Terpyridine diketone compounds, or salts thereof, and methods for their preparation and use

Abstract

The present invention relates to a compound represented by general formula (I) or its racemate or its isomer or its medicamentous salt, which belongs to the field of chemical medicines, and which can be used as a p38 / MK2 inhibitor to inhibit the production of cytokine TNFα and to treat diseases such as arthritis. [Formula 1] JPEG2024508868000214.jpg111109

Description

[Technical field]

[0001] The present invention belongs to the technical field of chemical medicines, and relates to a terpyridine diketone compound, or its racemate, or its isomer, or its medicamentable salt, as well as its preparation method and use. [Background technology]

[0002] Mitogen-activated protein kinases (MAPKs) are a conserved family of enzymes that mediate and propagate external stimuli using phosphorylation cascades, resulting in coordinated cellular responses to the environment. MAPKs are proline-directed serine / threonine-specific protein kinases that regulate cellular activities such as gene expression, mitosis, differentiation, and cell survival / apoptosis. To date, four distinct mammalian MAPKs have been identified: extracellular signaling kinase (ERK1 and ERK2), c-jun N-terminal kinase-1 (JNK1-3), p38MAPK (p38α, p38β, p38γ, and p38δ), and ERK5.

[0003] Scientific exploration of this pathway from biological, cellular and in vivo perspectives is primarily driven by the availability of well-potent and selective small molecule inhibitors of p38MAPK that target the α subtype of p38MAPK and, to a lesser extent, the β subtype. p38αMAPK is the major subtype involved in immune and inflammatory responses. Its function is therefore critical for the production and activity of multiple pro-inflammatory cytokines in cells such as macrophages, monocytes, synoviocytes and endothelial cells. The pro-inflammatory cytokines include TNFα, IL-1, IL-6 and IL-8, for example COX2 and iNOS, which are the main sources of eicosanoids and nitric oxide, respectively, at sites of inflammation. In addition, the p38MAPK pathway regulates the expression of matrix metalloproteinases (MMPs), including MMP2, MMP9 and MMP13.

[0004] The use of selective and effective inhibitors has facilitated the discovery of several families of p38 MAPK substrates, including transcription factors, MAPKAP kinases, and other enzymes. MAPKAP kinases (MK2, MK-3, and PRAK) are selectively phosphorylated by p38 MAPK, whereas phosphorylation of MSK1 / 2, MNK1 / 2, and RSKb is catalyzed by both p38 MAPK and ERK. Activation of RSKb is thought to function in cell survival, although substrate identification is difficult due to the lack of specific inhibitors.

[0005] MK-2, MK-3 and PRAK share similar substrate specificity when phosphorylated and activated by p38 MAPK. All of these kinases can phosphorylate the small heat shock protein Hsp27. Studies have shown that PRAK- and MK3-deficient mice do not show any resistance to endotoxic shock or reduced cytokine production induced by lipopolysaccharide (LPS). In contrast, MK-2-deficient mice show resistance to endotoxic shock and impaired inflammatory responses, as well as a marked reduction in the production of cytokines such as TNFα, IFNγ and IL-6. Thus, the p38 / MK2 axis is specifically necessary and sufficient for the regulation of proinflammatory responses.

[0006] Taking advantage of the p38:MK2 interaction and using MK2 as a p38 substrate, novel inhibitors of p38α were discovered (Davidson et al.) that exhibit interesting properties. The inhibitors demonstrated substrate selectivity by inhibiting p38α-dependent phosphorylation of MK2 (Ki app 300nM) while preserving p38α-dependent phosphorylation of ATF2 (Ki app>20uM). Compared to conventional p38 ATP-competitive inhibitors that block p38-dependent phosphorylation of all p38 substrates, the novel inhibitors are unique in function. A second independent study also describes p38 inhibitors with unique mechanistic properties. This study shows a novel mechanism that selectively inhibits p38-dependent phosphorylation of MK2. Unlike Davidson et al.'s previous study, these mechanistically unique compounds compete with ATP and stabilize the p38 / MK2 complex.

[0007] Taken together, these two studies provide a clear proof of concept that selective p38 / MK2 axis blockade is achievable through the use of small molecule inhibitors. Compared to conventional p38 MAPK inhibitors, these p38 / MK2 inhibitors should retain or enhance efficacy and exhibit improved safety profiles in animal models of disease or in human clinical settings. Summary of the Invention

[0008] In view of the problems of the prior art, the present invention provides compounds that, as p38 / MK2 inhibitors, can inhibit the production of the cytokine TNFα, thereby regulating associated diseases such as inflammatory responses.

[0009] According to a first aspect, the present invention provides a compound of general formula (I), or a racemate thereof, or an isomer thereof, or a medicamentable salt thereof: [ka]

[0010] According to a second aspect, the present invention further provides a pharmaceutical composition comprising a therapeutically effective amount of any of the above compounds, or a pharma- ceutical acceptable salt thereof, and a pharma- ceutical acceptable carrier.

[0011] According to a third aspect, the present invention provides the use of a therapeutically effective amount of said compound or a pharma- ceutically acceptable salt thereof in the preparation of a medicament for treating a medical condition, wherein the medical condition is a p38 / MK2 associated disease and the compound is capable of modulating an associated disease such as an inflammatory response by inhibiting the production of the cytokine TNFα; in particular, the medical condition is selected from chronic inflammatory diseases, acute inflammatory diseases, and autoinflammatory diseases.

[0012] Specifically, the present invention is realized by the following embodiments. A compound represented by the general formula (I) or a racemate thereof, or an isomer thereof, or a medicamentable salt thereof, [ka] R 1 and R 1′ is independently selected from hydrogen, halogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an alkylcycloalkyl group, an alkylheterocycloalkyl group, a phenyl group, a heteroaryl group, a halogenated alkyl group, and a cyano group; or R 1 and R 1′ are cyclized together to form a cycloalkyl or heterocycloalkyl group; R 2 is selected from hydrogen, halogen, hydroxyl, cyano, alkyl, alkoxy, alkoxyalkyl, and halogenated alkyl; R 3 is independently selected from hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, a halogen, an alkoxy group, a cyano group, a halogenated alkoxy group, and a sulfonyl group; m is 0, 1, 2, or 3; R 4is selected from hydrogen, an alkyl group, a cycloalkyl group, an alkoxy group, and a halogenated alkyl group; R 5 is selected from hydrogen, an alkyl group, a cycloalkyl group, an alkoxy group, and a halogenated alkyl group; R 6 is selected from hydrogen, halogen, cyano, alkyl, cycloalkyl, and halogenated alkyl; Ring A is selected from aromatic rings and heteroaromatic rings; R 7 is independently selected from hydrogen, halogen, a cyano group, an alkyl group, a cycloalkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, and a sulfonyl group; n is 0, 1, 2, 3, 4, or 5; X is O, CH, or NH; R 8 , R 9 is independently selected from hydrogen, an alkyl group, a cycloalkyl group, an alkylcycloalkyl group, and a halogenated alkyl group, or R 8 and R 9 are compounds of general formula (I), or a racemic form thereof, or an isomer thereof, or a medicamentable salt thereof, characterized in that, taken together, they are cyclized to a cycloalkyl or heterocycloalkyl group.

[0013] In one preferred embodiment of the present invention, the alkyl group is 1-6 alkyl group, 1-6 the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, 1-ethylpropyl, 2-methylbutyl, tert-pentyl, 1,2-dimethylpropyl, isopentyl, neopentyl, n-hexyl, isohexyl, sec-hexyl, tert-hexyl, neohexyl, 2-methylpentyl, 1,2-dimethylbutyl, and 1-ethylbutyl; The alkoxy group is1-6 alkoxy groups, 1-6 the alkoxy group is selected from methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, sec-pentyloxy, 1-ethylpropoxy, 2-methylbutoxy, tert-pentyloxy, 1,2-dimethylpropoxy, isopentyloxy, neopentyloxy, n-hexyloxy, isohexyloxy, sec-hexyloxy, tert-hexyloxy, neohexyloxy, 2-methylpentyloxy, 1,2-dimethylbutoxy, and 1-ethylbutoxy; The alkoxyalkyl group is 1-4 Alkoxy C 1-4 alkyl groups, and further selected from methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, butoxymethyl, butoxyethyl, butoxypropyl, and butoxybutyl groups.

[0014] In one preferred embodiment of the present invention, the cycloalkyl group is 3-6 cycloalkyl groups, C 3-6 The cycloalkyl groups are selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups.

[0015] In one preferred embodiment of the present invention, the aromatic ring is selected from a 4-membered ring, a 4-membered ring-containing fused ring, a 5-membered ring, a 5-membered ring-containing fused ring, a 6-membered ring, a 6-membered ring-containing fused ring, and a biphenyl-type aromatic ring; the heteroaromatic ring means that one or more carbon atoms of the aromatic ring are replaced by heteroatoms. The aromatic ring includes a benzene ring and a naphthalene ring; The heteroaromatic ring may be selected from the group consisting of indazole, quinoline, isoquinoline, quinoxaline, indole, isoindole, cinnoline, quinazoline, phthalazine, purine, naphthyridine, pteridine, benzofuran, benzothiophene, benzoxazole, benzothiazole, benzisoxazole, benzisothiazole, benzoxadiazole, benzothiadiazole, benzotriazole, benzotriazine, benzimidazole, pyrazinopyrazole, pyrazinopyrimidine, pyrazinopyridazine, pyrazinotriazine, pyrimidopyrazole, pyrimidoimidazole, pyrimidotriazole, pyrimidotriazine, pyrimidopyridazine, pyridazinoimidazole, pyridazinopyrazole, pyridazinotriazole, pyridazinotriazine, triazinoimidazole, triazinopyrazole, triazinotriazole, pyridoxazole, pyridothiazole, pyridoisoxazole, pyridoisothiazole, pyrido pyridazinooxazole, pyridothiadiazole, pyridofuran, pyridopyrrole, pyrazinooxazole, pyrazinothiazole, pyrazinoisoxazole, pyrazinoisothiazole, pyrazinooxadiazole, pyrazinothiadiazole, pyrazinofuran, pyrazinopyrrole, pyrimidooxazole, pyrimidothiazole, pyrimidoisoxazole, pyrimidoisothiazole, pyrimidooxadiazole, pyrimidothiadiazole, pyrimidofuran, pyrimidopyrrole, pyridazinooxazole, pyridazinothiazole, pyridazinoisoxazole, pyridazinoisothiazole, pyridazinooxadiazole, pyridazinothiadiazole, pyridazinofuran, pyridazinopyrrole, triazinooxazole, triazinothiazole, triazinoisoxazole, triazinoisothiazole, triazinooxadiazole, triazinothiadiazole, triazinofuran, and triazinopyrrole. Specifically, for example, the naphthyridine is [ka] wherein the pyridoimidazole is selected from [ka] wherein the pyrazinoimidazole is selected from [ka] wherein the pyrazinotriazole is selected from [ka] wherein the pyrimidopyrazole is selected from [ka] wherein the pyrimidoimidazole is selected from [ka] wherein the pyrimidotriazole is selected from [ka] wherein the pyridazinoimidazole is selected from [ka] wherein the pyridazinotriazole is selected from [ka] wherein the triazinoimidazole is selected from [ka] wherein the pyridopyridazine is selected from [ka] wherein the pyridopyrazole is selected from [ka] wherein the pyridopyrimidine is selected from [ka] The pyridotriazine is selected from [ka] and the pyrimidotriazine is selected from [ka] is selected from. Specifically, for example, the heterocycloalkyl group is [ka] Selected from; The heteroaryl group is [ka] is selected from.

[0016] In one preferred embodiment of the invention, the halogen is selected from fluorine, chlorine, bromine, and iodine; A halogenated alkyl group means that one or more hydrogen atoms of an alkyl group are replaced with a halogen, and a halogenated alkoxy group means that one or more hydrogen atoms of an alkoxy group are replaced with a halogen; A heterocycloalkyl group means that one or more carbon atoms of a cycloalkyl group is replaced with a heteroatom. An alkylcycloalkyl group means that one or more hydrogen atoms of a cycloalkyl group are replaced by an alkyl group, and an alkylheterocycloalkyl group means that one or more hydrogen atoms of the heterocycloalkyl group are replaced by an alkyl group.

[0017] In one preferred embodiment of the invention, the heteroatoms are selected from nitrogen, oxygen, and sulfur, and there are one or more heteroatoms.

[0018] In one preferred embodiment of the present invention, the A ring is [ka] is selected from.

[0019] In one preferred embodiment of the invention, the compound, or a racemate thereof, or an isomer thereof, or a medicamentable salt thereof, has the structure of Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (If), or Formula (Ig). [ka] m is 0, 1, 2, or 3; n is 0, 1, 2, 3, 4, or 5; R 1 , R 1′ , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 is as defined above.

[0020] In one preferred embodiment of the invention, m is 0 or 1; n is 0, 1, or 2; The A ring is [ka] Selected from; R 1 , R 1′ is selected from hydrogen, a methyl group, an ethyl group, or R 1 and R 1′ Together, [ka] cyclized to; R 2 is selected from hydrogen, hydroxyl, difluoromethyl, and cyano; R 3 is selected from hydrogen, a methyl group, a methoxy group, chlorine, and bromine; R 4is selected from a methyl group, a cyclopropyl group, a methoxy group, an ethyl group, a fluoromethyl group, and a trifluoromethyl group; R 5 is selected from a methyl group; R 6 is selected from chlorine, hydrogen, and bromine; R 7 is selected from hydrogen, fluorine, chlorine, bromine, a cyclopropyl group, a methoxy group, a cyano group, a methyl group, and a trifluoromethyl group; R 8 , R 9 is hydrogen.

[0021] In one preferred embodiment of the invention, the compound, or a racemate thereof, or an isomer thereof, or a medicamentable salt thereof, is [ka] JPEG0007648043000025.jpg165129JPEG0007648043000026.jpg204129JPEG0007648043000027.jpg164129JPEG0007648043000028.jpg172129JPEG0007648043000029.jpg123129 is selected.

[0022] In one preferred embodiment of the present invention, the pharma- ceutically acceptable salt is prepared from the compound, or a racemate thereof, or an isomer thereof, or a medicamentable salt thereof, and a pharma- ceutically acceptable acid or base.

[0023] In one preferred embodiment of the invention, one or more hydrogen atoms of the compound, or a racemate thereof, or an isomer thereof, or a medicamentable salt thereof, are replaced with a deuterium isotope.

[0024] The present invention further provides a pharmaceutical composition comprising a therapeutically effective amount of the compound, or a racemate thereof, or an isomer thereof, or a medicamentable salt thereof, and a pharma- ceutically acceptable carrier.

[0025] The present invention further provides the use of said compound, or its racemate, or its isomer, or its medicament salt, in the preparation of a medicament for treating a disease, wherein said disease is a p38 / MK2 associated disease, specifically selected from chronic inflammatory diseases and acute inflammatory diseases, with the chronic inflammatory disease being preferably rheumatoid arthritis.

[0026] Compared to prior art compounds, the compounds of the present invention have improved TNFα activity, solubility and in vivo PK effects.

[0027] For the sake of clarity, general terms used in the description of compounds are defined herein.

[0028] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. Certain terms or phrases, unless otherwise defined, are to be understood in their general sense, rather than indefinite or uncertain. Trade names appearing herein are intended to mean the corresponding commercial product, or its active ingredients. As used herein, "pharmaceutical acceptable" means those compounds, materials, compositions and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reaction, or other problem or complication, and are consistent with a reasonable benefit / risk ratio.

[0029] The term "pharmaceutical salt" refers to a salt of a compound of the present invention, prepared from a compound having a particular substituent in the present invention and a pharma- ceutically acceptable acid or base.

[0030] In addition to salt forms, the compounds provided by the present invention also exist in prodrug forms. Prodrugs of the compounds described herein are easily converted to the compounds of the present invention under physiological conditions through chemical changes. Also, precursor drugs can be converted to the compounds of the present invention by chemical or biochemical methods in the in vivo environment.

[0031] Some compounds of the present invention can exist in unsolvated or solvated forms, including hydrated forms. In general, the solvated forms correspond to the unsolvated forms, and both are included within the scope of the present invention.

[0032] The compounds of the present invention can exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, atropisomers, and racemic and other mixtures thereof, such as mixtures enriched in enantiomers or diastereomers, all of which are within the scope of the present invention. Substituents such as alkyl groups may have other asymmetric carbon atoms. All of these isomers and mixtures thereof are within the scope of the present invention.

[0033] Optically active (R)- and (S)-isomers, D- and L-isomers, and atropisomers, etc., can be prepared by chiral synthesis or chiral agents or other conventional techniques. Enantiomers of certain compounds of the invention can be prepared by asymmetric synthesis or derivatization with chiral auxiliaries. The resulting mixture of diastereomers is separated and the auxiliary is cleaved to provide the pure desired enantiomer. Alternatively, if the molecule contains a basic (e.g., amino) or acidic (e.g., carboxyl) functional group, the salt of the diastereomer is formed with an appropriate optically active acid or base, and then the non-diastereomers are resolved by conventional methods known in the art and then recovered to obtain the pure enantiomers. Separation of enantiomers and diastereomers is also generally accomplished by chromatographic methods. The above chromatographic methods use chiral stationary phases, optionally coupled with chemical derivatization methods (e.g., carbamates from amines).

[0034] The atoms of the molecules of the compounds of the present invention are isotopes, and isotope derivatization can usually have the effects of extending half-life, decreasing removal rate, stabilizing metabolism, and increasing activity in the body.In one embodiment, at least one atom is replaced with an atom having the same atomic number (proton number) and a different mass number (sum of protons and neutrons).Examples of isotopes contained in the compounds of the present invention include hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms, phosphorus atoms, sulfur atoms, fluorine atoms, and chlorine atoms, which are respectively: 2 H, 3 H, 13 C. 14 C. 15 N, 17 O. 18 O. 31 P, 32 P, 35 S, 18 F, 36 In particular, radioisotopes that emit radiation upon decay, such as 3 H or 14 C can be used for pharmaceutical preparations or local anatomical examination of compounds in vivo. Stable isotopes do not decay or change according to their amount, and are not radioactive, so they can be used safely. When the atoms constituting the molecules of the compounds of the present invention are isotopes, the isotopes can be converted by general methods by using a reagent containing the corresponding isotope instead of the reagent used for synthesis.

[0035] The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, deuterium ( 2 H), iodine-125( 125 I) or C-14( 14 Compounds can be labeled with radioactive isotopes, such as C. All variations in the isotopic composition of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0036] Additionally, the compounds of the present invention may contain one or more hydrogen atoms that are isotopes of deuterium ( 2H), the compounds of the present invention have the effects of extending the half-life, reducing the elimination rate, stabilizing the metabolism, and enhancing the activity in the body after deuteration.

[0037] The method for producing the isotope derivative usually includes a phase transfer catalyst method. For example, a preferred deuteration method uses a phase transfer catalyst (e.g., tetraalkylammonium salt, NBu4HSO4). Compared with using deuterated silane (e.g., triethyldeuterated silyl) in the presence of acid (e.g., methanesulfonic acid) or employing reduction of sodium deuterated borate with Lewis acid such as aluminum trichloride, exchanging methylene protons of diphenylmethane compounds with a phase transfer catalyst introduces relatively high deuterium.

[0038] The term "pharmaceutical acceptable carrier" refers to any formulation carrier or vehicle that delivers an effective amount of the active agent of the present invention, does not inhibit the biological activity of the active agent, and has no toxicity or side effects on the host or patient, and representative carriers include water, oil, vegetable and mineral, salve base, lotion base, ointment base, etc. These bases include suspending agents, viscosity modifiers, transdermal enhancers, etc. These formulations are known to those skilled in the art of cosmetics or topical medicine. For other information regarding carriers, see Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.

