Pyridine nitrogen oxide derivative as well as pharmaceutical composition, preparation method and application thereof

Abstract

The invention relates to a pyridine nitrogen oxide derivative and application thereof, and particularly provides a pyridine nitrogen oxide compound as shown in a formula (I) or pharmaceutically acceptable salt thereof, and the pyridine nitrogen oxide compound or the pharmaceutically acceptable salt thereof can be used for preparing medicines, especially medicines for preventing and / or treating p38MAPK / MK2 pathway mediated diseases or symptoms. Each group in the formula (I) is as defined in the specification. # imgabs0 #

Description

[0001] This application claims the priority benefit of a prior application filed by the applicant with the China National Intellectual Property Administration on December 11, 2023, with the patent application number 202311692916.3 and the title "Pyridine N-oxide Derivatives and Their Pharmaceutical Compositions, Preparation Methods and Uses". The full text of the prior application is incorporated into this disclosure by reference. Technical Field

[0002] This disclosure belongs to the field of medicine, and specifically relates to a pyridine N-oxide derivative and its pharmaceutical composition, preparation method and use. Background Art

[0003] Biological signal transduction involves specific protein-protein interactions and post-translational modifications, regulating genetic and epigenetic processes in response to internal and external environmental effects. Mitogen-activated protein kinase MAPK (mitogen-activated proteinkinase) is a group of serine-threonine protein kinases that can be activated by different internal and external cellular stresses, and is an important transmitter for signals to be conducted from the cell surface to the nucleus interior. Stress factors include cytokines, neurotransmitters, hormones, cellular stress, and cell adhesion, etc.

[0004] As a subfamily of the MAPK family, p38 MAPK responds to external signals and inflammatory cytokines in cells. After being activated, p38 MAPK phosphorylates and activates various downstream protein kinases and transcription factors, thereby playing complex biological roles. p38 MAPK includes four members, namely p38α, p38β, p38γ, and p38δ. Among them, p38α is considered to play an important role in the signal pathway of the inflammatory process, while the biological functions of other isomers have not been fully discovered, but they have pleiotropy. Research shows that p38β plays an important role in the cell protection mechanism, and mitogen-activated protein kinase MKK3 (MAP Kinase Kinase 3) mediates the effect of p38δ on the proliferation and survival of late-stage colorectal cancer (CRC) cells. As an attractive target in the field of drug development, there are multiple inhibitor drugs of p38 MAPK entering clinical research. So far, no drug has been approved for marketing. According to public information, some candidate compounds have failed in the clinical research stage. Therefore, developing a safe and effective p38 MAPK inhibitor is the main challenge faced by drug development in this field currently.

[0005] p38 MAPK can regulate more than 60 substrates and perform different physiological functions [Cell 2013(152), 924]. Therefore, selectively inhibiting the activation of p38 MAPK downstream effectors is the main strategy to avoid side effects / insufficient efficacy caused by the overall inhibition of p38 MAPK. MAPK-activated protein kinase 2 (MK2) is a direct substrate downstream of p38 MAPK and can be activated by p38α and p38β. As the first discovered p38 MAPK substrate, MK2 can regulate the expression of inflammatory factors at the transcriptional and post-transcriptional levels, thus playing an important role in the regulation of multiple inflammatory diseases. Studies have shown that MK2 can increase the expression of inflammatory factors such as TNF-α, IL-6, IL-8, and COX-2 by stabilizing the AU-rich elements of mRNA. In a mouse model of postoperative ileus [The Journal of surgical research 2013(185), 102], MK2 inhibitors can reduce the expression of inflammatory factors such as MIP-1α, TNF-α, IL-6, and IL-1β. At the same time, it was found that there was a reduction in the infiltration of polymorphonuclear leukocytes, mast cells, and mononuclear macrophages and an improvement in the contractile performance of intestinal smooth muscle. In a mouse model of collagen-induced arthritis (CIA) [Journal of immunology 2006(177), 1913], knocking out the MK2 gene can reduce the occurrence of collagen-induced arthritis. Compared with wild-type mice, the incidence and severity of collagen-induced arthritis in MK2 - / - and MK2 + / - mice are reduced, and the expression of inflammatory factors TNF-α and IL-6 is also reduced to varying degrees. In a mouse model of hypercholesterolemia with MK2 knockout [Circ Res 2007(101), 1104], lipid deposition and macrophages in the large arteries of mice are reduced, and the expression of inflammatory factors such as VCAM-1 and MCP-1 is reduced. In addition, studies have shown that inhibiting MK2 can be used for the development of anti-tumor drugs [Cancer cell 2007(11), 175]. Therefore, it is necessary to find new small molecule inhibitors to selectively regulate the p38 MAPK / MK2 pathway, inhibit p38 MAPK-dependent MK2 activity while maintaining the selectivity of other p38 MAPK substrates (such as ATF2 and MK5), and improve the safety of drugs while maintaining the therapeutic effect.

[0006] Currently, the publicly disclosed p38 MAPK / MK2 inhibitors include WO2022212489A1, WO2023016535A1, WO2023001282A1, and CN115636814A, etc. Summary of the Invention

[0007] The present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0008]

[0009] wherein:

[0010] R 1 is selected from

[0011] R 1a and R 1b are the same or different and each independently selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl and 3- to 8-membered cycloalkyl;

[0012] or R 1a and R 1b together with the carbon to which they are attached form a 3- to 8-membered cycloalkyl or a 3- to 8-membered heterocyclic group, said 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclic group being optionally substituted with one or more substituents selected from halogen or C 1-6 alkyl;

[0013] R 1c and R 1d are the same or different and each independently selected from H, D, halogen, cyano, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl and 3- to 8-membered cycloalkyl;

[0014] or R 1c and R 1d together with the carbon to which they are attached form a 3- to 8-membered cycloalkyl or a 3- to 8-membered heterocyclic group, said 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclic group being optionally substituted with one or more substituents selected from halogen or C 1-6 alkyl;

