), p is 2.

In some embodiments of the compounds of formula (VIII), R ¹³ Is hydrogen, deuterium, halogen or C ₁ -C ₆ An alkyl group.

In some embodiments of the compounds of formula (VIII), R ¹⁴ Is hydrogen, deuterium, halogen or C ₁ -C ₆ An alkyl group.

In some embodiments of the compounds disclosed herein, each R ^a Independently C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with 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 Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Amino groupAlkyl, C ₁ -C ₆ Heteroalkyl substitution. In some embodiments of the compounds disclosed herein, each R ^a Independently C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, cycloalkyl or heterocycloalkyl; wherein each alkyl, cycloalkyl and heterocycloalkyl is independently optionally substituted with 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 Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl substitution. In some embodiments of the compounds disclosed herein, each R ^a Independently C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compounds disclosed herein, each R ^a Independently C ₁ -C ₆ Alkyl or C ₁ -C ₆ A haloalkyl group. In some embodiments of the compounds disclosed herein, each R ^a Independently C ₁ -C ₆ An alkyl group.

In some embodiments of the compounds disclosed herein, each R ^b Independently hydrogen, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with 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 Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl substitution. In some embodiments of the compounds disclosed herein, each R ^b Independently hydrogen, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, cycloalkyl or heterocycloalkyl; wherein each alkyl, cycloalkyl and heterocycloalkyl is independently optionally substituted with 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 Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl substitution. In some embodiments of the compounds disclosed herein, each R ^b Independently hydrogen, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compounds disclosed herein, each R ^b Independently hydrogen, C ₁ -C ₆ Alkyl or C ₁ -C ₆ A haloalkyl group. In some embodiments of the compounds disclosed herein, each R ^b Independently hydrogen or C ₁ -C ₆ An alkyl group.

In some embodiments of the compounds disclosed herein, each R ^c And R is ^d Independent and independentThe ground is hydrogen, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with 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 Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl substitution. In some embodiments of the compounds disclosed herein, each R ^c And R is ^d Independently hydrogen, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, cycloalkyl or heterocycloalkyl; wherein each alkyl, cycloalkyl and heterocycloalkyl is independently optionally substituted with 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 Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl substitution. In some embodiments of the compounds disclosed herein, each R ^c And R is ^d Independently isHydrogen, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compounds disclosed herein, each R ^c And R is ^d Independently hydrogen, C ₁ -C ₆ Alkyl or C ₁ -C ₆ A haloalkyl group. In some embodiments of the compounds disclosed herein, each R ^c And R is ^d Independently hydrogen or C ₁ -C ₆ An alkyl group.

In some embodiments of the compounds disclosed herein, R ^c And R is ^d Together with the atoms to which they are attached form a moiety optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH ₃ 、-NH ₂ 、-NHCH ₃ 、-N(CH ₃ ) ₂ 、-C(＝O)CH ₃ 、-C(＝O)OH、-C(＝O)OCH ₃ 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl or C ₁ -C ₆ Heteroalkyl-substituted heterocycloalkyl.

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 When R is ^c And R is ^d The heterocycloalkyl groups formed when taken together are independently substituted with one, two, three or four 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 When R is ^c And R is ^d The heterocycloalkyl groups formed when taken together are independently substituted with one, two or three substituents as defined herein. In some embodiments of the compounds disclosed herein, each R ^A 、R ^B 、R ^C 、R ^D 、R ^E 、R ¹² 、R ^a 、R ^b 、R ^c 、R ^d When R is ^c And R is ^d The heterocycloalkyl groups formed when taken together are independently substituted with one or two substituents as defined herein. In some embodiments of the compounds disclosed herein, each R ^A 、R ^B 、R ^C 、R ^D 、R ^E 、R ¹² 、R ^a 、R ^b 、R ^c 、R ^d When R is ^c And R is ^d The heterocycloalkyl groups formed when taken together are independently substituted with one substituent as defined herein.

Any combination of the above groups of various variables is contemplated herein. Throughout the specification, the groups and substituents thereof are chosen by the skilled person to provide stable moieties and compounds.

In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, is one of the compounds in table 1.

TABLE 1

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* Any given stereochemistry.

In some embodiments, the compound of formula (I) is selected from:

/>or a pharmaceutically acceptable salt, solvate, N-oxide or stereoisomer thereof.

In some embodiments, the compound of formula (II) is selected from: or a pharmaceutically acceptable salt, solvate, N-oxide or stereoisomer thereof.

In some embodiments, the compound of formula (III) is selected from:

/>

or a pharmaceutically acceptable salt, solvate, N-oxide or stereoisomer thereof.

In some embodiments, the compound of formula (IV) is selected from:

In some embodiments, the compound of formula (V) is selected from:

In some embodiments, the compound of formula (VI) is selected from:

/>

In some embodiments, the compound of formula (VII) is selected from:

Other forms of the compounds disclosed herein

Isomers/stereoisomers

In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds provided herein include all cis (cis), trans (trans), cis (syn), trans (anti), trans (entgegen) (E) and cis (zusammen) (Z) isomers and their corresponding mixtures. In some cases, the compounds described herein have one or more chiral centers, and each center exists in either the R configuration or the S configuration. The compounds described herein include all diastereomers, enantiomers and epimeric forms and their corresponding mixtures. In further embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereomers resulting from individual preparation steps, combinations, or interconversions may be used in the applications described herein. In some embodiments, the compounds described herein are prepared as individual stereoisomers thereof by reacting a racemic mixture of the compounds with an optically active resolving agent to form a pair of diastereomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, diastereomers have different physical properties (e.g., melting point, boiling point, solubility, reactivity, etc.), and are separated by taking advantage of these differences. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably by separation/resolution techniques based on solubility differences. In some embodiments, the optically pure enantiomer is then recovered along with the resolving agent by any practical means that does not result in racemization.

In some embodiments, the compounds described herein contain a rotation-hindered bond, such that two separate rotamers or atropisomers can be separated. In some embodiments, the atropisomer isWherein each a corresponds to a suitable R group as defined in each of formulas (I) to (VIII). In some embodiments, it may be advantageous to isolate these atropisomers and find them to have different biological activities. In some embodiments, the atropisomer is +.>In some embodiments, the atropisomer is +.>

Labeling compounds

In some embodiments, the compounds described herein are present 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, compounds disclosed herein include isotopically-labeled compounds, which are identical to those described herein, but for the replacement of one or more atoms by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of isotopes that can be incorporated into compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as respectively ² H、 ³ H、 ¹³ C、 ¹⁴ C、 ^l5 N、 ¹⁸ O、 ¹⁷ O、 ³¹ P、 ³² P、 ³⁵ S、 ¹⁸ F and F ³⁶ Cl. The compounds described herein, as well as pharmaceutically acceptable salts, solvates or stereoisomers thereof, containing the above-described isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds, for example, for incorporation of radioactive isotopes such as ³ H and ¹⁴ those of C, useful in drug and/or substrate tissue distribution assays. Tritiated (i.e., ³ h) And carbon-14 (i.e., ¹⁴ c) Isotopes because of their ease of preparation and detectability. In addition, the use of heavy isotopes such as deuterium (i.e., ² h) Substitution may result in certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements.

Pharmaceutically acceptable salts

In some embodiments, the compounds described herein are present in the form of pharmaceutically acceptable salts thereof. 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.

In some embodiments, the compounds described herein have acidic or basic groups and thus react with any of a variety 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 compound in its free form with a suitable acid or base and isolating the salt thus formed.

Examples of pharmaceutically acceptable salts include those prepared by reacting the compounds described herein with an inorganic, organic or inorganic base, such salts include acetates, acrylates, adipates, alginates, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyne-1, 4-dioate, camphoronate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, caprate, digluconate, dihydrogen phosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, glycolate, hemi-sulfate, heptanoate, caprate, hexyne-1, 6-dioate, hydroxybenzoate, gamma-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogen phosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, pamoate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, undecyl tosylate and xylene sulfonate.

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

In some embodiments, those compounds described herein that contain free acid groups are reacted with a suitable base (such as a hydroxide, carbonate, bicarbonate, sulfate of a pharmaceutically acceptable metal cation), with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include alkali metal salts or alkaline earth metal salts such as lithium, sodium, potassium, calcium, magnesium, and aluminum salts, and the like. Illustrative examples of the base include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N ⁺ (C _1-4 Alkyl group ₄ Etc.

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

Solvates of the formula

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

Solvates contain a stoichiometric or non-stoichiometric amount of solvent, and in some embodiments are formed with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water or alcoholates are formed when the solvent is an alcohol. Solvates of the compounds described herein may be conveniently prepared or formed during the processes described herein. Furthermore, the compounds provided herein may exist in unsolvated forms as well as solvated forms. In general, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein.

Tautomers

In some cases, the compounds exist in tautomeric forms. The compounds described herein include all possible tautomers within the formulae described herein. Tautomers are compounds that can be interconverted by migration of a hydrogen atom with the transition of a single bond and an adjacent double bond. In a bonding arrangement where tautomerism may occur, there will be a chemical equilibrium of the tautomers. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of tautomers depends on several factors, including temperature, solvent and pH.

Therapeutic method

Described herein are compounds and compositions that are generally useful for inhibiting 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 p38MAP kinase, MK2, or mutants thereof.

MAP kinase activated protein kinase 2 ("MK 2") is an enzyme encoded by the MAPKAPK2 gene in humans. The gene codes for a member of the Ser/Thr protein kinase family. The kinase is regulated by direct phosphorylation of p38MAP kinase. This kinase, together with the p38MAP kinase, is known to be involved in many cellular processes including stress and inflammatory responses, nuclear export, regulation of gene expression and cell proliferation. Heat shock protein HSP27 has been shown to be one of the in vivo substrates for this kinase. Two transcript variants of the gene have been found encoding two different isoforms.

MK2 is a multidomain protein consisting of an N-terminal proline rich domain, a catalytic domain, a self-inhibiting domain and a Nuclear Export Signal (NES) and a Nuclear Localization Signal (NLS) at the C-terminus. Two isoforms of human MK2 have been characterized. One isoform consists of 400 amino acids and the other isoform consists of 370 residues, which is considered a splice variant lacking the C-terminal NLS. MK2 is located in the nucleus and upon binding to and phosphorylation by p38, MK2 NES becomes functional and both kinases co-transport from the nucleus to the cytoplasm. Interestingly, transport of the MK2/p38 complex does not require catalytically active MK2, as the active site mutant Asp207Ala is still transported to the cytoplasm. It is believed that p38 phosphorylates human MK2 at residues T222, S272 and T334 activates the enzyme by inducing conformational changes in the self-inhibiting domain, thereby exposing the active site for substrate binding. Mutations in murine MK2 at two self-inhibiting domain residues W332A and K326E demonstrate an increase in basal activity, and deletion of the C-terminus of the self-inhibiting domain confers constitutive activity to the enzyme, providing additional evidence for the role of the domain in inhibiting MK2 activity.

Diseases or disorders associated with MK2 that are treated by the compounds disclosed herein include autoimmune disorders, chronic inflammatory disorders, acute inflammatory disorders, auto-inflammatory disorders, fibrotic disorders, metabolic disorders, oncological disorders, and cardiovascular or cerebrovascular disorders.

In some embodiments, the MK 2-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, cryptopyrene related periodic syndrome, mu Keer-Weiles syndrome, familial cold autoinflammatory syndrome, neonatal multiple system inflammatory disease, TNF receptor related periodic syndrome, acute and chronic pancreatitis, atherosclerosis, gout, ankylosing spondylitis, fibrotic disorders (e.g., liver fibrosis or idiopathic pulmonary fibrosis), kidney disease, sarcoidosis, scleroderma, allergies, diabetes (e.g., type 1 or type 2 diabetes), diabetic retinopathy, stell's disease, vasculitis, sarcoidosis, pulmonary inflammation, acute respiratory distress syndrome, wet and dry age-related macular degeneration, autoimmune hemolytic syndrome, autoimmune inflammatory hepatitis, autoimmune neuropathy, autoimmune ovarian failure, autoimmune orchitis, autoimmune thrombocytopenia, silica gel implant-related autoimmune diseases, sjogren's syndrome, familial mediterranean fever, systemic lupus erythematosus, vasculitis syndrome (e.g., temporal arteritis, high-an arteritis and giant cell arteritis, behcet's disease or Wegener's granulomatosis), vitiligo, secondary hematological manifestations of autoimmune diseases (e.g., anemia), drug-induced autoimmunity, thyroiditis, pituitary inflammation, idiopathic thrombocytopenic purpura, metal-induced autoimmunity, myasthenia gravis, vitiligo, pemphigus, autoimmune deafness (e.g., meniere's disease), goodpasture's syndrome, graves 'disease, HW-related autoimmune syndrome, grin-Bali's disease, edison's disease, antiphospholipid syndrome, asthma, atopic dermatitis, celiac disease, kurthia syndrome, dermatomyositis, idiopathic adrenal atrophy, idiopathic thrombocytopenia, kawasaki syndrome, lanbert-Eaton syndrome, pernicious anemia, pollinosis, polyarteritis nodosa, primary biliary cirrhosis, primary sclerosing cholangitis, raynaud's syndrome, leider's syndrome, recurrent polychondritis, schmidt's syndrome, thyrotoxicosis, sepsis, septic shock, endotoxic shock, toxic shock caused by exotoxins, gram negative sepsis, toxic shock syndrome, glomerulonephritis, peritonitis, interstitial inflammation caused by hypoxia, chronic Obstructive Pulmonary Disease (COPD), vasculitis, anti-host reaction (e.g., graft), graft versus host disease), allograft rejection (e.g., acute allograft rejection or chronic allograft rejection), early transplant rejection (e.g., acute allograft 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, enterocolitis, sinusitis, uveitis, ocular inflammation, optic neuritis, gastric ulcer, esophagitis, peritonitis, periodontitis, dermatomyositis, gastritis, myocarditis, inflammation of the brain, trauma, enterocolitis, sinusitis, uveitis, ocular inflammation, optic neuritis, gastric ulcer, esophagitis, peri-peritonitis, and inflammation of the brain, myositis, polymyalgia, pneumonia, bronchitis.

In some embodiments, the MK 2-mediated disease or disorder is a fibrotic disorder. Exemplary fibrotic conditions include systemic sclerosis/scleroderma, lupus nephritis, connective tissue disease, wound healing, surgical scarring, spinal cord injury, CNS scarring, acute lung injury, pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis or cystic fibrosis), chronic obstructive pulmonary disease, adult respiratory distress syndrome, acute lung injury, drug-induced lung injury, glomerulonephritis, chronic kidney disease (e.g., diabetic nephropathy), hypertension-induced kidney disease, gut or gastrointestinal fibrosis, kidney fibrosis, liver or gall bladder fibrosis, liver fibrosis (e.g., non-alcoholic steatohepatitis, hepatitis c, or hepatocellular carcinoma), liver cirrhosis (e.g., primary biliary cirrhosis or cirrhosis due to fatty liver disease (e.g., alcoholic and nonalcoholic steatosis), radiation-induced fibrosis (e.g., head-neck, gastrointestinal or pulmonary), primary sclerosing cholangitis, restenosis, cardiac fibrosis (e.g., endocardial myocardial fibrosis or atrial fibrosis), ocular scarring, fibrosis, fibrotic cancer, fibromas (fibroids), fibromas (fibromas), fibroadenomas, fibrosarcomas, graft arterial disease, keloids, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis, and nephrogenic systemic fibrosis.

In some embodiments, the MK 2-mediated disease or disorder is a metabolic disorder. Exemplary metabolic disorders include obesity, steroid resistance, glucose intolerance, and metabolic syndrome.

In some embodiments, the MK2 mediated disease or disorder is a neoplastic disease or disorder. Exemplary neoplastic diseases or disorders include cancer. In some embodiments, exemplary neoplastic diseases or conditions include angiogenic conditions, multiple myeloma, leukemia (e.g., acute lymphoblastic leukemia, acute and chronic myelogenous leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, or promyelocytic leukemia), lymphoma (e.g., B-cell lymphoma, T-cell lymphoma, mantle cell lymphoma, hairy cell lymphoma, burkitt's lymphoma, mast cell tumor, hodgkin's disease or non-hodgkin's disease), myelodysplastic syndrome, fibrosarcoma, rhabdomyosarcoma; astrocytomas, neuroblastomas, gliomas and schwannomas; melanoma, seminoma, teratocarcinoma, osteosarcoma, pigment xeroderma, keratoacanthoma, thyroid follicular carcinoma, kaposi's sarcoma, melanoma, teratoma, rhabdomyosarcoma, metastatic and bone disorders, as well as bone, oral/pharyngeal, esophageal, laryngeal, gastric, intestinal, colon, rectal, lung (e.g., non-small cell lung or small cell lung), liver, pancreatic, neural, brain (e.g., glioma or glioblastoma multiforme), head and neck, throat, ovarian, uterine, prostate, testicular, bladder, kidney, breast, gall bladder, cervical, thyroid, prostate and skin cancers.

In some embodiments, the MK 2-mediated disorder is a cardiovascular or cerebrovascular disorder. Exemplary cardiovascular disorders include atherosclerosis, restenosis in the coronary arteries, acute coronary syndrome, myocardial infarction, heart allograft vascular disease, and stroke. Exemplary cerebrovascular disorders include central nervous system disorders with inflammatory or apoptotic components, alzheimer's disease, parkinson's disease, huntington's disease, amyotrophic lateral sclerosis, spinal cord injury, neuronal ischemia, and peripheral neuropathy.

Administration of drugs

In certain embodiments, compositions containing the compounds described herein are administered for prophylactic and/or therapeutic treatment. In certain therapeutic applications, the composition is administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially inhibit at least one symptom of the disease or condition. The amount effective for such use will depend on the severity and course of the disease or condition, the previous treatment, the patient's health, weight and response to the drug, and the judgment of the treating physician. The therapeutically effective amount is optionally determined by methods including, but not limited to, up-dosing and/or dose-range clinical trials.

In prophylactic applications, compositions containing the compounds described herein are administered to patients susceptible to or otherwise at risk of a particular disease, disorder, or condition. Such an amount is defined as a "prophylactically effective amount or dose". In this use, the precise amount will also depend on the health, weight, etc. of the patient. When used in a patient, the effective amount for such use will depend on the severity and course of the disease, disorder or condition, previous treatments, the patient's health and response to the drug, and the judgment of the treating physician. In one aspect, prophylactic treatment comprises administering a pharmaceutical composition comprising 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 recurrence of symptoms of the disease or condition.

In certain embodiments where the condition of the patient is not improved, administration of the compound is chronically administered, i.e., for an extended period of time, including the entire duration of the patient's life, at the discretion of the physician, to ameliorate or otherwise control or limit the symptoms of the disease or condition in the patient.

In certain embodiments where the patient's condition does improve, the dosage of the administered drug is temporarily reduced or temporarily suspended for a period of time (i.e., a "drug holiday"). In specific embodiments, the length of the drug holiday is between 2 days and 1 year, including, for 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. For example, the dose reduction during drug holidays is only 10% -100%, including, for example, only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% and 100%.

Once the patient condition improves, a maintenance dose is administered as necessary. Subsequently, in specific embodiments, the dosage or frequency of administration, or both, is reduced to a level that maintains an improved disease, disorder, or condition as the symptoms change. However, in certain embodiments, the patient requires long-term intermittent or daily treatment after any recurrence of symptoms.

The amount of a given agent corresponding to such amount varies depending on factors such as the particular compound, the disease condition and its severity, the identity of the subject or host in need of treatment (e.g., body weight, sex), but is nevertheless determined based on the specifics surrounding the case, including, for example, the particular agent administered, the route of administration, the condition being treated, and the subject or host being treated.

However, generally, the dosage for adult treatment is generally in the range of 0.01mg to 5000mg per day. In one aspect, the dosage for adult treatment is from about 1mg to about 1000mg per day. In one embodiment, the desired dose is conveniently provided as a single dose or as divided doses administered simultaneously or at appropriate intervals, for example two, three, four or more sub-doses per day.

In one embodiment, a daily dosage of the compounds described herein, or pharmaceutically acceptable salts thereof, is from about 0.01mg/kg body weight to about 50mg/kg body weight. In some embodiments, the daily dose or the amount of active agent in the dosage form is below or above the ranges indicated herein, based on a number of variables relevant to the individual treatment regimen. In various embodiments, the daily dose and unit dose will vary depending upon a number of variables including, but not limited to, the activity of the compound used, the disease or condition to be treated, the mode of administration, the needs of the individual subject, the severity of the disease or condition to be treated, and the judgment of the physician.

Toxicity and therapeutic efficacy of such treatment regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including but not limited to LD ₁₀ And ED ₉₀ Is measured. The dose ratio between toxic effect and therapeutic effect is the therapeutic index, expressed as LD ₅₀ With ED ₅₀ The ratio between. In certain embodiments, the data obtained from cell culture assays and animal studies are used in formulating a range of therapeutically effective daily doses and/or a therapeutically effective unit dose for use in a mammal, including a human. In some embodiments, the daily dosage of a compound described herein is at least one dose including ED with minimal toxicity ₅₀ Within a circulating concentration range of (2). In certain embodiments, the daily dose range and/or unit dose varies within this range, depending on the dosage form employed and the route of administration employed.

In any of the foregoing aspects are further embodiments, wherein an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof: (a) systemic administration to a mammal; and/or (b) orally administering to the mammal; and/or (c) intravenously administering to the mammal; and/or (d) administering to the mammal by injection; and/or (e) topical administration to a mammal; and/or (f) non-systemic or topical administration to a mammal.

In any of the foregoing aspects are additional embodiments, including a single administration of an effective amount of a compound, including additional embodiments, wherein (i) the compound is administered once per day; or (ii) administering the compound to the mammal multiple times over the course of a day.

In any of the foregoing aspects are additional embodiments, including multiple administrations of an effective amount of the compound, including additional embodiments, wherein (i) the compound is administered continuously or intermittently: such as in a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) administering the compound to the mammal every 8 hours; (iv) administering the compound to the subject every 12 hours; (v) administering the compound to the subject every 24 hours. In additional or alternative embodiments, the method comprises a drug holiday, wherein administration of the compound is temporarily suspended or the dose of the administered compound is temporarily reduced; at the end of the drug holiday, administration of the compound is resumed. In one embodiment, the length of the drug holiday varies from 2 days to 1 year.

Route of administration

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, for example, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.

In certain embodiments, the compounds as described herein are administered in a local rather than systemic manner, e.g., by direct injection of the compounds into an organ, typically in the form of a depot formulation or sustained release formulation. In particular embodiments, the depot is administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Furthermore, in other embodiments, the drug is delivered in a targeted drug delivery system, for example in liposomes coated with organ specific antibodies. In such embodiments, the liposome targets and is selectively absorbed by the organ. In other embodiments, the compounds as described herein are provided in a quick release formulation, in an extended release formulation, or in an intermediate release formulation. In other embodiments, the compounds described herein are administered topically.

Pharmaceutical composition/formulation

The compounds described herein, alone or in combination with pharmaceutically acceptable carriers, excipients or diluents, are administered to a subject in need thereof in the form of a pharmaceutical composition according to standard pharmaceutical practice. In one embodiment, the compounds of the invention may be administered to an animal. These compounds may be administered orally or parenterally, including intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.

In another aspect, provided herein are pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, and at least one pharmaceutically acceptable excipient. Pharmaceutical compositions are formulated in conventional manner using one or more pharmaceutically acceptable excipients which facilitate processing of the active compound into a pharmaceutically acceptable formulation. The appropriate formulation depends on the route of administration selected. An overview of the pharmaceutical compositions described herein can be found, for example, in Remington: the Science and Practice of Pharmacy, nineteenth edition (Easton, pa.: mack Publishing Company, 1995); hoover, john e., remington's Pharmaceutical Sciences, mack Publishing co., easton, pennsylvania1975; liberman, h.a. and Lachman, l. Edit, pharmaceutical Dosage Forms, marcel Decker, new York, n.y.,1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, seventeenth edition (Lippincott Williams & Wilkins 1999), such disclosures being incorporated herein by reference.

In some embodiments, the pharmaceutically acceptable excipient is selected from the group consisting of carriers, binders, fillers, suspending agents, flavoring agents, sweeteners, disintegrants, dispersants, surfactants, lubricants, colorants, diluents, solubilizers, wetting agents, plasticizers, stabilizers, permeation enhancers, wetting agents, defoamers, antioxidants, preservatives, and any combination thereof.

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

Pharmaceutical compositions comprising the compounds described herein, or pharmaceutically acceptable salts, solvates, N-oxides, or stereoisomers thereof, are prepared in a conventional manner, such as, by way of example only, by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compressing processes.

Pharmaceutical compositions for oral use are obtained by: one or more solid excipients are mixed with one or more of the compounds described herein, the resulting mixture is optionally ground, and the mixture of granules is processed, if necessary, after adding suitable adjuvants, to obtain tablets or dragee cores. Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations, such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, microcrystalline cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose; or others such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If desired, disintegrating agents are added, such as crosslinked sodium carboxymethyl cellulose, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. In some embodiments, colorants or pigments are added to the tablet or dragee coating to identify or characterize different combinations of active compound doses.

Pharmaceutical compositions for oral administration include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Push-fit capsules contain the active ingredient in admixture with fillers (such as lactose), binders (such as starches) and/or lubricants (such as talc or magnesium stearate) and, optionally, stabilizers. In soft capsules, the active compounds are dissolved or suspended in a suitable liquid, such as fatty oils, liquid paraffin or liquid polyethylene glycols. In some embodiments, a stabilizer is added.

Pharmaceutical compositions for parenteral use are formulated as infusions or injections. In some embodiments, pharmaceutical compositions suitable for injection or infusion include sterile aqueous solutions, dispersions, or sterile powders comprising 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, and the like), vegetable oils, non-toxic glycerides, and any combination thereof. In some embodiments, the pharmaceutical composition further comprises a preservative to prevent microbial growth.

Combination of two or more kinds of materials

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

In some embodiments, the additional therapeutic agent is selected from the group consisting of an anti-inflammatory agent, an anti-atherosclerosis agent, an immunosuppressant, an immunomodulatory agent, a cytostatic agent, an antiproliferative agent, an angiogenesis inhibitor, a kinase inhibitor, a cytokine blocker, and an inhibitor of a cell adhesion molecule.

In some embodiments, the additional therapeutic agent is selected from the group consisting of NSAIDs, immunosuppressants, immunomodulatory agents, cytostatic agents, antiproliferatives, angiogenesis inhibitors, biopharmaceuticals, steroids, vitamin D3 analogues, 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 tolnaproxen, aspirin, niacin, HMG CoA reductase inhibitors (e.g., atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin), colesevelam, colestipol, gemfibrozil, probucol, and antomine.

In some embodiments, the additional therapeutic agent is selected from the group consisting of corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs) (e.g., ibuprofen, naproxen, acetaminophen, aspirin, fenoprofen (Nalfon), flurbiprofen (asaid), ketoprofen, oxaprozin (Daypro), sodium diclofenac (Voltaren), potassium diclofenac (Cataflam), etodolac (Lodine), indomethacin (Indocin), ketorolac (Toradol), sulindac (Clinoril), tolmetin (Tolectin), meclofenamic acid (Meclomen), mefenamic acid (Ponstel), nabumetone (relfen), piroxicam (Feldene), cox-2 inhibitors (e.g., celecoxib (Celebrex)), immunosuppressives (e.g., methotrexate (Rheumatrex), leflunomide (Arava), azathioprine (imura), cyclosporin (Neoral, sandimmune), tacrolimus and cyclophosphamide (Cytoxan), CD20 blockers (Rituximab), tumor Necrosis Factor (TNF) blockers (e.g., etanercept (Enbrel), infliximab (Remicade) and adalimumab (Humira)), abapple (CTLA 4-Ig) and interleukin 1 receptor antagonists (e.g., anakinret), interleukin 6 inhibitors (e.g., acteba), interleukin 17 inhibitors (e.g., AIN 457), janus kinase inhibitors (e.g., tofacitinib), syk inhibitors (e.g., R788) and chloroquine and derivatives thereof.

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-VEGFR 2 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- β inhibitor, a KIT inhibitor, a Flt3 tyrosine kinase inhibitor, a PDGF receptor family inhibitor, a Flt3 tyrosine kinase inhibitor, a RET tyrosine kinase receptor family inhibitor, a VEGF-3 receptor antagonist, a Raf protein kinase family inhibitor, an angiogenesis inhibitor, an Erb2 inhibitor, an mTOR inhibitor, an IGF-1R antibody, a NFkB inhibitor, a proteasome inhibitor, a chemotherapeutic agent, and a glucose lowering agent.

In some embodiments, the additional therapeutic agent is administered concurrently with the compounds 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 compounds disclosed herein. In some embodiments, the additional therapeutic agent is administered more frequently than the compounds disclosed herein. In some embodiments, the additional therapeutic agent is administered prior to administration of the compounds disclosed herein. In some embodiments, the additional therapeutic agent is administered after administration of the compounds disclosed herein.

Examples

Intermediates 1, 2, 3

Step 1: preparation of ethyl 3, 5-difluoropicolinate：

A solution of 3, 5-difluoropyridine-2-carboxylic acid (50.00 g,314.28mmol,1.00 eq.) in ethanol (200 ml) was cooled using an ice bath followed by dropwise addition of SOCl at 0deg.C ₂ (50 mL,689.25mmol,2.20 eq.). The resulting mixture was stirred under nitrogen at 60 ℃ for 3 hours. The reaction was monitored by LCMS. The mixture was brought to room temperature. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography to give ethyl 3, 5-difluoropicolinate (59 g, 100%) as a colorless liquid. LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝188.1。

Step 2: preparation of (3, 5-difluoropyridin-2-yl) methanol：

To a stirred solution of ethyl 3, 5-difluoropyridine-2-carboxylate (40.00 g,213.74mmol,1.00 eq.) in ethanol (300 ml) under nitrogen atmosphere at 0℃was added NaBH in portions ₄ (20.22 g,534.34mmol,2.50 eq.). The resulting mixture was stirred at 0 ℃ under nitrogen atmosphere for 30 minutes. The resulting mixture was stirred at room temperature under nitrogen for 2 hours. The reaction was monitored by LCMS.With saturated NH ₄ The reaction was quenched with Cl (aqueous solution) at 0 ℃. EtOH was removed under reduced pressure. The aqueous layer was basified to pH 10 with saturated Na2CO3 (aqueous solution, 300 mL) followed by extraction with EtOAc (3×300 mL). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated in vacuo to give (3, 5-difluoropyridin-2-yl) methanol (26.6 g, 85.76%) as a colorless liquid. LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝146.1。

Step 3: preparation of 2- (chloromethyl) -3, 5-difluoropyridine：

To a stirred solution of (3, 5-difluoropyridin-2-yl) methanol (34.00 g,234.31mmol,1.00 eq.) in DCM (500 ml) was added DMF (160 mg) and then cooled using an ice-water bath. SOCl was added dropwise to the above mixture under nitrogen atmosphere ₂ (40 mL,551.40mmol,2.35 eq.). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated in vacuo to give 2- (chloromethyl) -3, 5-difluoropyridine (34.75 g, 90.68%) as a tan semisolid. LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝164.0。 ¹ H NMR (400 MHz, chloroform-d) δ8.35 (d, 1H), 7.28 (td, 1H), 4.73 (d, 2H).

Intermediate 4-7

Step 1: preparation of 2, 2-dimethyl-6- (2-oxopropyl) -1, 3-dioxin-4-one：

A solution of LiHMDS (3.16L, 3.16mol,1.50 eq., 1M in THF) in THF (1000 mL) was treated with 2, 6-trimethyl-1, 3-dioxan-4-one (300 g,2.11mol,1.00 eq.) under nitrogen at-20deg.C for 1 hour followed by dropwise addition of ZnEt at-20deg.C over 2 hours ₂ (3.16L, 3.16mol,1.50 eq., 1M in hexane). The resulting mixture was stirred at-20 ℃ for 30 minutes under nitrogen atmosphere. To the above mixture was added acetylimidazole (348.58 g,3.16mol,1.50 eq.) at-10 ℃. The resulting mixture was stirred at room temperature overnight. Monitoring of the reaction by LCMS Should be. The reaction was quenched by the addition of 1L of water/THF (1:1) at-10 ℃. The mixture was acidified to pH 1-2 with 2MHCl (aq). The resulting mixture was extracted with EtOAc (3X 5L). The combined organic layers were washed with brine (3X 5L), dried over anhydrous Na ₂ SO ₄ And (5) drying. 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-d ₆ )δ5.35(s,1H),3.35(s,2H),2.25(s,3H),1.72(d,6H)。

Step 2: preparation of 2' -chloro-4-hydroxy-5 ', 6-dimethyl- [1,4' -bipyridine]-2-one：

A solution of 2, 2-dimethyl-6- (2-oxopropyl) -1, 3-dioxin-4-one (200.00 g,1.08mol,1.00 eq.) and 2-chloro-5-methylpyridin-4-amine (154.83 g,1.08mol,1.00 eq.) in dioxane (2000 mL) was stirred under nitrogen at 90℃for 3.5 hours. The mixture was cooled to room temperature. The reaction was monitored by LCMS. Dropwise adding H into the mixture ₂ SO ₄ (60 mL,1.12mol,1.05 eq.). The resulting mixture was stirred at 90℃for a further 1 hour. The mixture was cooled to room temperature. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. H was added to the resulting mixture ₂ O (1000 mL) and stirred for 30 minutes. The precipitated solid was collected by filtration and taken up in Et ₂ O (3X 50 mL) was washed. This gives 2' -chloro-4-hydroxy-5 ', 6-dimethyl- [1,4' -bipyridine as a yellow solid]-2-one (150 g, 55.11%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝251.0。 ¹ H NMR(300MHz,DMSO-d ₆ )δ10.82(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)。

Step 3: preparation of 2' -chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy) -5', 6-dimethyl-2H- [1,4' -biphenylene Pyridine compound]-2-one：

To 2' -chloro-4-hydroxy-5 ', 6-dimethyl- [1,4' -bipyridine]-2-one (20.00 g,79.78mmol,1.00 eq.), 2- (chloromethyl) -3, 5-difluoropyridine (15.66 g,95.74mmol,1.20 eq.), K ₂ CO ₃ (33.08g，239.35mmol，3.00An equivalent) and 18-crown-6 (2.11 g,7.98mmol,0.10 equivalent) in DMF (50 ml). The resulting mixture was stirred under nitrogen at 60 ℃ for 3 hours. The reaction was monitored by LCMS. The residue was dissolved in EA (1500 mL). The organic layer was washed with water (3X 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 as a yellow solid]-5', 6-dimethyl- [1,4' -bipyridine]-2-one (23 g, 76.3%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝378.0。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.59(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)。

Step 4: preparation of 2', 3-dichloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]5', 6-dimethyl- [1,4' ] and bipyridine (P)]-2-one：

To 2' -chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy at room temperature under a nitrogen atmosphere ]-5', 6-dimethyl- [1,4' -bipyridine]To a stirred solution of 2-ketone (1.00 g,2.65mmol,1.00 eq.) and NCS (0.37 g,2.78mmol,1.05 eq.) in ACN (25 mL) was added dropwise 2, 2-dichloroacetic acid (0.17 g,1.32mmol,0.50 eq.). The resulting mixture was stirred under nitrogen at 60 ℃ 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 2X 100mL of water and brine (100 mL), over anhydrous Na ₂ SO ₄ And (5) drying. 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 as a yellow solid]-5', 6-dimethyl- [1,4' -bipyridine]2-Ketone (901 mg, 82.57%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝411.9。

Intermediate 8-10

Step 1: preparation of 2' -bromo-4-hydroxy-5 ', 6-dimethyl- [1,4' -bipyridine]-2-one：

A mixture of 2, 2-dimethyl-6- (2-oxopropyl) -1, 3-dioxin-4-one (22.16 g, 120.292 mmol,1.5 eq.) and 2-bromo-5-methylpyridin-4-amine (15 g,80.197mmol,1.00 eq.) in 1, 4-dioxane (200 mL) was stirred at 90℃for 2 hours, H was added dropwise to the above mixture at room temperature under an air atmosphere ₂ SO ₄ (7.87 g,80.197mmol,1 eq.). The resulting mixture was stirred at 90℃for a further 1 hour. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. H was added to the resulting mixture ₂ O (40 mL) and the slurry was stirred for 10 min. The precipitated solid was collected by filtration and taken up in Et ₂ O (3X 10 mL) and then dried in vacuo to give 2' -bromo-4-hydroxy-5 ', 6-dimethyl- [1,4' -bipyridine as a yellow solid]2-Ketone (22.7 g, crude). The crude mixture was used directly in the next step without further purification. LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝294.9。

Step 2:2' -chloro-4- [ (4-methoxyphenyl) methoxy group]-5', 6-dimethyl- [1,4' -bipyridine]-2-one：

To 2' -bromo-4-hydroxy-5 ', 6-dimethyl- [1,4' -bipyridine at room temperature under nitrogen atmosphere]To a stirred mixture of 2-ketone (42.00 g,142.307mmol,1 eq.) and 2- (chloromethyl) -3, 5-difluoropyridine (46.55 g,284.614mmol,2 eq.) in DMF (450 mL) was added K ₂ CO ₃ (98.34 g, 711.53mmol, 5.00 eq.) and 18-crown-6 (3.76 g,14.231mmol,0.10 eq.). The resulting mixture was stirred under nitrogen at 60 ℃ for 2 hours. The reaction was monitored by LCMS. The desired product was detectable 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 with Na ₂ SO ₄ And (5) drying. 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 as a yellow oil ]-5', 6-dimethyl- [1,4' -bipyridine]-2-one (48.5 g, 80.72%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝424.0。

Step 3: preparation of 2' -bromo-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]5', 6-dimethyl- [1,4' ] and bipyridine (P)]-2-one：

To 2' -bromo-4- [ (3, 5-difluoropyridin-2-yl) methoxy at room temperature under a nitrogen atmosphere]-5', 6-dimethyl- [1,4' -bipyridine]To a stirred mixture of 2-ketone (12 g, 28.426 mmol,1 eq.) and NCS (3.79 g, 28.426 mmol,1 eq.) in 2-propanol (21 mL) was added dropwise 2, 2-dichloroacetic acid (1.2 mL,2.870mmol,0.10 eq.). The resulting mixture was stirred under nitrogen at 60 ℃ for 2 hours. The reaction was monitored by LCMS. The desired product was detectable 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 as a white solid]-5', 6-dimethyl- [1,4' -bipyridine]-2-one (7.40 g, 57.02%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝457.9。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.60(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 to 16

Step 1:2' -chloro-4- [ (4-methoxyphenyl) methoxy group]-5', 6-dimethyl- [1,4' -bipyridine]-2-one：

To 2' -chloro-4-hydroxy-5 ', 6-dimethyl- [1,4' -bipyridine]To a solution of 2-one (85.00 g,339.08mmol,1.00 eq.) in DMF (300 mL) was added 4-methoxybenzyl chloride (159.31 g,1017.23mmol,3.00 eq.) K ₂ CO ₃ (187.45 g,1356.31mmol,4.00 eq.) and 18-crown-6 (4.48 g,16.95mmol,0.05 eq.). The mixture was heated at 60℃for 3 hours. The reaction was monitored by LCMS. The mixture was cooled 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 with Na ₂ SO ₄ And (5) drying. The solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2' -chloro-4- [ (4-methoxyphenyl) methoxy as an off-white solid]-5', 6-dimethyl- [1,4' -bipyridine]2-Ketone (24 g, 19.09%). LC-MS (ES+H, m/z):[M+H] ⁺ ＝371.0。

Step 2: preparation of 2' - (1-ethoxyvinyl) -4- [ (4-methoxyphenyl) methoxy]5', 6-dimethyl-) [1,4' -bipyridine]-2-one：

To 2' -chloro-4- [ (4-methoxyphenyl) methoxy]-5', 6-dimethyl- [1,4' -bipyridine]To a stirred solution of 2-ketone (24.00 g,64.72mmol,1.00 eq.) and tributyl (1-ethoxyvinyl) stannane (28.05 g,77.67mmol,1.20 eq.) in dioxane (200 mL) was added Pd (PPh) ₃ ) ₂ Cl ₂ (2.27 g,3.23mmol,0.05 eq.). The resulting mixture was stirred under nitrogen at 100 ℃ for 10 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was filtered and the filter cake was washed with EA (100 mL). The filtrate was concentrated under reduced pressure. The crude product 2' - (1-ethoxyvinyl) -4- [ (4-methoxyphenyl) methoxy ]-5', 6-dimethyl- [1,4' -bipyridine]-2-one (32 g) was used in the next step without further purification. LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝407.1。

Step 3: preparation of 2' -acetyl-4- [ (4-methoxyphenyl) methoxy]-5', 6-dimethyl- [1,4' -bipyramid Pyridine and pyridine]-2-one：

To 2' - (1-ethoxyvinyl) -4- [ (4-methoxyphenyl) methoxy group at 0℃under nitrogen atmosphere]-5', 6-dimethyl- [1,4' -bipyridine]To a stirred solution of 2-ketone (32 g,78.72mmol,1.00 eq.) in THF (200 mL) was added dropwise concentrated HCl (20 mL). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. At 0deg.C with saturated Na ₂ CO ₃ The aqueous solution basifies the mixture to pH 10. The resulting mixture was extracted with EA (2X 100 mL). The combined organic layers were washed with saturated aqueous NaCl solution (200 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. 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 as an off-white solid]-5', 6-dimethyl- [1,4' -bipyridine]2-Ketone (20 g,81.63%, two steps). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝379.1。

Step 4: preparation of 2' -acetyl-3-chloro-)4-hydroxy-5 ', 6-dimethyl- [1,4' -bipyridine]-2-one：

At room temperature, to 2' -acetyl-4- [ (4-methoxyphenyl) methoxy ]-5', 6-dimethyl- [1,4' -bipyridine]To a stirred mixture of 2-ketone (19.00 g,50.21mmol,1.00 eq.) and NCS (7.44 g,55.72mmol,1.10 eq.) in i-PrOH (100.00 mL) was added 2, 2-dichloroacetic acid (0.39 g,3.02mmol,0.06 eq.). And the mixture was stirred under nitrogen at 60 ℃ for 5 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The precipitated solid was collected by filtration and washed with cold i-PrOH (10 mL). The resulting solid was dissolved in DCM (100 mL). TFA (100 mL) was added to the above mixture at 0deg.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. By using Et ₂ O (50 mL) was triturated to purify the residue. This gives 2' -acetyl-3-chloro-4-hydroxy-5 ', 6-dimethyl- [1,4' -bipyridine as a pale yellow solid]-2-one (14 g, crude, TFA salt). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝293.0。

Step 5: preparation of 2' -acetyl-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]5', 6-dimethyl-) [1,4' -bipyridine]-2-one：

2' -acetyl-3-chloro-4-hydroxy-5 ', 6-dimethyl- [1,4' -bipyridine]-2-one (TFA salt) (14.00 g,34.42mmol,1.00 eq.) K ₂ CO ₃ A mixture of (14.27 g,103.25mmol,3.00 eq.) 18-crown-6 (0.91 g,3.44mmol,0.10 eq.) and 2- (chloromethyl) -3, 5-difluoropyridine (8.44 g,51.60mmol,1.50 eq.) in DMF (100.00 mL) was stirred under nitrogen at 60℃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 as an off-white solid ]-5', 6-dimethyl- [1,4' -bipyridine]2-Ketone (11 g,52.38%, two steps). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝420.0。

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' -bipyridine]-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,26.20mmol,1.00 eq.) in DMF-DMA (50 mL) was stirred under nitrogen at 100deg.C for 12 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure.

Intermediate 17-22

Step 1: preparation of N- (2-chloro-5-methylpyridin-4-yl) -2, 2-trifluoroacetamide：

To a stirred solution of 2-chloro-5-methylpyridin-4-amine (5.00 g,35.07mmol,1.00 eq.) and trifluoroacetic anhydride (14.73 g,70.13mmol,2.00 eq.) in DCM (100 mL) under nitrogen at 0deg.C was added TEA (14.19 g,140.26mmol,4.00 eq.) dropwise. The resulting mixture was stirred at room temperature under nitrogen overnight. The reaction was monitored by LCMS. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with EtOAc (3X 100 mL). The combined organic layers were washed with brine (3X 100 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. 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-trifluoroacetamide (7.60 g, 90.69%) as a pale yellow solid. LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝239.1。

Step 2: preparation of N- (2- (1-ethoxyvinyl) -5-methylpyridin-4-yl) -2, 2-trifluoroacetamide：

To a stirred solution of N- (2-chloro-5-methylpyridin-4-yl) -2, 2-trifluoroacetamide (7.50 g,31.44mmol,1.00 eq.) and tributyl (1-ethoxyvinyl) stannane (34.06 g,94.30mmol,3.00 eq.) in dioxane (100 mL) at room temperature under nitrogen was added bis (triphenylphosphine) palladium chloride (1.10 g,1.57mmol,0.05 eq.) in portions. The resulting mixture was stirred overnight at 120 ℃ under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was filtered and the filter cake was washed with EA (100 mL). The filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝275.0。

Step 3: preparation of 1- (4-amino-5-methylpyridin-2-yl) ethanone：

To N- [2- (1-ethoxyvinyl) -5-methylpyridin-4-yl at room temperature]To a stirred solution of 2, 2-trifluoroacetamide (11 g,40.11mmol,1.00 eq.) in THF (120 mL) was added dropwise concentrated HCl (10 mL). 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). With Et ₂ O (8X 200 mL) washes the resulting mixture. With saturated NaHCO ₃ The aqueous layer was basified (aqueous solution) to pH 8. The resulting mixture was extracted with EtOAc (3X 200 mL). The combined organic layers were washed with brine (3X 200 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. 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-d ₆ )δ8.02(s,1H),7.16(s,1H),6.07(s,2H),2.52(s,3H),2.07(s,3H)。

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,26.64mmol,1.00 eq.) and triiodomethane (31.46 g,79.90mmol,3.00 eq.) in THF (50 mL) at room temperature under nitrogen was added dropwise tert-butyl nitrite (5.49 g,53.27mmol,2.00 eq.). The resulting mixture was stirred under nitrogen at 80 ℃ for 3 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with EtOAc (3X 200 mL). The combined organic layers were washed with brine (3X 200 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. 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-d ₆ )δ8.54(s,1H),8.27(s,1H),2.60(s,3H),2.42(s,3H)。

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,7.66mmol,1.00 eq.) in DMF-DMA (20 mL) was stirred under nitrogen at 100deg.C for 4 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was diluted with DMF (20 mL). To the above mixture was added 2-hydroxy-2-methylpropionamidine (1.17 g,11.49mmol,1.50 eq.) in portions under nitrogen. The resulting mixture was stirred under nitrogen at 100 ℃ for an additional 1.5 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was diluted with water (150 mL). The resulting mixture was extracted with EtOAc (3X 150 mL). The combined organic layers were washed with brine (3X 150 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. 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 as an off-white solid]Propan-2-ol (2.07 g, 76.07%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝355.9。 ¹ H NMR(300MHz,DMSO-d ₆ )δ9.09(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)。

Step 6: preparation of 2- {4- [ 5-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyri-dine Pyridin-2-yl]Pyrimidin-2-yl } propan-2-ols ：

To 2- [4- (4-iodo-5-methylpyridin-2-yl) pyrimidin-2-yl at room temperature under nitrogen atmosphere]To a stirred solution of propan-2-ol (200 mg,0.56mmol,1.00 eq.) and bis (pinacolato) diboron (356 mg,1.41mmol,2.50 eq.) in dioxane (5 mL) was added Pd (dppf) Cl in portions ₂ (16 mg,0.03mmol,0.05 eq.) and KOAc (221 mg,2.25mmol,4.00 eq.). The resulting mixture was stirred overnight at 120 ℃ under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was diluted with water (25 mL). The resulting mixture was extracted with EtOAc (3X 25 mL). Will be combined withThe organic layer was washed with brine (3X 25 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. 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, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl as a brown solid]Pyrimidin-2-yl } propan-2-ol (150 mg, 74.99%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ = 274.1 (mass signal of boric acid). ¹ H NMR(300MHz,DMSO-d ₆ )δ8.92(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

Step 1: preparation of 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-3', 6-dimethyl-2' - (trimethylmethyl) Stannyl) - [1,4' -bipyridine]-2-one：

To 2', 3-dichloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy ]-3', 6-dimethyl- [1,4' -bipyridine]-2-one (1.00 g,2.42mmol,1.00 eq.) Sn ₂ Me ₆ (6.36 g,19.40mmol,8.00 eq.) Pd (PPh) was added to a stirred solution of 1, 4-dioxane (20 mL) ₃ ) ₂ Cl ₂ (681 mg,0.97mmol,0.40 eq.) and AsPh ₃ (0.29 g,0.97mmol,0.40 eq.). The resulting mixture was stirred under nitrogen at 100 ℃ for 12 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was diluted with EA (200 mL). The combined organic layers were washed with KF (aq) (3X 100 mL). By anhydrous Na ₂ SO ₄ The organic layer was dried. After filtration, the filtrate was concentrated under reduced pressure. The crude product (1.78 g) was used in the next step without further purification. LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝542.3。

Step 2: preparation of 2' - (6-bromopyridin-2-yl) -3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-5',6- Dimethyl- [1,4' -bipyridine]-2-one：

To 3-chloro-4- [ (3, 5-difluoropyridin-2-yl)) Methoxy group]-5', 6-dimethyl-2 ' - (trimethylstannyl) - [1,4' -bipyridine]Pd (PPh) was added to a stirred solution of 2-ketone (2.00 g,3.70mmol,1.00 eq.) and 2, 6-dibromo-pyridine (2.63 g,11.10mmol,3.00 eq.) in 1, 4-dioxane (20 mL) ₃ ) ₂ Cl ₂ (0.52 g,0.74mmol,0.20 eq.) the resulting mixture was stirred under nitrogen at 80℃for 2 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with EtOAc (3X 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. 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 as a yellow solid]-5', 6-dimethyl- [1,4' -bipyridine]2-Ketone (640 mg, 33.9%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝535.1。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.82(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-d ₆ )δ-120.14,-120.17,-122.36,-122.39。

Intermediate 25-30

Step 1: preparation of 2', 3-dichloro-4- [ (4-methoxyphenyl) methoxy group]-5', 6-dimethyl- [1,4' -bipyramid Pyridine and pyridine]-2-one：

To 2' -chloro-4- [ (4-methoxyphenyl) methoxy group at room temperature under nitrogen atmosphere]-5', 6-dimethyl- [1,4' -bipyridine]To a stirred mixture of 2-ketone (5 g, 13.4813 mmol,1 eq.) and 2, 2-dichloroacetic acid (0.17 mL,1.348mmol,0.1 eq.) in i-PrOH (20.00 mL, 261.704 mmol,19.41 eq.) was added NCS (1.80 g, 13.4813 mmol,1 eq.). The resulting mixture was stirred under nitrogen at 60 ℃ for 2 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. This isTo give 2', 3-dichloro-4- [ (4-methoxyphenyl) methoxy group as a yellow solid]-5', 6-dimethyl- [1,4' -bipyridine]2-Ketone (4.9 g, 90%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝405.1。

Step 2: 3-chloro-2' - (1-ethoxyvinyl) -4- [ (4-methoxyphenyl) methoxy]5', 6-dimethyl-) [1,4' -bipyridine]-2-one：

To 2', 3-dichloro-4- [ (4-methoxyphenyl) methoxy group at room temperature under nitrogen atmosphere]-5', 6-dimethyl- [1,4' -bipyridine]To a stirred solution of 2-ketone (5 g,12.33mmol,1.00 eq.) and dibutyl (1-ethoxyvinyl) propylstannane (12.85 g,37.01mmol,3.00 eq.) in 1, 4-dioxane (55 mL) was added Pd (PPh ₃ ) ₂ Cl ₂ (0.26 g,0.37mmol,0.03 eq.). The resulting mixture was stirred under nitrogen at 120 ℃ 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。

Step 3:2' -acetyl-3-chloro-4- [ (4-methoxyphenyl) methoxy]-5', 6-dimethyl- [1,4' -bipyramid Pyridine and pyridine]-2-one

To 3-chloro-2' - (1-ethoxyvinyl) -4- [ (4-methoxyphenyl) methoxy at room temperature under a nitrogen atmosphere]-5', 6-dimethyl- [1,4' -bipyridine]To a stirred mixture of 2-ketone (4.00 g,9.07mmol,1.00 eq.) in THF (200 mL) was added HCl (4 mL) dropwise. The resulting mixture was stirred at room temperature under 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 2X 200mL of brine. By anhydrous Na ₂ SO ₄ The organic layer was dried. 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 as a yellow solid]-5', 6-dimethyl- [1,4' -bipyridine]2-Ketone (2.90 g, 77.43%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝413.1。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.83(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)。

Step 4: 3-chloro-2' - [ (2E) -3- (dimethylamino) prop-2-enoyl]-4- [ (4-methoxyphenyl) methoxy Base group]-5', 6-dimethyl- [1,4' -bipyridine]-2-one：

To 2' -acetyl-3-chloro-4- [ (4-methoxyphenyl) methoxy at room temperature under nitrogen atmosphere]-5', 6-dimethyl- [1,4' -bipyridine]2-Ketone (2.90 g,7.02mmol,1.00 eq.) in DMF-DMA (25 mL). The resulting mixture was stirred overnight at 100 ℃ under 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 as a yellow solid]-4- [ (4-methoxyphenyl) methoxy group]-5', 6-dimethyl- [1,4' -bipyridine]2-Ketone (3.26 g, 99.18%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝470.1。

Step 5: 3-chloro-2' - [2- (2-hydroxy-prop-2-yl) pyrimidin-4-yl]-4- [ (4-methoxyphenyl) methoxy group]- 5', 6-dimethyl- [1,4' -bipyridine]-2-one：

To 3-chloro-2' - [ (2E) -3- (dimethylamino) prop-2-enoyl at room temperature under nitrogen atmosphere ]-4- [ (4-methoxyphenyl) methoxy group]-5', 6-dimethyl- [1,4' -bipyridine]-2-one (3.30 g,7.05mmol,1.00 eq.) and K ₂ CO ₃ (2.92 g,21.15mmol,3.00 eq.) to a stirred mixture of IPA (33 mL) was added 2-hydroxy-2-methylpropionamidine hydrochloride (1.95 g,14.10mmol,2.00 eq.). The resulting mixture was stirred under nitrogen at 80 ℃ for 2 hours. The reaction was monitored by LCMS. The resulting mixture was diluted with EtOAc (200 mL). The resulting mixture was washed with 2X 200ml of brine. By anhydrous Na ₂ SO ₄ The organic layer was dried. 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。

Step 6: 3-chloro-4-hydroxy-2' - [2- (2-hydroxy-prop-2-yl) pyrimidin-4-yl]5', 6-dimethyl- [1,4' ] and bipyridine (P)]-2-one：

At room temperature under nitrogen atmosphere, to 3-chloro-2' - [2- (2-hydroxy-prop-2-yl) pyrimidin-4-yl]-4- [ (4-methoxyphenyl) methoxy group]-5', 6-dimethyl- [1,4' -bipyridine]-2-Ketone (3.70 g,7.29mmol,1.00 eq.) in CH ₂ Cl ₂ TFA (15 mL) was added to the stirred solution in (50 mL). The resulting mixture was stirred at room temperature under 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 2X 200ml of brine. By anhydrous Na ₂ SO ₄ The organic layer was dried. 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 ] as a yellow solid]-5', 6-dimethyl- [1,4' -bipyridine]2-Ketone (2.50 g, 88.55%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝387.1。 ¹ H NMR(400MHz,DMSO-d ₆ )δ11.62(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 to 33

Step 1: preparation of 4-methoxypyrimidine-2-carboxylic acid ethyl ester：

Et is added to a stirred solution of 2-chloro-4-methoxypyrimidine (100.00 g,691.75mmol,1.00 eq.) in EtOH (6.00L) in a pressure tank ₃ N (140.00 g,1383.50mmol,2.00 eq.) and Pd (dppf) Cl ₂ (10.00 g,13.66mmol,0.05 eq.). The mixture was purged with nitrogen for 2 minutes and then pressurized with carbon monoxide to 50atm at 100 ℃ 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-d ₆ )δ8.66(d,1H),7.16(d,1H),4.36(q,2H),3.98(s,3H),1.34(t,3H)。

Step 2: preparation of 4-hydroxypyrimidine-2-carboxylic acidEthyl ester：

To a stirred solution of ethyl 4-methoxypyrimidine-2-carboxylate (83.50 g,458.34mmol,1.00 eq.) in MeCN (1.00L) at room temperature under a nitrogen atmosphere was added dropwise TMSI (262 ml,1833.36mmol,4.00 eq.) over 1 hour. The resulting mixture was stirred at 50 ℃ overnight. The desired product was detectable by LCMS. The mixture was cooled 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 steps were 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。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.14(d,1H),6.60(d,1H),4.34(q,2H),1.32(t,3H)。

Step 3: preparation of 4-chloropyrimidine-2-carboxylic acid ethyl ester：

POCl was added dropwise to a stirred mixture of ethyl 4-hydroxypyrimidine-2-carboxylate (33.00 g,196.25mmol,1.00 eq.) in DCE (1.20L) under nitrogen at 0℃over 2 hours ₃ (73 mL,785.00mmol,4.00 eq.). The resulting mixture was stirred at 50 ℃ overnight. The desired product was detectable by LCMS. The mixture was cooled to room temperature. The reaction was quenched by the addition of water/ice (600 mL) at 0 ℃. With saturated Na ₂ CO ₃ The mixture was basified (in aqueous solution) to pH 7-8. By CH ₂ Cl ₂ The resulting mixture was extracted (3X 800 mL). The combined organic layers were washed with brine (2X 800 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. 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-d ₆ )δ8.98(d,1H),7.97(d,1H),4.40(q,2H),1.34(t,3H)。

Intermediate 34

Step 1: preparation of 2' -bromo-4- [ (4-methoxyphenyl) methoxy]-5', 6-dimethyl- [1,4' -bipyridine]-2- Ketone compounds：

To 2' -bromo-4-hydroxy-5 ', 6-dimethyl- [1,4' -bipyridine]To a solution of 2-ketone (7.00 g,23.72mmol,1.00 eq.) in DMF (50 mL) was added PMBCl (11.14 g,71.15mmol,3.00 eq.) K ₂ CO ₃ (13.11 g,94.872mmol,4.00 eq.) and 18-crown-6 (310 mg,1.19mmol,0.05 eq.). The mixture was stirred at 60℃for 3 hours. The reaction was monitored by LCMS. The mixture was cooled 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) then with Na ₂ SO ₄ And (5) drying. The solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2' -bromo-4- [ (4-methoxyphenyl) methoxy as an off-white solid]-5', 6-dimethyl- [1,4' -bipyridine]2-Ketone (5.5 g, 55.84%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝415.0/417.0。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.48(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)。

Step 2: preparation of 2' -bromo-3-chloro-4- [ (4-methoxyphenyl) methoxy]-5', 6-dimethyl- [1,4' -bipyramid Pyridine and pyridine]-2-one：

To 2' -bromo-4- [ (4-methoxyphenyl) methoxy at room temperature]-5', 6-dimethyl- [1,4' -bipyridine]To a stirred mixture of 2-ketone (5.50 g,13.24mmol,1.00 eq.) and NCS (1.95 g,14.57mmol,1.10 eq.) in IPA (20 mL) was added 2, 2-dichloroacetic acid (100 mg,0.80mmol,0.06 eq.). The mixture was stirred under nitrogen at 60 ℃ for 3 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The precipitated solid was collected by filtration to give 2' -bromo-3-chloro-4- [ (4-methoxyphenyl) methoxy as a white solid]-5', 6-dimethyl- [1,4' -bipyridine]-2-one (3 g, 50.37%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝451.1。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.51(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

Step 1: preparation of 3-chloro-5-fluoropyridine-2-carboxylic acid ethyl ester：

A solution of 3-chloro-5-fluoropyridine-2-carboxylic acid (4.50 g,25.63mmol,1.00 eq.) in EtOH (100 mL) was cooled with an ice bath. SOCl was added dropwise to the above mixture at 0deg.C over 3 minutes ₂ (6.13 g,51.53mmol,2.01 eq.). The resulting mixture was stirred at room temperature for an additional 3 hours. The reaction was monitored by LCMS. The mixture was brought to room temperature. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography to give ethyl 3-chloro-5-fluoropyridine-2-carboxylate (4.40 g, 84.29%) as a colorless liquid. LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝203.9。

Step 2: preparation of (3-chloro-5-fluoropyridin-2-yl) methanol：

To a stirred solution of ethyl 3-chloro-5-fluoropyridine-2-carboxylate (2.10 g,10.31mmol,1.00 eq.) in EtOH (30 mL) under nitrogen at 0deg.C was added NaBH in portions ₄ (0.98 g,25.90mmol,2.51 eq.). The resulting mixture was stirred at 0 ℃ under nitrogen atmosphere for 30 minutes. The resulting mixture was stirred at room temperature under nitrogen for 2 hours. The reaction was monitored by LCMS. With saturated NH ₄ The reaction was quenched with Cl (aqueous solution) at 0 ℃. The resulting mixture was concentrated under reduced pressure to remove EtOH, then extracted with EA (3X 30 ml). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated in vacuo to give (3-chloro-5-fluoropyridin-2-yl) methanol (2 g, 95.24%) as a yellow oil. LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝162.0。

Step 3: preparation of 3-chloro-2- (chloromethyl) -5-fluoropyridine ：

Stirring of (3-chloro-5-fluoropyridin-2-yl) methanol (2.10 g,12.99mmol,1.00 eq.) in DCM (30 mL) at 0deg.C under nitrogenDMF (0.1 mL,1.30mmol,0.10 eq.) was added to the stirred solution. Drop SOCl under nitrogen atmosphere ₂ (2.3 mL,32.49mmol,2.50 eq.). 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。

Intermediate 38-41

Step 1: preparation of 2-bromo-3, 5-dimethyl-4-nitropyridine：

POBr was added dropwise to a stirred solution of 3, 5-dimethyl-4-nitropyridin-1-ol (5.00 g,29.38mmol,1.00 eq.) in DCE (100 mL) at 0℃under nitrogen atmosphere ₃ (12.64 g,44.07mmol,1.50 eq.). The resulting mixture was stirred under nitrogen at 60 ℃ for 2 hours. The reaction was monitored by LCMS. The mixture was brought to room temperature. Saturated Na at 0deg.C ₂ CO ₃ The residue was basified (in aqueous solution) to pH 10. The reaction was poured into water (100 mL) at room temperature. The resulting mixture was extracted with EtOAc (3X 300 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 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) δ8.24 (s, 1H), 2.35 (s, 3H), 2.25 (s, 3H).