[0039] The term "excipient" generally refers to a carrier, diluent and / or vehicle necessary to prepare an effective pharmaceutical composition.

[0040] For a drug or pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of drug or agent used that is non-toxic but capable of achieving the desired effect. For an oral dosage form in the present invention, the "effective amount" of one active agent in the composition refers to the amount required to obtain the desired effect when used in combination with another active agent in the composition. The determination of the effective amount varies from person to person and depends on the age and general condition of the recipient, and also on the specific active agent, and the appropriate effective amount in each individual case can be determined by one skilled in the art based on routine testing.

[0041] The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to chemical entities that can effectively treat a targeted disorder, disease, or condition.

[0042] "Optional" or "optionally" means that a subsequently described event or circumstance may, but need not, occur, and the description includes instances when the event or circumstance occurs as well as instances when the event or circumstance does not occur.

[0043] [ka] represents a connecting bond.

[0044] The compounds of the present invention can be prepared by various synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combination with other chemical synthetic methods, and equivalent alternatives known to those skilled in the art, and preferred embodiments include, but are not limited to, those of the present invention. [Brief description of the drawings]

[0045] [Figure 1] FIG. 1 is a schematic diagram of the crystal structure of a single molecule of compound 1A. [Diagram 2] FIG. 2 is a crystal parameter diagram of the crystal structure of Compound 1A. [Diagram 3] FIG. 2 is a diagram showing atomic coordinates and isotropic displacement parameters of the crystal structure of compound 1A. [Figure 4] FIG. 1 is a bond length parameter diagram of the crystal structure of compound 1A. [Diagram 5] This is a bond angle parameter diagram of the crystal structure of compound 1A. [Figure 6] FIG. 2 is a diagram showing dihedral angle parameters of the crystal structure of compound 1A. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0046] The present invention will be described in more detail below using examples, but the embodiments of the present invention are not limited to these.

[0047] Example 1 [ka] The synthetic route for compound No. 1 is as follows. Step A: Synthesis of 2-(bromomethyl)-3,5-difluoropyridine. [ka] Triphenylphosphine (PPh3, 813.5 mg, 3.11 mmol) and carbon tetrabromide (CBr4, 823.8 mg, 2.48 mmol) were added sequentially to tetrahydrofuran (THF, 5.0 ml) containing (3,5-difluoro-2-pyridine)methanol (300.0 mg, 2.07 mmol) at 0°C, and the mixture was allowed to react at room temperature (rt) for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 10 / 1). 372.4 mg of 2-(bromomethyl)-3,5-difluoropyridine (yield: 86.5%) was obtained as a colorless oil. LC-MS: RT = 1.89 min, [M + H] + =208.01. Step B: Synthesis of 3″-chloro-4″-((3,5-difluoropyridin-2-yl)methoxy)-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione. [ka] 2-(Bromomethyl)-3,5-difluoropyridine (37.4 mg, 0.18 mmol) and potassium carbonate (K2CO3, 33.12 mg, 0.24 mmol) were added to N,N-dimethylformamide (DMF, 2.0 ml) containing 3″-chloro-4″-hydroxy-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione (50.0 mg, 0.12 mmol) at room temperature, and the mixture was allowed to react at room temperature for 2 hours. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 ml x 3 times). The organic phases were combined, washed with saturated saline (20 ml x 2 times), dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 0). 28.0 mg of 3″-chloro-4″-((3,5-difluoropyridin-2-yl)methoxy)-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione (yield: 53.7%) was obtained as a white solid. LC-MS: RT=1.86min, [M+H] + =529.22. 1 HNMR(400MHz,DMSO)δ8.68(s,1H),8.60(d,J=2.3Hz,1H),8.13-8.05(m,1H),7.85(dd,J=6.9,2.1Hz,1H),7.78(s,1H),7.69(dd,J=7.0, 2.1Hz,1H),6.79(s,1H),6.42(t,J=7.0Hz,1H),5.47(d,J=1.6Hz,2H),5.22(s,1H),2.07(s,3H),2.00(s,3H),1.47(s,3H),1.46(s,3H). Using supercritical fluid chromatography (AS-H column), the racemic compound of Example 1 was separated with a mobile phase of carbon dioxide and isopropanol, and the atropisomers of Compounds 1A and 1B of Examples were eluted in that order. [ka] Example 1A compound: RT=4.21 min (SFC, AS-H, 0.46 cm I.D.×15 cm L column, isogradient method with 30% isopropanol, flow rate 2.5 mL / min and cycle time 10 min); [a] D 25= -1.68 ° (MeOH,Rudolph Autopol I automatic polarimeter); 1 HNMR(400MHz,DMSO)δ8.68(s,1H),8.59(d,J=2.3Hz,1H),8.11-8.05(m,1H),7.85(dd,J=6.9,2.0Hz,1H),7.79(s,1H),7.69(dd,J=7.0, 2.0Hz,1H),6.80(s,1H),6.42(t,J=6.9Hz,1H),5.48(d,J=1.2Hz,2H),5.23(s,1H),2.07(s,3H),2.00(s,3H),1.47(s,3H),1.46(s,3H). A schematic diagram of the crystal structure of a single molecule is shown in FIG. 1, a crystal parameter diagram of the crystal structure is shown in FIG. 2, an atomic coordinate and isotropic displacement parameter diagram of the crystal structure is shown in FIG. 3, a bond length parameter diagram of the crystal structure is shown in FIG. 4, a bond angle parameter diagram of the crystal structure is shown in FIG. 5, and a dihedral angle parameter diagram of the crystal structure is shown in FIG. 6. Example 1B compound: RT=4.68 min (SFC, AS-H, 0.46 cm ID×15 cm L column, isogradient of 30% isopropanol, flow rate 2.5 mL / min and cycle time 10 min). D 25 +1.64 ° (MeOH,Rudolph Autopol I automatic polarimeter); 1HNMR(500MHz,DMSO)δ8.68(s,1H),8.59(d,J=2.3Hz,1H),8.11-8.06(m,1H),7.85(dd,J=6.9,2.1Hz,1H),7.78(s,1H),7.69(dd,J=7.0, 2.1Hz,1H),6.80(s,1H),6.42(t,J=6.9Hz,1H),5.47(d,J=1.3Hz,2H),5.24(s,1H),2.07(s,3H),2.00(s,3H),1.47(s,3H),1.46(s,3H).

[0048] Example 2 [ka] The synthetic route for compound No. 2 is as follows. Step A: Synthesis of 2′-chloro-4-hydroxy-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one. [ka] At room temperature, 2-chloro-5-methylpyridin-4-amine (2.3 g, 1.61 mmol) was dissolved in dioxane (Dioxane, 40.0 ml), 2,2-dimethyl-6-(2-oxopropyl)-4H-1,3-dioxin-4-one (2.0 g, 1.07 mmol) was added, the temperature was raised to 90°C, and the reaction was carried out for 5 hours. 10N aqueous sulfuric acid solution was added dropwise, and the reaction was continued for 2 hours since no solid was produced. After the reaction was complete, the solvent was removed by rotary evaporation, and an appropriate amount of water was added to precipitate a pale yellow precipitate. The precipitate was stirred for 0.5 hours, filtered, and washed twice with water to obtain the product, 2'-chloro-4-hydroxy-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one (yield: 30.9%) as an ocher solid, 1.25 g. LC-MS: RT=1.65 min, [M+H] + =251.09. Step B: Synthesis of 2′-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one. [ka] At room temperature, 2-(bromomethyl)-3,5-difluoropyridine (1.55 g, 7.47 mmol) and potassium carbonate (1.37 g, 9.96 mmol) were added to N,N-dimethylformamide (15.0 ml) containing 2'-chloro-4-hydroxy-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one (1.25 g, 4.98 mmol), and the mixture was allowed to react at room temperature for 2 hours. After the reaction was completed, the mixture was quenched by adding water, extracted with ethyl acetate (30 ml x 3 times), and the organic phases were combined, washed with saturated saline (20 ml x 2 times), dried over anhydrous sodium sulfate, and concentrated. The residue obtained was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 0). 1.08 g of pale yellow solid 2'-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one (yield: 57.4%) was obtained. LC-MS: RT = 1.91 min, [M + H] + =378.24. Step C: Synthesis of 4″-((3,5-difluoropyridin-2-yl)methoxy)-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione. [ka] At room temperature, 2'-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one (100.0 mg, 0.26 mmol), 3-(2-hydroxypropan-2-yl)pyridin-2(1H)-one (60.1 mg, 0.39 mmol), cuprous iodide (CuI, 9.5 mg, 0.05 mmol) and potassium carbonate (71.8 mg, 0.52 mmol) were dissolved in dioxane (2.0 ml), N,N-dimethylethylenediamine was added dropwise, and the mixture was heated to 110 ° C. and subjected to microwave reaction for 1 hour. The reaction was completed, and the mixture was filtered under suction, rinsed with dichloromethane, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane=1 / 0). 26.0 mg of a white solid, 4″-((3,5-difluoropyridin-2-yl)methoxy)-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione (yield: 20.2%), was obtained. LC-MS:RT=1.82min, [M+H] + =495.24. 1 HNMR(400MHz,DMSO)δ8.64(s,1H),8.59(d,J=2.4Hz,1H),8.07(ddd,J=10.0,9.3,2.4Hz,1H),7.84(dd,J=6.9,2.1Hz,1H),7.70(s,1H),7.70-7.66(m,1 H),6.41(t,J=6.9Hz,1H),6.13(d,J=1.7Hz,1H),6.04(d,J=2.5Hz,1H),5.2 5(s,2H),5.22(s,1H),2.08(s,3H),1.90(s,3H),1.47(s,3H),1.46(s,3H).

[0049] Example 3 [ka] The synthetic route for compound No. 3 is as follows. Step A: Synthesis of 2-bromomethylpyridine. [ka] Triphenylphosphine (813.5 mg, 3.11 mmol) and carbon tetrabromide (823.8 mg, 2.48 mmol) were added to tetrahydrofuran (5.0 ml) containing 2-pyridinemethanol (225.6 mg, 2.07 mmol) at 0° C., and the mixture was allowed to react at room temperature for 1 hour. The reaction was completed and concentrated. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate=10 / 1). 322.3 mg of 2-bromomethylpyridine (yield: 90.5%) was obtained as a colorless oil. Step B: Synthesis of 3″-chloro-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-4″-((pyridin-2-yl)methoxy)-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione. [ka] 2-Bromomethylpyridine (31.0 mg, 0.18 mmol) and potassium carbonate (33.12 mg, 0.24 mmol) were added to N,N-dimethylformamide (2.0 ml) containing 3″-chloro-4″-hydroxy-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione (50.0 mg, 0.12 mmol) at room temperature, and the mixture was allowed to react at room temperature for 2 hours. After the reaction was completed, the mixture was quenched by adding water, extracted with ethyl acetate (20 ml x 3 times), and the organic phases were combined, washed with saturated saline (20 ml x 2 times), dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 0). 29.0 mg of a white solid was obtained, synthesizing 3"-chloro-3-(2-hydroxypropan-2-yl)-5',6"-dimethyl-4"-((pyridin-2-yl)methoxy)-2H,2"H-[1,2':4',1"-terpyridine]-2,2"-dione (yield: 49.0%). LC-MS: RT=1.77min, [M+H] + =493.34. Nuclear magnetic resonance data: 1HNMR(400MHz,DMSO-d6)δ8.67(s,1H),8.61-8.58(m,1H),7.91(td,J=7.7,1.8H z,1H),7.84(dt,J=5.5,2.8Hz,1H),7.77(s,1H),7.68(dd,J=7.0,2.1Hz,1H),7. 58(d,J=7.8Hz,1H),7.39(dd,J=7.0,5.3Hz,1H),6.76(s,1H),6.41(t,J=6.9Hz, 1H),5.42(s,2H),5.21(s,1H),2.06(s,3H),1.99(s,3H),1.45(d,J=4.1Hz,6H).

[0050] Example 4 [ka] The synthetic route for compound No. 4 is as follows. Step A: Synthesis of 2,2-dimethyl-6-(2-oxopropyl)-4H-1,3-dioxin-4-one. [ka] At room temperature, 2,2,6-trimethyl-4H-1,3-dioxin-4-one (30g, 211.27mmol) was dissolved in tetrahydrofuran (100ml), protected with nitrogen gas, cooled to -70℃, added lithium bis(trimethylsilyl)amide (LiHMDS, 290ml, 1M) dropwise and reacted for 2 hours; added diethylzinc (ZnEt2, 290ml, 1M) and reacted for 0.5 hours; slowly raised to -20℃ within 1.5 hours, added 1-acetylimidazole (28g, 253.52mmol) and reacted for 3 hours. After the reaction was completed, the reaction mixture was poured into ice water to quench the reaction, adjusted to pH=3-4 with 6N hydrochloric acid, extracted with ethyl acetate (50ml x 3 times), the organic phases were combined, dried, and purified by column chromatography (eluent: n-hexane / ethyl acetate=4 / 1) to obtain 19g of yellow solid 2,2-dimethyl-6-(2-oxopropyl)-4H-1,3-dioxin-4-one (yield: 49%). LC-MS: RT=1.65min, [M+H] +=185.13. Step B: Synthesis of 2′-bromo-4-hydroxy-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one. [ka] At room temperature, 2-bromo-5-methylpyridin-4-amine (5 g, 26.74 mmol) was dissolved in dioxane (100 ml), 2,2-dimethyl-6-(2-oxopropyl)-4H-1,3-dioxin-4-one (5.9 g, 32.09 mmol) was added, the temperature was raised to 90°C, and the reaction was carried out for 5 hours. 10N aqueous sulfuric acid solution was added dropwise, and the reaction was continued for 2 hours since no solid was produced. After the reaction was complete, the mixture was concentrated to remove the solvent, and water was added to precipitate a pale yellow precipitate. The precipitate was stirred for 0.5 hours, filtered, and washed twice with water to obtain 6 g of the product 2'-bromo-4-hydroxy-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one (yield: 76%) as an ocher solid. LC-MS: RT=1.66 min, [M+H] + =295.11. Step C: Synthesis of 2′-bromo-3-chloro-4-hydroxy-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one. [ka] At room temperature, 2'-bromo-4-hydroxy-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one (200 mg, 0.68 mmol) was dissolved in isopropanol (Propan-2-ol, 5 ml), and NCS (N-chlorosuccinimide, 62 mg, 0.37 mmol) and one drop of dichloroacetic acid (2,2-dichloroacetic acid) were added. The mixture was heated to 60°C and reacted for 6 hours. After the reaction was completed, it was quenched by adding water, extracted with ethyl acetate, the organic phases were combined, dried and evaporated to dryness on a rotary evaporator, and purified by column chromatography (ethyl acetate) to obtain 100 mg of the product 2'-bromo-3-chloro-4-hydroxy-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one (yield: 83%) as a white solid. LC-MS: RT=1.68 min, [M+H] + =329.06. Step D: Synthesis of 3-(2-hydroxypropan-2-yl)pyridin-2(1H)-one. [ka] A solution of methylmagnesium bromide (CHMgBr) in tetrahydrofuran (5.47 ml, 1 mol / 1 ml) was added dropwise to tetrahydrofuran (5.0 ml) containing 3-acetyl-2(1H)-pyridinone (500.0 mg, 3.65 mmol) at -78°C, and the mixture was allowed to react for 3 hours after slowly warming to room temperature. After the reaction was completed, the reaction mixture was quenched by adding water, and extracted with a mixture of dichloromethane and isopropanol (dichloromethane / isopropanol=3 / 1, 30ml x 5 times). The organic phases were combined, washed with saturated saline (30ml x 2 times), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol=10 / 1). 496.0mg of 3-(2-hydroxypropan-2-yl)pyridin-2(1H)-one (yield: 19.0%) was obtained as a white solid. LC-MS: RT=1.33min, [M+H] + =154.14. Step E: Synthesis of 3″-chloro-4″-hydroxy-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione. [ka] At room temperature, 2'-bromo-3-chloro-4-hydroxy-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one (100.0 mg, 0.30 mmol), 3-(2-hydroxypropan-2-yl)pyridin-2(1H)-one (93 mg, 0.61 mmol), cuprous iodide (12 mg, 0.06 mmol) and potassium carbonate (84 mg, 0.61 mmol) were dissolved in dioxane (4 ml), one drop of dimethylethylenediamine was added, and the mixture was heated to 100 ° C. and subjected to a microwave reaction for 1 hour. After the reaction was completed, it was filtered and washed with ethyl acetate, and the filtrate was dried on a rotary evaporator and purified on a column (ethyl acetate) to obtain 67 mg of the product 3″-chloro-4″-hydroxy-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione (yield: 55%) as a white solid. LC-MS: RT=1.70 min, [M+H] + =402.20. Step F: Synthesis of 3″-chloro-4″-((2,4-difluorobenzyl)oxy)-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione. [ka] 4-Chloro-2-fluorobenzyl bromide (36 mg, 0.17 mmol) and potassium carbonate (24 mg, 0.17 mmol) were added to N,N-dimethylformamide (2.0 ml) containing 3″-chloro-4″-hydroxy-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione (35 mg, 0.09 mmol) at room temperature, and the mixture was allowed to react at room temperature for 1 hour. After the reaction was completed, the mixture was quenched by adding water, extracted with ethyl acetate (20 ml x 3 times), and the organic phases were combined, washed with saturated saline (20 ml x 2 times), dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 0). 11.0 mg of 3"-chloro-4"-((2,4-difluorobenzyl)oxy)-3-(2-hydroxypropan-2-yl)-5',6"-dimethyl-2H,2"H-[1,2':4',1"-terpyridine]-2,2"-dione (yield: 24%) was obtained as a white solid. LC-MS: RT = 1.95 min, [M+H] + =528.13.

[0051] Example 5 [ka] The synthetic route for compound No. 5 is as follows. Step A: Synthesis of 2-(bromomethyl)-3-fluoro-5-chloropyridine. [ka] At 0° C., triphenylphosphine (325 mg, 1.24 mmol) and carbon tetrabromide (406 mg, 1.24 mmol) were added to tetrahydrofuran (5.0 ml) containing (3-fluoro-5-chloropyridine-2-pyridine)methanol (200 mg, 1.24 mmol), and the mixture was allowed to react at room temperature for 1 hour. The reaction was completed and concentrated. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate=10 / 1). 142 mg of colorless oily substance 2-(bromomethyl)-3-fluoro-5-chloropyridine (yield: 51%) was obtained. Step B: Synthesis of 3″-chloro-4″-((3-fluoro-5-chloropyridin-2-yl)methoxy)-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione. [ka] 2-(Bromomethyl)-3-fluoro-5-chloropyridine (38 mg, 0.17 mmol) and potassium carbonate (24 mg, 0.17 mmol) were added to N,N-dimethylformamide (2.0 ml) containing 3″-chloro-4″-hydroxy-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione (35 mg, 0.09 mmol) at room temperature, and the mixture was allowed to react at room temperature for 1 hour. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 ml x 3 times). The organic phases were combined, washed with saturated saline (20 ml x 2 times), dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 0). 14 mg of white solid 3"-chloro-4"-((3-fluoro-5-chloropyridin-2-yl)methoxy)-3-(2-hydroxypropan-2-yl)-5',6"-dimethyl-2H,2"H-[1,2':4',1"-terpyridine]-2,2"-dione (yield: 53.7%) was obtained. LC-MS: RT=1.91 min, [M+H] + =545.17.