[0015] each R 2 is the same or different and each independently selected from H, halogen, cyano, hydroxy, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl and 3- to 8-membered cycloalkyl;

[0016] R 3a and R 3bidentical or different, and each independently selected from H, halogen, cyano, hydroxy, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, and 3- to 8-membered cycloalkyl;

[0017] R 4 is selected from H, halogen, C 1-6 alkyl, and C 1-6 haloalkyl;

[0018] R 5 is selected from H, halogen, C 1-6 alkyl, and C 1-6 haloalkyl;

[0019] R 6 and R 7 are identical or different, and each independently selected from H, D, halogen, and C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more substituents selected from halogen, cyano, hydroxy, and amino;

[0020] each R 8 is identical or different, and each independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano, hydroxy, amino, nitro, and 3- to 8-membered cycloalkyl;

[0021] q is selected from 0, 1, 2, 3, and 4;

[0022] t is selected from 0, 1, 2, 3, and 4.

[0023] In some embodiments, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is a compound of formula (I-1) or formula (I-2) or a pharmaceutically acceptable salt thereof,

[0024]

[0025] wherein:

[0026] R 1 、R 2 、R 3a 、R 3b 、R 4 、R 5 、R 6 、R 7 、R8 , q, and t are as defined in this disclosure.

[0027] In some embodiments, this disclosure provides a compound of formula (I), formula (I-1), or formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from

[0028] R 1a and R 1b are the same or different and each independently selected from H or methyl;

[0029] or R 1a and R 1b together with the carbon to which they are attached form a 3- to 6-membered cycloalkyl;

[0030] R 1c and R 1d are the same or different and each independently selected from H or methyl;

[0031] or R 1c and R 1d together with the carbon to which they are attached form a 3- to 6-membered cycloalkyl.

[0032] In some embodiments, this disclosure provides a compound of formula (I), formula (I-1), or formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 1 is

[0033] R 1a is H or methyl;

[0034] R 1c and R 1d are the same or different and each independently selected from H or methyl.

[0035] In some embodiments, this disclosure provides a compound of formula (I), formula (I-1), or formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 1 is

[0036] R 1a and R 1b are the same or different and each independently selected from H or methyl;

[0037] or R 1a and R 1b together with the carbon to which they are attached form a 3- to 6-membered cycloalkyl, such as cyclopropyl;

[0038] R 1c and R 1d are the same or different and each independently selected from H or methyl.

[0039] In some embodiments, the present disclosure provides a compound represented by formula (I), formula (I-1) or formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 1 is

[0040] R 1a is H or methyl;

[0041] R 1c and R 1d are the same or different and each independently selected from H or methyl.

[0042] In some embodiments, the present disclosure provides a compound represented by formula (I), formula (I-1) or formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from

[0043] In some embodiments, the present disclosure provides a compound represented by formula (I), formula (I-1) or formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from

[0044] In some embodiments, the present disclosure provides a compound represented by formula (I), formula (I-1) or formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 2 is H or a halogen.

[0045] In some embodiments, the present disclosure provides a compound represented by formula (I), formula (I-1) or formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 2 is H or F.

[0046] In some embodiments, the present disclosure provides a compound represented by formula (I), formula (I-1) or formula (I-2), or a pharmaceutically acceptable salt thereof, wherein is selected from

[0047] In some embodiments, the present disclosure provides a compound represented by formula (I), formula (I-1) or formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 3a is selected from a halogen or C 1-6 alkyl.

[0048] In some embodiments, the present disclosure provides a compound represented by formula (I), formula (I-1) or formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 3a is methyl.

[0049] In some embodiments, the present disclosure provides a compound of formula (I), formula (I-1), or formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 3b is selected from H or halogen.

[0050] In some embodiments, the present disclosure provides a compound of formula (I), formula (I-1), or formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 3b is H or F.

[0051] In some embodiments, the present disclosure provides a compound of formula (I), formula (I-1), or formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 4 is halogen.

[0052] In some embodiments, the present disclosure provides a compound of formula (I), formula (I-1), or formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 4 is Cl.

[0053] In some embodiments, the present disclosure provides a compound of formula (I), formula (I-1), or formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 5 is C 1-6 alkyl.

[0054] In some embodiments, the present disclosure provides a compound of formula (I), formula (I-1), or formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 5 is methyl.

[0055] In some embodiments, the present disclosure provides a compound of formula (I), formula (I-1), or formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 are the same or different and each independently is H or D.

[0056] In some embodiments, the present disclosure provides a compound of formula (I), formula (I-1), or formula (I-2), or a pharmaceutically acceptable salt thereof, wherein each R 8 is the same or different and each independently is selected from H, halogen, C 1-6 alkyl, and C 1-6 haloalkyl.

[0057] In some embodiments, the present disclosure provides a compound of formula (I), formula (I-1), or formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 8 is halogen.

[0058] In some embodiments, the present disclosure provides a compound of formula (I), formula (I-1) or formula (I-2) or a pharmaceutically acceptable salt thereof, wherein R 8 is F.

[0059] In some embodiments, the present disclosure provides a compound of formula (I), formula (I-1) or formula (I-2) or a pharmaceutically acceptable salt thereof, wherein is R 8a and R 8b are the same or different and each independently selected from H, halogen, C 1-6 alkyl and C 1-6 haloalkyl.

[0060] In some embodiments, the present disclosure provides a compound of formula (I), formula (I-1) or formula (I-2) or a pharmaceutically acceptable salt thereof, wherein is R 8a and R 8b are the same or different and each independently is halogen.

[0061] In some embodiments, the present disclosure provides a compound of formula (I), formula (I-1) or formula (I-2) or a pharmaceutically acceptable salt thereof, wherein is R 8a and R 8b are both F.