Step 2: preparation of 2-bromo-3, 5-dimethylpyridin-4-amine：

2-bromo-3, 5-dimethyl-4-nitropyridine (5.40 g,23.37mmol,1.00 eq.), fe (2.61 g,46.74mmol,5.00 eq.) and CaCl ₂ (12.97 g,116.86mmol,5.00 eq.) in EtOH (60 mL) was stirred under nitrogen at 90deg.C for 3 hours. The reaction was monitored by LCMS. The mixture was brought to room temperature. The resulting mixture was filtered, and the filter was washed with ethanol (500 mL)And (5) cake. The filtrate was concentrated under reduced pressure. The residue was dissolved in EtOAc (500 mL). With saturated Na ₂ CO ₃ (aqueous) (2X 300 mL) the EtOAc layer was washed. By anhydrous Na ₂ SO ₄ The organic layer was dried. After filtration, the filtrate was concentrated under reduced pressure. 2-bromo-3, 5-dimethylpyridin-4-amine (4.60 g, 97.89%) was obtained as a white solid. LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝201.0/203.0。 ¹ H NMR(400MHz,DMSO-d ₆ )δ7.57(s,1H),5.90(s,2H),2.14(s,3H),1.99(s,3H)。

Step 3: preparation of 2 '-bromo-4-hydroxy-3', 5', 6-trimethyl- [1,4' -bipyridine]-2-one：

A solution of 2-bromo-3, 5-dimethylpyridin-4-amine (2.30 g,11.43mmol,1.00 eq.) and 2, 2-dimethyl-6- (2-oxopropyl) -1, 3-dioxin-4-one (2.11 g,11.43mmol,1.00 eq.) in dioxane (15 mL) was stirred under nitrogen at 90℃for 3.5 hours. The mixture was cooled to room temperature. The reaction was monitored by LCMS. Dropping H into the mixture at 0deg.C ₂ SO ₄ (1.12 g,11.43mmol,1.00 eq.). The resulting mixture was stirred at 90℃for a further 1 hour. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography to give 2 '-bromo-4-hydroxy-3', 5', 6-trimethyl- [1,4' -bipyridine as a tan oil]2-Ketone (1.70 g, 62.46%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝309.2/311.2。 ¹ H NMR (400 MHz, chloroform-d) δ8.25 (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).

Step 4: preparation of 2' -bromo-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-3',5', 6-trimethyl- [1,4' -biphenol Pyridine compound]-2-one：

2 '-bromo-4-hydroxy-3', 5', 6-trimethyl- [1,4' -bipyridine]-2-one (1.70 g,5.49mmol,1.00 eq), 2- (chloromethyl) -3, 5-difluoropyridine (1.35 g,8.24mmol,1.50 eq), 18-crown-6 (0.15 g,0.55mmol,0.10 eq) and K ₂ CO ₃ (3.04 g,21.99mmol,4.00 eq.) in DMF (15 mL) was stirred under nitrogen at 60℃for 4 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. Will beThe residue was dissolved in EA (400 mL). The mixture was washed with water (3X 200 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. 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 as a yellow-green solid ]-3',5', 6-trimethyl- [1,4' -bipyridine]2-Ketone (1.60 g, 66.70%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝436.2/438.2。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.60(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)。

Intermediate 42-56

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Step 1: preparation of 2-chloro-3-fluoro-5-iodopyridin-4-amine：

To 2-chloro-3-fluoropyridin-4-amine (5.00 g,34.11mmol,1.00 eq.) in CH at room temperature under nitrogen ₃ To a stirred solution of CN (150 mL) was added NIS (9.21 g,40.94mmol,1.20 eq.) and 4-methylbenzene-1-sulfonic acid hydrate (0.32 g,1.70mmol,0.05 eq.) in portions. The resulting mixture was stirred overnight at 70 ℃ under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was diluted with water (300 mL). The resulting mixture was extracted with EtOAc (3X 150 mL). The combined organic layers were washed with brine (3X 150 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. 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-d ₆ )δ8.10(s,1H),6.69(s,2H)。

Step 2: preparation of 2-chloro-3-fluoro-5-methylpyridin-4-amine：

To 2-chloro-3-fluoro-5-iodopyridin-4-amine (9.00 g,33.03mmol,1.00 eq.) and methylboronic acid (3.95 g,66.06mmol,2.00 eq.) in toluene (200 mL) and H at room temperature under a nitrogen atmosphere ₂ Added to the stirred mixture in O (20 mL) Cs ₂ CO ₃ (16.14 g,49.55mmol,1.50 eq.) PCy ₃ (0.46 g,1.65mmol,0.05 eq.) and Pd (OAc) ₂ (0.37 g,1.65mmol,0.05 eq.). The resulting mixture was stirred overnight at 100 ℃ under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was diluted with water (500 mL). The resulting mixture was extracted with EtOAc (3X 200 mL). The combined organic layers were washed with brine (3X 200 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. 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) delta 7.75 (s, 1H), 4.36 (s, 2H), 2.15 (s, 3H).

Step 3: preparation of 2 '-chloro-3' -fluoro-4-hydroxy-5 ', 6-dimethyl- [1,4' -bipyridine]-2-one：

To a stirred solution of 2-chloro-3-fluoro-5-methylpyridin-4-amine (3.00 g,18.68mmol,1.00 eq.) in 1, 4-dioxane (100 mL) was added 2, 2-dimethyl-6- (2-oxopropyl) -1, 3-dioxin-4-one (6.88 g,37.36mmol,2.00 eq.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred under nitrogen at 90 ℃ for 2 hours. The mixture was cooled to room temperature. H was added dropwise to the above mixture at room temperature ₂ SO ₄ (1.83 g,18.68mmol,1.00 eq.). The resulting mixture was stirred at 90℃for a further 2 hours. The reaction was monitored by LCMS. The mixture was cooled 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' -bipyridine as a brown solid]2-Ketone (3.00 g, 59.77%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝269.1。 ¹ H NMR(300MHz,DMSO-d6)δ11.03(s,1H),8.42(s,1H),6.05(d,1H),5.61(d,1H),2.06(s,3H),1.89(s,3H)。

Step 4: preparation of 2' -chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-3 '-fluoro-5', 6-dimethyl- [1, 4' -bipyridines]-2-one：

To 2 '-chloro-3' -fluoro-4-hydroxy-5 ', 6-dimethyl- [1,4' -bipyridine at room temperature under nitrogen atmosphere]To a stirred mixture of 2-ketone (2.00 g,7.44mmol,1.00 eq.) and 2- (chloromethyl) -3, 5-difluoropyridine (1.83 g,11.16mmol,1.50 eq.) in DMF (60 mL) was added Cs ₂ CO ₃ (7.28 g,22.33mmol,3.00 eq.) and 18-crown-6 (196.7 mg,0.74mmol,0.10 eq.). The resulting mixture was stirred overnight at 70 ℃ under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was diluted with water (150 mL). The resulting mixture was extracted with EtOAc (3X 100 mL). The combined organic layers were washed with brine (3X 100 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. 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 as a yellow solid]-3' -fluoro-5 ', 6-dimethyl- [1,4' -bipyridine]2-Ketone (2.00 g, 67.89%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝396.1。 ¹ H NMR(300MHz,DMSO-d6)δ8.60(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)。

Step 5: preparation of 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-3' -fluoro-5 ', 6-dimethyl-2 ' - (tris) Methyl stannyl) - [1,4' -bipyridine]-2-one：

To 2', 3-dichloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy group at room temperature under nitrogen atmosphere]-3' -fluoro-5 ', 6-dimethyl- [1,4' -bipyridine]-2-one (500 mg,1.16mmol,1.00 eq.) and Sn ₂ Me ₆ (761.56 mg,2.32mmol,2.00 eq.) Pd (PPh) was added to a stirred solution of dioxane (8 mL) ₃ ) ₂ Cl ₂ (163.15 mg,0.23mmol,0.20 eq.) and AsPh ₃ (71.18 mg,0.23mmol,0.20 eq.). The resulting mixture was stirred under nitrogen at 80 ℃ for 1 hour. The reaction was monitored by LCMS. The mixture was cooled 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。

Intermediate 47-48

Step 1: preparation of (3, 5-difluoropyridin-2-yl) methanol-d 2-ol：

To 5-chloro-3-fluoropyridine-2-carboxylic acid ethyl ester (500.00 g,2671.71mmol,1.00 eq.) under nitrogen at 0deg.C in CD ₃ NaBD was added in portions to a stirred solution of OD (500 mL) and THF (1000 mL) ₄ (111.84 g,2671.71mmol,1.00 eq.). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. By adding D at 0 ℃ ₂ The resulting mixture was quenched with O (200 mL) and stirred at 0deg.C for 30 min. The mixture was diluted with EtOAc (2000 mL) and washed with water (2000 mL) and brine (2000 mL). By anhydrous Na ₂ SO ₄ The organic layer was dried. After filtration, the filtrate was concentrated under reduced pressure to give (3, 5-difluoropyridin-2-yl) methane-d 2-ol methanol (360.00 g, 91.5%) as a yellow oil. LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝148.1。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.44(d,1H),7.88(ddd,1H),5.37(s,1H)。

Step 2: preparation of 2- (chloromethyl-d 2) -3, 5-difluoropyridine：

To a stirred solution of (3, 5-difluoropyridin-2-yl) methane-d 2-ol (300.00 g,2039.13mmol,1.00 eq.) in DCM (1000 mL) under nitrogen at 0deg.C was added DMF (14.91 g,203.91mmol,0.10 eq.) and SOCl dropwise ₂ (606.44 g,5097.84mmol,2.50 eq.). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated in vacuo to give 2- (chloromethyl-d 2) -3, 5-difluoropyridine (320.00 g, 94.7%) as a yellow oil, which was used in the next step without further purification. LC-MS (ES+H, M/z) [ M+H ] ] ⁺ ＝166.1。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.48(d,1H),8.04-7.93(m,1H)。

Intermediate 49-53

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Step 1: preparation of 2' -chloro-4- [ (3, 5-difluoropyridin-2-yl) (2H 2) methoxy]-3 '-fluoro-5', 6-dimethyl- [1,4' -bipyridine]-2-one：

To 2 '-chloro-3' -fluoro-4-hydroxy-5 ', 6-dimethyl- [1,4' -bipyridine at room temperature under nitrogen atmosphere]-2-one (1.70 g,6.32mmol,1.00 eq.) and 2- [ chloro (2H 2) methyl]To a stirred mixture of 3, 5-difluoropyridine (1.57 g,9.49mmol,1.50 eq.) in DMF (60 mL) was added Cs ₂ CO ₃ (6.18 g,18.98mmol,3.00 eq.) and 18-crown-6 (0.17 g,0.63mmol,0.10 eq.). The resulting mixture was stirred under nitrogen at 70 ℃ for 2 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was diluted with water (150 mL). The resulting mixture was extracted with EtOAc (3X 100 mL). The combined organic layers were washed with brine (3X 100 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. 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 2) methoxy as a yellow solid]-3' -fluoro-5 ', 6-dimethyl- [1,4' -bipyridine]2-Ketone (1.40 g, 55.62%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝398.1。

Step 2: preparation of 2', 3-dichloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy ]-3 '-fluoro-5', 6-dimethyl- [1,4' -bipyridine]-2-one：

To 2' -chloro-4- [ (3, 5-difluoropyridin-2-yl) (2H 2) methoxy at room temperature under a nitrogen atmosphere]-3' -fluoro-5 ', 6-dimethyl- [1,4' -bipyridine]To a stirred solution of 2-ketone (1.40 g,3.52mmol,1.00 eq.) and NCS (0.61 g,4.57mmol,1.30 eq.) in i-PrOH was added dropwise dichloroacetic acid (0.05 g,0.35mmol,0.10 eq.). The resulting mixture was stirred under nitrogen at 60 ℃ 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 (3X 50 mL). The combined organic layers were washed with brine (3X 50 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel,concentrating the filtrate under reduced pressure to give 2', 3-dichloro-4- [ (3, 5-difluoropyridin-2-yl) (2H 2) methoxy as a yellow solid]-3' -fluoro-5 ', 6-dimethyl- [1,4' -bipyridine]2-Ketone (1.2 g, 78.88%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝432.0。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.59(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)。

Step 3: 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) (2H 2) methoxy]2'- (1-ethoxyvinyl) -3' -) Fluoro-5 ', 6-dimethyl- [1,4' -bipyridine]-2-one：

To 2', 3-dichloro-4- [ (3, 5-difluoropyridin-2-yl) (2H 2) methoxy at room temperature under a nitrogen atmosphere ]-3' -fluoro-5 ', 6-dimethyl- [1,4' -bipyridine]To a stirred solution of 2-ketone (1.20 g,2.77mmol,1.00 eq.) and tributyl (1-ethoxyvinyl) stannane (2.01 g,5.55mmol,2.00 eq.) in 24.00mL dioxane was added Pd (PPh) ₃ ) ₂ Cl ₂ (0.10 g,0.14mmol,0.05 eq.). The resulting mixture was stirred under nitrogen at 120 ℃ for 2 hours. The reaction was monitored by LCMS. The desired product was detectable by LCMS. The mixture was cooled 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。

Step 4: preparation of 2' -acetyl-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) (2H 2) methoxy]-3 '-fluoro-5', 6-dimethyl- [1,4' -bipyridine]-2-one：

The mixture was diluted with 1, 4-dioxane (80 mL) and HCl (0.94 g,25.65mmol,10.00 eq.) was then added dropwise at 0deg.C. The resulting mixture was stirred at room temperature for an additional 30 minutes. The desired product was detectable by LCMS. With saturated NaHCO ₃ The mixture was basified (aqueous) to pH 8. The resulting mixture was extracted with EtOAc (3X 100 mL). The combined organic layers were washed with brine (3X 10 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. 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 2) methoxy as a yellow solid ]-3' -fluoro-5 ', 6-dimethyl- [1,4' -bipyridine]-2-one (880 mg,78.01％)。LC-MS:(ES+H,m/z):[M+H] ⁺ ＝440.20。

step 5: preparation of 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) (2H 2) methoxy]-2' - [ (2E) -3- (dimethyl) Amino) prop-2-enoyl]-3' -fluoro-5 ', 6-dimethyl- [1,4' -bipyridine]-2-one：

2' -acetyl-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) (2H 2) methoxy]-3' -fluoro-5 ', 6-dimethyl- [1,4' -bipyridine]A solution of 2-ketone (660 mg,2.00mmol,1.00 eq.) in DMF-DMA (6 mL) was stirred under nitrogen at 100deg.C for 2 hours. The desired product was detectable by LCMS. The mixture was cooled to room temperature. The precipitated solid was collected by filtration and washed with hexane (3×2 mL). This gives 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) (2H 2) methoxy as a yellow solid]-2' - [ (2E) -3- (dimethylamino) prop-2-enoyl]-3' -fluoro-5 ', 6-dimethyl- [1,4' -bipyridine]2-Ketone (760 mg, 76.75%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝495.1。

Intermediate 54-55

Step 1: preparation of 2 '-bromo-4- ((3, 5-difluoropyridin-2-yl) methoxy-d 2) -5', 6-dimethyl-2H- [1, 4' -bipyridines]-2-one：

To 2' -bromo-4-hydroxy-5 ', 6-dimethyl- [1,4' -bipyridine at room temperature]-2-one (100.00 g,338.82mmol,1.00 eq.), 18-crown-6 (5.37 g,3.00mmol,0.40 eq.) and K ₂ CO ₃ To a stirred mixture of (42.14 g,304.94mmol,3.00 eq.) in DMF (200 mL) was added 2- (chloromethyl-d 2) -3, 5-difluoropyridine (27.75 g,152.47mmol,1.50 eq.). The resulting mixture was stirred at 60℃for 2.5 hours under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was filtered and the filter cake was washed with EtOAc (3X 500 mL). The filtrate was diluted with EA (3000 mL). The resulting mixture was washed with brine (3X 2000 mL) and water (5X 2000 mL). By anhydrous Na ₂ SO ₄ The organic layer was dried. After filtration, the filtrate was concentrated under reduced pressure. By using Et2O [ ]3X 250 ml) trituration to purify the residue and drying it under reduced pressure to give 2' -bromo-4- ((3, 5-difluoropyridin-2-yl) methoxy-d 2) -5', 6-dimethyl-2H- [1,4' -bipyridine as a white solid]-2-one (90 g, 62.8%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝424.0。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.59(d,1H),8.48(s,1H),8.08(ddd,1H),7.73(s,1H),6.13(dd,1H),6.03(d,1H),1.97(s,3H),1.85(s,3H)。

Step 2: preparation of 2 '-bromo-3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy-d 2) -5', 6-dimethyl-2H- [1,4' -bipyridine]-2-one：

To 2' -bromo-4- ((3, 5-difluoropyridin-2-yl) methoxy-d 2) -5', 6-dimethyl-2H- [1,4' -bipyridine at room temperature]To a stirred solution of 2-ketone (100.00 g,235.71mmol,1.00 eq.) and NCS (37.77 g,282.85mmol,1.20 eq.) in IPA (500 mL) was added dropwise 2, 2-dichloroacetic acid (3.04 g,23.57mmol,0.10 eq.). The resulting mixture was stirred under nitrogen at 60 ℃ for 1 hour. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The precipitated solid was collected by filtration and washed with cold IPA (4X 30 mL) to give 2' -bromo-3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy-d 2) -5', 6-dimethyl-2H- [1,4' -bipyridine as a white solid ]2-Ketone (60.00 g, 55.5%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝458.0。 ¹ H NMR300MHz,DMSO-d ₆ )δ8.60(d,1H),8.52(s,1H),8.10(ddd,1H),7.81(s,1H),6.80(d,1H),1.96(s,6H)。

Intermediate 56-57

Step 1: preparation of 2- (6-bromopyridin-2-yl) propan-2-ol：

To a stirred solution of 2, 6-dibromo-pyridine (25.00 g,105.53mmol,1.00 eq.) in toluene (50 ml) was added dropwise n-BuLi (46.43 ml,116.08mmol,1.10 eq., 2.5M in THF) under nitrogen at-50 ℃. The resulting mixture was stirred under nitrogen at-50 ℃ for 30 minutes. at-50deg.C in 10 minAcetone (9.19 g,158.29mmol,1.5 eq.) was added dropwise. The resulting mixture was stirred at-50℃for a further 1 hour. The reaction was monitored by LCMS. With saturated NH ₄ The reaction was quenched at-10 ℃. The resulting mixture was extracted with EtOAc (3X 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-d ₆ )δ7.73(t,1H),7.68(dd,1H),7.46(dd,1H),5.33(s,1H),1.43(s,6H)。

Step 2: preparation of 2-bromo-6- (2-hydroxy-prop-2-yl) pyridin-1-ium-1-alkoxide：

To a stirred solution of 2- (6-bromopyridin-2-yl) propan-2-ol (5.00 g,23.14mmol,1.00 eq.) in DCM (50 ml) under nitrogen at 0deg.C was added m-CPBA (11.98 g,69.42mmol,3.00 eq.) in portions. The resulting mixture was stirred under nitrogen at 50 ℃ for 24 hours. The reaction was monitored by LCMS. The mixture was brought to 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-alkoxide (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-d ₆ )δ7.91(dd,1H),7.69(dd,1H),7.33(t,1H),6.70–6.04(m,1H),1.58(s,6H)。

Example 1

Step 1: preparation of 2- (5-bromo-2-chloro-3-fluorophenoxymethyl) -3, 5-difluoropyridine：

5-bromo-2-chloro-1, 3-difluorobenzene (6.00 g,26.38mmol,1.00 eq), (3, 5-difluoropyridin-2-yl) methanol (3.83 g,26.38mmol,1.00 eq), 18-crown-6 (0.70 g,2.64mmol,0.10 eq) and K ₂ CO ₃ A mixture of (10.94 g,79.15mmol,3.00 eq.) in DMF (100 mL) was stirred overnight at 80℃under nitrogen. Monitoring by LCMSAnd (3) reacting. 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- (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-d ₆ )δ8.58(d,1H),8.07(td,1H),7.49(t,1H),7.42(dd,1H),5.41(d,2H)。

Step 2: preparation of 2- (2-chloro-3-fluoro-5-methylphenoxymethyl) -3, 5-difluoropyridine：

2- (5-bromo-2-chloro-3-fluorophenoxymethyl) -3, 5-difluoropyridine (3.00 g,8.51mmol,1.00 eq.), methylboronic acid (0.76 g,12.77mmol,1.50 eq.), pd (dppf) Cl ₂ (313 mg,0.43mmol,0.05 eq.) and K ₂ CO ₃ (3.53 g,25.53mmol,3.00 eq.) in dioxane: H ₂ The mixture in o=10:1 (100 mL) was stirred overnight at 80 ℃ under 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-d ₆ )δ8.57(d,1H),8.08-8.03(m,1H),7.06(s,1H),6.88(dd,1H),5.30(d,2H),2.32(s,3H)。

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,4.52mmol,1.00 eq.) and NBS (514 mg,4.52mmol,1.00 eq.) in MeCN was stirred overnight at 80℃under nitrogen. 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。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.57(d,1H),8.09-8.04(m,1H),7.32(d,1H),5.36(d,2H),2.39(s,3H)。

Step 4: preparation of 3- { 5-chloro-4- [ (2, 4-difluorophenyl) methoxy ]]-2-methyl-6-oxopyrimidin-1-yl } -N-) methoxy-N, 4-dimethylbenzamides：

2- {4- [ 5-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl]Pyrimidin-2-yl } propan-2-ol (50 mg,0.18mmol,1.00 eq.), 2- (4-bromo-2-chloro-3-fluoro-5-methylphenoxymethyl) -3, 5-difluoropyridine (62 mg,0.17mmol,1.20 eq.), pd (dppf) Cl ₂ (10 mg,0.01mmol,0.10 eq.) and Cs ₂ CO ₃ (138 mg,0.42mmol,3.00 eq.) in dioxane: H ₂ The mixture in o=20:1 (1 mL) was stirred under nitrogen atmosphere at 100 ℃ 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 ] as an off-white solid ]-2-fluoro-6-methylphenyl } -5-methylpyridin-2-yl) pyrimidin-2-yl]Propan-2-ol (50 mg, crude). The crude product (50 mg) was purified by preparative HPLC and the pure fractions concentrated and lyophilized to give 2- [4- (4- { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy ] as an off-white solid]-2-fluoro-6-methylphenyl } -5-methylpyridin-2-yl) pyrimidin-2-yl]Propan-2-ol (13 mg, 13%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝515.15。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.95(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

Step 1: preparation of 3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy) -5', 6-dimethyl-2' - (trimethylmethyl) Stannyl) -2H- [1,4' -bipyridine]-2-one：

To 2', 3-dichloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy at room temperature under nitrogen]5', 6-dimethyl- [1,4' ] andbipyridine (P)]To a mixture of 2-one (500 mg,1.21mmol,1.00 eq.) and hexamethyl-dittanine (477 mg,1.46mmol,1.20 eq.) in dioxane (10 mL) was added Pd (PPh) ₃ ) ₂ Cl ₂ (170 mg,0.24mmol,0.20 eq.) and AsPh ₃ (74 mg,0.24mmol,0.20 eq.). The mixture was stirred overnight at 80 ℃ under nitrogen atmosphere. The reaction was monitored by LCMS. The desired product was detectable by LCMS. The mixture was used directly in the next step. LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝542.1。

Step 2: preparation of 2- { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy ]-5', 6-dimethyl-2-oxo- [1,4' -bipyridine]-2' -yl } -1, 3-thiazole-4-carboxylic acid ethyl ester：

To the reaction mixture of the last step was added ethyl 2-bromo-1, 3-thiazole-4-carboxylate (432.59 mg,1.83 mmol,1.50 eq.) Pd (PPh) under nitrogen at room temperature ₃ ) ₂ Cl ₂ (170 mg,0.24mmol,0.20 eq.). The mixture was stirred overnight at 80 ℃ under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was first purified by silica gel column chromatography to give a crude product (210 mg). The crude product (210 mg) was further purified by preparative HPLC and the pure fractions concentrated to give 2- { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy as a white solid]-5', 6-dimethyl-2-oxo- [1,4' -bipyridine]-2' -yl } -1, 3-thiazole-4-carboxylic acid ethyl ester (160 mg,24.74%, two steps). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝533.1。

Step 3: preparation of 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-2' - [4- (2-hydroxy-prop-2-yl) -1, 3-thiazol-2-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one：

To 2- { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy group under nitrogen at 0 ℃]-5', 6-dimethyl-2-oxo- [1,4' -bipyridine]Ethyl-2' -yl } -1, 3-thiazole-4-carboxylate (100 mg,0.19mmol,1.00 eq.) in THF (5 mL) was added dropwise CH ₃ MgBr (0.6 mL,0.56mmol,3.00 eq.). The mixture was stirred at room temperature under nitrogen for 3 hours. The reaction was monitored by LCMS. The reaction was quenched with MeOH (1 mL). Will beThe resulting mixture was concentrated under reduced pressure. The residue was purified directly by preparative HPLC and the pure fractions were concentrated and lyophilized to give 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy as a white solid]-2' - [4- (2-hydroxy-prop-2-yl) -1, 3-thiazol-2-yl ]]-5', 6-dimethyl- [1,4' -bipyridine]-2-one (20.3 mg, 21%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝518.8。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.72(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, example 3A and example 3B

Step 1: preparation of 1- (benzyloxy) cyclopropane-1-carboxylic acid methyl ester：

A solution of methyl 1-hydroxycyclopropane-1-carboxylate (3.00 g,25.84mmol,1.00 eq.) in DMF (20 mL) was treated with NaH (0.93 g,38.75mmol,1.50 eq., 60% wt.) under nitrogen at 0deg.C for 30 minutes, followed by dropwise addition of benzyl bromide (8.84 g,51.67mmol,2.00 eq.) at 0deg.C. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS and TLC. The reaction was quenched by the addition of water/ice (150 mL) at 0 ℃. The resulting mixture was extracted with EtOAc (3X 150 mL). The combined organic layers were washed with brine (1X 150 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. 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-d ₆ )δ7.47–7.23(m,5H),4.60(s,2H),3.69(s,3H),1.37–1.16(m,4H)。

Step 2: preparation of 1- (benzyloxy) cyclopropane-1-carboxamidine hydrochloride：

Under nitrogen atmosphere at 0 ℃ to NH ₄ Cl (2.50 g,46.74mmol,9.64 eq.) in toluene (20 mL,188.00mmol,38.77 eq.) with stirringTrimethylaluminum (19.25 mL,534.09mmol,110.15 eq.) was added dropwise to the compound. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 30 minutes. A solution of methyl 1- (benzyloxy) cyclopropane-1-carboxylate (1.00 g,4.85mmol,1.00 eq.) in toluene (10 mL) was added dropwise to the above mixture over 10 min at room temperature. The resulting mixture was stirred at 80 ℃ overnight. The reaction was monitored by LCMS. The reaction was quenched by the addition of MeOH (10 mL) at 0 ℃. The resulting mixture was filtered and the filter cake was washed with EtOH (5X 20 mL). The filtrate was concentrated under reduced pressure. This gave 1- (benzyloxy) cyclopropane-1-carboxamidine hydrochloride (1.00 g, 91%) as a white solid. LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝191.1。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.85(d,4H),7.56–7.23(m,5H),4.57(s,2H),1.48(s,4H)。

Step 3: preparation of 2' - {2- [1- (benzyloxy) cyclopropyl ]]Pyrimidin-4-yl } -3-chloro-4- [ (3, 5-difluoropyridine-2-) Radical) methoxy radical ]-5', 6-dimethyl- [1,4' -bipyridine]-2-one：

2' -acetyl-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-5', 6-dimethyl- [1,4' -bipyridine]A solution of 2-keto (200 mg,0.48mmol,1.00 eq.) in DMF-DMA (5 mL) was stirred overnight at 100deg.C under nitrogen. The resulting mixture was concentrated in vacuo. To the above mixture were added 1- (benzyloxy) cyclopropane-1-carboxamidine hydrochloride (324 mg,1.43mmol,3.00 eq.) and K ₂ CO ₃ (399mg, 2.86mmol,6 eq.) in IPA (5 mL). The resulting mixture was stirred at 100 ℃ overnight. 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 as a white solid]Pyrimidin-4-yl } -3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-5', 6-dimethyl- [1,4' -bipyridine]-2-one (185 mg, 65%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝602.2。

Step 4: preparation of 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-2' - [2- (1-hydroxycyclopropyl) azoxystrobin Pyridin-4-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one：

2' - {2- [1- (benzyloxy) cyclopropyl ]]Pyrimidin-4-yl } -3-chloro-4- [ (3, 5-difluoropyridin-2-yl)Methoxy group]-5', 6-dimethyl- [1,4' -bipyridine]A mixture of 2-ketone (150 mg,0.25mmol,1.00 eq.) and AlCl3 (199mg, 1.49mmol,6.00 eq.) in toluene (10 mL) was stirred under nitrogen at room temperature 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, the pure fractions concentrated and lyophilized to give 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy as a white solid ]-2' - [2- (1-hydroxycyclopropyl) pyrimidin-4-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one (26.3 mg, 21%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝511.85。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.91–8.84(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。

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' -bipyridine]-2-one and rel-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methyl Oxy group]-2' - [2- (1-hydroxycyclopropyl) pyrimidin-4-yl]-5', 6-dimethyl- [1,4' -bipyridine]-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,0.059mmol,1.00 eq.) was isolated by preparative chiral HPLC. The 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, 13.6mg, 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, 11.8mg, ee% = 99.8%) as a white solid.

Example 3A (isomer 1)：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝511.80。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.90–8.83(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。

Example 3B (isomer 2) ：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝511.80。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.90–8.83(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, 4B

Step 1: preparation of 3-hydroxy-2, 2-dimethylpropionamidine hydrochloride：

Under nitrogen atmosphere at 0 ℃ to NH ₄ AlMe was added dropwise to a stirred mixture of Cl (9.15 g,171.02mmol,5.00 eq.) in toluene (40 mL) ₃ (85.51 mL,2M in toluene, 171.02mmol,5.00 eq.). The resulting mixture was stirred under nitrogen at 0 ℃ for 10 minutes and then at room temperature until no more gas was produced. A solution of ethyl 3-hydroxy-2, 2-dimethylpropionate (5.00 g,34.20mmol,1.00 eq.) in toluene was added dropwise to the above mixture at room temperature. The resulting mixture was stirred at 80 ℃ overnight. The reaction was monitored by LCMS. The reaction was quenched by the addition of MeOH (30 mL) at 0 ℃. 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. This gave 3-hydroxy-2, 2-dimethylpropionamidine hydrochloride (4 g, crude) as a white solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.04(s,2H),8.62(s,2H),5.43(t,1H),3.48(d,2H),1.18(s,6H)。

Step 2: preparation of 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-2'-[2-(1-hydroxy-2-methylpropane 2-yl) pyrimidin-4-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one：

2' -acetyl-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy ]-5', 6-dimethyl- [1,4' -bipyridine]A solution of 2-ketone (450 mg,0.95mmol,1.00 eq.) in DMF-DMA (6 mL) was stirred overnight at 100deg.C under nitrogen. The reaction was monitored by LCMS. The resulting mixture was brought to room temperature and concentrated under reduced pressure. The crude product (550 mg) was used in the next step without further purification. To a solution of the above crude product in IPA (20 mL) was added 3-hydroxy-2, 2-dimethylpropionamidine HCl salt (1.80 g crude 2, 11.58mmol,10.00 eq.) and K ₂ CO ₃ (1.60 g,11.58mmol,10.00 eq.) then the mixture was stirred overnight at 80℃under nitrogen. The reaction was monitored by LCMS. The resulting mixture was brought to room temperature and diluted with EtOAc (100 mL). The combined organic layers were washed with brine (3X 100 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. 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 as an off-white solid]-2' - [2- (1-hydroxy-2-methylpropan-2-yl) pyrimidin-4-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one (450 mg, 73.59%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝528.25。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.93(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。

Step 3: preparation of rel-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-2' - [2- (1-hydroxy-2-methyl) Propan-2-yl) pyrimidin-4-yl ]-5', 6-dimethyl- [1,4' -bipyridine]2-one and rel-3-chloro-4- [ (3, 5-difluoropyridine ] 2-yl) methoxy]-2' - [2- (1-hydroxy-2-methylpropan-2-yl) pyrimidin-4-yl]-5', 6-dimethyl- [1,4' -bipyramid Pyridine and pyridine]-2-one：

The racemate 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 (example 4a,18mg, 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 4.23 mg, 234% = 4.4%).

Example 4A：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝528.2。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.92(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。

Example 4B：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝528.2。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.92(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 and 5B

Step 1: preparation of 2- (4- { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy)]-5', 6-dimethyl-2-oxo Substituted- [1,4' -bipyridines]-2' -yl } pyrimidin-2-yl) -2-methylpropanaldehyde：

To a stirred mixture of Dess-Martin (428 mg,1.00mmol,1.50 eq.) in DCM (10 mL) under nitrogen at room temperature was added 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' -bipyridine]-2-one (350 mg,0.66mmol,1.00 g)Amount) of the solution in DCM (5 mL). The resulting mixture was stirred at room temperature under 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). With 3X 100mL saturated NaHCO ₃ The resulting mixture was washed with the solution. The combined organic layers were washed with brine (1X 100 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2- (4- { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy) as a white solid]-5', 6-dimethyl-2-oxo- [1,4' -bipyridine]-2' -yl } pyrimidin-2-yl) -2-methylpropanaldehyde (260 mg, 74.57%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝526.2。

Step 2: preparation of 3-chloro-2' - [2- (1, 1-difluoro-2-methylpropan-2-yl) pyrimidin-4-yl]-4- [ (3, 5-difluoro) Pyridin-2-yl) methoxy]-5', 6-dimethyl- [1,4' -bipyridine]-2-one：

To 2- (4- { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy group at 0℃under a nitrogen atmosphere]-5', 6-dimethyl-2-oxo- [1,4' -bipyridine]To a solution of 2' -yl } pyrimidin-2-yl) -2-methylpropanaldehyde (260 mg,0.49mmol,1.00 eq.) in DCE (10 mL) was added BAST (547 mg,2.47mmol,5.00 eq.) dropwise, and the mixture was stirred overnight at 80 ℃. The reaction was monitored by LCMS. The resulting mixture was brought to room temperature and diluted with EtOAc (100 mL). The combined organic layers were washed with brine (3X 100 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-chloro-2' - [2- (1, 1-difluoro-2-methylpropan-2-yl) pyrimidin-4-yl as a white solid]-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-5', 6-dimethyl- [1,4' -bipyridine]-2-one (195 mg, 69.90%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝548.2。 ¹ HNMR(400MHz,DMSO-d ₆ )δ9.00(d,1H),8.87(s,1H),8.62(d,1H),8.51(s,1H),8.27(d,1H),8.11(ddd,1H),6.85(s,1H),6.75(t,1H),5.50(d,2H),2.10(s,3H),1.98(s,3H),1.45(d,6H)。 ¹⁹ F NMR(377MHz,DMSO)δ-120.11,-120.13,-122.29,-122.31,-128.77。

Step 3: preparation of rel-3-chloro-2' - [2- (1, 1-difluoro-2-methylpropan-2-yl) pyrimidin-4-yl ]]-4-[(3,5- Difluoro pyridin-2-yl) methoxy]-5', 6-dimethyl- [1,4' -bipyridine]-2-one and rel-3-chloro-2' - [2- (1, 1-di-) Fluoro-2-methylpropan-2-yl) pyrimidin-4-yl]-4- [ (3, 5-difluoropyridin-2-yl) methoxy]5', 6-dimethyl- [1,4' ] and bipyridine (P)]-2-one：

The racemate 3-chloro-2 ' - [2- (1, 1-difluoro-2-methylpropan-2-yl) pyrimidin-4-yl ] -4- [ (3, 5-difluoropyridin-2-yl) methoxy ] -5', 6-dimethyl- [1,4' -bipyridin ] -2-one (135 mg) was separated by preparative chiral HPLC to give rel-3-chloro-2 ' - [2- (1, 1-difluoro-2-methylpropan-2-yl) pyrimidin-4-yl ] -4- [ (3, 5-difluoropyridin-2-yl) methoxy ] -5', 6-dimethyl- [1,4' -bipyridin ] -2-one (example 5a,53mg, ee% = 100%) and rel-3-chloro-2 ' - [2- (1, 1-difluoro-2-methylpropan-2-yl) pyrimidin-4-yl ] -4- [ (3, 5-difluoropyridin-2-yl) methoxy ] -5', 6-dimethyl- [1,4' -bipyridin ] -2-one (example 5mg, 5% = 100%).

Example 5A：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝548.2。 ¹ H NMR(400MHz,DMSO-d ₆ )δ9.00(d,1H),8.88(s,1H),8.62(d,1H),8.51(s,1H),8.28(d,1H),8.18–8.05(m,1H),6.98–6.54(m,2H),5.50(d,2H),2.11(s,3H),1.98(s,3H),1.45(s,6H)。 ¹⁹ F NMR(377MHz,DMSO)δ-120.12,-120.14,-122.29,-122.31,-128.77。

Example 5B：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝548.2。 ¹ H NMR(400MHz,DMSO-d ₆ )δ9.00(d,1H),8.88(s,1H),8.62(d,1H),8.51(s,1H),8.28(d,1H),8.16–8.07(m,1H),6.95–6.55(m,2H),5.50(d,2H),2.11(s,3H),1.98(s,3H),1.45(s,6H)。 ¹⁹ F NMR(377MHz,DMSO)δ-120.11,-120.14,-122.28,-122.31,-128.77。

Examples 6, 6A, 6B, 6C, 6D

Step 1: preparation of 2-cyclopropyl-2- [ (trimethylsilyl) oxy]Propionitrile (Propionitrile)：

ZnI is added in portions to a stirred solution of cyclopropylmethanone (10.00 g,118.90mmol,1.00 eq.) and trimethylsilylcyanide (14.15 g,142.60mmol,1.20 eq.) in THF (150 mL) at room temperature under nitrogen atmosphere ₂ (1.90 g,5.90mmol,0.05 eq.). The mixture was stirred at room temperature under nitrogen overnight. The reaction was monitored by TLC. The resulting mixture was concentrated under reduced pressure. The mixture was diluted with water (50 mL). By CH ₂ Cl ₂ The resulting mixture was extracted (3X 200 mL). The combined organic layers were washed with brine (2X 50 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2-cyclopropyl-2- [ (trimethylsilyl) oxy as a colorless oil]Propionitrile (12.00 g, 55.06%). ¹ HNMR (300 MHz, chloroform-d) δ1.65 (s, 3H), 1.25-1.11 (m, 1H), 0.70-0.49 (m, 4H), 0.24 (s, 9H).

Step 2: preparation of 2-formamidino-2, 2-dimethyl acetic acid methyl ester HCl salt：

To a stirred solution of methyl 2-cyano-2, 2-dimethylacetate (12.00 g,94.40mmol,1.00 eq.) in MeOH (30 mL) under nitrogen at 0deg.C was added HCl (236 mL,944.0mmol,10.00 eq., 4M CH) dropwise ₃ OH solution). The mixture was stirred at room temperature under nitrogen for 7 hours. The resulting mixture was concentrated in vacuo. CH of the above mixture at 0deg.C for 20 min ₃ NH was added dropwise to OH (30.00 mL) solution ₃ Solution (470 mL,1.88mol,20.00 eq, 4M CH ₃ OH solution). The resulting mixture was stirred at room temperature overnight. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The product was precipitated by addition of EtOH (30 mL). The resulting mixture was filtered and the filter cake was washed with EtOH (2X 30 mL). The filtrate was concentrated under reduced pressure. By using Et ₂ O (3X 20 mL) was triturated to purify the residue. This yielded methyl 2-formamidino-2, 2-dimethyl acetate HCl salt (3 g, 22.05%) as a yellow semi-solid. LC-MS (ES+H, M/z) [ M+H ]]+＝129.3。 ¹ H NMR(300MHz,DMSO-d ₆ )δ5.94(s,1H),1.50(s,3H),1.40–1.24(m,1H),0.58–0.30(m,4H)。

Step 3: preparation of 3-chloro-2' - [2- (1-cyclopropyl-1-hydroxyethyl) pyrimidin-4-yl]-4- [ (3, 5-difluoropyrazine) Pyridin-2-yl) methoxy]-5', 6-dimethyl- [1,4' -bipyridine]-2-one：

To 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy at room temperature under a nitrogen atmosphere]-2' - [ (2E) -3- (dimethylamino) prop-2-enoyl]-5', 6-dimethyl- [1,4' -bipyridine]To a stirred mixture of 2-ketone (50 mg,0.10mmol,1.00 eq.) and 2-cyclopropyl-2-hydroxypropionamidine HCl salt (108 mg,0.84mmol,8.00 eq.) in i-PrOH (1 mL) was added K in portions ₂ CO ₃ (2910 mg,2.10mmol,20.00 eq.). The resulting mixture was stirred overnight at 80 ℃ under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EtOAc (3X 30 mL). The combined organic layers were washed with brine (2X 5 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase combi-flash chromatography. The pure fractions were concentrated in vacuo to give 3-chloro-2' - [2- (1-cyclopropyl-1-hydroxyethyl) pyrimidin-4-yl as a white solid]-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-5', 6-dimethyl- [1,4' -bipyridine]2-Ketone (13.0 mg, 22.87%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝539.90。 ¹ H NMR(400MHz,DMSO-d ₆ )δ9.00(dd,1H),8.86(s,1H),8.78(d,1H),8.61(d,1H),8.26(dd,1H),8.13–8.08(m,1H),6.85(s,1H),5.50(s,2H),4.92(d,1H),2.11(s,3H),1.98(d,3H),1.56(s,3H),1.43–1.36(m,1H),0.48–0.37(m,1H),0.41–0.29(m,2H),0.17–0.11(m,1H)。 ¹⁹ F NMR(377MHz,DMSO)δ-120.13,-122.30。

Step 4: preparation of rel-3-chloro-2' - [2- (1-cyclopropyl-1-hydroxyethyl) pyrimidin-4-yl ]]-4- [ (3, 5-difluoro) Pyridin-2-yl) methoxy]-5', 6-dimethyl- [1,4' -bipyridine]-2-one, rel-3-chloro-2' - [2- (1-cyclopropyl-1- ] Hydroxyethyl) pyrimidin-4-yl]-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-5', 6-dimethyl- [1,4' -bipyridine]- 2-one, rel-3-chloro-2' - [2- (1-cyclopropyl-1-hydroxyethyl) pyrimidin-4-yl]-4- [ (3, 5-difluoropyridin-2-yl) methyl Oxy group]-5', 6-dimethyl- [1,4' -bipyridine]-2-keto, rel-3-chloro-2' - [2- (1-cyclopropyl-1-hydroxyethyl) azotemic acid Pyridin-4-yl]-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-5', 6-dimethyl- [1,4' -bipyridine]-2-one：

The racemate 3-chloro-2 ' - [2- (1-cyclopropyl-1-hydroxyethyl) pyrimidin-4-yl ] -4- [ (3, 5-difluoropyridin-2-yl) methoxy ] -5', 6-dimethyl- [1,4' -bipyridin ] -2-one (200 mg) was separated by preparative chiral HPLC to give a first elution peak (80 mg, example 6a & b) and a second elution peak (80 mg, example 6c & d).

The first eluting peak was further separated by preparative chiral HPLC to give rel-3-chloro-2 '- [2- (1-cyclopropyl-1-hydroxyethyl) pyrimidin-4-yl ] -4- [ (3, 5-difluoropyridin-2-yl) methoxy ] -5', 6-dimethyl- [1,4 '-bipyridin ] -2-one (example 6a,29.3mg, ee=95.3%) and rel-3-chloro-2' - [2- (1-cyclopropyl-1-hydroxyethyl) pyrimidin-4-yl ] -4- [ (3, 5-difluoropyridin-2-yl) methoxy ] -5', 6-dimethyl- [1,4' -bipyridin ] -2-one (example 6b,32.3mg, ee=98.7%) as a white solid.

Example 6A：

LC-MS:(ES+H,m/z):[M+H]+＝539.90。 ¹ H NMR(300MHz,DMSO-d ₆ )δ9.01(d,1H),8.86(s,1H),8.80(s,1H),8.62(d,1H),8.27(d,1H),8.11(td,1H),6.85(s,1H),5.50(s,2H),4.93(s,1H),2.11(s,3H),1.99(s,3H),1.57(s,3H),1.42–1.36(m,1H),0.49–0.46(m,1H),0.41–0.37(m,2H),0.13–0.12(m,1H)。 ¹⁹ F NMR(282MHz,DMSO)δ-120.13,-120.15,-122.30,-122.33。

Example 6B：

LC-MS:(ES+H,m/z):[M+H]+＝540.10。 ¹ H NMR(300MHz,DMSO-d ₆ )δ9.00(d,1H),8.86(s,1H),8.78(s,1H),8.61(d,1H),8.26(d,1H),8.10(td,1H),6.85(s,1H),5.50(s,2H),4.91(s,1H),2.11(s,3H),1.98(s,3H),1.56(s,3H),1.44–1.38(m,1H),0.49–0.46(m,1H),0.41–0.37(m,2H),0.13–0.12(m,1H)。 ¹⁹ F NMR(282MHz,DMSO)δ-120.14,-120.16,-122.31,-122.33。

The second elution peak above was further separated by preparative chiral HPLC to give rel-3-chloro-2 '- [2- (1-cyclopropyl-1-hydroxyethyl) pyrimidin-4-yl ] -4- [ (3, 5-difluoropyridin-2-yl) methoxy ] -5', 6-dimethyl- [1,4 '-bipyridin ] -2-one (example 6c,28.0mg, ee=99.5%) and rel-3-chloro-2' - [2- (1-cyclopropyl-1-hydroxyethyl) pyrimidin-4-yl ] -4- [ (3, 5-difluoropyridin-2-yl) methoxy ] -5', 6-dimethyl- [1,4' -bipyridin ] -2-one (example 6d,28.8mg, ee=95.1%) as a white solid.

Example 6C：

LC-MS:(ES+H,m/z):[M+H]+＝540.2。 ¹ H NMR(300MHz,DMSO-d ₆ )δ9.00(d,1H),8.86(s,1H),8.79(s,1H),8.61(d,1H),8.26(d,1H),8.10(td,1H),6.84(s,1H),5.50(s,2H),4.94(s,1H),2.11(s,3H),1.98(s,3H),1.56(s,3H),1.42–1.35(m,1H),0.48–0.44(m,1H),0.40–0.38(m,2H),0.13–0.12(m,1H)。 ¹⁹ F NMR(282MHz,DMSO)δ-120.14,-120.16,-122.32,-122.34。

Example 6D：

LC-MS:(ES+H,m/z):[M+H]+＝540.2。 ¹ H NMR(300MHz,DMSO-d ₆ )δ9.00(d,1H),8.86(s,1H),8.78(s,1H),8.61(d,1H),8.26(d,1H),8.10(td,1H),6.85(s,1H),5.50(s,2H),4.94(s,1H),2.11(s,3H),1.98(s,3H),1.56(s,3H),1.44–1.38(m,1H),0.50–0.48(m,1H),0.39–0.34(m,2H),0.13–0.12(m,1H)。 ¹⁹ F NMR(282MHz,DMSO)δ-120.14,-120.16,-122.31,-122.33。

Example 7

Step 1: preparation of 2' -chloro-4-hydroxy-5 ' -methoxy-6-methyl- [1,4' -bipyridine]-2-one：

To a stirred solution of 2, 2-dimethyl-6- (2-oxopropyl) -1, 3-dioxin-4-one (1.16 g,6.31mmol,1.00 eq.) in 1, 4-dioxane (17 mL) was added 2-chloro-5-methoxypyridin-4-amine (1.00 g,6.31mmol,1.00 eq.) at room temperature. The resulting mixture was stirred under nitrogen at 90 ℃ for 3 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. H was added to the above mixture at room temperature ₂ SO ₄ (0.5 mL). The resulting mixture was stirred under nitrogen at 90 ℃ for 1 hour. The reaction was monitored by LCMS. The mixture was cooled to room temperature. H was added to the above mixture at room temperature ₂ O (10 mL). The resulting mixture was filtered and the filter cake was washed with diethyl ether (2X 10 mL). Concentrating the filter cake under reduced pressure to obtain 2' -chloro-4-hydroxy-5 ' -methoxy-6-methyl- [1,4' -bipyridine as brown yellow solid]-2-one (990 mg, crude). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝267.1。

Step 2: preparation of 2' -chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-5 '-methoxy-6-methyl- [1,4' ] Bipyridine (P)]-2-one：

To 2' -chloro-4-hydroxy-5 ' -methoxy-6-methyl- [1,4' -bipyridine at room temperature ]To a stirred solution of 2-ketone (990 mg, crude) and 2- (chloromethyl) -3, 5-difluoropyridine (911 mg,5.57mmol,1.50 eq.) in DMF (20 mL) was added 18-crown-6 (10 mg,0.04mmol,0.01 eq.) and K ₂ CO ₃ (1.54 g,11.14mmol,3.00 eq.). The resulting mixture was stirred under nitrogen at 60 ℃ for 4 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography to give 2' -chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy as a pale yellow solid]-5 '-methoxy-6-methyl- [1,4' -bipyridine]2-Ketone (79mg, 31.8%,2 steps). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝394.0。

Step 3: preparation of 4- [ (3, 5-difluoropyridin-2-yl) methoxy]-2'- (1-ethoxyvinyl) -5' -methoxyl 1,4' -bipyridine-6-yl-methyl-6-methyl]-2-one：

To 2' -chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy at room temperature]-5 '-methoxy-6-methyl- [1,4' -bipyridine]Pd (PPh) was added to a stirred solution of 2-ketone (79mg, 2.01mmol,1.00 eq.) and tributyl (1-ethoxyvinyl) stannane (1.45 g,4.01mmol,2.00 eq.) in 1, 4-dioxane (20 mL) ₃ ) ₂ Cl ₂ (141 mg,0.20mmol,0.10 eq.). The resulting mixture was stirred under nitrogen at 100 ℃ for 2 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. Filtering the resulting mixture The cake was washed with EA (2X 20 mL). The filtrate was concentrated under reduced pressure to give 4- [ (3, 5-difluoropyridin-2-yl) methoxy as a yellow oil]-2' - (1-ethoxyvinyl) -5' -methoxy-6-methyl- [1,4' -bipyridine]-2-one (860 mg, crude). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝430.0。

Step 4: preparation of 2' -acetyl-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-5' -methoxy-6-methyl-) [1,4' -bipyridine]-2-one：

At 0℃to 4- [ (3, 5-difluoropyridin-2-yl) methoxy]-2' - (1-ethoxyvinyl) -5' -methoxy-6-methyl- [1,4' -bipyridine]To a stirred solution of 2-keto (860 mg, crude) in THF (10 mL) was added HCl (0.20 mL,6.59mmol,28.27 eq.) dropwise. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. The mixture was basified with saturated sodium carbonate solution. The resulting mixture was extracted with EA (3X 50 mL). The combined organic layers were washed with brine (50 mL) and concentrated under reduced pressure. The residue was purified by flash chromatography to give 2' -acetyl-4- [ (3, 5-difluoropyridin-2-yl) methoxy as a white solid]-5 '-methoxy-6-methyl- [1,4' -bipyridine]2-Ketone (540 mg,67.1%,2 steps). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝402.0。

Step 5: preparation of 2' -acetyl-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy ]-5' -methoxy-6-methyl Base- [1,4' -bipyridine]-2-one：

To 2' -acetyl-4- [ (3, 5-difluoropyridin-2-yl) methoxy at room temperature]-5 '-methoxy-6-methyl- [1,4' -bipyridine]To a stirred solution of 2-ketone (500 mg,1.25mmol,1.00 eq.) and NCS (175 mg,1.31mmol,1.05 eq.) in MeCN (10 mL) was added 2, 2-dichloroacetic acid (16 mg,0.12mmol,0.10 eq.). The resulting mixture was stirred under nitrogen at 60 ℃ for 1 hour. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. Purification of the residue by flash chromatography gives 2' -acetyl-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-5 '-methoxy-6-methyl- [1,4' -bipyridine]-2-one (420 mg, 77.36%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝436.1。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.76(s,1H),8.60(d,1H),8.16–8.03(m,1H),7.96(s,1H),6.73(s,1H),5.48(d,2H),4.02(s,3H),2.65(s,3H),1.94(s,3H)。

Step 6: preparation of 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-2' - [2- (2-hydroxy-prop-2-yl) azoxystrobin Pyridin-4-yl]-5 '-methoxy-6-methyl- [1,4' -bipyridine]-2-one：

2' -acetyl-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-5 '-methoxy-6-methyl- [1,4' -bipyridine]A solution of 2-ketone (370 mg,0.85mmol,1.00 eq.) in DMF-DMA (3 mL) was stirred under nitrogen at 100deg.C for 12 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. To a solution of the above mixture in DMF (5 mL) was added 2-hydroxy-2-methylpropionamidine hydrochloride (353 mg,2.55mmol,3.00 eq.) and K at room temperature ₂ CO ₃ (587 mg,4.25mmol,5.00 eq.). The resulting mixture was stirred under nitrogen at 80 ℃ for an additional 4 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography to give the product. The crude product was further purified by preparative HPLC to give the pure fraction. The pure fractions were concentrated in vacuo and then lyophilized to give 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy as a white solid]-2' - [2- (2-hydroxy-prop-2-yl) pyrimidin-4-yl]-5 '-methoxy-6-methyl- [1,4' -bipyridine]-2-one (120.9 mg, 26.82%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝529.90。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.93(d,1H),8.80(s,1H),8.73(s,1H),8.61(d,1H),8.18(d,1H),8.10(ddd,1H),6.77(s,1H),5.50(s,2H),5.23(s,1H),4.01(s,3H),2.00(s,3H),1.53(d,6H)。 ¹⁹ F NMR(377MHz,DMSO)δ-120.16,-122.38。

Example 8

Step 1: preparation of 4- ((3, 5-difluoropyridin-2-yl) methoxy) -5', 6-dimethyl-2' - (trimethylstannane Radical) -2H- [1,4' -bipyridine]-2-one：

To 2' -chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy at room temperature under nitrogen]-5', 6-dimethyl- [1,4' -bipyridine]To a mixture of 2-one (1.10 g,2.91mmol,1.00 eq.) and hexamethyldisiloxane (1.14 g,3.48mmol,1.20 eq.) in dioxane (20 mL) was added Pd (PPh ₃ ) ₂ Cl ₂ (0.41 g,0.58mmol,0.20 eq.) and AsPh ₃ (0.18 g,0.58mmol,0.20 eq.). The mixture was stirred overnight at 80 ℃ under nitrogen atmosphere. The reaction was monitored by LCMS. The desired product was detectable by LCMS. The mixture was used directly in the next step. LC-MS (ES+H, M/z) [ M+H ] ] ⁺ ＝508.1。

Step 2: preparation of 2- (4-bromo-2-chloro-3-fluoro-5-methylphenoxymethyl) -3, 5-difluoropyridine：

To the reaction mixture of the last step was added ethyl 2-bromothiazole-4-carboxylate (680 mg,2.91mmol,1.00 eq.) Pd (PPh) under nitrogen at room temperature ₃ ) ₂ Cl ₂ (0.41 g,0.58mmol,0.20 eq.). The mixture was stirred overnight at 80 ℃ under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was first purified by silica gel column chromatography to give a crude product (300 mg). The crude product (300 mg) was further purified by preparative HPLC and the pure fractions concentrated to give 2- {4- [ (3, 5-difluoropyridin-2-yl) methoxy as a white solid]-2,5 '-dimethyl-6-oxo- [1,4' -bipyridine]-2' -yl } -1, 3-thiazole-4-carboxylic acid ethyl ester (160 mg,11.0%, two steps). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝499.0。

Step 3: preparation of 4- [ (3, 5-difluoropyridin-2-yl) methoxy]-2' - [4- (2-hydroxy-prop-2-yl) -1, 3-thia-tion Azol-2-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one：

To 2- {4- [ (3, 5-difluoropyridin-2-yl) methoxy group under nitrogen at 0 ℃]-2,5 '-dimethyl-6-oxo- [1,4' -bipyridine]Ethyl-2' -yl } -1, 3-thiazole-4-carboxylate (160 mg,0.32mmol,1.00 eq.) in THF (5 mL) was added dropwise CH ₃ MgBr in THF (1.0 mL,0.96mmol,3.00 eq., 1M). The mixture is put inStir at room temperature under nitrogen 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 purified directly by preparative HPLC and the pure fractions were concentrated and lyophilized to give 4- [ (3, 5-difluoropyridin-2-yl) methoxy group as a white solid]-2' - [4- (2-hydroxy-prop-2-yl) -1, 3-thiazol-2-yl ]]-5', 6-dimethyl- [1,4' -bipyridine]-2-one (20 mg, 12.9%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝485.0。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.68(s,1H),8.60(d,1H),8.11-8.06(m,1H),7.91(s,1H),7.53(s,1H),6.16(d,1H),6.05(d,1H),5.26(s,2H),5.22(s,1H),2.06(s,3H),1.88(s,3H),1.50(s,6H)。 ¹⁹ F NMR(377MHz,DMSO)δ-120.29,-122.43。

Examples 9, 9A, 9B

Step 1: preparation of 1- (3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy) -5', 6-dimethyl-2-oxo- 2H- [1,4' -bipyridine]-2' -yl) -1H-pyrazole-5-carboxylic acid methyl ester：

To 2' -bromo-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy at room temperature]-5', 6-dimethyl- [1,4' -bipyridine]To a stirred solution of 2-ketone (200 mg,0.44mmol,1.00 eq.) and methyl 1H-pyrazole-3-carboxylate (110 mg,0.88mmol,2.00 eq.) in 1, 4-dioxane (5 mL) was added K ₂ CO ₃ (121 mg,0.88mmol,2.00 eq.), cuI (17 mg,0.09mmol,0.20 eq.) and N1, N2-dimethylcyclohexane-1, 2-diamine (25 mg,0.18mmol,0.40 eq.). The resulting mixture was stirred overnight at 90 ℃ under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was purified directly by reverse phase combi-flash chromatography. The pure fractions were concentrated in vacuo to give 1- (3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy) -5', 6-dimethyl-2-oxo-2H- [1,4' -bipyridine) as a pale yellow solid ]-2' -yl) -1H-pyrazole-5-carboxylic acid methyl ester (180 mg, 81.89%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝502.10。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.76(d,1H),8.67–8.58(m,2H),8.14–8.05(m,1H),8.01(s,1H),7.05(d,1H),6.80(s,1H),5.49(s,2H),3.86(s,3H),2.06(s,3H),2.00(s,3H)。

Step 2: preparation of 3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy) -2' - (5- (2-hydroxypropan-2-yl) propanoic acid) room 1H-pyrazol-1-yl) -5', 6-dimethyl-2H- [1,4' -bipyridine]-2-one：

To 1- { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy group at-30℃under nitrogen atmosphere]-5', 6-dimethyl-2-oxo- [1,4' -bipyridine]To a stirred solution of methyl-2' -yl } pyrazole-3-carboxylate (150 mg,0.30mmol,1.00 eq.) in THF (8 mL) was added MeMgBr (3 mL,2.99mmol,10.00 eq., 1M in THF) dropwise. The resulting mixture was warmed to room temperature and stirred under nitrogen atmosphere for 30 minutes. The reaction was monitored by LCMS. With saturated NH ₄ The reaction was quenched with Cl (aqueous solution) at room temperature. The residue was purified by reverse phase flash chromatography to give the product. The crude product was further purified by preparative HPLC. The pure fractions were concentrated in vacuo and then lyophilized to give 3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy) -2' - (5- (2-hydroxypropan-2-yl) -1H-pyrazol-1-yl) -5', 6-dimethyl-2H- [1,4' -bipyridine) as a white solid]-2-one (25 mg, 16.67%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝502.14 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.61(d,1H),8.57–8.49(m,2H),8.14–8.05(m,1H),7.79(s,1H),6.81(s,1H),6.57(d,1H),5.49(s,2H),5.11(s,1H),2.01(d,6H),1.48(s,6H)。 ¹⁹ F NMR(377MHz,DMSO)δ-120.15,-122.32。

Step 3: preparation of rel-3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy) -2' - (3- (2-hydroxypropyl-2-) 1H-pyrazol-1-yl) -5', 6-dimethyl-2H- [1,4' -bipyridine]-2-one and rel-3-chloro-4- ((3, 5-difluoropyrazine) Pyridin-2-yl) methoxy) -2' - (3- (2-hydroxy-prop-2-yl) -1H-pyrazol-1-yl) -5', 6-dimethyl-2H- [1,4' -bipyramid Pyridine and pyridine]-2-one：

The racemate 3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy) -2' - (3- (2-hydroxypropyl-2-yl) -1H-pyrazol-1-yl) -5', 6-dimethyl-2H- [1,4' -bipyridin ] -2-one (80 mg) was isolated by chiral preparative HPLC. The pure fractions were concentrated under reduced pressure to give rel-3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy) -2'- (3- (2-hydroxypropan-2-yl) -1H-pyrazol-1-yl) -5', 6-dimethyl-2H- [1,4 '-bipyridin ] -2-one (example 9a,34mg, ee=100%) and rel-3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy) -2' - (3- (2-hydroxypropan-2-yl) -1H-pyrazol-1-yl) -5', 6-dimethyl-2H- [1,4' -bipyridin ] -2-one (example 9b,32.9mg, ee=100%) as white solids.