[0052] Example 6 [ka] The synthetic route for compound number 6 is as follows. Step A: Synthesis of 2-bromomethylpyridazine. [ka] Triphenylphosphine (813.5 mg, 3.11 mmol) and carbon tetrabromide (823.8 mg, 2.48 mmol) were added to tetrahydrofuran (5.0 ml) containing 2-pyridazinemethanol (227.7 mg, 2.07 mmol) at 0° C., and the mixture was allowed to react at room temperature for 1 hour. The reaction was completed and concentrated. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate=10 / 1). 328.5 mg of 2-bromomethylpyridazine (yield: 91.7%) was obtained as a colorless oil. Step B: 3″-chloro-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-4″-((pyridazin-3-yl)methoxy)-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione. [ka] 2-Bromomethylpyridazine (31.1 mg, 0.18 mmol) and potassium carbonate (33.1 mg, 0.24 mmol) were added to N,N-dimethylformamide (2.0 ml) containing 3″-chloro-4″-hydroxy-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione (50.0 mg, 0.12 mmol) at room temperature, and the mixture was allowed to react at room temperature for 2 hours. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 ml x 3 times). The organic phases were combined, washed with saturated saline (20 ml x 2 times), dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 0). 30.5 mg of 3″-chloro-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-4″-((pyridazin-3-yl)methoxy)-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione (yield: 51.4%) was obtained as a white solid. LC-MS:RT=1.68min, [M+H] + =494.26. Nuclear Magnetic Resonance Data: 1HNMR(400MHz,DMSO-d6)δ9.26(dd,J=4.7,1.8Hz,1H),8.68(s,1H),7.88-7.82(m,3H),7.77(s,1H),7.68(dd,J=7.0,2.0 Hz,1H),6.82(s,1H),6.41(t,J=6.9Hz,1H),5.65(s,2H),5.21(s,1H),2.07(s,3H),2.00(s,3H),1.45(d,J=4.0Hz,6H).

[0053] Example 7 [ka] The synthetic route for compound No. 7 is as follows. Step A: Synthesis of 3″-chloro-3-(2-hydroxypropan-2-yl)-4″-((3-methoxypyridin-2-yl)methoxy)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione. [ka] 2-(Bromomethyl)-3-methoxypyridine (36.4 mg, 0.18 mmol) and potassium carbonate (33.1 mg, 0.24 mmol) were added to N,N-dimethylformamide (2.0 ml) containing 3″-chloro-4″-hydroxy-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione (50.0 mg, 0.12 mmol) at room temperature, and the mixture was allowed to react at room temperature for 2 hours. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 ml x 3 times). The organic phases were combined, washed with saturated saline (20 ml x 2 times), dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 0). 24 mg of white solid 3″-chloro-3-(2-hydroxypropan-2-yl)-4″-((3-methoxypyridin-2-yl)methoxy)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione (yield: 38.3%) was obtained. LC-MS: RT=1.79 min, [M+H] + =523.28. Nuclear Magnetic Resonance Data: 1 HNMR(400MHz,DMSO-d6)δ8.67(s,1H),8.20-8.16(m,1H),7.84(dd,J=6.9,2 .0Hz,1H),7.77(s,1H),7.68(dd,J=7.0,2.1Hz,1H),7.56(d,J=8.4Hz,1H),7 .44(dd,J=8.4,4.6Hz,1H),6.76(s,1H),6.41(t,J=6.9Hz,1H),5.36(s,2H) ,5.21(s,1H),3.88(s,3H),2.06(s,3H),1.98(s,3H),1.45(d,J=4.2Hz,6H).

[0054] Example 8 [ka] The synthetic route for compound number 8 is as follows. Step A: Synthesis of 4-(((3″-chloro-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2,2″-dioxo-2H,2″H-[1,2 2′:4′,1″-terpyridine]-4″-yl)oxy)methyl)-3-fluorobenzonitrile. [ka] 4-(Bromomethyl)-3-fluorobenzonitrile (38.16 mg, 0.18 mmol) and potassium carbonate (33.12 mg, 0.24 mmol) were added to N,N-dimethylformamide (2.0 ml) containing 3″-chloro-4″-hydroxy-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione (50.0 mg, 0.12 mmol) at room temperature, and the mixture was allowed to react at room temperature for 2 hours. After the reaction was completed, the mixture was quenched by adding water, extracted with ethyl acetate (20 ml x 3 times), and the organic phases were combined, washed with saturated saline (20 ml x 2 times), dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 0). 26.5 mg of white solid 4-(((3"-chloro-3-(2-hydroxypropan-2-yl)-5',6"-dimethyl-2,2"-dioxo-2H,2"H-[1,2 2':4',1"-terpyridine]-4"-yl)oxy)methyl)-3-fluorobenzonitrile (yield: 41.3%) was obtained. LC-MS: RT = 1.79 min, [M+H] + =535.23. Nuclear Magnetic Resonance Data: 1 HNMR(400MHz,DMSO-d6)δ8.68(s,1H),7.97(d,J=9.6Hz,1H),7.83(dt,J=10.8,3.4Hz,3H),7.77(s,1H),7.68(dd,J=7.0,2.0Hz ,1H),6.80(s,1H),6.41(t,J=6.9Hz,1H),5.49(s,2H),5.21(s,1H),2.07(d,J=8.7Hz,3H),2.00(s,3H),1.45(d,J=3.9Hz,6H).

[0055] Example 9 [ka] The synthetic route for compound number 9 is as follows. Step A: Synthesis of 3″-chloro-4″-((4-chloro-2-fluorobenzyl)oxy)-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione. [ka] 4-Chloro-2-fluorobenzyl bromide (122 mg, 0.50 mmol) and potassium carbonate (69 mg, 0.50 mmol) were added to N,N-dimethylformamide (2.5 ml) containing 3″-chloro-4″-hydroxy-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione (100 mg, 0.25 mmol) at room temperature, and the mixture was allowed to react at room temperature for 1 hour. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 ml x 3 times). The organic phases were combined, washed with saturated saline (20 ml x 2 times), dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 0). 50 mg of white solid 3″-chloro-4″-((4-chloro-2-fluorobenzyl)oxy)-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione (yield: 36%) was obtained. LC-MS: RT=2.02min, [M+H] + =544.18. 1 HNMR(400MHz,DMSO-d6)δ8.67(s,1H),7.84(dd,J=6.9,2.1Hz,1H),7.77(s,1H),7.72-7.61(m,2H),7.55(dd,J=10.0,2.0Hz,1H),7.40 (dd,J=8.3,1.8Hz,1H),6.79(s,1H),6.41(t,J=7.0Hz,1H),5.37(s,2H),5.21(s,1H),2.06(s,3H),2.00(s,3H),1.45(d,J=3.9Hz,6H).

[0056] Example 10 [ka] The synthetic route for compound No. 10 is as follows. Step A: Synthesis of 3″-chloro-4″-((5-(trifluoromethyl)pyridin-2-yl)methoxy)-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione. [ka] 2-(Bromomethyl)-(5-trifluoromethyl)pyridine (43.2 mg, 0.18 mmol) and potassium carbonate (33.12 mg, 0.24 mmol) were added to N,N-dimethylformamide (2.0 ml) containing 3″-chloro-4″-hydroxy-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione (50.0 mg, 0.12 mmol) at room temperature, and the mixture was allowed to react at room temperature for 2 hours. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 ml x 3 times). The organic phases were combined, washed with saturated saline (20 ml x 2 times), dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 0). 11.0 mg of 3″-chloro-4″-((5-(trifluoromethyl)pyridin-2-yl)methoxy)-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione (yield: 16.3%) was obtained as a white solid. LC-MS: RT=1.93min, [M+H] + =561.23.

[0220]

[0057] Example 11 [ka] The synthetic route for compound No. 11 is as follows. Step A: Synthesis of 3″-chloro-4″-((pyridin-4-yl)methoxy)-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione. [ka] 4-(Bromomethyl)pyridine (45.5 mg, 0.18 mmol) and potassium carbonate (33.12 mg, 0.24 mmol) were added to N,N-dimethylformamide (2.0 ml) containing 3″-chloro-4″-hydroxy-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione (50.0 mg, 0.12 mmol) at room temperature, and the mixture was allowed to react at room temperature for 2 hours. After the reaction was completed, the mixture was quenched by adding water, extracted with ethyl acetate (20 ml x 3 times), and the organic phases were combined, washed with saturated saline (20 ml x 2 times), dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 0). 10.0 mg of 3"-chloro-4"-((pyridin-4-yl)methoxy)-3-(2-hydroxypropan-2-yl)-5',6"-dimethyl-2H,2"H-[1,2':4',1"-terpyridine]-2,2"-dione (yield: 16.9%) was obtained as a white solid. LC-MS: RT = 1.61 min, [M+H] + =493.24.

[0058] Example 12 [ka] The synthetic route for compound No. 12 is as follows. Step A: Synthesis of 3″-chloro-4″-((3-methylpyridin-2-yl)methoxy)-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione. [ka] 2-(Chloromethyl)-3-methylpyridine (71 mg, 0.50 mmol) and potassium carbonate (69 mg, 0.50 mmol) were added to N,N-dimethylformamide (2.5 ml) containing 3″-chloro-4″-hydroxy-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione (100 mg, 0.25 mmol) at room temperature, and the mixture was allowed to react at room temperature for 4 hours. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 ml x 3 times). The organic phases were combined, washed with saturated saline (20 ml x 2 times), dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 0). 21.0 mg of 3″-chloro-4″-((3-methylpyridin-2-yl)methoxy)-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione (yield: 16%) was obtained as a white solid. LC-MS: RT=1.75 min, [M+H] + =507.21.

[0059] Example 13 [ka] The synthetic route for compound No. 13 is as follows. Step A: Synthesis of 2-(((3″-chloro-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2,2″-dione-2H,2″H-[1,2′:4′,1″-terpyridine]-4″-yl)oxy)methyl)-3-fluorobenzonitrile. [ka] 2-(Bromomethyl)-3-fluorobenzonitrile (38.16 mg, 0.18 mmol) and potassium carbonate (33.12 mg, 0.24 mmol) were added to N,N-dimethylformamide (2.0 ml) containing 3″-chloro-4″-hydroxy-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione (50.0 mg, 0.12 mmol) at room temperature, and the mixture was allowed to react at room temperature for 2 hours. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 ml x 3 times). The organic phases were combined, washed with saturated saline (20 ml x 2 times), dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 0). 29.5 mg of 2-(((3"-chloro-3-(2-hydroxypropan-2-yl)-5',6"-dimethyl-2,2"-dione-2H,2"H-[1,2':4',1"-terpyridine]-4"-yl)oxy)methyl)-3-fluorobenzonitrile (yield: 45.9%) was obtained as a white solid. LC-MS: RT=1.88min, [M+H] + =535.21. 1 HNMR(400MHz,DMSO)δ8.70(s,1H),7.92-7.84(m,2H),7.82(s,1H),7.80-7.73(m,2H),7.70(dd,J=7.0,2.1Hz,1H), 6.88(s,1H),6.43(t,J=6.9Hz,1H),5.46(s,2H),5.23(s,1H),2.09(s,3H),2.05(s,3H),1.48(s,3H),1.47(s,3H).

[0060] Example 14 [ka] The synthetic route for compound No. 14 is as follows. Step A: Synthesis of 3″-chloro-4″-((5-chloropyridin-2-yl)methoxy)-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione. [ka] 2-(Bromomethyl)-5-chloropyridine (36.9 mg, 0.18 mmol) and potassium carbonate (33.12 mg, 0.24 mmol) were added to N,N-dimethylformamide (2.0 ml) containing 3″-chloro-4″-hydroxy-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione (50.0 mg, 0.12 mmol) at room temperature, and the mixture was allowed to react at room temperature for 2 hours. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 ml x 3 times). The organic phases were combined, washed with saturated saline (20 ml x 2 times), dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 0). 14.6 mg of white solid 3″-chloro-4″-((5-chloropyridin-2-yl)methoxy)-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione (yield: 23.1%) was obtained. LC-MS: RT=1.89 min, [M+H] + =527.20.

[0061] Example 15 [ka] The synthetic route for compound No. 15 is as follows. Step A: Synthesis of 3″-chloro-4″-((2,6-difluorophenyl)methoxy)-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione. [ka] 2-(Bromomethyl)-1,3-difluorobenzene (37.26 mg, 0.18 mmol) and potassium carbonate (33.12 mg, 0.24 mmol) were added to N,N-dimethylformamide (2.0 ml) containing 3″-chloro-4″-hydroxy-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione (50.0 mg, 0.12 mmol) at room temperature, and the mixture was allowed to react at room temperature for 2 hours. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 ml x 3 times). The organic phases were combined, washed with saturated saline (20 ml x 2 times), dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 0). 15.31 mg of 3″-chloro-4″-((2,6-difluorophenyl)methoxy)-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione (yield: 24.1%) was obtained as a white solid. LC-MS: RT=1.93min, [M+H] + =528.21.

[0062] Example 16 [ka] The synthetic route for compound No. 16 is as follows. Step A: Synthesis of 2-(bromomethyl)-3-fluoro-5-bromopyridine. [ka] At 0°C, triphenylphosphine (267 mg, 1.02 mmol) and carbon tetrabromide (334 mg, 1.02 mmol) were added sequentially to tetrahydrofuran (10 ml) containing (3-fluoro-5-bromopyridine-2-pyridine)methanol (210 mg, 1.02 mmol), and the mixture was allowed to react at room temperature for 1 hour. The reaction was completed and concentrated. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate=10 / 1). 200 mg of colorless oily substance 2-(bromomethyl)-3-fluoro-5-bromopyridine (yield: 73%) was obtained. Step B: Synthesis of 3″-chloro-4″-((3-fluoro-5-bromopyridin-2-yl)methoxy)-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione. [ka] 2-(Bromomethyl)-3-bromo-5-fluoropyridine (134 mg, 0.50 mmol) and potassium carbonate (39 mg, 0.50 mmol) were added to N,N-dimethylformamide (2.0 ml) containing 3″-chloro-4″-hydroxy-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione (100 mg, 0.25 mmol) at room temperature, and the mixture was allowed to react at room temperature for 1 hour. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 ml x 3 times). The organic phases were combined, washed with saturated saline (20 ml x 2 times), dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 0). 14 mg of white solid 3"-chloro-4"-((3-fluoro-5-bromopyridin-2-yl)methoxy)-3-(2-hydroxypropan-2-yl)-5',6"-dimethyl-2H,2"H-[1,2':4',1"-terpyridine]-2,2"-dione (yield: 53.7%) was obtained. LC-MS: RT=1.91 min, [M+H] + =589.13.

[0063] Example 17 [ka] The synthetic route for compound No. 17 is as follows. Step A: Synthesis of 3″-chloro-4″-((2,3-difluorobenzyl)oxy)-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione. [ka] 2,3-Difluorobenzyl bromide (31 mg, 0.149 mmol) and potassium carbonate (35 mg, 0.50 mmol) were added to N,N-dimethylformamide (2.5 ml) containing 3″-chloro-4″-hydroxy-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione (50 mg, 0.124 mmol) at room temperature, and the mixture was allowed to react at room temperature for 1 hour. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 ml x 3 times). The organic phases were combined, washed with saturated saline (20 ml x 2 times), dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 0). 6.8 mg of 3″-chloro-4″-((2,3-difluorobenzyl)oxy)-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione (yield: 10%) was obtained as a white solid. LC-MS: RT=1.97min, [M+H] + =528.18.

[0064] Example 18 [ka] The synthetic route for compound No. 18 is as follows. Step A: Synthesis of 3″-chloro-4″-((2,5-difluorobenzyl)oxy)-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione. [ka] 2,5-Difluorobenzyl bromide (31 mg, 0.149 mmol) and potassium carbonate (35 mg, 0.50 mmol) were added to N,N-dimethylformamide (2.5 ml) containing 3″-chloro-4″-hydroxy-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione (50 mg, 0.124 mmol) at room temperature, and the mixture was allowed to react at room temperature for 1 hour. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 ml x 3 times). The organic phases were combined, washed with saturated saline (20 ml x 2 times), dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 0). 7.8 mg of 3″-chloro-4″-((2,5-difluorobenzyl)oxy)-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione (yield: 12%) was obtained as a white solid. LC-MS: RT=1.93min, [M+H] + =528.21.

[0065] Example 19 [ka] The synthetic route for compound No. 19 is as follows. Step A: Synthesis of 3″-chloro-4″-((3-chloropyridin-2-yl)methoxy)-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione. [ka] 3-Chloro-2-(chloromethyl)pyridine (29.2 mg, 0.18 mmol) and potassium carbonate (33.12 mg, 0.24 mmol) were added to N,N-dimethylformamide (2.0 ml) containing 3″-chloro-4″-hydroxy-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione (50.0 mg, 0.12 mmol) at room temperature, and the mixture was allowed to react at 60° C. for 4 hours. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 ml x 3 times). The organic phases were combined, washed with saturated saline (20 ml x 2 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 0). 19.8 mg of 3″-chloro-4″-((3-chloropyridin-2-yl)methoxy)-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione (yield: 31.3%) was obtained as a white solid. LC-MS: RT=1.84min, [M+H] + =527.20. Nuclear Magnetic Resonance Data: 1 HNMR(400MHz,DMSO-d6)δ8.67(s,1H),8.59(dd,J=4.7,1.4Hz,1H),8.05(dd,J= 8.1,1.4Hz,1H),7.84(dd,J=6.9,2.1Hz,1H),7.78(s,1H),7.68(dt,J=9.0,2.0 Hz,1H),7.51(dd,J=8.1,4.7Hz,1H),6.76(s,1H),6.41(t,J=7.0Hz,1H),5.48( d,J=12.4Hz,2H),5.21(s,1H),2.07(s,3H),1.98(s,3H),1.46(d,J=4.1Hz,6H).

[0066] Example 20 [ka] The synthetic route for compound No. 20 is as follows. Step A: Synthesis of 3″-chloro-4″-((3-fluoropyridin-2-yl)methoxy)-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione. [ka] At room temperature, 3-fluoro-2-(chloromethyl)pyridine (26.2 mg, 0.18 mmol) and potassium carbonate (33.12 mg, 0.24 mmol) were added to N,N-dimethylformamide (2.0 ml) containing 3″-chloro-4″-hydroxy-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione (50.0 mg, 0.12 mmol), and the mixture was heated to 60° C. and reacted for 4 hours. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 ml x 3 times). The organic phases were combined, washed with saturated saline (20 ml x 2 times), dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 0). 23.0 mg of white solid 3"-chloro-4"-((3-fluoropyridin-2-yl)methoxy)-3-(2-hydroxypropan-2-yl)-5',6"-dimethyl-2H,2"H-[1,2':4',1"-terpyridine]-2,2"-dione (yield: 37.5%) was obtained. LC-MS: RT=1.79 min, [M+H] + =511.20. Nuclear Magnetic Resonance Data: 1 HNMR(400MHz,DMSO-d6)δ8.67(s,1H),8.51-8.47(m,1H),7.86-7.82(m,2H),7.78(s,1H),7.68(dd,J=7.0,2.1Hz,1H),7.57(dt,J=8.6 ,4.4Hz,1H),6.80(s,1H),6.41(t,J=6.9Hz,1H),5.48(d,J=1.6Hz,2H),5.21(s,1H),2.07(s,3H),1.99(s,3H),1.46(d,J=4.1Hz,6H).

