A substituted bipyridinone-aryl(hetero) ring compound and a preparation method and application thereof

Abstract

This application belongs to the field of chemical drug technology and relates to a compound represented by general formula (I), or its racemate, isomer, or pharmaceutically usable salt, which, as a p38 / MK2 inhibitor, can inhibit the production of cytokine TNFα and be used to treat diseases such as arthritis.

Description

Technical Field

[0001] This invention belongs to the field of chemical pharmaceutical technology and relates to a substituted bipyridone-aromatic (heterocyclic) compound, or its isomer, racemate, or pharmaceutically usable salt thereof, and its preparation method and application. Background Technology

[0002] Mitogen-activated protein kinases (MAPKs) are a conserved family of enzymes that use phosphorylation cascades to transmit and deliver external stimuli in order to produce coordinated cellular responses to the environment. MAPKs are proline-guided serine / threonine-specific protein kinases that regulate cellular activities such as gene expression, mitosis, differentiation, and cell survival / apoptosis. To date, four distinct classes of mammalian MAPKs have been identified: extracellular signal transduction kinases (ERK1 and ERK2), c-jun N-terminal kinase-1 (JNK1-3), p38MAPKs (p38α, p38β, p38γ, and p38δ), and ERK5.

[0003] Scientific investigation of this pathway from a biological, cellular, and in vivo perspective is primarily achieved through the availability of highly effective, selective small-molecule inhibitors targeting the α-isomer of p38MAPK and, to a lesser extent, the β-isomer. p38αMAPK is a major isomer involved in immune and inflammatory responses. Therefore, its function is crucial for the production and activity of various pro-inflammatory cytokines in cells such as macrophages, monocytes, synovial cells, and endothelial cells, including TNFα, IL-1, IL-6, and IL-8. p38MAPK is also responsible for inducing key inflammatory enzymes, such as COX2 and iNOS, which are major sources of arachidonic acid and nitric oxide at inflammatory sites, respectively. Furthermore, 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 p38MAPK substrates, including transcription factors, MAPKAP kinases, and other enzymes. MAPKAP kinases (MK2, MK-3, and PRAK) are selectively phosphorylated by p38MAPK, while phosphorylation of MSK1 / 2, MNK1 / 2, and RSKb is catalyzed by both p38MAPK and ERK. Although substrate identification is challenging due to the lack of specific inhibitors, RSKb activation is thought to play a role in cell survival.

[0005] Once phosphorylated and activated by p38MAPK, MK-2, MK-3, and PRAK share similar substrate specificity. All of these kinases phosphorylate the small heat shock protein Hsp27. Studies have shown that PRAK- and MK3-deficient mice do not exhibit any tolerance to endotoxin shock or lipopolysaccharide (LPS)-induced reductions in cytokine production. In contrast, MK-2-deficient mice show tolerance to endotoxin shock and impaired inflammatory responses, as well as a significant reduction in the production of cytokines such as TNFα, IFNγ, and IL-6. Therefore, the p38 / MK2 axis is particularly necessary and sufficient for regulating pro-inflammatory responses.

[0006] By utilizing the p38:MK2 interaction and using MK2 as a p38 substrate, a novel p38α inhibitor exhibiting properties of interest was discovered (Davidson et al.). This inhibitor demonstrates substrate selectivity by preventing p38α-dependent phosphorylation of MK2 (Ki app 300 nM) while preserving p38α-dependent phosphorylation of ATF2 (Ki app > 20 μM). This novel inhibitor functions uniquely compared to conventional p38ATP-competitive inhibitors that block p38-dependent phosphorylation of all p38 substrates. A second independent study also described a p38 inhibitor with unique mechanistic properties. This work demonstrated a novel mechanism for selectively inhibiting p38-dependent phosphorylation of MK2. Unlike previous studies by Davidson et al., these compounds with unique mechanisms compete with ATP and stabilize the p38 / MK2 complex.

[0007] In summary, these two studies clearly demonstrate the concept that selective p38 / MK2 axis blockade can be achieved using small molecule inhibitors. Compared to conventional p38MAPK 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 existing in the prior art, this application provides a substituted bipyridone-aromatic (heterocyclic) compound, or its isomer, racemate, or pharmaceutically acceptable salt thereof, as a p38 / MK2 inhibitor. This compound can inhibit the production of the cytokine TNFα, thereby regulating inflammatory responses and related diseases.

[0009] In a first aspect, this application provides a compound of general formula (I), or its isomers, racemates, or pharmaceutically acceptable salts thereof:

[0010]

[0011] In a second aspect, the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of any of the compounds described above or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0012] Thirdly, the present invention also provides the use of a therapeutically effective amount of the above-described compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a condition, said condition being a p38 / MK2-related disease, wherein the compound can inhibit the production of the cytokine TNFα, thereby regulating inflammatory responses and other related diseases; specifically, said condition is selected from chronic inflammatory diseases, acute inflammatory diseases, and autoinflammatory diseases.