Example 9A：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝502.2。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.60(d,1H),8.54(s,1H),8.51(d,1H),8.14-8.08(m,1H),7.78(s,1H),6.80(d,1H),6.56(d,1H),5.48(d,2H),5.09(s,1H),2.01(s,3H),2.00(s,3H),1.48(s,6H)。 ¹⁹ F NMR(282MHz,DMSO)δ-120.15,-120.17,-120.34,-122.37。

Example 9B：

Example 10

Step 1: preparation of 4-chloro-6-cyclopropylpyrimidine-2-carboxylic acid ethyl ester：

To ethyl 4, 6-dichloropyrimidine-2-carboxylate (500 mg,2.262mmol,1.00 eq.) and cyclopropylboronic acid (194.30 mg,2.262mmol,1 eq.) in toluene (5 mL) and H at room temperature under a nitrogen atmosphere ₂ Pd (dppf) Cl was added to a stirred solution in O (0.5 mL) ₂ (37.48 mg,0.068mmol,0.03 eq.) and Cs ₂ CO ₃ (1474.03 mg,4.524mmol,2 eq). The resulting mixture was stirred under nitrogen at 100 ℃ for 1 hour. The reaction was monitored by LCMS. The resulting mixture was diluted with water (2 mL). The aqueous layer was extracted with EtOAc (3X 5 mL). By silica gel column chromatographyThe residue was purified to give ethyl 4-chloro-6-cyclopropylpyrimidine-2-carboxylate (410 mg, 79.97%) as a yellow oil. MS (ES+H, M/z) [ M+H ]] ⁺ ＝227.0

Step 2: preparation of 4-cyclopropyl-6- (trimethylstannyl) pyrimidine-2-carboxylic acid ethyl ester：

To 4-chloro-6-cyclopropylpyrimidine-2-carboxylic acid ethyl ester (400 mg,1.765mmol,1.00 eq.) and Sn under nitrogen at room temperature ₂ Me ₆ (636.01 mg,1.942mmol,1.10 eq.) Pd (PPh) was added to a stirred solution of 1, 4-dioxane (2 ml) ₃ ) ₂ Cl ₂ (247.74 mg,0.353mmol,0.2 eq.) and AsPh ₃ (162.13 mg,0.529mmol,0.3 eq.). The resulting mixture was stirred overnight at 80 ℃ under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was used directly in the next step without further purification. MS (ES+H, M/z) [ M+H ]] ⁺ ＝357.0

Step 3: preparation of 4- { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-5', 6-dimethyl-2-oxo- [1,4' -bipyridine]-2' -yl } -6-cyclopropyl pyrimidine-2-carboxylic acid ethyl ester：

To a stirred solution of ethyl 4-cyclopropyl-6- (trimethylstannyl) pyrimidine-2-carboxylate (630 mg,1.775mmol,1.00 eq.) in 1, 4-dioxane (5 ml) at room temperature under nitrogen was added 2' -bromo-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-5', 6-dimethyl- [1,4' -bipyridine]-2-one (405.19 mg,0.887mmol,0.50 eq.) and AsPh ₃ (108.68 mg,0.355mmol,0.2 eq.) Pd (PPh) ₃ ) ₂ Cl ₂ (373.66 mg, 0.284 mmol,0.3 eq.). The resulting mixture was stirred under nitrogen at 80 ℃ for 2 days. The reaction was monitored by LCMS. The resulting mixture was diluted with water (5 mL). The aqueous layer was extracted with EtOAc (3X 10 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (PE/EA 1:1) to give 4- { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy as a yellow solid]-5', 6-dimethyl-2-oxo- [1,4' -bipyridine]-2' -yl } -6-cyclopropylpyrimidine-2-carboxylic acid ethyl ester (70 mg, 6.95%). MS (ES+H, M/z) [ M+H ]] ⁺ ＝568.3

Step 4: preparation of 3-chloro-2' - [ 6-cyclopropyl-2- (2-hydroxy-prop-2-yl) pyrimidin-4-yl]-4- [ (3, 5-difluoro) Pyridin-2-yl) methoxy]-5', 6-dimethyl- [1,4' -bipyridine]-2-one：

To 4- { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy group at 0℃under a nitrogen atmosphere ]-5', 6-dimethyl-2-oxo- [1,4' -bipyridine]To a stirred solution of ethyl-2' -yl } -6-cyclopropylpyrimidine-2-carboxylate (70 mg,0.123mmol,1.00 eq.) in THF (1 ml) was added MeMgBr (44.09 mg,0.369mmol,3 eq.). The resulting mixture was stirred under nitrogen at 0 ℃ for 1 hour. The reaction was monitored by LCMS. With saturated NH ₄ The reaction was quenched with Cl (aqueous solution) at 0 ℃. The resulting mixture was extracted with EtOAc (3X 5 mL). After filtration, the filtrate was concentrated under reduced pressure. Purification of the crude product (60 mg) by preparative HPLC gave 3-chloro-2' - [ 6-cyclopropyl-2- (2-hydroxypropyl-2-yl) pyrimidin-4-yl as a white solid]-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-5', 6-dimethyl- [1,4' -bipyridine]2-Ketone (17.2 mg, 25.19%). MS (ES+H, M/z) [ M+H ]] ⁺ ＝554.1 ¹ HNMR(300MHz,DMSO-d ₆ )δ8.84(s,1H),8.63(s,1H),8.61(d,1H),8.15(s,1H),8.10(t,1H),6.84(s,1H),5.58–5.41(m,2H),5.14(s,1H),2.38–2.25(m,1H),2.10(s,3H),1.98(s,3H),1.48(s,3H),1.47(s,3H),1.18-1.08(m,4H)。 ¹⁹ F NMR(282MHz,DMSO)δ-120.10,-120.13,-122.24,-122.27。

Example 11

Step 1: preparation of 1- { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-5', 6-dimethyl-2-oxo- [1,4' -bipyridine]-2' -yl } -5-methyl-1, 2, 4-triazole-3-carboxylic acid ethyl ester：

2' -bromo-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-5', 6-dimethyl- [1,4' -bipyridine]-2-one (400 mg,0.876mmol,1.00 eq), 5-methyl-1H-1, 2, 4-triazole-3-carboxylic acid ethyl ester (271.8 mg, 1.7512 mmol,2 eq), K ₂ CO ₃ (242.12 mg, 1.751mmol, 2 eq.) 1R, 2R) -N1, N2-dimethylcyclohexane A mixture of 1, 2-diamine (249.18 mg, 1.751mmol, 2.00 eq.) and CuI (41.7 mg,0.220mmol,0.25 eq.) in 1, 4-dioxane (6 mL) was stirred overnight at 100deg.C under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was cooled to room temperature. The resulting mixture was poured into 20ml of water. The resulting mixture was extracted with EtOAc (3X 20 mL). The combined organic layers were washed with brine (20 ml), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 1- { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy ] as a yellow solid]-5', 6-dimethyl-2-oxo- [1,4' -bipyridine]-2' -yl } -5-methyl-1, 2, 4-triazole-3-carboxylic acid ethyl ester (240 mg, y=49.03%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝531.1。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.72(s,1H),8.60(d,1H),8.10(t,1H),7.96(s,1H),6.81(s,1H),5.49(s,2H),4.35(q,2H),2.82(s,3H),2.09(s,3H),1.99(s,3H),1.32(t,3H)。

Step 2: preparation of 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-2' - [3- (2-hydroxy-prop-2-yl) -5-) Methyl-1, 2, 4-triazol-1-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one：

At N ₂ To 1- { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy group at-30℃under an atmosphere]-5', 6-dimethyl-2-oxo- [1,4' -bipyridine]To a stirred solution of ethyl-2' -yl } -5-methyl-1, 2, 4-triazole-3-carboxylate (200 mg,0.377mmol,1.00 eq.) in THF (10 mL) was added dropwise magnesium bromide (3.77 mL,10 eq., 1M in THF). The mixture obtained is put in N ₂ Stirred at room temperature. The reaction was monitored by LCMS. By addition of saturated NH at room temperature ₄ The reaction was quenched with Cl (20 mL). The resulting mixture was extracted with EtOAc (3X 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. Purification of the crude product by preparative HPLC gave 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy as a white solid]-2' - [3- (2-hydroxy-prop-2-yl) -5-methyl-1, 2, 4-triazol-1-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one (22.4 mg, y=11.2%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝517.25。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.66(s,1H),8.61(d,1H),8.14-8.07(m,1H),7.84(s,1H),6.82(s,1H),5.50(d,2H),5.15(s,1H),2.78(s,3H),2.07(s,3H),2.00(s,3H),1.51(s,6H)。 ¹⁹ F NMR(282MHz,DMSO)δ-120.127,-120.151,-122.289,-122.313。

Example 12

To 2', 3-dichloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy at room temperature]-5', 6-dimethyl- [1,4' -bipyridine]To a solution of 2-one (500 mg,1.213mmol,1.00 eq.) and hexamethyl-dittanine (476.88 mg, 1.266 mmol,1.2 eq.) in 1, 4-dioxane (10 ml) was added Pd (PPh) ₃ ) ₂ Cl ₂ (170.27 mg,0.243mmol,0.2 eq.) and AsPh ₃ (74.29 mg,0.243mmol,0.2 eq.). The resulting mixture was stirred overnight at 80 ℃ under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was used directly in the next step without further purification. LC-MS (ES+H, M/z) [ M+H ] ] ⁺ ＝542.1。

Step 2: preparation of 5- (3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy) -5', 6-dimethyl-2-oxo- 2H- [1,4' -bipyridine]-2' -yl) -1,2, 4-thiadiazole-3-carboxylic acid methyl ester：

Methyl 5-bromo-1, 2, 4-thiadiazole-3-carboxylate (136.16 mg,0.611mmol,0.50 eq.) CuI (232.52 mg,1.221mmol,1 eq.) and Pd (PPh) at room temperature ₃ ) ₂ Cl ₂ (171.39 mg,0.244mmol,0.2 eq.) was added to the reaction solution of the previous step (assuming 100% yield). The resulting mixture was stirred under nitrogen at 80 ℃ for 2 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography to give 5- (3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy as a yellow solidPhenyl) -5', 6-dimethyl-2-oxo-2H- [1,4' -bipyridine]-2' -yl) -1,2, 4-thiadiazole-3-carboxylic acid methyl ester (150 mg,23.63%, two steps). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝520.0。

Step 3: preparation of 3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy) -2' - (3- (2-hydroxypropan-2-yl) -1, 2, 4-thiadiazol-5-yl) -5', 6-dimethyl-2H- [1,4' -bipyridine]-2-one：

To 5- (3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy) -5', 6-dimethyl-2-oxo-2H- [1,4' -bipyridine) at 0℃under a nitrogen atmosphere ]Methyl-2' -yl) -1,2, 4-thiadiazole-3-carboxylate (150 mg,0.289mmol,1 eq.) in THF (5 mL) under stirring ₃ MgBr (0.58 mL,0.578mmol,2 eq., 1M in THF). The resulting mixture was stirred under nitrogen at 0 ℃ for 1 hour. The reaction was monitored by LCMS. The reaction was quenched by the addition of MeOH (5 mL) at 0 ℃. The resulting mixture was concentrated under reduced pressure. The mixture was purified by preparative HPLC to give the crude product (50 mg). The crude product was further purified by preparative HPLC to give 3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy) -2' - (3- (2-hydroxypropan-2-yl) -1,2, 4-thiadiazol-5-yl) -5', 6-dimethyl-2H- [1,4' -bipyridine) as a white solid]2-Ketone (21.3 mg, 14.04%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝520.1。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.85(s,1H),8.61(d,1H),8.16(s,1H),8.11(td,1H),6.82(s,1H),5.49(s,2H),5.46(s,1H),2.11(s,3H),1.99(s,3H),1.61(s,3H),1.60(s,3H)。 ¹⁹ F NMR(377MHz,DMSO)δ-120.13,-120.15,-122.31,-122.33。

Example 13

Step 1: preparation of 1- { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-5', 6-dimethyl-2-oxo- [1,4' -bipyridine]-2' -yl } pyrazole-4-carboxylic acid ethyl ester：

To 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy at room temperature under a nitrogen atmosphere]-2',5', 6-trisMethyl- [1,4' -bipyridine]-2-one (300 mg,0.766mmol,1 eq.) 1H-pyrazole-4-carboxylic acid ethyl ester (215 mg, 1.284 mmol,2.00 eq.) K ₂ CO ₃ (212 mg,1.534mmol,2.00 eq.) and CuI (36.5 mg,0.192mmol,0.25 eq.) were added to a stirred solution of 1, 4-dioxane (4 mL), and (1S, 2S) -N1, N2-dimethylcyclohexane-1, 2-diamine (218 mg,1.53 mmol,2.00 eq.). The reaction was monitored by LCMS. The desired product was detectable by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 1- { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy ] as a yellow solid ]-5', 6-dimethyl-2-oxo- [1,4' -bipyridine]-2' -yl } pyrazole-4-carboxylic acid ethyl ester (260 mg, 65.82%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝516.1。 ¹ H NMR(400MHz,DMSO-d ₆ )δ9.03(s,1H),8.65(s,1H),8.61(d,1H),8.23(s,1H),8.14-8.06(m,1H),7.96(s,1H),6.81(s,1H),5.50-5.57(m,2H),4.28(q,2H),2.05(s,3H),1.99(s,3H),1.32(t,3H)。

Step 2: preparation of 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-2' - [4- (2-hydroxy-prop-2-yl) pyr-idine Azol-1-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one：

1- { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy was added to a 3-neck round bottom flask]-5', 6-dimethyl-2-oxo- [1,4' -bipyridine]A solution of ethyl-2' -yl } pyrazole-4-carboxylate (200 mg, 0.3838 mmol,1 eq.) in THF (5 mL). After nitrogen substitution, the temperature of the reaction system was reduced to-10 ℃. MeMgBr (4 mL,34.719mmol,10 eq.) was added dropwise to the above mixture at-10deg.C. The resulting mixture was stirred at room temperature for an additional 1 hour. The reaction was monitored by LCMS. The desired product was detectable by LCMS. Purification of the crude product by preparative HPLC gave 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy as a white solid]-2' - [4- (2-hydroxy-prop-2-yl) pyrazol-1-yl]-5', 6-dimethyl- [1,4' -bipyridine]2-Ketone (28.4 mg, 13.68%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝502.10。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.60(d,1H),8.55(s,1H),8.44(d,1H),8.15–8.05(m,1H),7.82–7.74(m,2H),6.82–6.77(m,1H),5.48(d,2H),5.05(s,1H),2.06–1.96(m,6H),1.47(s,6H)。 ¹⁹ F NMR(377MHz,DMSO)δ-120.13,-120.15,-122.32,-122.34。

Example 14

Step 1: preparation of 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-5', 6-dimethyl-2' - [6- (propane-1-) En-2-yl) pyridin-2-yl ]- [1,4' -bipyridyl]-2-one：

To 2' - (6-bromopyridin-2-yl) -3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy at room temperature under a nitrogen atmosphere]-5', 6-dimethyl- [1,4' -bipyridine]-2-one (150 mg,0.281mmol,1 eq.) and 4, 5-tetramethyl-2- (prop-1-en-2-yl) -1,3, 2-dioxaborolan (70.84 mg,0.422mmol,1.5 eq.) in dioxane (2 mL) and H ₂ CsF (85.38 mg,0.562mmol,2 eq.) and Pd (PPh) were added to a stirred solution in O (0.2 mL) ₃ ) ₄ (64.95 mg,0.056mmol,0.2 eq.). The resulting mixture was stirred under nitrogen at 90 ℃ for 2 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. With saturated NH ₄ Cl (aq) (10 mL) quenched the reaction at room temperature. The resulting mixture was extracted with EtOAc (3X 40 mL). The combined organic layers were washed with brine (1X 50 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE/EA 1:1) to give 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy as a white solid]-5', 6-dimethyl-2' - [6- (prop-1-en-2-yl) pyridin-2-yl]- [1,4' -bipyridyl]-2-one (200 mg, 86.28%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝495.2。

Step 2: preparation of 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy ]-2' - [6- (1, 2-dihydroxypropane-2-) Radical) pyridin-2-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one：

To 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy at room temperature under a nitrogen atmosphere]-5', 6-dimethyl-2' - [6- (prop-1-en-2-yl) pyridin-2-yl]- [1,4' -bipyridyl]-2-one (200 mg,0.242mmol,1 eq., 60%) and NMO (56.81 mg, 0.481mmol)l,2.00 eq.) K was added to a stirred solution of THF (3 mL) and t-BuOH (1 mL) ₂ OsO ₄ .2H ₂ O (44.67 mg,0.121mmol,0.50 eq.). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 3 hours. The reaction was monitored by LCMS. Filtering the resulting mixture; the filter cake was washed with THF (2X 3 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography. This gives 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy) as a white solid]-2' - [6- (1, 2-dihydroxypropan-2-yl) pyridin-2-yl]-5', 6-dimethyl- [1,4' -bipyridine]2-Ketone (42.6 mg, 33.22%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝529.10。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.77(s,1H),8.61(d,1H),8.36(d,1H),8.25(m,1H),8.10(m,1H),7.93(m,1H),7.67(m,1H),6.82(s,1H),5.49(s,2H),5.20-5.16(m,1H),4.59-4.55(m,1H),3.69–3.48(m,2H),2.06(s,3H),1.98(s,3H),1.43(s,3H)。 ¹⁹ F NMR(377MHz,DMSO)δ-120.12,-120.14,-122.33,-122.35。

Example 15

Step 1: preparation of 3-chloro-2' - [2- (2-hydroxy-prop-2-yl) pyrimidin-4-yl ]]-4- [ (4-methoxyphenyl) methoxy Base group]-5', 6-dimethyl- [1,4' -bipyridine]-2-one：

To 2' -acetyl-3-chloro-4- [ (4-methoxyphenyl) methoxy]-5', 6-dimethyl- [1,4' -bipyridine ]A stirred solution of 2-ketone (2 g,4.84mmol,1.00 eq.) in DMF-DMA (30 mL). The resulting mixture was stirred under nitrogen at 100 ℃ for 12 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. K is added to the stirred solution of the above mixture at room temperature ₂ CO ₃ (3.35 g,24.22mmol,5 eq.) and 2-hydroxy-2-methylpropionamidine hydrochloride (2.01 g,14.53mmol,3 eq.) in DMF (30 mL). The resulting mixture was stirred under nitrogen at 80 ℃ for 4 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. Purification of the residue by reverse phase flash chromatographyThe remainder gave 3-chloro-2' - [2- (2-hydroxypropyl-2-yl) pyrimidin-4-yl as a white solid]-4- [ (4-methoxyphenyl) methoxy group]-5', 6-dimethyl- [1,4' -bipyridine]2-Ketone (1.6 g, 65.17%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝507.1。

Step 2: preparation of 3-chloro-4-hydroxy-2' - [2- (2-hydroxy-prop-2-yl) pyrimidin-4-yl ]]-5', 6-dimethyl- [1, 4' -bipyridines]-2-one：

At room temperature, to 3-chloro-2' - [2- (2-hydroxy-propan-2-yl) pyrimidin-4-yl]-4- [ (4-methoxyphenyl) methoxy group]-5', 6-dimethyl- [1,4' -bipyridine]A stirred solution of 2-ketone (1.6 g,3.16mmol,1.00 eq.) and TFA (5 mL,67.32mmol,21.33 eq.) in DCM (10 mL). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure and the residue was purified by trituration with ether (10 mL) to give 3-chloro-4-hydroxy-2' - [2- (2-hydroxypropan-2-yl) pyrimidin-4-yl) ]-5', 6-dimethyl- [1,4' -bipyridine]-2-one (1 g, yellow semi-solid, TFA salt). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝387.0。

Step 3: preparation of 3-chloro-2' - [2- (2-hydroxy-prop-2-yl) pyrimidin-4-yl ]]-5', 6-dimethyl-2-oxo- [1, 4' -bipyridines]-4-yl triflate：

To 3-chloro-4-hydroxy-2' - [2- (2-hydroxypropan-2-yl) pyrimidin-4-yl at 0deg.C]-5', 6-dimethyl- [1,4' -bipyridine]To a stirred solution of 2-one (1 g, assuming 100% yield, 2.58mmol,1.00 eq.), lutidine (415.6 mg,3.88mmol,1.5 eq.) and DMAP (31.6 mg,0.26mmol,0.1 eq.) in DCM (10 mL) was added dropwise Tf ₂ O (948.2 mg,3.36mmol,1.3 eq.). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. Purification of the residue by flash chromatography gave 3-chloro-2' - [2- (2-hydroxypropan-2-yl) pyrimidin-4-yl ] as a yellow oil]-5', 6-dimethyl-2-oxo- [1,4' -bipyridine]-4-yl triflate (4816 mg,29.63%,2 steps). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝519.0。

Step 4: preparation of 2- { 3-chloro-2' - [2- (2-hydroxypropyl-2-yl)) Pyrimidin-4-yl]-5', 6-dimethyl-2-oxo- [1,4' -bipyridine]-4-yl } acetonitrile：

At room temperature, to 3-chloro-2' - [2- (2-hydroxy-propan-2-yl) pyrimidin-4-yl ]-5', 6-dimethyl-2-oxo- [1,4' -bipyridine]-4-yl triflate (360 mg,0.69mmol,1.00 eq.) and Zn (CN) ₂ To a stirred solution of (48.89 mg,0.42mmol,0.6 eq.) in DMF (4 mL) was added Pd (PPh) ₃ ) ₄ (80.17 mg,0.07mmol,0.1 eq.). The resulting mixture was stirred under nitrogen at 100 ℃ for 2 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography to give 2- { 3-chloro-2' - [2- (2-hydroxypropan-2-yl) pyrimidin-4-yl ] as a yellow solid]-5', 6-dimethyl-2-oxo- [1,4' -bipyridine]-4-yl } acetonitrile (190 mg, 66.79%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝396.0。

Step 5: preparation of 3-chloro-2' - [2- (2-hydroxy-prop-2-yl) pyrimidin-4-yl ]]-5', 6-dimethyl-2-oxo- [1, 4' -bipyridines]-4-formic acid：

To 3-chloro-2' - [2- (2-hydroxy-prop-2-yl) pyrimidin-4-yl at room temperature under nitrogen atmosphere]-5', 6-dimethyl-2-oxo- [1,4' -bipyridine]To a stirred solution of 4-nitrile (190 mg,0.48mmol,1.00 eq.) in EtOH (10 mL) was added NaOH (96 mg,2.40mmol,5.00 eq.). The resulting mixture was stirred at 100℃for a further 2 hours. The reaction was monitored by LCMS. The mixture was acidified using citric acid. The resulting mixture was diluted with EA (3X 50 mL). The resulting mixture was washed with aqueous NaCl (50 mL). By anhydrous Na ₂ SO ₄ The organic layer was dried. After filtration, the filtrate was concentrated under reduced pressure to give 3-chloro-2' - [2- (2-hydroxypropan-2-yl) pyrimidin-4-yl ] as a white solid]-5', 6-dimethyl-2-oxo- [1,4' -bipyridine]-4-formic acid (290 mg, crude) which was used without further purification. LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝415.1。

Step 6: preparation of 3-chloro-4- (hydroxymethyl) -2' - [2- (2-hydroxy-propan-2-yl) pyrimidin-4-yl]-5', 6-Dimetho Base- [1,4' -bipyridine]-2-one：

To 3-chloro-2' - [2- (2-hydroxypropan-2-yl) at room temperature under nitrogen atmosphere) Pyrimidin-4-yl]-5', 6-dimethyl-2-oxo- [1,4' -bipyridine]To a stirred solution of 4-carboxylic acid (250 mg,0.603mmol,1.00 eq.) in THF (10 mL) was added CDI (117.26 mg,0.724mmol,1.20 eq.) in portions. The resulting mixture was stirred at room temperature for 1 hour. The mixture was added dropwise to NaBH at 0℃over 5 minutes ₄ (68.40 mg, 1.09 mmol,3.00 eq.) in THF (10 mL) and H ₂ In solution in O (4 mL). The resulting mixture was stirred at room temperature for an additional 1 hour. By addition of saturated NaHCO ₃ (20 mL) the reaction was quenched at 0deg.C. The resulting mixture was extracted with DCM (3X 20 mL). The combined organic layers were concentrated under reduced pressure. Purification of the residue by reverse phase flash chromatography gave 3-chloro-4- (hydroxymethyl) -2' - [2- (2-hydroxypropyl-2-yl) pyrimidin-4-yl as a brown solid ]-5', 6-dimethyl- [1,4' -bipyridine]-2-one (60 mg, 24.84%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝401.1。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.98(d,1H),8.87(s,1H),8.69(s,1H),8.25(d,1H),6.66(s,1H),5.74–5.65(m,1H),5.26(s,1H),4.60–4.50(m,2H),2.10(s,3H),1.98(s,3H),1.53(s,3H),1.52(s,3H)。

Step 7: preparation of 3-chloro-4- { [ (3, 5-difluoropyridin-2-yl) oxy]Methyl } -2' - [2- (2-hydroxypropyl-2-) Base) pyrimidin-4-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one：

3-chloro-4- (hydroxymethyl) -2' - [2- (2-hydroxy-propan-2-yl) pyrimidin-4-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one (40 mg,0.100mmol,1 eq.) 2,3, 5-trifluoropyridine (26.56 mg,0.200mmol,2 eq.) and Cs ₂ CO ₃ A mixture of (97.54 mg,0.300mmol,3 eq.) in dioxane (4 mL) was stirred under nitrogen at 80℃for 5 hours. The reaction was monitored by LCMS. The resulting mixture was diluted with EA (50 mL). The resulting mixture was washed with 2X 50mL NaCl (aqueous solution). By anhydrous Na ₂ SO ₄ The organic layer was dried. After filtration, the filtrate was concentrated under reduced pressure. Purification of the crude product by preparative HPLC gave 3-chloro-4- { [ (3, 5-difluoropyridin-2-yl) oxy as a grey solid]Methyl } -2' - [2- (2-hydroxy-prop-2-yl) pyrimidin-4-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one (7 mg, 13.14%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝514.10。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.98(dd,1H),8.88(s,1H),8.72(s,1H),8.31–8.21(m,1H),8.13(d,1H),8.07(ddd,1H),6.56(s,1H),5.60–5.43(m,2H),5.26(s,1H),2.11(s,3H),1.96(s,3H),1.53(s,3H),1.52(s,3H)。 ¹⁹ F NMR(377MHz,DMSO)δ-133.74,-134.05。

Example 16

Step 1: preparation of 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]2' - (6-vinylpyridin-2-yl) the preparation of 5', 6-dimethyl- [1,4' -bipyridine ]-2-one：

To 2' - (6-bromopyridin-2-yl) -3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy at room temperature]-5', 6-dimethyl- [1,4' -bipyridine]-2-one (150 mg,0.281mmol,1 eq.) K ₂ CO ₃ (77.68 mg,0.562mmol,2 eq.) and 2-vinyl-4, 5-tetramethyl-1, 3, 2-dioxaborolan (86.57 mg,0.562mmol,2 eq.) in 1, 4-dioxane (2.5 mL) and H ₂ Pd (dppf) Cl was added to the stirred mixture in O (0.5 mL) ₂ -CH ₂ Cl ₂ (22.89 mg,0.028mmol,0.1 eq.). The resulting mixture was stirred under nitrogen at 100 ℃ for 2 hours. The reaction was monitored by LCMS. The reaction was cooled to room temperature. Purification of the crude product by reverse phase combi-flash gave 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy as a white solid]-2' - (6-vinylpyridin-2-yl) -5', 6-dimethyl- [1,4' -bipyridine]-2-one (100 mg, 73.99%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝481.12。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.79(d,1H),8.61(d,1H),8.33(d,1H),8.30(d,1H),8.15–8.05(m,1H),8.00–7.91(m,1H),7.60–7.53(m,1H),6.94–6.85(m,1H),6.82(s,1H),6.47–6.37(m,1H),5.56–5.45(m,3H),2.07(s,3H),1.98(s,3H)。

Step 2: preparation of 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-2' - [6- (1, 2-dihydroxyethyl) picolide Pyridin-2-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one：

In nitrogen atmosphereAt room temperature, NMO (48.72 mg,0.416mmol,2 eq.) and 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-2' - (6-vinylpyridin-2-yl) -5', 6-dimethyl- [1,4' -bipyridine ]To a stirred mixture of 2-ketone (100 mg,0.208mmol,1 eq.) in THF (1.5 mL) and t-BuOH (0.5 mL) was added K ₂ OsO4.2H ₂ O (38.31 mg,0.104mmol,0.5 eq.). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 15 hours. The reaction was monitored by LCMS. The reaction was quenched with saturated sodium thiosulfate (aqueous) (40 mL) and extracted with EtOAc (3×40 mL). By anhydrous Na ₂ SO ₄ The combined organic layers were dried. After filtration, the filtrate was concentrated under reduced pressure. Purification of the crude product (100 mg) by preparative HPLC gave 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy as a white solid]-2' - [6- (1, 2-dihydroxyethyl) pyridin-2-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one (46.6 mg, 43.35%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝515.12。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.77(s,1H),8.61(d,1H),8.32–8.22(m,2H),8.15–8.06(m,1H),7.94(t,1H),7.54(d,1H),6.82(s,1H),5.49(s,2H),5.44(t,1H),4.72–4.58(m,2H),3.81–3.68(m,1H),3.62–3.48(m,1H),2.07(s,3H),1.98(s,3H)。 ¹⁹ F NMR(377MHz,DMSO)δ-120.136,-120.154,-122.345,-122.364。

Example 17

Step 1: preparation of 2-bromo-5-methyl-1, 3-thiazole-4-carboxylic acid：

To a stirred solution of methyl 2-bromo-5-methyl-1, 3-thiazole-4-carboxylate (5.5 g, 23.294 mmol,1.00 eq.) in THF (25 ml) at room temperature under nitrogen atmosphere was added a solution of LiOH (1.12 g,46.768mmol,2.01 eq.) in water (25 ml). The resulting mixture was stirred under nitrogen at 50 ℃ for 30 minutes. The reaction was monitored by LCMS. The mixture was acidified to pH4 with concentrated HCl. The resulting mixture was extracted with EtOAc (3X 100 mL) and dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give a red solid2-bromo-5-methyl-1, 3-thiazole-4-carboxylic acid (5 g, 96.65%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝221.9。 ¹ H NMR(400MHz,DMSO-d ₆ )δ13.17(s,1H),2.67(s,3H)。

Step 2: preparation of tert-butyl N- (2-bromo-5-methyl-1, 3-thiazol-4-yl) carbamate：

DPPA (6.82 g,24.768mmol,1.1 eq.) was added dropwise to a stirred solution of 2-bromo-5-methyl-1, 3-thiazole-4-carboxylic acid (5 g,22.516mmol,1.00 eq.) and 2-methylpropan-2-ol (16.69 g,225.160mmol,10.00 eq.) in 1, 2-dimethoxyethane (50 mL) under nitrogen atmosphere at 0deg.C. The resulting mixture was stirred overnight at 90 ℃ under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with EA (100 mL). The resulting mixture was washed with water (3X 100 mL) and NaCl (aqueous solution) (100 mL). The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl N- (2-bromo-5-methyl-1, 3-thiazol-4-yl) carbamate (3.7 g, 56.05%) as a white solid. LC-MS (ES+H, M/z) [ M+H-56 ]] ⁺ ＝238.9。 ¹ H NMR(300MHz,DMSO-d ₆ )δ9.07(s,1H),2.19(d,3H),1.43(s,9H)。

Step 3: preparation of 4- (trimethylstannyl) pyrimidine-2-carboxylic acid ethyl ester：

To 4-chloropyrimidine-2-carboxylic acid ethyl ester (1.5 g,8.039mmol,1.00 eq.) and Sn at room temperature under nitrogen atmosphere ₂ Me ₆ (6.58 g,20.084mmol,2.50 eq.) Pd (PPh) was added to a stirred solution of 1, 4-dioxane (10 ml) ₃ ) ₂ Cl ₂ (1.69 g,2.412mmol,0.30 eq.) and AsPh ₃ (0.49 g,1.608mmol,0.2 eq.). The resulting mixture was stirred overnight at 80 ℃ under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with EA (100 mL) and washed with 5X 100mL of water and NaCl (aqueous solution) (100 mL) over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, 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 ]] ⁺ ＝317.0

Step 4: preparation of 4- {4- [ (tert-Butoxycarbonyl) amino group]-5-methyl-1, 3-thiazol-2-yl } pyrimidine-2-carboxylic acid Esters of：

To a stirred solution of ethyl 4- (trimethylstannyl) pyrimidine-2-carboxylate (2.5 g,7.938mmol,1.00 eq.) and tert-butyl N- (2-bromo-5-methyl-1, 3-thiazol-4-yl) carbamate (1.86 g,6.350mmol,0.8 eq.) in 1, 4-dioxane (20 ml) at room temperature under nitrogen was added CuI (1.51 g,7.938mmol,1 eq.) and Pd (PPh ₃ ) ₂ Cl ₂ (1.11 g,1.588mmol,0.2 eq.). The resulting mixture was stirred under nitrogen at 80 ℃ for 2 hours. The mixture was cooled to room temperature. The reaction was monitored by LCMS. The reaction mixture was partitioned between EA (100 mL) and water (100 mL). The organic layer was extracted with EtOAc (2X 200 mL) and the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 4- {4- [ (tert-butoxycarbonyl) amino as a white solid ]-5-methyl-1, 3-thiazol-2-yl } pyrimidine-2-carboxylic acid ethyl ester (650 mg, 22.47%). LC-MS (ES+H, M/z) [ M+H-56 ]] ⁺ ＝309.1。

Step 5: preparation of 4- (4-amino-5-methyl-1, 3-thiazol-2-yl) pyrimidine-2-carboxylic acid ethyl ester：

To 4- {4- [ (tert-butoxycarbonyl) amino group at room temperature under nitrogen atmosphere]To a stirred solution of ethyl 5-methyl-1, 3-thiazol-2-yl } pyrimidine-2-carboxylate (650 mg,1.784mmol,1 eq.) in DCM (2 ml) was added a solution of HCl (gas) in 1, 4-dioxane (2 ml). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 30 minutes. The reaction was monitored by LCMS. The resulting mixture was diluted with EA (100 mL). The resulting mixture was washed with water (3X 100 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give ethyl 4- (4-amino-5-methyl-1, 3-thiazol-2-yl) pyrimidine-2-carboxylate (440 mg, 93.33%) as a yellow solid. LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝265.1。

Step 6: preparation of 4- [4- (4-hydroxy-2-methyl-6-oxopyridin-1-yl) -5-methyl-1, 3-thiazol-2-yl] Pyrimidine-2-carboxylic acid ethyl ester：

4- (4-amino-5-methyl-1, 3-thiazol-2-yl) pyrimidine-2-carboxylic acid ethyl ester (440 mg,1.665mmol,1 eq.) and 2, 2-dimethyl-6- (2-oxopropyl) -1, 3-dioxin-4-A solution of the ketone (613.27 mg,3.330mmol,2 eq.) in dioxane (5 mL) was stirred under nitrogen at 90deg.C for 3 hours. The mixture was cooled to room temperature. The reaction was monitored by LCMS. Dropwise adding H into the mixture ₂ SO ₄ (163.28 mg,1.665mmol,1 eq.). The resulting mixture was stirred at 90℃for a further 1 hour. The mixture was cooled to room temperature. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. H was added to the resulting mixture ₂ O (25 mL) and stirred for 30 minutes. The precipitated solid was collected by filtration and washed with Et2O (3×50 mL). This gives 4- [4- (4-hydroxy-2-methyl-6-oxopyridin-1-yl) -5-methyl-1, 3-thiazol-2-yl ] as a yellow solid]Pyrimidine-2-carboxylic acid ethyl ester (380 mg, 61.29%).

Step 7: preparation of 4- (4- {4- [ (3, 5-difluoropyridin-2-yl) methoxy)]2-methyl-6-oxopyridin-1- Methyl-5-methyl-1, 3-thiazol-2-yl) -pyrimidine-2-carboxylic acid ethyl ester：

To 4- [4- (4-hydroxy-2-methyl-6-oxopyridin-1-yl) -5-methyl-1, 3-thiazol-2-yl ] at room temperature under a nitrogen atmosphere]To a stirred solution of pyrimidine-2-carboxylic acid ethyl ester (380 mg,1.020mmol,1 eq.) and 2- (chloromethyl) -3, 5-difluoropyridine (417.22 mg,2.550mmol,2.5 eq.) in DMF (10 ml) was added 18-crown-6 (80.91 mg,0.306mmol,0.3 eq.) and K ₂ CO ₃ (423.08 mg,3.060mmol,3 eq.). The resulting mixture was stirred under nitrogen at 60 ℃ for 2 hours. The mixture was cooled to room temperature. The reaction was monitored by LCMS. The reaction mixture was partitioned between EA (100 mL) and water (100 mL). The organic layer was washed with water (200 mL) and then with Na ₂ SO ₄ And (5) drying. The solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 4- (4- {4- [ (3, 5-difluoropyridin-2-yl) methoxy) as a white solid]-ethyl 2-methyl-6-oxopyridin-1-yl } -5-methyl-1, 3-thiazol-2-yl) pyrimidine-2-carboxylate (350 mg, 68.67%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝500.1。

Step 8: preparation of 4- (4- { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy)]-6-methyl-2-oxopyridine- 1-yl } -5-methyl-1, 3-thiazol-2-yl) pyrimidine-2-carboxylic acid ethyl ester：

To 4- (4- {4- [ (3, 5-difluoropyridin-2-yl) methoxy group at room temperature under nitrogen atmosphere]Ethyl-2-methyl-6-oxopyridin-1-yl } -5-methyl-1, 3-thiazol-2-yl) -pyrimidine-2-carboxylate (350 mg, 0.709 mmol,1 eq.) and NCS (121.64 mg,0.91 mmol,1.3 eq.) were added to a stirred solution in IPA (5 ml). The resulting mixture was stirred under nitrogen at 50 ℃ for 2 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The reaction mixture was partitioned between EA (10 mL) and water (10 mL). The organic layer was extracted with EtOAc (3X 50 mL). The resulting mixture was concentrated under reduced pressure. The crude product (300 mg) was purified by preparative HPLC to give 4- (4- { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy) as a yellow oil ]-6-methyl-2-oxopyridin-1-yl } -5-methyl-1, 3-thiazol-2-yl) pyrimidine-2-carboxylic acid ethyl ester (150 mg, 40.09%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝534.1。 ¹ H NMR(300MHz,DMSO-d ₆ )δ9.11(d,1H),8.61(d,1H),8.21(d,1H),8.18–8.04(m,1H),6.79(s,1H),5.52(d,2H),4.44(q,2H),2.34(s,3H),2.05(s,3H),1.38(t,3H)。

Step 9: preparation of 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-1- {2- [2- (2-hydroxy-prop-2-yl) Pyrimidin-4-yl]-5-methyl-1, 3-thiazol-4-yl } -6-methylpyridin-2-one：

To 4- (4- { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy group at 0℃under a nitrogen atmosphere]To a stirred solution of ethyl-6-methyl-2-oxopyridin-1-yl } -5-methyl-1, 3-thiazol-2-yl) pyrimidine-2-carboxylate (150 mg,0.281mmol,1 eq.) in THF was added MeMgBr (335.00 mg,2.810mmol,10 eq.). The resulting mixture was stirred under nitrogen at 0 ℃ for 30 minutes. The reaction was monitored by LCMS. The reaction was quenched with MeOH at 0 ℃. The resulting mixture was concentrated under reduced pressure. Purification of the crude product (150 mg) by preparative HPLC gave 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy as a white solid]-1- {2- [2- (2-hydroxy-prop-2-yl) pyrimidin-4-yl]-5-methyl-1, 3-thiazol-4-yl } -6-methylpyridin-2-one (30.5 mg, 20.88%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝520.1。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.97(d,1H),8.61(d,1H),8.17–8.04(m,1H),7.89(d,1H),6.78(s,1H),5.52(d,2H),5.17(s,1H),2.32(s,3H),2.05(d,3H),1.57(s,6H)。 ¹⁹ F NMR(282MHz,DMSO)δ-120.21,-120.24,-122.44,-122.46。

Examples 18A, 18B, 18C, 18D

Step 1: preparation of 5H,6H-1 lambda 5-cyclopenta [ b ]]Pyridine-1, 7-diones：

To 5H, 6H-cyclopenta [ b ] under nitrogen at 0 ℃ ]To a stirred solution of pyridin-7-one (5 g,37.552mmol,1.00 eq.) in DCM (150 ml) was added m-CPBA (12.96 g,75.104mmol,2.00 eq.) in portions. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 18 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 5h,6h-1λ5-cyclopenta [ b ] as a black solid]Pyridine-1, 7-dione (4 g, 71.42%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝150.1。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.17(d,1H),7.55(t,1H),7.44(d,1H),3.02(t,2H),2.64(t,2H)。

Step 2: preparation of 2-chloro-5H, 6H-cyclopenta [ b ]]Pyridin-7-ones：

To 5H,6H-1λ5-cyclopenta [ b ] under nitrogen atmosphere at 0deg.C]To a stirred solution of pyridine-1, 7-dione (3.5 g, 23.463 mmol,1.00 eq.) in DCE (80 mL) was added POCl dropwise ₃ (17.99 g,117.330mmol,5 eq.). The resulting mixture was stirred under nitrogen at 80 ℃ for 2 hours. The reaction was monitored by LCMS. The mixture was brought to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2-chloro-5 h,6 h-cyclopenta [ b ] as a black solid]Pyridin-7-one (1.28 g, 32.55%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝168.0。 ¹ HNMR(400MHz,DMSO-d ₆ )δ8.15(d,1H),7.72(d,1H),3.09(t,2H),2.71(t,2H)。

Step 3: preparation of 2- (trimethylstannyl) -5H, 6H-cyclopenta [ b ]]Pyridin-7-ones：

2-chloro-5H, 6H-cyclopenta [ b ]]Pyridin-7-one (250 mg,1.492mmol,1 eq.) Pd (PPh) ₃ ) ₂ Cl ₂ (209.41 mg,0.298mmol,0.20 eq.) AsPh ₃ (91.36 mg,0.298mmol,0.2 eq.) and Sn ₂ Me ₆ A mixture of (488.74 mg,1.492mmol,1 eq.) in dioxane (8 mL) was stirred overnight at 80deg.C under nitrogen. The reaction was monitored by LCMS. The resulting mixture was used directly in the next step without further purification. LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝298.0。

Step 4: preparation of 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-5', 6-dimethyl-2' - { 7-oxo- 5H, 6H-cyclopenta [ b ]]Pyridin-2-yl } - [1,4' -bipyridine]-2-one：

2' -bromo-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy was reacted at room temperature]-5', 6-dimethyl- [1,4' -bipyridine]-2-one (328.67 mg,0.719mmol,0.6 eq.) d (PPh) ₃ ) ₂ Cl ₂ (168.39 mg,0.240mmol,0.20 eq.) and CuI (228.44 mg,1.199mmol,1 eq.) were added to the reaction solution of the previous step. The resulting mixture was stirred under nitrogen at 80 ℃ for 2 hours. The reaction was monitored by LCMS. The mixture was brought to room temperature. The resulting mixture was diluted with EA (200 mL), saturated NaHCO 3X 150mL ₃ (aqueous solution) washing. The organic layer was concentrated under reduced pressure. And purified by silica gel column chromatography to give a crude product. Purification of the crude product by reverse phase flash chromatography gives 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy as a white solid ]-5', 6-dimethyl-2' - { 7-oxo-5 h,6 h-cyclopenta [ b ]]Pyridin-2-yl } - [1,4' -bipyridine]2-Ketone (110 mg,18.02%, two steps). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝508.8。 ¹ H NMR (300 MHz, chloroform-d) delta 8.71 (s, 1H), 8.68 (d, 1H), 8.43 (s, 1H), 8.40 (s, 1H), 8.02 (d, 1H), 7.39-7.31 (m, 1H), 6.39 (s, 1H), 5.46 (s, 2H), 3.22 (t, 2H), 2.84 (t, 2H), 2.19 (s, 3H), 2.01 (s, 3H).

Step 5: preparation of 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-2' - { 7-hydroxy-5H, 6H, 7H-cyclopentene [b]Pyridin-2-yl } -5', 6-dimethyl- [1,4' -bipyridine]-2-one：

To 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy at 0℃under a nitrogen atmosphere]-5', 6-dimethyl-2' - { 7-oxo-5 h,6 h-cyclopenta [ b ]]Pyridine compound-2-yl } - [1,4' -bipyridine]To a stirred solution of 2-one (400 mg,0.786mmol,1 eq.) in THF (10 ml) was added NaBH in portions ₄ (59.47 mg, 1.578mmol, 2 eq.). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. With saturated NH ₄ The reaction was quenched with Cl (aqueous solution) at 0 ℃. The resulting mixture was extracted with EtOAc. The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy as a white solid]-2' - { 7-hydroxy-5H, 6H, 7H-cyclopenta [ b ] ]Pyridin-2-yl } -5', 6-dimethyl- [1,4' -bipyridine]-2-one (135 mg, 33.62%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝510.8。

Step 6: preparation of rel- (R) -3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy) -2' - (7-hydroxy-6, 7- dihydro-5H-cyclopenta [ b ]]Pyridin-2-yl) -5', 6-dimethyl-2H- [1,4' -bipyridine]-2-one, rel- (R) -3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy) -2' - (7-hydroxy-6, 7-dihydro-5H-cyclopenta [ b ]]Pyridin-2-yl) -5', 6-di methyl-2H- [1,4' -bipyridine]-2-one, rel- (R) -3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy) -2' - (7- Hydroxy-6, 7-dihydro-5H-cyclopenta [ b ]]Pyridin-2-yl) -5', 6-dimethyl-2H- [1,4' -bipyridine]2-Ketone and rel- (R) -3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy) -2' - (7-hydroxy-6, 7-dihydro-5H-cyclopenta [ b ]]Pyridine-2- Phenyl) -5', 6-dimethyl-2H- [1,4' -bipyridine]-2-one：

3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy ] -2' - { 7-hydroxy-5H, 6H, 7H-cyclopenta [ b ] pyridin-2-yl } -5', 6-dimethyl- [1,4' -bipyridin ] -2-one (135 mg,0.264mmol,1 eq.) was isolated by preparative HPLC to give 2 peaks. The first peak (53 mg) was isolated by preparative chiral HPLC to give example 18A (18.3 mg) and example 18B (16.9 mg) as white solids. The second peak (45 mg) was isolated by preparative chiral HPLC to give example 18C (14.1 mg) and example 18D (14.3 mg) as white solids.

Example 18A：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝510.80。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.77(s,1H),8.61(d,1H),8.26(d,1H),8.24(s,1H),8.15–8.01(m,1H),7.82(d,1H),6.80(d,1H),5.50(d,2H),5.42(d,1H),5.07–4.93(m,1H),3.05–2.91(m,1H),2.88–2.71(m,1H),2.45–2.33(m,1H),2.08(s,3H),1.99(s,3H),1.91–1.78(m,1H)。 ¹⁹ F NMR(377MHz,DMSO)δ-120.15,-120.17,-122.34,-122.36。

Example 18B: LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝510.85。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.76(s,1H),8.60(d,1H),8.25(d,1H),8.23(s,1H),8.13–8.02(m,1H),7.82(d,1H),6.79(d,1H),5.49(d,2H),5.41(d,1H),5.06–4.92(m,1H),3.04–2.93(m,1H),2.87–2.74(m,1H),2.46–2.34(m,1H),2.07(s,3H),1.99(s,3H),1.91–1.79(m,1H)。 ¹⁹ F NMR(377MHz,DMSO)δ-120.15,-120.17,-122.36,-122.37。

Example 18C: LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝510.85。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.76(s,1H),8.61(d,1H),8.26(d,1H),8.24(s,1H),8.13–8.05(m,1H),7.82(d,1H),6.80(d,1H),5.49(d,2H),5.37(d,1H),5.02–4.93(m,1H),3.06–2.94(m,1H),2.85–2.73(m,1H),2.45–2.33(m,1H),2.07(s,3H),1.98(s,3H),1.93–1.82(m,1H)。 ¹⁹ F NMR(377MHz,DMSO)δ-120.14,-120.16,-122.34,-122.36。

Example 18D: LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝510.85。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.76(s,1H),8.61(d,1H),8.26(d,1H),8.25(s,1H),8.13–8.06(m,1H),7.83(d,1H),6.80(d,1H),5.49(d,2H),5.39(d,1H),5.02–4.93(m,1H),3.06–2.94(m,1H),2.85–2.73(m,1H),2.45–2.33(m,1H),2.07(s,3H),1.98(s,3H),1.91–1.86(m,1H)。 ¹⁹ F NMR(377MHz,DMSO)δ-120.12,-120.15,-122.31,-122.33。

Examples 19A and 19B

Step 1: preparation of 2- (5-methyl-1H-pyrazol-3-yl) propan-2-ol：

To a stirred solution of 5-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (3 g,19.459mmol,1 eq.) in THF (100 mL) under nitrogen at 0deg.C was added MeMgBr (97.30 mL,97.295mmol,5 eq.) dropwise.

The reaction was monitored by LCMS. With saturated NH ₄ Cl (aq) was quenched at 0deg.C, extracted with EtOAc (3X 1L) and dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The crude 2- (5-methyl-1H-pyrazol-3-yl) propan-2-ol (2.9 g, 88.24%) was used in the next step without further purification. LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝141.09。

Step 2: preparation of 3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy) -2' - (3- (2-hydroxypropan-2-yl) -5- methyl-1H-pyrazol-1-yl) -5', 6-dimethyl-2H- [1,4' -bipyridine]-2-one：

To 2- (5-methyl-1H-pyrazol-3-yl) propan-2-ol (184.18 mg,1.314mmol,2 eq.) under nitrogen at room temperature ₂ CO ₃ (181.58 mg,1.314mmol,2 eq.) and 2' -bromo-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-5', 6-dimethyl- [1,4' -bipyridine ]To a stirred mixture of 2-one (300 mg,0.657mmol,1.00 eq.) in 1, 4-dioxane (5 mL) was added (1 s,2 s) -N1, N2-dimethylcyclohexane-1, 2-diamine (37.38 mg,0.263mmol,0.4 eq.) and CuI (25.02 mg,0.131mmol,0.2 eq.). The resulting mixture was stirred overnight at 100 ℃ under nitrogen atmosphere. After cooling to room temperature, the resulting mixture was poured into water (100 mL) and then extracted with EtOAc (3×100 mL). By anhydrous Na ₂ SO ₄ The combined organic layers were dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 240mg of crude product which was further purified by preparative HPLC to give 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy as a white solid]-2' - [3- (2-hydroxy-prop-2-yl) -5-methylpyrazol-1-yl ]]-5', 6-dimethyl- [1,4' -bipyridine]-2-one (140 mg, 41.17%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝516.1。

Step 3: preparation of rel-3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy) -2' - (3- (2-hydroxypropyl-2-) Phenyl) -5-methyl-1H-pyrazol-1-yl) -5', 6-dimethyl-2H- [1,4' -bipyridine]2-one and rel-3-chloro-4- ((3, 5-) Difluoro-pyridin-2-yl) methoxy) -2'- (3- (2-hydroxy-prop-2-yl) -5-methyl-1H-pyrazol-1-yl) -5', 6-dimethyl- & lt/EN & gt 2H- [1,4' -bipyridine ]-2-one：

The racemate (3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy ] -2' - [3- (2-hydroxypropan-2-yl) -5-methylpyrazol-1-yl ] -5', 6-dimethyl- [1,4' -bipyridin ] -2-one (140 mg) was separated by preparative chiral HPLC to give rel-3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy) -2' - (3- (2-hydroxypropan-2-yl) -5-methyl-1H-pyrazol-1-yl) -5', 6-dimethyl-2H- [1,4' -bipyridin ] -2-one (example 19a,27.7 mg) and rel-3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy) -2' - (3- (2-hydroxypropan-2-yl) -5-methyl-pyrazol-1-yl) -5', 6-dimethyl-2H- [1,4' -bipyridin ] -2-one (example 19b, 35.1 g) as a white solid.

Example 19A：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝516.1。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.60(d,1H),8.54(s,1H),8.16–8.05(m,1H),7.75(s,1H),6.80(s,1H),6.30(s,1H),5.48(d,2H),4.98(s,1H),2.63(s,3H),2.01(s,3H),1.99(s,3H),1.44(s,6H)。 ¹⁹ F NMR(377MHz,DMSO)δ-120.155,-120.173,-122.342,-122.361。

Example 19B：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝516.1。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.60(d,1H),8.54(s,1H),8.16–8.05(m,1H),7.75(s,1H),6.80(s,1H),6.30(s,1H),5.48(d,2H),4.98(s,1H),2.63(s,3H),2.01(s,3H),1.99(s,3H),1.44(s,6H)。 ¹⁹ F NMR(377MHz,DMSO)δ-120.150,-120.176,-122.336,-122.362。

Examples 20A and 20B

Step 1: preparation of 2- (5-cyclopropyl-1H-pyrazol-3-yl) propan-2-ol：

At N ₂ at-30deg.C under atmosphereTo a stirred solution of 5-cyclopropyl-1H-pyrazole-3-carboxylic acid ethyl ester (500 mg,2.775mmol,1 eq.) in THF (10 mL) was added dropwise magnesium bromide (13.87 mL,5 eq., 1M in THF). The mixture obtained is put in N ₂ Stirred at room temperature for 1 hour under an atmosphere. The reaction was monitored by LCMS. By addition of saturated NH at room temperature ₄ The reaction was quenched with Cl (10 mL). The resulting mixture was extracted with EtOAc (3X 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give 2- (5-cyclopropyl-1H-pyrazol-3-yl) propan-2-ol (517 mg, crude) as a yellow solid. LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝167.2。

Step 2: preparation of racemate 3-chloro-2' - [ 5-cyclopropyl-3- (2-hydroxy-prop-2-yl) pyrazol-1-yl ]]-4- [ (3, 5-difluoropyridin-2-yl) methoxy group]-5', 6-dimethyl- [1,4' -bipyridine]-2-one：

2' -bromo-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-5', 6-dimethyl- [1,4' -bipyridine]-2-one (300 mg,0.657mmol,1 eq.) 2- (5-cyclopropyl-1H-pyrazol-3-yl) propan-2-ol (218.39 mg,1.314mmol,2 eq.) (1R, 2R) -N1, N2-dimethylcyclohexane-1, 2-diamine (186.89 mg,1.314mmol,2 eq.) K ₂ CO ₃ A mixture of (181.58 mg,1.314mmol,2 eq.) and CuI (31.28 mg,0.164mmol,0.25 eq.) in 1, 4-dioxane (3 mL) was stirred under nitrogen at 100deg.C for 2 hours. The reaction was monitored by LCMS. The resulting mixture was cooled to room temperature and poured into 10mL of water. The resulting mixture was extracted with EtOAc (3X 10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the crude product which was further purified by preparative HPLC to give 3-chloro-2' - [ 5-cyclopropyl-3- (2-hydroxypropyl-2-yl) pyrazol-1-yl as a white solid ]-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-5', 6-dimethyl- [1,4' -bipyridine]-2-one (230 mg, 59.59%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝542.2。

Step 3: preparation of rel-3-chloro-2' - [ 5-cyclopropyl-3- (2-hydroxy-prop-2-yl) pyrazol-1-yl ]]-4-[(3,5- Difluoro pyridin-2-yl) methoxy]-5', 6-dimethyl- [1,4' -bipyridine]2-one (example 20A) and rel-3-chloro-2' -) [ 5-cyclopropyl-3- (2-hydroxy-prop-2-yl) pyrazol-1-yl]-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-5', 6-Dimetho Base- [1,4' -bipyridine]2-Ketone (example 20B)：

The racemate (230 mg) was separated by preparative chiral HPLC to give example 20A (78.4 mg) as a white solid and example 20B (90.2 mg) as a white solid.

Example 20A：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝541.90。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.61(d,1H),8.57(s,1H),8.15–8.06(m,1H),7.74(s,1H),6.81(s,1H),6.12(s,1H),5.49(d,2H),4.96(s,1H),2.81–2.73(m,1H),2.03(s,3H),2.01(s,3H),1.42(s,6H),1.04–0.93(m,2H),0.74–0.62(m,2H)。 ¹⁹ F NMR(282MHz,DMSO)δ-120.14,-120.17,-122.33,-122.36。

Example 20B：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝541.90。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.61(d,1H),8.57(s,1H),8.19–8.03(m,1H),7.74(s,1H),6.81(s,1H),6.12(s,1H),5.49(d,2H),4.96(s,1H),2.81–2.73(m,1H),2.03(s,3H),2.01(s,3H),1.42(s,6H),1.03–0.94(m,2H),0.78–0.61(m,2H)。 ¹⁹ F NMR(282MHz,DMSO)δ-120.14,-120.17,-122.33,-122.35。

Examples 21A and 21B

Step 1: preparation of 1- (hydroxymethyl) cyclopropane-1-carboxamidine hydrochloride：

Under nitrogen atmosphere at 0 ℃ to NH ₄ Cl (556.54 mg,10.405mmol,5 eq.) was added drop wise to a stirred mixture of toluene (10 mL) ₃ (5.2 mL,10.405mmol,5 eq., 2M in toluene). The resulting mixture was stirred at 0℃for 10 minutes under a nitrogen atmosphere, howeverAfter which the mixture was stirred at room temperature until no more gas was produced. To the above mixture was added dropwise a solution of ethyl 1- (hydroxymethyl) cyclopropane-1-carboxylate (300 mg,2.081mmol,1 eq.) in toluene at room temperature. The resulting mixture was stirred at 80 ℃ overnight. The reaction was monitored by LCMS. The reaction was quenched by the addition of MeOH (10 mL) at 0 ℃. The resulting mixture was filtered and the filter cake was washed with MeOH (50 mL). The filtrate was concentrated under reduced pressure. The residue was dissolved in MeOH (30 mL). The resulting mixture was filtered and the filter cake was washed with MeOH (15 mL). The filtrate was concentrated under reduced pressure. This gave 1- (hydroxymethyl) cyclopropane-1-carboxamidine hydrochloride (230 mg, crude) as a white solid. ¹ H NMR(300MHz,DMSO-d ₆ )δ8.99(s,2H),8.72(s,2H),5.41(t,1H),3.52(d,2H),1.21–1.12(m,2H),0.99–0.90(m,2H)。

Step 2: preparation of 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-2' - {2- [1- (hydroxymethyl) cyclopropyl ]] Pyrimidin-4-yl } -5', 6-dimethyl- [1,4' -bipyridine]-2-one：

To 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy at room temperature under a nitrogen atmosphere]-2' - [ (2E) -3- (dimethylamino) prop-2-enoyl]-5', 6-dimethyl- [1,4' -bipyridine]To a stirred mixture of 2-one (150 mg,0.316mmol,1.00 eq.) and 1- (hydroxymethyl) cyclopropan-1-carboxamidine hydrochloride (216.33 mg,1.896mmol,6 eq., assuming 100% yield) in IPA (3 mL) was added K ₂ CO ₃ (436.53 mg,1.896mmol,10 eq.). The resulting mixture was stirred overnight at 80 ℃ under nitrogen atmosphere. The mixture was cooled to room temperature. The resulting mixture was filtered and the filter cake was washed with MeOH (3X 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE/EA 1:4) to give 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy as a pale yellow solid]-2' - {2- [1- (hydroxymethyl) cyclopropyl ]]Pyrimidin-4-yl } -5', 6-dimethyl- [1,4' -bipyridine]-2-one (75 mg, 45%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝526.1。

Step 3: preparation of (isomer 1) rel-3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy) -2' - (2- (1- (hydroxymethyl) cyclopropyl) pyrimidin-4-yl) -5', 6-dimethyl-2H- [1,4' -bipyridine ]2-Ketone and (isomer 2) rel-3- Chloro-4-/v(3, 5-difluoropyridin-2-yl) methoxy) -2'- (2- (1- (hydroxymethyl) cyclopropyl) pyrimidin-4-yl) -5', 6-dimethyl 1,4' -bipyridyl-2H- []-2-one：

3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy ] -2' - {2- [1- (hydroxymethyl) cyclopropyl ] pyrimidin-4-yl } -5', 6-dimethyl- [1,4' -bipyridin ] -2-one (70 mg) was isolated by preparative chiral-HPLC to give rel-3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy) -2' - (2- (1- (hydroxymethyl) cyclopropyl) pyrimidin-4-yl) -5', 6-dimethyl-2H- [1,4' -bipyridin ] -2-one (example 21A, isomer 1, 18.4mg, ee = 100%) and rel-3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy) -2' - (2- (1- (hydroxymethyl) cyclopropyl) pyrimidin-4-yl) -5', 6-dimethyl-2H- [1,4' -bipyridin ] -2-one (example 21B, isomer 2, 99.1 g = ee = 100%) as a white solid.