[0067] Example 21 [ka] The synthetic route for compound No. 21 is as follows. Step A: Synthesis of 3″-chloro-4″-((5-fluoropyridin-2-yl)methoxy)-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione. [ka] 2-(Bromomethyl)-5-fluoropyridine (34.38 mg, 0.18 mmol) and potassium carbonate (33.12 mg, 0.24 mmol) were added to N,N-dimethylformamide (2.0 ml) containing 3″-chloro-4″-hydroxy-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione (50.0 mg, 0.12 mmol) at room temperature, and the mixture was allowed to react at room temperature for 2 hours. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 ml x 3 times). The organic phases were combined, washed with saturated saline (20 ml x 2 times), dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 0). 11.0 mg of 3″-chloro-4″-((5-fluoropyridin-2-yl)methoxy)-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione (yield: 18.0%) was obtained as a white solid. LC-MS:RT=1.82min, [M+H] + =511.23.

[0068] Example 22 [ka] The synthetic route for compound No. 22 is as follows. Step A: Synthesis of 3″-chloro-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-4″-((pyrimidin-4-yl)methoxy)-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione. [ka] 4-(Bromomethyl)pyrimidine (31.1 mg, 0.18 mmol) and potassium carbonate (33.1 mg, 0.24 mmol) were added to N,N-dimethylformamide (2.0 ml) containing 3″-chloro-4″-hydroxy-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione (50.0 mg, 0.12 mmol) at room temperature, and the mixture was allowed to react at room temperature for 2 hours. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 ml x 3 times). The organic phases were combined, washed with saturated saline (20 ml x 2 times), dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 0). 31.5 mg of 3″-chloro-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-4″-((pyrimidin-4-yl)methoxy)-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione (yield: 53.2%) was obtained as a white solid. LC-MS: RT=1.70 min, [M+H] + =494.19. Nuclear Magnetic Resonance Data: 1 HNMR(400MHz,DMSO-d6)δ9.22(s,1H),8.92(s,1H),8.68(s,1H),7.85(dd,J=7.0,2.1Hz,1H),7.77(s,1H),7.71-7.63( m,2H),6.73(s,1H),6.41(t,J=7.0Hz,1H),5.48(s,2H),5.21(s,1H),2.06(s,2H),1.98(s,3H),1.45(d,J=4.1Hz,6H).

[0069] Example 23 [ka] The synthetic route for compound No. 23 is as follows. Step A: Synthesis of 3″-chloro-4″-((3,4-difluorobenzyl)oxy)-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione. [ka] 3,4-Difluorobenzyl bromide (31 mg, 0.149 mmol) and potassium carbonate (35 mg, 0.50 mmol) were added to N,N-dimethylformamide (2.5 ml) containing 3″-chloro-4″-hydroxy-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione (50 mg, 0.124 mmol) at room temperature, and the mixture was allowed to react at room temperature for 1 hour. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 ml x 3 times). The organic phases were combined, washed with saturated saline (20 ml x 2 times), dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 0). 6.5 mg of white solid 3"-chloro-4"-((3,4-difluorobenzyl)oxy)-3-(2-hydroxypropan-2-yl)-5',6"-dimethyl-2H,2"H-[1,2':4',1"-terpyridine]-2,2"-dione (yield: 10%) was obtained. LC-MS: RT=1.95 min, [M+H] + =528.22.

[0070] Example 24 [ka] Compound No. 24 is prepared in the following manner. Step A: Synthesis of 2′-bromo-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one. [ka] At room temperature, 2-(bromomethyl)-3,5-difluoropyridine (160 mg, 0.77 mmol) and potassium carbonate (177 mg, 1.28 mmol) were added to an N,N-dimethylformamide solution (2.0 ml) containing 2'-bromo-3-chloro-4-hydroxy-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one (211 mg, 0.64 mmol), and the mixture was allowed to react at room temperature for 1 hour. After the reaction was completed, water (10.0 ml) was added to precipitate a solid, which was then filtered. The filter cake was washed twice with water and dried under reduced pressure to obtain 290 mg of a pale yellow solid substance, 2'-bromo-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one (yield: 99%). LC-MS: RT=1.91 min, [M+H] + =458.03. Step B: Synthesis of 3-acetyl-3″-chloro-4″-((3,5-difluoropyridin-2-yl)methoxy)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione. [ka] At room temperature, 2'-bromo-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one (100 mg, 0.22 mmol), 3-acetylpyridin-2(1H)-one (36 mg, 0.26 mmol), potassium carbonate (60 mg, 0.44 mmol), cuprous iodide (8 mg, 0.044 mmol) and dimethylethylenediamine (8 mg, 0.087 mmol) were contained in a 1,4-dioxane solution (5.0 ml) degassed, protected with nitrogen gas, and heated to 100 °C for 1 hour in a microwave reaction. After the reaction was completed, the mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane=1 / 0). 105 mg of 3-acetyl-3″-chloro-4″-((3,5-difluoropyridin-2-yl)methoxy)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione (yield: 93.7%) was obtained as a white solid. LC-MS: RT=1.84 min, [M+H] + =513.16. Step C: Synthesis of 3″-chloro-4″-((3,5-difluoropyridin-2-yl)methoxy)-3-(1-hydroxyethyl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione. [ka] Sodium borohydride (6 mg, 0.15 mmol) was added to a methanol solution (MeOH, 2.0 ml) containing 3-acetyl-3″-chloro-4″-((3,5-difluoropyridin-2-yl)methoxy)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione (50 mg, 0.097 mmol) at 0° C., and the mixture was warmed to room temperature and reacted for 0.5 hours. After the reaction was completed, the reaction mixture was quenched by adding water, extracted with ethyl acetate (3 ml x 3 times), and the organic phases were combined, washed with saturated saline (5 ml x 2 times), dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 0). 36 mg of 3″-chloro-4″-((3,5-difluoropyridin-2-yl)methoxy)-3-(1-hydroxyethyl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione (yield: 72%) was obtained as a white solid. LC-MS: RT=1.84min, [M+H] + =513.16. 1HNMR(400MHz,DMSO)δ8.67(s,1H),8.59(d,J=2.3Hz,1H),8.12-8.04(m,1H) ,7.89-7.83(m,1H),7.79(d,J=11.5Hz,1H),7.60-7.53(m,1H),6.79(s,1H) ,6.43(t,J=6.9Hz,1H),5.49(t,J=9.4Hz,2H),5.15-5.08(m,1H),4.73(dd, J=10.7,5.6Hz,1H),2.06(s,3H),2.00(s,3H),1.26(dd,J=8.8,6.3Hz,3H).

[0071] Example 25 [ka] The synthetic route for compound No. 25 is as follows. Step A: Synthesis of 2-(bromomethyl)-3-chloro-5-fluoropyridine. [ka] At 0°C, triphenylphosphine (813.5 mg, 3.11 mmol) and carbon tetrabromide (823.8 mg, 2.48 mmol) were added to tetrahydrofuran (5.0 ml) containing (3-chloro-5-fluoropyridin-2-yl)methanol (334.4 mg, 2.07 mmol), and the mixture was warmed to room temperature and reacted for 1 hour. The reaction was completed and concentrated. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate=10 / 1). 380.6 mg of colorless oily substance 2-(bromomethyl)-3-chloro-5-fluoropyridine (yield: 81.9%) was obtained. Step B: Synthesis of 3″-chloro-4″-((3-chloro-5-fluoropyridin-2-yl)methoxy)-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione. [ka] 2-(Bromomethyl)-3-chloro-5-fluoropyridine (40.4 mg, 0.18 mmol) and potassium carbonate (33.12 mg, 0.24 mmol) were added to N,N-dimethylformamide (2.0 ml) containing 3″-chloro-4″-hydroxy-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione (50.0 mg, 0.12 mmol) at room temperature, and the mixture was allowed to react at room temperature for 2 hours. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 ml x 3 times). The organic phases were combined, washed with saturated saline (20 ml x 2 times), dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 0). 15.31 mg of 3″-chloro-4″-((3-chloro-5-fluoropyridin-2-yl)methoxy)-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione (yield: 25.7%) was obtained as a white solid. LC-MS: RT=1.89 min, [M+H] + =545.17.

[0072] Example 26 [ka] Compound No. 26 is prepared by the following method. Step A: Synthesis of 3-(2-hydroxybutan-2-yl)pyridin-2(1H)-one. [ka] At room temperature, 3-acetylpyridin-2(1H)-one (300.0 mg, 2.2 mmol) was dissolved in tetrahydrofuran (10.0 ml), the mixture was purged with nitrogen gas three times, the temperature was lowered to -20°C, ethylmagnesium bromide (EtMgBr, 6.6 ml, 1.0 mol / l) was slowly added dropwise, and after the addition was completed, the temperature was slowly raised to room temperature and the mixture was allowed to react for 1 hour. The reaction was completed and quenched at 0°C by adding saturated ammonium chloride solution (25.0 ml), extracted with ethyl acetate (15 ml x 5 times), the organic phases were combined, washed with saturated saline (10 ml x 1 time), dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 3). 200.0 mg of colorless oily substance 3-(2-hydroxybutan-2-yl)pyridin-2(1H)-one (yield: 54.1%) was obtained. LC-MS: RT = 1.57 min, [M + H] + =168.17. Step B: Synthesis of 3″-chloro-4″-((3,5-difluoropyridin-2-yl)methoxy)-3-(2-hydroxybutan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione. [ka] At room temperature, 2'-bromo-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one (200.0 mg, 0.5 mmol), 3-(2-hydroxybutan-2-yl)pyridin-2(1H)-one (109.7 mg, 0.6 mmol), potassium carbonate (138.0 mg, 1.0 mmol) were dissolved in 1,4-dioxane (5.0 ml), cuprous iodide (18.2 mg, 1.0 mmol), dimethylethylenediamine (0.01 ml) were added, and the mixture was replaced with nitrogen gas three times. The mixture was heated to 100 ° C. and subjected to microwave reaction for 1 hour. After the reaction was completed, the reaction mixture was quenched by adding water, extracted with ethyl acetate (20 ml x 4 times), and the organic phases were combined, washed with saturated saline (10 ml x 1 time), dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 1 / 20). 90.0 mg of off-white solid 3"-chloro-4"-((3,5-difluoropyridin-2-yl)methoxy)-3-(2-hydroxybutan-2-yl)-5',6"-dimethyl-2H,2"H-[1,2':4',1"-terpyridine]-2,2"-dione (yield: 34.6%) was obtained. LC-MS: RT=1.89 min, [M+H] + =543.27.

[0073] Example 27 [ka] The synthetic route for compound No. 27 is as follows. Step A: Synthesis of (3-fluoro-5-cyclopropylpyridin-2-yl)methanol. [ka] At room temperature, cyclopropylboronic acid (177 mg, 2.24 mmol), palladium catalyst (Pd(dppf)Cl2, 82 mg, 0.11 mmol), and potassium carbonate (309 mg, 2.24 mmol) were added to a mixed solvent (dioxane / water = 5 / 1.18 ml) containing (3-fluoro-5-bromopyridin-2-yl)methanol (230 mg, 1.12 mmol), and the mixture was heated to 100 ° C. and reacted for 8 hours. After the reaction was completed, the mixture was filtered, the filtrate was concentrated, diluted with water, extracted with ethyl acetate (10 ml x 3 times), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 10) to obtain 80 mg of colorless liquid (3-fluoro-5-cyclopropylpyridin-2-yl)methanol (yield: 43%). Step B: Synthesis of 2-(bromomethyl)-3-fluoro-5-cyclopropylpyridine. [ka] At 0°C, triphenylphosphine (126 mg, 0.48 mmol) and carbon tetrabromide (157 mg, 0.48 mmol) were added to tetrahydrofuran (5 ml) containing (3-fluoro-5-cyclopropylpyridin-2-yl)methanol (80 mg, 0.48 mmol), and the mixture was allowed to react at room temperature for 1 hour. The reaction was completed and concentrated. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate=10 / 1) to obtain 40 mg of colorless oily substance 2-(bromomethyl)-3-fluoro-5-cyclopropylpyridine (yield: 36%). Step C: Synthesis of 3″-chloro-4″-((3-fluoro-5-cyclopropylpyridin-2-yl)methoxy)-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione. [ka] 2-(Bromomethyl)-3-fluoro-5-cyclopropylpyridine (40 mg, 0.17 mmol) and potassium carbonate (48 mg, 0.35 mmol) were added to N,N-dimethylformamide (2.0 ml) containing 3″-chloro-4″-hydroxy-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione (68 mg, 0.17 mmol) at room temperature, and the mixture was allowed to react at room temperature for 1 hour. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 ml x 3 times). The organic phases were combined, washed with saturated saline (20 ml x 2 times), dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 0). 1.07 mg of 3″-chloro-4″-((3-fluoro-5-cyclopropylpyridin-2-yl)methoxy)-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione (yield: 1%) was obtained as a white solid. LC-MS: RT=1.91 min, [M+H] + =551.21.

[0074] Example 28 [ka] The synthetic route for compound No. 28 is as follows. Step A: Synthesis of 3″-chloro-4″-((pyrazin-2-yl)methoxy)-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione. [ka] 2-Bromomethylpyrazine (31.14 mg, 0.18 mmol) and potassium carbonate (33.12 mg, 0.24 mmol) were added to N,N-dimethylformamide (2.0 ml) containing 3″-chloro-4″-hydroxy-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione (50.0 mg, 0.12 mmol) at room temperature, and the mixture was allowed to react at room temperature for 2 hours. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 ml x 3 times). The organic phases were combined, washed with saturated saline (20 ml x 2 times), dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 0). 12.0 mg of 3″-chloro-4″-((pyrazin-2-yl)methoxy)-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione (yield: 20.3%) was obtained as a white solid. LC-MS: RT=1.72 min, [M+H] + =494.23.

[0075] Example 29 [ka] Compound No. 29 is prepared by the following method. Step A: Synthesis of 3-acetyl-4-methylpyridin-2(1H)-one. [ka] At room temperature, 4-methyl-2-oxo-1,2-dihydropyridine-3-nitrile (350.0 mg, 2.6 mmol) was dissolved in tetrahydrofuran (10.0 ml), the mixture was purged with nitrogen gas three times, the temperature was lowered to -20°C, methylmagnesium bromide (2.2 ml, 3.0 mol / l) was added dropwise, and after the dropwise addition was completed, the temperature was slowly raised to room temperature and the reaction was carried out for 2 hours, the temperature was raised to 40°C and the reaction was carried out for 1 hour, 10 ml of 1 mol / l hydrochloric acid was added, the temperature was lowered to room temperature and the reaction was carried out for 1 hour. After the reaction was completed, 25.0 ml of saturated sodium bicarbonate solution was added to quench the reaction, followed by extraction with ethyl acetate (15 ml x 3 times). The organic phases were combined, washed with saturated saline (10 ml x 1 time), dried over anhydrous sodium sulfate, and concentrated. 350.0 mg of 3-acetyl-4-methylpyridin-2(1H)-one (yield: 89.1%) was obtained as a pale yellow solid. LC-MS: RT=1.21 min, [M+H] + =152.10. Step B: Synthesis of 3-(2-hydroxypropan-2-yl)-4-methylpyridin-2(1H)-one. [ka] At room temperature, 3-acetyl-4-methylpyridin-2(1H)-one (350.0 mg, 2.3 mmol) was dissolved in tetrahydrofuran (10.0 ml), purged with nitrogen gas three times, cooled to -20°C, and methylmagnesium bromide (MeMgBr, 2.3 ml, 3.0 mol / l) was added dropwise. After the dropwise addition was completed, the temperature was slowly raised to room temperature and the reaction was carried out for 2 hours. The reaction was completed, quenched by adding saturated ammonium chloride solution (30.0 ml), extracted with ethyl acetate (15 ml x 5 times), the organic phases were combined, washed with saturated saline (10 ml x 1 time), dried over anhydrous sodium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 1 / 20). 106.0 mg of 3-(2-hydroxypropan-2-yl)-4-methylpyridin-2(1H)-one (yield: 27.5%) was obtained as a pale yellow solid. LC-MS: RT = 1.57 min, [M + H] + = 168.17. Step C: Synthesis of 3″-chloro-4″-((3,5-difluoropyridin-2-yl)methoxy)-3-(2-hydroxypropan-2-yl)-4,5′,6″-trimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione. [ka] At room temperature, 2'-bromo-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one (100.0 mg, 0.2 mmol), 3-(2-hydroxybutan-2-yl)-4-methylpyridin-2(1H)-one (54.8 mg, 0.3 mmol), potassium carbonate (58.0 mg, 0.4 mmol) were dissolved in 1,4-dioxane (5.0 ml), cuprous iodide (8.0 mg, 0.4 mmol), dimethylethylenediamine (0.01 ml) were added, and the mixture was replaced with nitrogen gas three times. The mixture was heated to 100 ° C. and subjected to microwave reaction for 1 hour. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 ml x 4 times). The organic phases were combined, washed with saturated saline (10 ml x 1 time), dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 1 / 20). 50.0 mg of a pale yellow solid, 3"-chloro-4"-((3,5-difluoropyridin-2-yl)methoxy)-3-(2-hydroxypropan-2-yl)-4,5',6"-trimethyl-2H,2"H-[1,2':4',1"-terpyridine]-2,2"-dione (yield: 43.9%) was obtained. LC-MS: RT=1.89min, [M+H]+=543.24. 1 HNMR(400MHz,DMSO):δ=8.66(s,1H),8.59(d,J=2.4Hz,1H),8.10-8.05(m,1H),7.74(d,J=1.7Hz,1H),6.79(s,1H),6.21(d,J =7.3Hz,1H),5.90(s,1H),5.47(d,J=1.5Hz,2H),3.57(s,1H),2.44(s,3H),2.06(s,3H),1.99(s,3H),1.53(d,J=3.3Hz,6H).

[0076] Example 30 [ka] A specific synthesis route for compound No. 30 is as follows. Step A: Synthesis of 3″-chloro-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-4″-((pyridin-3-yl)methoxy)-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione. [ka] 3-Bromomethylpyridine (31.0 mg, 0.18 mmol) and potassium carbonate (33.12 mg, 0.24 mmol) were added to N,N-dimethylformamide (2.0 ml) containing 3″-chloro-4″-hydroxy-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione (50.0 mg, 0.12 mmol) at room temperature, and the mixture was allowed to react at room temperature for 2 hours. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 ml x 3 times). The organic phases were combined, washed with saturated saline (20 ml x 2 times), dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 0). 29.6 mg of white solid 3″-chloro-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-4″-((pyridin-3-yl)methoxy)-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione (yield: 40.1%) was obtained. LC-MS:RT=1.64min, [M+H] + =493.22. Nuclear Magnetic Resonance Data: 1 HNMR(400MHz,DMSO-d6)δ8.71(d,J=1.7Hz,1H),8.67(s,1H),8.59(dd,J=4.8,1. 5Hz,1H),7.91(d,J=7.9Hz,1H),7.84(dd,J=6.9,2.0Hz,1H),7.77(s,1H),7.68(d d,J=7.0,2.1Hz,1H),7.48(dd,J=7.8,4.8Hz,1H),6.77(s,1H),6.41(t,J=7.0Hz ,1H),5.40(s,2H),5.21(s,1H),2.06(s,3H),2.00(s,3H),1.45(d,J=3.8Hz,6H).