[0013] Specifically, the present invention is achieved through the following technical solution:

[0014] A compound of general formula (I), or an isomer thereof, a racemic mixture thereof, or a pharmaceutically acceptable salt thereof.

[0015]

[0016] Among them, ring A is selected from aromatic rings and heteroaromatic rings, and R... 1 Selected from hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, alkylheterocycloalkyl, haloalkyl, cyano, alkoxy, p is 0, 1, 2, 3, 4 or 5;

[0017] R 2 Independently selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, halogen, -O-alkyl, cyano, haloalkoxy, sulfone, where m is 0, 1, 2 or 3;

[0018] R 3 Selected from hydrogen, alkyl, cycloalkyl, -O-alkyl, and haloalkyl;

[0019] R 4 Selected from hydrogen, alkyl, cycloalkyl, -O-alkyl, and haloalkyl;

[0020] R 5 Selected from hydrogen, halogen, cyano, alkyl, cycloalkyl, and haloalkyl;

[0021] The B ring is selected from aromatic rings and heteroaromatic rings, and the R ring... 6 Independently selected from hydrogen, halogen, cyano, alkyl, cycloalkyl, haloalkyl, -O-alkyl, haloalkoxy, sulfone, where n is 0, 1, 2, 3, 4 or 5;

[0022] X is O, CH2 or NH, and Y is CH or N;

[0023] R 7 R 8 Independently selected from hydrogen, alkyl, cycloalkyl, alkylcycloalkyl, haloalkyl, or R 7and R 8 They can cyclize together to form cycloalkyl and heterocycloalkyl groups.

[0024] As a preferred embodiment of the present invention, the alkyl group is selected from C. 1-6 alkyl group, the C 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.

[0025] The alkoxy group is selected from C. 1-6 Alkoxy, the C 1-6 The alkoxy group is selected from methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, sec-pentoxy, 1-ethylpropoxy, 2-methylbutoxy, tert-pentoxy, 1,2-dimethylpropoxy, isopentoxy, neopentoxy, n-hexyloxy, isohexyloxy, sec-hexyloxy, tert-hexyloxy, neohexyloxy, 2-methylpentoxy, 1,2-dimethylbutoxy, and 1-ethylbutoxy; the alkoxyalkyl group is selected from C 1-4 Alkoxy C 1-4 The alkyl group is further selected from methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl.

[0026] As a preferred embodiment of the present invention, the cycloalkyl group is selected from C 3-6 cycloalkanes, C 3-6 The cycloalkane is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0027] As a preferred embodiment of the present invention, the aromatic ring is selected from four-membered rings, fused rings containing four-membered rings, five-membered rings, fused rings containing five-membered rings, six-membered rings, fused rings containing six-membered rings, and biphenyl-type aromatic rings; the heteroaromatic ring refers to an aromatic ring in which at least one carbon atom is replaced by a heteroatom.

[0028] The aromatic ring includes a benzene ring and a naphthalene ring;

[0029] The heteroaromatic rings include indazole, quinoline, isoquinoline, quinoxaline, indole, isoindole, cyclophosphine, quinazoline, phthalazine, purine, naphthidine, pteridine, benzofuran, benzothiophene, benzoxazole, benzothiazole, benzoisoxazole, benzoisothiazole, benzoxadiazole, benzothiazole, benzotriazole, benzotriazine, benzoimidazine, pyrazinopyrazole, pyrazinopyrimidine, pyrazinopyridazine ... Oxadiazole, pyridothiadiazole, pyridofuran, pyridopyrrole, pyrazinoxazole, pyrazinthiazole, pyrazinisoxazole, pyrazinisothiaazole, pyrazinoxadiazole, pyrazinthiadiazole, pyrazinfuran, pyrazinpyrrole, pyrimidinoxazole, pyrimidinthiaazole, pyrimidinisothiaazole, pyrimidinoxadiazole, pyrimidinthiadiazole, pyrimidinfuran, pyrimidinpyrrole, pyrazinoxazole, pyrazinthiaazole, pyrazinisothiaazole, pyrazinoxadiazole, pyrazinthiadiazole, pyrazinfuran, pyrazinpyrrole, triazinoxazole, triazinthiaazole, triazinisothiaazole, triazinoxadiazole, triazinthiadiazole, triazinfuran, triazinpyrrole.