Example 21A：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝526.15。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.85(t,2H),8.62(d,1H),8.36(s,1H),8.15–8.06(m,2H),6.84(s,1H),5.49(d,2H),4.56(t,1H),3.97(d,2H),2.09(s,3H),1.97(s,3H),1.38–1.32(m,1H),1.26–1.20(m,1H),1.10–1.04(m,2H)。 ¹⁹ F NMR(377MHz,DMSO)δ-120.10,-120.12,-122.31,-122.33。

Example 21B：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝526.15。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.85(t,2H),8.62(d,1H),8.36(s,1H),8.15–8.06(m,2H),6.84(s,1H),5.49(d,2H),4.56(t,1H),3.97(d,2H),2.09(s,3H),1.97(s,3H),1.38–1.31(m,1H),1.27–1.17(m,1H),1.10–1.05(m,2H)。 ¹⁹ F NMR(377MHz,DMSO)δ-120.10,-120.12,-122.31,-122.32。

Examples 22A and 22B

Step 1: 5-fluoro-4-methylpyridine-2-carboxylic acid methyl ester：

In the airPd (dppf) Cl was added to a stirred mixture of 2-bromo-3-fluoro-5-methylpyridine (3.00 g,15.78mmol,1.00 eq.) and DIEA (10.20 g,78.94mmol,5.00 eq.) in MeOH (14 mL) at room temperature under an atmosphere ₂ (0.58 g,0.78mmol,0.05 eq.). The resulting mixture was stirred at 110℃for 5 hours under a carbon monoxide atmosphere (30 atm). The reaction was monitored by LCMS. The desired product was detectable by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give ethyl 3-fluoro-5-methylpyridine-2-carboxylate (2.48 g, 92.86%) as an off-white solid. LC-MS (ES+H, M/z) [ M+H ] ] ⁺ ＝170.2。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.58(d,1H),8.08(d,1H),3.89(s,3H),2.36(s,3H)。

Step 2: (5-fluoro-4-methylpyridin-2-yl) methanol：

To a stirred solution of methyl 5-fluoro-4-methylpyridine-2-carboxylate (1.00 g,5.91mmol,1.00 eq.) in THF (8 mL) and MeOH (2 mL) at room temperature under nitrogen atmosphere was added NaBH in portions ₄ (1.12 g,29.56mmol,5.00 eq.). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The desired product was detectable by LCMS. The reaction was quenched with water (50 mL) at room temperature. The resulting mixture was extracted with EtOAc (100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The crude product (700 mg) was used in the next step without further purification. LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝142.2。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.33(d,1H),7.42–7.38(m,1H),5.44(t,1H),4.51(d,2H),2.29(s,3H)。

Step 3:2- (chloromethyl) -5-fluoro-4-methylpyridine：

SOCl was added dropwise to a stirred solution of (5-fluoro-4-methylpyridin-2-yl) methanol (700 mg,2.80mmol,1.00 eq.) in DCM (6 mL) at room temperature under nitrogen atmosphere ₂ (1.5 mL) and DMF (362 mg,2.80mmol,1.00 eq.). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The desired product was detectable by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product was taken up (838 mg) was used in the next step without further purification. LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝160.0。

Step 4: 3-chloro-4- [ (5-fluoro-4-methylpyridin-2-yl) methoxy]-2' - [2- (2-hydroxy-prop-2-yl) azoxystrobin Pyridin-4-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one：

To 3-chloro-4-hydroxy-2' - [2- (2-hydroxypropan-2-yl) pyrimidin-4-yl ] at room temperature under nitrogen atmosphere]-5', 6-dimethyl- [1,4' -bipyridine]To a stirred mixture of 2-ketone (500 mg,1.29mmol,1.00 eq.) and 2- (chloromethyl) -5-fluoro-4-methylpyridine (778 mg,4.87mmol,4.00 eq.) in DMF (4 ml) was added K ₂ CO ₃ (891 mg,6.44mmol,4.99 eq.) and 18-crown-6 (34 mg,0.13mmol,0.10 eq.). The resulting mixture was stirred under nitrogen at 60 ℃ for 2 hours. The reaction was monitored by LCMS. The desired product was detectable by LCMS. The residue was purified by silica gel column chromatography to give the crude product (280 mg) which was further purified by preparative HPLC to give 3-chloro-4- [ (5-fluoro-4-methylpyridin-2-yl) methoxy as a white solid]-2' - [2- (2-hydroxy-prop-2-yl) pyrimidin-4-yl]-5', 6-dimethyl- [1,4' -bipyridine]2-one (200 mg, 30.34%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝510.2。

Step 5: rel-3-chloro-4- [ (5-fluoro-4-methylpyridin-2-yl) methoxy ]-2' - [2- (2-hydroxypropyl-2-yl) Pyrimidin-4-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one and rel-3-chloro-4- [ (5-fluoro-4-methylpyridin-2-yl) Methoxy group]-2' - [2- (2-hydroxy-prop-2-yl) pyrimidin-4-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one：

The racemate (200 mg) was separated by preparative chiral HPLC to give example 22A (73 mg,99.4%, ee=100%) as a white solid and example 22B (69.8 mg,99.4%, ee=98.8%) as a white solid.

Example 22A：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝510.15。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.97(d,1H),8.86(s,1H),8.68(s,1H),8.51(d,1H),8.24(d,1H),7.58(d,1H),6.81(s,1H),5.38(d,2H),5.25(s,1H),2.35(d,3H),2.11(s,3H),1.98(s,3H),1.53(s,6H)。 ¹⁹ F NMR(377MHz,DMSO)δ-133.88。

Example 22B：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝510.10。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.97(d,1H),8.86(s,1H),8.68(s,1H),8.51(d,1H),8.24(d,1H),7.58(d,1H),6.83–6.78(m,1H),5.38(d,2H),5.25(s,1H),2.35(d,3H),2.11(s,3H),1.98(s,3H),1.53(s,6H)。 ¹⁹ F NMR(377MHz,DMSO)δ-133.88。

Examples 23A and 23B

Step 1: preparation of 3-fluoro-5-methylpyridine-2-carboxylic acid methyl ester：

2-bromo-3-fluoro-5-methylpyridine (3 g,15.788mmol,1 eq.) Pd (dppf) Cl ₂ A mixture of (1.16 g,1.579mmol,0.1 eq.) and DIEA (10.20 g,78.940mmol,5 eq.) in MeOH (30 mL) was stirred under a carbon monoxide atmosphere (30 atm) at 110℃for 3 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 methyl 3-fluoro-5-methylpyridine-2-carboxylate (2.54 g, 94.54%) as an off-white solid. LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝170.1。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.43–8.34(m,1H),7.80–7.70(m,1H),3.88(s,3H),2.40(t,3H)。

Step 2: preparation of (3-fluoro-5-methylpyridin-2-yl) methanol：

3-fluoro-5-methylpyridine-2-carboxylic acid methyl ester (500 mg,2.956mmol,1 eq.) and NaBH ₄ A mixture of (447.32 mg, 11.284 mmol,4 eq.) in THF (4 mL) and methanol (1 mL) was stirred at room temperature for 2 hours. The reaction was monitored by LCMS. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3X 10 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give (3-fluoro-5-methyl) as a yellow solidPyridin-2-yl) methanol (400 mg, 95.88%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝142.1。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.22(d,1H),7.56-7.43(m,1H),5.23(t,1H),4.59–4.48(m,2H),2.32(s,3H)。

Step 3: preparation of 2- (chloromethyl) -3-fluoro-5-methylpyridine：

(3-fluoro-5-methylpyridin-2-yl) methanol (387 mg,2.742mmol,1 eq.) DMF (20.04 mg,0.274mmol,0.1 eq.) and SOCl ₂ (1.5 mL,20.677mmol,7.54 eq.) in CH ₂ Cl ₂ The mixture in (3 mL) was stirred at room temperature for 2 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to give 2- (chloromethyl) -3-fluoro-5-methylpyridine (638 mg, crude) as a yellow solid. LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝160.0。

Step 4: preparation of 3-chloro-4- [ (3-fluoro-5-methylpyridin-2-yl) methoxy]-2' - [2- (2-hydroxypropyl-2-yl) Pyrimidin-4-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one：

2- (chloromethyl) -3-fluoro-5-methylpyridine (412.55 mg,2.586mmol,2 eq.) 3-chloro-4-hydroxy-2' - [2- (2-hydroxy-prop-2-yl) pyrimidin-4-yl) ]-5', 6-dimethyl- [1,4' -bipyridine]-2-one (500 mg,1.293mmol,1.00 eq.) K ₂ CO ₃ A mixture of (893.17 mg, 6.460 mmol,5 eq.) and 18-crown-6 (34.16 mg,0.129mmol,0.1 eq.) in DMF was stirred overnight at 60℃under nitrogen. The reaction was monitored by LCMS. The resulting mixture was cooled to room temperature and poured into 10mL of water. The resulting mixture was extracted with EtOAc (3X 10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the crude product which was further purified by preparative HPLC to give 3-chloro-4- [ (3-fluoro-5-methylpyridin-2-yl) methoxy as a white solid]-2' - [2- (2-hydroxy-prop-2-yl) pyrimidin-4-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one (149 mg, 22.15%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝510.1。

Step 5: preparation of rel-3-chloro-4- [ (3-fluoro-5-methylpyridin-2-yl) methoxy]2' - [2- (2-hydroxypropyl- ] 2-yl) pyrimidin-4-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one and rel-3-chloro-4- [ (3-fluoro-5-methylpyridine ] 2-yl) methoxy]-2' - [2- (2-hydroxy-prop-2-yl) pyrimidin-4-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one：

The racemate (149 mg) was separated by preparative chiral HPLC to give example 23A (64.4 mg,99.2%, ee=100%) as a white solid and example 23B (57.6 mg,99.5%, ee=99.8%) as a white solid.

Example 23A：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝510.10。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.97(d,1H),8.86(s,1H),8.69(s,1H),8.36(s,1H),8.24(d,1H),7.75–7.67(m,1H),6.85(s,1H),5.45(d,2H),5.25(s,1H),2.39(s,3H),2.11(s,3H),1.98(s,3H),1.54(s,3H),1.53(s,3H)。 ¹⁹ F NMR(377MHz,DMSO)δ-126.190。

Example 23B：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝510.10。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.97(d,1H),8.86(s,1H),8.69(s,1H),8.36(s,1H),8.24(d,1H),7.74–7.69(m,1H),6.85(s,1H),5.45(d,2H),5.25(s,1H),2.39(s,3H),2.11(s,3H),1.98(s,3H),1.54(s,3H),1.53(s,3H)。 ¹⁹ F NMR(282MHz,DMSO)δ-126.192。

Examples 24A and 24B

Step 1: preparation of 1- (6-bromo-3-fluoropyridin-2-yl) ethanone：

To 2-bromo-5-fluoropyridine (20 g, 113.640 mmol,1 eq.) under Et at-78deg.C under nitrogen ₂ To a stirred solution of O (500 mL) was added dropwise t-BuLi (50.00 mL,125.008mmol,1.1 eq.). The resulting mixture was stirred under nitrogen at-78 ℃ for 2 hours. N-methoxy-N-methylacetamide (12.89 g,125.008mmol,1.1 eq.) was added dropwise to the above under nitrogen at-78 ℃In solution. The resulting mixture was stirred under nitrogen at-78 ℃ for 1 hour. The mixture was allowed to warm to room temperature. The reaction was monitored by LCMS. By addition of saturated NH ₄ The reaction was quenched with Cl (aq) (500 mL). The organic phase was collected. The aqueous layer was extracted with EtOAc (2X 500 mL). By anhydrous Na ₂ SO ₄ The combined organic layers were dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 1- (6-bromo-3-fluoropyridin-2-yl) ethanone (12 g, 46.49%) as a reddish semi-solid. LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝220.0。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.03–7.95(m,1H),7.94–7.85(m,1H),2.58(s,3H)。

Step 2: preparation of 1- [ 3-fluoro-6- (trimethylstannyl) pyridin-2-yl]Ethyl ketone：

Pd (PPh) was added to a stirred mixture of 1- (6-bromo-3-fluoropyridin-2-yl) ethanone (1.2 g,5.504mmol,1 eq.) and Sn2Me6 (7.21 g,22.016mmol,4 eq.) in 1, 4-dioxane (20 mL) at room temperature ₃ ) ₂ Cl ₂ (0.77 g,1.101mmol,0.2 eq.) and AsPh ₃ (0.34 g,1.101mmol,0.2 eq.). The resulting mixture was stirred overnight at 80 ℃ under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was poured into EA (200 mL) and washed with 5×200mL KF (aqueous solution). By anhydrous Na ₂ SO ₄ The organic layer was dried. After filtration, the filtrate was concentrated under reduced pressure to give 1- [ 3-fluoro-6- (trimethylstannyl) pyridin-2-yl]Ethanone (crude). The crude product was used directly in the next step without further purification. LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝304.0

Step 3: preparation of 1- {6' -acetyl-5 ' -fluoro-5-methyl- [2,2' -bipyridine]-4-yl } -3-chloro-4- [ (3, 5-) Difluoro pyridin-2-yl) methoxy]-6-methylpyridin-2-one：

To 1- [ 3-fluoro-6- (trimethylstannyl) pyridin-2-yl at room temperature]Ethanone (1190.10 mg,3.942mmol,3 eq.) and 2' -bromo-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-5', 6-dimethyl- [1,4' -bipyridine]Pd was added to a stirred solution of 2-keto (600 mg,1.314mmol,1.00 eq.) in 1, 4-dioxane (15 mL)(PPh ₃ ) ₂ Cl ₂ (92.22 mg,0.131mmol,0.1 eq.) and CuI (250.22 mg,1.314mmol,1 eq.). The resulting mixture was stirred under nitrogen at 80 ℃ for 3 hours. The mixture was cooled to room temperature. The reaction was monitored by LCMS. The resulting mixture was poured into water (200 mL) and extracted with EtOAc (3×200 mL). By anhydrous Na ₂ SO ₄ The combined organic layers were dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 1- {6' -acetyl-5 ' -fluoro-5-methyl- [2,2' -bipyridine as a white solid]-4-yl } -3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-6-methylpyridin-2-one (500 mg, 51.66%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝515.1。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.81(s,1H),8.70–8.64(m,1H),8.64–8.59(m,1H),8.34(s,1H),8.15–8.07(m,1H),8.07–8.00(m,1H),6.83(s,1H),5.49(s,2H),2.73(s,3H),2.08(s,3H),1.98(s,3H)。

Step 4: preparation of 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-1- [5 '-fluoro-6' - (2-hydroxypropyl-2-) Phenyl) -5-methyl- [2,2' -bipyridine]-4-yl]-6-methylpyridin-2-one：

To 1- {6' -acetyl-5 ' -fluoro-5-methyl- [2,2' -bipyridine under nitrogen atmosphere at 0 ℃]-4-yl } -3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]To a stirred mixture of 6-methylpyridin-2-one (450 mg,0.874mmol,1 eq.) in THF (6 mL) was added MeMgBr (2.91 mL,8.740mmol,10 eq.) dropwise. The resulting mixture was stirred under nitrogen at 0 ℃ for 1 hour. The reaction was monitored by LCMS. With saturated NH ₄ The reaction was quenched with Cl (aqueous solution) at 0 ℃. The resulting mixture was extracted with EtOAc (3X 100 mL). By anhydrous Na ₂ SO ₄ The combined organic layers were dried. After filtration, the filtrate was concentrated under reduced pressure. Purification of the crude product by preparative HPLC gave 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy as a white solid ]-1- [5' -fluoro-6 ' - (2-hydroxy prop-2-yl) -5-methyl- [2,2' -bipyridine]-4-yl]-6-methylpyridin-2-one (80 mg, 24.19%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝531.1。

Step 5: preparation of rel-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-1- [5 '-fluoro-6' - (2-hydroxy) Propan-2-yl) -5-methyl- [2,2' -bipyridine]-4-yl]-6-methylpyridin-2-one and rel-3-chloro-4- [ (3, 5-difluoropyridine) Pyridin-2-yl) methoxy]-1- [5' -fluoro-6 ' - (2-hydroxy prop-2-yl) -5-methyl- [2,2' -bipyridine]-4-yl]-6-methyl group Pyridin-2-ones：

The racemate 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy ] -1- [5' -fluoro-6 ' - (2-hydroxypropyl-2-yl) -5-methyl- [2,2' -bipyridin ] -4-yl ] -6-methylpyridin-2-one (80 mg) was isolated by preparative chiral HPLC to give rel-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy ] -1- [5' -fluoro-6 ' - (2-hydroxypropyl-2-yl) -5-methyl- [2,2' -bipyridin ] -4-yl ] -6-methylpyridin-2-one (example 24a,18.6mg,98.8%, ee=100%) and rel-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy ] -1- [5' -fluoro-6 ' - (2-hydroxypropyl-2-yl) -5-methyl- [2,2' -bipyridin ] -4-yl ] -6-methylpyridin-2-one (example 24b, 99.98.5 mg, 5% ee=100%) as a white solid.

Example 24A ：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝531.25。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.77(s,1H),8.62(d,1H),8.49(s,1H),8.43–8.35(m,1H),8.17–8.05(m,1H),7.90–7.78(m,1H),6.83(s,1H),5.49(s,2H),5.46(s,1H),2.07(s,3H),1.99(s,3H),1.55(s,6H)。 ¹⁹ F NMR(377MHz,DMSO)δ-119.955,-120.122,-120.148,-122.312,-122.337。

Example 24B：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝531.25。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.77(s,1H),8.62(d,1H),8.49(s,1H),8.43–8.35(m,1H),8.17–8.05(m,1H),7.90–7.78(m,1H),6.83(s,1H),5.49(s,2H),5.46(s,1H),2.06(s,3H),1.99(s,3H),1.55(s,6H)。 ¹⁹ F NMR(377MHz,DMSO)δ-119.954,-120.119,-120.144,-122.307,-122.332。

Examples 25, 25A, 25B

Step 1: 3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy) -5', 6-dimethyl-2' - (1H-pyrazol-3-one) Radical) -2H- [1,4' -bipyridine]-2-one：

To 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy at room temperature]-2' - [ (2E) -3- (dimethylamino) prop-2-enoyl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one (960 mg,2.022mmol,1.00 eq.) and K ₂ CO ₃ (558.77 mg,4.044mmol,2 eq.) to a stirred solution of ACN (10 mL) was added hydrazine (20 mL,1M in THF, 20.220mmol,10 eq.). The resulting mixture was stirred overnight at 80 ℃ under nitrogen atmosphere. The reaction was monitored by LCMS. The desired product was detectable by LCMS. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (2X 20 mL). By anhydrous Na ₂ SO ₄ The combined organic layers were dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography to give 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy as a yellow solid]-5', 6-dimethyl-2 ' - (1H-pyrazol-3-yl) - [1,4' -bipyridine]-2-one (450 mg, 50.15%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝444.1。 ¹ H NMR(400MHz,DMSO-d ₆ )δ13.11(s,1H),8.67(s,1H),8.61(d,1H),8.16–8.05(m,1H),7.81(s,2H),6.87(d,1H),6.80(s,1H),5.49(s,2H),2.02(s,3H),1.98(s,3H)。

Step 2:2- (3- (3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy) -5', 6-dimethyl-2-oxo-2H-) [1,4' -bipyridine]-2' -yl) -1H-pyrazol-1-yl) -2-methylpropanoic acid ethyl ester：

To 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy at room temperature]-5', 6-dimethyl-2 ' - (1H-pyrazol-3-yl) - [1,4' -bipyridine]-2-one (450 mg,1.014mmol,1 eq.) and K ₂ CO ₃ To a stirred solution of (280.25 mg,2.028mmol,2 eq.) in DMF (5 mL) was added dropwise ethyl α -bromoisobutyrate (988.82 mg,5.070mmol,5 eq.). The resulting mixture was stirred overnight at 80 ℃ under nitrogen atmosphere. The reaction was monitored by LCMS. LCMS was normal. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (2X 20 mL). By anhydrous Na ₂ SO ₄ The combined organic layers were dried. After filtrationThe filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography to give 2- (3- { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy) as a yellow solid]-5', 6-dimethyl-2-oxo- [1,4' -bipyridine]-2' -yl } pyrazol-1-yl) -2-methylpropanoic acid ethyl ester (220 mg, 38.89%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝558.3。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.66(s,1H),8.61(d,1H),8.13–8.06(m,1H),8.02(d,1H),7.75(s,1H),6.89(d,1H),6.79(s,1H),5.48(s,2H),4.18–4.00(m,2H),2.01(s,3H),1.96(s,3H),1.82(s,6H),1.11(t,3H)。

Step 3: 3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy) -2' - (1- (1-hydroxy-2-methylpropan-2- 1H-pyrazol-3-yl) -5', 6-dimethyl-2H- [1,4' -bipyridine]-2-one：

To 2- (3- { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy at room temperature ]-5', 6-dimethyl-2-oxo- [1,4' -bipyridine]Ethyl-2' -yl } pyrazol-1-yl) -2-methylpropionate (160 mg,0.287mmol,1 eq.) was added NaBH to a stirred solution in THF (3 mL) and MeOH (1 mL) ₄ (54.24 mg,1.435mmol,5 eq.). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 4 hours. The reaction was monitored by LCMS. LCMS was normal. By addition of saturated NH ₄ The resulting mixture was quenched with aqueous Cl and then poured into water (20 mL). The resulting mixture was extracted with EtOAc (2X 15 mL). By anhydrous Na ₂ SO ₄ The combined organic layers were dried. After filtration, the filtrate was concentrated under reduced pressure to give 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy as a pale yellow solid]-2' - [1- (1-hydroxy-2-methylpropan-2-yl) pyrazol-3-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one (100 mg, 67.59%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝515.9。

Step 4: rel-3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy) -2' - (1- (1-hydroxy-2-methylpropanej-o) 2-yl) -1H-pyrazol-3-yl) -5', 6-dimethyl-2H- [1,4' -bipyridine]-2-one and rel-3-chloro-4- ((3, 5-difluoro) Pyridin-2-yl) methoxy) -2'- (1- (1-hydroxy-2-methylpropan-2-yl) -1H-pyrazol-3-yl) -5', 6-dimethyl-2H- [1,4' -bipyridine]-2-one：

The racemate was separated by chiral preparative HPLC to give rel-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy ] -2'- [1- (1-hydroxy-2-methylpropan-2-yl) pyrazol-3-yl ] -5', 6-dimethyl- [1,4 '-bipyridin ] -2-one (example 25a,41.6mg, ee=100%) and rel-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy ] -2' - [1- (1-hydroxy-2-methylpropan-2-yl) pyrazol-3-yl ] -5', 6-dimethyl- [1,4' -bipyridin ] -2-one (example 25b,47.3mg, ee=99.9%) as a white solid.

Example 25A：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝516.10。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.65(s,1H),8.61(d,1H),8.16–8.07(m,1H),7.88(d,1H),7.77(s,1H),6.87–6.73(m,2H),5.49(s,2H),4.99(t,1H),3.70–3.57(m,2H),2.01(s,3H),1.98(s,3H),1.51(s,6H)。 ¹⁰ F NMR(282MHz,DMSO)δ-120.16,-120.18,-122.36,-122.39。

Example 25B：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝516.15。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.64(s,1H),8.61(d,1H),8.15–8.06(m,1H),7.87(d,1H),7.77(s,1H),6.84–6.75(m,2H),5.52–5.45(m,2H),4.97(t,1H),3.66–3.58(m,2H),2.00(s,3H),1.98(s,3H),1.50(s,6H)。 ¹⁹ F NMR(377MHz,DMSO)δ-120.16,-120.18,-122.37,-122.39。

Examples 26A and 26B

Step 1: preparation of 3-hydroxycyclobutane-1-carboxamidine：

Under nitrogen atmosphere at 0 ℃ to NH ₄ To a stirred mixture of Cl (2.06 g,38.420mmol,5 eq.) in toluene (10 mL) was added AlMe3 (19.21 mL,38.420mmol,5 eq.) dropwise. The resulting mixture was stirred under nitrogen at 0 ℃ for 10 minutes and then at room temperature until no more gas was produced. To the above mixture was added dropwise methyl 3-hydroxycyclobutane-1-carboxylate (1 g,7.684 mmol) at room temperature1 equivalent) of a solution in toluene. The resulting mixture was stirred at 80 ℃ overnight. The reaction was monitored by LCMS. The reaction was quenched by the addition of MeOH (20 mL) at 0 ℃. The resulting mixture was filtered and the filter cake was washed with MeOH (150 mL). The filtrate was concentrated under reduced pressure. The residue was dissolved in EtOH (20 mL). The resulting mixture was filtered and the filter cake was washed with EtOH (10 mL). The filtrate was concentrated under reduced pressure. This gave 3-hydroxycyclobutane-1-carboxamidine (1.1 g, crude) as a white solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ8.93(s,1H),8.82(s,2H),5.42(d,1H),4.43–4.33(m,1H),2.79–2.71(m,1H),2.49–2.42(m,2H),2.11–2.06(m,2H)。

Step 2: preparation of 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-2' - [2- (3-hydroxycyclobutyl) azoxystrobin Pyridin-4-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one：

3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy ]-2' - [ (2E) -3- (dimethylamino) prop-2-enoyl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one (150 mg,0.316mmol,1.00 eq.) K ₂ CO ₃ A mixture of (873.08 mg,6.320mmol,20 eq.) and 3-hydroxycyclobutane-1-carboxamidine (360.55 mg,3.160mmol,10 eq.) in IPA (8 mL) was stirred overnight at 80℃under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was brought to room temperature. The resulting mixture was diluted with EA (200 mL). The resulting mixture was washed with 2X 100mL water. The organic layer was concentrated under reduced pressure. Purification of the residue by preparative TLC (EA) gave 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-2' - [2- (3-hydroxycyclobutyl) pyrimidin-4-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one (150 mg, crude). The crude product was further purified by reverse phase combi-flash chromatography. The pure fractions were concentrated under reduced pressure to give 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy as a white solid]-2' - [2- (3-hydroxycyclobutyl) pyrimidin-4-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one (110 mg, 66.22%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝526.3。

Step 3: preparation of rel-3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy) -2' - (2- (3-hydroxycyclobutyl) Pyrimidin-4-yl) -5', 6-dimethyl-2H- [1,4' -bipyridine ]-2-one and rel-3-chloro-4- ((3, 5-difluoropyridin-2-yl)) Methoxy) -2' - (2- (3-hydroxycyclobutyl) pyrimidin-4-yl) -5', 6-dimethyl-2H- [1,4' -bipyridine]-2-one：

3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy ] -2' - [2- (3-hydroxycyclobutyl) pyrimidin-4-yl ] -5', 6-dimethyl- [1,4' -bipyridin ] -2-one (100 mg,0.190mmol,1 eq.) was isolated by preparative chiral HPLC to give rel-3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy) -2' - (2- (3-hydroxycyclobutyl) pyrimidin-4-yl) -5', 6-dimethyl-2H- [1,4' -bipyridin ] -2-one (example 26A,40.4mg, 40.40%) and rel-3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy) -2' - (2- (3-hydroxycyclobutyl) pyrimidin-4-yl) -5', 6-dimethyl-2H- [1,4' -bipyridin ] -2-one (example 26B,32.3mg, 32.3%). [ cis/trans=4/1 ] in cyclobutene ring

Example 26A: LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝525.85。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.92(d,1H),8.87(s,1H),8.61(d,1H),8.32(s,1H),8.18(d,1H),8.13–8.04(m,1H),6.83(d,1H),5.50(d,2H),5.18(d,1H),4.14–4.04(m,1H),3.23–3.14(m,1H),2.60–2.55(m,2H),2.33–2.23(m,2H),2.10(s,3H),1.98(s,3H)。 ¹⁹ F NMR(377MHz,DMSO)δ-120.10,-120.12,-122.28,-122.30。

Example 26B: LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝525.85。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.92(d,1H),8.87(s,1H),8.61(d,1H),8.33(s,1H),8.18(d,1H),8.14–8.02(m,1H),6.83(d,1H),5.50(d,2H),5.16(d,1H),4.15–4.04(m,1H),3.23–3.15(m,1H),2.63–2.55(m,2H),2.33–2.22(m,2H),2.10(s,3H),1.98(s,3H)。 ¹⁹ F NMR(377MHz,DMSO)δ-120.11,-120.13,-122.32,-122.34。

Examples 27A and 27B

Step 1: preparation of 4-formylpyridine-2-carboxylic acid methyl ester：

To methyl 4-bromopyridine-2-carboxylate (10 g,46.28mmol,1.00 eq.) and TMEDA (10.76 g,92.57mmol,2.00 eq.) in toluene (130 mL) to which Pd (AcO) was added ₂ (1.04 g,4.62mmol,0.10 eq.) and bis (adamantan-1-yl) (butyl) phosphine (3.32 g,9.25mmol,0.20 eq.). The resulting mixture was stirred at 100℃overnight under a carbon monoxide/hydrogen (15 atm/15 atm) atmosphere. The desired product was detectable by LCMS. The resulting mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The resulting mixture was filtered and the filter cake was washed with EtOAc (3X 20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 4-formylpyridine-2-carboxylate (1.70 g, crude) as a yellow solid. LC-MS (ES+H, M/z) [ M+H+H ] ₂ O] ⁺ ＝183.8

Step 2: preparation of 4- (difluoromethyl) pyridine-2-carboxylic acid methyl ester：

To a stirred solution of crude methyl 4-formylpyridine-2-carboxylate (1.50 g,9.08mmol,1.00 eq.) in DCM (8 mL) at room temperature under nitrogen was added BAST (6.03 g,27.24mmol,3.00 eq.) dropwise. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The resulting mixture was slowly poured into ice water (50 mL). By CH ₂ Cl ₂ The resulting mixture was extracted (3X 20 mL). By anhydrous Na ₂ SO ₄ The combined organic layers were dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 4- (difluoromethyl) pyridine-2-carboxylate (480 mg, 28.24%) as a pale yellow oil. LC-MS (ES+H, M/z) [ M+H ] ] ⁺ ＝188.1。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.94–8.86(m,1H),8.19(s,1H),7.90–7.82(m,1H),7.22(t,1H),3.92(s,3H)。

Step 3: preparation of [4- (difluoromethyl) pyridin-2-yl]Methanol：

Methyl 4- (difluoromethyl) pyridine-2-carboxylate (430 mg,2.29mmol,1.00 eq.) and NaBH ₄ A mixture of (347 mg,9.19mmol,4.00 eq.) in THF (4 mL) and methanol (1 mL) was stirred at room temperature under nitrogen for 2 hours. The reaction was monitored by LCMS. The reaction was quenched with water (10 mL) at room temperature. The resulting mixture was extracted with EtOAc (3X 30 mL). The combined organic layersWashed with brine (30 mL), over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give [4- (difluoromethyl) pyridin-2-yl ] as a yellow solid]Methanol (328 mg, 89.71%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝160.1。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.65(d,1H),7.64(s,1H),7.43(d,1H),7.13(t,1H),5.59(t,1H),4.63(d,2H)

Step 4: preparation of 2- (chloromethyl) -4- (difluoromethyl) pyridine：

Will [4- (difluoromethyl) pyridin-2-yl]Methanol (328 mg,2.06mmol,1.00 eq.), DMF (15 mg,0.20mmol,0.1 eq.) and SOCl ₂ (1.5 mL) in CH ₂ Cl ₂ The mixture in (3 mL) was stirred at room temperature for 2 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to give 2- (chloromethyl) -4- (difluoromethyl) pyridine (700 mg, crude) as a yellow solid. LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝178.0。

Step 5: preparation of 3-chloro-4- { [4- (difluoromethyl) pyridin-2-yl]Methoxy } -2' - [2- (2-hydroxypropyl-2-) Base) pyrimidin-4-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one：

2- (chloromethyl) -4- (difluoromethyl) pyridine (201 mg,1.13mmol,2.00 eq.) 3-chloro-4-hydroxy-2' - [2- (2-hydroxy-prop-2-yl) pyrimidin-4-yl)]-5', 6-dimethyl- [1,4' -bipyridine]-2-one (220 mg,0.57mmol,1.00 eq.) K ₂ CO ₃ A mixture of (399mg, 2.84mmol,5.00 eq.) and 18-crown-6 (15 mg,0.06mmol,0.10 eq.) in DMF (3 mL) was stirred overnight at 60℃under nitrogen. The reaction was monitored by LCMS. The resulting mixture was cooled to room temperature and poured into 10mL of water. The resulting mixture was extracted with EtOAc (3X 30 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the crude product which was further purified by preparative HPLC to give 3-chloro-4- { [4- (difluoromethyl) pyridin-2-yl]Methoxy } -2' - [2- (2-hydroxy-prop-2-yl) pyrimidin-4-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one (136 mg, 45.29%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝528.2。

Step 6: preparation of rel-3-chloro-4- { [4- (difluoromethyl) pyridin-2-yl]Methoxy } -2' - [2- (2-hydroxypropion- ] 2-yl) pyrimidin-4-yl]-5', 6-dimethyl- [1,4' -bipyridine ]-2-one and rel-3-chloro-4- { [4- (difluoromethyl) pyrazine Pyridin-2-yl]Methoxy } -2' - [2- (2-hydroxy-prop-2-yl) pyrimidin-4-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2- Ketone compounds：

The racemate (136 mg) was separated by preparative chiral HPLC to give example 27A (56.3 mg,99.6%, ee=100%) as a white solid and example 27B (53.3 mg,99.4%, ee=99.2%) as a white solid.

Example 27A：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝528.10。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.98(d,1H),8.87(s,1H),8.82(d,1H),8.70(s,1H),8.25(d,1H),7.79(s,1H),7.61(d,1H),7.42-7.02(t,1H)6.84(s,1H),5.54(s,2H),5.26(s,1H),2.11(s,3H),1.99(s,3H),1.54(s,3H),1.53(s,3H)。 ¹⁹ F NMR(282MHz,DMSO)δ-115.08。

Example 27B：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝528.10。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.98(d,1H),8.87(s,1H),8.82(d,1H),8.70(s,1H),8.25(d,1H),7.79(s,1H),7.61(d,1H),7.41-7.02(t,1H),6.84(s,1H),5.54(s,2H),5.26(s,1H),2.11(s,3H),1.99(s,3H),1.54(s,3H),1.53(s,3H)。 ¹⁹ F NMR(282MHz,DMSO)δ-115.08。

Examples 28A and 28B

Step 1: preparation of 3-chloro-5-methylpyridazine：

5-methylpyridazin-3-ol (5.00 g) in POCl ₃ The solution in (50 mL) was stirred under nitrogen at 80℃for 3 hours. The reaction was monitored by LCMS. The reaction was quenched with ice at room temperature. Basifying the mixture with aqueous NaOH to pH9. The resulting mixture was extracted with EtOAc (3X 100 mL). By anhydrous Na ₂ SO ₄ The combined organic layers were dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-chloro-5-methylpyridazine (1.4 g, 23.98%) as a brown liquid. LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝129.1。 ¹ H NMR(400MHz,DMSO-d ₆ )δ9.14(d,1H),7.81(d,1H),2.37(s,3H)。

Step 2: preparation of 5-methylpyridazine-3-carboxylic acid methyl ester：

Pd (dppf) Cl was added to a stirred solution of DIEA (2.01 g,15.55mmol,2.00 eq.) and 3-chloro-5-methylpyridazine (1.00 g,7.77mmol,1.00 eq.) in MeOH (10 mL) at room temperature under nitrogen atmosphere ₂ CH ₂ Cl ₂ (0.63 g,0.77mmol,0.10 eq.). The resulting mixture was stirred overnight at 100 ℃ under carbon monoxide atmosphere. The reaction was monitored by LCMS. The resulting mixture was cooled to room temperature. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography to give methyl 5-methylpyridazine-3-carboxylate (1.00 g, 84.49%) as a pale yellow solid. LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝153.2。 ¹ H NMR(400MHz,DMSO-d ₆ )δ9.32(d,1H),8.12-8.06(m,1H),3.96(s,3H),2.42(s,3H)。

Step 3: preparation of (5-methylpyridazin-3-yl) methanol：

To a stirred solution of methyl 5-methylpyridazine-3-carboxylate (500 mg,3.28mmol,1.00 eq.) in THF (3 mL) and MeOH (1 mL) at room temperature was added NaBH ₄ (621 mg,16.43mmol,5.00 eq.). The resulting mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS. The resulting mixture was diluted with water (10 mL). By CHCl ₃ And isopropyl alcohol (3:1) (3X 10 mL) to extract the resulting mixture. By anhydrous Na ₂ SO ₄ The combined organic layers were dried. After filtration, the filtrate was concentrated under reduced pressure to give (5-methylpyridazin-3-yl) methanol (280 mg, 68.64%) as a pale yellow solid. LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝125.2。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.98(d,1H),7.54(d,1H),5.60(s,1H),4.72(s,2H),2.34(s,3H)。

Step (a)4: preparation of 3- (chloromethyl) -5-methylpyridazine：

(5-methylpyridazin-3-yl) methanol (280 mg,2.25mmol,1.00 eq.) DMF (16 mg,0.22mmol,0.10 eq.) and SOCl ₂ (1.5 mL) in CH ₂ Cl ₂ The mixture in (3 mL) was stirred at room temperature for 2 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to give 3- (chloromethyl) -5-methylpyridazine (280 mg, crude) as a yellow solid. LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝143.1。

Step 5: preparation of 3-chloro-2' - [2- (2-hydroxy-prop-2-yl) pyrimidin-4-yl ]]-5', 6-dimethyl-4- [ (5-methyl) Pyridazin-3-yl) methoxy]- [1,4' -bipyridyl]-2-one：

3- (chloromethyl) -5-methylpyridazine (147 mg,1.03mmol,2 eq.) 3-chloro-4-hydroxy-2' - [2- (2-hydroxy-propan-2-yl) pyrimidin-4-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one (200 mg,0.51mmol,1.00 eq.) K ₂ CO ₃ A mixture of (317 mg,2.58mmol,5.00 eq.) and 18-crown-6 (13 mg,0.05mmol,0.10 eq.) in DMF (2 mL) was stirred overnight at 60℃under nitrogen. The reaction was monitored by LCMS. The resulting mixture was cooled to room temperature and poured into 10mL of water. The resulting mixture was extracted with EtOAc (3X 10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the crude product which was further purified by preparative HPLC to give 3-chloro-2' - [2- (2-hydroxypropan-2-yl) pyrimidin-4-yl as a white solid ]-5', 6-dimethyl-4- [ (5-methylpyridazin-3-yl) methoxy]- [1,4' -bipyridyl]-2-one (60 mg, 23.54%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝493.1。

Step 6: preparation of rel-3-chloro-2' - [2- (2-hydroxy-prop-2-yl) pyrimidin-4-yl ]]5', 6-dimethyl-4- [ (5-) Methyl pyridazin-3-yl) methoxy]- [1,4' -bipyridyl]2-ketone and rel-3-chloro-2' - [2- (2-hydroxy-prop-2-yl) pyrimidine ] 4-yl group]-5', 6-dimethyl-4- [ (5-methylpyridazin-3-yl) methoxy]- [1,4' -bipyridyl]-2-one：

The racemate was separated by preparative chiral HPLC (60 mg) to give example 28A (19.1 mg,98.7%, ee=100%) as a white solid and example 28B (18.4 mg,98.7%, ee=100%) as a white solid.

Example 28A：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝493.20。 ¹ H NMR(400MHz,DMSO-d ₆ )δ9.15(s,1H),8.97(d,1H),8.87(s,1H),8.69(s,1H),8.24(d,1H),7.71(s,1H),6.86(s,1H),5.63(s,2H),5.27(s,1H),2.41(s,3H),2.11(s,3H),1.99(s,3H),1.54(s,3H),1.53(s,3H)。

Example 28B：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝493.25。 ¹ H NMR(400MHz,DMSO-d ₆ )δ9.15(s,1H),8.98(d,1H),8.87(s,1H),8.69(s,1H),8.24(d,1H),7.71(s,1H),6.86(s,1H),5.63(s,2H),5.27(s,1H),2.42(s,3H),2.11(s,3H),1.99(s,3H),1.54(s,3H),1.53(s,3H)。

Examples 29A and 28B

Step 1: preparation of 2-chloro-5-ethylpyridin-4-amine：

To 2-chloro-5-iodopyridin-4-amine (5.50 g,21.61mmol,1.00 eq.) and boric acid, ethyl- (3.19 g,43.22mmol,2.00 eq.) in toluene (500 mL) and H at room temperature under nitrogen ₂ Cs was added to the stirred mixture in O (50 mL) ₂ CO ₃ (21.13 g,64.84mmol,3.00 eq.) and Pd (dppf) Cl ₂ (880.38 mg,1.08mmol,0.05 eq.). The resulting mixture was stirred overnight at 100 ℃ under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The reaction was poured into water (1.5L) at room temperature. The resulting mixture was extracted with EtOAc (2X 500 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. 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-chloro-5-ethylpyridin-4-amine (1.60) as a white solidg，47.27％)。LC-MS:(ES+H,m/z):[M+H] ⁺ ＝157.1。 ¹ H NMR (400 MHz, chloroform-d) delta 7.87 (s, 1H), 6.55 (s, 1H), 4.33 (br, 2H), 2.46 (q, 2H), 1.24 (t, 3H).

Step 2: preparation of 2' -chloro-5 ' -ethyl-4-hydroxy-6-methyl- [1,4' -bipyridine]-2-one：

To a stirred solution of 2-chloro-5-ethylpyridin-4-amine (1.60 g,10.21mmol,1.00 eq.) in 1, 4-dioxane (40 mL) was added 2, 2-dimethyl-6- (2-oxopropyl) -1, 3-dioxin-4-one (3.76 g,20.43mmol,2.00 eq.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred under nitrogen at 90 ℃ for 2 hours. The mixture was cooled to room temperature. Dropwise adding concentrated H into the mixture at room temperature ₂ SO ₄ (1.00 g,10.21mmol,1.00 eq.). The resulting mixture was stirred at 90℃for a further 2 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (50 mL). The precipitated solid was collected by filtration and washed with water (3×20 mL). The residue was purified by trituration with hexane (200 mL) to give 2' -chloro-5 ' -ethyl-4-hydroxy-6-methyl- [1,4' -bipyridine as a brown solid ]-2-one (1.4 g, 51.77%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝265.2。 ¹ H NMR(300MHz,DMSO-d ₆ )δ10.86(br,1H),8.50(s,1H),7.55(s,1H),5.98(d,1H),5.59(d,1H),2.41–2.26(m,2H),1.84(s,3H),1.07(t,3H)。

Step 3: preparation of 2' -chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-5 '-ethyl-6-methyl- [1,4' -biphenyl Pyridine compound]-2-one：

To 2' -chloro-5 ' -ethyl-4-hydroxy-6-methyl- [1,4' -bipyridine at room temperature under nitrogen atmosphere]To a stirred solution of 2-ketone (1.20 g,4.53mmol,1.00 eq.) and 2- (chloromethyl) -3, 5-difluoropyridine (1.11 g,6.80mmol,1.50 eq.) in DMF (50 mL) was added 18-crown-6 (0.12 g,0.45mmol,0.10 eq.) and K ₂ CO ₃ (1.25 g,9.06mmol,2.00 eq.). The resulting mixture was stirred overnight at 60 ℃ under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The reaction was quenched with water (50 mL) at room temperature. The resulting mixture was extracted with EtOAc (3X 50 mL)And (3) an object. The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. 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' -chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy as a yellow solid]-5 '-ethyl-6-methyl- [1,4' -bipyridine]2-one (1.40 g, 78.82%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝392.1。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.60(d,1H),8.53(s,1H),8.12–8.04(m,1H),7.60(s,1H),6.14(dd,1H),6.04(d,1H),5.25(d,2H),2.45–2.23(m,2H),1.86(s,3H),1.08(t,3H)。

Step 4: preparation of 4- [ (3, 5-difluoropyridin-2-yl) methoxy ]-2'- (1-ethoxyvinyl) -5' -ethyl- 6-methyl- [1,4' -bipyridine]-2-one：

To 2' -chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy at room temperature under a nitrogen atmosphere]-5 '-ethyl-6-methyl- [1,4' -bipyridine]Pd (PPh) was added to a stirred solution of 2-one (1.40 g,3.57mmol,1.00 eq.) and tributyl (1-ethoxyvinyl) stannane (2.58 g,7.14mmol,2.00 eq.) in 1, 4-dioxane (20 mL) ₃ ) ₂ Cl ₂ (125 mg,0.18mmol,0.05 eq.). The resulting mixture was stirred overnight at 100 ℃ under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The reaction was quenched with water (100 mL) at room temperature. The resulting mixture was extracted with EtOAc (3X 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. 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 4- [ (3, 5-difluoropyridin-2-yl) methoxy as a yellow solid]-2' - (1-ethoxyvinyl) -5' -ethyl-6-methyl- [1,4' -bipyridine]2-Ketone (1.40 g, 91.66%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝428.1。

Step 5: preparation of 2' -acetyl-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-5' -ethyl-6-methyl- [1, 4' -bipyridines ]-2-one：

At 0℃to 4- [ (3, 5-difluoropyridin-2-yl) methoxy]-2' - (1-ethoxyvinyl) -5' -ethyl-6-methyl- [1,4' ] methyl ]Bipyridine (P)]To a stirred solution of 2-one (1.40 g,3.27mmol,1.00 eq.) in THF (10 mL) was added dropwise concentrated HCl (1 mL). The resulting mixture was stirred at room temperature for 1 hour. The reaction was monitored by LCMS. The reaction was poured into water (50 mL) at room temperature. The resulting mixture was extracted with EtOAc (3X 30 mL). The combined organic layers were washed with brine (40 mL). The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography and the pure fractions were concentrated in vacuo to give 2' -acetyl-4- [ (3, 5-difluoropyridin-2-yl) methoxy as a brown oil]-5 '-ethyl-6-methyl- [1,4' -bipyridine]2-Ketone (1.10 g, 84.09%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝400.1。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.84(s,1H),8.59(d,1H),8.10–8.05(m,1H),7.77(s,1H),6.14(dd,1H),6.04(d,1H),5.25(d,2H),2.67(s,3H),2.48–2.34(m,2H),1.81(s,3H),1.12(t,3H)。

Step 6: preparation of 2' -acetyl-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-5' -ethyl-6-methyl Base- [1,4' -bipyridine]-2-one：

To 2' -acetyl-4- [ (3, 5-difluoropyridin-2-yl) methoxy at room temperature under a nitrogen atmosphere]-5 '-ethyl-6-methyl- [1,4' -bipyridine]To a stirred solution of 2-ketone (1.00 g,2.50mmol,1.00 eq.) in isopropyl alcohol (20 mL) was added NCS (0.37 g,2.75mmol,1.10 eq.) and dichloroacetic acid (0.02 g,0.15mmol,0.06 eq.). The resulting mixture was stirred under nitrogen at 60 ℃ for 1.5 hours. The reaction was monitored by LCMS. The reaction was quenched by the addition of water (60 mL) at room temperature. The resulting mixture was extracted with EtOAc (3X 25 mL). The combined organic layers were washed with brine (30 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and the pure fractions were concentrated in vacuo to give 2' -acetyl-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy as a yellow solid ]-5 '-ethyl-6-methyl- [1,4' -bipyridine]-2-one (800 mg, 73.65%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝434.2。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.88(s,1H),8.61(d,1H),8.14–8.07(m,1H),7.88(s,1H),6.80(s,1H),5.48(d,2H),2.68(s,3H),2.47-2.30(m,2H),1.91(s,3H),1.12(t,3H)。

Step 7: preparation of 3-chloro-4- [ (3, 5-difluoropyrazine)Pyridin-2-yl) methoxy]-2' - [ (2E) -3- (dimethylamino) Prop-2-enoyl]-5 '-ethyl-6-methyl- [1,4' -bipyridine]-2-one：

2' -acetyl-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy was added to DMF-DMA (4 mL) at room temperature under nitrogen atmosphere]-5 '-ethyl-6-methyl- [1,4' -bipyridine]2-Ketone (400 mg,0.92mmol,1.00 eq.). The resulting mixture was stirred overnight at 100 ℃ under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was used in the next step without further purification. LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝489.2。

Step 8: preparation of 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-5 '-ethyl-2' - [2- (2-hydroxypropion- ] 2-yl) pyrimidin-4-yl]-6-methyl- [1,4' -bipyridine]-2-one：

To 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy at room temperature under a nitrogen atmosphere]-2' - [ (2E) -3- (dimethylamino) prop-2-enoyl]-5 '-ethyl-6-methyl- [1,4' -bipyridine]To a stirred solution of 2-keto (450 mg,0.92mmol,1.00 eq.) in dimethylformamide (10 mL) was added 2-hydroxy-2-methylpropionamidine hydrochloride (1.27 g,2.76mmol,10.00 eq.) and K ₂ CO ₃ (1.28 g,2.76mmol,10.00 eq.). The resulting mixture was stirred overnight at 80 ℃ under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was poured into water (100 mL) at room temperature. The resulting mixture was extracted with EtOAc (3X 100 mL). The combined organic layers were washed with brine (5X 100 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC and concentrated under reduced pressure. Purification of the crude product by preparative HPLC, concentration of the pure fraction under reduced pressure gives 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy as a white solid]-5 '-ethyl-2' - [2- (2-hydroxy-prop-2-yl) pyrimidin-4-yl]-6-methyl- [1,4' -bipyridine]-2-one (105 mg, 21.61%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝528.3。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.98(d,1H),8.90(s,1H),8.68(s,1H),8.61(d,1H),8.25(d,1H),8.16–8.03(m,1H),6.85(s,1H),5.50(s,2H),5.27(s,1H),2.50-2.35(m,2H),1.99(s,3H),1.54(s,3H),1.53(s,3H),1.15(s,3H)。

Step 9: preparation (example 29A, isomer 1) rel-3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy) 5' -ethyl-2 ' - (2- (2-hydroxy-prop-2-yl) pyrimidin-4-yl) -6-methyl-2H- [1,4' -bipyridine]-2-Ketone and (examples) 28B, isomer 2) rel-3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy) -5 '-ethyl-2' - (2- (2-hydroxypropyl-2-) Yl) pyrimidin-4-yl) -6-methyl-2H- [1,4' -bipyridine]-2-one：

The racemic mixture (100 mg) was separated by preparative chiral HPLC and the pure fractions concentrated under reduced pressure then freeze-dried to give rel-3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy) -5 '-ethyl-2' - (2- (2-hydroxypropan-2-yl) pyrimidin-4-yl) -6-methyl-2H- [1,4 '-bipyridin ] -2-one (example 29A, isomer 1, 36.2mg, ee=100%) as a white solid and rel-3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy) -5' -ethyl-2 '- (2- (2-hydroxypropan-2-yl) pyrimidin-4-yl) -6-methyl-2H- [1,4' -bipyridin ] -2-one (example 29B, isomer 2, 32.3mg, ee=100%) as a white solid.

Example 29A：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝528.10。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.98(d,1H),8.90(s,1H),8.68(s,1H),8.61(d,1H),8.24(d,1H),8.16–8.03(m,1H),6.85(s,1H),5.50(s,2H),5.25(s,1H),2.50-2.34(m,2H),1.98(s,3H),1.54(s,3H),1.53(s,3H),1.15(t,3H)。

¹⁹ F NMR(282MHz,DMSO)δ-120.12,-120.15,-122.31,-122.34。

Example 29B：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝528.10。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.98(d,1H),8.90(s,1H),8.68(s,1H),8.61(d,1H),8.24(d,1H),8.16–8.03(m,1H),6.85(s,1H),5.50(s,2H),5.25(s,1H),2.51-2.37(m,2H),1.98(s,3H),1.54(s,3H),1.53(s,3H),1.15(t,3H)。

¹⁹ F NMR(282MHz,DMSO)δ-120.12,-120.15,-122.32,-122.34。

Example 30

Step 1: preparation of 4- (3-methyl-4-nitropyrrol-1-yl) pyrimidine-2-carboxylic acid ethyl ester：

Cs was added to a stirred solution of ethyl 4-chloropyrimidine-2-carboxylate (1.00 g,5.35mmol,1.00 eq.) and 3-methyl-4-nitro-1H-pyrazole (0.89 g,7.02mmol,1.31 eq.) in DMF (10 mL) at room temperature under nitrogen ₂ CO ₃ (3.49 g,10.71mmol,2.00 eq.). The resulting mixture was stirred under nitrogen at 50 ℃ for 3 hours. The mixture was cooled to room temperature. With saturated NH ₄ The reaction was quenched with Cl (aqueous solution) at room temperature. The resulting mixture was extracted with EtOAc (3X 20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give ethyl 4- (3-methyl-4-nitropyrrol-1-yl) pyrimidine-2-carboxylate (1.00 g, 67.55%) as a white solid. LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝278.1。

Step 2: preparation of 4- (4-amino-3-methylpyrazol-1-yl) pyrimidine-2-carboxylic acid ethyl ester：

To a solution of ethyl 4- (3-methyl-4-nitropyrazol-1-yl) pyrimidine-2-carboxylate (1.00 g,3.60mmol,1.00 eq.) in 15mL EtOH was added Pd/C (0.38 g, sufficient, 10 wt%). The mixture was hydrogenated at room temperature under 30atm hydrogen pressure for 40 minutes, and the reaction was monitored by LCMS. The resulting mixture was filtered through a pad of celite and concentrated under reduced pressure. The residue was purified by trituration with diethyl ether (5 mL). The precipitated solid was collected by filtration. This gave ethyl 4- (4-amino-3-methylpyrazol-1-yl) pyrimidine-2-carboxylate (0.86 g, 96.43%) as a yellow solid. LC-MS (ES+H, M/z) [ M+H ] ] ⁺ ＝248.1。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.76(d,1H),7.79(d,1H),7.77(s,1H),4.54(br,2H),4.38(q,2H),2.19(s,3H),1.35(t,3H)。

Step 3: preparation of 4- [4- (4-hydroxy-2-methyl-6-oxopyri-dine)Pyridin-1-yl) -3-methylpyrazol-1-yl]Pyrimidine 2-Carboxylic acid ethyl ester：

A solution of 4- (4-amino-3-methylpyrazol-1-yl) pyrimidine-2-carboxylic acid ethyl ester (0.86 g,3.47mmol,1.00 eq.) and 2, 2-dimethyl-6- (2-oxopropyl) -1, 3-dioxin-4-one (1.60 g,8.69mmol,2.50 eq.) in dioxane (10 mL) was stirred under nitrogen at 80℃for 3 hours. The mixture was cooled to room temperature. Dropwise adding concentrated H into the mixture at room temperature ₂ SO ₄ (0.29 mL,35.48mmol,1.00 eq.). The resulting mixture was stirred at 80℃for a further 1 hour. The mixture was cooled to room temperature. The resulting mixture was concentrated in vacuo. The residue was dissolved in water (1 mL). The residue was purified by reverse phase combi-flash chromatography. This gives 4- [4- (4-hydroxy-2-methyl-6-oxopyridin-1-yl) -3-methylpyrazol-1-yl ] as a brown solid]Pyrimidine-2-carboxylic acid ethyl ester (0.80 g, 64.73%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝356.1。 ¹ H NMR(300MHz,DMSO-d ₆ )δ10.75(br,1H),9.02(d,1H),8.81(s,1H),8.07(d,1H),5.94(s,1H),5.57(d,1H),4.40(q,2H),2.07(s,3H),2.00(s,3H),1.36(t,3H)。

Step 4: preparation of 4- (4- {4- [ (3, 5-difluoropyridin-2-yl) methoxy)]2-methyl-6-oxopyridin-1- Methyl } -3-methylpyrazol-1-yl) pyrimidine-2-carboxylic acid ethyl ester：

To 4- [4- (4-hydroxy-2-methyl-6-oxopyridin-1-yl) -3-methylpyrazol-1-yl ] at room temperature under a nitrogen atmosphere ]Pyrimidine-2-carboxylic acid ethyl ester (0.70 g,1.97mmol,1.00 eq.) and Na ₂ CO ₃ To a stirred solution of (0.42 g,3.94mmol,2.00 eq.) in DMF (5 mL) was added 2- (chloromethyl) -3, 5-difluoropyridine (0.48 g,2.95mmol,1.50 eq.) and 18-crown-6 (0.20 g,0.78mmol,0.40 eq.). The resulting mixture was stirred under nitrogen at 60 ℃ for 2 hours. The mixture was cooled to room temperature. With saturated NH ₄ The reaction was quenched with Cl (aqueous solution) at room temperature. The resulting mixture was extracted with EtOAc (3X 20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 4- (4- {4- [ (3, 5-difluoropyridine) as a yellow solid-2-yl) methoxy]-2-methyl-6-oxopyridin-1-yl } -3-methylpyrazol-1-yl) pyrimidine-2-carboxylic acid ethyl ester (0.50 g, 52.61%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝483.2

Step 5: preparation of 4- (4- { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy)]-6-methyl-2-oxopyridine- 1-yl } -3-methylpyrazol-1-yl) pyrimidine-2-carboxylic acid ethyl ester：

To 4- (4- {4- [ (3, 5-difluoropyridin-2-yl) methoxy group at room temperature under nitrogen atmosphere]To a stirred solution of ethyl-2-methyl-6-oxopyridin-1-yl } -3-methylpyrazol-1-yl) pyrimidine-2-carboxylate (0.50 g,1.03mmol,1.00 eq.) and dichloroacetic acid (13 mg,0.10mmol,0.10 eq.) in propan-2-ol (2 mL) was added NCS (0.15 g,1.14mmol,1.10 eq.). The resulting mixture was stirred under nitrogen at 60 ℃ for 2 hours. The mixture was cooled to room temperature. The precipitated solid was collected by filtration and washed with 2-propanol (3×1 mL). This gives 4- (4- { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy) as a white solid ]-6-methyl-2-oxopyridin-1-yl } -3-methylpyrazol-1-yl) pyrimidine-2-carboxylic acid ethyl ester (0.45 g, 84.00%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝517.1

Step 6: preparation of 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-1- {1- [2- (2-hydroxy-prop-2-yl) Pyrimidin-4-yl]-3-methylpyrazol-4-yl } -6-methylpyridin-2-one：

To 4- (4- { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy group at-10℃under nitrogen atmosphere]To a stirred solution of ethyl-6-methyl-2-oxopyridin-1-yl } -3-methylpyrazol-1-yl) pyrimidine-2-carboxylate (330 mg,0.64mmol,1.00 eq.) in THF (2 mL) was added MeMgBr (3.2 mL,6.40mmol,10 eq., 2M in THF). The resulting mixture was stirred at 0 ℃ for 20 minutes under nitrogen atmosphere. With saturated NH ₄ The reaction was quenched with Cl (aqueous solution) at room temperature. The resulting mixture was extracted with EtOAc (3X 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase combi-flash chromatography. This gives 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy) as a white solid]-1-{1-[2-(2-Hydroxy prop-2-yl) pyrimidin-4-yl]-3-methylpyrazol-4-yl } -6-methylpyridin-2-one (77 mg, 24.08%). LC-MS (ES+H, M/z) [ M+H ] ] ⁺ ＝503.05。 ¹ H NMR(300MHz,DMSO-d ₆ )δ9.20(s,1H),8.90(d,1H),8.60(d,1H),8.10(m,1H),7.76(d,1H),6.77(s,1H),5.49(d,2H),5.17(s,1H),2.13(s,3H),2.10(s,3H),1.53(s,3H),1.52(s,3H)。 ¹⁹ F NMR(282MHz,DMSO)δ-120.19,-120.21,-122.42,-122.44。

Examples 31A and 31B

To 2' -bromo-4- [ (4-methoxybenzene) at room temperatureRadical) methoxy radical]-5', 6-dimethyl- [1,4' -bipyridine]To a stirred mixture of 2-ketone (5.50 g,13.24mmol,1.00 eq.) and NCS (1.95 g,14.57mmol,1.10 eq.) in IPA (20 mL) was added 2, 2-dichloroacetic acid (100 mg,0.80mmol,0.06 eq.). The mixture was stirred under nitrogen at 60 ℃ for 3 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The precipitated solid was collected by filtration to give 2' -bromo-3-chloro-4- [ (4-methoxyphenyl) methoxy as a white solid ]-5', 6-dimethyl- [1,4' -bipyridine]-2-one (3 g, 50.37%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝451.1。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.51(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)。

Step 3: preparation of 3-chloro-2' - (2-cyclopropylacetyl) -4- [ (4-methoxyphenyl) methoxy]-5', 6-Dimetho Base- [1,4' -bipyridine]-2-one：

To 2' -bromo-3-chloro-4- [ (4-methoxyphenyl) methoxy at room temperature under nitrogen atmosphere]-5', 6-dimethyl- [1,4' -bipyridine]To a stirred mixture of 2-ketone (1.50 g,3.34mmol,1.00 eq.) in toluene (50 mL) was added i-PrMgCl (3.34 mL,6.67mmol,2 eq., 2M in THF). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. 2-cyclopropyl-N-methoxy-N-methylacetamide (22.39 g,16.68mmol,5.00 eq.) was added dropwise to the above mixture over 5 minutes at room temperature. The resulting mixture was stirred at room temperature overnight. The reaction was monitored by LCMS. By addition of saturated NH ₄ Cl (aq) (10 mL) quenched the reaction at 0deg.C. The resulting mixture was extracted with EtOAc (3X 100 mL). The combined organic layers were washed with brine (2X 100 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-chloro-2' - (2-cyclopropylacetyl) -4- [ (4-methoxyphenyl) methoxy as a yellow solid ]-5', 6-dimethyl- [1,4' -bipyridine]2-one (520 mg, 34.42%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝453.2。

Step 4/5: preparation of 3-chloro-2' - [ 5-cyclopropyl-2- (2-hydroxy-propan-2-yl) pyrimidin-4-yl]-4- [ (4-methyl)Oxygen gas Phenyl) methoxy]-5', 6-dimethyl- [1,4' -bipyridine]-2-one：

A solution of 3-chloro-2 ' - (2-cyclopropylacetyl) -4- [ (4-methoxyphenyl) methoxy ] -5', 6-dimethyl- [1,4' -bipyridin ] -2-one (520 mg,1.15mmol,1.00 eq.) in DMF-DMA (4 mL) was stirred overnight at 100deg.C under nitrogen. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure to give 3-chloro-2 ' - [ (2Z) -2-cyclopropyl-3- (dimethylamino) prop-2-enoyl ] -4- [ (4-methoxyphenyl) methoxy ] -5', 6-dimethyl- [1,4' -bipyridin ] -2-one (550 mg, crude). The crude product was used directly in the next step without further purification.

The crude product (assuming 100% yield, 1.00 eq.) was redissolved in IPA (3 mL) and 2-hydroxy-2-methylpropionamidine hydrochloride (1.11 g,10.83mmol,10.00 eq.) and K were added ₂ CO ₃ (1.50 g,10.83mmol,10.00 eq.). The resulting mixture was stirred at 80℃for 12 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was filtered and the filter cake was washed with MeOH (3X 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-chloro-2' - [ 5-cyclopropyl-2- (2-hydroxypropyl-2-yl) pyrimidin-4-yl as a pale yellow solid ]-4- [ (4-methoxyphenyl) methoxy group]-5', 6-dimethyl- [1,4' -bipyridine]-2-one (270 mg, 45.59%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝547.2。

Step 6: preparation of 3-chloro-2' - [ 5-cyclopropyl-2- (2-hydroxy-propan-2-yl) pyrimidin-4-yl]-4-hydroxy-5', 6- Dimethyl- [1,4' -bipyridine]-2-one：

To 3-chloro-2' - [ 5-cyclopropyl-2- (2-hydroxypropan-2-yl) pyrimidin-4-yl ] at room temperature under nitrogen atmosphere]-4- [ (4-methoxyphenyl) methoxy group]-5', 6-dimethyl- [1,4' -bipyridine]To a stirred solution of 2-one (270 mg,0.49mmol,1.00 eq.) in DCM (3 mL) was added TFA (1 mL). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with hexane (10 mL) to give 3-chloro-2' - [ 5-cyclopropyl-2- (2-hydroxypropyl-2-yl) pyrimidin-4- ] as a yellow oilBase group]-4-hydroxy-5 ', 6-dimethyl- [1,4' -bipyridine]-2-one (180 mg, 85.43%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝427.2。

Step 7: preparation of 3-chloro-2' - [ 5-cyclopropyl-2- (2-hydroxy-propan-2-yl) pyrimidin-4-yl]-4- [ (3, 5-difluoro) Pyridin-2-yl) methoxy]-5', 6-dimethyl- [1,4' -bipyridine]-2-one：

To 3-chloro-2' - [ 5-cyclopropyl-2- (2-hydroxypropan-2-yl) pyrimidin-4-yl ] at room temperature under nitrogen atmosphere ]-4-hydroxy-5 ', 6-dimethyl- [1,4' -bipyridine]To a stirred mixture of 2-ketone (175 mg,0.41mmol,1.00 eq.) and 2- (chloromethyl) -3, 5-difluoropyridine (74 mg,0.45mmol,1.10 eq.) in DMF (2 mL) was added 18-crown-6 (5.42 mg,0.02mmol,0.05 eq.) and K ₂ CO ₃ (169.96 mg,1.23mmol,3.00 eq.). The resulting mixture was stirred overnight at 60 ℃ under nitrogen atmosphere. The mixture was cooled to room temperature. The resulting mixture was diluted with EA (20 mL) and then with H ₂ O (3X 20 mL) and the organic layer was concentrated under reduced pressure. The resulting mixture was purified by preparative HPLC to give 3-chloro-2' - [ 5-cyclopropyl-2- (2-hydroxypropyl-2-yl) pyrimidin-4-yl as a pale yellow solid]-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-5', 6-dimethyl- [1,4' -bipyridine]-2-one (45 mg, 19.82%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝554.1。

Step 8: preparation (example 31A, isomer 1) rel-3-chloro-2' - (5-cyclopropyl-2- (2-hydroxypropyl-2-yl) Pyrimidin-4-yl) -4- ((3, 5-difluoropyridin-2-yl) methoxy) -5', 6-dimethyl-2H- [1,4' -bipyridine]-2-ones rel-3-chloro-2' - (5-cyclopropyl-2- (2-hydroxy-propan-2-yl) pyrimidin-4-yl) -4- ((3, 5-difluoropyridin-2-yl) methoxy Phenyl) -5', 6-dimethyl-2H- [1,4' -bipyridine]-2-one：

3-chloro-2 ' - [ 5-cyclopropyl-2- (2-hydroxypropan-2-yl) pyrimidin-4-yl ] -4- [ (3, 5-difluoropyridin-2-yl) methoxy ] -5', 6-dimethyl- [1,4' -bipyridin ] -2-one (racemate, 40 mg) was isolated by preparative chiral HPLC to give example 31A (11.1 mg, ee=98.5%) as a pale yellow solid and example 31B (11.1 mg, ee=99.6%) as a pale yellow solid.