[0062] In some embodiments, the present disclosure provides a compound of formula (I), formula (I-1) or formula (I-2) or a pharmaceutically acceptable salt thereof, wherein R 1 is R 2 is H or halogen; R 3a is halogen or C 1-6 alkyl; R 3b is H or halogen; R 4 is Cl; R 5 is C 1-6 alkyl; R 6 and R 7 are the same or different and each independently is H or D; is R 8a and R 8b are the same or different and each independently is halogen.

[0063] In some embodiments, exemplary specific compounds of the compound of formula (I), formula (I-1) or formula (I-2) include, but are not limited to, the structures in Table A below:

[0064] Table A

[0065]

[0066]

[0067] In some embodiments, the exemplary specific compounds of the compounds represented by formula (I), formula (I-1) or formula (I-2) further include, but are not limited to, the structures in Table B below:

[0068] Table B

[0069]

[0070]

[0071] In another aspect of the present disclosure, isotopically labeled compounds represented by formula (I), formula (I-1) or formula (I-2), or compounds shown in Table A or Table B are provided, and the isotopic labeling is preferably deuterium (D or 2 H) substituting hydrogen ( 1 H).

[0072] In another aspect of the present disclosure, a method for preparing a compound represented by formula (I) or a pharmaceutically acceptable salt thereof is provided, which comprises the following steps:

[0073]

[0074] The compound of formula (IA) and the compound of formula (IB) undergo a coupling reaction in the presence of a catalyst to obtain the compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

[0075] wherein: X is a halogen; preferably Br;

[0076] R w is -B(OH) 2 or

[0077] R 1 、R 2 、R 3a 、R 3b 、R 4 、R 5 、R 6 、R 7 、R 8 、q and t are as defined in formula (I).

[0078] In another aspect of the present disclosure, there is provided a pharmaceutical composition comprising at least one therapeutically effective amount of a compound represented by formula (I), formula (I-1) or formula (I-2), or a compound shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0079] In another aspect of the present disclosure, there is also provided the use of a compound represented by formula (I), formula (I-1) or formula (I-2), or a compound shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the preparation of a medicament as a p38 kinase inhibitor.

[0080] The present disclosure also provides the use of a compound represented by formula (I), formula (I-1) or formula (I-2), or a compound shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament for preventing and / or treating a p38 kinase-mediated disease or disorder; preferably, the p38 kinase-mediated disease is a disease related to the p38 MAPK / MK2 pathway.

[0081] The present disclosure also provides the use of a compound represented by formula (I), formula (I-1) or formula (I-2), or a compound shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament for preventing and / or treating autoimmune diseases, inflammatory diseases, cardiovascular diseases, central nervous system diseases and cancers; preferably, the use in the preparation of a medicament for preventing and / or treating arthritis, psoriasis, systemic lupus erythematosus, diabetes, leukemia, lymphoma, atherosclerosis and Alzheimer's disease.

[0082] The present disclosure also provides a method for inhibiting p38 kinase, which comprises administering to a patient in need a therapeutically effective amount of a compound represented by formula (I), formula (I-1) or formula (I-2), or a compound shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or the aforementioned isotope-labeled compound, or the aforementioned pharmaceutical composition comprising the same.

[0083] The present disclosure also provides a method for preventing and / or treating a p38 kinase-mediated disease or disorder, which comprises administering to a patient in need a therapeutically effective amount of a compound represented by formula (I), formula (I-1) or formula (I-2), or a compound shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or the aforementioned isotope-labeled compound, or the aforementioned pharmaceutical composition comprising the same; preferably, the p38 kinase-mediated disease is a disease related to the p38 MAPK / MK2 pathway.

[0084] The present disclosure also provides a method for preventing and / or treating autoimmune diseases, inflammatory diseases, cardiovascular diseases, central nervous system diseases, and cancers, which comprises administering to a patient in need a therapeutically effective amount of a compound represented by formula (I), formula (I-1), or formula (I-2), or a compound shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the foregoing.

[0085] The present disclosure also provides a method for preventing and / or treating arthritis, psoriasis, systemic lupus erythematosus, diabetes, leukemia, lymphoma, atherosclerosis, and Alzheimer's disease, which comprises administering to a patient in need a therapeutically effective amount of a compound represented by formula (I), formula (I-1), or formula (I-2), or a compound shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the foregoing.

[0086] The present disclosure also provides a compound represented by formula (I), formula (I-1), or formula (I-2), or a compound shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or the foregoing pharmaceutical composition, which is used as a drug.

[0087] The present disclosure also provides a compound represented by formula (I), formula (I-1), or formula (I-2), or a compound shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or the foregoing pharmaceutical composition, which is used as a p38 kinase inhibitor.

[0088] The present disclosure also provides a compound represented by formula (I), formula (I-1), or formula (I-2), or a compound shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the foregoing, which is used as a drug for preventing and / or treating a p38 kinase-mediated disease or disorder; preferably, the p38 kinase-mediated disease is a disease related to the p38 MAPK / MK2 pathway.

[0089] The present disclosure also provides a compound represented by formula (I), formula (I-1), or formula (I-2), or a compound shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the foregoing, which is used as a drug for preventing and / or treating autoimmune diseases, inflammatory diseases, cardiovascular diseases, central nervous system diseases, and cancers.

[0090] The present disclosure also provides a compound represented by formula (I), formula (I-1), or formula (I-2), or a compound shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the foregoing, which is used as a drug for preventing and / or treating arthritis, psoriasis, systemic lupus erythematosus, diabetes, leukemia, lymphoma, atherosclerosis, and Alzheimer's disease.

[0091] The p38 kinase-mediated diseases described in the present disclosure are selected from autoimmune diseases, inflammatory diseases, cardiovascular diseases, central nervous system diseases, and cancers.