[0030] Specifically, for example, the naphthidine is selected from The pyridine-imidazol is selected from... The pyrazinimidazole is selected from... The pyrazinazole is selected from The pyrimidopyrazole is selected from The pyrimidinimidazole is selected from... The pyrimidotriazole is selected from The pyridazinimidazole is selected from The pyridazintriazole is selected from The triazinimidazole is selected from The pyridopyridazine is selected from The pyridinepyrazole is selected from The pyridine-pyrimidine is selected from The pyridotriazine is selected from The pyrimidine triazine is selected from

[0031] Specifically, for example, heterocyclic alkyl groups are selected from

[0032] The heteroaryl group is selected from

[0033] In a preferred embodiment of the present invention, the halogen is selected from fluorine, chlorine, bromine, and iodine;

[0034] Haloalkyl refers to an alkyl group in which at least one hydrogen atom is replaced by a halogen, and haloalkoxy refers to an alkoxy group in which at least one hydrogen atom is replaced by a halogen.

[0035] Alkylcycloalkyl refers to a cycloalkyl group in which at least one hydrogen atom is replaced by an alkyl group;

[0036] Heterocyclic alkyl refers to a cycloalkyl group in which at least one carbon atom is replaced by a heteroatom; alkyl heterocyclic alkyl refers to a cycloalkyl group in which at least one hydrogen atom is replaced by an alkyl group.

[0037] As a preferred embodiment of the present invention, the heteroatom is selected from nitrogen, oxygen, and sulfur, and there are one or more heteroatoms.

[0038] As a preferred embodiment of the present invention, the compound, or its isomer, racemate, or pharmaceutically acceptable salt thereof, has a structure of formula (Ia) or (Ib):

[0039]

[0040] Where m is 0, 1, 2, or 3; n is 0, 1, 2, 3, 4, or 5; p is 0, 1, 2, 3, 4, or 5; R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 Ring A and ring B are defined as above.

[0041] As a preferred embodiment of the present invention, ring A is selected from: Ring B is selected from

[0042] R 1 Independently selected from hydrogen or methyl, p is 0, 1 or 2;

[0043] R 2 Selected from hydrogen;

[0044] R 3 Selected from methyl and ethyl;

[0045] R 4 Selected from methyl;

[0046] R 5 Selected from chlorine or bromine;

[0047] R 6 Selected from fluorine, n = 2;

[0048] R 7 R 8 It is hydrogen.

[0049] As a preferred embodiment of the present invention, the compound, or its isomer, racemate, or pharmaceutically acceptable salt thereof, is selected from:

[0050]

[0051]

[0052]

[0053]

[0054] As a preferred embodiment of the present invention, the pharmaceutically acceptable salt refers to the compound, or its isomer, its racemate, or its pharmaceutically acceptable salt, prepared with a pharmaceutically acceptable acid or base.

[0055] As a preferred embodiment of the present invention, one or more hydrogen atoms of the compound, or its isomer, racemate, or pharmaceutically usable salt thereof, are substituted with the isotope deuterium.

[0056] The present invention further provides a pharmaceutical composition comprising a therapeutically effective amount of the compound, or an isomer thereof, a racemic mixture thereof, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0057] The present invention further provides the pharmaceutical use of the said compound, or its isomers, racemates, or pharmaceutically usable salts thereof, specifically, its use in the preparation of medicaments for treating diseases, said diseases being p38 / MK2-related diseases, specifically selected from chronic inflammatory diseases and acute inflammatory diseases, wherein the chronic inflammatory disease is preferably rheumatoid arthritis.

[0058] The compounds of the present invention have improved TNFα and / or p38 / MK2 activity compared to compounds of the prior art.

[0059] The compounds of the present invention can be prepared by the following methods:

[0060] The compounds of the present invention can be obtained through a similar synthetic route, by constructing a pyrimidine ring through a ring-closing reaction of an R-substituted amidine reagent and a common intermediate to obtain the R-substituted target product. At the same time, the R group can be further converted into an R' group to obtain the R' substituted target product.

[0061]

[0062] Furthermore, by using intermediate compounds with different substituents according to the preparation method described above, R in the following structure is obtained. 1 -R 8 Specific compounds with different substituents, including but not limited to compounds 1-4 mentioned above.

[0063]

[0064] For clarity, this article defines the general terminology used in the description of compounds.

[0065] Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient. The term "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0066] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of the present invention, prepared by reacting a compound having specific substituents discovered in the present invention with a pharmaceutically acceptable acid or base.

[0067] In addition to the salt form, the compounds provided by this invention also exist in prodrug form. The prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to be converted into the compounds of this invention. Furthermore, the prodrugs can be converted into the compounds of this invention in the in vivo environment via chemical or biochemical methods.

[0068] Some compounds of this invention may exist in non-solventized or solvated forms, including hydrated forms. Generally, solvated and non-solventized forms are equivalent and both are included within the scope of this invention.

[0069] The compounds of this invention can exist in specific geometric or stereoisomeric forms. This invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, transisomers, racemic mixtures thereof, and other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this invention.