Example 31A：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝554.30。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.81(s,1H),8.60(d,1H),8.57(s,1H),8.18(s,1H),8.15–8.05(m,1H),6.83(s,1H),5.49(d,2H),5.08(s,1H),2.75(td,1H),2.10(s,3H),2.00(s,3H),1.50(s,3H),1.50(s,3H),1.01–0.90(m,2H),0.82–0.75(m,2H)。 ¹⁹ F NMR(377MHz,DMSO)δ-120.14,-120.16,-122.33,-122.35。

Example 31B：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝554.10。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.81(s,1H),8.60(d,1H),8.57(s,1H),8.18(s,1H),8.10(ddd,1H),6.83(s,1H),5.49(d,2H),5.08(s,1H),2.81–2.70(m,1H),2.10(s,3H),2.00(s,3H),1.50(s,3H),1.50(s,3H),1.02–0.88(m,2H),0.84–0.73(m,2H)。 ¹⁹ F NMR(377MHz,DMSO)δ-120.14,-120.16,-122.34,-122.36。

Examples 32A, 32B, 32C, 32D

Step 1: preparation of 2- (trimethylstannyl) -5H, 6H-cyclopenta [ b ]]Pyridin-7-ones：

2-chloro-5H, 6H-cyclopenta [ b ]]Pyridin-7-one (250 mg,1.492mmol,1.00 eq.) Pd (PPh) ₃ ) ₂ Cl ₂ (209 mg,0.298mmol,0.20 eq.) AsPh ₃ (91 mg,0.298mmol,0.20 eq.) and Sn ₂ Me ₆ A mixture of (488 mg,1.492mmol,1.00 eq.) in dioxane (8 mL) was stirred overnight at 80deg.C under nitrogen. The reaction was monitored by LCMS. The resulting mixture was used directly in the next step without further purification. LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝298.0。

Step 2: preparation of 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-5', 6-dimethyl-2' - { 7-oxo- 5H, 6H-cyclopenta [ b ]]Pyridin-2-yl } - [1,4' -bipyridine]-2-one：

At the room temperature of the glass fiber reinforced plastic film,2' -bromo-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-5', 6-dimethyl- [1,4' -bipyridine]-2-one (328 mg,0.719mmol,0.6 eq.) d (PPh) ₃ ) ₂ Cl ₂ (168 mg,0.240mmol,0.20 eq.) and CuI (228 mg,1.199mmol,1 eq.) were added to the reaction solution of the previous step. The resulting mixture was stirred under nitrogen at 80 ℃ for 2 hours. The reaction was monitored by LCMS. The mixture was brought to room temperature. The resulting mixture was diluted with EA (200 mL), saturated NaHCO 3X 150mL ₃ (aqueous solution) washing. The organic layer was concentrated under reduced pressure and purified by silica gel column chromatography to give the crude product. The crude product was further purified by reverse phase combi-flash chromatography to give 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy as a white solid]-5', 6-dimethyl-2' - { 7-oxo-5 h,6 h-cyclopenta [ b ]]Pyridin-2-yl } - [1,4' -bipyridine]2-Ketone (110 mg,18.02%, two steps). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝508.8。 ¹ H NMR (300 MHz, chloroform-d) delta 8.71 (s, 1H), 8.68 (d, 1H), 8.43 (s, 1H), 8.40 (s, 1H), 8.02 (d, 1H), 7.39-7.31 (m, 1H), 6.39 (s, 1H), 5.46 (s, 2H), 3.22 (t, 2H), 2.84 (t, 2H), 2.19 (s, 3H), 2.01 (s, 3H).

Step 3: preparation of 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-2' - { 7-hydroxy-7-methyl-5H, 6H- Cyclopenta [ b ]]Pyridin-2-yl } -5', 6-dimethyl- [1,4' -bipyridine]-2-one：

To 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy at-10℃under nitrogen atmosphere]-5', 6-dimethyl-2' - { 7-oxo-5 h,6 h-cyclopenta [ b ]]Pyridin-2-yl } - [1,4' -bipyridine]To a stirred solution of 2-ketone (200 mg,0.393mmol,1.00 eq.) in THF (10 mL) was added MeMgBr (1.31 mL,3.93mmol,10.00 eq., 3M in THF) dropwise. The resulting mixture was stirred under nitrogen at-10 ℃ for 1 hour. The reaction was monitored by LCMS. By addition of saturated NH ₄ Cl (aq) (20 mL) quenched at-10deg.C. The resulting mixture was extracted with EtOAc (3X 50 mL). By anhydrous Na ₂ SO ₄ The combined organic layers were dried. After filtration, the filtrate was concentrated under reduced pressure to give 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy as a yellow solid]-2' - { 7-hydroxy-7-methyl-5H, 6H-cyclopenta [ b ]]Pyridin-2-yl } -5', 6-dimethyl- [1,4' -bipyridine]-2-one (220 mg, crude). LC-MS:(ES+H,m/z):[M+H] ⁺ ＝525.2。

Step 4: preparation of rel- (R) -3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy) -2' - (7-hydroxy-7-methyl Phenyl-6, 7-dihydro-5H-cyclopenta [ b ]]Pyridin-2-yl) -5', 6-dimethyl-2H- [1,4' -bipyridine]2-one, rel- (R) -3- Chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy) -2' - (7-hydroxy-7-methyl-6, 7-dihydro-5H-cyclopenta [ b ]]Pyridine-2- Phenyl) -5', 6-dimethyl-2H- [1,4' -bipyridine]-2-one, rel- (R) -3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy Radical) -2' - (7-hydroxy-7-methyl-6, 7-dihydro-5H-cyclopenta [ b ]]Pyridin-2-yl) -5', 6-dimethyl-2H- [1,4' -bipyramid Pyridine and pyridine]-2-one and rel- (R) -3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy) -2' - (7-hydroxy-7-methyl-6, 7-di- hydrogen-5H-cyclopenta [ b ]]Pyridin-2-yl) -5', 6-dimethyl-2H- [1,4' -bipyridine]-2-one：

3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy ] -2' - { 7-hydroxy-7-methyl-5H, 6H-cyclopenta [ b ] pyridin-2-yl } -5', 6-dimethyl- [1,4' -bipyridin ] -2-one (220 mg, crude) was isolated by preparative HPLC to give 2 fractions. The first peak (50 mg) was isolated by preparative chiral HPLC to give example 32A (17.8 mg,95.7% purity, ee=100%) and example 32B (17.3 mg,95.0% purity, ee= 97.17%) as white solids. The second peak (60 mg) was isolated by preparative chiral HPLC to give example 32C (22.8 mg,97.8% purity, ee= 98.67%) and example 32D (23.5 mg,97.3% purity, ee= 96.46%) as white solids.

Example 32A：

LC-MS:(ES+H,m/z):[M+H]+＝525.1。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.76(s,1H),8.61(d,1H),8.26(d,1H),8.24(d,1H),8.15–8.04(m,1H),7.80(d,1H),6.83(d,1H),5.50(d,2H),5.12(s,1H),3.03–2.88(m,1H),2.86–2.73(m,1H),2.19–2.09(m,2H),2.07(s,3H),1.98(s,3H),1.47(s,3H)。 ¹⁹ F NMR(377MHz,DMSO)δ-120.13,-120.15,-122.31,-122.33。

Example 32B：

LC-MS:(ES+H,m/z):[M+H]+＝525.1。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.76(s,1H),8.61(d,1H),8.26(d,1H),8.24(d,1H),8.15–7.99(m,1H),7.80(d,1H),6.83(d,1H),5.50(d,2H),5.13(s,1H),3.02–2.87(m,1H),2.86–2.75(m,1H),2.20–2.10(m,2H),2.07(s,3H),1.98(s,3H),1.47(s,3H)。 ¹⁹ F NMR(377MHz,DMSO)δ-120.12,-120.14,-122.28,-122.30。

Example 32C：

LC-MS:(ES+H,m/z):[M+H]+＝525.1。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.76(s,1H),8.61(d,1H),8.27(d,1H),8.25(d,1H),8.15–8.04(m,1H),7.80(d,1H),6.82(d,1H),5.49(d,2H),5.12(s,1H),3.05–2.89(m,1H),2.83–2.74(m,1H),2.15–2.09(m,2H),2.07(s,3H),1.98(s,3H),1.50(s,3H)。 ¹⁹ F NMR(377MHz,DMSO)δ-120.14,-120.16,-122.33,-122.35。

Example 32D：

LC-MS:(ES+H,m/z):[M+H]+＝525.1。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.76(s,1H),8.61(d,1H),8.27(d,1H),8.25(d,1H),8.13–8.04(m,1H),7.80(d,1H),6.82(d,1H),5.49(d,2H),5.12(s,1H),3.03–2.87(m,1H),2.85–2.73(m,1H),2.19–2.08(m,2H),2.07(s,3H),1.98(s,3H),1.50(s,3H)。 ¹⁹ F NMR(377MHz,DMSO)δ-120.14,-120.16,-122.33,-122.35。

Examples 33A and 33B

Step 1: preparation of 2-methylthiophene-3-amine：

To a stirred solution of LAH (14.49 g,381.70mmol,2.00 eq.) in 1, 4-dioxane was added dropwise a solution of methyl 3-aminothiophene-2-carboxylate (30.00 g,190.85mmol,1.00 eq.) in nitrogen at 95 ℃. The resulting mixture was stirred under nitrogen at 95 ℃ for 1.5 hours. The mixture was cooled to room temperature. The reaction was monitored by LCMS. LCMS was normal. The mixture was cooled to 0 ℃. To the above mixture were added water (14.5 mL), 15% aqueous NaOH (43.5 mL) and water (14.5 mL). The obtained mixture is treated in the following conditionStirred at room temperature for 1 hour. The resulting mixture was filtered and the filter cake was washed with EtOAc (3X 50 mL). The filtrate was concentrated under reduced pressure to give 2-methylthiophene-3-amine (19.00 g, 87.96%) as a black oil. LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝114.0。 ¹ H NMR(300MHz,DMSO-d ₆ )δ6.94(d,1H),6.50(d,1H),4.48(br,2H),2.11(s,3H)。

Step 2: preparation of N- (2-methylthiophene-3-yl) acetamide：

To 2-methylthiophene-3-amine (10.00 g,88.35mmol,1.00 eq.) and CH at room temperature ₃ To a stirred solution of COOK (11.27 g,114.86mmol,1.30 eq.) in toluene was added Ac in portions ₂ O (10.86 mL,114.86mmol,1.30 eq.). The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in DCM (30 mL). The combined organic layers were washed with brine (3X 30 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give N- (2-methylthiophene-3-yl) acetamide (11.80 g, 86.04%) as a yellow solid. LC-MS (ES+H, M/z) [ M+H ]]+＝156.1。 ¹ H NMR(300MHz,DMSO-d ₆ )δ9.41(s,1H),7.22–7.11(m,2H),2.27(s,3H),2.01(s,3H)。

Step 3: preparation of N- (5-bromo-2-methylthiophene-3-yl) acetamide：

N- (2-methylthiophene-3-yl) acetamide (11.80 g,76.02mmol,1.00 eq.) and 1-bromopyrrolidine-2, 5-dione (13.53 g,76.02mmol,1.00 eq.) were added to a stirred solution of acetonitrile at room temperature under an air atmosphere. The resulting mixture was stirred at room temperature for 3 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with brine (50 mL) and taken up in CH ₂ Cl ₂ (3X 20 mL) extraction. The organic layer was then taken up in anhydrous Na ₂ SO ₄ Dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give N- (5-bromo-2-methylthiophene-3-yl) acetamide (16.00 g, 89.90%) as a yellow solid. LC-MS (ES+H, M/z) [ M+H ]]+＝233.9。 ¹ H NMR(400MHz,DMSO-d ₆ )δ9.52(s,1H),7.25(s,1H),2.22(s,3H),2.00(s,3H)。

Step 4: preparation of N- [ 2-methyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) thiophene ] 3-yl]Acetamide compound：

To a stirred solution of N- (5-bromo-2-methylthiophene-3-yl) acetamide (10.00 g,42.71mmol,1.00 eq.) and 4, 5-tetramethyl-2- (tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,3, 2-dioxaborolan (14.10 g,55.53mmol,1.30 eq.) in 1, 4-dioxane (50 mL) at room temperature under nitrogen was added CH ₃ COOK (12.58 g,128.14mmol,3.00 eq.) and Pd (dppf) Cl ₂ (1.56 g,2.13mmol,0.10 eq.). The resulting mixture was stirred under nitrogen at 100 ℃ for 12 hours. The mixture was cooled to room temperature. The reaction was monitored by LCMS. The resulting mixture was filtered and the filter cake was washed with 1, 4-dioxane (3×10 mL). Concentrating the filtrate under reduced pressure to give N- [ 2-methyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) thiophen-3-yl as black solid]Acetamide (11.00 g, crude). The crude product was used directly in the next step without further purification. LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝282.2。

Step 5: preparation of 4- (4-acetamido-5-methylthiophene-2-yl) pyrimidine-2-carboxylic acid ethyl ester：

To N- [ 2-methyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) thiophen-3-yl at room temperature under nitrogen atmosphere]Acetamide (9.00 g,32.00mmol, 1.00 eq. Assuming 100% yield) and ethyl 4-chloropyrimidine-2-carboxylate (7.76 g,41.61mmol,1.30 eq.) in 1, 4-dioxane/H ₂ K was added to the stirred solution in O (50 mL/10 mL) ₂ CO ₃ (13.27 g,96.02mmol,3.00 eq.) and Pd (dppf) Cl ₂ .CH ₂ Cl ₂ (2.61 g,3.20mmol,0.10 eq.). The resulting mixture was stirred under nitrogen at 80 ℃ for 2 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with brine (50 mL) and extracted with DCM (3×50 mL). The organic layer was then taken up in anhydrous Na ₂ SO ₄ Dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 4- (4-acetamido-5-methylthiophene-2-yl) pyrimidine-2-methyl as a brown solidEthyl acetate (4.70 g, 48.09%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝306.1。 ¹ H NMR(300MHz,DMSO-d ₆ )δ9.64(s,1H),8.85(d,1H),8.18(s,1H),8.03(d,1H),4.44-4.32(m,2H),2.38(s,3H),2.07(s,3H),1.38-1.31(m,3H)。

Step 6: preparation of 4- (4-amino-5-methylthiophene-2-yl) pyrimidine-2-carboxylic acid methyl ester：

To a stirred solution of ethyl 4- (4-acetamido-5-methylthiophene-2-yl) pyrimidine-2-carboxylate (4.70 g,15.39mmol,1.00 eq.) under nitrogen at room temperature was added a solution of HCl (g) in MeOH (10 ml,4m in MeOH). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 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 methyl 4- (4-amino-5-methylthiophene-2-yl) pyrimidine-2-carboxylate (2.70 g, 70.37%) as a brown solid. LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝250.0。 ¹ HNMR(300MHz,DMSO-d ₆ )δ8.78(d,1H),7.84(d,1H),7.46(s,1H),4.81(s,2H),3.91(s,3H),2.22(s,3H)。

Step 7: preparation of 4- [4- (4-hydroxy-2-methyl-6-oxopyridin-1-yl) -5-methylthiophene-2-yl]Pyrimidine 2-Carboxylic acid methyl ester：

To a stirred solution of methyl 4- (4-amino-5-methylthiophene-2-yl) pyrimidine-2-carboxylate (1.70 g,6.81mmol,1.00 eq.) and 2, 2-dimethyl-6- (2-oxopropyl) -1, 3-dioxin-4-one (1.63 g,8.86mmol,1.30 eq.) in 1, 4-dioxane (30 mL) at room temperature under nitrogen atmosphere. The resulting mixture was stirred under nitrogen at 90 ℃ for 2 hours. The mixture was cooled to room temperature. Concentrated H was added dropwise to the above mixture at room temperature over 1 minute ₂ SO ₄ (0.67 g,6.81mmol,1.00 eq.). The resulting mixture was stirred at 90℃for a further 1 hour. The mixture was cooled to room temperature. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. By using Et ₂ O (100 mL) was triturated to purify the residue. The precipitated solid was collected by filtration and taken up in Et ₂ O-washing (5X 6 mL) afforded 4- [4- (4-hydroxy-2-methyl-6-oxopyridin-1-yl) -5-methylthiophene-2-yl as a brown solid]Pyrimidine-2-carboxylic acid methyl ester(2.00g，82.06％)。LC-MS:(ES+H,m/z):[M+H] ⁺ ＝358.0。 ¹ H NMR(400MHz,DMSO-d ₆ )δ10.75(s,1H),8.94–8.91(m,1H),8.12–8.08(m,1H),8.01(d,1H),5.95(d,1H),5.59(d,1H),3.93(s,3H),2.20(s,3H),1.94(s,3H)。

Step 8: preparation of 4- (4- {4- [ (3, 5-difluoropyridin-2-yl) methoxy)]2-methyl-6-oxopyridin-1- Methyl } -5-methylthiophene-2-yl) pyrimidine-2-carboxylate：

To 4- [4- (4-hydroxy-2-methyl-6-oxopyridin-1-yl) -5-methylthiophene-2-yl at room temperature under a nitrogen atmosphere]To a stirred solution of pyrimidine-2-carboxylic acid methyl ester (1.20 g,3.35mmol,1.00 eq.) and 2- (chloromethyl) -3, 5-difluoropyridine (600.42 mg,3.69mmol,1.10 eq.) in DMF (3 mL) was added 18-crown-6 (90.12 mg,0.33mmol,0.10 eq.) and K ₂ CO ₃ (2.32 g,16.79mmol,5.00 eq.). The resulting mixture was stirred under nitrogen at 60 ℃ for 3 hours. The mixture was cooled to room temperature. The reaction was monitored by LCMS. The resulting mixture was poured into water (20 mL) and then extracted with EtOAc (3X 10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 4- (4- {4- [ (3, 5-difluoropyridin-2-yl) methoxy) as a tan solid]-methyl 2-methyl-6-oxopyridin-1-yl } -5-methylthiophene-2-yl) pyrimidine-2-carboxylate (900 mg, 55.32%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝485.0。

Step 9: preparation of 4- (4- { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy)]-6-methyl-2-oxopyridine- 1-yl } -5-methylthiophene-2-yl) pyrimidine-2-carboxylic acid methyl ester：

To 4- (4- {4- [ (3, 5-difluoropyridin-2-yl) methoxy group at room temperature under nitrogen atmosphere]To a stirred solution of methyl-2-methyl-6-oxopyridin-1-yl } -5-methylthiophene-2-yl) pyrimidine-2-carboxylate (900 mg,1.85mmol,1.00 eq.) and NCS (322 mg,2.41mmol,1.30 eq.) in IPA (4 mL) was added dropwise 2, 2-dichloroacetic acid (24 mg,0.18mmol,0.10 eq.). The resulting mixture was stirred under nitrogen at 60 ℃ for 1 hour. Cooling the mixture to the chamberTemperature. The reaction was monitored by LCMS. The resulting mixture was poured into brine (50 mL) and extracted with DCM (3×50 mL). The organic layer was then taken up in anhydrous Na ₂ SO ₄ Dried and concentrated under reduced pressure. The residue was purified by reverse phase combi-flash chromatography to give 4- (4- { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy) as a yellow solid ]-6-methyl-2-oxopyridin-1-yl } -5-methylthiophene-2-yl) pyrimidine-2-carboxylic acid methyl ester (420 mg, 43.57%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝519.0。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.94(d,1H),8.60(d,1H),8.13–8.08(m,1H),8.08(d,1H),8.07(d,1H),6.77–6.74(m,1H),5.48(d,2H),3.94(s,3H),2.23(s,3H),2.06(s,3H)。

Step 10: preparation of 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-1- {5- [2- (2-hydroxy-prop-2-yl) Pyrimidin-4-yl]-2-methylthiophene-3-yl } -6-methylpyridin-2-one：

To 4- (4- { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy group at 0℃under a nitrogen atmosphere]Methyl-6-methyl-2-oxopyridin-1-yl } -5-methylthiophene-2-yl) pyrimidine-2-carboxylate (380 mg,0.73mmol,1.00 eq.) was added dropwise to a stirred solution of MeMgBr (3.66 mL,7.32mmol,10.00 eq., 2M in THF) in THF (3 mL). The resulting mixture was stirred under nitrogen at 0 ℃ for 1 hour. The reaction was monitored by LCMS. By addition of saturated NH ₄ Cl (aq) (20 mL) quenched the reaction at 0deg.C. The resulting mixture was extracted with EtOAc (3X 20 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase combi-flash chromatography to give crude 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy as a pale yellow solid]-1- {5- [2- (2-hydroxy-prop-2-yl) pyrimidin-4-yl]-2-methylthiophene-3-yl } -6-methylpyridin-2-one (154 mg, crude). The crude product (154 mg) was further purified by preparative HPLC to give 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy as a pale yellow solid ]-1- {5- [2- (2-hydroxy-prop-2-yl) pyrimidin-4-yl]-2-methylthiophene-3-yl } -6-methylpyridin-2-one (100 mg, 26.31%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝519.1。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.80(d,1H),8.60(d,1H),8.16–8.03(m,1H),7.99(s,1H),7.75(d,1H),6.75(s,1H),5.48(s,2H),5.03(s,1H),2.22(s,3H),2.06(s,3H),1.52(s,6H)。

Step 11: preparation of rel-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]1- {5- [2- (2-hydroxy-propyl- ] 2-yl) pyrimidin-4-yl]-2-methylthiophene-3-yl } -6-methylpyridin-2-one and rel-3-chloro-4- [ (3, 5-difluoropyridin- ] 2-yl) methoxy]-1- {5- [2- (2-hydroxy-prop-2-yl) pyrimidin-4-yl]-2-methylthiophene-3-yl } -6-methylpyridin-2- Ketone compounds：

The racemic mixture (100.00 mg) was separated by preparative HPLC to give rel-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy ] -1- {5- [2- (2-hydroxypropan-2-yl) pyrimidin-4-yl ] -2-methylthiophene-3-yl } -6-methylpyridin-2-one (example 33A, isomer 1, 26.20mg, ee=100%) and rel-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy ] -1- {5- [2- (2-hydroxypropan-2-yl) pyrimidin-4-yl ] -2-methylthiophene-3-yl } -6-methylpyridin-2-one (example 33B, isomer 2, 33.50mg, ee=99.70%) as a pale yellow solid.

Example 33A：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝519.0。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.80(d,1H),8.61(d,1H),8.15-8.06(m,1H),8.00(s,1H),7.76(d,1H),6.76(s,1H),5.48(s,2H),5.03(s,1H),2.22(s,3H),2.07(s,3H),1.53(s,6H)。 ¹⁹ F NMR(282MHz,DMSO)δ-120.17,-120.20,-122.40,-122.43。

Example 33B：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝519.0。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.80(d,1H),8.61(d,1H),8.17–8.04(m,1H),8.00(s,1H),7.75(d,1H),6.76(s,1H),5.48(s,2H),5.03(s,1H),2.22(s,3H),2.07(s,3H),1.53(s,6H)。 ¹⁹ F NMR(282MHz,DMSO)δ-120.17,-120.20,-122.40,-122.43。

Examples 34A, 34B, 34C, 34D

Step 1: preparation of 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]2' - (6-vinylpyridin-2-yl) the preparation of 5', 6-dimethyl- [1,4' -bipyridine]-2-one：

To 2' - (6-bromopyridin-2-yl) -3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy at room temperature]-5', 6-dimethyl- [1,4' -bipyridine]-2-one (220 mg,0.41mmol,1.00 eq.) K ₂ CO ₃ (114 mg,0.82mmol,2.00 eq.) and 2-vinyl-4, 5-tetramethyl-1, 3, 2-dioxaborolan (128 mg,0.82mmol,2.00 eq.) in 1, 4-dioxane (3.50 mL) and H ₂ Pd (dppf) Cl was added to the stirred mixture in O (0.70 mL) ₂ -CH ₂ Cl ₂ (35 mg,0.04mmol,0.10 eq.). The resulting mixture was stirred under nitrogen at 100 ℃ for 2 hours. The mixture was cooled to room temperature. The reaction was monitored by LCMS. Purification of the mixture by reverse phase combi-flash gave 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy as a white solid]-2' - (6-vinylpyridin-2-yl) -5', 6-dimethyl- [1,4' -bipyridine]-2-one (180 mg, 90.45%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝481.0。

At room temperature, NMO (88 mg,0.75mmol,2.00 eq.) and 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-2' - (6-vinylpyridin-2-yl) -5', 6-dimethyl- [1,4' -bipyridine ]To a stirred mixture of 2-ketone (180 mg,0.38mmol,1.00 eq.) in THF (2 mL) and t-BuOH (0.66 mL) was added K ₂ OsO ₄ .2H ₂ O (78 mg,0.19mmol,0.50 eq.). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 15 hours. The reaction was monitored by LCMS. The reaction was quenched with saturated sodium thiosulfate (aqueous) (30 mL) and extracted with EtOAc (3×40 mL). By anhydrous Na ₂ SO ₄ The combined organic layers were dried. After filtration, the filtrate was concentrated under reduced pressure. Purification of the crude product by preparative HPLC (150 mg) gave 3-chloro-4- [ (3, 5-difluoropyridine) as a white solid-2-yl) methoxy]-2' - [6- (1, 2-dihydroxyethyl) pyridin-2-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one (80 mg, 41.50%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝515.1。

Step 3: preparation of rel-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-2' - [6- (1, 2-dihydroxyethyl) Radical) pyridin-2-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one, rel-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) Methoxy group]-2' - [6- (1, 2-dihydroxyethyl) pyridin-2-yl]-5', 6-dimethyl- [1,4' -bipyridine]2-Ketone, rel- 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-2' - [6- (1, 2-dihydroxyethyl) pyridin-2-yl]-5', 6-Dimetho Base- [1,4' -bipyridine]-2-one and rel-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy ]-2' - [6- (1, 2-dihydroxyl) Pyrid-2-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one：

The racemate 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy ] -2' - [6- (1, 2-dihydroxyethyl) pyridin-2-yl ] -5', 6-dimethyl- [1,4' -bipyridin ] -2-one (120 mg) was separated by preparative chiral HPLC to give two peaks. The first peak was isolated by preparative chiral SFC to give example 34A (10.2 mg, ee=99.32%) and example 34B (8.3 mg, ee=96.92%) as white solids. The second peak was isolated by preparative chiral SFC to give example 34C (16 mg, ee=100%) and example 34D (10.6 mg, ee=98.18%) as white solids.

Example 34A：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝515.05。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.77(s,1H),8.61(d,1H),8.30(s,1H),8.26(d,1H),8.11(td,1H),7.94(t,1H),7.54(d,1H),6.82(s,1H),5.49(d,2H),5.45(d,1H),4.74–4.58(m,2H),3.83–3.69(m,1H),3.62–3.48(m,1H),2.07(s,3H),1.97(s,3H)。 ¹⁹ F NMR(377MHz,DMSO)δ-120.13,-120.15,-122.34,-122.36。

Example 34B：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝515.10。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.77(s,1H),8.61(d,1H),8.30(s,1H),8.26(d,1H),8.11(td,1H),7.94(t,1H),7.54(d,1H),6.82(s,1H),5.49(d,2H),5.45(d,1H),4.74–4.58(m,2H),3.83–3.69(m,1H),3.62–3.48(m,1H),2.07(s,3H),1.97(s,3H)。 ¹⁹ F NMR(377MHz,DMSO)δ-120.13,-120.15,-122.34,-122.36。

Example 34C：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝515.10。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.78(s,1H),8.62(d,1H),8.30(s,1H),8.29–8.23(m,1H),8.11(ddd,1H),7.95(t,1H),7.55(d,1H),6.83(s,1H),5.50(d,2H),5.45(d,1H),4.74–4.55(m,2H),3.83–3.72(m,1H),3.66–3.47(m,1H),2.07(s,3H),1.98(s,3H)。 ¹⁹ F NMR(377MHz,DMSO)δ-120.13,-120.15,-122.34,-122.36。

Example 34D：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝515.05。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.78(s,1H),8.62(d,1H),8.30(s,1H),8.29–8.23(m,1H),8.11(ddd,1H),7.95(t,1H),7.55(d,1H),6.83(s,1H),5.50(d,2H),5.45(d,1H),4.74–4.55(m,2H),3.83–3.72(m,1H),3.66–3.47(m,1H),2.07(s,3H),1.98(s,3H)。 ¹⁹ F NMR(377MHz,DMSO)δ-120.13,-120.15,-122.34,-122.36。

Examples 35A, 35B, 35C, 35D

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Step 1: preparation of 2-cyclopropyl-2-hydroxyacetamides：

To ethyl 2-cyclopropyl-2-glycolate (1.20 g,8.33mmol,1.00 eq.) in acetone (20 mL) and H at room temperature under nitrogen ₂ MnO was added to the stirred solution in O (20 mL) ₂ (1.45 g,16.66mmol,2.00 eq.). The resulting mixture was stirred at room temperature under nitrogen overnight. The reaction was monitored by TLC (PE: ea=1:1, rf=0.2). The resulting mixture was filtered and the filtrate concentrated in vacuo to give 2-cyclopropyl-2-hydroxyacetamide (1.00 g, crude) as a white solid. ¹ H NMR(300MHz,DMSO-d6)δ7.24–6.91(m,2H),5.16(s,1H),3.56–3.41(m,1H),1.17–0.87(m,1H),0.43–0.23(m,4H)。

Step 2&3: preparation of 2-cyclopropyl-2-hydroxy acetamidine hydrochloride：

To a stirred solution of 2-cyclopropyl-2-hydroxyacetamide (800 mg,6.949mmol,1.00 eq.) in THF (10 mL) under nitrogen atmosphere at 0 ℃ was added triethyloxonium tetrafluoroborate (1716 mg,9.034mmol,1.30 eq.). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 3 hours. The resulting mixture was concentrated under reduced pressure to give crude ethyl 2-cyclopropyl-2-hydroxyethylenimate. The residue was dissolved in methanol (20 mL) and NH was added to the mixture at 0deg.C over 5 minutes ₃ (g) MeOH (20 mL). The resulting mixture was stirred at room temperature for an additional 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in EA (20 mL). The resulting mixture was filtered, a solution of HCl (gas) in 1, 4-dioxane (5 mL) was added to the filtrate at 0 ℃, and the resulting mixture was stirred at 0 ℃ for 2 hours under a nitrogen atmosphere. The precipitated solid was collected by filtration and washed with EA (3×10 mL). This gave 2-cyclopropyl-2-hydroxyacetamidine hydrochloride (400 mg, 38.35%) as a white solid. ¹ H NMR(300MHz,DMSO-d ₆ )δ9.21–8.54(m,4H),6.69–5.55(m,1H),3.94(d,1H),1.21–1.01(m,1H),0.68–0.52(m,1H),0.54–0.25(m,3H)。

Step 4: preparation of 3-chloro-2' - {2- [ cyclopropyl (hydroxy) methyl ]]Pyrimidin-4-yl } -4- [ (3, 5-difluoropyridin-2- ] Radical) methoxy radical ]-5', 6-dimethyl- [1,4' -bipyridine]-2-one：

2-cyclopropyl-2-hydroxy acetamidine hydrochloride (284 mg,1.89mmol,3.00 eq.) 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-2' - [ (2E) -3- (dimethylamino) prop-2-enoyl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one (300 mg,0.63mmol,1.00 eq.) and K ₂ CO ₃ A mixture of (873 mg,6.32mmol,10.00 eq.) in IPA was stirred overnight at 80deg.C under nitrogen. The reaction was monitored by LCMS. The resulting mixture was cooled to room temperature and poured into 10mL of water. The resulting mixture was extracted with EtOAc (3X 10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the crude product which was further purified by preparative HPLC to give 3-chloro-2' - {2- [ cyclopropyl (hydroxy) methyl ] as a white solid]Pyrimidin-4-yl } -4- [ (3, 5-difluoropyridin-2-yl) methoxy]-5', 6-dimethyl- [1,4' -bipyridine]-2-one (190 mg, 56.16%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝526.0。

Step 5: preparation of rel-3-chloro-2' - {2- [ cyclopropyl (hydroxy) methyl ]]Pyrimidin-4-yl } -4- [ (3, 5-difluoropyri-dine) Pyridin-2-yl) methoxy]-5', 6-dimethyl- [1,4' -bipyridine ]-2-Ketone (example 35A)&B&C&D)：

The racemate was separated by preparative chiral HPLC (190 mg) to give a mixture of examples 35a & b as a white solid (90 mg) and a mixture of examples 35c & d as a white solid (85 mg).

The first racemate (90 mg) was separated by preparative chiral HPLC to give example 35A (33.4 mg,99.2%, ee=100%) as a white solid and example 35B (30.3 mg,99.7%, ee=100%) as a white solid.

The second racemate (85 mg) was separated by preparative chiral HPLC to give example 35C (26.7 mg,99.8%, ee=100%) as a white solid and example 35D (23.8 mg,99.4%, ee=100%) as a white solid.

Example 35A：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝526.1。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.97(d,1H),8.87(s,1H),8.62(d,1H),8.59(s,1H),8.26(d,1H),8.16–8.06(m,1H),6.85(s,1H),5.50(d,2H),5.22(d,1H),4.20(t,1H),2.12(s,3H),1.98(s,3H),1.39–1.29(m,1H),0.50–0.37(m,4H)。 ¹⁹ F NMR(282MHz,DMSO)δ-120.14,-120.17,-122.32,-122.35。

Example 35B：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝526.1。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.97(d,1H),8.87(s,1H),8.62(d,1H),8.56(s,1H),8.26(d,1H),8.16–8.06(m,1H),6.85(s,1H),5.50(d,2H),5.23(d,1H),4.20(t,1H),2.12(s,3H),1.99(s,3H),1.38–1.24(m,1H),0.49–0.34(m,4H)。 ¹⁹ F NMR(282MHz,DMSO)δ-120.14,-120.16,-122.32,-122.34。

Example 35C：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝526.1。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.97(d,1H),8.87(s,1H),8.61(d,1H),8.56(s,1H),8.26(d,1H),8.16–8.04(m,1H),6.84(s,1H),5.50(d,2H),5.23(d,1H),4.20(t,1H),2.11(s,3H),1.98(s,3H),1.40–1.29(m,1H),0.49–0.36(m,4H)。 ¹⁹ F NMR(282MHz,DMSO)δ-120.14,-120.16,-122.32,-122.34。

Example 35D：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝526.1。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.97(d,1H),8.88(s,1H),8.62(d,1H),8.60(s,1H),8.27(d,1H),8.16–8.04(m,1H),6.85(s,1H),5.51(d,2H),5.22(d,1H),4.20(t,1H),2.12(s,3H),1.99(s,3H),1.39–1.28(m,1H),0.46–0.38(m,4H)。 ¹⁹ F NMR(282MHz,DMSO)δ-120.14,-120.17,-122.32,-122.35。

Examples 36A, 36B, 36C, 36D

Step 1: preparation of 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-5', 6-dimethyl-2' - [6- (propane-1-) En-2-yl) pyridin-2-yl]- [1,4' -bipyridyl]-2-one：

To 2' - (6-bromopyridin-2-yl) -3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy at room temperature under a nitrogen atmosphere]-5', 6-dimethyl- [1,4' -bipyridine]-2-one (300 mg,0.56mmol,1.00 eq.) and 4, 5-tetramethyl-2- (prop-1-en-2-yl) -1,3, 2-dioxaborolan (142 mg,0.84mmol,1.50 eq.) in dioxane (4 mL) and H ₂ CsF (170 mg,1.12mmol,2.00 eq.) and Pd (PPh) were added to a stirred solution in O (0.4 mL) ₃ ) ₄ (130 mg,0.11mmol,0.20 eq.). The resulting mixture was stirred under nitrogen at 90 ℃ for 2 hours. Make the following stepsThe mixture was cooled to room temperature. Pouring the reactant into saturated NH at room temperature ₄ Cl (aqueous) (20 mL). The resulting mixture was extracted with EtOAc (3X 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. Purification of the residue by preparative TLC gave 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy as a white solid]-5', 6-dimethyl-2' - [6- (prop-1-en-2-yl) pyridin-2-yl]- [1,4' -bipyridyl]-2-one (200 mg, 71.94%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝495.2

Step 2: preparation of 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-2' - [6- (1, 2-dihydroxypropane-2-) Radical) pyridin-2-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one：

To 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy at room temperature under a nitrogen atmosphere]-5', 6-dimethyl-2' - [6- (prop-1-en-2-yl) pyridin-2-yl]- [1,4' -bipyridyl]To a stirred solution of 2-ketone (200 mg,0.24mmol,1.00 eq.) and NMO (57 mg,0.48mmol,2.00 eq.) in THF (3 mL) and t-BuOH (1 mL) was added K ₂ OsO ₄ .2H ₂ O (45 mg,0.12mmol,0.50 eq.). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 3 hours. The resulting mixture was filtered and the filter cake was washed with THF (2×3 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase combi-flash chromatography. This gives 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy) as a white solid]-2' - [6- (1, 2-dihydroxypropan-2-yl) pyridin-2-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one (120 mg, 56.34%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝529.10。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.77(s,1H),8.61(d,1H),8.36(d,1H),8.25(m,1H),8.10(m,1H),7.93(m,1H),7.67(m,1H),6.82(s,1H),5.49(s,2H),5.19(d,1H),4.59(m,1H),3.69–3.48(m,2H),2.49(s,3H),2.06(s,3H),1.43(s,3H)。 ¹⁹ F NMR(377MHz,DMSO)δ-120.12,-120.14,-122.33,-122.35。

Step 3: preparation of rel-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]2' - [6- (1, 2-dihydroxypropane) 2-yl) pyridin-2-yl]-5', 6-dimethyl- [1,4' -bipyridine]2-Ketone, rel-3-chloro-4- [ (3, 5-)Difluoropyridine-2- Radical) methoxy radical]-2' - [6- (1, 2-dihydroxypropan-2-yl) pyridin-2-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2- Ketone, rel-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-2' - [6- (1, 2-dihydroxypropan-2-yl) pyridin-2- ] Base group]-5', 6-dimethyl- [1,4' -bipyridine]-2-one and rel-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]- 2' - [6- (1, 2-dihydroxypropan-2-yl) pyridin-2-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one：

3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy ] -2' - [6- (1, 2-dihydroxypropan-2-yl) pyridin-2-yl ] -5', 6-dimethyl- [1,4' -bipyridin ] -2-one (120 mg) was isolated by preparative chiral HPLC to give example 36A (11.6 mg, ee=100%) as a white solid, example 36B (13.1 mg, ee=99.34%) and a mixture of example 36c & d (56.0 mg). The mixture of examples 36C & D (56.0 mg) was further separated by preparative chiral HPLC to give example 36C (10.4 mg, ee=100%) and example 36D (11.5 mg, ee=99.78%) as white solids.

Example 36A：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝529.05。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.77(s,1H),8.62(d,1H),8.36(d,1H),8.26(m,1H),8.11(m,1H),7.94(m,1H),7.67(m,1H),6.83(s,1H),5.49(d,2H),5.20(d,1H),4.60(m,1H),3.60(m,2H),2.07(s,3H),1.98(s,3H),1.44(s,3H)。 ¹⁹ F NMR(282MHz,DMSO)δ-120.11,-120.14,-122.30,-122.33。

Example 36B：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝529.05。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.77(s,1H),8.62(d,1H),8.36(d,1H),8.26(m,1H),8.11(m,1H),7.94(m,1H),7.67(m,1H),6.83(s,1H),5.49(d,2H),5.20(d,1H),4.60(m,1H),3.60(m,2H),2.07(s,3H),1.98(s,3H),1.44(s,3H)。 ¹⁹ F NMR(282MHz,DMSO)δ-120.11,-120.14,-122.31,-122.33。

Example 36C：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝529.10。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.76(s,1H),8.60(d,1H),8.35(s,1H),8.25(d,1H),8.16–7.98(m,1H),7.94(m,1H),7.66(m,1H),6.82(s,1H),5.48(d,2H),5.24(s,1H),4.64(m,1H),3.60(m,2H),2.06(s,3H),1.98(s,3H),1.43(s,3H)。 ¹⁹ F NMR(282MHz,DMSO)δ-120.04,-120.06,-122.13,-122.16。

Example 36D：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝529.10。1H NMR(300MHz,DMSO-d ₆ )δ8.76(s,1H),8.60(d,1H),8.35(s,1H),8.25(d,1H),8.16–7.98(m,1H),7.94(m,1H),7.66(m,1H),6.82(s,1H),5.48(d,2H),5.24(s,1H),4.64(m,1H),3.60(m,2H),2.06(s,3H),1.98(s,3H),1.43(s,3H)。 ¹⁹ F NMR(282MHz,DMSO)δ-120.09,-120.11,-122.26,-122.28。

Examples 37A and 37B

Step 1: preparation of (4Z) -5- (dimethylamino) -2, 2-dimethyl-3-oxopent-4-enoic acid methyl ester：

To a 250mL round bottom flask was added methyl 2, 2-dimethyl-3-oxobutanoate (4 g,27.745mmol,1 eq.) and DMF-DMA (25 mL) at room temperature. The resulting mixture was stirred overnight at 100 ℃ under nitrogen atmosphere. The mixture was cooled to room temperature. 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 ]] ⁺ ＝200.1。

Step 2: preparation of methyl 2-methyl-2- (1H-pyrazol-3-yl) propanoate：

To a 100mL round bottom flask was added (4Z) -5- (dimethylamino) -2, 2-dimethyl-3-oxopent-4-enoic acid methyl ester (1.50 g, crude) and hydrazine (10 mL,1M in THF) at room temperature. The resulting mixture was stirred at room temperature under nitrogen overnight. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase combi-flash chromatography. This gave methyl 2-methyl-2- (1H-pyrazol-3-yl) propionate (500 mg, 10.86%) as a colorless oil.LC-MS:(ES+H,m/z):[M+H] ⁺ ＝169.2。 ¹ H NMR (300 MHz, chloroform-d) delta 7.60-7.53 (m, 1H), 7.25-6.98 (m, 1H), 6.30-6.21 (m, 1H), 3.72 (s, 3H), 1.64 (s, 6H).

Step 3: preparation of 2- (1- { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy)]-5', 6-dimethyl-2-oxo Substituted- [1,4' -bipyridines]-2' -yl } pyrazol-3-yl) -2-methylpropanoic acid methyl ester：

Methyl 2-methyl-2- (1H-pyrazol-3-yl) propionate (220 mg,1.31mmol,1.50 eq.) and 2' -bromo-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy at room temperature]-5', 6-dimethyl- [1,4' -bipyridine]To a solution of 2-ketone (400 mg,0.87mmol,1.00 eq.) in 1, 4-dioxane (6 mL) was added CuI (33 mg,0.17mmol,0.20 eq.) K ₂ CO ₃ (185 mg,1.75mmol,2.00 eq.) and (1S, 2S) -N1, N2-dimethylcyclohexane-1, 2-diamine (49 mg,0.35mmol,0.40 eq.). The resulting mixture was stirred under nitrogen at 80 ℃ for 3 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The reaction was poured into water (100 mL) and extracted with EtOAc (3X 100 mL). By anhydrous Na ₂ SO ₄ The combined organic layers were dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2- (1- { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy) as a white solid]-5', 6-dimethyl-2-oxo- [1,4' -bipyridine]-2' -yl } pyrazol-3-yl) -2-methylpropanoic acid methyl ester (350 mg, 73.46%). LC-MS (ES+H, M/z) [ M+H ] ] ⁺ ＝544.3。 ¹ H NMR (400 MHz, chloroform-d) delta 8.47-8.43 (m, 1H), 8.43-8.40 (m, 1H), 8.38 (s, 1H), 7.73 (s, 1H), 7.36-7.30 (m, 1H), 6.43-6.35 (m, 2H), 5.45-5.40 (m, 2H), 3.68 (s, 3H), 2.09 (s, 3H), 2.03 (s, 3H), 1.62 (s, 3H), 1.60 (s, 3H).

Step 4: preparation of 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-2' - [3- (1-hydroxy-2-methylpropane ] 2-yl) pyrazol-1-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one：

To 2- (1- { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy at 0 ℃C]-5', 6-dimethyl-2-oxo- [1,4' -bipyridine]-2' -yl } pyrazol-3-yl) -2-methylpropanoic acid methyl ester (300 mg,0.55mmol,1.00 eq.) in DCM (3 mL) and MeOH (3 mL)Adding NaBH in portions to the stirred solution of (2) ₄ (625 mg,16.56mmol,30.00 eq.). The resulting mixture was stirred at room temperature overnight. The reaction was poured into water (100 ml) and used with CH ₂ Cl ₂ (3X 100 mL) extraction. By anhydrous Na ₂ SO ₄ The combined organic layers were dried. 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 as a white solid]-2' - [3- (1-hydroxy-2-methylpropan-2-yl) pyrazol-1-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one (100 mg, 35.14%). LC-MS (ES+H, M/z) [ M+H ] ] ⁺ ＝516.3。

Step 5: preparation of rel-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-2' - [3- (1-hydroxy-2-methyl) Propan-2-yl) pyrazol-1-yl]-5', 6-dimethyl- [1,4' -bipyridine]2-one and rel-3-chloro-4- [ (3, 5-difluoropyridine ] 2-yl) methoxy]-2' - [3- (1-hydroxy-2-methylpropan-2-yl) pyrazol-1-yl]-5', 6-dimethyl- [1,4' -bipyramid Pyridine and pyridine]-2-one：

The racemate 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy ] -2' - [3- (1-hydroxy-2-methylpropan-2-yl) pyrazol-1-yl ] -5', 6-dimethyl- [1,4' -bipyridin ] -2-one (80 mg) was isolated by preparative chiral SFC to give rel-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy ] -2' - [3- (1-hydroxy-2-methylpropan-2-yl) pyrazol-1-yl ] -5', 6-dimethyl- [1,4' -bipyridin ] -2-one (example 37a,28.6mg, ee=97.82%) and rel-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy ] -2' - [3- (1-hydroxy-2-methylpropan-2-yl) pyrazol-1-yl ] -5', 6-dimethyl- [1,4' -bipyridin ] -2-one as a white solid (example 37a,28.6mg, ee=97.82%).

Example 37A：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝516.05。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.67–8.59(m,1H),8.54(s,1H),8.52–8.45(m,1H),8.17–8.03(m,1H),7.80(s,1H),6.81(s,1H),6.57–6.45(m,1H),5.49(s,2H),4.64(t,1H),3.47(d,2H),2.01(s,6H),1.25(s,6H)。 ¹⁹ F NMR(377MHz,DMSO)δ-120.148,-120.173,-122.343,-122.369。

Example 37B：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝516.05。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.69–8.59(m,1H),8.54(s,1H),8.52–8.47(m,1H),8.17–8.06(m,1H),7.80(s,1H),6.81(s,1H),6.56–6.46(m,1H),5.49(s,2H),4.64(t,1H),3.47(d,2H),2.01(s,6H),1.25(s,6H)。 ¹⁹ F NMR(377MHz,DMSO)δ-120.145,-120.170,-122.340,-122.365。

Examples 38A and 38B

Step 1: preparation of 4- { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-5', 6-dimethyl-2-oxo- [1,4' -bipyridine]-2' -yl } pyridine-2-carboxylic acid methyl ester ：

To 2' -bromo-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy at room temperature under nitrogen atmosphere]-5', 6-dimethyl- [1,4' -bipyridine]-2-one (500 mg,1.09mmol,1.00 eq.) and methyl 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine-2-carboxylate (576 mg,2.19mmol,2.00 eq.) in dioxane (15 mL) and H ₂ CsF (332 mg,2.19mmol,2.00 eq.) and Pd (dppf) Cl were added to a stirred mixture in O (3 ml) ₂ (80 mg,0.11mmol,0.10 eq.). The resulting mixture was stirred at 100℃for a further 2 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was filtered and the filter cake was washed with EtOAc (3X 50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 4- { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy ] as a yellow solid]-5', 6-dimethyl-2-oxo- [1,4' -bipyridine]-2' -yl } pyridine-2-carboxylic acid methyl ester (400 mg, 71.23%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝513.1。

Step 2: preparation of 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-2' - [2- (2-hydroxy-prop-2-yl) pyri-dine Pyridin-4-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one：

At 0 ℃ under nitrogen atmosphere, to4- { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy ]-5', 6-dimethyl-2-oxo- [1,4' -bipyridine]To a stirred solution of methyl-2' -yl } pyridine-2-carboxylate (400 mg,0.78mmol,1.00 eq.) in THF (20 mL) was added MeMgBr (2.60 mL,7.80mmol,10.00 eq., 3M in THF) dropwise. The resulting mixture was stirred under nitrogen at 0 ℃ for 1 hour. By addition of saturated NH ₄ Cl (aq) (20 mL) quenched the reaction at 0deg.C. The resulting mixture was extracted with EtOAc (3X 40 mL). The combined organic layers were washed with brine (1X 200 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC. This gives 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy) as a white solid]-2' - [2- (2-hydroxy-prop-2-yl) pyridin-4-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one (100 mg, 25.00%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝512.9。

Step 3: preparation of rel-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]2' - [2- (2-hydroxypropyl-2-) Radical) pyridin-4-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one and rel-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) Methoxy group]-2' - [2- (2-hydroxy-prop-2-yl) pyridin-4-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one：

3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy ] -2' - [2- (2-hydroxypropyl-2-yl) pyridin-4-yl ] -5', 6-dimethyl- [1,4' -bipyridin ] -2-one (140 mg) was isolated by preparative chiral HPLC to give example 38A (41.3 mg, ee=100%) and example 38B (43.8 mg, ee=100%) as white solids.

Example 38A：

LC-MS:(ES+H,m/z):[M+H]+＝513.10。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.84(s,1H),8.65–8.57(m,2H),8.39(d,1H),8.18(s,1H),8.11(td,1H),7.92(dd,1H),6.83(s,1H),5.50(d,2H),5.33(s,1H),2.08(s,3H),1.99(s,3H),1.50(s,3H),1.49(s,3H)。 ¹⁹ F NMR(282MHz,DMSO)δ-120.14,-120.16,-122.33,-122.36。

Example 38B：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝513.10。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.84(s,1H),8.65–8.57(m,2H),8.39(t,1H),8.18(s,1H),8.11(ddd,1H),7.91(dd,1H),6.83(s,1H),5.50(d,2H),5.32(s,1H),2.08(s,3H),1.99(s,3H),1.50(s,3H),1.49(s,3H)。 ¹⁹ F NMR(282MHz,DMSO)δ-120.14,-120.16,-122.33,-122.36。

Examples 39A and 39B

Step 1: preparation of 4-hydroxy-oxazolidine-4-carboxamide：

4-hydroxy-oxazolidine-4-carboxylic acid methyl ester (3 g,18.73mmol,1.00 eq.) in NH ₃ (g) The solution in MeOH (30 mL, 4M) was stirred under nitrogen at 80℃for 2 hours. The resulting mixture was cooled to room temperature. The resulting mixture was concentrated in vacuo to give 4-hydroxy-dioxane-4-carboxamide (2.70 g, 99.31%) as a white solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ7.15(d,2H),5.30(s,1H),3.83–3.48(m,4H),2.09–1.75(m,2H),1.42–1.17(m,2H)。

Step 2: preparation of 4-hydroxy-oxaalkane-4-formamidine hydrochloride：

To a solution of 4-hydroxydioxane-4-carboxamide (2.70 g,18.60mmol,1.00 eq.) in THF (60 mL) was added triethyloxonium tetrafluoroborate (5.30 g,27.90mmol,1.50 eq.) in portions under nitrogen atmosphere at 0 ℃. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 3 hours. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in MeOH (40 mL). Adding NH dropwise to the above solution at 0deg.C ₃ (g) MeOH (30 ml,4 m) solution. The resulting mixture was stirred at room temperature for an additional 3 hours. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in EA (50 mL). To the above solution was added dropwise a solution of HCl (gas) in 1, 4-dioxane (10 ml,7 m) at 0 ℃. The resulting mixture was stirred at room temperature for an additional 30 minutes. The precipitated solid was collected by filtration and washed with EA (10 mL). The filter cake was concentrated in vacuo. This gave 4-hydroxy-dioxane-4-formamidine hydrochloride (330 mg, 9.82%) as a white solid.

Step 3: preparation of 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-2' - [2- (4-hydroxyoxan-4-yl) Pyrimidin-4-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one：

4-hydroxy-oxazolidine-4-carboxamidine hydrochloride (380 mg,2.10mmol,5.00 eq.) K ₂ CO ₃ (580 mg,4.20mmol,10.00 eq.) and 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-2' - [ (2E) -3- (dimethylamino) prop-2-enoyl]-5', 6-dimethyl- [1,4' -bipyridine]A mixture of 2-ketone (200 mg,0.42mmol,1.00 eq.) in IPA (5 mL) was stirred overnight at 80℃under nitrogen. The reaction was monitored by LCMS. The resulting mixture was cooled to room temperature. The resulting mixture was diluted with EA (200 mL). The resulting mixture was diluted with water (2X 100 mL). The organic layer was concentrated under reduced pressure. By preparative TLC (EA 0.1% Et ₃ N) purification of the residue to give 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-2' - [2- (4-hydroxyoxalan-4-yl) pyrimidin-4-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one (200 mg, crude). The crude product was further purified by preparative HPLC to give 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy as a white solid]-2' - [2- (4-hydroxyoxalan-4-yl) pyrimidin-4-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one (150 mg, 64.06%). LC-MS (ES+H, M/z) [ M+H ] ] ⁺ ＝556.1。 ¹ H NMR(400MHz,DMSO-d ₆ )δ9.07(s,2H),8.76(s,2H),6.29(br,1H),3.81–3.70(m,2H),3.69–3.64(m,2H),2.20–1.95(m,2H),1.58–1.52(m,2H)。

Step 4: preparation of rel-3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy) -2' - (2- (4-hydroxytetrahydro) o- 2H-pyran-4-yl) pyrimidin-4-yl) -5', 6-dimethyl-2H- [1,4' -bipyridine]2-one and rel-3-chloro-4- ((3, 5-) Difluoro-pyridin-2-yl) methoxy) -2'- (2- (4-hydroxytetrahydro-2H-pyran-4-yl) pyrimidin-4-yl) -5', 6-dimethyl- 2H- [1,4' -bipyridine]-2-one：

3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy ] -2' - [2- (4-hydroxyoxalan-4-yl) pyrimidin-4-yl ] -5', 6-dimethyl- [1,4' -bipyridin ] -2-one (150 mg) was isolated by preparative chiral HPLC to give rel-3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy) -2' - (2- (4-hydroxytetrahydro-2H-pyran-4-yl) pyrimidin-4-yl) -5', 6-dimethyl-2H- [1,4' -bipyridin ] -2-one (example 39A, isomer 1, 37.2mg, ee=99.58%) and rel-3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy) -2' - (2- (4-hydroxytetrahydro-2H-pyran-4-yl) pyrimidin-4-yl) -5', 6-dimethyl-2H- [1,4' -bipyridin ] -2-one (example 39.99.3 mg, 35% ee=3.35%.

Example 39A：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝555.85。 ¹ H NMR(400MHz,DMSO-d ₆ )δ9.01(d,1H),8.87(s,1H),8.64(d,1H),8.61(d,1H),8.26(d,1H),8.15–8.06(m,1H),6.85(d,1H),5.50(d,2H),5.33(s,1H),3.88–3.67(m,4H),2.35–2.15(m,2H),2.11(s,3H),1.98(s,3H),1.72–1.60(m,2H)。 ¹⁹ F NMR(377MHz,DMSO)δ-120.13,-120.15,-122.31,-122.32。

Example 39B：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝555.90。 ¹ H NMR(400MHz,DMSO-d ₆ )δ9.01(d,1H),8.87(s,1H),8.64(d,1H),8.61(d,1H),8.26(d,1H),8.14–8.06(m,1H),6.85(d,1H),5.50(d,2H),5.33(s,1H),3.85–3.67(m,4H),2.35–2.16(m,2H),2.11(s,3H),1.98(s,3H),1.75–1.60(m,2H)。 ¹⁹ F NMR(377MHz,DMSO)δ-120.13,-120.15,-122.30,-122.32。

Examples 40A and 40B

Step 1: preparation of 2-chloro-5-cyclopropylpyridin-4-amine：

To 2-chloro-5-iodopyridin-4-amine (5.00 g,19.64mmol,1.00 eq.) cyclopropylboronic acid (1.69 g,19.64mmol,1.00 eq.) in toluene (30 mL) and H at room temperature under a nitrogen atmosphere ₂ Pd (dppf) Cl was added to the stirred solution in O (3 mL) ₂ (0.72 g,0.98mmol,0.05 eq.). The resulting mixture was stirred overnight at 100 ℃ under nitrogen atmosphere. The reaction was monitored by TLC. The mixture was cooled to room temperature. By adding water (50mL) quench the reaction. The resulting mixture was extracted with EtOAc (3X 30 mL). The combined organic layers were washed with brine (100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and the pure fractions were concentrated in vacuo to give 2-chloro-5-cyclopropylpyridin-4-amine (2.50 g, 75.45%) as a yellow oil. ¹ H NMR(300MHz,DMSO-d ₆ )δ7.60(s,1H),6.51(s,1H),6.28(s,2H),1.67-1.43(m,1H),0.98–0.75(m,2H),0.64–0.43(m,2H)。

Step 2: preparation of 2' -chloro-5 ' -cyclopropyl-4-hydroxy-6-methyl- [1,4' -bipyridine]-2-one：

To a stirred solution of 2-chloro-5-cyclopropylpyridin-4-amine (2.40 g,14.23mmol,1.00 eq.) and 2, 2-dimethyl-6- (2-oxopropyl) -1, 3-dioxin-4-one (5.24 g,28.46mmol,2.00 eq.) in 1, 4-dioxane (72 mL) at room temperature under nitrogen. The resulting mixture was stirred under nitrogen at 90 ℃ for 2 hours. The mixture was cooled to room temperature. H was added dropwise to the above mixture at room temperature ₂ SO ₄ (1.40 g,14.23mmol,1.00 eq.). The resulting mixture was stirred at 90℃for a further 1 hour. The reaction was monitored by LCMS. The mixture was cooled to room temperature and then concentrated to remove the solvent, followed by the addition of water (20 ml). The precipitated solid was collected by filtration and taken up in Et ₂ O (3X 10 mL) to give 2' -chloro-5 ' -cyclopropyl-4-hydroxy-6-methyl- [1,4' -bipyridine as a white solid]2-Ketone (2.80 g, 71.09%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝277.1。 ¹ H NMR(400MHz,DMSO-d ₆ )δ10.84(br,1H),8.20(s,1H),7.52(s,1H),6.04-5.91(m,1H),5.66-5.54(m,1H),1.88(s,3H),1.51-1.35(m,1H),1.00–0.80(m,3H),0.73–0.55(m,1H)。

Step 3: preparation of 2 '-chloro-5' -cyclopropyl-4- [ (3, 5-difluoropyridin-2-yl) methoxy]6-methyl- [1,4' ] Bipyridine (P)]-2-one：

To 2' -chloro-5 ' -cyclopropyl-4-hydroxy-6-methyl- [1,4' -bipyridine at room temperature under nitrogen atmosphere]To a stirred solution of 2-ketone (2.90 g,10.48mmol,1.00 eq.) and 2- (chloromethyl) -3, 5-difluoropyridine (3.43 g,20.96mmol,2.00 eq.) in DMF (50 mL) was added K ₂ CO ₃ (5.79g，41.92mmol，4.00 equivalents) and 18-crown-6 (277 mg,1.04mmol,0.10 equivalents). The resulting mixture was stirred under nitrogen at 60 ℃ for 1 hour. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The reaction was poured into water (100 mL) at room temperature. The resulting mixture was extracted with EtOAc (3X 50 mL). The combined organic layers were washed with brine (5X 100 mL) and the filtrate concentrated under reduced pressure. The residue was purified by silica gel column chromatography and the pure fractions were concentrated in vacuo to give 2 '-chloro-5' -cyclopropyl-4- [ (3, 5-difluoropyridin-2-yl) methoxy as a yellow solid]-6-methyl- [1,4' -bipyridine]2-Ketone (3.00 g, 70.89%). LC-MS (ES+H, M/z) [ M+H ] ] ⁺ ＝404.1。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.62-8.57(m,1H),8.22(s,1H),8.13-8.02(m,1H),7.57(s,1H),6.19-6.11(m,1H),6.08-6.01(m,1H),5.29-5.17(m,2H),1.90(s,3H),1.48-1.34(m,1H),0.99–0.90(m,1H),0.91–0.82(m,2H),0.74–0.60(m,1H)。

Step 4: preparation of 5' -cyclopropyl-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-2' - (1-ethoxyethylene) Phenyl) -6-methyl- [1,4' -bipyridine]-2-one：

To 2 '-chloro-5' -cyclopropyl-4- [ (3, 5-difluoropyridin-2-yl) methoxy at room temperature under nitrogen atmosphere]-6-methyl- [1,4' -bipyridine]Pd (PPh) was added to a stirred solution of 2-one (3.00 g,7.42mmol,1.00 eq.) and tributyl (1-ethoxyvinyl) stannane (5.37 g,14.85mmol,2.00 eq.) in 1, 4-dioxane (30 mL) ₃ )Cl ₂ (260 mg,0.37mmol,0.05 eq.). The resulting mixture was stirred overnight at 100 ℃ under nitrogen atmosphere. The reaction was monitored by TLC. The mixture was cooled to room temperature. The resulting mixture was filtered and concentrated under reduced pressure to give 5' -cyclopropyl-4- [ (3, 5-difluoropyridin-2-yl) methoxy as a yellow solid]-2'- (1-ethoxyvinyl) -6-methyl- [1,4' -bipyridine]2-Ketone (1.80 g, crude).