[0092] The diseases mediated by p38 kinase described in the present disclosure are selected from arthritis, psoriasis, systemic lupus erythematosus, diabetes, leukemia, lymphoma, atherosclerosis, and Alzheimer's disease.

[0093] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg - 1000 mg.

[0094] In some embodiments, based on the total weight of the composition, the pharmaceutical composition contains 0.01 - 99.99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotope-labeled compound. In certain embodiments, the pharmaceutical composition contains 0.1 - 99.9% of the aforementioned compound or its pharmaceutically acceptable salt and its isotope-labeled compound. In certain embodiments, the pharmaceutical composition contains 0.5% - 99.5% of the aforementioned compound or its pharmaceutically acceptable salt or its isotope-labeled compound. In certain embodiments, the pharmaceutical composition contains 1% - 99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotope-labeled compound.

[0095] In certain embodiments, based on the total weight of the composition, the pharmaceutical composition contains 0.01% - 99.99% of one or more pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition contains 0.1% - 99.9% of one or more pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition contains 1% - 99% of one or more pharmaceutically acceptable excipients.

[0096] When used as a drug, the compounds of the present disclosure can be administered in the form of a pharmaceutical composition. These compositions can be prepared in a manner well-known in the pharmaceutical art and can be administered by various routes, depending on whether local or systemic treatment is required and the area being treated. They can be administered locally (e.g., transdermally, dermally, ocularly, and mucosally including intranasally, vaginally, and rectally), by the pulmonary route (e.g., by inhalation or insufflation of powders or aerosols, including via nebulizers; intratracheally, intranasally), orally, or parenterally. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion; or intracranially, e.g., intrathecally or intraventricularly. It can be administered parenterally in a single large dose form, or can be administered, for example, by a continuous perfusion pump.

[0097] When preparing the compositions of the present disclosure, the active ingredient is usually mixed with excipients, and the compositions can be in the following forms: tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (solid or dissolved in a liquid solvent), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injection solutions, and sterile packaged powders.

[0098] The "excipient" described in the present disclosure refers to components other than the active ingredient, such as diluents, fillers, absorbents, wetting agents, binders, disintegrants, lubricants, etc.

[0099] On the other hand, the pharmaceutically acceptable salts of the compounds described in the present disclosure can be inorganic salts or organic salts. If these compounds have a basic center, they can form acid addition salts; if these compounds have an acidic center, they can form base addition salts; if these compounds contain both an acidic center (such as a carboxyl group) and a basic center (such as an amino group), they can also form internal salts.

[0100] On the other hand, the compounds of the present disclosure can exist in specific geometric or stereoisomeric forms. For example, cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereoisomers, (D)- isomers, (L)- isomers, racemic mixtures and other mixtures, as well as enantiomer- or diastereoisomer- enriched mixtures, all of these mixtures are within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All of these isomers and their mixtures are included within the scope of the present disclosure.

[0101] In the chemical structure of the compounds described in the present disclosure, the bond represents an unspecified configuration, and represents an absolute configuration, that is, if there are chiral isomers in the chemical structure, the bond can be or contain both two configurations, and represents the presence of axial chirality.

[0102] The bond represents an unspecified configuration, including cis (E) or trans (Z) configurations.

[0103] In addition, the compounds and intermediates of the present disclosure can also exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. "Tautomers" refer to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton migration, such as keto-enol isomerization, imine-enamine isomerization, and lactam-lactim isomerization. All tautomeric forms of all compounds in the present disclosure are within the scope of the present disclosure. The names of compounds named in a single way do not exclude any tautomers.

[0104] The present disclosure also includes isotopically labeled compounds of the present disclosure that have the same structures as those described herein, but in which one or more atoms are replaced with atoms having an atomic weight or mass number different from the atomic weight or mass number commonly found in nature. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I, and 36 Cl, etc. All isotopic compositions of the compounds of the present disclosure, whether radioactive or not, are included within the scope of the present disclosure.

[0105] Unless otherwise specified, when a position is specifically designated as deuterium (D), that position should be understood to have a deuterium abundance greater than the natural abundance of deuterium (which is 0.015%) by at least 1000-fold (i.e., at least 10% deuterium incorporation). The deuterium in the compounds of the examples can have an abundance greater than the natural abundance of deuterium by at least 1000-fold, at least 2000-fold, at least 3000-fold, at least 4000-fold, at least 5000-fold, at least 6000-fold, or higher. Each available hydrogen atom attached to a carbon atom can be independently replaced with a deuterium atom. Those skilled in the art can refer to relevant literature to synthesize deuterated forms of the compounds. Commercially available deuterated starting materials can be used in the preparation of deuterated compounds, or they can be synthesized using conventional techniques with deuterated reagents, including but not limited to deuterated borane, tetrahydrofuran solution of trideuterated borane, deuterated lithium aluminum hydride, deuterated iodoethane, and deuterated iodomethane, etc.

[0106] "Therapeutically effective amount" of the present disclosure refers to the amount of an active compound or drug that a researcher, veterinarian, physician, or other clinician, etc. seeks in an organization, system, animal, individual, or human to cause a biological or medical response, and it includes one or more of the following: (1) Preventing diseases: For example, preventing a disease, disorder, or condition in an individual who is susceptible to a disease, disorder, or condition but has not yet experienced or presented the pathology or symptoms of the disease. (2) Suppressing diseases: For example, suppressing a disease, disorder, or condition (i.e., preventing the further development of the pathology and / or symptoms) in an individual who is experiencing or presenting the pathology or symptoms of a disease, disorder, or condition. (3) Alleviating diseases: For example, alleviating a disease, disorder, or condition (i.e., reversing the pathology and / or symptoms) in an individual who is experiencing or presenting the pathology or symptoms of a disease, disorder, or condition. For a drug or a pharmacological active agent, "therapeutically effective amount" refers to a sufficient amount of the drug or agent that is non-toxic but can achieve the desired effect. The determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate effective amount in a specific case can be determined by those skilled in the art through routine tests.