[0070] Optically active (R)- and (S)- isomers, as well as D- and L- isomers, transisomers, etc., can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. To obtain an enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated, and the auxiliary group is cleaved to provide the desired enantiomer in pure form. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a salt of the diastereomeric isomer is formed with a suitable optically active acid or base, followed by diastereomeric resolution using conventional methods known in the art, and then the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomeric isomers is typically accomplished by using chromatography employing a chiral stationary phase and optionally combined with chemical derivatization (e.g., from amines to carbamates).

[0071] The atoms in the compounds of this invention are isotopes. Isotope derivatization can typically prolong half-life, reduce clearance rate, stabilize metabolism, and enhance in vivo activity. Furthermore, one embodiment is included, wherein at least one atom is replaced by an atom having the same number of atoms (protons) but different mass numbers (protons and neutrons). Examples of isotopes included in the compounds of this invention include hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms, phosphorus atoms, sulfur atoms, fluorine atoms, and chlorine atoms, each comprising... 2 H, 3 H, 13 C 14 C 15 N、 17 O、 18 O、 31 P, 32 P, 35 S, 18 F, 36 Cl. In particular, radioactive isotopes that emit radiation as they decay, such as 3 H or 14 C can be used for local anatomical examination of pharmaceutical preparations or compounds in vivo. Stable isotopes neither decay nor change with quantity and are not radioactive, therefore they can be used safely. When the atoms constituting the compounds of this invention are isotopes, the isotopes can be converted according to common methods by replacing the reagents used in the synthesis with reagents containing the corresponding isotopes.

[0072] The compounds of this invention may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compounds may be labeled with radioactive isotopes, such as deuterium. 2 H), Iodine-125 125 I) or C-14 14C). All isotopic variations of the compounds of the present invention, regardless of radioactivity, are included within the scope of the present invention.

[0073] Furthermore, one or more hydrogen atoms in the compound of the present invention are coated with the isotope deuterium ( 2 The compounds of this invention, after being substituted with H), have the effects of prolonged half-life, reduced clearance rate, metabolic stabilization, and increased in vivo activity.

[0074] The preparation methods of the isotope derivatives typically include phase-transfer catalysis. For example, a preferred deuteration method employs a phase-transfer catalyst (e.g., tetraalkylammonium salt, NBu4HSO4). Using a phase-transfer catalyst to exchange the methylene protons of a diphenylmethane compound results in the introduction of higher levels of deuterium than reduction with deuterated silanes (e.g., triethyldeuterated silane) in the presence of an acid (e.g., methanesulfonic acid) or with Lewis acids such as aluminum trichloride using sodium deuterated borate.

[0075] The term "pharmaceutically acceptable carrier" refers to any formulation carrier or medium capable of delivering an effective amount of the active substance of this invention without interfering with the biological activity of the active substance and without toxic side effects on the host or patient. Representative carriers include water, oil, vegetables and minerals, ointment bases, lotion bases, and ointment bases. These bases include suspending agents, thickeners, and transdermal penetration enhancers. Their formulations are well known to those skilled in the art of cosmetics or topical pharmaceuticals. For further information on carriers, see Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.

[0076] The term "excipient" generally refers to the carrier, diluent, and / or medium required to formulate an effective pharmaceutical composition.

[0077] For pharmaceuticals or pharmacologically active agents, the term "effective amount" or "therapeutic effective amount" refers to a sufficient quantity of a drug or agent that is non-toxic but achieves the desired effect. For the oral dosage forms of this invention, the "effective amount" of one active substance in the composition refers to the quantity required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount varies from person to person, depending on the recipient's age and general condition, as well as the specific active substance. A suitable effective amount in any given case can be determined by a person skilled in the art through routine testing.

[0078] The terms “active ingredient,” “therapeutic agent,” “active substance,” or “active agent” refer to a chemical entity that can effectively treat a target disorder, disease, or symptom.

[0079] "Optional" or "optionally" means that the event or condition described below may occur but is not required to occur, and the description includes both the scenario in which said event or condition occurs and the scenario in which said event or condition does not occur.

[0080] Indicates a connection key.

[0081] The compounds of the present invention can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present invention. Detailed Implementation

[0082] The present application will be described in further detail below with reference to the embodiments, but the implementation of the present application is not limited thereto.

[0083] Example 1

[0084] Synthesis of 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2′-(2-phenylpyrimidin-4-yl)-2H-[1,4′-bipyridine]-2-one

[0085]

[0086] The specific synthesis route is as follows:

[0087] Step A: Synthesis of 2,2-dimethyl-6-(2-oxopropyl)-4H-1,3-diox-4-one

[0088]

[0089] At room temperature, 30 g of 2,2,6-trimethyl-4H-1,3-dioxin-4-one (211.27 mmol) was dissolved in 100 mL of tetrahydrofuran under nitrogen protection. The mixture was cooled to -70°C, and bis(trimethylsilylaminolithium) (290 mL, 1 M) was added dropwise over 2 hours. Then, 290 mL of diethylzinc (1 M) was added over 0.5 hours. The mixture was then slowly heated to -20°C over 1.5 hours, and 28 g of 1-acetylimidazole (253.52 mmol) was added over 3 hours.