Step 5: preparation of 2 '-acetyl-5' -cyclopropyl-4- [ (3, 5-difluoropyridin-2-yl) methoxy]6-methyl-) [1,4' -bipyridine]-2-one：

To 5' -cyclopropyl-4- [ (3, 5-difluoropyridin-2-yl) methoxy at 0℃under nitrogen atmosphere]-2'- (1-ethoxyvinyl) -6-methyl- [1,4' -biPyridine compound]To a stirred solution of 2-one (1.80 g,4.09mmol,1.00 eq.) in THF (20 mL) was added dropwise concentrated HCl (2 mL). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The reaction was poured into water (40 ml) at room temperature. The resulting mixture was extracted with EtOAc (3X 30 mL). The combined organic layers were washed with brine (3×50 mL) and the filtrate concentrated under reduced pressure. The residue was purified by silica gel column chromatography and the pure fractions were concentrated in vacuo to give 2 '-acetyl-5' -cyclopropyl-4- [ (3, 5-difluoropyridin-2-yl) methoxy as a yellow solid ]-6-methyl- [1,4' -bipyridine]2-Ketone (1.40 g,45.81%, two steps). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝412.1。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.63-8.57(m,1H),8.47(s,1H),8.12-8.04(m,1H),7.75(s,1H),6.18-6.11(m,1H),6.08-6.02(m,1H),5.24(d,2H),2.64(s,3H),1.86(s,3H),1.56-1.43(m,1H),1.14–0.94(m,3H),0.88–0.76(m,1H)。

Step 6: preparation of 2 '-acetyl-3-chloro-5' -cyclopropyl-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-6-alpha-methyl ester Base- [1,4' -bipyridine]-2-one：

To 2 '-acetyl-5' -cyclopropyl-4- [ (3, 5-difluoropyridin-2-yl) methoxy at room temperature under nitrogen atmosphere]-6-methyl- [1,4' -bipyridine]To a stirred solution of 2-ketone (1.20 g,2.91mmol,1.00 eq.) and NCS (506 mg,3.79mmol,1.30 eq.) in DCM (10 mL) was added 2, 2-dichloroacetic acid (18 mg,0.14mmol,0.05 eq.). The resulting mixture was stirred at room temperature under nitrogen overnight. The reaction was monitored by LCMS. The reaction was poured into water (30 ml) at room temperature. By CH ₂ Cl ₂ The resulting mixture was extracted (3X 20 mL). The combined organic layers were washed with brine (3X 30 mL) and the filtrate concentrated under reduced pressure. The residue was purified by silica gel column chromatography and the pure fractions were concentrated in vacuo to give 2 '-acetyl-3-chloro-5' -cyclopropyl-4- [ (3, 5-difluoropyridin-2-yl) methoxy as a yellow solid]-6-methyl- [1,4' -bipyridine]-2-one (700 mg, 53.83%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝446.0。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.66-8.57(m,1H),8.51(s,1H),8.16-8.03(m,1H),7.86(s,1H),6.81(s,1H),5.47(s,2H),2.65(s,3H),1.96(s,3H),1.57–1.40(m,1H),1.15-1.05(m,1H),1.04-0.95(m,2H),0.91-0.75(m,1H)。

Step 7: preparation of 3-chloro-5' -cyclopropyl-4- [ (3, 5-difluoropyridin-2-yl) methoxy ]-2' - [ (2E) -3- (di) Methylamino) prop-2-enoyl]-6-methyl- [1,4' -bipyridine]-2-one：

To 2 '-acetyl-3-chloro-5' -cyclopropyl-4- [ (3, 5-difluoropyridin-2-yl) methoxy at room temperature under nitrogen atmosphere]-6-methyl- [1,4' -bipyridine]A stirred solution of 2-ketone (680 mg,1.52mmol,1.00 eq.) in DMF-DMA (20 mL). The resulting mixture was stirred under nitrogen at 100 ℃ for 3 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure to give 3-chloro-5' -cyclopropyl-4- [ (3, 5-difluoropyridin-2-yl) methoxy as a yellow solid]-2' - [ (2E) -3- (dimethylamino) prop-2-enoyl]-6-methyl- [1,4' -bipyridine]-2-one (440 mg, crude). The crude product mixture was used directly in the next step without further purification. LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝501.2。

Step 8: preparation of 3-chloro-5' -cyclopropyl-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-2' - [2- (2-hydroxy) Propan-2-yl) pyrimidin-4-yl]-6-methyl- [1,4' -bipyridine]-2-one：

To 3-chloro-5' -cyclopropyl-4- [ (3, 5-difluoropyridin-2-yl) methoxy at room temperature under nitrogen atmosphere]-2' - [ (2E) -3- (dimethylamino) prop-2-enoyl]-6-methyl- [1,4' -bipyridine]To a stirred solution of 2-ketone (440 mg,0.87mmol,1.00 eq.) and 2-hydroxy-2-methylpropionamidine hydrochloride (608 mg,4.39mmol,5.00 eq.) in DMF (5 mL) was added K ₂ CO ₃ (264 mg,2.63mmol,3.00 eq.). The resulting mixture was stirred overnight at 80 ℃ under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was poured into water (40 mL) at 0 ℃. The resulting mixture was extracted with EtOAc (3X 30 mL). The combined organic layers were washed with brine (5X 50 mL) and the filtrate concentrated under reduced pressure. The residue was purified by preparative TLC and the pure fractions concentrated in vacuo to give 3-chloro-5' -cyclopropyl-4- [ (3, 5-difluoropyridin-2-yl) methoxy as a white solid]-2' - [2- (2-hydroxy-prop-2-yl) pyrimidin-4-yl]-6-methyl- [1,4' -bipyridine]-2-Ketone ]120mg,14.57%, two steps). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝540.1。

Step 9: preparation of rel-3-chloro-5' -cyclopropyl-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-2'-[2-(2- Hydroxy prop-2-yl) pyrimidin-4-yl]-6-methyl- [1,4' -bipyridine]-2-one and rel-3-chloro-5' -cyclopropyl-4- [ (3, 5- ] Difluoro pyridin-2-yl) methoxy]-2' - [2- (2-hydroxy-prop-2-yl) pyrimidin-4-yl]-6-methyl- [1,4' -bipyridine]-2- Ketone compounds：

The racemate (100 mg) was separated by preparative chiral HPLC to give example 40A (30.9 mg,98.2% purity, ee=100%) as a white solid and example 40B (37.7 mg,96.9% purity, ee=99.48%) as a white solid.

Example 40A：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝540.10。 ¹ H NMR(300MHz,DMSO-d ₆ )δ9.00-8.93(m,1H),8.66(s,1H),8.63–8.60(m,1H),8.56(s,1H)8.25-8.18(m,1H),8.15-8.07(m,1H),6.86(s,1H),5.52-5.48(m,2H),5.26(s,1H),2.03(s,3H),1.56-1.50(m,7H),1.14-1.07(m,1H),1.03-0.95(m,2H),0.87-0.78(m,1H)。 ¹⁹ F NMR(282MHz,DMSO)δ-120.11,-120.13,-122.29,-122.31。

Example 40B：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝539.85。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.99-8.94(m,1H),8.66(s,1H),8.63-8.60(m,1H),8.56(s,1H),8.23-8.19(m,1H),8.15-8.06(m,1H),6.86(s,1H),5.54-5.45(m,2H),5.26(s,1H),2.03(s,3H),1.57-1.50(m,7H),1.17-1.05(m,1H),1.02–0.93(m,2H),0.88-0.77(m,1H)。 ¹⁹ FNMR(282MHz,DMSO)δ-120.10,-120.12,-122.27,-122.29。

Examples 41A and 41B

Step 1: preparation of 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-5', 6-dimethyl-2' - (trimethyl)Nail base Stannyl) - [1,4' -bipyridine]-2-one：

To 2', 3-dichloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy group at room temperature under nitrogen atmosphere]-5', 6-dimethyl- [1,4' -bipyridine]-2-one (500 mg,1.21mmol,1.00 eq.) and Sn ₂ Me ₆ (1.59 g,4.85mmol,4.00 eq.) AsPh was added to a stirred mixture in dioxane (10 mL) ₃ (185 mg,0.61mmol,0.50 eq.) and Pd (PPh) ₃ ) ₂ Cl ₂ (170 mg,0.24mmol,0.20 eq.). The resulting mixture was stirred overnight at 80 ℃ under nitrogen atmosphere. The mixture was cooled to room temperature. The resulting mixture was diluted with ethyl acetate (50 mL). The resulting mixture was washed with 5X 20mL of saturated KF aqueous solution. The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy as a brown semisolid]-5', 6-dimethyl-2 ' - (trimethylstannyl) - [1,4' -bipyridine]-2-one (700 mg, crude). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝541.9。

Step 2: preparation of 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-2' - [2- (1-hydroxycyclobutyl) azoxystrobin Pyridin-4-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one：

To 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy at room temperature under a nitrogen atmosphere]-5', 6-dimethyl-2 ' - (trimethylstannyl) - [1,4' -bipyridine]To a stirred mixture of 2-one (700 mg, assuming 100% yield, 0.93mmol,1.00 eq.) and 2- (1-hydroxycyclobutyl) pyrimidin-4-yl triflate (827 mg,2.78mmol,3.00 eq.) in dioxane (10 mL) was added Pd (PPh) ₃ ) ₂ Cl ₂ (194 mg,0.29mmol,0.30 eq.) and CuI (176 mg,0.96mmol,1.00 eq.). The resulting mixture was stirred under nitrogen at 100 ℃ for 2 hours. The mixture was cooled to room temperature. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3X 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. Purification of the residue by silica gel column chromatography givesThe crude product (200 mg) was further purified by preparative HPLC to give 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy ] as a white solid]-2' - [2- (1-hydroxycyclobutyl) pyrimidin-4-yl]-5', 6-dimethyl- [1,4' -bipyridine]2-Ketone (60 mg,12.33%,2 steps). LC-MS (ES+H, M/z) [ M+H ] ] ⁺ ＝526.2。

Step 3: preparation of rel-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-2' - [2- (1-hydroxycyclobutyl) Pyrimidin-4-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one and rel-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methyl Oxy group]-2' - [2- (1-hydroxycyclobutyl) pyrimidin-4-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one：

The racemate 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy ] -2' - [2- (1-hydroxycyclobutyl) pyrimidin-4-yl ] -5', 6-dimethyl- [1,4' -bipyridin ] -2-one (60 mg) was separated by preparative chiral HPLC to give example 41A (21.6 mg, ee=100%) as an off-white solid and example 41B (20.7 mg, ee=100%) as an off-white solid.

Example 41A：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝526.20。 ¹ H NMR(400MHz,DMSO-d ₆ )δ9.02(d,1H),8.87(s,1H),8.63(s,1H),8.62–8.60(d,1H),8.26(d,1H),8.15–8.05(m,1H),6.84(s,1H),5.68(s,1H),5.50(s,2H),2.72–2.58(m,2H),2.34–2.24(m,2H),2.11(s,3H),1.98(s,3H),1.96–1.76(m,2H)。 ¹⁹ F NMR(377MHz,DMSO)δ-120.13,-120.15,-122.30,-122.32。

Example 41B：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝526.15。 ¹ H NMR(400MHz,DMSO-d ₆ )δ9.02(d,1H),8.87(s,1H),8.63(s,1H),8.62–8.60(d,1H),8.26(d,1H),8.11(ddd,1H),6.84(s,1H),5.68(s,1H),5.50(s,2H),2.71–2.59(m,2H),2.35–2.54(m,2H),2.11(s,3H),1.98(s,3H),1.96–1.78(m,2H)。 ¹⁹ F NMR(377MHz,DMSO)δ-120.13,-120.15,-122.31,-122.33。

Step 4: preparation of 1- (4-methoxypyrimidin-2-yl) cyclobutan-1-ol：

At 0 ℃ under nitrogen atmosphere, toTo a stirred solution of 2-iodo-4-methoxypyrimidine (8.00 g,33.90mmol,1.00 eq.) in toluene (50 mL) was added dropwise i-PrMgCl (3.83 g,37.29mmol,1.10 eq., 2M in THF). The resulting mixture was stirred at 0 ℃ under nitrogen atmosphere for 30 minutes. A solution of cyclobutanone (3.09 g,44.07mmol,1.30 eq.) in toluene (2 mL) was added dropwise to the above mixture over 2 minutes at 0deg.C. The resulting mixture was stirred at room temperature for an additional 1 hour. The reaction was monitored by LCMS. With saturated NH ₄ The reaction was quenched with Cl (aqueous solution) at 0 ℃. The resulting mixture was extracted with EtOAc (3X 100 mL). The combined organic layers were washed with brine (2X 100 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 1- (4-methoxypyrimidin-2-yl) cyclobutan-1-ol (2.10 g, 34.38%) as a yellow oil. LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝183.0。

Step 5: preparation of 2- (1-hydroxycyclobutyl) pyrimidin-4-ol：

To a stirred solution of 1- (4-methoxypyrimidin-2-yl) cyclobutan-1-ol (2.10 g,11.65mmol,1.00 eq.) in MeCN (20 mL) at room temperature under nitrogen was added TMSI (9.33 g,46.61mmol,4.00 eq.). The resulting mixture was stirred at room temperature under nitrogen overnight. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with hexane/EA (3/1) (3X 20 mL) to give 2- (1-hydroxycyclobutyl) pyrimidin-4-ol as a pale yellow solid (1.33 g, 68.68%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝167.1。

Step 6: preparation of 2- (1-hydroxycyclobutyl) pyrimidin-4-yl triflate：

Tf was added dropwise to a stirred mixture of 2- (1-hydroxycyclobutyl) pyrimidin-4-ol (1 g,6.018mmol,1 eq.) and pyridine (1.43 g,18.05mmol,3 eq.) in DCM (10 mL) under nitrogen at 0deg.C ₂ O (3.40 g,12.04mmol,2 eq.). The resulting mixture was stirred under nitrogen at 0 ℃ for 5 minutes. The reaction was monitored by LCMS. The residue was purified by silica gel column chromatography to give 2- (1-hydroxycyclobutyl) pyrimidin-4-yl triflate (900 mg, 50.15%) as a yellow oil. LC-MS:(ES+H,m/z):[M+H] ⁺ ＝299.1。

examples 42A and 42B

Step 1: preparation of 2-methyl-5- (trimethylstannyl) -1,2, 4-triazole-3-carboxylic acid methyl ester：

To 5-bromo-2-methyl-1, 2, 4-triazole-3-carboxylic acid methyl ester (500 mg,2.27mmol,1.00 eq.) and Sn at room temperature under nitrogen atmosphere ₂ Me ₆ (2.98 g,9.08mmol,4.00 eq.) Pd (PPh) was added to a stirred solution of 1, 4-dioxane ₃ ) ₂ Cl ₂ (478 mg,0.68mmol,0.30 eq.) and AsPh ₃ (208 mg,0.68mmol,0.30 eq.). The resulting mixture was stirred at 80 ℃ overnight. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was diluted with EtOAc (100 mL). The residue was washed with KF (5X 300 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, 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 ]] ⁺ ＝306.1。

Step 2: preparation of 5- { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy ]-5', 6-dimethyl-2-oxo- [1,4' -bipyridine]-2' -yl } -2-methyl-1, 2, 4-triazole-3-carboxylic acid methyl ester：

To 2-methyl-5- (trimethylstannyl) -1,2, 4-triazole-3-carboxylic acid methyl ester (500 mg,1.64mmol,1.00 eq.) and 2' -bromo-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy group at room temperature under nitrogen atmosphere]-5', 6-dimethyl- [1,4' -bipyridine]To a stirred mixture of 2-ketone (450 mg,0.98mmol,0.60 eq.) in dioxane (40 mL) was added Pd (PPh) ₃ ) ₂ Cl ₂ (230 mg,0.32mmol,0.20 eq.) and CuI (313 mg,1.64mmol,1.00 eq.). The resulting mixture was stirred under nitrogen at 80 ℃ for 2 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. Purifying the residue by silica gel column chromatographyThe remainder gave 5- { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy ] as a yellow solid]-5', 6-dimethyl-2-oxo- [1,4' -bipyridine]-2' -yl } -2-methyl-1, 2, 4-triazole-3-carboxylic acid methyl ester (100 mg, 11.76%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝517.2

Step 3: preparation of 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-2' - [5- (2-hydroxy-prop-2-yl) -1-) Methyl-1, 2, 4-triazol-3-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one：

To 5- { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy group at 0℃under a nitrogen atmosphere ]-5', 6-dimethyl-2-oxo- [1,4' -bipyridine]To a stirred solution of methyl-2' -yl } -2-methyl-1, 2, 4-triazole-3-carboxylate (300 mg,0.58mmol,1.00 eq.) in THF (30 mL) was added MeMgBr (1.93 mL,5.80mmol,10.00 eq.) dropwise. The resulting mixture was stirred under nitrogen at 0 ℃ for 1 hour. The reaction was monitored by LCMS. By addition of saturated NH ₄ Cl (aq) (10 mL) quenched the reaction at 0deg.C. The resulting mixture was extracted with EtOAc (3X 100 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC. This gives 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy) as a white solid]-2' - [5- (2-hydroxy-prop-2-yl) -1-methyl-1, 2, 4-triazol-3-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one (100 mg, 33.33%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝517.4。

Step 3: preparation of rel-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-2' - [5- (2-hydroxypropyl-2-) 1-methyl-1, 2, 4-triazol-3-yl]-5', 6-dimethyl- [1,4' -bipyridine]2-one and rel-3-chloro-4- [ (3, 5-) Difluoro pyridin-2-yl) methoxy]-2' - [5- (2-hydroxy-prop-2-yl) -1-methyl-1, 2, 4-triazol-3-yl]-5', 6-Dimetho Base- [1,4' -bipyridine ]-2-one：

The racemate 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy ] -2' - [5- (2-hydroxypropyl-2-yl) -1-methyl-1, 2, 4-triazol-3-yl ] -5', 6-dimethyl- [1,4' -bipyridin ] -2-one (55 mg) was separated by preparative chiral HPLC to give example 42A (26.2 mg,99.0% purity, ee=100%) and example 42B (26.0 mg,99.4% purity, ee=100%) as a white solid.

Example 42A：

LC-MS:(ES+H,m/z):[M+H]+＝517.10。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.70-8.76(m,1H),8.56-8.66(m,1H),8.11(t,1H),7.84(s,1H),6.80(s,1H),5.73(s,1H),5.49(s,2H),4.09(s,3H),2.05(s,3H),1.96(s,3H),1.59(s,6H)。 ¹⁹ FNMR(282MHz,DMSO)δ-120.14,-120.16,-122.33,-122.36。

Example 42B：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝517.10。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.73(s,1H),8.61(s,1H),8.10(t,1H),7.84(s,1H),6.80(s,1H),5.73(s,1H),5.48(s,2H),4.09(s,3H),2.05(s,3H),1.96(s,3H),1.58(s,6H)。 ¹⁹ F NMR(282MHz,DMSO)δ-120.13,-120.16,-122.32,-122.35。

Examples 43A and 43B

Step 1: preparation of N- {2- [ (tert-Butyldimethylsilyl) oxy ]]Ethyl } -N-methyl guanidine：

At room temperature, to pyrazole-1-carboxamidine (1.00 g,9.08mmol,1.00 eq.) and {2- [ (tert-butyldimethylsilyl) oxy]Ethyl } (meth) amine (1.72 g,9.08mmol,1.00 eq.) to a mixture in MeCN (15 mL) was added TEA (2.76 g,27.24mmol,3.00 eq.). The resulting mixture was stirred overnight at 60 ℃ under nitrogen atmosphere. The mixture was cooled to room temperature. 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 ]] ⁺ ＝232.1。

Step 2: preparation of 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-2' - {2- [ (2-hydroxyethyl) (methyl) Radical) amino group]Pyrimidin-4-yl } -5', 6-dimethyl- [1,4' -bipyridine ]-2-one：

At room temperature, to N- {2- [ (tert-butyldimethylsilyl) oxy ]]Ethyl } -N-methyl guanidine (682 mg,2.94mmol,2.00 eq.) and 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-2' - [ (2E) -3- (dimethylamino) prop-2-enoyl]-5', 6-dimethyl- [1,4' -bipyridine]To a solution of 2-one (700 mg,1.47mmol,1.00 eq.) in IPA (15 mL) was added K ₂ CO ₃ (2037 mg,14.74mmol,10.00 eq.). The resulting mixture was stirred overnight at 80 ℃ under nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was monitored by LCMS. The reaction was poured into water (300 ml) using CH ₂ Cl ₂ (3X 300 mL) extraction. By anhydrous Na ₂ SO ₄ The combined organic layers were dried. After filtration, the filtrate was concentrated under reduced pressure. Purification of the residue by reverse phase flash chromatography gives 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy as a white solid]-2' - {2- [ (2-hydroxyethyl) (methyl) amino group]Pyrimidin-4-yl } -5', 6-dimethyl- [1,4' -bipyridine]-2-one (230 mg, 29.50%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝529.2。

Step 3: preparation of rel-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-2' - {2- [ (2-hydroxyethyl) (methyl) amino group]Pyrimidin-4-yl } -5', 6-dimethyl- [1,4' -bipyridine]2-Ketone (example 43A) and rel-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy group]-2' - {2- [ (2-hydroxyethyl) (methyl) amino group]Pyrimidin-4-yl } -5', 6-di Methyl- [1,4' -bipyridine]2-Ketone (example 43B)：

The racemate 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy ] -2' - {2- [ (2-hydroxyethyl) (methyl) amino ] pyrimidin-4-yl } -5', 6-dimethyl- [1,4' -bipyridin ] -2-one (230 mg) was isolated by preparative chiral SFC to give rel-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy ] -2' - {2- [ (2-hydroxyethyl) (methyl) amino ] pyrimidin-4-yl } -5', 6-dimethyl- [1,4' -bipyridin ] -2-one (example 43a,90.1mg, ee = 100.00%) and rel-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy ] -2' - {2- [ (2-hydroxyethyl) (methyl) amino ] pyrimidin-4-yl } -5', 6-dimethyl- [1,4' -bipyridin ] -2-one (example 43b, 99.58 mg, ee = 3.58 mg) as a white solid.

Example 43A：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝529.1。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.81(s,1H),8.66–8.58(m,1H),8.55–8.47(m,1H),8.25(s,1H),8.17–8.05(m,1H),7.50(d,1H),6.83(s,1H),5.49(s,2H),5.03–4.37(br,1H),3.86–3.68(m,2H),3.66–3.58(m,2H),3.22(s,3H),2.07(s,3H),1.96(s,3H)。 ¹⁹ F NMR(377MHz,DMSO)δ-120.109,-120.134,-122.296,-122.322。

Example 43B：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝529.1。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.81(s,1H),8.65–8.58(m,1H),8.55–8.48(m,1H),8.25(s,1H),8.17–8.03(m,1H),7.50(d,1H),6.83(s,1H),5.49(s,2H),4.69(br,1H),3.85–3.69(m,2H),3.66–3.56(m,2H),3.22(s,3H),2.07(s,3H),1.96(s,3H)。 ¹⁹ F NMR(377MHz,DMSO)δ-120.104,-120.130,-122.287,-122.312。

Examples 44A and 44B

Step 1: preparation of 1- { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-5', 6-dimethyl-2-oxo- [1,4' -bipyridine]-2' -yl } pyrazole-3-carboxylic acid methyl ester：

To 2' -bromo-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-5', 6-dimethyl- [1,4' -bipyridine]To a stirred mixture of 2-ketone (1.00 g,2.19mmol,1.00 eq.) and methyl 1H-pyrazole-3-carboxylate (552 mg,4.38mmol,2.00 eq.) in 1, 4-dioxane (20 ml) was added CuI (83 mg,0.43mmol,0.20 eq.), K ₂ CO ₃ (605 mg,4.38mmol,2.00 eq.) and N1, N2-dimethylcyclohexane-1, 2-diamine (124 mg,0.87mmol,0.40 eq.). The resulting mixture was stirred under nitrogen at 90 ℃ for 3 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature atmosphere. The residue was purified by silica gel column chromatography to give 1- { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy as a white solid]-5', 6-dimethyl-2-oxo- [1,4' -bipyridines]-2' -yl } pyrazole-3-carboxylic acid methyl ester (1.00 g, 90.9%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝502.1。

Step 2: preparation of 1- { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy ] -5', 6-dimethyl-2-oxo- [1,4' -bipyridin ] -2' -yl } pyrazole-3-carboxylic acid:

1- { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-5', 6-dimethyl-2-oxo- [1,4' -bipyridine]Methyl-2' -yl } pyrazole-3-carboxylate (1.00 g,1.99mmol,1.00 eq.) and LiOH (47 mg,1.99mmol,1.00 eq.) in THF (6 mL) and H ₂ The solution in O (6 mL) was stirred under nitrogen at room temperature for 2 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to give 1- { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy as a white solid as a crude product (Li salt)]-5', 6-dimethyl-2-oxo- [1,4' -bipyridine ]-2' -yl } pyrazole-3-carboxylic acid (0.90 g, 92.50%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝488.0。

Step 3: preparation of 1- { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy ] -5', 6-dimethyl-2-oxo- [1,4' -bipyridin ] -2' -yl } -N-cyclopropylpyrazole-3-carboxamide:

1- { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-5', 6-dimethyl-2-oxo- [1,4' -bipyridine]A mixture of 2' -yl } pyrazole-3-carboxylic acid (900 mg,1.84mmol,1.00 eq), HATU (2.10 g,5.53mmol,3.00 eq), DIEA (1.19 g,9.22mmol,5.00 eq) in DMF (30 ml) was stirred for 15 min, then aminocyclopropane (105 mg,1.84mmol,1.00 eq) was added and the resulting mixture stirred for a further 2 h at 80 ℃. The reaction was monitored by LCMS. The reaction was poured into water (300 mL) at room temperature. The resulting mixture was extracted with EtOAc (3X 100 mL). The combined organic layers were washed with brine (5X 300 mL) and the filtrate concentrated under reduced pressure. The residue was purified by preparative HPLC. This gives 1- { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy ] as a white solid]-5', 6-dimethyl-2-oxo- [1,4' -bipyridine]-2' -yl } -N-cyclopropylpyrazole-3-carboxamide (250 mg, 25.70%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝527.1。

Step 4: preparation of rel-1- { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy ]-5', 6-dimethyl-2-oxo Substitution- [1 ] the number of the components to be processed,4' -bipyridines]-2' -yl } -N-cyclopropylpyrazole-3-carboxamide and rel-1- { 3-chloro-4- [ (3, 5-difluoropyridine ] 2-yl) methoxy]-5', 6-dimethyl-2-oxo- [1,4' -bipyridine]-2' -yl } -N-cyclopropylpyrazole-3-carboxamide：

1- { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy ] -5', 6-dimethyl-2-oxo- [1,4' -bipyridin ] -2' -yl } -N-cyclopropylpyrazole-3-carboxamide (200 mg) was isolated by preparative chiral HPLC to give example 44A (88.0 mg, ee=100.0%) and example 44B (69.6 mg, ee=100.0%) as white solids.

Example 44A：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝527.05。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.68(d,1H),8.65–8.58(m,2H),8.38(d,1H),8.11(m,1H),8.00(s,1H),6.91(d,1H),6.85(s,1H),5.51(s,2H),2.83(m,1H),2.06(s,3H),2.02(s,3H),0.75–0.61(m,2H),0.64-0.56(m,2H)。 ¹⁹ F NMR(282MHz,DMSO)δ-120.17,-120.20,-122.35,-122.37。

Example 44B：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝527.05。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.68(d,1H),8.65–8.58(m,2H),8.38(d,1H),8.16-8.04(m,1H),8.00(s,1H),6.91(d,1H),6.85(s,1H),5.51(s,2H),2.83(m,1H),2.06(s,3H),2.02(s,3H),0.75–0.63(m,2H),0.64-0.56(m,2H)。 ¹⁹ F NMR(282MHz,DMSO)δ-120.17,-120.20,-122.34,-122.37。

Examples 45A and 45B

Step 1: preparation of 5' -bromo-4-hydroxy-2 ', 6-dimethyl- [1,3' -bipyridine]-2-one：

A solution of 5-bromo-2-methylpyridin-3-amine (10.00 g,53.46mmol,1.00 eq.) and 2, 2-dimethyl-6- (2-oxopropyl) -1, 3-dioxin-4-one (19.70 g,106.92mmol,2.00 eq.) in 1, 4-dioxane (100 mL) was stirred under nitrogen at 80℃for 2 hours. At 0 ℃ to the aboveDropwise adding H into the mixture ₂ SO ₄ (3.99 mL,74.85mmol,1.40 eq.). The resulting mixture was stirred under nitrogen at 80 ℃ for a further 2 hours. The reaction was monitored by LCMS. The mixture was brought to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in water (50 mL) and Et ₂ O (100 mL). The precipitated solid was collected by filtration and taken up in Et ₂ O (3X 10 mL) to give 5' -bromo-4-hydroxy-2 ', 6-dimethyl- [1,3' -bipyridine as a white solid]2-Ketone (15.00 g, 95.06%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝294.9。

Step 2: preparation of 5' -bromo-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-2', 6-dimethyl- [1,3' -bipyramid Pyridine and pyridine]-2-one：

To 5' -bromo-4-hydroxy-2 ', 6-dimethyl- [1,3' -bipyridine under nitrogen at room temperature]To a stirred solution of 2-ketone (5.40 g,18.29mmol,1.00 eq.) and 2- (chloromethyl) -3, 5-difluoropyridine (5.98 g,36.59mmol,2.00 eq.) in DMF (100 mL) was added K ₂ CO ₃ (10.00 g,73.18mmol,4.00 eq.) and 18-crown-6 (1.45 g,5.48mmol,0.30 eq.). The resulting mixture was stirred under nitrogen at 60 ℃ for 6 hours. The reaction was monitored by LCMS. The mixture was brought to room temperature. With saturated NH ₄ The reaction was quenched with Cl (aqueous solution) at room temperature. The aqueous layer was extracted with EtOAc (3X 300 mL). The residue was purified by silica gel column chromatography to give 5' -bromo-4- [ (3, 5-difluoropyridin-2-yl) methoxy as a pale yellow solid]-2', 6-dimethyl- [1,3' -bipyridine]2-Ketone (4.30 g, 55.66%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝422.0。

Step 3: preparation of 2-propanol (3X 3 mL) gave 5' -bromo-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy Base group]-2', 6-dimethyl- [1,3' -bipyridine]-2-one：

To 5' -bromo-4- [ (3, 5-difluoropyridin-2-yl) methoxy at room temperature under a nitrogen atmosphere]-2', 6-dimethyl- [1,3' -bipyridine]To a stirred solution of 2-ketone (4.90 g,11.60mmol,1.00 eq.) and NCS (1.55 g,11.60mmol,1.00 eq.) in IPA (25 mL) was added 2, 2-dichloroacetic acid (0.45 g,3.48mmol,0.30 eq.). The resulting mixture was stirred under nitrogen at 60℃for 2 hoursWhen (1). The precipitated solid was collected by filtration and washed with 2-propanol (3×3 mL) to give 5' -bromo-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy as a white solid]-2', 6-dimethyl- [1,3' -bipyridine]2-Ketone (3.00 g, 56.61%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝457.9。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.73(d,1H),8.60(d,1H),8.19(d,J＝2.2Hz,1H),8.15–8.02(m,1H),6.80(d,1H),5.48(d,2H),2.15(s,3H),1.96(s,3H)。

Step 4: preparation of 5' -acetyl-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]2', 6-dimethyl-) [1,3' -bipyridine]-2-one：

To 5' -bromo-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy at room temperature]-2', 6-dimethyl- [1,3' -bipyridine]Pd (PPh) was added to a stirred mixture of 2-ketone (2.40 g,5.25mmol,1.00 eq.) and tributyl (1-ethoxyvinyl) stannane (3.80 g,10.51mmol,2.00 eq.) in 1, 4-dioxane (10 ml) ₃ ) ₂ Cl ₂ (0.74 g,1.05mmol,0.20 eq.). The resulting mixture was stirred overnight at 120 ℃ under nitrogen atmosphere. The mixture was cooled to room temperature. The resulting mixture was filtered and the filter cake was washed with EA (3X 30 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was dissolved in THF (20 mL). HCl (2 mL) was added dropwise to the above mixture at 0deg.C. The resulting mixture was stirred at room temperature for an additional 1 hour. With saturated NaHCO ₃ The residue was basified (aqueous) to pH 9. The resulting mixture was extracted with EtOAc (3X 200 mL). The combined organic layers were washed with brine (1X 100 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5' -acetyl-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy as a yellow oil]-2', 6-dimethyl- [1,3' -bipyridine]2-Ketone (1.80 g, 81.59%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝420.1。 ¹ H NMR(300MHz,DMSO-d ₆ )δ9.09(d,1H),8.61(d,1H),8.27(d,1H),8.15–7.95(m,1H),6.82(s,1H),5.49(d,2H),2.64(s,3H),2.27(s,3H),1.95(s,3H)。

Step 5: preparation of 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-5' - [ (2Z) -3- (dimethylamino) Prop-2-enoyl]-2', 6-dimethyl- [1,3' -bipyridine]-2-one：

To a 250mL round bottom flask at room temperature was added 5' -acetyl-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-2', 6-dimethyl- [1,3' -bipyridine]2-one (1.80 g,4.28mmol,1.00 eq.) and DMF-DMA (30 mL). The resulting mixture was stirred at 80 ℃ overnight. The mixture was cooled to room temperature. The resulting mixture was concentrated in vacuo to give 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy as a yellow solid]-5' - [ (2Z) -3- (dimethylamino) prop-2-enoyl]-2', 6-dimethyl- [1,3' -bipyridine]-2-one (crude). The crude product was used directly in the next step without further purification. LC-MS (ES+H, M/z) [ M+H ] ] ⁺ ＝475.0。

Step 6: preparation of 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-5' - [2- (2-hydroxy-prop-2-yl) azoxystrobin Pyridin-4-yl]-2', 6-dimethyl- [1,3' -bipyridine]-2-one：

To 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy at room temperature under an air atmosphere]-5' - [ (2Z) -3- (dimethylamino) prop-2-enoyl]-2', 6-dimethyl- [1,3' -bipyridine]-2-one (1.00 g,2.10mmol,1.00 eq.) and K ₂ CO ₃ (1.74 g,12.63mmol,6.00 eq.) 2-hydroxy-2-methylpropionamidine (1.08 g,10.53mmol,5.00 eq.) was added to a stirred mixture of 2-propanol (20 ml). The resulting mixture was stirred at 80℃for 12 hours. The mixture was cooled to room temperature and then poured into water (200 mL). The resulting mixture was extracted with EtOAc (3X 300 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. 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 as a yellow solid]-5' - [2- (2-hydroxy-prop-2-yl) pyrimidin-4-yl]-2', 6-dimethyl- [1,3' -bipyridine]2-Ketone (750 mg, 69.30%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝514.4。

Step 7: preparation of rel-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-5' - [2- (2-hydroxypropyl-2-) Base) pyrimidin-4-yl]-2', 6-dimethyl- [1,3' -bipyridine]-2-one and rel-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) Methoxy group]-5' - [2- (2-hydroxy-prop-2-yl) pyrimidin-4-yl]-2', 6-dimethyl- [1,3' -bipyridine]-2-one：

The racemic mixture (750 mg) was separated by preparative chiral HPLC to give rel-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy ] -5'- [2- (2-hydroxypropan-2-yl) pyrimidin-4-yl ] -2', 6-dimethyl- [1,3 '-bipyridin ] -2-one (example 45a:260.7mg, ee=100%) and rel-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy ] -5' - [2- (2-hydroxypropan-2-yl) pyrimidin-4-yl ] -2', 6-dimethyl- [1,3' -bipyridin ] -2-one (example 45b:286.4mg, ee=100%) as yellow solids.

Example 45A：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝514.00。 ¹ H NMR(300MHz,DMSO-d ₆ )δ9.48(d,1H),8.93(d,1H),8.73(d,1H),8.62(d,1H),8.16–8.11(m,1H),8.09(s,1H),6.85(d,1H),5.51(d,2H),5.23(s,1H),2.29(s,3H),1.99(s,3H),1.55(s,3H),1.54(s,3H)。 ¹⁹ F NMR(282MHz,DMSO)δ-120.14,-120.16,-122.34,-122.36。

Example 45B：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝514.20。 ¹ H NMR(300MHz,DMSO-d ₆ )δ9.48(d,1H),8.93(d,1H),8.73(d,1H),8.62(d,1H),8.15–8.10(m,1H),8.09(d,1H),6.85(d,1H),5.51(d,2H),5.23(s,1H),2.29(s,3H),1.99(s,3H),1.55(s,3H),1.54(s,3H)。 ¹⁹ F NMR(282MHz,DMSO)δ-120.14,-120.16,-122.34,-122.36。

Examples 46A and 46B

Step 1: preparation of 2-methyl-1- (1H-pyrazol-3-yl) propan-2-ol：

To a stirred solution of ethyl 2- (1H-pyrazol-3-yl) acetate (1.50 g,9.73mmol,1.00 eq.) in THF (15 mL) at-5℃under a nitrogen atmosphere was added dropwise a solution of MeMgBr in THF (22.70 mL,68.11mmol,7.00 eq.). The resulting mixture was subjected to nitrogen atmosphere at 0℃CStirring is carried out for 2 hours. The reaction was monitored by LCMS. With saturated NH ₄ The reaction was quenched with Cl (aqueous solution) at room temperature. The resulting mixture was extracted with EtOAc (7X 10 mL). By anhydrous Na ₂ SO ₄ The combined organic layers were dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2-methyl-1- (1H-pyrazol-3-yl) propan-2-ol (600 mg, 43.99%) as a yellow oil. LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝141.3。

Step 2: preparation of 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-2' - [3- (2-hydroxy-2-methylpropyl) Radical) pyrazol-1-yl radical]-5', 6-dimethyl- [1,4' -bipyridine]-2-one：

To 2' -bromo-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy at room temperature under nitrogen atmosphere]-5', 6-dimethyl- [1,4' -bipyridine]To a stirred solution of 2-ketone (500 mg,1.09mmol,1.00 eq), 2-methyl-1- (1H-pyrazol-3-yl) propan-2-ol (230 mg,1.64mmol,1.50 eq) and (1R, 2R) -N1, N2-dimethylcyclohexane-1, 2-diamine (311 mg,2.19mmol,2.00 eq) in dioxane (7 mL) was added CuI (417 mg,2.19mmol,2.00 eq) and K ₂ CO ₃ (302 mg,2.19mmol,2.00 eq.). The resulting mixture was stirred overnight at 80 ℃ under nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was monitored by LCMS. With saturated NH ₄ The reaction was quenched with Cl (aqueous solution) at room temperature. The resulting mixture was extracted with EtOAc (3X 30 mL). The combined organic layers were washed with brine (1X 30 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. 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 as a white solid]-2' - [3- (2-hydroxy-2-methylpropyl) pyrazol-1-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one (500 mg, 88.51%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝516.2。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.60(d,1H),8.54(t,1H),8.51(d,1H),8.10(m,1H),7.77(s,1H),6.80(d,1H),6.45(d,1H),5.48(d,2H),4.43(s,1H),2.72(s,2H),2.01(s,3H),2.00(s,3H),1.14(s,3H),1.12(s,3H)。

Step 3: preparation of rel-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-2' - [3- (2-hydroxy)Base-2-methyl Propyl) pyrazol-1-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one and rel-3-chloro-4- [ (3, 5-difluoropyridin-2- ] Radical) methoxy radical]-2' - [3- (2-hydroxy-2-methylpropyl) pyrazol-1-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2- Ketone compounds：

3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy ] -2' - [3- (2-hydroxy-2-methylpropyl) pyrazol-1-yl ] -5', 6-dimethyl- [1,4' -bipyridin ] -2-one (500 mg,0.996mmol,1 eq.) was isolated by preparative HPLC to give rel-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy ] -2' - [3- (2-hydroxy-2-methylpropyl) pyrazol-1-yl ] -5', 6-dimethyl- [1,4' -bipyridin ] -2-one (example 46A) (208.1 mg,97.7% purity, ee=100%) and rel-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy ] -2' - [3- (2-hydroxy-2-methylpropyl) pyrazol-1-yl ] -5', 6-dimethyl- [1,4' -bipyridin ] -2-one (example 46B) (example 243.9% purity, 96% ee=100%).

Example 46A: LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝516.05。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.60(d,1H),8.54(t,1H),8.51(d,1H),8.10(m,1H),7.77(s,1H),6.80(d,1H),6.45(d,1H),5.48(d,2H),4.43(s,1H),2.72(s,2H),2.01(s,3H),2.00(s,3H),1.14(s,3H),1.12(s,3H)。 ¹⁹ F NMR(377MHz,DMSO)δ-120.15,-120.17,-122.35,-122.37。

Example 46B：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝516.00。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.60(d,1H),8.54(t,1H),8.51(d,1H),8.10(m,1H),7.77(s,1H),6.80(d,1H),6.45(d,1H),5.48(d,2H),4.43(s,1H),2.72(s,2H),2.01(s,3H),2.00(s,3H),1.14(s,3H),1.12(s,3H)。 ¹⁹ F NMR(377MHz,DMSO)δ-120.15,-120.16,-122.35,-122.37。

Examples 47A and 47B

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Step 1: preparation of 1- { 3-chloro-4- [ 4-methoxyphenyl) methoxyBase group]-5', 6-dimethyl-2-oxo- [1,4' -bi Pyridine compound]-2' -yl } pyrazole-3-carboxylic acid methyl ester：

To 2' -bromo-3-chloro-4- [ (4-methoxyphenyl) methoxy at room temperature]-5', 6-dimethyl- [1,4' -bipyridine]-2-one (2.00 g,4.44mmol,1.00 eq.) 1H-pyrazole-3-carboxylic acid methyl ester (673 mg,5.33mmol,1.20 eq.) K ₂ CO ₃ To a mixture of (1229 mg,8.89mmol,2.00 eq.) and (1S, 2S) -N1, N2-dimethylcyclohexane-1, 2-diamine (255 mg,1.77mmol,0.40 eq.) in 1, 4-dioxane (20 mL) was added CuI (169 mg,0.88mmol,0.20 eq.). The resulting mixture was stirred under nitrogen at 80 ℃ for 2 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The reaction was poured into water (100 mL) and then extracted with EtOAc (3×100 mL). By anhydrous Na ₂ SO ₄ The combined organic layers were dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 1- { 3-chloro-4- [ (4-methoxyphenyl) methoxy as a white solid]-5', 6-dimethyl-2-oxo- [1,4' -bipyridine]-2' -yl } pyrazole-3-carboxylic acid methyl ester (800 mg, 36.35%). LC-MS (ES+H, M/z) [ M+H ] ] ⁺ ＝495.0。 ¹ H NMR (400 MHz, chloroform-d) delta 8.59 (d, 1H), 8.45 (s, 1H), 7.92 (s, 1H), 7.42-7.37 (m, 2H), 6.99-6.96 (m, 2H), 6.96-6.94 (m, 1H), 6.15 (s, 1H), 5.23 (s, 2H), 3.95 (s, 3H), 3.85 (s, 3H), 2.14 (s, 3H), 1.98 (s, 3H).

Step 2: preparation of 1- { 3-chloro-4-hydroxy-5 ', 6-dimethyl-2-oxo- [1,4' -bipyridine]2' -yl pyrazoles 3-Carboxylic acid methyl ester：

To 1- { 3-chloro-4- [ (4-methoxyphenyl) methoxy group at room temperature]-5', 6-dimethyl-2-oxo- [1,4' -bipyridine]Methyl-2' -yl } pyrazole-3-carboxylate (700 mg,1.41mmol,1.00 eq.) was added to a mixture of DCM (6.00 mL) followed by TFA (2.00 mL). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to give the crude product 1- { 3-chloro-4-hydroxy-5 ', 6-dimethyl-2-oxo- [1,4' -bipyridine as a yellow oil]-2' -yl } pyrazole-3-carboxylic acid methyl ester (1 g, crude product) which was used in the next step without further purification. LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝375.2。

Step 3: preparation of 1- { 3-chloro-4- [ (3-chloro-5-fluoropyridin-2-yl) methoxy]-5', 6-dimethyl-2-oxo- [1,4' -bipyridine]-2' -yl } pyrazole-3-carboxylic acid methyl ester：

To 1- { 3-chloro-4-hydroxy-5 ', 6-dimethyl-2-oxo- [1,4' -bipyridine at room temperature ]-2' -yl } pyrazole-3-carboxylic acid methyl ester (1.00 g,2.66mmol,1.00 eq.) K ₂ CO ₃ To a mixture of (1.11 g,8.00mmol,3.00 eq.) and 3-chloro-2- (chloromethyl) -5-fluoropyridine (0.96 g,5.32mmol,2.00 eq.) in DMF (15.00 mL) was added 18-crown-6 (0.35 g,1.33mmol,0.50 eq.). The resulting mixture was stirred under nitrogen at 60 ℃ for 3 hours. The reaction was monitored by LCMS. The desired product was detectable by LCMS. The reaction was poured into water (200 mL) and extracted with EtOAc (3×200 mL). By anhydrous Na ₂ SO ₄ The combined organic layers were dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 1- { 3-chloro-4- [ (3-chloro-5-fluoropyridin-2-yl) methoxy as a white solid]-5', 6-dimethyl-2-oxo- [1,4' -bipyridine]-2' -yl } pyrazole-3-carboxylic acid methyl ester (600 mg, 43.38%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝518.1。 ¹ H NMR (400 MHz, chloroform-d) δ8.59 (d, 1H), 8.46 (s, 1H), 8.45 (s, 1H), 7.92 (s, 1H), 7.62-7.57 (m, 1H), 6.98 (d, 1H), 6.31 (s, 1H), 5.47 (s, 2H), 3.95 (s, 3H), 2.15 (s, 3H), 2.00 (s, 3H).

Step 4: preparation of 3-chloro-4- [ (3-chloro-5-fluoropyridin-2-yl) methoxy]-2' - [3- (2-hydroxy-prop-2-yl) pyri-dine Azol-1-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one：

To 1- { 3-chloro-4- [ (3-chloro-5-fluoropyridin-2-yl) methoxy group at 0℃under nitrogen atmosphere ]-5', 6-dimethyl-2-oxo- [1,4' -bipyridine]To a stirred solution of methyl-2' -yl } pyrazole-3-carboxylate (400 mg,0.77mmol,1.00 eq.) in THF (10 mL) was added MeMgBr (2.57 mL,7.72mmol,10.00 eq.) dropwise. The resulting mixture was stirred under nitrogen at 0 ℃ for 1 hour. The reaction was monitored by LCMS. The desired product was detectable by LCMS. With saturated NH ₄ Cl (aqueous) (150 ml) quenched the reaction at 0deg.C. The resulting mixture was extracted with EtOAc (3X 150 mL). By anhydrous Na ₂ SO ₄ The combined organic layers were dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography. The resulting mixture was concentrated under reduced pressure to give 3-chloro-4- [ (3-chloro-5-fluoropyridin-2-yl) methoxy as a white solid]-2' - [3- (2-hydroxy-prop-2-yl) pyrazol-1-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one (130 mg, 32.50%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝518.2。

Step 5: preparation of rel-3-chloro-4- [ (3-chloro-5-fluoropyridin-2-yl) methoxy]2' - [3- (2-hydroxypropyl-2-) Radical) pyrazol-1-yl radical]-5', 6-dimethyl- [1,4' -bipyridine]-2-one and rel-3-chloro-4- [ (3-chloro-5-fluoropyridine-2-) Radical) methoxy radical]-2' - [3- (2-hydroxy-prop-2-yl) pyrazol-1-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one：

The racemate 3-chloro-4- [ (3-chloro-5-fluoropyridin-2-yl) methoxy ] -2' - [3- (2-hydroxypropyl-2-yl) pyrazol-1-yl ] -5', 6-dimethyl- [1,4' -bipyridin ] -2-one (130 mg) was separated by preparative chiral HPLC to give rel-3-chloro-4- [ (3-chloro-5-fluoropyridin-2-yl) methoxy ] -2' - [3- (2-hydroxypropyl-2-yl) pyrazol-1-yl ] -5', 6-dimethyl- [1,4' -bipyridin ] -2-one (example 47a,38.2mg, ee=100.00%) and rel-3-chloro-4- [ (3-chloro-5-fluoropyridin-2-yl) methoxy ] -2' - [3- (2-hydroxypropyl-2-yl) pyrazol-1-yl ] -5', 6-dimethyl- [1,4' -bipyridin ] -2-one (example 47a, 36.00 mg, ee=100.00%) as a white solid.

Example 47A：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝518.2。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.68(d,1H),8.54(s,1H),8.51(d,1H),8.29–8.22(m,1H),7.78(s,1H),6.77(s,1H),6.56(d,1H),5.50(s,2H),5.09(s,1H),2.01(s,3H),1.99(s,3H),1.48(s,6H)。 ¹⁹ F NMR(377MHz,DMSO)δ-124.16,-124.20。

Example 47B：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝518.20。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.68(d,1H),8.54(s,1H),8.51(d,1H),8.30–8.21(m,1H),7.78(s,1H),6.77(s,1H),6.56(d,1H),5.50(s,2H),5.09(s,1H),2.01(s,3H),1.99(s,3H),1.48(s,6H)。 ¹⁹ F NMR(377MHz,DMSO)δ-124.21。

Examples 48A and 48B

Step 1: preparation of 1- (2, 2-diethoxyethyl) cyclopropyl-1-ol：

To 3, 3-diethoxypropionate (30.00 g,157.69mmol,1.00 eq.) and Ti (Oi-Pr) 4 (67.20 g,236.54mmol,1.50 eq.) in Et under nitrogen at 0deg.C ₂ To a stirred mixture of O (200 mL) and THF (50 mL) was added dropwise a solution of EtMgBr in 2-methyl-THF (2M, 233.6mL,630.784mmol,4.00 eq). The resulting mixture was stirred at room temperature under nitrogen overnight. The reaction was monitored by TLC (PE/ea=7:1, rf=0.4). The reaction was quenched by the addition of water (400 mL) at 0deg.C. With Et ₂ O (2X 500 mL) extraction of the resulting mixture, combining the organic phases and passing through anhydrous Na ₂ SO ₄ And (5) drying. 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 1- (2, 2-diethoxyethyl) cyclopropan-1-ol (8.00 g, 29.12%) as a yellow liquid. ¹ H NMR (300 MHz, chloroform-d) delta 4.81 (t, 1H), 3.70-3.76 (m, 3H), 3.62-3.55 (m, 2H), 1.91 (d, 2H), 1.25 (t, 6H), 0.78 (d, 2H), 0.47-0.44 (m, 2H).

Step 2: preparation of 1- (2, 2-diethoxyethyl) cyclopropylacetate：

To 1- (2, 2-diethoxyethyl) cyclopropan-1-ol (8.00 g,45.91mmol,1.00 eq.) and DMAP (6.17 g,50.50mmol,1.10 eq.) in Et under nitrogen at 0deg.C ₂ Acetic anhydride (7.03 g,68.87mmol,1.50 eq.) was added dropwise to a stirred solution of O (100 mL). The resulting mixture was stirred under nitrogen at 0 ℃ for 1 hour. The reaction was monitored by TLC (PE/ea=10:1, rf=0.5). With saturated NaHCO ₃ (aqueous solution) the reaction was quenched at 0 ℃. With Et ₂ O (3X 100 mL) extracts the aqueous layer. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography and the pure fractions were concentrated under reduced pressure to give a yellow liquid1- (2, 2-diethoxyethyl) cyclopropylacetate (7.00 g, 70.49%). ¹ H NMR (400 MHz, chloroform-d) δ4.71 (t, 1H), 3.63 (q, 2H), 3.52 (q, 2H), 2.08 (d, 2H), 1.98 (s, 3H), 1.20 (t, 6H), 0.89-0.83 (m, 2H), 0.77-0.74 (m, 2H).

Step 3: preparation of [1- (acetoxy) cyclopropyl ]]Acetic acid：

To 1- (2, 2-diethoxyethyl) cyclopropylacetate (7.00 g,32.36mmol,1.00 eq.) in THF (40 mL) and H at room temperature ₂ To a stirred solution of O (80 mL) was added in portions potassium hydrogen persulfate (8.16 g,48.54mmol,1.50 eq.). The resulting mixture was stirred at room temperature overnight. The reaction was monitored by TLC (100% EA, rf=0.1). The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with EtOAc (5X 200 mL). By anhydrous Na ₂ SO ₄ The combined organic layers were dried. After filtration, the filtrate was concentrated under reduced pressure to give [1- (acetoxy) cyclopropyl ] as a yellow oil ]Acetic acid (6 g, crude). ¹ H NMR (400 MHz, chloroform-d) δ2.82 (s, 2H), 2.02 (s, 3H), 1.03-0.97 (m, 2H), 0.90-0.86 (m, 2H).

Step 4: preparation of ethyl 2- (1-hydroxycyclopropyl) acetate：

To [1- (acetoxy) cyclopropyl ] at room temperature]To a stirred solution of acetic acid (6.00 g,37.93mmol,1.00 eq.) in EtOH (200 mL) was added dropwise H ₂ SO ₄ (60 drops). The resulting mixture was stirred at room temperature overnight. The reaction was monitored by TLC (PE/ea=10:1, rf=0.5). With saturated NaHCO ₃ The reaction was quenched at room temperature. The aqueous layer was extracted with EtOAc (3X 200 mL). The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography and the pure fractions were concentrated under reduced pressure to give ethyl 2- (1-hydroxycyclopropyl) acetate (1.50 g, 32.15%) as a yellow liquid. ¹ H NMR (300 MHz, chloroform-d) δ4.22 (q, 2H), 2.60 (s, 2H), 1.32 (t, 3H), 0.88 (dd, 2H), 0.55-0.48 (m, 2H).

Step 5: preparation of 2- (1-hydroxycyclopropyl) acetamidine hydrochloride：

Under nitrogen atmosphere at 0 ℃ to NH ₄ Cl (927 mg,17.34mmol,5.00 eq.) AlMe was added dropwise to a stirred mixture of toluene (20 mL) ₃ (8mL,2M toluene solution, 17.34mmol,5.00 eq). The resulting mixture was stirred under nitrogen at 0 ℃ for 10 minutes and then at room temperature until no more gas was produced. A solution of ethyl 2- (1-hydroxycyclopropyl) acetate (500 mg,3.46mmol,1.00 eq.) in toluene was added dropwise to the above mixture at room temperature. The resulting mixture was stirred at 80 ℃ overnight. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The reaction was quenched by the addition of MeOH (10 mL) at 0 ℃. The resulting mixture was filtered and the filter cake was washed with MeOH (6X 30 mL). The filtrate was concentrated under reduced pressure. The residue was dissolved in EtOH (8 mL). The resulting mixture was filtered and the filter cake was washed with EtOH (5 mL). The filtrate was concentrated under reduced pressure. This gave 2- (1-hydroxycyclopropyl) acetamidine hydrochloride as an orange oil (450 mg, crude). ¹ H NMR(300MHz,DMSO-d ₆ )δ9.01–8.72(m,4H),5.76(s,1H),2.60(s,2H),0.65(s,4H)。

Step 6: preparation of 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-2' - {2- [ (1-hydroxycyclopropyl) methyl Base group]Pyrimidin-4-yl } -5', 6-dimethyl- [1,4' -bipyridine]-2-one：

To 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy at room temperature]-2' - [ (2E) -3- (dimethylamino) prop-2-enoyl]-5', 6-dimethyl- [1,4' -bipyridine]To a stirred solution of 2-ketone (315 mg,0.66mmol,1.00 eq.) and 2- (1-hydroxycyclopropyl) acetamidine hydrochloride (300 mg,1.99mmol,3.00 eq.) in DMF (10 mL) was added K ₂ CO ₃ (1.84 g,13.28mmol,20.00 eq.). The resulting mixture was stirred at 60 ℃ overnight. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was diluted with water (20 mL). The aqueous layer was extracted with EtOAc (3X 20 mL). The resulting mixture was concentrated in vacuo. Purification of the crude product by preparative HPLC gave 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy as a white solid]-2' - {2- [ (1-hydroxycyclopropyl) methyl group]Pyrimidin-4-yl } -5', 6-dimethyl- [1,4' -bipyridine]2-Ketone (69.0 mg, 19.76%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝526.1。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.92(d,1H),8.87(s,1H),8.61(d,1H),8.31(s,1H),8.22(d,1H),8.11–8.08(m,1H),6.83(s,1H),5.50(d,2H),5.27(s,1H),3.23–3.10(m,2H),2.09(s,3H),1.97(s,3H),0.66–0.59(m,4H)。

Step 7: preparation of rel-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-2' - {2- [ (1-hydroxycyclopropyl) Radical) methyl radical]Pyrimidin-4-yl } -5', 6-dimethyl- [1,4' -bipyridine ]2-one and rel-3-chloro-4- [ (3, 5-difluoropyridine ] 2-yl) methoxy]-2' - {2- [ (1-hydroxycyclopropyl) methyl group]Pyrimidin-4-yl } -5', 6-dimethyl- [1,4' -bipyridine]- 2-Ketone：

The racemate was separated by preparative chiral HPLC (69 mg) to give example 48A (26.0 mg,98.7% purity, ee=100%) as a white solid and example 48B (27.3 mg,99.2% purity, ee=100%) as a white solid.

Example 48A：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝526.20。 ¹ H NMR(400MHz,DMSO-d ₆ )δ

8.92(d,1H),8.87(s,1H),8.61(d,1H),8.31(s,1H),8.22(d,1H),8.11–8.08(m,1H),6.83(s,1H),5.50(d,2H),5.27(s,1H),3.23–3.10(m,2H),2.09(s,3H),1.97(s,3H),0.66–0.59(m,4H)。 ¹⁹ F NMR(282MHz,DMSO)δ-120.13,-120.15,-122.32,-122.35。

Example 48B：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝526.20。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.92(d,1H),8.87(s,1H),8.61(d,1H),8.31(s,1H),8.22(d,1H),8.11–8.08(m,1H),6.83(s,1H),5.50(d,2H),5.27(s,1H),3.23–3.10(m,2H),2.09(s,3H),1.97(s,3H),0.66–0.59(m,4H)。 ¹⁹ F NMR(282MHz,DMSO)δ-120.13,-120.15,-122.32,-122.35。

Examples 49A and 49B

Step 1: preparation of 2' -bromo-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-3',5', 6-trimethyl- [1, 4' -bipyridines]-2-one：

To 2' -bromo-4- [ (3, 5-difluoropyridin-2-yl) methoxy at room temperature under an air atmosphere]-3',5', 6-trimethyl- [1,4' -bipyridine]To a stirred solution of 2-ketone (2.60 g,5.96mmol,1.00 eq.) and NCS (954 mg,7.15mmol,1.20 eq.) in IPA (10 mL) was added dropwise 2, 2-dichloroacetic acid (76 mg,0.59mmol,0.10 eq.). The resulting mixture was stirred under nitrogen at 60 ℃ for 1 hour. The reaction was monitored by LCMS. The precipitated solid was collected by filtration and washed with IPA (5 mL) to give 2' -bromo-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy as a white solid]-3',5', 6-trimethyl- [1,4' -bipyridine ]2-Ketone (2.48 g, 88.40%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝470.1/472.1。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.60(d,1H),8.38(s,1H),8.13–8.04(m,1H),6.87(d,1H),5.49(d,2H),2.02(s,3H),1.94(s,3H),1.92(s,3H)。

Step 2: preparation of 2' -bromo-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-3',5', 6-trimethyl- [1,4' -biphenol Pyridine compound]-2-one：

To 2' -bromo-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy at room temperature under an air atmosphere]-3',5', 6-trimethyl- [1,4' -bipyridine]To a stirred mixture of 2-one (1.50 g,3.18mmol,1.00 eq.) and tributyl (1-ethoxyvinyl) stannane (3.45 g,9.56mmol,3.00 eq.) in 1, 4-dioxane (5 mL) was added bis (triphenylphosphine) palladium dichloride (223 mg,0.31mmol,0.10 eq.). The resulting mixture was stirred under nitrogen at 100 ℃ for 12 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was filtered and the filter cake was washed with ethyl EA (3X 50 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 ]] ⁺ ＝462.2。

Step 3: preparation of 2' -acetyl-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-3',5', 6-trimethyl Base- [1,4' -bipyridine]-2-one：

HCl (2 mL) was added dropwise to a stirred solution of the above residue in THF (20 mL) at 0deg.C under nitrogen. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. Saturated Na at 0deg.C ₂ CO ₃ The residue was basified (in aqueous solution) to pH 10. The resulting mixture was extracted with EtOAc (3X 100 mL). The combined organic layers were 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 as a white solid]-3',5', 6-trimethyl- [1,4' -bipyridine]2-Ketone (480 mg,75.61%, two steps). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝434.2。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.66(s,1H),8.61(d,1H),8.13–8.04(m,1H),6.88(d,1H),5.49(d,2H),2.66(s,3H),2.11(s,3H),2.04(s,3H),1.88(s,3H)。

Step 4: preparation of 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-2' - [ (2E) -3- (dimethylamino) Prop-2-enoyl]-3',5', 6-trimethyl- [1,4' -bipyridine]-2-one：

2' -acetyl-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-3',5', 6-trimethyl- [1,4' -bipyridine]A solution of 2-one (980 mg) in DMF-DMA (5 mL) was stirred under nitrogen at 100deg.C for 3 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated in vacuo. The crude product was used directly in the next step without further purification. LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝489.2。

Step 5: preparation of 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-2' - [2- (2-hydroxy-prop-2-yl) azoxystrobin Pyridin-4-yl]-3',5', 6-trimethyl- [1,4' -bipyridine]-2-one：

3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-2' - [ (2E) -3- (dimethylamino) prop-2-enoyl ]-3',5', 6-trimethyl- [1,4' -bipyridine]-2-one (1100 mg, assuming 100% yield, 2.25mmol,1.00 eq.), 2-hydroxy-2-methylpropionamidine (689 mg,6.75mmol,3.00 eq.), K ₂ CO ₃ A mixture of (1500 mg,11.25mmol,5.00 eq.) in propan-2-ol (10 mL) was stirred under nitrogen at 80℃for 12 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was diluted with EA (300 mL) and washed with water (1X 100 mL). The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the crude product. The crude product was isolated by preparative HPLC to give a white solid3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy group of the body]-2' - [2- (2-hydroxy-prop-2-yl) pyrimidin-4-yl]-3',5', 6-trimethyl- [1,4' -bipyridine]2-Ketone (400 mg,33.67%, two steps). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝528.0。

Step 6: preparation of rel-3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy) -2' - (2- (2-hydroxypropyl-2-) Yl) pyrimidin-4-yl) -3',5', 6-trimethyl-2H- [1,4' -bipyridine]-2-one and rel-3-chloro-4- ((3, 5-difluoropyrazine) Pyridin-2-yl) methoxy) -2'- (2- (2-hydroxy-prop-2-yl) pyrimidin-4-yl) -3',5', 6-trimethyl-2H- [1,4' -bipyramid Pyridine and pyridine]-2-one：

The racemate (190 mg) was separated by preparative chiral HPLC to give rel-3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy) -2'- (2- (2-hydroxypropyl-2-yl) pyrimidin-4-yl) -3',5', 6-trimethyl-2H- [1,4' -bipyridin ] -2-one (example 49a:66.6mg,96.8% purity, ee=100%) and rel-3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy) -2'- (2- (2-hydroxypropyl-2-yl) pyrimidin-4-yl) -3',5', 6-trimethyl-2H- [1,4' -bipyridin ] -2-one (example 49b:73.0mg,97.9% purity, ee=99.34%) as a white solid.