[0077] Example 31 [ka] Compound No. 31 is prepared by the following method. Step A: Synthesis of 3-acetyl-4-methoxypyridin-2(1H)-one. [ka] Methylmagnesium bromide (1.33 ml, 4.00 mmol, 3 mol / ml) was added to a tetrahydrofuran solution (4.0 ml) containing 4-methoxy-2-oxo-1,2-dihydropyridine-3-carbonitrile (200 mg, 1.33 mmol) at 0°C, the mixture was warmed to room temperature and reacted for 1 hour, and an aqueous hydrochloric acid solution (1 ml, 1 mol / ml) was added and the reaction was continued at room temperature for 1 hour. After the reaction was completed, the reaction mixture was quenched by adding water, extracted with ethyl acetate (5 ml x 3 times), and the organic phases were combined, washed with saturated saline (5 ml x 2 times), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 0) to obtain 150 mg of a pale yellow solid substance, 3-acetyl-4-methoxypyridin-2(1H)-one (yield: 67.6%). LC-MS: RT = 1.93 min, [M + H] + =168.01. Step B: Synthesis of 3-(2-hydroxypropan-2-yl)-4-methoxypyridin-2(1H)-one. [ka] Methylmagnesium bromide (0.90 ml, 2.69 mmol, 3 mol / ml) was added to a tetrahydrofuran solution (4.0 ml) containing 3-acetyl-4-methoxypyridin-2(1H)-one (150 mg, 0.90 mmol) at 0° C., and the mixture was warmed to room temperature and reacted for 1 hour. After the reaction was completed, the reaction mixture was quenched by adding water, extracted with ethyl acetate (5 ml x 3 times), and the organic phases were combined, washed with saturated saline (5 ml x 2 times), dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by chromatography (eluent: ethyl acetate / n-hexane=1 / 0). 65 mg of pale yellow solid material 3-(2-hydroxypropan-2-yl)-4-methoxypyridin-2(1H)-one (yield: 39.6%) was obtained. LC-MS: RT=1.95 min, [M+H]+=184.12. Step C: Synthesis of 3″-chloro-4″-((3,5-difluoropyridin-2-yl)methoxy)-3-(2-hydroxypropan-2-yl)-4-methoxy-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione. [ka] At room temperature, 2'-bromo-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one (82 mg, 0.18 mmol), 3-(2-hydroxypropan-2-yl)-4-methoxypyridin-2(1H)-one (58 mg, 0.32 mmol), potassium carbonate (50 mg, 0.36 mmol), cuprous iodide (7 mg, 0.036 mmol) and dimethylethylenediamine (6 mg, 0.072 mmol) were degassed in 1,4-dioxane solution (4.0 ml), protected with nitrogen gas, and heated to 100 ° C. for 1 hour in a microwave reaction. After the reaction was completed, the mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane=1 / 0). 75 mg of a pale yellow solid, 3″-chloro-4″-((3,5-difluoropyridin-2-yl)methoxy)-3-(2-hydroxypropan-2-yl)-4-methoxy-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione (yield: 75%) was obtained. LC-MS: RT=1.88min, [M+H] + =559.19.1 HNMR(400MHz,DMSO)δ8.67(s,1H),8.59(d,J=2.4Hz,1H),8.10-8.06(m,1H),8.00(d,J=7.9Hz,1H),7.75(s,1H),7.59(s,1H) ,6.78(s,1H),6.60(d,J=8.0Hz,1H),5.47(d,J=2.0Hz,2H),3.91(s,3H),2.07(s,3H),1.99(s,3H),1.46(s,3H),1.43(s,3H).

[0078] Example 32 [ka] Compound No. 32 is prepared by the following method. Step A: Synthesis of 3-acetyl-5-bromopyridin-2(1H)-one. [ka] A solution of methylmagnesium bromide in tetrahydrofuran (1.0 ml, 2.0 mol / l) was slowly added dropwise to a solution of 5-bromo-2-oxo-1,2-dihydropyridine-3-carbonitrile (199.0 mg, 1.0 mmol) in tetrahydrofuran (4.0 ml) at -40°C, and the mixture was slowly warmed to room temperature and reacted for 2 hours. After the reaction was completed, the reaction mixture was quenched by adding dilute aqueous hydrochloric acid (4.0 ml, 1.0 mol / l), the pH was adjusted to neutral with saturated sodium bicarbonate solution, and the mixture was extracted with dichloromethane (20 ml x 3 times). The organic phases were combined, washed with saturated saline (20 ml x 2 times), dried over anhydrous sodium sulfate, and concentrated. The residue was used directly in the next reaction. LC-MS: RT=1.57 min, [M+H] + =216.02. Step B: Synthesis of 5-bromo-3-(2-hydroxypropan-2-yl)pyridin-2(1H)-one. [ka] A solution of methylmagnesium bromide in tetrahydrofuran (1.0 ml, 2.0 mol / l) was slowly added dropwise to a solution of 3-acetyl-5-bromopyridin-2(1H)-one (216.0 mg, 1.0 mmol) in tetrahydrofuran (4.0 ml) at -40°C, and the mixture was slowly warmed to room temperature and reacted for 2 hours. The reaction was completed, quenched by adding dilute aqueous hydrochloric acid (4.0ml, 1.0mol / l), adjusted to neutral pH with saturated sodium bicarbonate solution, extracted with dichloromethane (20ml x 3 times), combined organic phase, washed with saturated saline (20ml x 2 times), dried over anhydrous sodium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 2 / 1). 150mg of white solid 5-bromo-3-(2-hydroxypropan-2-yl)pyridin-2(1H)-one (yield: 64.7%) was obtained. LC-MS: RT = 1.63min, [M+H] + =234.08. Step C: Synthesis of 5-bromo-3″-chloro-4″-((3,5-difluoropyridin-2-yl)methoxy)-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione. [ka] At room temperature, 2'-bromo-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one (137.0 mg, 0.30 mmol), 5-bromo-3-(2-hydroxypropan-2-yl)pyridin-2(1H)-one (141.5 mg, 0.61 mmol), cuprous iodide (12 mg, 0.06 mmol) and potassium carbonate (84 mg, 0.61 mmol) were dissolved in dioxane (4 ml), dimethylethylenediamine was added dropwise, the mixture was protected with nitrogen gas, and the temperature was raised to 100 ° C. and the mixture was subjected to a microwave reaction for 1 hour. After the reaction was completed, the mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane=1 / 0). 129.6 mg of white solid 5-bromo-3″-chloro-4″-((3,5-difluoropyridin-2-yl)methoxy)-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione (yield: 71.1%) was obtained. LC-MS: RT=1.97min, [M+H] + =609.14. Nuclear magnetic resonance data: 1 HNMR(400MHz,DMSO-d6)δ8.67(s,1H),8.59(d,J=2.3Hz,1H),8.14-8.04(m,2H),7.77(s,1H),7.72(d,J=2. 8Hz,1H),6.78(s,1H),5.47(d,J=1.5Hz,2H),5.28(s,1H),2.07(s,3H),1.98(s,3H),1.45(d,J=4.0Hz,6H).

[0079] Example 33 [ka] Compound No. 33 is prepared by the following method. Step A: Synthesis of 3-acetyl-5-chloropyridin-2(1H)-one. [ka] NCS (500 mg, 3.67 mmol) was added to N,N-dimethylformamide (5 ml) containing 3-acetylpyridin-2(1H)-one (500 mg, 3.67 mmol) at room temperature, and the mixture was heated to 80° C. and reacted for 3 hours. The reaction was completed, quenched by adding water, extracted with ethyl acetate (30ml x 3 times), the organic phases were combined, washed with saturated saline (30ml x 2 times), dried over anhydrous sodium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1). 300mg of 3-acetyl-5-chloropyridin-2(1H)-one (yield: 54%) was obtained as a pale yellow solid. LC-MS: RT = 1.68min, [M+H] + =172.07. Step B: Synthesis of 3-(2-hydroxypropan-2-yl)-5-chloropyridin-2(1H)-one. [ka] A solution of methylmagnesium bromide in tetrahydrofuran (3 ml, 1 mol / ml) was added dropwise to tetrahydrofuran (20 ml) containing 3-acetyl-5-chloropyridin-2(1H)-one (300 mg, 1.75 mmol) at -78°C, and the mixture was allowed to warm slowly to room temperature and react for 3 hours. After the reaction was completed, the reaction mixture was quenched by adding water, and extracted with a mixture of dichloromethane and isopropanol (dichloromethane / isopropanol=3 / 1, 30ml x 5 times). The organic phases were combined, washed with saturated saline (30ml x 2 times), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol=10 / 1). 150mg of 3-(2-hydroxypropan-2-yl)-5-chloropyridin-2(1H)-one (yield: 46%) was obtained as a white solid. LC-MS: RT=1.59min, [M+H] + =188.10. Step C: Synthesis of 3″,5-dichloro-4″-((3,5-difluoropyridin-2-yl)methoxy)-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2′-dione. [ka] At room temperature, 2'-bromo-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one (80 mg, 0.18 mmol), 3-(2-hydroxypropan-2-yl)-5-chloropyridin-2(1H)-one (33 mg, 0.18 mmol), cuprous iodide (7 mg, 0.04 mmol) and potassium carbonate (48 mg, 0.35 mmol) were dissolved in dioxane (4 ml), dimethylethylenediamine was added dropwise, and the mixture was heated to 100 ° C. and subjected to microwave reaction for 1 hour. After the reaction was completed, the mixture was filtered, rinsed with ethyl acetate, and the filtrate was concentrated and purified by preparative high performance liquid chromatography to obtain 50 mg of the product 3″,5-dichloro-4″-((3,5-difluoropyridin-2-yl)methoxy)-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2′-dione (yield: 51%) as a white solid from the obtained crude product. LC-MS: RT=1.93min, [M+H] + =563.18. 1 HNMR(400MHz,DMSO-d6)δ8.67(s,1H),8.59(d,J=2.3Hz,1H),8.14-8.01(m,2H),7.78(s,1H),7.65(d,J=3 .0Hz,1H),6.78(s,1H),5.47(d,J=1.4Hz,2H),5.29(s,1H),2.07(s,3H),1.98(s,3H),1.50-1.42(m,6H).

[0080] Example 34 [ka] The synthetic route for compound No. 34 is as follows. Step A: Synthesis of 3-acetyl-6-methylpyridin-2(1H)-one. [ka] A solution of methylmagnesium bromide in tetrahydrofuran (5.47 ml, 1 mol / ml) was added dropwise to 6-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (500 mg, 3.73 mmol) in tetrahydrofuran (20 ml) at -78°C, and the mixture was allowed to warm slowly to room temperature and react for 3 hours. After the reaction was completed, the mixture was quenched by adding water, extracted with a mixture of dichloromethane and isopropanol (dichloromethane / isopropanol = 3 / 1, 30ml x 5 times), and the organic phases were combined, washed with saturated saline (30ml x 2 times), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to obtain 300mg of 3-acetyl-6-methylpyridin-2(1H)-one (yield: 53%) as a pale yellow solid. LC-MS: RT = 1.29min, [M + H] + =152.15. Step B: Synthesis of 3-(2-hydroxypropan-2-yl)-6-methylpyridin-2(1H)-one. [ka] A solution of methylmagnesium bromide in tetrahydrofuran (3 ml, 1 mol / ml) was added dropwise to tetrahydrofuran (20 ml) containing 3-acetyl-6-chloropyridin-2(1H)-one (300 mg, 1.98 mmol) at -78°C, and the mixture was allowed to warm slowly to room temperature and react for 3 hours. After the reaction was completed, the reaction mixture was quenched by adding water, extracted with a mixture of dichloromethane and isopropanol (dichloromethane / isopropanol=3 / 1, 30ml x 5 times), and the organic phases were combined, washed with saturated saline (30ml x 2 times), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol=10 / 1). 200mg of 3-(2-hydroxypropan-2-yl)-6-methylpyridin-2(1H)-one (yield: 60%) was obtained as a white solid. LC-MS: RT=1.52min, [M+H] + =168.20. Step C: Synthesis of 3″-chloro-4″-((3,5-difluoropyridin-2-yl)methoxy)-3-(2-hydroxypropan-2-yl)-5′,6,6″-trimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione. [ka] At room temperature, 2'-bromo-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one (80 mg, 0.18 mmol), 3-(2-hydroxypropan-2-yl)-6-methylpyridin-2(1H)-one (30 mg, 0.18 mmol), cuprous iodide (7 mg, 0.04 mmol) and potassium carbonate (48 mg, 0.35 mmol) were dissolved in dioxane (4 ml), dimethylethylenediamine was added dropwise, and the mixture was heated to 100 ° C. and subjected to microwave reaction for 1 hour. After the reaction was completed, the mixture was filtered, rinsed with ethyl acetate, and the filtrate was concentrated and purified by preparative high performance liquid chromatography to obtain 2.49 mg of the product 3″-chloro-4″-((3,5-difluoropyridin-2-yl)methoxy)-3-(2-hydroxypropan-2-yl)-5′,6,6″-trimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione (yield: 3%) as a white solid from the obtained crude product. LC-MS: RT=1.88min, [M+H] + =543.18.

[0081] Example 35 [ka] The synthetic route for compound No. 35 is as follows. Step A: Synthesis of 3″-chloro-4″-((3,5-difluoropyridin-2-yl)methoxy)-3-(2-hydroxypropan-2-yl)-5,5′,6″-trimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione. [ka] At room temperature, trimethylboroxine (0.02 ml, 0.16 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (1.17 mg, 0.0016 mmol), and sodium carbonate (33.9 mg, 0.32 mmol) were added to a mixed solvent (2.0 ml, toluene / water = 3 / 1) containing 5-bromo-3″-chloro-4″-((3,5-difluoropyridin-2-yl)methoxy)-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione (100 mg, 0.16 mmol), protected with nitrogen gas, heated to 90°C, and reacted for 2 hours. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 ml x 3 times). The organic phases were combined, washed with saturated saline (20 ml x 2 times), dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 0). 15.4 mg of 3″-chloro-4″-((3,5-difluoropyridin-2-yl)methoxy)-3-(2-hydroxypropan-2-yl)-5,5′,6″-trimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione (yield: 17.8%) was obtained as a white solid. LC-MS: RT=1.89 min, [M+H] + =543.25.

[0082] Example 36 [ka] The synthetic route for compound No. 36 is as follows. Step A: Synthesis of 3-(bromomethyl)-2-methoxypyridine. [ka] Triphenylphosphine (5.65 g, 21.56 mmol) and carbon tetrabromide (5.72 g, 17.24 mmol) were added to dichloromethane (30.0 ml) containing (2-methoxypyridin-3-yl)methanol (2.0 g, 14.37 mmol) at 0° C., and the mixture was allowed to react at room temperature for 1 hour. The reaction was completed and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane). 2.95 g of yellow oily substance 3-(bromomethyl)-2-methoxypyridine (yield: 97.7%) was obtained. LCMS: RT=1.97 min, [M+H] + =202.03. Step B: Synthesis of 2-(2-methoxypyridin-3-yl)acetonitrile. [ka] At room temperature, trimethylcyanosilane (3.60 ml, 28.68 mmol) and a solution of tetrabutylammonium fluoride in tetrahydrofuran (28.7 ml, 1.0 mol / l) were added to acetonitrile (30.0 ml) containing 3-(bromomethyl)-2-methoxypyridine (2.9 g, 14.34 mmol), and the mixture was allowed to react at 80° C. for 1 hour. The reaction was completed, quenched by adding water, extracted with ethyl acetate (30ml x 3 times), the organic phases were combined, washed first with saturated saline (20ml x 2 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane). 1.90g of 2-(2-methoxypyridin-3-yl)acetonitrile (yield: 88.82%) was obtained as a white solid. LCMS: RT=1.73min, [M+H] + =149.17. Step C: Synthesis of 2-(2-methoxypyridin-3-yl)-2-methylpropionitrile. [ka] At room temperature, sodium hydride (2.0 g, 0.05 mmol, 60% dispersed in paraffin oil) in tetrahydrofuran (15.0 ml) was added with 2-(2-methoxypyridin-3-yl)acetonitrile (1.90 g, 0.013 mmol) in tetrahydrofuran (5.0 ml), and the mixture was reacted at room temperature for 2 hours, followed by the addition of iodomethane and the reaction continued overnight. The reaction was completed, quenched by adding water, extracted with ethyl acetate (30ml x 3 times), the organic phases were combined, washed with saturated saline (20ml x 2 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane). 2.17g of 2-(2-methoxypyridin-3-yl)-2-methylpropionitrile (yield: 94.2%) was obtained as a colorless liquid. LCMS: RT=1.89min, [M+H] + =177.11. Step D: Synthesis of 2-(2-methoxypyridin-3-yl)-2-methylpropionaldehyde. [ka] A solution of diisobutylaluminum hydride in toluene (12.15 ml, 1.5 mol / l) was added to dichloromethane (200.0 ml) containing 2-(2-methoxypyridin-3-yl)-2-methylpropionitrile (2.17 g, 12.23 mmol) at -78°C, and the mixture was allowed to react by heating to room temperature. The reaction was completed, quenched by adding water, dichloromethane was removed by evaporation, dilute hydrochloric acid was added and stirred for 30 minutes, extracted with ethyl acetate (30ml x 3 times), the organic phases were combined, washed first with saturated saline (20ml x 2 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane). 1.56g of 2-(2-methoxypyridin-3-yl)-2-methylpropionaldehyde (yield: 70.9%) was obtained as a colorless liquid. LCMS: RT=1.91min, [M+H] + =180.16. Step E: Synthesis of 3-(1,1-difluoro-2-methylpropan-2-yl)-2-methoxypyridine. [ka] Diethylaminosulfur trifluoride (2.13 ml, 17.34 mol / l) was added to 2-(2-methoxypyridin-3-yl)-2-methylpropionaldehyde (1.56 g, 8.67 mmol) in dichloromethane (20.0 ml) at 0° C., and the mixture was allowed to react at room temperature. The reaction was completed, quenched by adding water, extracted with dichloromethane (30ml x 3 times), the organic phases were combined, washed with saturated saline (20ml x 2 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane). 700.0mg of 3-(1,1-difluoro-2-methylpropan-2-yl)-2-methoxypyridine (yield: 40.0%) was obtained as a colorless liquid. LCMS: RT=2.05min, [M+H] + =202.15. Step F: Synthesis of 3-(1,1-difluoro-2-methylpropan-2-yl)pyridin-2(1H)-one. [ka] Sodium iodide (780.7 mg, 5.2 mmol) and chlorotrimethylsilane (660.0 μl, 5.2 mmol) were added to acetonitrile (7.0 ml) containing 3-(1,1-difluoro-2-methylpropan-2-yl)-2-methoxypyridine (700.0 mg, 3.47 mmol) at room temperature, and the mixture was allowed to react at 65°C. The reaction was completed, quenched by adding water, adjusted to pH 8 with saturated sodium carbonate, extracted with ethyl acetate (30ml x 3 times), the organic phases were combined, washed first with saturated saline (20ml x 2 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1 / 20). 533.0mg of yellow oily substance 3-(1,1-difluoro-2-methylpropan-2-yl)pyridin-2(1H)-one (yield: 81.6%) was obtained. LCMS: RT = 1.68min, [M + H] + =188.16. Step G: Synthesis of 3″-chloro-3-(1,1-difluoro-2-methylpropan-2-yl)-4″-((3,5-difluoropyridin-2-yl)methoxy)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione. [ka] At room temperature, 2'-bromo-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one (100.0 mg, 0.22 mmol), 3-(1,1-difluoro-2-methylpropan-2-yl)pyridin-2(1H)-one (49.6 mg, 0.26 mmol), cuprous iodide (9.5 mg, 0.05 mmol) and potassium carbonate (60.7 mg, 0.44 mmol) were dissolved in dioxane (2.0 ml), N,N-dimethylethylenediamine was added dropwise, and the mixture was subjected to a microwave reaction at 80 ° C. for 1 hour. The reaction was completed, filtered under suction, the filter cake was washed with dichloromethane, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate). 28.0 mg of white solid 3″-chloro-3-(1,1-difluoro-2-methylpropan-2-yl)-4″-((3,5-difluoropyridin-2-yl)methoxy)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione (yield: 22.6%) was obtained. LCMS: RT=1.99 min, [M+H] + =563.17.