[0090] After the reaction was complete, the mixture was quenched in ice water, the pH was adjusted to 3-4 with 6N hydrochloric acid, and the mixture was extracted with ethyl acetate (50 mL × 3 times). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography (eluent: n-hexane / ethyl acetate = 4 / 1) to give 19 g of a yellow solid, 2,2-dimethyl-6-(2-oxopropyl)-4H-1,3-diox-4-one (yield: 49%). LC-MS: RT = 1.65 min, [M+H] + =185.13.

[0091] Step B: Synthesis of 2′-bromo-4-hydroxy-5′,6-dimethyl-2H-[1,4′-bipyridine]-2-one

[0092]

[0093] At room temperature, 5 g of 2-bromo-5-methylpyridin-4-amine (26.74 mmol) was dissolved in 100 mL of dioxane, and 5.9 g of 2,2-dimethyl-6-(2-oxopropyl)-4H-1,3-diox-4-one (32.09 mmol) was added. The mixture was heated to 90 °C and reacted for 5 hours. 10 N sulfuric acid was added dropwise until no more solid was produced, and the reaction was continued for 2 hours.

[0094] After the reaction was complete, the mixture was concentrated, water was added, and the mixture was stirred for 0.5 hours. The mixture was then filtered, and the filter cake was washed twice with water. 6 g of a light brown solid, 2′-bromo-4-hydroxy-5′,6-dimethyl-2H-[1,4′-bipyridine]-2-one, was collected (yield: 76%). LC-MS: RT = 1.66 min, [M+H] + =295.11.

[0095] Step C: Synthesis of 2′-bromo-3-chloro-4-hydroxy-5′,6-dimethyl-2H-[1,4′-bipyridine]-2-one

[0096]

[0097] At room temperature, 2′-bromo-4-hydroxy-5′,6-dimethyl-2H-[1,4′-bipyridine]-2-one (200 mg, 0.68 mmol) was dissolved in isopropanol (5 mL), NCS (62 mg, 0.37 mmol) and one drop of dichloroacetic acid were added, and the mixture was heated to 60°C and reacted for 6 hours.

[0098] After the reaction was complete, the mixture was quenched with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography (ethyl acetate) to give 100 mg of the white solid product 2′-bromo-3-chloro-4-hydroxy-5′,6-dimethyl-2H-[1,4′-bipyridine]-2-one (yield: 83%). LC-MS: RT = 1.68 min, [M+H] + =329.06.

[0099] Step D: Synthesis of 2′-bromo-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one

[0100]

[0101] At room temperature, 2-(bromomethyl)-3,5-difluoropyridine (2.50 g, 12.20 mmol) and potassium carbonate (3.36 g, 24.40 mmol) were added to N,N-dimethylformamide (20 mL) containing 2′-bromo-3-chloro-4-hydroxy-5′,6-dimethyl-2H-[1,4′-bipyridine]-2-one (4 g, 12.20 mmol) and reacted at room temperature.

[0102] After the reaction was complete, the mixture was quenched with water, extracted with ethyl acetate (30 mL × 3 times), the organic phases were combined, washed with saturated brine (30 mL × 2 times), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 0) to give 2.50 g of a white solid 2′-bromo-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one (yield: 45%). LC-MS: RT = 1.93 min, [M+H + =456.05.

[0103] Step E: Synthesis of 2′-acetyl-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one

[0104]

[0105] At room temperature, 2′-bromo-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one (1 g, 2.19 mmol), tributyl(1-ethoxyvinyl)tin (791 mg, 2.19 mmol), and PdCl2(PPh3)2 (158 mg, 0.22 mmol) were dissolved in 1,4-dioxane (7 mL) and microwaved at 100 °C for 2 hours. The mixture was filtered and washed with ethyl acetate. The solution was concentrated, and the residue was dissolved in tetrahydrofuran (2 mL) and concentrated hydrochloric acid was added until complete hydrolysis. The residue was concentrated and purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 0) to give 400 mg of a yellow oil, 2′-acetyl-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one (yield: 44%). LC-MS: RT = 1.86 min, [M+H] + =420.12.