Example 49A：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝528.00。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.97(d,1H),8.70(s,1H),8.61(d,1H),8.16–8.05(m,1H),7.90(d,1H),6.89(s,1H),5.50(d,2H),5.22–5.00(m,1H),2.21(s,3H),2.06(s,3H),1.95(s,3H),1.53(s,6H)。 ¹⁹ F NMR(377MHz,DMSO)δ-120.13,-120.15,-122.31,-122.32。

Example 49B：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝528.00。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.97(d,1H),8.70(s,1H),8.61(d,1H),8.17–8.06(m,1H),7.90(d,1H),6.89(d,1H),5.50(d,2H),5.12(s,1H),2.21(s,3H),2.06(s,3H),1.95(s,3H),1.54(s,6H)。 ¹⁹ F NMR(377MHz,DMSO)δ-120.13,-120.15,-122.30,-122.32。

Examples 50A, 50B

Step 1: preparation of 2- (1H-pyrazol-3-yl) propan-2-ol：

To a stirred solution of methyl 1H-pyrazole-3-carboxylate (5.00 g,39.64mmol,1.00 eq.) in THF under nitrogen at 0deg.C was added dropwise magnesium bromide (132 mL,3M in 2-MeTHF, 396.46mmol,10.00 eq.). The resulting mixture was stirred under nitrogen at 0 ℃ for 1 hour. The reaction was monitored by LCMS. With saturated NH ₄ The reaction was quenched with Cl (aqueous solution) at 0 ℃. The resulting mixture was extracted with EtOAc (3X 100 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. This gave 2- (1H-pyrazol-3-yl) propan-2-ol (3.00 g, crude) as a yellow oil. The crude product was used directly in the next step without further purification. LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝127.08。

Step 2: preparation of 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-2' - [3- (2-hydroxy-prop-2-yl) pyri-dine Azol-1-yl]-3',5', 6-trimethyl- [1,4' -bipyridine]-2-one：

To 2' -bromo-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy at room temperature under nitrogen atmosphere]-3',5', 6-trimethyl- [1,4' -bipyridine]To a stirred mixture of 2-ketone (300 mg,0.63mmol,1.00 eq.) and 2- (1H-pyrazol-3-yl) propan-2-ol (160 mg,1.27mmol,2.00 eq.) in dioxane (15 mL) was added K ₂ CO ₃ (176 mg,1.27mmol,2.00 eq.), cuI (242 mg,1.27mmol,2.00 eq.) and (1R, 2R) -1-N, 2-N-dimethylcyclohexane-1, 2-diamine (181 mg,1.27mmol,2.00 eq.). The resulting mixture was stirred overnight at 80 ℃ under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was filtered and the filter cake was washed with EtOAc (3X 50 mL). The filtrate was concentrated under reduced pressure. Purification of the residue by preparative HPLC gave 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy as a white solid]-2' - [3- (2-hydroxy-prop-2-yl) pyrazol-1-yl]-3',5', 6-trimethyl- [1,4' -bipyridine]-2-one (120)mg，36.49％)。LC-MS:(ES+H,m/z):[M+H] ⁺ ＝516.3。

Step 3: preparation of rel-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]2' - [3- (2-hydroxypropyl-2-) Radical) pyrazol-1-yl radical]-3',5', 6-trimethyl- [1,4' -bipyridine]-2-one and rel-3-chloro-4- [ (3, 5-difluoropyridin-2- ] Radical) methoxy radical]-2' - [3- (2-hydroxy-prop-2-yl) pyrazol-1-yl]-3',5', 6-trimethyl- [1,4' -bipyridine]-2-one：

Isolation of 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy ] -2'- [3- (2-hydroxypropan-2-yl) pyrazol-1-yl ] -3',5', 6-trimethyl- [1,4' -bipyridin ] -2-one (120 mg) by preparative chiral HPLC gave example 50A (31.7 mg,99.7% purity, ee=100%) and example 50B (66.5 mg,99.8% purity, ee=100%) as white solids.

Example 50A：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝516.2。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.61(d,1H),8.47(s,1H),8.23(d,1H),8.11(ddd,1H),6.88(d,1H),6.51(d,1H),5.50(d,2H),5.05(s,1H),2.08(s,3H),2.01(s,3H),1.87(s,3H),1.48(s,3H),1.47(s,3H)。 ¹⁹ F NMR(282MHz,DMSO)δ-120.12,-120.14,-122.29,-122.32。

Example 50B：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝516.2。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.61(d,1H),8.47(s,1H),8.23(d,1H),8.10(ddd,1H),6.88(d,1H),6.51(d,1H),5.50(d,2H),5.05(s,1H),2.08(s,3H),2.01(s,3H),1.87(s,3H),1.48(s,3H),1.43(s,3H)。 ¹⁹ F NMR(282MHz,DMSO)δ-120.12,-120.14,-122.29,-122.31。

Examples 51A and 51B

Step 1: preparation of 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-5', 6-dimethyl-2' - (trimethylmethyl) Stannyl) - [1,4' -bipyridine]-2-one：

To 2', 3-dichloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy group at room temperature under nitrogen atmosphere]-5', 6-dimethyl- [1,4' -bipyridine]-2-one (1.00 g,2.4mmol,1.00 eq.) and Sn ₂ Me ₆ (3.18 g,9.70mmol,4.00 eq.) AsPh was added to a stirred solution of dioxane (20 mL) ₃ (222 mg,0.72mmol,0.3 eq.) and Pd (PPh) ₃ ) ₂ Cl ₂ (510 mg,0.72mmol,0.30 eq.). The resulting mixture was stirred overnight at 80 ℃ under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was diluted with EtOAc (100 mL). The resulting mixture was washed with 4X 300mL KF (aqueous solution). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. This gives 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy ] as a brown solid]-5', 6-dimethyl-2 ' - (trimethylstannyl) - [1,4' -bipyridine]2-Ketone (1.30 g crude). The crude product was used directly in the next step without further purification. LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝542.0。

Step 2: preparation of 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy ]-2' - [6- (2-hydroxy-prop-2-yl) pyr-idine Oxazin-2-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one：

To 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy at room temperature under a nitrogen atmosphere]-5', 6-dimethyl-2 ' - (trimethylstannyl) - [1,4' -bipyridine]To a stirred mixture of 2-ketone (500 mg,0.92mmol,1.00 eq.) and 2- (6-bromopyrazin-2-yl) propan-2-ol (200 mg,0.92mmol,1.00 eq.) in dioxane (15 mL) was added CuI (176 mg,0.925mmol,1.00 eq.) and Pd (PPh) ₃ ) ₂ Cl ₂ (129 mg,0.18mmol,0.20 eq.). The resulting mixture was stirred under nitrogen at 80 ℃ for 3 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy as a yellow solid]-2' - [6- (2-hydroxy-prop-2-yl) pyrazin-2-yl ]]-5', 6-dimethyl- [1,4' -bipyridine]-2-one (130 mg, crude). By reversed phase flash chromatographyPurifying the crude product. The pure fractions were concentrated under reduced pressure to give 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy as a white solid]-2' - [6- (2-hydroxy-prop-2-yl) pyrazin-2-yl ]]-5', 6-dimethyl- [1,4' -bipyridine]-2-one (100 mg, 21.04%). LC-MS (ES+H, M/z) [ M+H ] ] ⁺ ＝514.2。

Step 3: preparation of rel-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]2' - [6- (2-hydroxypropyl-2-) Radical) pyrazin-2-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one and rel-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) Methoxy group]-2' - [6- (2-hydroxy-prop-2-yl) pyrazin-2-yl ]]-5', 6-dimethyl- [1,4' -bipyridine]-2-one：

3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy ] -2' - [6- (2-hydroxypropyl-2-yl) pyrazin-2-yl ] -5', 6-dimethyl- [1,4' -bipyridin ] -2-one (250 mg) was isolated by preparative chiral HPLC to give example 51A (37.0 mg,99.6% purity, ee=100%) and example 51B (60.4 mg,98.0% purity, ee=100%) as white solids.

Example 51A：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝514.2。 ¹ H NMR(300MHz,DMSO-d ₆ )δ9.49(s,1H),9.03(s,1H),8.91(s,1H),8.68(d,1H),8.40(s,1H),8.18(ddd,1H),6.90(s,1H),5.60(s,1H),5.53(d,2H),2.16(s,3H),2.05(s,3H),1.61(s,3H),1.60(s,3H)。 ¹⁹ F NMR(282MHz,DMSO)δ-120.12,-120.15,-122.30,-122.32。

Example 51B：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝514.1。 ¹ H NMR(400MHz,DMSO-d ₆ )δ9.42(s,1H),8.97(s,1H),8.84(s,1H),8.62(d,1H),8.35(s,1H),8.15(ddd,1H),6.84(s,1H),5.53(s,1H),5.49(d,2H),2.10(s,3H),1.99(s,3H),1.54(s,3H),1.53(s,3H)。 ¹⁹ F NMR(377MHz,DMSO)δ-120.11,-120.13,-122.29,-122.31。

Example 4: preparation of 2- (6-bromopyrazin-2-yl) propan-2-ol：

To a stirred solution of 2, 6-dibromopyrazine (5.00 g,21.01mmol,1.00 eq.) in toluene (125 mL) at-78deg.C under nitrogen was added dropwise n-BuLi (8.4 m) over 15 minL,2.5M in hexane, 21.01mmol,1.00 eq). The resulting mixture was stirred under nitrogen at-78 ℃ for 30 minutes. Acetone (1.83 g,31.52mmol,1.50 eq.) was added dropwise to the above mixture over 30 minutes at-78 ℃. The resulting mixture was stirred at-78 ℃ for an additional 1 hour. The reaction was monitored by LCMS. By addition of saturated NH ₄ Cl (aq) (20 mL) quenched the reaction at 0deg.C. The resulting mixture was extracted with EtOAc (3X 100 mL). The combined organic layers were washed with brine (1X 200 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2- (6-bromopyrazin-2-yl) propan-2-ol (3.00 g, 65.75%) as a yellow oil. LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝217.2。

Examples 52A, 52B

Step 1: preparation of 2' -chloro-4-hydroxy-3 ', 6-dimethyl-2H- [1,4' -bipyridine]-2-one：

A solution of 2-chloro-3-methylpyridin-4-amine (5.00 g,35.06mmol,1.00 eq.) and 2, 2-dimethyl-6- (2-oxopropyl) -1, 3-dioxin-4-one (9.69 g,52.60mmol,1.50 eq.) in 1, 4-dioxane was stirred under nitrogen at 90℃for 3 hours. The reaction was brought to room temperature and monitored by LCMS. H was added dropwise to the above mixture at room temperature under nitrogen atmosphere ₂ SO ₄ (3.44 g,35.06mmol,1.00 eq.). The resulting mixture was stirred under nitrogen at 90 ℃ for an additional 1 hour. The mixture was cooled to room temperature. The reaction was monitored by LCMS. The resulting mixture was concentrated, then water (10 mL) was added and the slurry was stirred at room temperature for an additional 10 minutes. Diethyl ether (10 mL) was then added and the mixture was stirred at room temperature for an additional 10 minutes. The solid was collected by filtration to give 2' -chloro-4-hydroxy-3 ', 6-dimethyl- [1,4' -bipyridine as a white solid ]2-Ketone (5.40 g, 61.0%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝251.0。

Step 2: preparation of 2' -chloro-4- ((3, 5-difluoropyridin-2-yl)) Methoxy) -3', 6-dimethyl-2H- [1,4' -bi Pyridine compound]-2-one：

To 2' -chloro-4-hydroxy-3 ', 6-dimethyl- [1,4' -bipyridine at room temperature under nitrogen atmosphere]To a stirred mixture of 2-ketone (5.00 g,19.94mmol,1.00 eq.) and 2- (chloromethyl) -3, 5-difluoropyridine (13.05 g,79.78mmol,4.00 eq.) in DMF (50 mL) was added K ₂ CO ₃ (27.57 g,199.46mmol,10.00 eq.) and 18-crown-6 (2.64 g,9.97mmol,0.5 eq.). The resulting mixture was stirred under nitrogen at 60 ℃ for a further 6 hours. The mixture was cooled to room temperature. The reaction was monitored by LCMS. The resulting mixture was diluted with ethyl acetate (400 mL). The organic layer was washed with water (100 mL) and brine (100 mL) then with Na ₂ SO ₄ And (5) drying. The solution 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 as a white solid]-3', 6-dimethyl- [1,4' -bipyridine]2-Ketone (5.22 g, 60.3%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝378.0。

Step 3: preparation of 2', 3-dichloro-4- ((3, 5-difluoropyridin-2-yl) methoxy) -3', 6-dimethyl-2H- [1, 4' -bipyridines]-2-one：

To 2' -chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy at room temperature under a nitrogen atmosphere ]-3', 6-dimethyl- [1,4' -bipyridine]To a stirred mixture of 2-ketone (5.00 g,13.23mmol,1.00 eq.) and 2, 2-dichloroacetic acid (0.34 g,2.64mmol,0.2 eq.) in i-PrOH (15 mL) was added NCS (1.77 g,13.23mmol,1.00 eq.). The resulting mixture was stirred under nitrogen at 60 ℃ for 2 hours. The mixture was cooled to room temperature. The reaction was monitored by LCMS. The precipitated solid was collected by filtration and washed with IPA (2X 10 mL) to give 2', 3-dichloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy as a white solid]-3', 6-dimethyl- [1,4' -bipyridine]2-Ketone (3.82 g, 64.4%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝411.9。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.60(d,1H),8.46(d,1H),8.15–8.03(m,1H),7.49(d,1H),6.82(s,1H),5.49(d,2H),2.03(s,3H),1.96(s,3H)。

Step 4: preparation of 3-chloro-4- ((3, 5-difluoropyridin-2-yl)) Methoxy) -2' - (3- (2-hydroxy-prop-2-yl) propan-2-yl) 1H-pyrazol-1-yl) -3', 6-dimethyl-2H- [1,4' -bipyridine]-2-one：

To 2', 3-dichloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy group at room temperature under nitrogen atmosphere]-3', 6-dimethyl- [1,4' -bipyridine]2-Ketone (500 mg,1.21mmol,1.00 eq), 2- (1H-pyrazol-3-yl) propan-2-ol (459 mg,3.64mmol,3.00 eq) to a stirred mixture of 1, 4-dioxane was added (1R, 2R) -N1, N2-dimethylcyclohexane-1, 2-diamine (345 mg,0.48mmol,2.00 eq), cuI (230 mg,0.24mmol,1.00 eq), K ₂ CO ₃ (335 mg,2.42mmol,2.00 eq.) and NaI (803 mg,2.42mmol,2.00 eq.). The resulting mixture was stirred overnight at 100 ℃ under nitrogen atmosphere. The mixture was cooled to room temperature. The desired product was detectable by LCMS. The resulting mixture was diluted with EA (100 mL), then washed with water (2X 50 mL) and brine (50 mL), over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy) -2' - (3- (2-hydroxypropyl-2-yl) -1H-pyrazol-1-yl) -3', 6-dimethyl-2H- [1,4' -bipyridine]-2-one (350 mg,57.5%, crude) which was further purified by preparative HPLC. This gives 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy) as a white solid]-2' - [3- (2-hydroxy-prop-2-yl) pyrazol-1-yl]-3', 6-dimethyl- [1,4' -bipyridine]-2-one (90 mg, 14.8%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝502.1。

Step 5: preparation of rel-3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy) -2' - (3- (2-hydroxypropyl-2-) 1H-pyrazol-1-yl) -3', 6-dimethyl-2H- [1,4' -bipyridine]-2-one and rel-3-chloro-4- ((3, 5-difluoropyrazine) Pyridin-2-yl) methoxy) -2' - (3- (2-hydroxy-prop-2-yl) -1H-pyrazol-1-yl) -3', 6-dimethyl-2H- [1,4' -bipyramid Pyridine and pyridine]-2-one：

The racemate was isolated by preparative chiral HPLC (350 mg), the pure fractions concentrated in vacuo and lyophilized to give example 52A (32.4 mg,99.4% purity, ee=100%) as a white solid and example 52B (32.2 mg,99.0% purity, ee=99.6%) as a white solid.

Example 52A：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝502.1。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.60(d,1H),8.53(d,1H),8.28(d,1H),8.12–8.06(m,1H),7.45(d,1H),6.82(s,1H),6.52(d,1H),5.49(d,2H),5.08(s,1H),2.12(s,3H),1.99(s,3H),1.48(s,3H),1.47(s,3H)。 ¹⁹ F NMR(377MHz,DMSO)δ-120.13,-120.15.,-122.31,-122.33。

Example 52B：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝502.1。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.61(s,1H),8.54(d,1H),8.29(s,1H),8.14–8.05(m,1H),7.48–7.42(m,1H),6.83(s,1H),6.53(s,1H),5.49(s,2H),5.08(s,1H),2.13(s,3H),2.00(s,3H),1.48(s,3H),1.47(s,3H)。 ¹⁹ F NMR(377MHz,DMSO)δ-120.13,-120.15.,-122.31,-122.33。

Examples 53A and 53B

Step 1: preparation of 2', 3-dichloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-3 '-fluoro-5', 6-dimethyl- [1,4' -bipyridine]-2-one：

To 2' -chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy at room temperature under a nitrogen atmosphere]-3' -fluoro-5 ', 6-dimethyl- [1,4' -bipyridine]To a stirred solution of 2-ketone (1.90 g,4.80mmol,1.00 eq.) and NCS (0.83 g,6.21mmol,1.30 eq.) in DCM (40 mL) was added dropwise 2, 2-dichloroacetic acid (61 mg,0.48mmol,0.1 eq.). The resulting mixture was stirred at room temperature under nitrogen overnight. The reaction was monitored by LCMS. The resulting mixture was poured into water (100 mL). The resulting mixture was extracted with EtOAc (3X 50 mL). The combined organic layers were washed with brine (3X 50 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. 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-difluoropyrazine) as a yellow solid Pyridin-2-yl) methoxy]-3' -fluoro-5 ', 6-dimethyl- [1,4' -bipyridine]2-Ketone (1.80 g, 87.15%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝429.8。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.61(d,1H),8.49(s,1H),8.15–8.03(m,1H),6.90(s,1H),5.52(d,2H),2.08(s,3H),2.03(s,3H)。

Step 2: preparation of 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]2'- (1-ethoxyvinyl) -3' -) Fluoro-5 ', 6-dimethyl- [1,4' -bipyridine]-2-one：

To 2', 3-dichloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy group at room temperature under nitrogen atmosphere]-3' -fluoro-5 ', 6-dimethyl- [1,4' -bipyridine]-2-one (800 mg,1.86mmol,1.00 eq.) and Pd (PPh) ₃ ) ₂ Cl ₂ To a stirred solution of (65 mg,0.09mmol,0.05 eq.) in 1, 4-dioxane (10 ml) was added tributyl (1-ethoxyvinyl) stannane (1.34 g,3.72mmol,2.00 eq.). The resulting mixture was stirred under nitrogen at 100 ℃ for 2 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was poured into water (80 mL). The resulting mixture was extracted with EtOAc (3X 100 mL). The combined organic layers were washed with brine (3X 10 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. 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 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy as a white solid]-2'- (1-ethoxyvinyl) -3' -fluoro-5 ', 6-dimethyl- [1,4' -bipyridine ]-2-one (700 mg, 80.80%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝466.0。

Step 3: preparation of 2' -acetyl-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-3 '-fluoro-5', 6-di Methyl- [1,4' -bipyridine]-2-one：

To 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy at 0℃under a nitrogen atmosphere]-2'- (1-ethoxyvinyl) -3' -fluoro-5 ', 6-dimethyl- [1,4' -bipyridine]To a stirred solution of 2-ketone (700 mg,1.50mmol,1.00 eq.) in THF (30 mL) was added concentrated HCl (3 mL). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. The resulting mixture was poured into water (100)mL). The resulting mixture was extracted with EtOAc (3X 100 mL). The combined organic layers were washed with brine (3X 10 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give 2' -acetyl-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy as a white solid]-3' -fluoro-5 ', 6-dimethyl- [1,4' -bipyridine]-2-one (680 mg, crude). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝438.0。

Step 4: preparation of 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-2' - [ (2E) -3- (dimethylamino) Prop-2-enoyl]-3' -fluoro-5 ', 6-dimethyl- [1,4' -bipyridine]-2-one：

To a 40mL sealed tube at room temperature was added 2' -acetyl-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy ]-3' -fluoro-5 ', 6-dimethyl- [1,4' -bipyridine]-2-one (680 mg,1.55mmol,1.00 eq.) and DMF-DMA (6 mL). The resulting mixture was stirred under nitrogen at 100 ℃ for 2 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure to give 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy as a brown solid]-2' - [ (2E) -3- (dimethylamino) prop-2-enoyl]-3' -fluoro-5 ', 6-dimethyl- [1,4' -bipyridine]-2-one (820 mg, crude). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝493.0。

Step 5: preparation of 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-3 '-fluoro-2' - [2- (2-hydroxypropyl-2-) Base) pyrimidin-4-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one (TFA salt)：

To 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy at room temperature under a nitrogen atmosphere]-2' - [ (2E) -3- (dimethylamino) prop-2-enoyl]-3' -fluoro-5 ', 6-dimethyl- [1,4' -bipyridine]To a stirred solution of 2-ketone (200 mg,0.41mmol,1.00 eq.) and 2-hydroxy-2-methyl-propionamidine hydrochloride (282 mg,2.03mmol,5.00 eq.) in DMF (4 ml) was added K ₂ CO ₃ (168 mg,1.22mmol,3.00 eq.). The resulting mixture was stirred under nitrogen at 80 ℃ for 3 hours. The reaction was monitored by LCMS. The resulting mixture was poured into water (80 mL). The resulting mixture was extracted with EtOAc (3X 100 mL). The combined organic layers were washed with brine (3X 10 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. Purification of the crude product by preparative HPLC gives 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy as a brown solid]-3 '-fluoro-2' - [2- (2-hydroxy-prop-2-yl) pyrimidin-4-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one (TFA salt) (130 mg, 60.23%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝532.1。

Step 6: preparation of rel-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-3 '-fluoro-2' - [2- (2-hydroxy) Propan-2-yl) pyrimidin-4-yl]-5', 6-dimethyl- [1,4' -bipyridine]2-one and rel-3-chloro-4- [ (3, 5-difluoropyridine ] 2-yl) methoxy]-3 '-fluoro-2' - [2- (2-hydroxy-prop-2-yl) pyrimidin-4-yl]-5', 6-dimethyl- [1,4' -bipyridine]- 2-Ketone：

3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-3 '-fluoro-2' - [2- (2-hydroxy-prop-2-yl) pyrimidin-4-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one (TFA salt) (130 mg) with NH ₃ H ₂ O basified to ph=9, then purified by preparative chiral HPLC, the pure fractions concentrated under pressure, then lyophilized to give (example 53A) (32.7 mg,98.0% purity, ee=100%) and (example 53B) (32.4 mg,98.0% purity, ee=100%) as a white solid.

Example 53A：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝532.0。 ¹ HNMR(300MHz,DMSO-d ₆ )δ9.03(d,1H),8.78(s,1H),8.61(d,1H),8.15-8.07(m,1H),8.04(d,1H),6.91(s,1H),5.53(d,2H),5.08(s,1H),2.18(s,3H),2.06(s,3H),1.53(s,3H),1.50(s,3H)。 ¹⁹ F NMR(282MHz,DMSO)δ-120.17,-120.19,-122.35,-122.38,-132.08。

Example 53B：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝532.0。 ¹ HNMR(300MHz,DMSO-d ₆ )δ9.03(d,1H),8.78(s,1H),8.61(d,1H),8.15-8.07(m,1H),8.04(d,1H),6.91(s,1H),5.53(d,2H),5.08(s,1H),2.18(s,3H),2.06(s,3H),1.53(s,3H),1.50(s,3H)。 ¹⁹ F NMR(282MHz,DMSO)δ-120.17,-120.19,-122.35,-122.37,-132.08。

Examples 54A and 54B

Step 1: preparation of 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy ]-3 '-fluoro-2' - [3- (2-hydroxypropyl-2-) Radical) pyrazol-1-yl radical]-5', 6-dimethyl- [1,4' -bipyridine]-2-one：

To 2', 3-dichloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy group at room temperature under nitrogen atmosphere]-3' -fluoro-5 ', 6-dimethyl- [1,4' -bipyridine]To a stirred mixture of 2-ketone (640 mg,2.04mmol,1.00 eq.) and 2- (1H-pyrazol-3-yl) propan-2-ol (516 mg,4.09mmol,2.00 eq.) in 1, 4-dioxane (10 mL) was added (1S, 2S) -N1, N2-dimethylcyclohexane-1, 2-diamine (290 mg,2.04mmol,1.00 eq.), cuI (38 mg,0.20mmol,0.10 eq.) and K ₂ CO ₃ (560 mg,4.09mmol,2.00 eq.). The resulting mixture was stirred overnight at 80 ℃ under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3X 50 mL). The combined organic layers were washed with brine (2X 50 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and the pure fractions were concentrated in vacuo to give the crude product. Purification of the crude product by preparative HPLC gave 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy as a white solid]-3 '-fluoro-2' - [3- (2-hydroxy-prop-2-yl) pyrazol-1-yl ]-5', 6-dimethyl- [1,4' -bipyridine]-2-one (100 mg, 9.40%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝520.0。

Step 2: preparation of rel-3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy) -3 '-fluoro-2' - (3- (2-hydroxy) Propan-2-yl) -1H-pyrazol-1-yl) -5', 6-dimethyl-2H- [1,4' -bipyridine]2-Ketone 9 (example 54A) and rel-3- Chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy) -3 '-fluoro-2' - (3- (2-hydroxypropan-2-yl) -1H-pyrazol-1-yl) propan-1-yl) 5', 6-dimethyl-2H- [1,4' -bipyridine]-2-Ketone (example 54)B)：

By preparative chiral separation of 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy ] -3 '-fluoro-2' - [3- (2-hydroxypropan-2-yl) pyrazol-1-yl ] -5', 6-dimethyl- [1,4' -bipyridin ] -2-one (100 mg), example 54A (25.4 mg,99.6% purity, ee=100%) and example 54B (27.6 mg,99.7% purity, ee=98.8%) were obtained as white solids.

Example 54A：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝520.1。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.61(d,1H),8.50(s,1H),8.36(d,1H),8.30-8.11(m,1H),6.90(s,1H),6.59(d,1H),5.53(s,2H),5.11(s,1H),2.11(s,3H),2.07(s,3H),1.47(s,3H),1.43(s,3H)。 ¹⁹ F NMR(282MHz,DMSO)δ-120.18,-120.21,-122.35,-122.38,-138.00。

Example 54B：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝520.1。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.61(d,1H),8.49(s,1H),8.35(d,1H),8.15–8.04(m,1H),6.90(s,1H),6.59(d,1H),5.53(s,2H),5.11(s,1H),2.11(s,3H),2.07(s,3H),1.47(s,3H),1.43(s,3H)。 ¹⁹ F NMR(282MHz,DMSO)δ-120.18,-120.21,-122.35,-122.38 -137.99。

Example 55

To 2', 3-dichloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy group at room temperature under nitrogen atmosphere]-5', 6-dimethyl- [1,4' -bipyridine]-2-one (2.00 g,4.85mmol,1.00 eq.) and Sn ₂ Me ₆ (6.36 g,19.41mmol,4.00 eq.) AsPh was added to a solution in dioxane (20 mL) ₃ (0.74 g,2.43mmol,0.50 eq.) Pd (PPh) ₃ ) ₂ Cl ₂ (0.68 g,0.97mmol,0.20 eq.). Will beThe resulting mixture was stirred under nitrogen at 80℃for 2 hours. The desired product was detected by LCMS and the mixture was cooled to room temperature. The resulting mixture was diluted with ethyl acetate (50 mL). The resulting mixture was washed with 5X 20mL of saturated KF aqueous solution. The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy as a brown semisolid]-5', 6-dimethyl-2 ' - (trimethylstannyl) - [1,4' -bipyridine]2-Ketone (3.00 g, crude). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝541.9。

Step 2: preparation of 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-2' - [2- (2-hydroxy-1-methoxy) Propan-2-yl) pyrimidin-4-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one：

To 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy at room temperature under a nitrogen atmosphere]-5', 6-dimethyl-2 ' - (trimethylstannyl) - [1,4' -bipyridine]To a stirred mixture of 2-ketone (1.60 g,2.96mmol,1.00 eq.) and 2- (4-chloropyrimidin-2-yl) -1-methoxypropan-2-ol (299.89 mg,1.48mmol,0.50 eq.) in dioxane (10 mL) was added Pd (PPh) ₃ ) ₂ Cl ₂ (623.24 mg,0.89mmol,0.30 eq.) and CuI (563.69 mg,2.96mmol,1.00 eq.). The resulting mixture was stirred under nitrogen at 100 ℃ for 2 hours. The desired product was detected by LCMS. The mixture was cooled to room temperature. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3X 50 mL). The combined organic layers were washed with brine (2X 50 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the crude product (200 mg) as a yellow oil, which was further purified by HP-Flash to give 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy as a white solid]-2' - [2- (2-hydroxy-1-methoxypropan-2-yl) pyrimidin-4-yl]-5', 6-dimethyl- [1,4' -bipyridine]2-one (60.8 mg,4.34%, racemate). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝544.15。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.98(d,1H),8.86(s,1H),8.75(s,0.5H),8.70(s,0.5H),8.61(d,1H),8.26(d,1H),8.15–8.05(m,1H),6.85(s,1H),5.50(s,2H),5.35(s,0.5H),5.31(s,0.5H),3.78-3.55(m,2H),3.18(s,1.5H),3.16(s,1.5H),2.11(s,3H),1.99(d,3H),1.48(s,1.5H),1.47(s,1.5H)。 ¹⁹ F NMR(377MHz,DMSO)δ-120.13,-120.15,-122.31,-122.33。

Step 3: preparation of 2-methoxy-1- (4-methyl-1-methoxy-2- (4-methoxypyrimidin-2-yl) propan-2-ol

A solution of 2-iodo-4-methoxypyrimidine (17.00 g,72.03mmol,1.00 eq.) in toluene (400 mL) was treated with i-PrMgCl (1.3 mol/L solution in THF, 46.82mL,93.64mmol,1.30 eq.) under nitrogen at 0deg.C for 0.5 h. LCMS showed complete consumption of the reaction and detection of a new peak. 1-methoxypropan-2-one (9.52 g,108.05mmol,1.50 eq.) was then added to the solution and the mixture was stirred at 0℃for 2 hours. LCMS showed the finding of the desired MS. By addition of saturated NH ₄ Cl (aq) (200 mL) quenched the reaction at room temperature. The resulting mixture was extracted with EtOAc (2X 200 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography. This gave 2-methoxy-1- (4-methyl-methoxy-2- (4-methoxypyrimidin-2-yl) propan-2-ol (5.20 g, 36.42%) as a yellow oil LC-MS (ES+H, M/z): [ M+H ]] ⁺ ＝199.2。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.51(d,1H),6.82(d,1H),4.99(s,1H),3.95(s,3H),3.66–3.55(m,2H),3.19(s,3H),1.42(s,3H)。

Step 4: preparation of 2-methoxy-1- (4-methyl-1-methoxy-2- (4-methoxypyrimidin-2-yl) propan-2-ol

To a 500mL round bottom flask was added a solution of 1-methoxy-2- (4-methoxypyrimidin-2-yl) propan-2-ol (5.00 g,25.22mmol,1.00 eq.) and sodium (ethylsulfanyl) in DMF (300 mL) at room temperature (25.46 g,302.69mmol,12.00 eq.). The resulting mixture was stirred overnight at 100 ℃ under nitrogen atmosphere. LCMS showed complete consumption of the reaction and found the desired MS. The mixture was cooled to room temperature and the reaction was acidified to pH 6 with HCl (4M in dioxane) and the resulting mixture concentrated under reduced pressure. However, the method is thatThe residue was then dissolved in ACN (100 mL) and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2- (2-hydroxy-1-methoxypropan-2-yl) pyrimidin-4-ol (4.20 g, 90.40%) as a yellow solid. LC-MS (ES+H, M/z) [ M+H ] ] ⁺ ＝185.2。

Step 5: preparation of 2- (4-chloropyrimidin-2-yl) -1-methoxypropan-2-ol

POCl was added dropwise to a solution of 2- (2-hydroxy-1-methoxypropan-2-yl) pyrimidin-4-ol (2.50 g,13.57mmol,1.00 eq.) in DCE (20 mL) at 0deg.C ₃ (3.80 mL,40.72mmol,3.00 eq.). The resulting mixture was stirred under nitrogen at 50 ℃ for 2 hours. The desired product was detected by LCMS. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2- (4-chloropyrimidin-2-yl) -1-methoxypropan-2-ol (350 mg, 12.73%) as a yellow oil. LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝203.2。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.86(d,1H),7.68(d,1H),5.32(s,1H),3.69(s,2H),3.26(s,3H),1.52(s,3H)。

Examples 56A and 56B

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Step 1&2: preparation of 4- { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-6-methyl-2-oxopyridine- 1-yl } -3 '-fluoro-5-methyl- [2,4' -bipyridine]-2' -methyl formate：

To a stirred solution of methyl 4-chloro-3-fluoropyridine-2-carboxylate (3 g, 15.025 mmol,1 eq) and 4, 5-tetramethyl-2- (tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,3, 2-dioxaborolan (16.07 g,63.300mmol,4 eq) in 1, 4-dioxane (200 mL) under nitrogen at room temperature was added AcOK (4.66 g,47.475mmol,3 eq) and XPhos Palladacycl gen.4 (113.48 mg,0.132mmol,0.05 eq). The resulting mixture was stirred under nitrogen at 80 ℃ for 1 hour. The reaction was monitored by LCMS. The mixture was cooled to room temperature. Subjecting the resulting mixture to no treatment Further purification was used directly in the next step. LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝200.0。

2' -bromo-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy was added to the above mixture at room temperature under a nitrogen atmosphere]-5', 6-dimethyl- [1,4' -bipyridine]-2-one (1.8 g,3.942mmol,1 eq.) K ₂ CO ₃ (1.63 g, 11.706 mmol,3 eq.) Pd (PPh 3) 4 (455.07 mg, 0.390 mmol,0.1 eq.) and H ₂ O (50 mL). The resulting mixture was stirred under nitrogen at 80℃for 1.5 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was poured into water (500 mL). The resulting mixture was extracted with EtOAc (3X 500 mL). The combined organic layers were washed with brine (3X 500 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. 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 pressure to give 4- { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy as a brown solid]-6-methyl-2-oxopyridin-1-yl } -3 '-fluoro-5-methyl- [2,4' -bipyridine]-methyl 2' -formate (800 mg, 38.23%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝531.2。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.90(s,1H),8.65(d,1H),8.60(d,1H),8.21(t,1H),8.11–8.07(m,1H),7.95(s,1H),6.81(s,1H),5.49(d,2H),3.93(s,3H),2.10(s,3H),1.98(s,3H)。

Step 3: preparation of 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-1- [3 '-fluoro-2' - (2-hydroxypropyl-2-) Phenyl) -5-methyl- [2,4' -bipyridine ]-4-yl]-6-methylpyridin-2-one：

To 4- { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy group at 0℃under a nitrogen atmosphere]-6-methyl-2-oxopyridin-1-yl } -3 '-fluoro-5-methyl- [2,4' -bipyridine]To a stirred solution of methyl-2' -formate (450 mg,0.84mmol,1.00 eq.) in THF (20 mL) was added dropwise CH ₃ MgBr (1.70 mL,5.08mmol,6.00 eq., 3.4M in 2-MeTHF). The resulting mixture was stirred under nitrogen at 0 ℃ for 1 hour. The reaction was monitored by LCMS. With saturated NH ₄ Cl (aq) (50 mL) quenched the reaction at 0deg.C. The resulting mixture was extracted with EtOAc (3X 30 mL). The combined organic layers were washed with brine (3×20 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. Purification of the residue by preparative TLC (EA) gave the crude product, which was further purified by preparative HPLC and the pure fractions were concentrated under pressure to give 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy as a white solid]-1- [3' -fluoro-2 ' - (2-hydroxy-prop-2-yl) -5-methyl- [2,4' -bipyridine]-4-yl]-6-methylpyridin-2-one (70 mg, 15.55%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝531.1。

Step 4: preparation of rel-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-1- [3 '-fluoro-2' - (2-hydroxy) Propan-2-yl) -5-methyl- [2,4' -bipyridine ]-4-yl]-6-methylpyridin-2-one and rel-3-chloro-4- [ (3, 5-difluoropyridine) Pyridin-2-yl) methoxy]-1- [3' -fluoro-2 ' - (2-hydroxy-prop-2-yl) -5-methyl- [2,4' -bipyridine]-4-yl]-6-methyl group Pyridin-2-ones：

The crude product (70 mg) was isolated by preparative chiral HPLC, the pure fractions concentrated under reduced pressure and lyophilized to give 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy ] -1- [3 '-fluoro-2' - (2-hydroxypropyl-2-yl) -5-methyl- [2,4 '-bipyridin ] -4-yl ] -6-methylpyridin-2-one (example 56a,21.8mg,36.33%, ee=100%) and 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy ] -1- [3' -fluoro-2 '- (2-hydroxypropyl-2-yl) -5-methyl- [2,4' -bipyridin ] -4-yl ] -6-methylpyridin-2-one as a white solid (example 56b,18.6mg,31.00%, ee=100%).

Example 56A：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝531.25。 ¹ HNMR(300MHz,DMSO-d ₆ )δ8.88(s,1H),8.61(d,1H),8.48(d,1H),8.19–8.05(m,1H),7.96–7.81(m,2H),6.82(s,1H),5.55–5.45(m,2H),5.37(s,1H),2.10(s,3H),1.99(s,3H),1.56(s,6H)。 ¹⁹ F NMR(282MHz,DMSO)δ-120.158,-120.177,-122.350,-122.368,-125.910。

Example 56B：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝531.25。 ¹ HNMR(300MHz,DMSO-d ₆ )δ8.88(s,1H),8.61(d,1H),8.48(d,1H),8.19–8.05(m,1H),7.96–7.81(m,2H),6.82(s,1H),5.55–5.45(m,2H),5.37(s,1H),2.10(s,3H),1.99(s,3H),1.56(s,6H)。 ¹⁹ F NMR(282MHz,DMSO)δ-120.140,-120.159,-122.310,-122.330,-125.923。

Examples 57A and 57B

Step 1: preparation of 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) (2H 2) methoxy]-3 '-fluoro-2' - [2- (2-hydroxy) Propan-2-yl) pyrimidin-4-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one：

To 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) (2H 2) methoxy at room temperature under a nitrogen atmosphere]-2' - [ (2E) -3- (dimethylamino) prop-2-enoyl]-3' -fluoro-5 ', 6-dimethyl- [1,4' -bipyridine]To a stirred solution of 2-ketone (0.76 g,1.53mmol,1.00 eq.) and 2-hydroxy-2-methylpropionamidine hydrochloride (1.06 g,7.68mmol,5.00 eq.) in i-PrOH (10 mL) was added K ₂ CO ₃ (1.06 g,7.68mmol,5.00 eq.). The resulting mixture was stirred under nitrogen at 80 ℃ for 2 hours. The desired product was detectable by LCMS. The resulting mixture was filtered and the filter cake was washed with i-PrOH (3X 3 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. This gives 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) (2H 2) methoxy as a yellow solid]-3 '-fluoro-2' - [2- (2-hydroxy-prop-2-yl) pyrimidin-4-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one (700 mg, 85.37%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝534.1。

Step 2: preparation of rel-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) (2H 2) methoxy]-3 '-fluoro-2' - [2- (2-) Hydroxy prop-2-yl) pyrimidin-4-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one and rel-3-chloro-4- [ (3, 5-difluoro) Pyridin-2-yl) (2H 2) methoxy]-3 '-fluoro-2' - [2- (2-hydroxy-prop-2-yl) pyrimidin-4-yl]-5', 6-dimethyl- [1, 4' -bipyridines]-2-one：

The racemic mixture (550 mg) was separated by preparative chiral HPLC to give rel-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) (2H 2) methoxy ] -3 '-fluoro-2' - [2- (2-hydroxypropan-2-yl) pyrimidin-4-yl ] -5', 6-dimethyl- [1,4' -bipyridin ] -2-one (example 57a,170.1mg,98.7% purity, 96.4% deuterium purity, ee=100%) and rel-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) (2H 2) methoxy ] -3 '-fluoro-2' - [2- (2-hydroxypropan-2-yl) pyrimidin-4-yl ] -5', 6-dimethyl- [1,4' -bipyridin ] -2-one (example 57b,194.9mg,98.8% purity, 96.5% deuterium purity, ee=98.6%)

Example 57A：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝534.00。 ¹ H NMR(300MHz,DMSO-d ₆ )δ9.03(d,1H),8.78(d,1H),8.61(d,1H),8.15–8.07(m,1H),8.04(d,1H),6.91(d,1H),5.09(s,1H),2.18(s,3H),2.06(s,3H),1.53(s,6H)。 ¹⁹ F NMR(282MHz,DMSO)δ-120.25,-120.28,-122.32,-122.34,-132.08。

Example 57B：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝534.1。 ¹ H NMR(300MHz,DMSO-d ₆ )δ9.03(d,1H),8.78(d,1H),8.61(d,1H),8.15–8.06(m,1H),8.04(d1H),6.91(d,1H),5.09(s,1H),2.18(s,3H),2.06(s,3H),1.53(s,6H)。 ¹⁹ F NMR(282MHz,DMSO)δ-120.25,-120.27,-122.31,-122.34,-132.07。

Example 58A

Step 1: preparation of 1- (3-fluoro-4-iodopyridin-2-yl) pyrazole-3-carboxylic acid methyl ester：

2, 3-difluoro-4-iodopyridine (50.00 g,207.49mmol,1.00 eq.) 1H-pyrazole-3-carboxylic acid methyl ester (23.53 g,186.74mmol,0.90 eq.) and Cs ₂ CO ₃ A mixture of (67.60 g,207.49mmol,1.00 eq.) in DMF (500 mL) was stirred under nitrogen at 100deg.C for 2 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was filtered and the filter cake was washed with EtOAc (3X 300 mL). The filtrate was concentrated under reduced pressure. The residue was purified by trituration with water (1000 mL). The precipitated solid was collected by filtration andit was treated with Et ₂ O (3X 100 mL) was washed. This gave methyl 1- (3-fluoro-4-iodopyridin-2-yl) pyrazole-3-carboxylate (40.00 g, 55.54%) as a white solid. LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝348.0。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.51(d,J＝2.7,1H),8.13–8.00(m,2H),7.03(d,J＝2.7Hz,1H),3.87(s,3H)。

Step 2: preparation of 1- {4- [ (tert-Butoxycarbonyl) amino group]-3-Fluoropyridin-2-yl } pyrazole-3-carboxylic acid methyl ester：

To a stirred mixture of methyl 1- (3-fluoro-4-iodopyridin-2-yl) pyrazole-3-carboxylate (50.00 g,144.06mmol,1.00 eq.) and tert-butyl carbamate (33.75 g,288.12mmol,2.00 eq.) in dioxane (200 mL) was added CsF (65.65 g,432.18mmol,3.00 eq.), xantphos (8.33 g,14.41mmol,0.10 eq.) and Pd2 (dba) 3 (6.59 g,7.20mmol,0.05 eq.) at room temperature under nitrogen. The resulting mixture was stirred under nitrogen at 100 ℃ for 2 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was filtered and the filter cake was washed with EtOAc (3X 400 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 1- {4- [ (tert-butoxycarbonyl) amino as a yellow solid ]-3-Fluoropyridin-2-yl } pyrazole-3-carboxylic acid methyl ester (42.2 g, 87.15%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝337.15。

Step 3: preparation of 1- (4-amino-3-fluoropyridin-2-yl) pyrazole-3-carboxylic acid methyl ester：

1- {4- [ (tert-Butoxycarbonyl) amino group]A solution of methyl-3-fluoropyridin-2-yl } pyrazole-3-carboxylate (50 g,148.67mmol,1.00 eq.) in DCM (500 mL) was treated with TFA (250 mL) under a nitrogen atmosphere at room temperature for 1 hour. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with DCM (250 mL). With saturated NaHCO ₃ The mixture was basified (aqueous) to pH 9. By CH ₂ Cl ₂ The resulting mixture was extracted (3X 250 mL). The combined organic layers were washed with brine (1X 1000 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give methyl 1- (4-amino-3-fluoropyridin-2-yl) pyrazole-3-carboxylate (31.36 g, 89.30%) as a white solid. LC-MS (E)S+H,m/z):[M+H] ⁺ ＝237.1

Step 4: preparation of [1- (4-amino-3-fluoro-5-iodopiperidin-2-yl) pyrazolidin-3-yl](methoxy) methanol：

Methyl 1- (4-amino-3-fluoropyridin-2-yl) pyrazole-3-carboxylate (40.00 g,169.34mmol,1.00 eq.), NIS (45.70 g,203.21mmol,1.20 eq.) and TsOH.H ₂ A solution of O (1.61 g,8.47mmol,0.05 eq.) in MeCN (250 mL) was stirred under nitrogen at 60℃for 2 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was diluted with ethyl acetate (500 mL). The combined organic layers were washed with brine (3X 500 mL), dried over anhydrous Na ₂ SO ₄ Drying to give [1- (4-amino-3-fluoro-5-iodopiperidin-2-yl) pyrazolidin-3-yl as a yellow solid](methoxy) methanol (58.7 g, 92.67%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝362.90。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.40(d,J＝2.6Hz,1H),8.24(s,1H),6.99(d,J＝2.6Hz,1H),6.78(s,2H),3.86(s,3H)。

Step 5: preparation of 1- (4-amino-3-fluoro-5-methylpyridin-2-yl) pyrazole-3-carboxylic acid methyl ester：

1- (4-amino-3-fluoro-5-iodopyridin-2-yl) pyrazole-3-carboxylic acid methyl ester (25.00 g,69.04mmol,1.00 eq.) Pd (dppf) Cl ₂ (5.01 g,6.90mmol,0.10 eq.) Cs ₂ CO ₃ A mixture of (67.49 g,207.12mmol,3.00 eq.) and trimethyl-1,3,5,2,4,6-trioxadiborane (87.05 g,345.20mmol,5.00 eq., 50 wt%) in dioxane (400 mL) was stirred under nitrogen at 100deg.C for 2 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was filtered and the filter cake was washed with ethyl acetate (3X 1000 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 1- (4-amino-3-fluoro-5-methylpyridin-2-yl) pyrazole-3-carboxylate (17.10 g, 99.01%) as a pale yellow solid. LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝251.2。

Step 6: preparation of 1- {3' -fluoro-4-hydroxy-2, 5' -dimethyl-6-oxo- [1,4' -bipyridine]-2' -yl } pyri-dine Azole-3-carboxylic acid methyl ester：

To a solution of methyl 1- (4-amino-3-fluoro-5-methylpyridin-2-yl) pyrazole-3-carboxylate (25.00 g,99.91mmol,1.00 eq.) and 2, 2-dimethyl-6- (2-oxopropyl) -1, 3-dioxin-4-one (36.78 g,199.82mmol,2.00 eq.) in dioxane (260 mL) was added Ti (Oi-Pr) 4 (2.84 g,9.99mmol,0.10 eq.) and the resulting mixture stirred under nitrogen at 90 ℃ for 1 hour. The reaction was monitored by LCMS. The mixture was cooled to room temperature. H was then added dropwise to the mixture at room temperature ₂ SO ₄ (9.79 g,99.91mmol,1.00 eq.). The resulting mixture was stirred under nitrogen at 90 ℃ for 1 hour. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. By using water (200 mL) and Et ₂ O (100 mL) was triturated to purify the residue. The precipitated solid was collected by filtration and washed with Et2O (3 x 100 mL) to give 1- {3' -fluoro-4-hydroxy-2, 5' -dimethyl-6-oxo- [1,4' -bipyridine as a brown solid]-2' -yl } pyrazole-3-carboxylic acid methyl ester (15.38 g, 42.97%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝359.0。

Step 7: preparation of 1- {4- [ (3, 5-difluoropyridin-2-yl) (2H 2) methoxy]-3 '-fluoro-2, 5' -dimethyl-6- Oxo- [1,4' -bipyridines]-2' -yl } pyrazole-3-carboxylic acid methyl ester：

To methyl 1- (3-fluoro-5-methylpyridin-2-yl) pyrazole-3-carboxylate (10.00 g,42.51mmol,1.00 eq.) and 2- [ chloro (2H 2) methyl at room temperature under nitrogen atmosphere]To a stirred mixture of 3, 5-difluoropyridine (10.52 g,63.77mmol,1.50 eq.) in DMF (100 mL) was added Cs ₂ CO ₃ (41.56 g,127.53mmol,3.00 eq.) and 18-crown-6 (1.12 g,4.25mmol,0.10 eq.). The resulting mixture was stirred under nitrogen at 70 ℃ for 2 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was diluted with EtOAc (500 mL). The organic layer was washed with water (5X 500 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 1- {4- [ (3, 5-difluoropyridin-2-yl) (2H 2) methoxy as a white solid]-3' -fluoro-2, 5' -dimethyl-6-oxo- [1,4' -bipyridine]-2' -yl } pyrazole-3-carboxylic acid methyl ester (7.25 g, 34.99%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝488.15。

Step 8: preparation of 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) (2H 2) methoxy]-2' - [ (2E) -3- (dimethyl) Amino) prop-2-enoyl]-3' -fluoro-5 ', 6-dimethyl- [1,4' -bipyridine]-2-one：

1- {4- [ (3, 5-difluoropyridin-2-yl) (2H 2) methoxy]-3' -fluoro-2, 5' -dimethyl-6-oxo- [1,4' -bipyridine]A mixture of methyl-2' -yl } pyrazole-3-carboxylate (10.00 g,20.52mmol,1.00 eq), NCS (3.56 g,26.68mmol,1.30 eq.) and 2, 2-dichloroacetic acid (0.26 g,2.05mmol,0.10 eq.) in i-PrOH (100 mL) was stirred under nitrogen at 60℃for 1 hour. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was diluted with EtOAc (200 mL). The resulting mixture was washed with 3X 200mL of water. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 1- { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) (2H 2) methoxy as a white solid ]-3' -fluoro-5 ', 6-dimethyl-2-oxo- [1,4' -bipyridine]-2' -yl } pyrazole-3-carboxylic acid methyl ester (6.20 g, 57.91%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝522.2。

Step 9: preparation of 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) (2H 2) methoxy]-3 '-fluoro-2' - [3- (2-hydroxy) Propan-2-yl) pyrazol-1-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one：

To 1- { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) (2H 2) methoxy at 0℃under a nitrogen atmosphere]-3' -fluoro-5 ', 6-dimethyl-2-oxo- [1,4' -bipyridine]To a stirred solution of methyl-2' -yl } pyrazole-3-carboxylate (5.00 g,9.58mmol,1.00 eq.) in THF (50 mL) was added dropwise CH ₃ MgBr (31.93 mL,95.80mmol,10.00 eq (3M in THF) the resulting mixture was stirred under nitrogen at 0deg.C for 2 hours the desired product was detectable by LCMS the mixture was cooled to 0deg.C by addition of saturated NH ₄ Cl (aq) (150 mL) quenched the reaction at 0deg.C. The resulting mixture was extracted with EtOAc (4X 300 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. 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 a white solid3-chloro-4- [ (3, 5-difluoropyridin-2-yl) (2H 2) methoxy group) ]-3 '-fluoro-2' - [3- (2-hydroxy-prop-2-yl) pyrazol-1-yl]-5', 6-dimethyl- [1,4' -bipyridine]2-Ketone (2.43 g, 48.61%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝522.1。

Step 10: preparation (example 58A) rel-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) (2H 2) methoxy]-3'- Fluoro-2' - [3- (2-hydroxy-prop-2-yl) pyrazol-1-yl]-5', 6-dimethyl- [1,4' -bipyridine]-2-one：

The racemic mixture was separated by preparative chiral SFC (17.50 g) to give rel-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) (2H 2) methoxy ] -3 '-fluoro-2' - [3- (2-hydroxypropan-2-yl) pyrazol-1-yl ] -5', 6-dimethyl- [1,4' -bipyridin ] -2-one (example 58a,6.49g, ee=100%).

Example 58A：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝522.15。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.61(d,J＝2.3Hz,1H),8.50(s,1H),8.37(d,J＝2.6Hz,1H),8.15–8.06(m,1H),6.91(s,1H),6.60(d,J＝2.6Hz,1H),5.13(s,1H),2.09(d,J＝16.1Hz,6H),1.48(s,6H)。 ¹⁹ F NMR(377MHz,DMSO)δ-120.25,-120.27,-122.29,-122.31,-137.97。

Examples 59A and 59B

Step 1: preparation of 3-hydroxy-2, 2-dimethylpropionamidine hydrochloride：

Under nitrogen atmosphere at 0 ℃ to NH ₄ AlMe was added dropwise to a stirred mixture of Cl (7.32 g,136.81mmol,5.00 eq.) in toluene (20 mL) ₃ (9.86 g,136.81mmol,5.00 eq.). The resulting mixture was stirred under nitrogen at 0 ℃ for 10 minutes, and then the mixture was warmed to room temperature until no more gas was produced. A solution of ethyl 3-hydroxy-2, 2-dimethylpropionate (4.00 g,27.36mmol,1.00 eq.) in Tol was added dropwise to the above mixture at room temperature. The resulting mixture was stirred at 80 ℃ overnight. The reaction was monitored by LCMS. The reaction was quenched by the addition of MeOH (50 mL) at 0 ℃. The resulting mixture was filtered and the filter cake was washed with MeOH (300 mL). The filtrate was concentrated under reduced pressure. The residue was dissolved in EtOH (20 mL). The resulting mixture was filtered and the filter cake was washed with EtOH (5 mL). The filtrate was concentrated under reduced pressure. This gave 3-hydroxy-2, 2-dimethylpropionamidine hydrochloride (2 g, 47.89%) as a white solid. ¹ H NMR(300MHz,DMSO-d ₆ )δ9.01(s,2H),8.61(s,2H),5.41(t,1H),3.46(d,2H),1.15(s,6H)。

Step 2: preparation of 3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy-d 2) -3 '-fluoro-2' - (2- (1-hydroxy-) - 2-methylpropan-2-yl) pyrimidin-4-yl) -5', 6-dimethyl-2H- [1,4' -bipyridine]-2-one：

To (E) -3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy-d 2) -2'- (3- (dimethylamino) acryloyl) -3' -fluoro-5 ', 6-dimethyl-2H- [1,4' -bipyridine)]To a solution of 2-one (500 mg,1.01mmol,1.00 eq.) in DMF (20 mL) was added 3-hydroxy-2, 2-dimethylpropionamidine hydrochloride (1.17 g,10.10mmol,10.00 eq.) and K ₂ CO ₃ (1.40 g,10.10mmol,10.00 eq.). The resulting mixture was stirred under nitrogen at 80 ℃ for 2 hours. The reaction was monitored by LCMS. The desired product was detectable by LCMS. The mixture was cooled to room temperature. The resulting mixture was poured into water (20 mL) and extracted with EtOAc (3X 20 mL). The combined organic layers were washed with brine (2X 10 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The crude residue was purified by HP-Flash (500 mg) to give the crude product (280 mg), which was further purified by preparative HPLC to give 3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy-d 2) -3 '-fluoro-2' - (2- (1-hydroxy-2-methylpropan-2-yl) pyrimidin-4-yl) -5', 6-dimethyl-2H- [1,4' -bipyridine as a yellow solid]2-one (180 mg, 32.51%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝548.2。

Step 3: preparation of rel-3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy-d 2) -3 '-fluoro-2' - (2- (1-hydroxy) 1-methyl-2-propan-2-yl) -pyrimidin-4-yl-5 ', 6-dimethyl-2H- [1,4' -bipyridin]2-one and rel-3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy-d 2) -3 '-fluoro-2' - (2- (1-hydroxy-2-methyl)Propan-2-yl) pyrimidin-4-yl 5', 6-dimethyl-2H- [1,4' -bipyridine]-2-one：

The racemate (180 mg) was separated by preparative chiral HPLC to give example 59A (66.6 mg,99.1% purity, 95.1% deuterium purity, ee=97.7%) and example 59B (62.0 mg,99.3% purity, 95.5% deuterium purity, ee=98.3%) as white solids.