[0083] Example 37 [ka] The synthetic route for compound No. 37 is as follows. Step A: Synthesis of 2-chloro-5-cyclopropylpyridin-4-amine. [ka] At room temperature, a 1,4-dioxane solution (20.0 ml) containing 2-chloro-5-iodopyridin-4-amine (1.0 g, 3.93 mmol), cyclopropylboronic acid (0.68 g, 7.86 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (290 mg, 0.39 mmol) and potassium carbonate (1.09 g, 7.86 mmol) was protected with nitrogen gas, heated to 100° C., and reacted for 24 hours. After the reaction was completed, it was quenched by adding water, extracted with ethyl acetate (20ml x 3 times), the organic phases were combined, first washed with saturated saline (20ml x 2 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 5). 580mg of 2-chloro-5-cyclopropylpyridin-4-amine (yield: 87.6%) was obtained. LCMS: RT = 0.7min, [M + H] + =169.09. Step B: Synthesis of 2′-chloro-5′-cyclopropyl-4-hydroxy-6-methyl-2H-[1,4′-bipyridin]-2-one. [ka] At room temperature, 2,2-dimethyl-6-(2-oxopropyl)-4H-1,3-dioxin-4-one (760 mg, 4.13 mmol) was added to 1,4-dioxane (10.0 ml) containing 2-chloro-5-cyclopropylpyridin-4-amine (580 mg, 3.44 mmol), and the mixture was heated to 90° C. and reacted for 2 hours. Sulfuric acid solution (1.5 mL, 10 mol / l) was then added dropwise, and the mixture was reacted at 90° C. for 2 hours. After the reaction was completed, the temperature was lowered to room temperature, water was added to precipitate a solid, which was filtered, rinsed twice with water, and dried under reduced pressure to obtain 550 mg of a pale yellow solid substance, 2'-chloro-5'-cyclopropyl-4-hydroxy-6-methyl-2H-[1,4'-bipyridin]-2-one (yield: 57.8%). LCMS: RT=1.70 min, [M+H] + =277.12. Step C: Synthesis of 2′,3-dichloro-5′-cyclopropyl-4-hydroxy-6-methyl-2H-[1,4′-bipyridin]-2-one. [ka] At room temperature, 2'-chloro-5'-cyclopropyl-4-hydroxy-6-methyl-2H-[1,4'-bipyridin]-2-one (300 mg, 1.08 mmol) in isopropanol (5.0 ml) was added with 1,2-dichloroethane (2.5 ml), N-chlorosuccinimide (159 mg, 1.19 mmol) and dichloroacetic acid (1 drop), mixed, heated to 65°C and reacted for 1 hour. After the reaction was completed, water (1.0 ml) was added to quench the reaction, the solvent was removed under reduced pressure, and the residue was slurried with ethyl acetate, filtered, and dried under reduced pressure to give 230 mg of pale yellow solid material, 2',3-dichloro-5'-cyclopropyl-4-hydroxy-6-methyl-2H-[1,4'-bipyridin]-2-one (yield: 68.2%). LCMS: RT=1.73 min, [M+H] + =311.10. Step D: Synthesis of 2′,3-dichloro-5′-cyclopropyl-4-((3,5-difluoropyridin-2-yl)methoxy)-6-methyl-2H-[1,4′-bipyridin]-2-one. [ka] At room temperature, 2-(bromomethyl)-3,5-difluoropyridine (136 mg, 0.66 mmol) and potassium carbonate (151 mg, 1.01 mmol) were added to an N,N-dimethylformamide solution (2.0 ml) containing 2',3-dichloro-5'-cyclopropyl-4-hydroxy-6-methyl-2H-[1,4'-bipyridin]-2-one (170 mg, 0.55 mmol), and the mixture was allowed to react at room temperature for 1 hour. After the reaction was completed, water (10.0 ml) was added to precipitate the solid, which was filtered, rinsed twice with water, and dried under reduced pressure to obtain 180 mg of pale yellow solid material 2',3-dichloro-5'-cyclopropyl-4-((3,5-difluoropyridin-2-yl)methoxy)-6-methyl-2H-[1,4'-bipyridin]-2-one (yield: 75%). LCMS: RT=1.96 min, [M+H] + =438.13. Step E: Synthesis of 3″-chloro-5′-cyclopropyl-4″-((3,5-difluoropyridin-2-yl)methoxy)-3-(2-hydroxypropan-2-yl)-6″-methyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione. [ka] At room temperature, 2',3-dichloro-5'-cyclopropyl-4-((3,5-difluoropyridin-2-yl)methoxy)-6-methyl-2H-[1,4'-bipyridin]-2-one (180 mg, 0.41 mmol), 3-(2-hydroxypropan-2-yl)-pyridin-2(1H)-one (75 mg, 0.49 mmol), potassium carbonate (114 mg, 0.82 mmol), cuprous iodide (16 mg, 0.082 mmol) and dimethylethylenediamine (15 mg, 0.16 mmol) in 1,4-dioxane (5.0 ml) were degassed, protected with nitrogen gas and subjected to a microwave reaction at 110 °C for 2 hours. After the reaction was completed, it was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate). 16 mg of pale yellow solid 3″-chloro-5′-cyclopropyl-4″-((3,5-difluoropyridin-2-yl)methoxy)-3-(2-hydroxypropan-2-yl)-6″-methyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione (yield: 7%) was obtained. LCMS: RT=1.89 min, [M+H] + =555.22. 1 HNMR(400MHz,DMSO-d6)δ8.59(d,J=2.4Hz,1H),8.40(s,1H),8.14-8.01(m,1H), 7.82(dd,J=6.9,2.0Hz,1H),7.75(s,1H),7.68(dd,J=7.1,2.1Hz,1H),6.80(s,1H ),6.40(t,J=6.9Hz,1H),5.47(s,2H),5.22(s,1H),2.02(s,3H),1.54-1.47(m,1 H),1.46(s,3H),1.44(s,3H),1.06-1.00(m,1H),0.89(m,2H),0.72-0.67(m,1H).

[0084] Example 38 [ka] The synthetic route for compound No. 38 is as follows. Step A: Synthesis of 2-methyl-2-(2-oxo-1,2-dihydropyridin-3-yl)propionitrile. [ka] Sodium iodide (255.0 mg, 1.7 mmol) and chlorotrimethylsilane (215.0 μl, 1.7 mmol) were added to acetonitrile (3.0 ml) containing 2-(2-methoxypyridin-3-yl)-2-methylpropionitrile (200.0 mg, 1.13 mmol) at room temperature, and the mixture was heated to 65° C. to react. The reaction was completed, quenched by adding water, adjusted to pH 8 with saturated sodium carbonate, extracted with ethyl acetate (30ml x 3 times), the organic phases were combined, washed first with saturated saline (20ml x 2 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1 / 20). 170.0mg of yellow oily substance 2-methyl-2-(2-oxo-1,2-dihydropyridin-3-yl)propionitrile (yield: 92.3%) was obtained. LCMS: RT = 1.56min, [M + H] + =163.13. Step B: Synthesis of 2-(3″-chloro-4″-((3,5-difluoropyridin-2-yl)methoxy)-5′,6″-dimethyl-2,2″-diketone-2H,2″H-[1,2′:4′,1″-terpyridin]-3-yl)-2-methylpropionitrile. [ka] At room temperature, 2'-bromo-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one (100.0 mg, 0.22 mmol), 2-methyl-2-(2-oxo-1,2-dihydropyridin-3-yl)propionitrile (42.6 mg, 0.26 mmol), cuprous iodide (9.5 mg, 0.05 mmol) and potassium carbonate (60.7 mg, 0.44 mmol) were dissolved in dioxane (2.0 ml), N,N-dimethylethylenediamine was added dropwise, and the mixture was subjected to a microwave reaction at 80 ° C. for 1 hour. The reaction was completed, filtered with suction, rinsed with dichloromethane, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate). 37.0 mg of 2-(3″-chloro-4″-((3,5-difluoropyridin-2-yl)methoxy)-5′,6″-dimethyl-2,2″-diketone-2H,2″H-[1,2′:4′,1″-terpyridin]-3-yl)-2-methylpropionitrile (yield: 31.2%) was obtained as a white solid. LCMS: RT=1.91 min, [M+H] + =538.20.

[0085] Example 39 [ka] The synthetic route for compound No. 39 is as follows. Step A: Synthesis of 2′-chloro-4-hydroxy-5′-methoxy-6-methyl-2H-[1,4′-bipyridin]-2-one. [ka] At room temperature, 2,2-dimethyl-6-(2-oxopropyl)-4H-1,3-dioxin-4-one (700 mg, 3.78 mmol) was added to 1,4-dioxane (10.0 ml) containing 2-chloro-4-amino-5-methoxypyridine (500 mg, 3.15 mmol), and the mixture was heated to 90° C. and reacted for 2 hours. A sulfuric acid solution (1.2 mL, 10 mol / l) was added dropwise, and the reaction was continued at 90° C. for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, and water was added to precipitate a solid, which was then filtered, rinsed twice with water, and dried under reduced pressure to obtain 540 mg of a pale yellow solid, 2'-chloro-4-hydroxy-5'-methoxy-6-methyl-2H-[1,4'-bipyridin]-2-one (yield: 64.3%). LCMS: RT=1.66 min, [M+H] + =267.04. Step B: Synthesis of 2′,3-dichloro-4-hydroxy-5′-methoxy-6-methyl-2H-[1,4′-bipyridin]-2-one. [ka] At room temperature, 2'-chloro-4-hydroxy-5'-methoxy-6-methyl-2H-[1,4'-bipyridin]-2-one (540 mg, 2.02 mmol) in isopropanol (6.0 ml) was added with 1,2-dichloroethane (3.0 ml), N-chlorosuccinimide (297 mg, 2.23 mmol) and dichloroacetic acid (3 drops), and the mixture was heated to 65°C and reacted for 1 hour. After the reaction was completed, water (1.0 ml) was added to quench, the solvent was removed under reduced pressure, ethyl acetate was added to form a slurry, filtered, and dried under reduced pressure to obtain 450 mg of pale yellow solid material 2',3-dichloro-4-hydroxy-5'-methoxy-6-methyl-2H-[1,4'-bipyridin]-2-one (yield: 73.9%). LCMS: RT=1.68 min, [M+H] + =301.09. Step C: Synthesis of 2′,3-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′-methoxy-6-methyl-2H-[1,4′-bipyridin]-2-one. [ka] At room temperature, 2-(bromomethyl)-3,5-difluoropyridine (180 mg, 0.87 mmol) and potassium carbonate (200 mg, 1.44 mmol) were added to an N,N-dimethylformamide solution (3.0 ml) containing 2',3-dichloro-4-hydroxy-5'-methoxy-6-methyl-2H-[1,4'-bipyridin]-2-one (217 mg, 0.72 mmol), and the mixture was allowed to react at room temperature for 1 hour. After the reaction was completed, water (10.0 ml) was added to precipitate the solid, which was filtered, rinsed twice with water, and dried under reduced pressure to obtain 220 mg of pale yellow solid material 2',3-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5'-methoxy-6-methyl-2H-[1,4'-bipyridin]-2-one (yield: 71.4%). LCMS: RT=1.89 min, [M+H] + =428.07. Step D: Synthesis of 3″-chloro-4″-((3,5-difluoropyridin-2-yl)methoxy)-3-(2-hydroxypropan-2-yl)-5′-methoxy-6″-methyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione. [ka] At room temperature, 2',3-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5'-methoxy-6-methyl-2H-[1,4'-bipyridin]-2-one (220 mg, 0.51 mmol), 3-(2-hydroxypropan-2-yl)-pyridin-2(1H)-one (118 mg, 0.77 mmol), potassium carbonate (132 mg, 1.02 mmol), cuprous iodide (49 mg, 0.26 mmol) and dimethylethylenediamine (46 mg, 0.51 mmol) in 1,4-dioxane (5.0 ml) were degassed, protected with nitrogen gas and subjected to a microwave reaction at 110 °C for 2 hours. After the reaction was completed, it was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate). 22 mg of pale yellow solid 3″-chloro-4″-((3,5-difluoropyridin-2-yl)methoxy)-3-(2-hydroxypropan-2-yl)-5′-methoxy-6″-methyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione (yield: 7.8%) was obtained. LCMS: RT=1.86 min, [M+H] + =545.21.

[0086] Example 40 [ka] The synthetic route for compound No. 40 is as follows. Step A: Synthesis of 3-bromo-2-((4-methoxybenzyl)oxy)pyridine. [ka] At room temperature, 4-methoxybenzyl alcohol (1.5 g, 11.0 mmol) and potassium tert-butoxide (1.34 g, 12.0 mmol) were added to 1,4-dioxane (30.0 ml) containing 3-bromo-2-chloropyridine (1.92 g, 10.0 mmol), and the mixture was heated to 100° C. and reacted for 12 hours. After the reaction was completed, it was quenched by adding water, extracted with ethyl acetate (50ml x 3 times), the organic phases were combined, first washed with saturated saline (50ml x 2 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 8). 2.85g of 3-bromo-2-((4-methoxybenzyl)oxy)pyridine (yield: 97.3%) was obtained as a yellow oily liquid. LCMS: RT = 2.18min, [M + H] + =294.05. Step B: Synthesis of 3-(3,6-dihydro-2H-pyran-4-yl)-2-((4-methoxybenzyl)oxy)pyridine. [ka] Tetrakis(triphenylphosphine)palladium (115.6 mg, 0.1 mmol) and sodium carbonate (270 mg, 2.5 mmol) were added to a solution of 3-bromo-2-((4-methoxybenzyl)oxy)pyridine (293.0 mg, 1.0 mmol) and 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (252.0 mg, 1.2 mmol) in a mixed solvent (4.0 ml, 1,4-dioxane / water=3 / 1) at room temperature, and the mixture was protected with nitrogen gas and heated to 100° C. for 12 hours to react. The reaction was completed, quenched by adding water, extracted with ethyl acetate (20ml x 3 times), the organic phases were combined, washed with saturated saline (20ml x 2 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 8). 194mg of yellow solid 3-(3,6-dihydro-2H-pyran-4-yl)-2-((4-methoxybenzyl)oxy)pyridine (yield: 65.3%) was obtained. LCMS: RT = 2.14min, [M+H] + =298.24. Step C: Synthesis of 3-(tetrahydro-2H-pyran-4-yl)pyridin-2(1H)-one. [ka] Wet palladium carbon (125.8 mg, 0.065 mmol) was added to a solution of 3-(3,6-dihydro-2H-pyran-4-yl)-2-((4-methoxybenzyl)oxy)pyridine (194.0 mg, 0.65 mmol) in a mixed solvent (4.0 ml, methanol / ethyl acetate = 2 / 1) at room temperature, and the mixture was replaced with hydrogen gas three times. The mixture was heated to 40°C in a hydrogen gas atmosphere and reacted for 12 hours. After the reaction was completed, it was filtered and concentrated. The pale yellow solid 3-(tetrahydro-2H-pyran-4-yl)pyridin-2(1H)-one was used directly in the next step. LCMS: RT=1.50 min, [M+H] + =180.15. Step C: Synthesis of 3″-chloro-4″-((3,5-difluoropyridin-2-yl)methoxy)-5′,6″-dimethyl-3-(tetrahydro-2H-pyran-4-yl)-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione. [ka] At room temperature, 2'-bromo-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one (137 mg, 0.30 mmol), 3-(tetrahydro-2H-pyran-4-yl)pyridin-2(1H)-one (109.2 mg, 0.61 mmol), cuprous iodide (12 mg, 0.06 mmol) and potassium carbonate (84 mg, 0.61 mmol) were dissolved in dioxane (4.0 ml), dimethylethylenediamine (1 drop) was added dropwise, and the mixture was protected with nitrogen gas and subjected to a microwave reaction at 80 ° C for 40 minutes. After the reaction was completed, the mixture was filtered, concentrated, and purified by silica gel column chromatography (eluent: ethyl acetate). 115.3 mg of 3″-chloro-4″-((3,5-difluoropyridin-2-yl)methoxy)-5′,6″-dimethyl-3-(tetrahydro-2H-pyran-4-yl)-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione (yield: 69.4%) was obtained as a white solid. LCMS: RT=1.86 min, [M+H] + =555.23.

[0087] Example 41 [ka] The synthetic route for compound No. 41 is as follows. Step A: Synthesis of 2′,3-dibromo-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one. [ka] At room temperature, N-bromosuccinimide (77 mg, 0.65 mmol) and dichloroacetic acid (1 drop) were added to isopropanol (3.0 ml) containing 2'-bromo-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one (250 mg, 0.59 mmol), and the mixture was heated to 65°C and reacted for 1 hour. After the reaction was completed, the mixture was cooled to room temperature, filtered, and dried under reduced pressure to obtain 230 mg of a white solid, 2',3-dibromo-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one (yield: 77.2%). LCMS: RT=1.93 min, [M+H] + =501.99. Step B: Synthesis of 3″-bromo-4″-((3,5-difluoropyridin-2-yl)methoxy)-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione. [ka] At room temperature, 2',3-dibromo-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one (100 mg, 0.20 mmol), 3-(2-hydroxypropan-2-yl)-pyridin-2(1H)-one (37 mg, 0.24 mmol), potassium carbonate (55 mg, 0.40 mmol), cuprous iodide (8 mg, 0.04 mmol) and dimethylethylenediamine (7 mg, 0.08 mmol) in 1,4-dioxane (2.0 ml) were degassed, protected with nitrogen gas and subjected to a microwave reaction at 80 °C for 1 hour. After the reaction was completed, it was filtered and concentrated. The mixture was purified by silica gel column chromatography (eluent: ethyl acetate). 47 mg of white solid 3″-bromo-4″-((3,5-difluoropyridin-2-yl)methoxy)-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione (yield: 41.2%) was obtained. LCMS: RT=1.87 min, [M+H] + =575.11.