[0107] "Pharmaceutically acceptable" of the present disclosure means that these compounds, materials, compositions, and / or dosage forms are suitable for contact with a patient's tissue within the scope of reasonable medical judgment without excessive toxicity, irritation, allergic reaction, or other problems or complications, have a reasonable benefit / risk ratio, and are effective for the intended use.

[0108] "Patient" of the present disclosure refers to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, and most preferably humans.

[0109] Beneficial effects

[0110] The present disclosure provides a small molecule compound having a pyridine N-oxide structure, which can be used as a p38 MAPK / MK2 pathway inhibitor, for example, the compounds shown in Formula (I), Formula (I-1), Formula (I-2), Table A, or Table B having a pyridine N-oxide structure. Such compounds or pharmaceutical compositions can be used to effectively treat or prevent diseases mediated by the p38 MAPK / MK2 pathway.

[0111] Term definitions and explanations

[0112] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0113] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched-chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 (such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, and more preferably an alkyl group containing 1 to 6 carbon atoms (C1-6 (alkyl). Non-limiting examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and various branched isomers thereof, etc. The alkyl can be substituted or unsubstituted.

[0114] The term "alkoxy" refers to -O-(alkyl), where alkyl is defined as described herein. Preferred alkoxy groups contain 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms (C 1-12 alkoxy), more preferably alkoxy groups containing 1 to 6 carbon atoms (C 1-6 alkoxy). Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, and butoxy. The alkoxy can be substituted or unsubstituted.

[0115] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, and the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms or 3 to 8 (e.g., 3, 4, 5, 6, 7, and 8) carbon atoms, more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyl includes spirocyclic, fused-ring, and bridged-ring cycloalkyl.

[0116] The term "spiroalkyl" refers to a polycyclic group having 5 to 20 members, where each monocyclic ring in the system shares a carbon atom (called a spiro atom), and it can contain one or more double bonds. It is preferably 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9, or 10 members). Spiroalkyl is classified into monospiroalkyl, dispiroalkyl, or polyspiroalkyl according to the number of spiro atoms shared between rings, preferably monospiroalkyl and dispiroalkyl. More preferably, it is 3-member / 5-member, 3-member / 6-member, 4-member / 4-member, 4-member / 5-member, 4-member / 6-member, 5-member / 5-member, or 5-member / 6-member monospiroalkyl. Non-limiting examples of spiroalkyl include:

[0117]

[0118] The term "fused cycloalkyl" refers to a fully carbon polycyclic group having 5 to 20 members, in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, and one or more of the rings may contain one or more double bonds. Preferably it has 6 to 14 members, more preferably 7 to 10 members (such as 7, 8, 9 or 10 members). It can be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably bicyclic alkyl groups of 3 / 4, 3 / 5, 3 / 6, 4 / 4, 4 / 5, 4 / 6, 5 / 4, 5 / 5, 5 / 6, 6 / 3, 6 / 4, 6 / 5 and 6 / 6. Non-limiting examples of fused cycloalkyl include:

[0119]

[0120] The term "bridged cycloalkyl" refers to a fully carbon polycyclic group having 5 to 20 members, in which any two rings share two non-directly connected carbon atoms, and it may contain one or more double bonds. Preferably it has 6 to 14 members, more preferably 7 to 10 members (such as 7, 8, 9 or 10 members). It can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl include:

[0121]

[0122] The cycloalkyl ring includes cycloalkyl (including monocyclic, spiro, fused and bridged) as described herein fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is cycloalkyl, and non-limiting examples include etc.; preferably The cycloalkyl may be substituted or unsubstituted.

[0123] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic ring substituent containing 3 to 20 ring atoms, one or more of which are heteroatoms selected from nitrogen, oxygen and sulfur, said sulfur being optionally oxidized (i.e., forming sulfoxide or sulfone), but excluding ring moieties of -O-O-, -O-S- or -S-S-, and the remaining ring atoms being carbon. Preferably, it contains 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) ring atoms, where 1 to 4 (e.g., 1, 2, 3 and 4) are heteroatoms; more preferably, it contains 3 to 8 ring atoms (e.g., 3, 4, 5, 6, 7 and 8), where 1 - 3 (e.g., 1, 2 and 3) are heteroatoms; more preferably, it contains 3 to 6 ring atoms, where 1 - 3 are heteroatoms; most preferably, it contains 5 or 6 ring atoms, where 1 - 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6 - tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups.

[0124] The term "spiroheterocyclic group" refers to a polycyclic heterocyclic group having 5 to 20 members, where each monocyclic ring in the system shares one atom (called the spiro atom), one or more of the ring atoms being heteroatoms selected from nitrogen, oxygen and sulfur, said sulfur being optionally oxidized (i.e., forming sulfoxide or sulfone), and the remaining ring atoms being carbon. It may contain one or more double bonds. Preferably, it has 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members). Spiroheterocyclic groups are classified into monospiroheterocyclic groups, dispiroheterocyclic groups or polyspiroheterocyclic groups according to the number of spiro atoms shared between rings, preferably monospiroheterocyclic groups and dispiroheterocyclic groups. More preferably, they are 3 - member / 5 - member, 3 - member / 6 - member, 4 - member / 4 - member, 4 - member / 5 - member, 4 - member / 6 - member, 5 - member / 5 - member or 5 - member / 6 - member monospiroheterocyclic groups. Non-limiting examples of spiroheterocyclic groups include:

[0125]