[0106] Step F: Synthesis of 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2′-(2-phenylpyrimidin-4-yl)-2H-[1,4′-bipyridine]-2-one

[0107]

[0108] At room temperature, N,N-dimethylformamide dimethyl acetal (40.0 mg, 0.33 mmol) was added to N,N-dimethylformamide (3.0 mL) containing 2′-acetyl-3-chloro-4-(3,5-difluoro-pyridin-2-ylmethoxy)-5′-methyl-[1,4′]bipyridinyl-2-one (70.0 mg, 0.17 mmol), and the mixture was heated to 55°C and reacted for 5 hours. The reaction solution was concentrated to half its volume, and benzalkonium hydrochloride (79.8 mg, 0.51 mmol) and potassium carbonate (46.0 mg, 0.34 mmol) were added. The mixture was then heated to 75°C and reacted for 4 hours.

[0109] After the reaction was complete, the mixture was quenched with water, extracted with ethyl acetate (20 mL × 3 times), the organic phases were combined, washed with saturated brine (20 mL × 2 times), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 0). 41.0 mg of a white solid, 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2′-(2-phenylpyrimidin-4-yl)-2H-[1,4′-bipyridine]-2-one, was obtained (yield: 45.4%). LC-MS: RT = 2.07 min, [M+H + =532.15.

[0110] Example 2

[0111] Synthesis of 2′-(2-(1H-pyrazol-1-yl)pyrimidin-4-yl)-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridine]-2-one

[0112]

[0113] The specific synthesis route is as follows:

[0114] Step A: Synthesis of 2-(methylthio)-4-(tributylmethanesulfonyl)pyrimidine

[0115]

[0116] At room temperature, hexabutyltin (2.32 g, 4.0 mmol), palladium triphenylphosphine acetate (148 mg, 0.2 mmol), and tetrabutylammonium fluoride (6 mL) were added to a tetrahydrofuran (3 mL) solution containing 4-iodo-2-methylthiopyrimidine (504 mg, 2.0 mmol), and the reaction was carried out under nitrogen protection for 12 hours.

[0117] After the reaction was completed, the mixture was concentrated, and the residue was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 8) to give 250 mg of a clear, oily liquid, 2-(methylthio)-4-(tributylmethylstannyl)pyrimidine (yield: 30.0%). LC-MS: RT = 3.37 min, [M+H] + =417.16.

[0118] Step B: Synthesis of 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2′-(2-(methylthio)pyrimidin-4-yl)-2H-[1,4′-bipyridine]-2-one

[0119] At room temperature, 2-(methylthio)-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridine]-2-one (206 mg, 0.5 mmol) and 2-(methylthio)-4-(tributylmethyltinyl)pyrimidine (208.5 mg, 0.5 mmol) and tetrakis(triphenylphosphine)palladium (115.5 mg, 0.1 mmol) were added to 1,4-dioxane (3 mL) containing 2′,3-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridine]-2-one (206 mg, 0.5 mmol) and reacted at 110°C for 18 hours under nitrogen protection.

[0120] After the reaction was complete, the mixture was quenched with water, extracted with ethyl acetate (20 mL × 3 times), the organic phases were combined, washed with saturated brine (20 mL × 2 times), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 0). 55 mg of a yellow solid, 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2′-(2-(methylthio)pyrimidin-4-yl)-2H-[1,4′-bipyridine]-2-one, was obtained (yield: 22.0%). LC-MS: RT = 2.00 min, [M+H + =502.19.

[0121] Step C: Synthesis of 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2′-(2-(methanesulfonyl)pyrimidin-4-yl)-2H-[1,4′-bipyridine]-2-one

[0122]

[0123] At room temperature, m-chloroperoxybenzoic acid (34.5 mg, 0.2 mmol) was added to dichloromethane (2 mL) containing 50 mg of 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2′-(2-(methylthio)pyrimidin-4-yl)-2H-[1,4′-bipyridine]-2-one (0.1 mmol) and reacted for 2 hours.

[0124] After the reaction was complete, the mixture was quenched with water, extracted with ethyl acetate (20 mL × 3 times), the organic phases were combined, washed with saturated brine (20 mL × 2 times), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 0). 15 mg of a yellow solid, 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2′-(2-(methanesulfonyl)pyrimidin-4-yl)-2H-[1,4′-bipyridine]-2-one, was obtained (yield: 28.1%). LC-MS: RT = 1.98 min, [M+H + =534.14.

[0125] Step D: Synthesis of 2′-(2-(1H-pyrazol-1-yl)pyrimidin-4-yl)-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridine]-2-one

[0126]

[0127] At room temperature, sodium hydrogen (13 mg, 0.6 mmol) was added to tetrahydrofuran (3 mL) containing 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2′-(2-(methanesulfonyl)pyrimidin-4-yl)-2H-[1,4′-bipyridine]-2-one (30 mg, 0.06 mmol), and the mixture was stirred for 10 minutes. Then, pyrazole (38 mg, 0.56 mmol) was added, and the reaction was allowed to proceed for 0.5 hours.