[0088] Example 42 [ka] The synthetic route for compound No. 42 is as follows. Step A: Synthesis of 2-chloro-5-ethylpyridin-4-amine. [ka] A mixture of 2-chloro-5-iodopyridin-4-amine (1.5 g, 5.9 mmol), ethylboronic acid (871.1 mg, 11.8 mmol), [1,1′-bis(triphenylphosphino)ferrocene]dichloropalladium (431.2 mg, 0.6 mmol) and potassium carbonate (1.6 g, 11.8 mmol) in 1,4-dioxane and water (20.0 ml, 1,4-dioxane:water=4:1) was protected with nitrogen gas and heated to 100° C. for 24 hours. After the reaction was completed, water was added to rinse, and the mixture was extracted with ethyl acetate (20 ml x 4 times). The organic phases were combined, washed with saturated saline (20 ml), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 5) to obtain 410.0 mg of 2-chloro-5-ethylpyridin-4-amine (yield: 44.5%) as a pale yellow solid. LCMS: RT = 0.47 min, [M + H] + =157.09. Step B: Synthesis of 2′-chloro-5′-ethyl-4-hydroxy-6-methyl-2H-[1,4′-bipyridin]-2-one. [ka] At room temperature, 2,2-dimethyl-6-(2-oxopropyl)-4H-1,3-dioxin-4-one (574.6 mg, 3.1 mmol) was added to 1,4-dioxane (10.0 ml) containing 2-chloro-5-ethylpyridin-4-amine (410.0 mg, 2.6 mmol), and the mixture was heated to 90° C. and reacted for 2 hours. Sulfuric acid solution (1.5 mL, 10 mol / l) was then added dropwise, and the mixture was reacted at 90° C. for 2 hours. After the reaction was completed, the temperature was lowered to room temperature, water was added to precipitate a solid, which was filtered, rinsed twice with water, and dried under reduced pressure to obtain 180.0 mg of a pale yellow solid substance, 2'-chloro-5'-ethyl-4-hydroxy-6-methyl-2H-[1,4'-bipyridin]-2-one (yield: 26.2%). LCMS: RT=1.70 min, [M+H] + =265.13. Step C: Synthesis of 2′,3-dichloro-5′-ethyl-4-hydroxy-6-methyl-2H-[1,4′-bipyridin]-2-one. [ka] At room temperature, 2'-chloro-5'-ethyl-4-hydroxy-6-methyl-2H-[1,4'-bipyridin]-2-one (180.0 mg, 0.7 mmol) in isopropanol (5.0 ml) was added with 1,2-dichloroethane (2.5 ml), N-chlorosuccinimide (100.1 mg, 0.7 mmol) and dichloroacetic acid (1 drop), and the mixture was heated to 65°C and reacted for 1 hour. After the reaction was completed, it was quenched by adding water, extracted with ethyl acetate (20 ml x 4 times), the organic phases were combined, first washed with saturated saline (10 ml), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 4 / 1) to obtain 230.0 mg of pale yellow solid material (crude product) 2',3-dichloro-5'-ethyl-4-hydroxy-6-methyl-2H-[1,4'-bipyridin]-2-one. LCMS: RT = 1.74 min, [M + H] + =299.12. Step D: Synthesis of 2′,3-dichloro-5′-ethyl-4-((3,5-difluoropyridin-2-yl)methoxy)-6-methyl-2H-[1,4′-bipyridin]-2-one. [ka] At room temperature, 2-(bromomethyl)-3,5-difluoropyridine (176.2 mg, 0.8 mmol) and potassium carbonate (212.5 mg, 1.5 mmol) were added to an N,N-dimethylformamide solution (2.0 ml) containing 2',3-dichloro-5'-ethyl-4-hydroxy-6-methyl-2H-[1,4'-bipyridin]-2-one (230.0 mg, 0.8 mmol), and the mixture was allowed to react at room temperature for 1 hour. The reaction was completed, quenched by adding water, extracted with ethyl acetate (20ml x 3 times), the organic phases were combined, washed with saturated saline (10ml), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 4 / 1). 91.0mg of yellow solid material 2',3-dichloro-5'-ethyl-4-((3,5-difluoropyridin-2-yl)methoxy)-6-methyl-2H-[1,4'-bipyridin]-2-one (yield: 27.7%) was obtained. LCMS: RT = 1.95min, [M+H] + =426.12. Step E: Synthesis of 3″-chloro-5′-ethyl-4″-((3,5-difluoropyridin-2-yl)methoxy)-3-(2-hydroxypropan-2-yl)-6″-methyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione. [ka] At room temperature, 2',3-dichloro-5'-ethyl-4-((3,5-difluoropyridin-2-yl)methoxy)-6-methyl-2H-[1,4'-bipyridin]-2-one (71.0 mg, 0.16 mmol), 3-(2-hydroxypropan-2-yl)-pyridin-2(1H)-one (38.3 mg, 0.25 mmol), potassium carbonate (146.1 mg, 0.3 mmol), cuprous iodide (15.8 mg, 0.08 mmol) and dimethylethylenediamine (15 mg, 0.16 mmol) in 1,4-dioxane (5.0 ml) were degassed, protected with nitrogen gas and subjected to a microwave reaction at 110 °C for 2 hours. After the reaction was completed, the mixture was filtered and concentrated. It was separated by preparative high performance liquid chromatography to obtain 3.0 mg of a white solid, 3″-chloro-5′-ethyl-4″-((3,5-difluoropyridin-2-yl)methoxy)-3-(2-hydroxypropan-2-yl)-6″-methyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione (yield: 3.3%). LCMS: RT=1.91 min, [M+H] + =543.20.

[0089] Example 43 [ka] The synthetic route for compound No. 43 is as follows. Step A: Synthesis of 3″-chloro-4″-((2,4,6-trifluorobenzyl)oxy)-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione. [ka] 2,4,6-Trifluorobenzyl bromide (45 mg, 0.20 mmol) and potassium carbonate (55 mg, 0.40 mmol) were added to N,N-dimethylformamide (3 ml) containing 3″-chloro-4″-((2,4,6-trifluorobenzyl)oxy)-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione (80 mg, 0.20 mmol) at room temperature, and the mixture was allowed to react at room temperature for 1 hour. The reaction was completed, quenched by adding water, extracted with ethyl acetate (20 ml x 3 times), the organic phases were combined, first washed with saturated saline (20 ml x 2 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate). 21 mg of white solid 3″-chloro-4″-((2,4,6-trifluorobenzyl)oxy)-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione (yield: 25%) was obtained. LCMS: RT=1.97 min, [M+H] + =546.21.

[0090] Example 44 [ka] The synthetic route for compound No. 44 is as follows. Step A: Synthesis of 1-(bromomethyl)-2,3,4-trifluorobenzene. [ka] Triphenylphosphine (813.5 mg, 3.11 mmol) and carbon tetrabromide (823.8 mg, 2.48 mmol) were added to tetrahydrofuran (5.0 ml) containing (2,3,4-trifluorophenyl)methanol (335.4 mg, 2.07 mmol) at 0° C., and the mixture was allowed to react at room temperature for 1 hour. The reaction was completed and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate=10 / 1). 388.0 mg of colorless oily substance 1-(bromomethyl)-2,3,4-trifluorobenzene (yield: 73.2%) was obtained. LCMS: RT=2.11 min. Step B: Synthesis of 3″-chloro-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-4″-((2,3,4-trifluorobenzyl)oxy)-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione. [ka] 1-(Bromomethyl)-2,3,4-trifluorobenzene (40.2 mg, 0.18 mmol) and potassium carbonate (33.12 mg, 0.24 mmol) were added to N,N-dimethylformamide (2.0 ml) containing 3″-chloro-4″-hydroxy-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione (50.0 mg, 0.12 mmol) at room temperature, and the mixture was allowed to react at room temperature for 2 hours. The reaction was completed, quenched by adding water, extracted with ethyl acetate (20 ml x 3 times), the organic phases were combined, washed first with saturated saline (20 ml x 2 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 0). 35.2 mg of white solid 3"-chloro-3-(2-hydroxypropan-2-yl)-5',6"-dimethyl-4"-((2,3,4-trifluorobenzyl)oxy)-2H,2"H-[1,2':4',1"-terpyridine]-2,2"-dione (yield: 53.7%) was obtained. LCMS: RT = 1.98 min, [M+H] + =546.20.

[0091] Example 45 [ka] The synthetic route for compound No. 45 is as follows. Step A: Synthesis of methyl 6-chloro-4-((4-methoxybenzyl)amino)nicotinate. [ka] Methyl 4,6-dichloronicotinate (7.0 g, 33.9 mmol), p-methoxybenzylamine (5.6 g, 40.8 mmol), and triethylamine (4.1 g, 40.8 mmol) were dissolved in acetonitrile (60.0 ml) at room temperature, and the mixture was allowed to react at room temperature for 12 hours. After the reaction was completed, the mixture was concentrated, water was added, and the mixture was extracted with ethyl acetate (20 ml x 4 times). The organic phases were combined, washed with saturated saline (20 ml), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane=1 / 3). 9.3 g of methyl 6-chloro-4-((4-methoxybenzyl)amino)nicotinate (yield: 89.6%) was obtained as a white solid. LCMS: RT=2.07 min, [M+H] + =307.13. Step B: Synthesis of (6-chloro-4-((4-methoxybenzyl)amino)pyridin-3-yl)methanol. [ka] Methyl 6-chloro-4-((4-methoxybenzyl)amino)nicotinate (9.3 g, 30.3 mmol) was dissolved in tetrahydrofuran (90.0 ml) at room temperature, lithium aluminum hydride (1.7 g, 45.5 mmol) was added in portions at 0° C., and the mixture was warmed to room temperature and reacted for 30 minutes. After the reaction was completed, 1.7 ml of water and 1.7 ml of 15% aqueous sodium hydroxide solution were added in an ice bath, and the mixture was filtered by suction and concentrated to obtain 5.0 g of a white solid (6-chloro-4-((4-methoxybenzyl)amino)pyridin-3-yl)methanol (yield: 60.0%). LCMS: RT=1.73 min, [M+H] + =1279.16. Step C: Synthesis of 2-chloro-5-(fluoromethyl)-N-(4-methoxybenzyl)pyridin-4-amine. [ka] At room temperature, (6-chloro-4-((4-methoxybenzyl)amino)pyridin-3-yl)methanol (5.0 g, 18.0 mmol) was dissolved in dichloromethane (100.0 ml), the temperature was lowered to 0°C, diethylaminosulfur trifluoride (4.3 g, 27.0 mmol) was added dropwise, and after the addition was completed, the mixture was allowed to react at 0°C for 30 minutes. After the reaction was completed, it was poured into saturated aqueous sodium bicarbonate solution, extracted with dichloromethane (30ml x 3 times), the organic phases were combined, washed with saturated saline (20ml), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane) to obtain 930.0mg of 2-chloro-5-(fluoromethyl)-N-(4-methoxybenzyl)pyridin-4-amine (yield: 18.4%) as a pale yellow liquid. LCMS: RT=1.93min, [M+H] + =281.17. Step D: Synthesis of 2-chloro-5-(fluoromethyl)pyridin-4-amine. [ka] At room temperature, 2-chloro-5-(fluoromethyl)-N-(4-methoxybenzyl)pyridin-4-amine (930.0 mg, 3.3 mmol) was dissolved in dichloromethane (10.0 ml), the temperature was lowered to 0°C, methanesulfonic acid (1.0 ml) was added dropwise, and after the addition was completed, the mixture was allowed to react at room temperature for 2 hours. After the reaction was completed, the reaction solution was slowly poured into saturated aqueous sodium bicarbonate solution, extracted with dichloromethane (10 ml x 3 times), the organic phases were combined, dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure to obtain 393.0 mg of a pale yellow solid, 2-chloro-5-(fluoromethyl)pyridin-4-amine (yield: 44.5%). LCMS: RT = 0.47 min, [M + H] + =161.08. Step E: Synthesis of 2′-chloro-5′-(fluoromethyl)-4-hydroxy-6-methyl-2H-[1,4′-bipyridin]-2-one. [ka] At room temperature, 2,2-dimethyl-6-(2-oxopropyl)-4H-1,3-dioxin-4-one (542.9 mg, 2.9 mmol) was added to 1,4-dioxane (10.0 ml) containing 2-chloro-5-(fluoromethyl)pyridin-4-amine (393.0 mg, 2.4 mmol), and the mixture was heated to 90° C. and reacted for 2 hours. A sulfuric acid solution (1.0 mL, 10 mol / l) was added dropwise, and the mixture was then reacted at 90° C. for 2 hours. After the reaction was completed, the temperature was lowered to room temperature, water was added to precipitate a solid, which was filtered, rinsed twice with water, and dried under reduced pressure to obtain 163.0 mg of a pale yellow solid substance, 2'-chloro-5'-(fluoromethyl)-4-hydroxy-6-methyl-2H-[1,4'-bipyridin]-2-one (yield: 25.3%). LCMS: RT=1.68 min, [M+H] + =269.12. Step F: Synthesis of 2′,3-dichloro-5′-(fluoromethyl)-4-hydroxy-6-methyl-2H-[1,4′-bipyridin]-2-one. [ka] At room temperature, 2'-chloro-5'-(fluoromethyl)-4-hydroxy-6-methyl-2H-[1,4'-bipyridin]-2-one (143.0 mg, 0.5 mmol) in isopropanol (5.0 ml) was added with 1,2-dichloroethane (2.5 ml), N-chlorosuccinimide (78.4 mg, 0.6 mmol) and dichloroacetic acid (1 drop), and the mixture was heated to 65°C and reacted for 1 hour. After the reaction was completed, it was quenched by adding water, extracted with ethyl acetate (10ml x 4 times), the organic phases were combined, first washed with saturated saline (10ml), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 4 / 1) to obtain 23.0mg of pale yellow solid material 2',3-dichloro-5'-(fluoromethyl)-4-hydroxy-6-methyl-2H-[1,4'-bipyridin]-2-one (yield: 15.2%). LCMS: RT = 1.68min, [M + H] + =303.07. Step G: Synthesis of 2′,3-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′-(fluoromethyl)-6-methyl-2H-[1,4′-bipyridin]-2-one. [ka] At room temperature, 2-(bromomethyl)-3,5-difluoropyridine (19.0 mg, 0.09 mmol) and potassium carbonate (20.9 mg, 0.15 mmol) were added to an N,N-dimethylformamide solution (5.0 ml) containing 2',3-dichloro-5'-(fluoromethyl)-4-hydroxy-6-methyl-2H-[1,4'-bipyridin]-2-one (23.0 mg, 0.07 mmol), and the mixture was allowed to react at room temperature for 1 hour. The reaction was completed, quenched by adding water, extracted with ethyl acetate (10ml x 3 times), the organic phases were combined, washed with saturated saline (10ml), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 6 / 1). 15.0mg of yellow solid material 2',3-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5'-(fluoromethyl)-6-methyl-2H-[1,4'-bipyridin]-2-one (yield: 49.9%) was obtained. LCMS: RT = 1.91min, [M+H] + =430.09. Step H: Synthesis of 3″-chloro-4″-((3,5-difluoropyridin-2-yl)methoxy)-5′-(fluoromethyl)-3-(2-hydroxypropan-2-yl)-6″-methyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione. [ka] At room temperature, 2',3-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5'-(fluoromethyl)-6-methyl-2H-[1,4'-bipyridin]-2-one (15.0 mg, 0.035 mmol), 3-(2-hydroxypropan-2-yl)-pyridin-2(1H)-one (8.0 mg, 0.052 mmol), potassium carbonate (9.6 mg, 0.07 mmol), cuprous iodide (3.3 mg, 0.0175 mmol) and dimethylethylenediamine (15 mg, 0.16 mmol) in 1,4-dioxane (5.0 ml) were degassed, protected with nitrogen gas and subjected to a microwave reaction at 100 °C for 1 hour. After the reaction was completed, the mixture was filtered and concentrated. It was separated by preparative high performance liquid chromatography to obtain 0.5 mg of a white solid, 3″-chloro-4″-((3,5-difluoropyridin-2-yl)methoxy)-5′-(fluoromethyl)-3-(2-hydroxypropan-2-yl)-6″-methyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione (yield: 2.6%). LCMS: RT=1.86 min, [M+H] + =547.20.

[0092] Example 46 [ka] The synthetic route for compound No. 46 is as follows. Step A: Synthesis of 2′-chloro-4-hydroxy-6-methyl-5′-(trifluoromethyl)-2H-[1,4′-bipyridin]-2-one. [ka] At room temperature, 2-chloro-5-trifluoromethylpyridin-4-amine (1.55 g, 7.6 mmol) was dissolved in dioxane (20 ml), and 2,2-dimethyl-6-(2-oxopropyl)-4H-1,3-dioxin-4-one (1.4 g, 7.6 mmol) was added. The temperature was raised to 90° C. and the reaction was carried out for 5 hours. Then, 10N aqueous sulfuric acid solution was added dropwise until no solid was generated, and the reaction was continued for 2 hours. After the reaction was completed, the mixture was concentrated, water was added, and a pale yellow precipitate was precipitated. The precipitate was stirred for 0.5 hours, filtered, and rinsed twice with water to obtain 1 g of ocher solid 2′-chloro-4-hydroxy-6-methyl-5′-(trifluoromethyl)-2H-[1,4′-bipyridin]-2-one (yield: 43%). LCMS: RT=1.75 min, [M+H] + =305.04. Step C: Synthesis of 2′,3-dichloro-4-hydroxy-6-methyl-5′-(trifluoromethyl)-2H-[1,4′-bipyridin]-2-one. [ka] 2'-Chloro-4-hydroxy-6-methyl-5'-(trifluoromethyl)-2H-[1,4'-bipyridin]-2-one (1 g, 3.28 mmol) was dissolved in isopropanol (30 ml) at room temperature, and NCS (540 mg, 3.28 mmol) was added thereto. Dichloroacetic acid (1 drop) was then added dropwise thereto, and the mixture was heated to 60°C and reacted for 6 hours. After the reaction was completed, it was quenched by adding water and extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography (ethyl acetate) to give 900 mg of the product 2',3-dichloro-4-hydroxy-6-methyl-5'-(trifluoromethyl)-2H-[1,4'-bipyridin]-2-one as a white solid (yield: 82%). LCMS: RT=1.78 min, [M+H] + =338.99. Step B: Synthesis of 2′,3-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy)-6-methyl-5′-(trifluoromethyl)-2H-[1,4′-bipyridin]-2-one. [ka] At room temperature, 2-(bromomethyl)-3,5-difluoropyridine (185 mg, 0.89 mmol) and potassium carbonate (246 mg, 1.78 mmol) were added to N,N-dimethylformamide (3 ml) containing 2',3-dichloro-4-hydroxy-6-methyl-5'-(trifluoromethyl)-2H-[1,4'-bipyridin]-2-one (300 mg, 0.89 mmol), and the mixture was allowed to react at room temperature for 1 hour. The reaction was completed, quenched by adding water, extracted with ethyl acetate (20ml x 3 times), the organic phases were combined, washed first with saturated saline (20ml x 2 times), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. Purification was performed by silica gel column chromatography (eluent: ethyl acetate). 150mg of 2',3-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy)-6-methyl-5'-(trifluoromethyl)-2H-[1,4'-bipyridin]-2-one (yield: 36%) was obtained as a white solid. LCMS: RT=1.98min, [M+H] + =466.04. Step E: Synthesis of 3″-chloro-4″-((3,5-difluoropyridin-2-yl)methoxy)-3-(2-hydroxypropan-2-yl)-6″-methyl-5′-(trifluoromethyl)-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione. [ka] At room temperature, 2',3-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy)-6-methyl-5'-(trifluoromethyl)-2H-[1,4'-bipyridin]-2-one (50 mg, 0.11 mmol), cuprous iodide (6 mg, 0.02 mmol) and potassium carbonate (61 mg, 0.22 mmol) were dissolved in dioxane (4 ml), and dimethylethylenediamine (1 drop) was added dropwise, followed by a microwave reaction at 80°C for 1 hour. After the reaction was completed, it was filtered, rinsed with ethyl acetate, concentrated and purified by column chromatography (eluent: ethyl acetate) to give 1 mg of the product 3″-chloro-4″-((3,5-difluoropyridin-2-yl)methoxy)-3-(2-hydroxypropan-2-yl)-6″-methyl-5′-(trifluoromethyl)-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione as a white solid. LCMS: RT=1.97 min, [M+H] + =583.20.

[0093] Comparative Example 1 The structure of the compound 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one is below. [ka] The synthetic route of the compound of Comparative Example 1 refers to the synthetic route of compound No. 49 in the specification of Chinese Patent No. CN201480032278.5. Using supercritical fluid chromatography (OD-H column), the racemic Comparative Example 1 compound was separated with a mobile phase of carbon dioxide and ethanol, and the atropisomers Comparative Examples 1A and 1B compounds were eluted in this order. [ka] Comparative Example 1A compound: RT = 4.47 min (SFC, OD-H, 0.46 cm I.D. x 15 cm L column, isocratic gradient of 40% ethanol, flow rate 2.5 mL / min and cycle time 10 min); [a] D 25 -0.66° (MeOH, Rudolph Autopol I automatic polarimeter). Comparative Example 1B compound: RT=4.68 min (SFC, OD-H, 0.46 cm I.D.×15 cm L column, isocratic gradient of 40% ethanol, flow rate 2.5 mL / min and cycle 10 min). [a] D 25 +0.68° (MeOH, Rudolph Autopol I automatic polarimeter).