[0126] The term "fused heterocyclic group" refers to a polycyclic heterocyclic group having 5 to 20 members, where each ring in the system shares an adjacent pair of atoms with other rings in the system, one or more of the rings may contain one or more double bonds, one or more of the ring atoms being heteroatoms selected from nitrogen, oxygen and sulfur, said sulfur being optionally oxidized (i.e., forming sulfoxide or sulfone), and the remaining ring atoms being carbon. Preferably, it has 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members). It can be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 3 - member / 4 - member, 3 - member / 5 - member, 3 - member / 6 - member, 4 - member / 4 - member, 4 - member / 5 - member, 4 - member / 6 - member, 5 - member / 4 - member, 5 - member / 5 - member, 5 - member / 6 - member, 6 - member / 3 - member, 6 - member / 4 - member, 6 - member / 5 - member and 6 - member / 6 - member bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

[0127]

[0128] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group having 5 to 14 members, in which any two rings share two non-adjacent atoms, which may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, and the sulfur may be optionally oxidized (i.e., form sulfoxide or sulfone), and the remaining ring atoms are carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

[0129]

[0130] The heterocyclic ring includes a heterocyclic group (including monocyclic, spiro heterocyclic, fused heterocyclic and bridged heterocyclic) as described herein fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, and non-limiting examples thereof include:

[0131] etc. The heterocyclic group may be substituted or unsubstituted.

[0132] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6 to 10 members, such as phenyl and naphthyl. The aryl ring includes an aryl ring as described herein fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples thereof include:

[0133]

[0134] Aryl may be substituted or unsubstituted.

[0135] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 (e.g., 1, 2, 3 and 4) heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 10 members (e.g., 5, 6, 7, 8, 9 or 10 members), more preferably 5 or 6 members, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl ring includes a heteroaryl as described herein fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples thereof include:

[0136]

[0137] The heteroaryl may be substituted or unsubstituted.

[0138] The terms “alkyl”, “alkoxy”, “cycloalkyl”, “heterocyclic group”, “aryl” and “heteroaryl” etc. in this article may be substituted or unsubstituted; when substituted, it may be substituted at any available connection point, and the substituents are preferably independently optionally selected from one or more identical or different substituents of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic group, aryl and heteroaryl.

[0139] The above-mentioned cycloalkyl, heterocyclic group, aryl and heteroaryl include residues derived from removing one hydrogen atom from the parent ring atom, or residues derived from removing two hydrogen atoms from the same or two different ring atoms of the parent, namely “divalent cycloalkyl”, “divalent heterocyclic group”, “arylene”, “heteroarylene”.

[0140] The term “cycloalkyloxy” refers to cycloalkyl-O-, where cycloalkyl is as defined herein.

[0141] The term “heterocyclic group oxy” refers to heterocyclic group -O-, where heterocyclic group is as defined herein.

[0142] The term “haloalkyl” means that the alkyl is substituted by one or more halogens, where alkyl is as defined herein.

[0143] The term “haloalkoxy” means that the alkoxy is substituted by one or more halogens, where alkoxy is as defined herein.

[0144] The term “hydroxyalkyl” means that the alkyl is substituted by one or more hydroxyl groups, where alkyl is as defined herein.

[0145] The term “halogen” refers to F, Cl, Br or I.

[0146] The term “hydroxy” refers to -OH.

[0147] The term “amino” refers to -NH 2 .

[0148] The term “cyano” refers to -CN.

[0149] The term “nitro” refers to -NO 2 .

[0150] The term “oxo group” or “oxo” refers to “=O”.

[0151] The term “carbonyl” refers to C=O.

[0152] The term “carboxyl” refers to -C(O)OH.

[0153] The term "carboxylate group" refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O)O-, where the alkyl and cycloalkyl are as defined herein.

[0154] "Optional" or "optionally" means that the subsequent described event or circumstance may but need not occur, and this description includes the cases where the event or circumstance occurs or does not occur. For example, "a heterocycloalkyl group optionally substituted by an alkyl group" means that the alkyl group may but need not be present, and this description includes the case where the heterocycloalkyl group is substituted by an alkyl group and the case where the heterocycloalkyl group is not substituted by an alkyl group.

[0155] "Substituted" means that one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, are independently replaced by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) what substitutions are possible or impossible without undue effort. For example, an amino or hydroxyl group with a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (such as olefinic) bond. Detailed Description of Embodiments

[0156] The technical solutions of the present disclosure will be further described in detail below in conjunction with specific embodiments. It should be understood that the following embodiments are only for illustrative explanation of the present disclosure and should not be construed as limiting the protection scope of the present disclosure. All technologies implemented based on the above content of the present disclosure are covered within the scope intended to be protected by the present disclosure.

[0157] Unless otherwise specified, the raw materials and reagents used in the following embodiments are all commercially available products or can be prepared by known methods.

[0158] For the experimental methods without specific conditions noted in the following embodiments, they are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0159] The structure of the compound is determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). The NMR shift (δ) is given in units of 10 -6 (ppm). The NMR measurement is performed using a Bruker Avance III 400 MHz nuclear magnetic resonance spectrometer, and the solvents for measurement are deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard is tetramethylsilane (TMS).

[0160] Mass spectrometry (MS) was determined by Waters 2767 HPLC / Waters SQD, Waters H-class UPLC-SQD2, and Agilent HPLC / Waters liquid chromatography-mass spectrometry

[0161] Chiral HPLC analysis was performed using a Shimadzu LC-20AD.

[0162] Thin layer chromatography silica gel plates used were GF254 silica gel plates from Chenghua Chemical Industry (Shanghai) Co., Ltd. The specifications of the silica gel plates used in thin layer chromatography (TLC) were 0.2 - 0.25 mm, and the specifications of the silica gel plates used for thin layer chromatography separation and purification of products were 0.4 - 0.5 mm.

[0163] Column chromatography generally used silica gel with a mesh size of 100 - 200 from Chenghua Chemical Industry (Shanghai) Co., Ltd. as the carrier.

[0164] Preparative high performance liquid chromatography used Waters HPLC, Gilson HPLC, and Biotage MPLC preparative chromatographs.

[0165] Chiral separation column chromatography used a Gilson GX-281 preparative HPLC.