[0128] After the reaction was complete, the mixture was quenched with water, extracted with ethyl acetate (20 mL × 2 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 10 / 1) to give 9 mg of a white solid 2′-(2-(1H-pyrazol-1-yl)pyrimidin-4-yl)-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridine]-2-one (yield: 31%). LC-MS: RT = 1.91 min, [M+H + =522.14.

[0129] Example 3

[0130] Synthesis of 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2′-(2-(3,5-dimethyl-1H-pyrazol-1-yl)pyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one

[0131]

[0132] The specific synthesis route is as follows:

[0133] Step A: Synthesis of 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2′-(2-(3,5-dimethyl-1H-pyrazol-1-yl)pyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one

[0134] At room temperature, sodium hydrogen (13 mg, 0.56 mmol) was added to tetrahydrofuran (3 mL) containing 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2′-(2-(methanesulfonyl)pyrimidin-4-yl)-2H-[1,4′-bipyridine]-2-one (30 mg, 0.06 mmol), and the mixture was stirred for 10 minutes. Then, 3,5-dimethyl-1H-pyrazole (51 mg, 0.56 mmol) was added, and the reaction was allowed to proceed for 0.5 hours.

[0135] After the reaction was complete, the mixture was quenched with water, extracted with ethyl acetate (20 mL × 2 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 10 / 1) to give 5 mg of a white solid 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2′-(2-(3,5-dimethyl-1H-pyrazol-1-yl)pyrimidin-4-yl)-2H-[1,4′-bipyridine]-2-one (yield: 16%). LC-MS: RT = 1.95 min, [M+H + =550.20.

[0136] Example 4

[0137] Synthesis of 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2′-(2-(4-methyl-1N-pyrazol-1-yl)pyrimidin-4-yl)-2N-[1,4′-bipyridin]-2-one

[0138]

[0139] The specific synthesis route is as follows:

[0140] Step A: Synthesis of 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2′-(2-(4-methyl-1N-pyrazol-1-yl)pyrimidin-4-yl)-2N-[1,4′-bipyridin]-2-one

[0141]

[0142] At room temperature, sodium hydrogen (13 mg, 0.56 mmol) was added to tetrahydrofuran (3 mL) containing 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2′-(2-(methanesulfonyl)pyrimidin-4-yl)-2H-[1,4′-bipyridine]-2-one (30 mg, 0.06 mmol), and the mixture was stirred for 10 minutes. Then, 4-methyl-1H-pyrazole (50 mg, 0.56 mmol) was added, and the reaction was allowed to proceed for 0.5 hours.

[0143] After the reaction was complete, the mixture was quenched with water, extracted with ethyl acetate (20 mL × 2 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 10 / 1) to give 13 mg of a white solid 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2′-(2-(4-methyl-1H-pyrazol-1-yl)pyrimidin-4-yl)-2H-[1,4′-bipyridine]-2-one (yield: 40%). LC-MS: RT = 1.93 min, [M+H + =536.21.

[0144] Example 5-32

[0145] For the synthetic routes of compounds numbered 5-32, please refer to the synthetic routes of compounds in Examples 1-4. The only difference is that the substituents of the intermediates are slightly different, depending on the target compound.

[0146]

[0147]

[0148]

[0149]

[0150]

[0151]

[0152]

[0153] Comparative Example 1

[0154] The structure of the compound 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(2-(2-hydroxypropyl-2-yl)pyrimidin-4-yl)-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one is as follows:

[0155]

[0156] The synthetic route of the compound in Comparative Example 1 is the same as that of the compound with specification number 49 in Chinese Patent No. CN201480032278.5.

[0157] Example 33: LPS-induced TNFα release from U937 experiment

[0158] Cytokine Regulation in Human Monocytes: The p38 pathway has been shown to be key to the biosynthesis of various pro-inflammatory cytokines, including TNFα, IL-1β, and IL-6. Therefore, inhibition of the p38 MAPK pathway reduces inflammatory responses by decreasing the biosynthesis of pro-inflammatory cytokines. This study demonstrates that half the amount of the compound of the present invention required to inhibit the biosynthesis of TNFα (a pro-inflammatory cytokine) is necessary. This reflects the effect of the compound of the present invention in reducing inflammation, which is beneficial for the treatment of many diseases, including chronic inflammatory conditions, acute inflammatory conditions, and autoinflammatory conditions. The efficacy and modality of the p38 inhibitor in blocking cytokine production were evaluated using the human U937 cell line.

[0159] Reagents and instruments:

[0160] 1640 medium, catalog number A10491-01, Gibco. Penicillin and streptomycin, catalog number 15140-122, Gibco. Fetal bovine serum, catalog number 10099-141C, Gibco. PBS, catalog number 10010-031, Gibco. LPS, catalog number L2880, Sigma. PMA, catalog number P1585, Sigma. Dimethyl sulfoxide, catalog number D8418-1L, Sigma. TNFα kit, catalog number K151QWD-4, MSD.