[0094] Example 47: Experiment on TNFα release in U937 induced by LPS Cytokine regulation in human monocytes: The p38 pathway has been shown to be key to the biosynthesis of multiple pro-inflammatory cytokines, including TNFα, IL-1β, and IL-6. Thus, inhibition of the p38 MAPK pathway reduces inflammatory responses by decreasing the biosynthesis of pro-inflammatory cytokines. This study shows that half the amount of the compound of the present invention is required to inhibit the biosynthesis of TNFα (a pro-inflammatory cytokine). This reflects the efficacy of the compound of the present invention in reducing inflammation, which is useful in treating many diseases, including chronic inflammatory diseases, acute inflammatory diseases, and autoinflammatory diseases. The human U937 cell line was used to evaluate the potency and efficacy of p38 inhibitors in blocking cytokine production. Reagents and equipment: 1640 Medium, Product No. A10491-01, Gibco. Penicillin-Streptomycin, Product No. 15140-122, Gibco. Fetal Bovine Serum, Product No. 10099-141C, Gibco. PBS, Product No. 10010-031, Gibco. LPS, Product No. L2880, Sigma. PMA, Product No. P1585, Sigma. Dimethyl Sulfoxide, Product No. D8418-1L, Sigma. TNFα Kit, Product No. K151QWD-4, MSD. 96-well plate, item number 3599, Corning. Plate shaker, item number QB-9002, QILINBEIER. Centrifuge, item number 5810R, Eppendorf. Carbon dioxide incubator, item number 371, Thermo. Counter, item number C10281, Gibco. Microscope, item number CKX41, OLYMPUS. MSD plate reader, 1201MESOSECTOR600, MSD Experimental cells: U937, ATCC, Catalog No. CRL-1593.2. Drug preparation: Approximately 2 mg of drug was weighed out and prepared into a 10 mM (based on free alkali) mother solution using DMSO, which was then diluted 10-fold to 1 mM, and then serially diluted 4-fold to 250 μM, 62.5 μM, 15.6 μM, 3.9 μM, 0.97 μM, 0.24 μM, and 0.061 μM. The diluted series of drugs in DMSO were then diluted 20-fold with culture medium to prepare working solutions. Testing Method: Day 0: 10,000 cells were seeded per well, stimulated with 20 ng / ml PMA for 48 h, and cultured at 37°C and 5% CO2; Day 2:1, the supernatant of differentiated U937 was removed, washed once with PBS, and 96 μl of 1640 medium was added; 2. 2 μl of a DMSO solution containing the compound at a final concentration of 0.1% was added and incubated at 37°C and 5% CO2 for 30 min; 3. 2 μl of LPS (final concentration 100 ng / ml) was added to stimulate the cells and incubated at 37°C and 5% CO2 for 4 h; 4. After centrifugation, the supernatant was collected and the TNFα content in the supernatant was measured by ELISA. Statistical method: The TNFα content corresponding to each well was calculated using the standard curve provided in the kit. Compound IC using nonlinear fitting equation in GraphPad 50 was calculated, and the experimental results are shown in Table 1.

[0095] [Table 1]

[0096] As can be seen from the experimental results in Table 1, the compounds of the present invention have obvious inhibitory activity against the production of TNFα, and can regulate associated diseases such as inflammatory responses.

[0097] Example 48: Solubility Measurement 1. Preparation of control solution Approximately 0.5 mg of the sample to be measured was weighed out and placed in a centrifuge tube. First, an appropriate amount of DMSO was added to completely dissolve the sample, and then methanol was added to make the total volume 1 ml. The samples to be measured were compound No. 1 and the compound of Comparative Example 1. 2. Preparation of test solutions Weigh out about 1.0 mg of each of the compounds of Comparative Example 1 and No. 1, and place them in two centrifuge tubes, respectively, and add 1 ml of PBS=2.0 and 7.4 buffer solution to the two centrifuge tubes. (If more pH values ​​need to be investigated, the preparation method can be analogized in this way.) 3. The prepared control solution and test solution were simultaneously placed in a 37°C water bath and heated for 1 hour, then removed after 1 hour and cooled to room temperature. After filtering through a 0.22μm filter membrane, the sample was added. 4. The concentration of the sample in the test solution was calculated based on C = (A × (ms / vs) / AS. The experimental results are shown in Table 2. Note: ms, vs, and AS are the weight, volume, and peak area of ​​the sample in the control solution, respectively; A is the peak area of ​​the test solution.

[0098] [Table 2]

[0099] As can be seen from the experimental results in Table 2, the compounds of Nos. 1, 2, 3 and 20 of the present invention have good dissolution performance, and are superior to the dissolution performance of the compound of Comparative Example 1.

[0100] Example 49: Pharmacokinetics Experiments 1. Reagents and equipment Polyethylene glycol 400 (lot number GORKREUT, Satsuen Chemical Technology (Shanghai) Co., Ltd.), DMSO (lot number 20200319, Guangdong Guanghua Technology Co., Ltd.), physiological saline (lot number C20052604, Jiangxi Kelun Pharmaceutical Industry Co., Ltd.). LCLC-MS equipment (ThermoFisher Ultimate3000UPLC, TSQ QUANTUMULTRA triple quadrupole mass spectrometer). 2. Experimental animals Five male beagle dogs, weighing 5 kg to 7 kg, were purchased from Beijing Marshall Biotechnology Co., Ltd. 3. Preparation of the formulation The test powder was precisely measured and completely dissolved in DMSO, then PEG-400 was added and mixed uniformly using a vortex and ultrasonic wave. Then, saline was added and mixed uniformly using a vortex and ultrasonic wave to make the concentration 0.5 mg / mL (DMSO:PEG-400:NS=5:60:35, V / V / V), and the powder was administered at 5 mL / kg for intragastric administration and 1 mL / kg for intravenous administration. 4. Collecting blood samples Dogs were administered a single dose intragastricly (n=3) or intravenously (n=2), after which approximately 1mL of blood was collected from the vein of the forelimb or hindlimb using a scalp needle at 5 min (no collection was performed in the case of intragastric administration), 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h. The blood was then placed in an EDTA-K2-containing anticoagulant blood collection tube, centrifuged at 4000 rpm for 10 min to separate plasma, which was then stored at -80°C for measurement. 5, bioanalysis A certain amount of sample was precisely weighed and dissolved in DMSO to 2mg / mL to prepare a stock solution. The stock solution was diluted with acetonitrile:water (1:1) to 30000, 10000, 3000, 1000, 300, 100, 50, 30, and 10ng / mL to obtain a standard curve working solution. 5μL of the working solution was added to 45μL of blank dog plasma and mixed uniformly by vortexing to prepare standard curve samples corresponding to plasma concentrations of 3000, 1000, 300, 100, 30, 10, 5, 3, and 1ng / mL. 30μL of the standard curve sample and the collected plasma sample (plasma 5-fold diluted at 5, 15, and 30 min after intravenous administration) were taken, and 150μL of propranolol acetonitrile solution (internal standard, 50ng / mL) was added to precipitate proteins, and 100μL of water was added and mixed uniformly with a vortex, then centrifuged at 4000rpm for 5min, and the supernatant was collected and analyzed by LC-MS. The LC-MS measurement conditions were as follows: Column: Waters ACQUITYTM PREMIER HSST3, 50*2.1mm, 1.8μm. Mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile, flow rate: 0.5 mL / min, gradient elution as shown in Table 3 below:

[0101] [Table 3]

[0102] 6. Data processing After measuring the drug blood concentration by LC-MS, the pharmacokinetic parameters after administration to beagle dogs were calculated using a non-compartment model using WinNonlin 6.1 software, and the results are shown in Table 4 below.

[0103] [Table 4] As can be seen from the experimental results in Table 4, compared with the compound of Comparative Example 1, the compound No. 1 of the present invention has higher oral exposure and bioavailability in dog PK.

[0104] Example 50: Screening experiment for p38α / MK2 complex kinase

[0105] [Table 5]

[0106] [Table 6]

[0107] Drug preparation: A certain amount of drug was weighed out and prepared into a 10 mM mother solution with DMSO, and the mother solution was diluted in two stages to 100 μM (100X working solution), and then diluted three-fold to 33.33 μM, 11.11 μM, 3.70 μM, 1.23 μM, 0.41 μM, 0.14 μM, 0.046 μM, 0.015 μM, and 0.005 μM. A DMSO control was also prepared. The DMSO drug dilution series was then diluted 25-fold with 1X IMAP Reaction Buffer to give 4X drug working solutions. Testing Method: a) Enzymes (MEK6 (active), p38α (inactive), MK2 (inactive), substrate (HSP27) and ATP) were placed in 1X IMAP reaction buffer. b) Add 10 μL of 2X enzyme & substrate working solution and 5 μL of 4X drug working solution to a black 384-well plate. After rapid centrifugation, 5 μL of ATP working solution was added to start the enzyme reaction. Ten gradient concentrations, duplicate measurements were performed for each group of compounds, and a DMSO control group and a negative control group (DMSO, no ATP) were also set up. The final concentrations of each component are shown in Table 7 below.

[0108] [Table 7]

[0109] c) After incubation at room temperature for 1 h, the enzyme reaction was stopped by adding 1X Progressive Binding Solution, and after incubation for 30 min, the fluorescence polarization (FP) signal [FP (Ex485 / Em520 / Em520nm)] was detected using a BMG PHERASTER FSX multifunctional microplate reader. Statistical method: IC of compounds using nonlinear fitting equations in GraphPad Prism7 50 was calculated and the results are shown in Table 8.

[0110] [Table 8]

[0111] As can be seen from the experimental results in Table 8, the compounds of the present invention have obvious inhibitory activity against the p38α / MK2 complex, and can regulate associated diseases such as inflammatory responses.

[0112] Example 51: Screening experiment for p38α kinase

[0113] [Table 9]

[0114] [Table 10]

[0115] Drug preparation: A certain amount of compound was weighed out, prepared in DMSO to a stock solution of 10 / 50 mM, and diluted 3-fold in DMSO to give 10 concentration points as compound working solutions. Testing Method: 50nL of diluted compound working solution was transferred to each well of a reaction plate (784075, Greiner) using Echo 655, and 2.5μL of p38α kinase solution (4ng / μL) was added and left at room temperature for 10 minutes, then 2.5μL of a mixture of kinase substrate (0.2mg / mL) and ATP (150μM) was added and reacted at room temperature for 60 minutes, then 4μL of ADP Glo reagent was added and incubated at room temperature for 40 minutes, 8μL of kinase detection reagent was added and incubated at room temperature for 40 minutes, and finally the luminescence signal was read using Envision2104. Analyzing data IC of compounds with nonlinear fitting equations in GraphPad Prism 8 50 was calculated, and the measurement results are shown in Table 11.

[0116] [Table 11]

[0117] As can be seen from the experimental results in Table 11, the compounds of the present invention have higher activity fold against p38α / (p38α / MK2 complex) and better selectivity compared to the conventional techniques. Note: p38α / MK2 complex kinase data taken from Example 50.

[0118] Example 52: Screening experiment for p38β kinase

[0119] [Table 12]

[0120] [Table 13]

[0121] Drug preparation: A certain amount of compound was weighed out, prepared in DMSO to a stock solution of 10 / 50 mM, and diluted 3-fold in DMSO to give 10 concentration points as compound working solutions. Testing Method: 50nL of diluted compound working solution was transferred to each well of a reaction plate (784075, Greiner) using Echo 655, and 2.5μL of p38β kinase solution (2ng / μL) was added and left at room temperature for 10 minutes, then 2.5μL of a mixture of kinase substrate (0.4mg / mL) and ATP (100μM) was added and reacted at room temperature for 60 minutes, then 4μL of ADP Glo reagent was added and incubated at room temperature for 40 minutes, 8μL of kinase detection reagent was added and incubated at room temperature for 40 minutes, and finally the luminescence signal was read using Envision 2104. Analyzing data IC of compounds with nonlinear fitting equations in GraphPad Prism 8 50 was calculated and the test results are shown in Table 14.

[0122] [Table 14]

[0123] As can be seen from the experimental results in Table 14, the compounds of the present invention have higher activity fold against p38β / (p38α / MK2 complex) and better selectivity compared to the conventional techniques. Note: p38α / MK2 complex kinase data taken from Example 50. The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples. Any other changes, modifications, substitutions, combinations, and simplifications made within the scope not departing from the spirit, substance, and principle of the present invention are all equivalent replacement forms, and all are included in the protection scope of the present invention.

Claims

1. A compound represented by the general formula (I), or a racemate thereof, or a stereoisomer thereof, or a medicamentable salt thereof, 【Chemistry 1】 R １ and R １′ are independently selected from hydrogen, halogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an alkylcycloalkyl group, an alkylheterocycloalkyl group, a phenyl group, a heteroaryl group, a halogenated alkyl group, and a cyano group; or R １ and R １′ are cyclized together to form a cycloalkyl or heterocycloalkyl group; R ２ is selected from hydrogen, halogen, hydroxyl, cyano, alkyl, alkoxy, alkoxyalkyl, and halogenated alkyl; R ３ is independently selected from hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, a halogen, an alkoxy group, a cyano group, and a halogenated alkoxy group; m is 0, 1, 2, or 3; R ４ is selected from hydrogen, an alkyl group, a cycloalkyl group, an alkoxy group, and a halogenated alkyl group; R ５ is selected from hydrogen, an alkyl group, a cycloalkyl group, an alkoxy group, and a halogenated alkyl group; R ６ is selected from hydrogen, halogen, cyano, alkyl, cycloalkyl, and halogenated alkyl; Ring A is selected from an aromatic ring and a heteroaromatic ring; R ７ is independently selected from hydrogen, halogen, cyano, alkyl, cycloalkyl, halogenated alkyl, alkoxy, and halogenated alkoxy; n is 0, 1, 2, 3, 4, or 5; X is O, CH ２ or NH; R ８ , R ９ are independently selected from hydrogen, alkyl groups, cycloalkyl groups, alkylcycloalkyl groups, and halogenated alkyl groups, or R ８ and R ９ are cyclized together to form a cycloalkyl group, or a heterocycloalkyl group, or a racemic form thereof, or a stereoisomer thereof, or a medicamentable salt thereof.

2. The alkyl group is C １－６ alkyl group, １－６ the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, 1-ethylpropyl, 2-methylbutyl, tert-pentyl, 1,2-dimethylpropyl, isopentyl, neopentyl, n-hexyl, isohexyl, sec-hexyl, tert-hexyl, neohexyl, 2-methylpentyl, 1,2-dimethylbutyl, and 1-ethylbutyl; The alkoxy group is １－６ alkoxy group, １－６ the alkoxy group is selected from methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, sec-pentyloxy, 1-ethylpropoxy, 2-methylbutoxy, tert-pentyloxy, 1,2-dimethylpropoxy, isopentyloxy, neopentyloxy, n-hexyloxy, isohexyloxy, sec-hexyloxy, tert-hexyloxy, neohexyloxy, 2-methylpentyloxy, 1,2-dimethylbutoxy, and 1-ethylbutoxy; The alkoxyalkyl group is １－４ Alkoxy C １－４ 2. The compound according to claim 1, or a racemic form thereof, or a stereoisomer thereof, or a medicamentable salt thereof, characterized in that the alkyl group is selected from alkyl groups, and further selected from methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, butoxymethyl, butoxyethyl, butoxypropyl, and butoxybutyl.

3. The cycloalkyl group is ３－６ cycloalkyl groups, C ３－６ 2. The compound according to claim 1, or a racemic form thereof, or a stereoisomer thereof, or a medicamentable salt thereof, characterized in that the cycloalkyl group is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

4. The compound according to claim 1, or its racemate, or its stereoisomer, or its medicamentous salt, characterized in that the aromatic ring is selected from a 4-membered ring, a 4-membered ring-containing fused ring, a 5-membered ring, a 5-membered ring-containing fused ring, a 6-membered ring, a 6-membered ring-containing fused ring, and a biphenyl-type aromatic ring; and the heteroaromatic ring means that one or more carbon atoms of the aromatic ring are replaced with a heteroatom.

5. 2. The compound according to claim 1, or a racemic form thereof, or a stereoisomer thereof, or a medicamentable salt thereof, characterized in that the halogen is selected from fluorine, chlorine, bromine, and iodine; the halogenated alkyl group means that one or more hydrogen atoms of an alkyl group are replaced with a halogen; the halogenated alkoxy group means that one or more hydrogen atoms of an alkoxy group are replaced with a halogen; the heterocycloalkyl group means that one or more carbon atoms of a cycloalkyl group are replaced with a heteroatom; the alkylcycloalkyl group means that one or more hydrogen atoms of a cycloalkyl group are replaced with an alkyl group; and the alkylheterocycloalkyl group means that one or more hydrogen atoms of a heterocycloalkyl group are replaced with an alkyl group.

6. 2. The compound according to claim 1, or a racemic form thereof, or a stereoisomer thereof, or a medicamentable salt thereof, characterized in that the heteroatoms are selected from nitrogen, oxygen, and sulfur, and the heteroatoms are one or more.

7. The A ring is one of the following groups: 【Chemistry 2】 2. The compound according to claim 1, or a racemate thereof, or a stereoisomer thereof, or a medicamentable salt thereof, characterized in that it is selected from:

8. The compounds have the following formulas (Ia) to (Ig): 【Chemistry 3】 The compound is selected from the group consisting of compounds represented by the formula: Wherein, in the formula: m is 0, 1, 2, or 3; n is 0, 1, 2, 3, 4, or 5; R １ , R １′ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , R ９ 2. The compound according to claim 1, or its racemate, or its stereoisomer, or its medicinal salt, characterized in that it is as defined in the compound according to claim 1, or its racemate, or its stereoisomer, or its medicinal salt.

9. m is 0 or 1; n is 0, 1, 2, or 3; The A ring is one of the following groups: 【Chemistry 4】 Selected from: R １ , R １′ is selected from hydrogen, a methyl group, an ethyl group, or R １ and R １′ Together, 【Chemistry 5】 cyclization to R ２ is selected from hydrogen, hydroxyl, difluoromethyl, and cyano; R ３ is selected from hydrogen, a methyl group, a methoxy group, chlorine, and bromine; R ４ is selected from a methyl group, a cyclopropyl group, a methoxy group, an ethyl group, a fluoromethyl group, and a trifluoromethyl group; R ５ is selected from a methyl group; R ６ is selected from chlorine, hydrogen, and bromine; R ７ is selected from hydrogen, fluorine, chlorine, bromine, a cyclopropyl group, a methoxy group, a cyano group, a methyl group, and a trifluoromethyl group; R ８ , R ９ 2. The compound according to claim 1, or a racemic form thereof, or a stereoisomer thereof, or a medicamentable salt thereof, characterized in that: is hydrogen.

10. The compounds are the following 1A, 1B, and 1-46: 【Chemistry 6】 【change】 【change】 【change】 【change】 【change】 2. The compound according to claim 1, characterized in that it is selected from the compounds represented by the formula:

11. The compound according to claim 1, or its racemate, or its stereoisomer, or its medicinal salt, characterized in that the medicinal salt is prepared from the compound, or its stereoisomer, or its racemate, and a pharma- ceutically acceptable acid or base.

12. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 11, or a racemate thereof, or a stereoisomer thereof, or a medicamentable salt thereof, and a pharma- ceutically acceptable carrier.

13. Use of a compound according to any one of claims 1 to 11, or a racemate thereof, or a stereoisomer thereof, or a medicament salt thereof, in the preparation of a medicament for treating a disease, comprising The disease is a p38 / MK2-associated disease and is selected from a chronic inflammatory disease and an acute inflammatory disease, and the chronic inflammatory disease is rheumatoid arthritis.

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