[0166] Unless otherwise specified in the examples, the reactions were carried out under a nitrogen atmosphere.

[0167] A nitrogen atmosphere means that the reaction flask was connected to a nitrogen balloon with a volume of approximately 1 liter.

[0168] A hydrogen atmosphere means that the reaction flask was connected to a hydrogen balloon with a volume of approximately 1 liter.

[0169] Unless otherwise specified in the examples, the reaction temperature was room temperature, and the temperature range was 20°C - 30°C.

[0170] Those skilled in the art should understand that the resolved chiral compounds can be distinguished by the order of retention times in a chiral chromatographic column. Therefore, the chiral compounds resolved according to the order of retention times are distinguished by the suffixes P1 and P2 in the numbering. That is, the suffix P1 corresponds to the chiral structure resolved first, and the suffix P2 corresponds to the chiral structure resolved later. If the absolute configuration of a compound is listed in the structural formula, it does not mean a one-to-one correspondence with the compounds with suffixes P1 and P2, but only indicates two existing forms of the absolute configuration. The absolute configuration of the compounds with suffixes P1 and P2 is subject to the absolute configuration objectively corresponding to a specific retention time.

[0171] Reagent names corresponding to reagent English abbreviations:

[0172] Reagent Abbreviation in English Reagent Name NCS N-Chlorosuccinimide DMF N,N-Dimethylformamide NaH Sodium Hydride TFA Trifluoroacetic Acid <![CDATA[H 2 O 2 > Hydrogen Peroxide AD-mix-β AD-Mixture-BETA (CAS: 148618-32-0) DIBAL-H Diisobutylaluminum Hydride

[0173] Synthesis of Intermediate Compound A1

[0174]

[0175] First Step: Synthesis of Compound A1-2

[0176] Thionyl chloride (22.43 g, 0.19 mol) was slowly added dropwise to a solution of Compound A1-1 (20 g, 0.13 mol) in ethanol (60 mL). The reaction mixture was heated to 60 °C and stirred at this temperature for 3 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain Compound A1-2 (20 g, crude product). The product was directly subjected to the next reaction without purification. MS m / z (ESI): 187.9 [M+1] + 。

[0177] Second Step: Synthesis of Compound A1-3

[0178] At 0 °C, sodium borohydride (6.48 g, 0.17 mol) was added portionwise to a solution of Compound A1-2 (16 g, 0.086 mol) in ethanol (60 mL). The reaction mixture was slowly warmed to room temperature and stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 - 1 / 5) to obtain Compound A1-3 (16 g). MS m / z (ESI): 146.1 [M+1] + 。

[0179] Third Step: Synthesis of Compound A1

[0180] Five drops of N,N-dimethylformamide were added to a solution of Compound A1-3 (1.80 g, 12.4 mmol) in dichloromethane (50 mL). The reaction mixture was stirred for ten minutes. At room temperature, thionyl chloride (1.77 g, 14.88 mmol) was slowly added to the above solution. The resulting mixture was stirred at room temperature for 1 hour. After the reaction was completed, 4 M ammonium chloride solution was added to the reaction solution until pH = 7, and it was extracted with dichloromethane (60 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 - 5 / 1) to obtain Compound A1 (1.80 g). 1 H NMR (400 MHz, CDCl 3 ) δ 8.35 (d, J = 2.4 Hz, 1H), 7.26 (ddd, J = 9.1, 8.0, 2.6 Hz, 1H), 4.72 (d, J = 2.1 Hz, 2H).

[0181] Synthesis of Intermediate Compound A2

[0182]

[0183] Step 1: Synthesis of Compound A2-2

[0184] Add NCS (10.6 g, 80 mmol) to a solution of Compound A2-1 (10 g, 53 mmol) in DMF (200 mL). The reaction mixture is stirred at 80 °C for 2 h. After the reaction is completed, the reaction solution is diluted with water (800 mL), extracted with ethyl acetate (200 mL × 3). The combined organic phases are dried over anhydrous sodium sulfate and filtered. The filtrate is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 1:1) to obtain Compound A2-2 (10 g). MS m / z (ESI): 221.7 [M+1] + 。

[0185] Step 2: Synthesis of Compound A2-3

[0186] At 0 °C, add NaH (2.16 g, 90 mmol) and methyl iodide (12.8 g, 90 mmol) successively to a solution of Compound A2-2 (10 g, 45 mmol) in DMF (100 mL). The reaction mixture is slowly warmed to room temperature and stirred for 16 h. After the reaction is completed, the reaction solution is quenched with water (300 mL), extracted with ethyl acetate (200 mL × 2). The combined organic phases are washed with saturated brine (100 mL × 1), dried over anhydrous sodium sulfate and filtered. The filtrate is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 5:1) to obtain Compound A2-3 (8 g). MS m / z (ESI): 236.0 [M+1] + 。

[0187] Step 3: Synthesis of Compound A2-4

[0188] Add Compound A2-3 (8 g, 34 mmol) to a mixed solution of TFA and H 2 O 2 (40 mL / 40 mL). The reaction mixture is stirred at 100 °C for 16 h. After the reaction is completed, the reaction solution is concentrated under reduced pressure. The residue is adjusted to pH = 8 with saturated sodium bicarbonate solution, extracted with ethyl acetate (100 mL × 2). The combined organic phases are concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 1:1) to obtain Compound A2-4 (2 g). MS m / z (ESI): 251.9 [M+1] + 。

[0189] Step 4: Synthesis of Compound A2-5

[0190] Aluminum trichloride (4.2 g, 32 mmol) and ethanethiol (2 g, 32 mmol) were successively added to a dichloromethane (40 mL) solution of compound A2-4 (1.6 g, 6.3 mmol), and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. Water (100 mL) was added to the residue, and a white solid was precipitated. After filtration, the filter cake was dried to obtain compound A2-5 (1 g). MS m / z (ESI): 237.9 [M+1] + 。