[0161] 96-well plate, item number 3599, Corning. Shaking plate shaker, item number QB-9002, Qilinbeier. Centrifuge, item number 5810R, Eppendorf. CO2 incubator, item number 371, Thermo. Counter, item number C10281, Gibco. Microscope, item number CKX41, OLYMPUS. MSD plate reader, 1201MESO SECTOR 600, MSD.

[0162] Experimental cells:

[0163] U937, ATCC, part number CRL-1593.2.

[0164] Drug preparation:

[0165] Weigh approximately 2 mg of the drug and prepare a 10 mM (based on free base) stock solution using DMSO. Dilute the stock solution 10-fold to 1 mM, then sequentially dilute it 4-fold to 250 μM, 62.5 μM, 15.6 μM, 3.9 μM, 0.97 μM, 0.24 μM, and 0.061 μM. Then, dilute each of these DMSO-concentrated drug solutions 20-fold with culture medium to prepare working solutions.

[0166] Experimental methods:

[0167] Day 0: Inoculate 10,000 cells / well, stimulate with 20 ng / ml PMA for 48 h, and incubate at 37°C and 5% CO2;

[0168] Day 2: 1. Remove the supernatant from the differentiated U937, wash once with PBS, and add 96 μl of 1640 medium;

[0169] 2. Add 2 μl of the compound containing (final concentration 0.1% DMSO), and incubate at 37°C with 5% CO2 for 30 min;

[0170] 3. Add 2 μl LPS (final concentration 100 ng / ml) to stimulate cells and incubate at 37°C and 5% CO2 for 4 h;

[0171] 4. Centrifuge, collect the supernatant, and use ELISA to determine the TNFα content in the supernatant.

[0172] Statistical methods:

[0173] The TNFα content for each well was calculated using the standard curve provided in the kit.

[0174] Calculate the compound IC using the GraphPad nonlinear fitting formula. 50 The experimental results are shown in Table 1.

[0175] Table 1. IC50 of the compounds of this invention inhibiting TNFα production. 50 value

[0176] Compound numbering <![CDATA[IC 50 (nM)]]> 3 2.98 Comparative Example 1 16.4(n＝6)

[0177] As can be seen from the experimental results in Table 1 above, the compounds of this invention have significant inhibitory activity on TNFα production and can regulate inflammatory responses and related diseases.

[0178] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. A compound of general formula (I), or an isomer thereof, a racemic mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that: Among them, ring A is selected from: Ring B is selected from R 1 Selected from hydrogen and alkyl groups, with p being 0, 1, or 2; R 2 Independently selected from hydrogen, m = 1; R 3 Selected from alkyl groups; R 4 Selected from alkyl groups; R 5 Selected from halogens; R 6 It is independently selected from halogens, where n is 0, 1, or 2; X is O, Y is CH or N; R 7 R 8 Independently selected from hydrogen, the alkyl group is selected from C. 1-6 Alkyl groups.

2. The compound according to claim 1, or its isomer, racemate, or pharmaceutically acceptable salt thereof, characterized in that, The C 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.

3. The compound according to claim 1, or its isomer, racemate, or pharmaceutically acceptable salt thereof, characterized in that, The halogen is selected from fluorine, chlorine, bromine, and iodine.

4. The compound according to claim 1, or its isomer, racemate, or pharmaceutically acceptable salt thereof, characterized in that, Selected from compounds having the following structure (Ia) or (Ib), or isomers thereof, racemates thereof, or pharmaceutically acceptable salts thereof: Where m, n, p, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 Ring A and ring B are as defined in claim 1.

5. The compound according to claim 1, or its isomer, racemate, or pharmaceutically acceptable salt thereof, characterized in that, R 1 Independently selected from hydrogen or methyl; R 3 Selected from methyl and ethyl; R 4 Selected from methyl; R 5 Selected from chlorine or bromine; R 6 Selected from fluorine, n is 2.

6. The compound according to claim 1, or its isomer, racemate, or pharmaceutically acceptable salt thereof, characterized in that, Selected from:

7. The compound according to claim 1, or an isomer thereof, a racemic mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that, The pharmaceutically acceptable salt refers to a compound, or its isomer, its racemate, or its pharmaceutically acceptable salt, prepared with a pharmaceutically acceptable acid or base.

8. A pharmaceutical composition, characterized in that, The compound comprising a therapeutically effective amount of any one of claims 1-7, or an isomer thereof, a racemic mixture thereof, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier thereof.

9. Use of the compound of any one of claims 1-7, or an isomer thereof, a racemic mixture thereof, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating a disease, said disease being a p38 / MK2-related disease selected from chronic and acute inflammatory conditions.

10. The pharmaceutical use according to claim 9, characterized in that, The chronic inflammatory condition mentioned is rheumatoid arthritis.

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