Example 59A：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝548.1。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.97(d,1H),8.77(s,1H),8.62(d,1H),8.17–8.06(m,1H),7.97(d,1H),6.91(s,1H),4.58(t,1H),3.69(d,2H),2.17(s,3H),2.05(s,3H),1.32(s,6H)。 ¹⁹ F NMR(282MHz,DMSO)δ-120.25,-120.27,-122.33,-122.35,-132.33。

Example 59B：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝548.1。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.97(d,1H),8.77(d,1H),8.62(d,1H),8.17–8.04(m,1H),7.97(d,1H),6.91(d,1H),4.58(t,1H),3.69(d,2H),2.17(s,3H),2.05(s,3H),1.32(s,6H)。 ¹⁹ F NMR(282MHz,DMSO)δ-120.25,-120.28,-122.33,-122.35,-132.33。

Examples 60A and 60B

Step 1: preparation of 1-tert-butyl 3-methyl-2- (4-methoxypyrimidin-2-yl) malonate：

To a stirred solution of 1-tert-butyl 3-methylmalonate (33.74 g,193.69mmol,4.00 eq.) in DMF (70 mL) was added NaH (6.97 g,290.53mmol,6.00 eq.) in portions at 0deg.C. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 30 minutes. To the above mixture was added 2-chloro-4-methoxypyrimidine (7.00 g,48.42mmol,1.00 eq). The resulting mixture was stirred overnight at 80 ℃ under nitrogen atmosphere. The reaction was monitored by LCMS. By addition of saturated NH ₄ Cl (aqueous) (100 mL) quench at 0deg.CAnd (3) reacting. The resulting mixture was extracted with EtOAc (3X 100 mL). The combined organic layers were washed with brine (200 ml), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 1-tert-butyl 3-methyl-2- (4-methoxypyrimidin-2-yl) malonate (6.50 g, 47.55%) as a yellow liquid. LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝283.1。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.51(d,1H),6.91(d,1H),4.96(s,1H),3.89(s,3H),3.70(s,3H),1.42(s,9H)。

Step 2: preparation of methyl 2- (4-methoxypyrimidin-2-yl) acetate：

To a stirred mixture of 1-tert-butyl 3-methyl 2- (4-methoxypyrimidin-2-yl) malonate (6.5 g,23.02mmol,1 eq.) in DCM (60 mL) was added TFA (30 mL) dropwise at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to give methyl 2- (4-methoxypyrimidin-2-yl) acetate (4.5 g, crude) as a yellow liquid. LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝183.1。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.47(d,1H),6.85(d,1H),3.90(s,3H),3.89(s,2H),3.65(s,3H)。

Step 3: preparation of methyl 2- (4-methoxypyrimidin-2-yl) -2-methylpropionate：

To a stirred mixture of methyl 2- (4-methoxypyrimidin-2-yl) acetate (4.41 g, assuming 100% yield, 24.20mmol,1.00 eq.) in THF (50 mL) was added dropwise LiHMDS (26.62 mL,26.62mmol,1.10 eq.) under nitrogen atmosphere at-78 ℃. The resulting mixture was stirred under nitrogen at-78 ℃ for 30 minutes. CH was added dropwise to the above mixture at-78deg.C under nitrogen atmosphere ₃ I (3.78 g,26.62mmol,1.10 eq.). The resulting mixture was stirred at room temperature for an additional 1 hour. LiHMDS (26.62 mL,26.62mmol,1.10 eq.) was then added dropwise to the above mixture at-78deg.C. The resulting mixture was stirred under nitrogen at-78 ℃ for 30 minutes. CH was added dropwise to the above mixture at-78deg.C under nitrogen atmosphere ₃ I (3.78 g,26.62mmol,1.10 eq.). The resulting mixture was stirred at room temperature for an additional 1 hour. The reaction was monitored by LCMS. With saturated NH ₄ The reaction was quenched with Cl (aqueous solution) at 0 ℃. The resulting mixture was extracted with EtOAc (3X 200 mL). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give methyl 2- (4-methoxypyrimidin-2-yl) -2-methylpropionate (4.75 g, 91.47%) as a yellow liquid. LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝211.05。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.47(d,1H),6.86(d,1H),3.89(s,3H),3.61(s,3H),1.52(s,6H)。

Step 4: preparation of methyl 2- (4-hydroxypyrimidin-2-yl) -2-methylpropionate：

A mixture of methyl 2- (4-methoxypyrimidin-2-yl) -2-methylpropionate (4.75 g,22.59mmol,1.00 eq.) and TMSI (18.08 g,90.37mmol,4.00 eq.) in ACN (50 mL) was stirred overnight at 80 ℃. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to give methyl 2- (4-hydroxypyrimidin-2-yl) -2-methylpropionate (8.24 g, crude) as a brown solid. LC-MS (ES+H, M/z) [ M+H ] ] ⁺ ＝197.1。

Step 6: preparation of 2- (4- { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy)]-3', 6-dimethyl-2-oxo Substituted- [1,4' -bipyridines]-2' -yl } pyrimidin-2-yl) -2-methylpropanoic acid methyl ester：

To 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-3', 6-dimethyl-2 ' - (trimethylstannyl) - [1,4' -bipyridine]To a stirred solution of 2-one (920 mg, assuming 100% yield, 1.70mmol,1.00 eq.) and methyl 2- (4-chloropyrimidin-2-yl) -2-methylpropionate (365 mg,1.70mmol,1.00 eq.) in 1, 4-dioxane (15 ml) was added Pd (PPh) ₃ ) ₂ Cl ₂ (238 mg,0.34mmol,0.20 eq.) and CuI (324 mg,1.70mmol,1.00 eq.). The resulting mixture was stirred under nitrogen at 120 ℃ for 2 hours. The reaction was monitored by LCMS. The desired product was detectable by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the crude product. The crude product was purified by reverse phase flash chromatography to give 2- (4- { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy) as a yellow oil]-3', 6-dimethyl-2-oxo- [1,4' -bipyridine]-2' -yl } pyrimidin-2-yl) Methyl 2-methylpropionate (250 mg,26.42%, two steps). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝556.1。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.98(d,1H),8.77(d,1H),8.60(d,1H),8.14-8.04(m,1H),7.94(d,1H),7.58(d,1H),6.83(s,1H),5.49(d,2H),3.59(s,3H),2.16(s,3H),1.96(s,3H),1.59(s,6H)。

Step 8: preparation of 2- (4- { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy) ]-3', 6-dimethyl-2-oxo Substituted- [1,4' -bipyridines]-2' -yl } pyrimidin-2-yl) -2-methylpropanoic acid：

To 2- (4- { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy group at room temperature under nitrogen atmosphere]-3', 6-dimethyl-2-oxo- [1,4' -bipyridine]To a stirred solution of methyl-2' -yl } pyrimidin-2-yl) -2-methylpropionate (300 mg,0.54mmol,1.00 eq.) in THF (6 mL) was added LiOH (26 mg,1.08mmol,2.00 eq.) dropwise in H ₂ O (3 mL). The resulting mixture was stirred under nitrogen at 80 ℃ for 2 hours. The reaction was monitored by LCMS. The desired product was detectable by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The resulting mixture (300 mg) was used in the next step without further purification. LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝542.3。

Step 9: preparation of 2- (4- { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy)]-3', 6-dimethyl-2-oxo Substituted- [1,4' -bipyridines]-2' -yl } pyrimidin-2-yl) -N, 2-dimethylpropionamide：

To 2- (4- { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy group at room temperature under nitrogen atmosphere]-3', 6-dimethyl-2-oxo- [1,4' -bipyridine]To a stirred solution of 2' -yl } pyrimidin-2-yl) -2-methylpropanoic acid (292 mg, assuming 100% yield, 0.55mmol,1.00 eq.) in ACN (3 mL) was added methylamine (0.8 mL,2m in THF) and NMI (454 mg,5.540mmol,10.00 eq.) and TCFH (776 mg,2.77mmol,5.00 eq.). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. The resulting mixture was diluted with EA (50 mL), then washed with water (2×50 mL) and brine (50 mL), and the organic layer was concentrated to give the crude product (300 mg), which was further purified by preparative HPLC to give a white color Solid 2- (4- { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy)]-3', 6-dimethyl-2-oxo- [1,4' -bipyridine]-2' -yl } pyrimidin-2-yl) -N, 2-dimethylpropionamide (160 mg,52.08%, two steps). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝555.3。

Step 10: preparation of rel-2- (4- (3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy) -3', 6-dimethyl-) 2-oxo-2H- [1,4' -bipyridines]-2' -yl) pyrimidin-2-yl) -N, 2-dimethylpropionamide and rel-2- (4- (3-chloro-4-) ((3, 5-difluoropyridin-2-yl) methoxy) -3', 6-dimethyl-2-oxo-2H- [1,4' -bipyridine]-2' -yl) pyrimidine-2- Radical) -N, 2-dimethylpropionamide：

The racemate (160 mg) was separated by preparative chiral HPLC to give rel-2- (4- (3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy) -3', 6-dimethyl-2-oxo-2H- [1,4' -bipyridin ] -2 '-yl) pyrimidin-2-yl) -N, 2-dimethylpropionamide (example 60a:44.2mg,99.6% purity, ee=100%) as a white solid and rel-2- (4- (3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy) -3', 6-dimethyl-2-oxo-2H- [1,4 '-bipyridin ] -2' -yl) pyrimidin-2-yl) -N, 2-dimethylpropionamide (example 60b:42.6mg,99.2% purity, ee=100%) as a white solid.

Example 60A：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝555.1。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.95(d,1H),8.77(d,1H),8.61(d,1H),8.15–8.05(m,1H),7.91(d,1H),7.57(d,1H),7.41(q,1H),6.83(s,1H),5.49(d,2H),2.54(d,3H),2.19(s,3H),1.96(s,3H),1.54(s,3H),1.54(s,3H)。 ¹⁹ F NMR(377MHz,DMSO)δ-120.14,-120.16,-122.34,-122.36。

Example 60B：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝555.1。 ¹ H NMR(400MHz,DMSO- _d6 )δ8.95(d,1H),8.77(d,1H),8.61(d,1H),8.14–8.05(m,1H),7.91(d,1H),7.57(d,1H),7.41(q,1H),6.83(s,1H),5.49(d,2H),2.55(d,3H),2.19(s,3H),1.96(s,3H),1.54(s,3H),1.54(s,3H)。 ¹⁹ F NMR(377MHz,DMSO)δ-120.14,-120.16,-122.34,-122.36。

Examples 61A and 61B

Step 1: preparation of 1- (2, 2-diethoxyethyl) cyclopropyl-1-ol：

To ethyl 3, 3-diethoxypropionate (10.00 g,52.56mmol,1.00 eq.) and Ti (Oi-Pr) under nitrogen at 0 ℃C ₄ (22.41 g,78.84mmol,1.50 eq.) in Et ₂ To a stirred mixture of O (80 mL) and THF (20 mL) was added dropwise a solution of EtMgBr in 2-methyl-THF (3.4M, 61mL,210.26mmol,4.00 eq.). The resulting mixture was stirred at room temperature under nitrogen overnight. The reaction was monitored by TLC (PE/ea=5:1, rf=0.3). The reaction was quenched by the addition of water (100 mL) at 0 ℃. With Et ₂ O (3X 100 mL) extraction of the resulting mixture, combining the organic phases and passing through anhydrous Na ₂ SO ₄ And (5) drying. 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 1- (2, 2-diethoxyethyl) cyclopropan-1-ol (6.60 g, 72.06%) as a yellow liquid. ¹ H NMR (300 MHz, chloroform-d) delta 4.82 (t, 1H), 3.79-3.70 (m, 3H), 3.59-3.55 (m, 2H), 1.91 (d, 2H), 1.28-1.23 (m, 6H), 0.81-0.76 (m, 2H), 0.49-0.44 (m, 2H).

Step 2: preparation of 1- (2, 2-diethoxyethyl) cyclopropylacetate：

To 1- (2, 2-diethoxyethyl) cyclopropan-1-ol (6.60 g,37.87mmol,1.00 eq.) and DMAP (5.09 g,41.66mmol,1.10 eq.) in Et at 0℃under nitrogen ₂ Acetic anhydride (5.80 g,56.81mmol,1.50 eq.) was added dropwise to a stirred solution of O (60 mL). The resulting mixture was stirred under nitrogen at 0 ℃ for 1 hour. The reaction was monitored by TLC (PE/ea=5:1, rf=0.4). With saturated NaHCO ₃ (aqueous solution) the reaction was quenched at 0 ℃. With Et ₂ O (3X 100 mL) extracts the aqueous layer. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography and the pure fractions were concentrated under reduced pressure to give 1- (2, 2-diethoxyethyl) cyclopropylacetate as a yellow liquid (7.00 g,crude product). ¹ H NMR (400 MHz, chloroform-d) delta 4.71 (t, 1H), 3.63-3.59 (m, 2H), 3.51-3.47 (m, 2H), 2.08 (d, 2H), 1.98 (s, 3H), 1.20 (t, 6H), 0.85-0.81 (m, 2H), 0.78-0.73 (m, 2H).

Step 3: preparation of [1- (acetoxy) cyclopropyl ]]Acetic acid：

To 1- (2, 2-diethoxyethyl) cyclopropylacetate (7.00 g,32.36mmol,1.00 eq.) in THF (25 mL) and H at room temperature ₂ To a stirred solution of O (50 mL) was added in portions potassium hydrogen persulfate (12.23 g,72.75mmol,1.50 eq.). The resulting mixture was stirred at room temperature overnight. The reaction was monitored by TLC (100% EA, rf=0.1). The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (5X 100 mL). By anhydrous Na ₂ SO ₄ The combined organic layers were dried. After filtration, the filtrate was concentrated under reduced pressure to give [1- (acetoxy) cyclopropyl ] as a yellow oil ]Acetic acid (5.00 g, crude). ¹ H NMR (300 MHz, chloroform-d) delta 2.85 (s, 2H), 2.04 (s, 3H), 1.06-0.99 (m, 2H), 0.93-0.90 (m, 2H).

Step 4: preparation of ethyl 2- (1-hydroxycyclopropyl) acetate：

To [1- (acetoxy) cyclopropyl ] at room temperature]To a stirred solution of acetic acid (4.00 g,25.29mmol,1.00 eq.) in EtOH (50 mL) was added dropwise H ₂ SO ₄ (40 drops). The resulting mixture was stirred at room temperature overnight. The reaction was monitored by TLC (PE/ea=10:1, rf=0.5). With saturated NaHCO ₃ The reaction was quenched at room temperature. The aqueous layer was extracted with EtOAc (3X 100 mL). The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography and the pure fractions were concentrated under reduced pressure to give ethyl 2- (1-hydroxycyclopropyl) acetate (2.50 g, 53.43%) as a yellow liquid. ¹ H NMR (400 MHz, chloroform-d) δ4.21 (q, 2H), 2.58 (s, 2H), 1.29 (t, 3H), 0.89-0.85 (m, 2H), 0.53-0.47 (m, 2H).

Step 5: preparation of 2- (1-hydroxycyclopropyl) acetamidine hydrochloride：

Under nitrogen atmosphere at 0 ℃ to NH ₄ AlMe was added dropwise to a stirred mixture of Cl (4.64 g,86.70mmol,5.00 eq.) in toluene (50 mL) ₃ (43 mL,2M toluene solution, 86.70mmol,5.00 equivalents). The resulting mixture was stirred under nitrogen at 0 ℃ for 10 minutes and then at room temperature until no more gas was produced. A solution of ethyl 2- (1-hydroxycyclopropyl) acetate (2.50 g,17.34mmol,1.00 eq.) in toluene was added dropwise to the above mixture at room temperature. The resulting mixture was stirred at 80 ℃ overnight. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The reaction was quenched by the addition of MeOH (30 mL) at 0 ℃. The resulting mixture was filtered and the filter cake was washed with MeOH (6X 50 mL). The filtrate was concentrated under reduced pressure. The residue was dissolved in EtOH (50 mL). The resulting mixture was filtered and the filter cake was washed with EtOH (20 mL). The filtrate was concentrated under reduced pressure. This gave 2- (1-hydroxycyclopropyl) acetamidine hydrochloride as an orange oil (2.4 g, crude). ¹ H NMR(300MHz,DMSO-d ₆ )δ8.98–8.72(m,4H),5.80(s,1H),2.62(s,2H),0.67(s,4H)。

Step 6: preparation of 3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy-d 2) -3 '-fluoro-2' - (2- ((1-hydroxy) Cyclopropyl) methyl) pyrimidin-4-yl) -5', 6-dimethyl-2H- [1,4' -bipyridine]-2-one：

To 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) (2H 2) methoxy at room temperature]-2' - [ (2E) -3- (dimethylamino) prop-2-enoyl]-3' -fluoro-5 ', 6-dimethyl- [1,4' -bipyridine]To a stirred solution of 2-ketone (500 mg,1.01mmol,1.00 eq.) and 2- (1-hydroxycyclopropyl) acetamidine hydrochloride (1.52 g,10.10mmol,10.00 eq.) in DMF (5 mL) was added K ₂ CO ₃ (2.79 g,20.20mmol,20.00 eq.). The resulting mixture was stirred at 60 ℃ overnight. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was diluted with water (20 mL). The aqueous layer was extracted with EtOAc (3X 20 mL). The resulting mixture was concentrated in vacuo. Purification of the crude product by preparative HPLC twice gave 3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy-d 2) -3 '-fluoro-2' - (2- ((1-hydroxycyclopropyl) methyl) pyrimidin-4-yl) -5', 6-dimethyl-2H- [1,4' -bipyridine as a yellow solid]2-one (180 mg, 32.63%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝546.3。

Step 7: preparation of rel-3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy-d 2) -3 '-fluoro-2' - (2- ((1- Hydroxycyclopropyl) methyl) pyrimidine -4-yl) -5', 6-dimethyl-2H- [1,4' -bipyridine]-2-ketone and rel-3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy-d 2) -3' -fluoro-2 ' - (2- ((1-hydroxycyclopropyl) methyl) pyrimidin-4-yl) -5', 6-di methyl-2H- [1,4' -bipyridine]-2-one：

The racemate (180 mg) was separated by preparative chiral HPLC, the pure fractions concentrated under reduced pressure and lyophilized to give example 61A (62.1 mg,98.9% purity, 95.3% deuterium purity, ee=100%) as a yellow solid and example 61B (65.6 mg,99.3% purity, 95.3% deuterium purity, ee=100%) as a white solid.

Example 61A：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝546.3。 ¹ H NMR(400MHz,DMSO-d6)δ8.95(d,1H),8.77(s,1H),8.61(d,1H),8.16–8.05(m,1H),8.00(d,1H),6.90(s,1H),5.33(s,1H),3.26–3.07(m,2H),2.17(s,3H),2.05(s,3H),0.59(s,4H)。 ¹⁹ F NMR(377MHz,DMSO)δ-120.25,-120.27,-122.33,-122.34,-132.52。

Example 61B：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝546.3。 ¹ H NMR(400MHz,DMSO-d6)δ8.95(d,1H),8.77(s,1H),8.61(d,1H),8.14–8.07(m,1H),8.00(d,1H),6.90(d,1H),5.33(s,1H),3.23–3.08(m,2H),2.17(s,3H),2.05(s,3H),0.59(s,4H)。 ¹⁹ F NMR(377MHz,DMSO)δ-120.24,-120.26,-122.32,-122.34,-132.51。

Examples 62A and 62B

Step 1: preparation of 4' - { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy group]-6-methyl-2-oxopyridin-1- 3' -fluoro-6- (2-hydroxy-prop-2-yl) -5' -methyl- [2,2' -bipyridine]-1-onium-1-alkoxide：

To 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-3 '-fluoro-5', 6-dimethyl-2 '- (trimethylstannyl) - [1,4' -bipyridine]2-Ketone (assuming 100% yield, 1.00g,to a reaction solution of 1.79mmol,1.00 eq.) was added 2-bromo-6- (2-hydroxy-propan-2-yl) pyridin-1-ium-1-alkoxide (0.83 g,3.58mmol,2.00 eq.), cuI (0.34 g,1.79mmol,1.00 eq.) and Pd (PPh) ₃ ) ₂ Cl ₂ (0.25 g,0.35mmol,0.20 eq.) the mixture was stirred under nitrogen at 80℃for 2 hours. The reaction was monitored by LCMS. The reaction was monitored by LCMS. The mixture was brought to room temperature. The residue was dissolved in EtOAc (200 mL). With saturated NaHCO ₃ (aqueous solution) (2X 100 mL) the resulting mixture was washed. The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give a crude product (400 mg). The crude product was isolated by preparative HPLC to give 4' - { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy as a white solid]-6-methyl-2-oxopyridin-1-yl } -3' -fluoro-6- (2-hydroxy-prop-2-yl) -5' -methyl- [2,2' -bipyridine]-1-onium-1-alkoxide (200 mg, 20.43%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝547.2。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.70(d,1H),8.60(d,1H),8.14–8.04(m,1H),7.82(dd,1H),7.75(dd,1H),7.60(t,1H),6.89(d,1H),6.62(s,1H),5.52(d,2H),2.17(s,3H),2.06(s,3H),1.60(s,6H)。

Step 2: preparation of rel-3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy) -3' -fluoro-6 "- (2-hydroxypropion ] 2-yl) -5', 6-dimethyl-2-oxo-2H- [1,4':2', 2' -terpyridine]1' -oxide and rel-3-chloro-4- ((3, 5-) Difluoro pyridin-2-yl) methoxy) -3' -fluoro-6 "- (2-hydroxy-propan-2-yl) -5', 6-dimethyl-2-oxo-2H- [1,4': 2', 2' -terpyridine]1 "-oxide：

The racemate (250 mg) was separated by preparative HPLC to give rel-3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy) -3 '-fluoro-6 "- (2-hydroxypropyl-2-yl) -5', 6-dimethyl-2-oxo-2H- [1,4':2',2" -terpyridin ]1 "-oxide (example 62a:78.2mg,98.1% purity, ee=100%) and rel-3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy) -3 '-fluoro-6" - (2-hydroxypropyl-2-yl) -5', 6-dimethyl-2-oxo-2H- [1,4':2',2 "-terpyridin ]1" -oxide (example 62b:78.6mg,98.7% purity, ee=98.7%) as a white solid.

Example 62A：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝547.1。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.69(d,1H),8.60(d,1H),8.18–8.01(m,1H),7.82(dd,1H),7.75(dd,1H),7.60(t,1H),6.88(d,1H),6.61(s,1H),5.51(d,2H),2.17(s,3H),2.05(s,3H),1.60(s,6H)。 ¹⁹ F NMR(377MHz,DMSO)δ-120.19,-120.21,-122.37,-122.39,-128.08。

Example 62B：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝547.1。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.69(d,1H),8.60(d,1H),8.13–8.05(m,1H),7.82(dd,1H),7.75(dd,1H),7.60(t,1H),6.88(d,1H),6.61(s,1H),5.51(d,2H),2.17(s,3H),2.05(s,3H),1.60(s,6H)。 ¹⁹ F NMR(377MHz,DMSO)δ-120.19,-120.21,-122.37,-122.39,-128.08。

Examples 63A and 63B

Step 1: preparation of 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]1- [ 3-fluoro-6' - (2-hydroxypropyl-2-) Phenyl) -5-methyl- [2,2' -bipyridine]-4-yl]-6-methylpyridin-2-one：

To the above mixture of step 3 was added 2- (6-bromopyridin-2-yl) propan-2-ol (754.34 mg,3.49mmol,3.00 eq.) Pd (PPh) at room temperature under nitrogen atmosphere ₃ ) ₂ Cl ₂ (163.36 mg,0.23mmol,0.20 eq.) and CuI (221.62 mg,1.16mmol,1.00 eq.). The resulting mixture was stirred under nitrogen at 80 ℃ for 1 hour. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3X 100 mL). The combined organic layers were washed with brine (3X 100 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. Purification of the crude product by preparative HPLC gave 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy as a white solid]-1- [ 3-fluoro-6' - (2-hydroxypropyl-2-yl)-5-methyl- [2,2' -bipyridine]-4-yl]-6-methylpyridin-2-one (286.00 mg, 46.29%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝531.00。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.69(d,1H),8.61(d,1H),8.15–8.05(m,1H),8.01–7.90(m,2H),7.75(dd,1H),6.89(s,1H),5.52(d,2H),5.31(s,1H),2.14(s,3H),2.05(s,3H),1.46(s,6H)。

Step 2: preparation of rel-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-1- [ 3-fluoro-6' - (2-hydroxy) Propan-2-yl) -5-methyl- [2,2' -bipyridine]-4-yl]-6-methylpyridin-2-one and rel-3-chloro-4- [ (3, 5-difluoropyridine) Pyridin-2-yl) methoxy]-1- [ 3-fluoro-6 '- (2-hydroxy-prop-2-yl) -5-methyl- [2,2' -bipyridine]-4-yl]-6-methyl group Pyridin-2-ones：

The racemic mixture was separated by preparative chiral HPLC (286.00 mg) to give rel-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy ] -1- [ 3-fluoro-6 '- (2-hydroxypropan-2-yl) -5-methyl- [2,2' -bipyridin ] -4-yl ] -6-methylpyridin-2-one (example 63a,65.1mg,99.2% purity, ee=99.9%) and rel-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy ] -1- [ 3-fluoro-6 '- (2-hydroxypropan-2-yl) -5-methyl- [2,2' -bipyridin ] -4-yl ] -6-methylpyridin-2-one (example 63b,59.0mg,99.6% purity, ee=99.9%).

Example 63A：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝531.1。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.69(d,1H),8.61(d,1H),8.18–8.04(m,1H),8.02–7.88(m,2H),7.75(dd,1H),6.89(s,1H),5.52(d,2H),5.30(s,1H),2.13(s,3H),2.04(s,3H),1.46(s,6H)。 ¹⁹ F NMR(282MHz,DMSO)δ-120.17,-120.20,-122.36,-122.39,-134.43。

Example 63B：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝531.05。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.69(d,1H),8.61(d,1H),8.18–8.04(m,1H),8.01–7.87(m,2H),7.75(dd,1H),6.89(d,1H),5.52(d,2H),5.30(s,1H),2.13(s,3H),2.04(s,3H),1.46(s,6H)。 ¹⁹ F NMR(282MHz,DMSO)δ-120.17,-120.19,-122.36,-122.39,-134.42。

Examples 64A and 64B

Step 1: preparation of 3-fluoro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine-2-methyl Acid methyl ester：

To a stirred mixture of methyl 4-chloro-3-fluoropyridine-2-carboxylate (2.00G, 10.55mmol,1.00 eq), bis (pinacolato) diboron (13.40G, 52.75mmol,5.00 eq) in dioxane (10 mL) was added AcOK (3.11G, 31.65mmol,3.00 eq) and XPhos Pd G3 (4476 mg,0.52mmol,0.05 eq) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80℃for a further 1.5 hours. The mixture was cooled to room temperature. The desired product was detectable by LCMS. The resulting mixture was used directly in the next step without further purification. LC-MS (ES+H, M/z) [ M+H ] ] ⁺ =200.1 (boric acid).

Step 2: preparation of 4- { 3-chloro-4- [ (3-chloro-5-fluoropyridin-2-yl) (2H 2) methoxy]-5', 6-dimethyl-2- Oxo- [1,4' -bipyridines]-2' -yl } -3-oxopyrazine-2-carboxylic acid methyl ester：

Bis (2' -bromo-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) (2H 2) methoxy was added to the above mixture at room temperature under a nitrogen atmosphere]-5', 6-dimethyl- [1,4' -bipyridine]-2-one) (1.96 g,2.13mmol,0.60 eq.) K ₂ CO ₃ (1.48 g,10.67mmol,3.00 eq.) Pd (dppf) Cl ₂ (520 mg,0.71mmol,0.20 eq.) and H ₂ O (2.5 mL). The resulting mixture was stirred under nitrogen at 80℃for 1.5 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was poured into water (50 mL). The resulting mixture was extracted with EtOAc (3X 50 mL). By anhydrous Na ₂ SO ₄ The combined organic layers were dried. 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 pressure to give 4- { 3-chloro-4- [ (3-chloro-5-fluoropyridin-2-yl) (2H 2) methoxy as a white solid]-5', 6-dimethyl-2-oxo- [1,4' -bipyridine]-2' -yl } -3-oxopyrazine-2-carboxylic acid methyl ester (450 mg, 23.07%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝533.0。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.91(s,1H),8.66(d,1H),8.61(d,1H),8.22(t,1H),8.10–8.07(m,1H),7.97(s,1H),6.82(s,1H),3.93(s,3H),2.11(s,3H),1.99(s,3H)。

Step 3: preparation of 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) (2H 2) methoxy ]-1- [3 '-fluoro-2' - (2-hydroxy) Propan-2-yl) -5-methyl- [2,4' -bipyridine]-4-yl]-6-methylpyridin-2-one：

To 4- { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) (2H 2) methoxy at 0℃under a nitrogen atmosphere]-6-methyl-2-oxopyridin-1-yl } -3 '-fluoro-5-methyl- [2,4' -bipyridine]To a stirred mixture of methyl-2' -formate (450 mg,0.84mmol,1.00 eq.) and LiCl (35 mg,0.84mmol,1 eq.) in THF (40 mL) was added dropwise CH ₃ MgI (4 mL,8.00mmol,21.32 eq, 2.0M in diethyl ether). The resulting mixture was stirred under nitrogen at 0 ℃ for 1 hour. The reaction was monitored by LCMS. Saturated NH at 0deg.C ₄ The reaction was quenched with Cl (aq, 50 mL). The resulting mixture was extracted with EtOAc (3X 30 mL). By anhydrous Na ₂ SO ₄ The combined organic layers were dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, the pure fraction was concentrated under pressure to give the crude product, which was further purified by preparative HPLC, the pure fraction was concentrated under pressure to give 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) (2H 2) methoxy as a white solid]-1- [3' -fluoro-2 ' - (2-hydroxy-prop-2-yl) -5-methyl- [2,4' -bipyridine]-4-yl]-6-methylpyridin-2-one (120 mg, 26.66%). LC-MS (ES+H, M/z) [ M+H ] ] ⁺ ＝533.1。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.88(s,1H),8.61(d,1H),8.48(d,1H),8.14–8.07(m,1H),7.91–7.88(m,2H),6.82(s,1H),5.37(s,1H),2.10(s,3H),2.00(s,3H),1.56(s,6H)。

Step 4: preparation of rel-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) (2H 2) methoxy]1- [3 '-fluoro-2' - (2-) Hydroxy prop-2-yl) -5-methyl- [2,4' -bipyridine]-4-yl]-6-methylpyridin-2-one and rel-3-chloro-4- [ (3, 5-di- Fluoropyridin-2-yl) (2H 2) methoxy]-1- [3 '-fluoro-2 ]'- (2-hydroxy-prop-2-yl) -5-methyl- [2,4' -bipyridine]-4- Base group]-6-methylpyridin-2-one：

The racemate (120 mg) was separated by preparative chiral HPLC, the pure fractions concentrated under reduced pressure and lyophilized to give example 64A (39.3 mg,97.6% purity, 97.3% deuterium purity, ee=100%) and example 64B (39.5 mg,98.4% purity, 97.9% deuterium purity, ee=100%) as white solids.

Example 64A：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝533.20。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.88(s,1H),8.60(d,1H),8.47(d,1H),8.12–8.07(m,1H),7.90–7.88(m,2H),6.81(s,1H),5.37(s,1H),2.09(s,3H),1.98(s,3H),1.56(s,6H)。 ¹⁹ F NMR(377MHz,DMSO)δ-120.25,-120.27,-122.33,-122.35,-125.91。

Example 64B：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝533.25。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.88(s,1H),8.60(d,1H),8.47(d,1H),8.12–8.07(m,1H),7.90–7.88(m,2H),6.81(s,1H),5.37(s,1H),2.09(s,3H),1.98(s,3H),1.56(s,6H)。 ¹⁹ F NMR(377MHz,DMSO)δ-120.25,-120.27,-122.33,-122.35,-125.91。

Examples 65A and 65B

Step 1: preparation of 3-fluoro-2- (methoxycarbonyl) pyridin-4-ylboronic acid：

To a stirred mixture of methyl 4-chloro-3-fluoropyridine-2-carboxylate (1.50G, 7.91mmol,1.00 eq.) and bis (pinacolato) diboron (10.05G, 39.56mmol,5.00 eq.) in dioxane (30 mL) was added potassium acetate (2.33G, 23.73mmol,3.00 eq.) and XPhos Pd G3 (0.33G, 0.39mmol,0.05 eq.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred under nitrogen at 80℃for 1.5 hours. The mixture was cooled to room temperature. The reaction was monitored by LCMS. The crude product mixture was not subjected to Further purification was used directly in the next step. LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝200.0。

Step 2: preparation of 4- { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) (2H 2) methoxy]-6-methyl-2-oxopyri-dine Pyridin-1-yl } -3,3 '-difluoro-5-methyl- [2,4' -bipyridine]-2' -methyl formate：

Bis (2' -bromo-3-chloro-4- [ (3, 5-difluoropyridin-2-yl) (2H 2) methoxy was added to the above mixture at room temperature under a nitrogen atmosphere]-5', 6-dimethyl- [1,4' -bipyridine]-2-one) (1.71 g,1.87mmol,0.70 eq.) K ₂ CO ₃ (1.11 g,8.01mmol,3.00 eq.) Pd (dppf) Cl ₂ (0.39 g,0.53mmol,0.20 eq.), dioxane (30 mL) and H ₂ O (3 mL). The resulting mixture was stirred at 80℃for a further 1.5 hours. The mixture was cooled to room temperature. The reaction was monitored by LCMS. The resulting mixture was poured into water (200 mL). The resulting mixture was filtered and the filter cake was washed with EtOAc (3X 200 mL). The combined organic layers were washed with brine (200 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 4- { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) (2H 2) methoxy as a yellow solid]-6-methyl-2-oxopyridin-1-yl } -3,3 '-difluoro-5-methyl- [2,4' -bipyridine]Methyl-2' -formate (1.00 g, 22.9%). LC-MS (ES+H, M/z) [ M+H ] ] ⁺ ＝551.1。

Step 3: preparation of 3-chloro-1- [3,3' -difluoro-2 ' - (2-hydroxypropyl-2-yl) -5-methyl- [2,4' -bipyridine]- 4-yl group]-4- [ (3, 5-difluoropyridin-2-yl) (2H 2) methoxy]-6-methylpyridin-2-one：

To 4- { 3-chloro-4- [ (3-fluoropyridin-2-yl) (2H 2) methoxy group at 0℃under nitrogen atmosphere]-6-methyl-2-oxopyridin-1-yl } -3,3 '-difluoro-5-methyl- [2,4' -bipyridine]To a stirred solution of methyl-2' -formate (850 mg,1.59mmol,1.00 eq.) in THF (80 mL) was added dropwise CH ₃ MgBr (5.32 mL,15.95mmol,10.00 eq., 3M in 2-MeTHF). The resulting mixture was stirred under nitrogen at 0 ℃ for 1.5 hours. The reaction was monitored by LCMS. The reaction was quenched with saturated NH4Cl (aq, 20 ml) at 0 ℃. The resulting mixture was extracted with EtOAc (3X 80 mL). The combined organic layers were washed with brine (3X 80 mL) and driedNa ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the crude product which was further purified by preparative HPLC and the pure fractions were concentrated under pressure to give 3-chloro-1- [3,3' -difluoro-2 ' - (2-hydroxypropyl-2-yl) -5-methyl- [2,4' -bipyridine as a white solid]-4-yl]-4- [ (3, 5-difluoropyridin-2-yl) (2H 2) methoxy]-6-methylpyridin-2-one (280 mg,85% purity, 31.9% yield). LC-MS (ES+H, M/z) [ M+H ] ] ⁺ ＝551.1。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.79(s,1H),8.61(d,1H),8.53(d,1H),8.12-8.10(m,1H),7.68(t,1H),6.92(s,1H),5.39(s,1H),2.19(s,3H),2.07(s,3H),1.56(s,6H)。

Step 4: preparation of rel-3-chloro-1- [3,3' -difluoro-2 ' - (2-hydroxypropyl-2-yl) -5-methyl- [2,4' -bipyramid Pyridine and pyridine]-4-yl]-4- [ (3, 5-difluoropyridin-2-yl) (2H 2) methoxy]-6-methylpyridin-2-one and rel-3-chloro-1- [3, 3' -difluoro-2 ' - (2-hydroxy-prop-2-yl) -5-methyl- [2,4' -bipyridine]-4-yl]-4- [ (3, 5-difluoropyridin-2-yl) (2H2) Methoxy group]-6-methylpyridin-2-one：

The racemate (270 mg) was separated by preparative chiral HPLC, the pure fractions concentrated under reduced pressure and lyophilized to give example 65A (61.8 mg,99.9% purity, ee=100%, 96.4% deuterium purity) as a white solid and example 65B (53.1 mg,99.8% purity, ee=99.3%, 96.6% deuterium purity) as a white solid.

Example 65A：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝551.3。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.79(s,1H),8.61(d,1H),8.53(d,1H),8.13-8.06(m,1H),7.68(t,1H),6.94(s,1H),5.38(s,1H),2.18(s,3H),2.06(s,3H),1.55(s,6H)。 ¹⁹ F NMR(282MHz,DMSO)δ-120.216,-120.284,-122.313,-122.350,-123.233,-123.343,-132.080,-132.190。

Example 65B：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝551.3。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.79(s,1H),8.60(d,1H),8.53(d,1H),8.12-8.06(m,1H),7.68(t,1H),6.91(s,1H),5.38(s,1H),2.18(s,3H),2.06(s,3H),1.55(s,6H)。 ¹⁹ F NMR(282MHz,DMSO)δ-120.211,-120.279,-122.305,-122.343,-123.230,-123.340,-132.074,-132.185

Examples 66A and 66B

Step 1: preparation of 4- (3-chloro-4- (2- (3, 5-difluoropyridin-2-yl) ethyl) -3 '-fluoro-5', 6-dimethyl-2- oxo-2H- [1,4' -bipyridines]-2' -yl) pyrimidine-2-carboxylic acid ethyl ester：

To 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy at room temperature]-3 '-fluoro-5', 6-dimethyl-2 '- (trimethylstannyl) - [1,4' -bipyridine]To 2-one (1 g crude) were added 4-chloropyrimidine-2-carboxylic acid ethyl ester (1302 mg,6.98mmol,3.00 eq.), pd (PPh 3) 2Cl2 (326 mg,0.46mmol,0.20 eq.) and CuI (447 mg,2.32mmol,1.00 eq.). The resulting mixture was stirred under nitrogen at 80 ℃ for 2 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3X 100 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 4- (3-chloro-4- (2- (3, 5-difluoropyridin-2-yl) ethyl) -3' -fluoro-5 ', 6-dimethyl-2-oxo-2H- [1,4' -bipyridine) as a yellow solid ]-2' -yl) pyrimidine-2-carboxylic acid ethyl ester (500 mg,39.50%, two steps). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝546.1。

Step 2: preparation of 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-3 '-fluoro-2' - {2- [ 2-hydroxy (1, 1, 3-2H 6) propan-2-yl]Pyrimidin-4-yl } -5', 6-dimethyl- [1,4' -bipyridine]-2-one：

To 4- { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy group at-10℃under nitrogen atmosphere]-3' -fluoro-5 ', 6-dimethyl-2-oxo- [1,4' -bipyridine]To a stirred solution of ethyl-2' -yl } pyrimidine-2-carboxylate (550 mg,1.00mmol,1.00 eq.) and LiCl (85 mg,2.01mmol,2.00 eq.) in THF (8 mL) was added dropwise iodine ((2H 3) methyl) magnesium (3.02 mL,3.00mmol,3 eq., 1)M). The resulting mixture was stirred at-10 ℃ for 30 minutes under nitrogen atmosphere. The reaction was monitored by LCMS. With saturated NH ₄ The reaction was quenched at-10 ℃. The resulting mixture was extracted with EtOAc (3X 50 mL). By anhydrous Na ₂ SO ₄ The combined organic layers were dried. After filtration, the filtrate was concentrated under reduced pressure. The crude product was isolated by preparative HPLC to give 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) methoxy]-3 '-fluoro-2' - {2- [ 2-hydroxy (1, 3-2H 6) propan-2-yl]Pyrimidin-4-yl } -5', 6-dimethyl- [1,4' -bipyridine]-2-one (50 mg, 9.23%). LC-MS (ES+H, M/z) [ M+H ] ] ⁺ ＝538.2。

Step 3: preparation of rel-3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy) -3 '-fluoro-2' - (2- (2-hydroxy) Propan-2-yl-1, 3-d 6) pyrimidin-4-yl) -5', 6-dimethyl-2H- [1,4' -bipyridine]2-one and rel-3- Chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy) -3 '-fluoro-2' - (2- (2-hydroxypropyl-2-yl-1, 3-d 6) azoxystrobin Pyridin-4-yl) -5', 6-dimethyl-2H- [1,4' -bipyridine]-2-one：

The racemic mixture (50 mg) was separated by preparative chiral HPLC to give rel-3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy) -3 '-fluoro-2' - (2- (2-hydroxypropyl-2-yl-1, 3-d 6) pyrimidin-4-yl) -5', 6-dimethyl-2H- [1,4' -bipyridin ] -2-one (example 66a:22.6mg,99.7% purity, ee=100%) and rel-3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy) -3 '-fluoro-2' - (2- (2-hydroxypropyl-2-yl-1, 3-d 6) pyrimidin-4-yl) -5', 6-dimethyl-2H- [1,4' -bipyridin ] -2-one (example 66b:21.2mg,99.6% purity, ee=100%) as a white solid.

Example 66A：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝538.2。 ¹ H NMR(400MHz,DMSO-d ₆ )δ9.02(d,1H),8.78(s,1H),8.61(d,1H),8.15–8.06(m,1H),8.04(d,1H),6.90(s,1H),5.53(d,2H),5.06(d,1H),2.18(s,3H),2.05(s,3H)。 ¹⁹ F NMR(377MHz,DMSO)δ-120.17,-120.19,-122.35,-122.36,-132.09。

Example 66B：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝538.2。 ¹ H NMR(400MHz,DMSO-d ₆ )δ9.02(d,1H),8.78(s,1H),8.61(d,1H),8.15–8.06(m,1H),8.04(d,1H),6.90(s,1H),5.52(d,2H),5.05(d,1H),2.18(s,3H),2.05(s,3H)。 ¹⁹ F NMR(377MHz,DMSO)δ-120.17,-120.19,-122.36,-122.38,-132.09。

Examples 67A and 67B

Step 1: preparation of 3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy-d 2) -3' -fluoro-5 ', 6-dimethyl-2 ' -) (trimethylstannyl) -2H- [1,4' -bipyridine]-2-one：

To 2', 3-dichloro-4- [ (3, 5-difluoropyridin-2-yl) (2H 2) methoxy at room temperature under a nitrogen atmosphere ]-3' -fluoro-5 ', 6-dimethyl- [1,4' -bipyridine]-2-one (2.00 g,4.62mmol,1.00 eq.) and Pd (PPh) ₃ ) ₂ Cl ₂ (649 mg,0.92mmol,0.20 eq.) AsPh was added to a stirred mixture of THF (20 mL) ₃ (283 mg,0.92mmol,0.20 eq.) and Sn ₂ Me ₆ (3.02 g,9.25mmol,2.00 eq.). The resulting mixture was stirred under nitrogen at 80 ℃ for 2 hours. The reaction was monitored by LCMS. The desired product was detectable by LCMS. The resulting mixture was used directly in the next step without further purification. LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝562.1。

Step 2: preparation of 4- (3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy-d 2) -3 '-fluoro-5', 6-dimethyl- 2-oxo-2H- [1,4' -bipyridines]-2' -yl) pyrimidine-2-carboxylic acid ethyl ester：

To 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) (2H 2) methoxy at room temperature under a nitrogen atmosphere]-3 '-fluoro-5', 6-dimethyl-2 '- (trimethylstannyl) - [1,4' -bipyridine]To a stirred mixture of 2-keto hydrofluoride (2.70 g,4.65mmol,1.00 eq.) and ethyl 4-chloropyrimidine-2-carboxylate (1.73 g,9.30mmol,2.00 eq.) in THF (20 ml) was added Pd (PPh) ₃ ) ₂ Cl ₂ (652 mg,0.93mmol,0.20 eq.) and CuI (885 mg,4.65mmol,1.00 eq.). The resulting mixture was stirred under nitrogen at 80 ℃ for 2 hours. The reaction was monitored by LCMS. The resulting mixture was cooled to room temperature and poured into 20mL of water. The resulting mixture was extracted with EtOAc (3X 20 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 4- (3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy-d 2) -3' -fluoro-5 ', 6-dimethyl-2-oxo-2H- [1,4' -bipyridine) as a white solid]-2' -yl) pyrimidine-2-carboxylic acid ethyl ester (860 mg, 33.75%). LC-MS (ES+H, M/z) [ M+H ]]+＝548.1。 ¹ H NMR (300 MHz, chloroform-d) δ9.08 (d, 1H), 8.70-8.63 (m, 1H), 8.42 (d, 1H), 8.20 (dd, 1H), 7.35-7.33 (m, 1H), 6.47 (d, 1H), 4.56 (q, 2H), 2.26 (s, 3H), 2.07 (s, 3H), 1.49 (t, 3H).

Step 3: preparation of 3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy-d 2) -3 '-fluoro-2' - (2- (2-hydroxy) Propan-2-yl-1, 3-d 6) pyrimidin-4-yl) -5', 6-dimethyl-2H- [1,4' -bipyridine]-2-one：

To 4- { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) (2H 2) methoxy at 0℃under a nitrogen atmosphere]-3' -fluoro-5 ', 6-dimethyl-2-oxo- [1,4' -bipyridine]To a stirred mixture of ethyl-2' -yl } pyrimidine-2-carboxylate (480 mg,0.87mmol,1.00 eq.) in THF was added dropwise iodine ((2H 3) methyl) magnesium (9 mL,8.76mmol,10.00 eq.). The resulting mixture was stirred under nitrogen at 0 ℃ for 1 hour. The reaction was monitored by LCMS. The desired product was detectable by LCMS. With saturated NH ₄ The reaction was quenched with Cl (aqueous solution) at 0 ℃. The resulting mixture was extracted with EtOAc (3X 20 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the crude product. Purification of the crude product by preparative HPLC afforded 3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy-d 2) -3 '-fluoro-2' - (2- (2-hydroxypropan-2-yl-1, 3-d 6) pyrimidin-4-yl) -5', 6-dimethyl-2H- [1,4' -bipyridine as a white solid]-2-one (65 mg, 13.74%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝540.2。

Step 4: manufacturing processPreparation of rel-3-chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy-d 2) -3 '-fluoro-2' - (2- (2-hydroxy) Propa-2-yl-1, 3-d 6) pyrimidin-4-yl) -5', 6-dimethyl-2H- [1,4' -bipyridine]2-one and rel-3- Chloro-4- ((3, 5-difluoropyridin-2-yl) methoxy-d 2) -3 '-fluoro-2' - (2- (2-hydroxypropyl-2-yl-1, 3- d6 Pyrimidin-4-yl) -5', 6-dimethyl-2H- [1,4' -bipyridine]-2-one：

The racemate (65 mg) was separated by preparative chiral HPLC to give example 67A (9.7 mg,97.4% purity, 98.9% deuterium purity, ee=97.44%) and example 67B (8.8 mg,98.4% purity, 98.6% deuterium purity, ee=97.02%) as a white solid.

Example 67A：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝540.10。 ¹ H NMR(300MHz,DMSO-d ₆ )δ9.03(d,1H),8.77(s,1H),8.61(d,1H),8.13-8.02(m,2H),6.90(s,1H),5.04(s,1H),2.17(s,3H),2.05(s,3H)。 ¹⁹ F NMR(282MHz,DMSO)δ-119.61,-119.66,-120.85,-120.87,-132.49。

Example 67B：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝540.2。 ¹ H NMR(300MHz,DMSO-d ₆ )δ9.03(d,1H),8.77(s,1H),8.61(d,1H),8.13-8.03(m,2H),6.90(s,1H),5.05(s,1H),2.17(s,3H),2.05(s,3H)。 ¹⁹ F NMR(282MHz,DMSO)δ-120.23,-120.25,-122.32,-122.34,-132.06。

Examples 68A and 68B

Step 1: preparation of 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) (2H 2) methoxy]-3 '-fluoro-5', 6-dimethyl- 2'- (trimethylstannyl) - [1,4' -bipyridine]-2-one：

2', 3-dichloro-4- [ (3, 5-difluoropyridin-2-yl) (2H 2) methoxy]-3' -fluoro-5 ', 6-dimethyl- [1,4' -bipyridine]-2-one (1.00 g,2.31mmol,1.00 eq.) Sn ₂ Me ₆ (1.51 g,4.62mmol,2.00 eq.) Pd (PPh) ₃ ) ₂ Cl ₂ (0.32 g,0.46mmol,0.20 eq.) AsPh ₃ (0.14 g,0.46mmol,0.20 eq.) in dioxane (10 mL) was stirred under nitrogen at 80deg.C for 2 hours. The reaction was monitored by LCMS. The resulting mixture was used directly in the next step without further purification. LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝562.1。

Step 2: preparation of 4' - { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) (2H 2) methoxy]-6-methyl-2-oxopyri-dine Pyridin-1-yl } -3' -fluoro-6- (2-hydroxy-prop-2-yl) -5' -methyl- [2,2' -bipyridine]-1-onium-1-alkoxide：

To the above mixture of step 1 were added 2-bromo-6- (2-hydroxypropan-2-yl) pyridin-1-ium-1-alkoxide (0.83 g,3.58mmol,2.00 eq.), cuI (0.34 g,1.79mmol,1.00 eq.) and Pd (PPh) ₃ ) ₂ Cl ₂ (0.25 g,0.35mmol,0.20 eq.) the mixture was stirred under nitrogen at 80℃for 2 hours. The reaction was monitored by LCMS. The mixture was brought to room temperature, then diluted with EtOAc (200 mL). With saturated NaHCO ₃ (aqueous solution) (2X 100 mL) the resulting mixture was washed. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the crude product. The crude product was isolated by preparative HPLC to give 4' - { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) (2H 2) methoxy group ]-6-methyl-2-oxopyridin-1-yl } -3' -fluoro-6- (2-hydroxy-prop-2-yl) -5' -methyl- [2,2' -bipyridine]-1-onium-1-alkoxide (140 mg, 11.00%). LC-MS (ES+H, M/z) [ M+H ]] ⁺ ＝549.2。 ¹ H NMR (300 MHz, chloroform-d) δ8.53 (s, 1H), 8.36 (d, 1H), 7.56 (dd, 1H), 7.49-7.39 (m, 2H), 7.34-7.26 (m, 1H), 6.46 (d, 1H), 2.20 (s, 3H), 2.10 (s, 3H), 1.67 (s, 3H), 1.63 (s, 3H).

Step 3: preparation of rel-4' - { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) (2H 2) methoxy]-6-methyl-2-oxo Substituted pyridin-1-yl } -3' -fluoro-6- (2-hydroxy-prop-2-yl) -5' -methyl- [2,2' -bipyridine]1-onium-1-alkoxide and rel-ene 4' - { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) (2H 2) methoxy]-6-methyl-2-oxopyridin-1-yl } -3' -fluoro-6- (2-hydroxy-prop-2-yl) -5 '-methyl- [2,2' -biPyridine compound]-1-onium-1-alkoxide：

The racemic mixture (140 mg) was separated by preparative chiral HPLC to give rel-4'- { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) (2H 2) methoxy ] -6-methyl-2-oxopyridin-1-yl } -3' -fluoro-6- (2-hydroxyprop-2-yl) -5 '-methyl- [2,2' -bipyridin ] -1-ium-1-alkoxide (example 68a:40.8mg,99.0% purity, ee=100.0%) and rel-4'- { 3-chloro-4- [ (3, 5-difluoropyridin-2-yl) (2H 2) methoxy ] -6-methyl-2-oxopyridin-1-yl } -3' -fluoro-6- (2-hydroxyprop-p-rop-2-yl) -5 '-methyl- [2,2' -bipyridin ] -1-ium-1-alkoxide (example 68b:40.3mg,98.2% purity, ee=100.0%) as a white solid.

Example 68A：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝549.25。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.70(s,1H),8.61(d,1H),8.14–8.04(m,1H),7.83(dd,1H),7.75(dd,1H),7.60(t,1H),6.89(d,1H),6.62(s,1H),2.17(s,3H),2.06(s,3H),1.61(s,3H),1.59(s,3H)。 ¹⁹ F NMR(282MHz,DMSO)δ-120.27,-120.29,-122.33,-122.36,-128.07。

Example 68B：

LC-MS:(ES+H,m/z):[M+H] ⁺ ＝549.20。 ¹ H NMR(300MHz,DMSO-d ₆ )δ8.70(s,1H),8.61(d,1H),8.17–8.01(m,1H),7.83(dd,1H),7.75(dd,1H),7.60(t,1H),6.89(d,1H),6.62(s,1H),2.17(s,3H),2.06(s,3H),1.61(s,3H),1.59(s,3H)。 ¹⁹ F NMR(282MHz,DMSO)δ-120.27,-120.29,-122.33,-122.36,-128.07。

Biological examples：

Protein expression and purification

Expression vectors for recombinant MK2 and PRAK kinases were constructed by cloning the codon optimized gene sequences of MK2 (Uniprot ID P49137, amino acid fragment F46-H400) or PRAK (Uniprot ID Q8IW41, amino acid fragment M1-Q471) into pGEX-4T1 (GE) to overexpress these kinases with an N-terminal GST tag. By growing the host in TB medium, it was grown with 0.5mM IPTG at about 0.8OD ₆₀₀ Inducing protein expression, then incubating the culture at 18℃for 14-20 hours, and then culturing in E.coliProtein expression was performed in BL 21. The harvested cells were resuspended in 100ml lysis buffer (50 mM Tris-HCl, pH8.0, 500mM NaCl, 1mM DTT, 5% glycerol and 1mM PMSF) per gram of wet cell mass and homogenized 3 times at 4℃in a microfluidizer (ATS, suzhou, china) at 14,000psi pressure. Cell lysates were clarified by centrifugation and the supernatant containing GST-fusion protein was purified by affinity chromatography using a GSH-Sepharose (GE) gravity flow column pre-equilibrated in buffer A (50 mM Tris-HCl, pH8.0, 500mM NaCl, 1mM DTT and 5% glycerol). After washing the column well with buffer A, bound GST-protein was eluted with buffer B (50 mM Tris, pH8.0, 500mM NaCl, 1mM DTT, 5% glycerol, 10mM glutathione) and then size exclusion purified on a Superdex 200 column equilibrated with buffer A. The purified protein was concentrated to about 1mg/ml and stored at-80 ℃.

Biochemical assay

This study evaluates the inhibitory potency of the compounds of the present invention on the p38/MK2 pathway and the p38/PRAK pathway. More specifically, the compound concentration (IC) that inhibited half of the maximum activation of MK2 or PRAK by p38 was determined ₅₀ ). MK2 activation studies were performed without or with a series of 10-point 1:3 dilutions of the compound of the invention at a maximum dose of 1 or 10. Mu.M, and PRAK activation studies were performed without or with a series of 10-point 1:3 dilutions of the compound of the invention at a maximum dose of 300. Mu.M. MK2 and PRAK activity were determined by the phosphorylation level of the FITC-conjugated HSP27 peptide.

Typical assays were performed in a volume of 20. Mu.L containing 60pM active p38α (Carna, catalog number 04-152), 10. Mu.M ATP, 1. Mu.MFITC-HSP 27 peptide (Sangon, catalog number P22354) and 1nM inactive MK2 or PRAK in 1 Xreaction buffer (20 mM HEPES, pH7.5, 10mM MgCl2, 1mM DTT, 0.01% Triton X-100, 0.01% BSA). After incubating the reaction mixture with various concentrations of the compound of the invention (200 nL) for 2 hours, 60 μl of 1XIMAP solution mixture (Molecular Devices, cat# R8127) was added to the reaction mixture and incubated for a further half hour. Then by Synergy with filter settings ^TM Neo2 multimode microplate reader read signal (Ex/em=485 nm/FITC FP-P pol 528nm andFITC FP-S pol 528nm)

the signals were then normalized to vehicle control and fitted in Xfit to generate IC ₅₀ . IC with formula "selectivity = PRAK ₅₀ IC for MK2 ₅₀ "to calculate MK2 selectivity over PRAK.

The data from the above assays are shown in Table 2.

TABLE 2

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Claims

1. A compound of formula (II) or a pharmaceutically acceptable salt, solvate, N-oxide or stereoisomer thereof:

wherein:

ring a is phenyl or heteroaryl;

or two R's on the same atom ^A Together forming oxo;

Or two R's on the same atom ^Aa Together forming oxo;

n is 0-4;

or R is ¹ And R is ² Together forming oxo;

x is-C (R) ³ ) ₂ -、-NR ⁴ -, -O-or-S-;

or two R ³ Together forming oxo;

R ⁷ is hydrogen, deuterium, halogen, -CN, -NO ₂ 、-OH、-OR ^a 、-NR ^c R ^d 、-C(＝O)R ^a 、-C(＝O)OR ^b 、-C(＝O)NR ^c R ^d 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkaneRadical, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, cycloalkyl or heterocycloalkyl;

ring B is heterocycloalkyl or heteroaryl;

or two R's on the same atom ^B Together forming oxo;

Or two R's on the same atom ^Ba Together forming oxo;

m is 0-4;

ring C is a 5 membered heteroaryl;

each R ^C Independently hydrogen, deuterium, halogen, -CN, -NO ₂ 、-OH、-OR ^a 、-OC(＝O)R ^a 、-OC(＝O)OR ^b 、-OC(＝O)NR ^c R ^d 、-SH、-SR ^a 、-S(＝O)R ^a 、-S(＝O) ₂ R ^a 、-S(＝O) ₂ NR ^c R ^d 、-S(＝O)(＝NR ^b )R ^a 、-SiR ^c R ^d OR ^b 、-NR ^c R ^d 、-NR ^b C(＝O)NR ^c R ^d 、-NR ^b C(＝O)R ^a 、-NR ^b C(＝O)OR ^b 、-NR ^b S(＝O) ₂ R ^a 、-C(＝O)R ^a 、-C(＝O)OR ^b 、-C(＝O)NR ^c R ^d 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (C) ₁ -C ₆ Alkyl) cycloalkyl, (C ₁ -C ₆ Alkyl) heterocycloalkyl, (C ₁ -C ₆ Alkyl) aryl or (C) ₁ -C ₆ Alkyl) heteroaryl; wherein said at least one ofThe alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally and independently substituted with one or more R ^Ca Substitution;

or two R's on the same atom ^Ca Together forming oxo;

p is 0-4;

each R ^a Independently C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁ -C ₆ Alkyl (cycloalkyl), C ₁ -C ₆ Alkyl (heterocycloalkyl), C ₁ -C ₆ Alkyl (aryl) or C ₁ -C ₆ Alkyl (heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl And heteroaryl are independently optionally substituted with 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 Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl or C ₁ -C ₆ Heteroalkyl substitution;

each R ^b Independently hydrogen, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁ -C ₆ Alkyl (cycloalkyl), C ₁ -C ₆ Alkyl (heterocycloalkyl), C ₁ -C ₆ Alkyl (aryl) or C ₁ -C ₆ Alkyl (heteroaryl); wherein the method comprises the steps of

Each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with 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 Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl or C ₁ -C ₆ Heteroalkyl substitution; and is also provided with

Each R ^c And R is ^d Independently hydrogen, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁ -C ₆ Alkyl (cycloalkyl), C ₁ -C ₆ Alkyl (heterocycloalkyl), C ₁ -C ₆ Alkyl (aryl) or C ₁ -C ₆ Alkyl (heteroaryl); wherein the method comprises the steps of

Each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with 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 Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl or C ₁ -C ₆ Heteroalkyl substitution;

provided that the compound is not

2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, wherein ring a is heteroaryl.

3. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, wherein ring a is pyridinyl.

4. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, wherein ring a is phenyl.

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, wherein each R ^A Independently halogen.

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, wherein N is 1 or 2.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, wherein R ¹ And R is ² Hydrogen or deuterium.

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, wherein X is-O-.

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, wherein R ⁵ Is hydrogen, deuterium, halogen, -CN, -OH, -OR ^a 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkynyl or cycloalkyl.

10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, wherein R ⁵ Is hydrogen, deuterium, halogen, -CN or C ₁ -C ₆ An alkyl group.

11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, wherein R ⁶ Is hydrogen, deuterium, halogen, -CN, -OH, -OR ^a 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkynyl or cycloalkyl.

12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, wherein R ⁶ Is hydrogen, deuterium, halogen, -CN or C ₁ -C ₆ An alkyl group.

13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, wherein R ⁷ Is hydrogen, deuterium, halogen, -CN, -OH, -OR ^a 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkynyl or cycloalkyl.

14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, wherein R ⁷ Is hydrogen, deuterium, halogen, -CN or C ₁ -C ₆ An alkyl group.

15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, wherein ring B is pyridinyl.

16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, wherein each R ^B Independently hydrogen, deuterium, halogen, -CN, -OH, -OR ^a 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkynyl or cycloalkyl.

17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, wherein each R ^B Independently halogen or C ₁ -C ₆ An alkyl group.

18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, wherein each R ^B Independently isC ₁ -C ₆ An alkyl group.

19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, wherein m is 1 or 2.

20. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, wherein ring C is thiazolyl, pyrazolyl, imidazolyl, oxazolyl, thiadiazole, or triazolyl.

21. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, wherein ring C is thiazolyl.

22. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, wherein ring C is pyrazolyl.

23. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, wherein ring C is imidazolyl.

24. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, wherein ring C is thiadiazole.

25. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, wherein ring C is triazolyl.

26. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, wherein each R ^C Independently hydrogen, deuterium, halogen, -CN, -OH, -OR ^a 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl or C ₁ -C ₆ A heteroalkyl group.

27. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, wherein each R ^C Independently C ₁ -C ₆ Hydroxyalkyl groups.

28. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, wherein p is 1 or 2.

29. A compound of formula (I) or a pharmaceutically acceptable salt, solvate, N-oxide or stereoisomer thereof:

wherein:

ring a is phenyl or heteroaryl;

or two R's on the same atom ^A Together forming oxo;

or two R's on the same atom ^Aa Together forming oxo;

n is 0-4;

or R is ¹ And R is ² Together forming oxo;

x is-C (R) ³ ) ₂ -、-NR ⁴ -, -O-or-S-;

or two R ³ Together forming oxo;

R ⁴ is hydrogen, -C (=O) R ^a 、-C(＝O)OR ^b 、-C(＝O)NR ^c R ^d 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkaneRadical, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, cycloalkyl or heterocycloalkyl;

z is N or CR ⁵ ；

ring B is cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

or two R's on the same atom ^B Together forming oxo;

or two R's on the same atom ^Ba Together forming oxo;

m is 0-4;

ring C is heterocycloalkyl or heteroaryl;

or two R's on the same atom ^C Together forming oxo;

or two R's on the same atom ^Ca Together forming oxo;

p is 0-4;

Each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently

Optionally substituted with 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 Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl or C ₁ -C ₆ Heteroalkyl substitution;

provided that it isNot->

30. The compound of claim 29, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, wherein ring a is heteroaryl.

31. The compound of claim 29, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, wherein ring a is pyridinyl.

32. The compound of any one of claims 26-31, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, wherein each R ^A Independently halogen.

33. The compound of any one of claims 26-32, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, wherein N is 1 or 2.

34. The compound of any one of claims 26-33, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, wherein R ¹ And R is ² Hydrogen or deuterium.

35. The compound of any one of claims 26-34, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, wherein X is-O-.

36. The compound of any one of claims 26-35, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, wherein R ⁵ Is hydrogen, deuterium, halogen, -CN, -OH, -OR ^a 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkynyl or cycloalkyl.

37. The compound of any one of claims 26-36, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, wherein R ⁵ Is hydrogen, deuterium, halogen, -CN or C ₁ -C ₆ An alkyl group.

38. The compound of any one of claims 26-37, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, wherein R ⁶ Is hydrogen, deuterium, halogen, -CN, -OH, -OR ^a 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl, C ₁ -C ₆ Heteroalkyl, C ₂ -C ₆ Alkynyl or cycloalkyl.

39. The compound of any one of claims 26-38, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, wherein R ⁶ Is hydrogen, deuterium, halogen, -CN or C ₁ -C ₆ An alkyl group.

40. The compound of any one of claims 26-39, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, wherein ring B is 6 membered heteroaryl.

41. The compound of any one of claims 26-40, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, wherein ring B is pyridinyl.

42. The compound of any one of claims 26-41, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, wherein each R ^B Is independently deuterium, halogen, -CN, -OH, -OR ^a 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₂ -C ₆ Alkynyl or cycloalkyl.

43. The compound of any one of claims 26-42, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, wherein each R ^B Independently halogen or C ₁ -C ₆ An alkyl group.

44. The compound according to any one of claims 26-43, or a pharmaceutically acceptable salt, solvate, N-oxide or stereoisomer thereof, wherein m is 1 or 2.

45. The compound of any one of claims 26-39, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, wherein Is->

46. The compound of any one of claims 26-39 or 45, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, whereinIs that

47. The compound of any one of claims 26-46, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, wherein ring C is 5 or 6 membered heteroaryl.

48. The compound of any one of claims 26-47, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, wherein ring C is pyrimidinyl.

49. The compound of any one of claims 26-48, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, wherein each R ^C Independently hydrogen, deuterium, halogen, -CN, -OH, -OR ^a 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl, C ₁ -C ₆ Aminoalkyl or C ₁ -C ₆ A heteroalkyl group.

50. The compound of any one of claims 26-49, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, wherein each R ^C Independently C ₁ -C ₆ Hydroxyalkyl groups.

51. The compound of any one of claims 26-50, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof, wherein p is 1 or 2.

52. A compound selected from the group consisting of the compounds found in table 1 or the specification, or a pharmaceutically acceptable salt, solvate, N-oxide or stereoisomer thereof.

53. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1-52, or a pharmaceutically acceptable salt, solvate, N-oxide or stereoisomer thereof, and a pharmaceutically acceptable excipient.

54. A method for treating a condition comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-52, 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, a oncological disorder, and a cardiovascular or cerebrovascular disorder.

55. A method of treating a p38 MAP kinase-mediated disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-52, or a pharmaceutically acceptable salt, solvate, N-oxide, or stereoisomer thereof.

56. A method of treating an MK 2-mediated disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1-52, or a pharmaceutically acceptable salt, solvate, N-oxide or stereoisomer thereof.