[0191] Step 5: Synthesis of compound A2

[0192] Potassium carbonate (1.16 g, 8.4 mmol) was added to a N,N-dimethylformamide (20 mL) solution of compound A2-5 (1 g, 4.2 mmol) and compound A1 (0.7 g, 4.2 mmol), and the reaction mixture was stirred at 65 °C for 3 hours. After the reaction was completed, the reaction solution was diluted with water (100 mL), extracted with ethyl acetate (100 mL × 3), the combined organic phases were washed with saturated brine (100 mL × 1), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 - 1 / 1) to obtain compound A2 (1 g). MS m / z (ESI): 364.7 [M+1] + 。

[0193] Example 1 (compounds 5,5-P1 and 5-P2)

[0194]

[0195] Step 1: Synthesis of compound 5b

[0196] 1,1'-Bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (488 mg, 0.59 mmol) was added to a mixed solution of compound 5a (3 g, 11.8 mmol), isopropenylboronic acid pinacol ester (1.98 g, 11.8 mmol) and potassium carbonate (3.2 g, 23.6 mmol) in 1,4-dioxane and water (50 mL / 10 mL), and the reaction mixture was stirred at 80 °C for 16 hours. After the reaction was completed, the reaction solution was diluted with water (200 mL), extracted with dichloromethane (40 mL × 3), the combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 - 20 / 1) to obtain compound 5b (2 g). 1 H NMR(400MHz,CDCl 3)δ 7.58–7.41 (m, 1H), 7.31–7.17 (m, 1H), 7.01–6.95 (m, 1H), 5.24–5.23 (m, 2H), 2.16–2.14 (m, 3H).

[0197] Step 2: Synthesis of Compound 5c

[0198] Compound 5b (2 g, 9.3 mmol) and AD-mix-β (20 g) were dissolved in a mixed solution of tert-butanol and water (40 mL / 40 mL), and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, the reaction solution was quenched by adding a sodium thiosulfate solution (40 mL), extracted with dichloromethane (50 mL × 3), and the combined organic phases were washed with saturated brine (50 mL × 1) and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 0 - 20 / 1) to obtain Compound 5c (900 mg). 1 H NMR (400 MHz, CDCl 3 )δ 7.66–7.57 (m, 1H), 7.51–7.47 (m, 1H), 7.05 (td, J = 7.9, 0.8 Hz, 1H), 4.00 (dd, J = 11.1, 1.1 Hz, 1H), 3.75 (dd, J = 11.0, 1.3 Hz, 1H), 1.58 (d, J = 1.4 Hz, 3H).

[0199] Step 3: Synthesis of Compound 5d

[0200] 1,1'-Bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (290 mg, 0.36 mmol) was added to a solution of Compound 5c (900 mg, 3.6 mmol), bis(pinacolato)diboron (1.35 g, 5.4 mmol) and potassium acetate (720 mg, 7.2 mmol) in 1,4-dioxane (20 mL), and the reaction mixture was stirred at 80 °C for 16 h. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 0 - 20 / 1) to obtain Compound 5d (1.1 g, crude product).

[0201] Step 4: Synthesis of Compound 5e

[0202] Tetrakis(triphenylphosphine)palladium (346 mg, 0.3 mmol) was added to a mixed solution of compound 5d (900 mg, crude product), 2,4-dichloro-5-methylpyridine (480 mg, 3.0 mmol), and sodium carbonate (516 mg, 6.0 mmol) in 1,4-dioxane and water (10 mL / 2 mL). The reaction mixture was stirred at 80 °C for 2 h. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 0 to 20 / 1) to obtain compound 5e (500 mg). MS m / z (ESI): 296.05 [M+1] + .

[0203] Step 5: Synthesis of compound 5f

[0204] 1,1'-Bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (138 mg, 0.17 mmol) was added to a solution of compound 5e (500 mg, 1.7 mmol), bis(pinacolato)diboron (863 mg, 3.4 mmol), and potassium acetate (333 mg, 7.2 mmol) in 1,4-dioxane (10 mL). The reaction mixture was stirred at 80 °C for 16 h. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain compound 5f (300 mg, crude product).

[0205] Step 6: Synthesis of compounds 5-1, 5-P1, and 5-P2

[0206] Palladium tetrakis(triphenylphosphine) (58 mg, 0.05 mmol) was added to a mixed solution of compound A2 (200 mg, 0.55 mmol), compound 5f (168 mg, crude product), and potassium carbonate (228 mg, 1.65 mmol) in 1,4-dioxane and water (4 mL / 0.4 mL). The reaction mixture was stirred at 90 °C for 3 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 2 to dichloromethane / methanol = 30 / 1) to obtain crude compound 5-1. Crude compound 5-1 was purified by preparative high performance liquid chromatography (preparative column: YMC Triart C18 12 nm 10u, 30*250 mm, flow rate: 40 mL / min, column temperature: room temperature, mobile phase: A: water (0.1% ammonia water) B: preparative acetonitrile) to obtain compound 5 (84.0 mg, yield 28.0%). Compound 5 was resolved by chiral preparative chromatography (preparative column: YMC CHIRALART cellulose-SC, 30*250 mm, flow rate: 30 mL / min, column temperature: room temperature, injection volume: 1 ml, mobile phase: A: n-hexane, B: ethanol) to obtain compound 5-P1 (23.4 mg) and compound 5-P2 (14.9 mg).

[0207] Compound 5-P1:

[0208] MS m / z (ESI): 546.05 [[M+1]] + . Chiral HPLC: retention time = 13.60 min, UV = 220 nm. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.69 (s, 1H), 8.58 (d, J = 2.4 Hz, 1H), 8.13–8.00 (m, 1H), 7.81–7.63 (m, 2H), 7.56–7.49 (m, 2H), 7.25 (t, J = 7.6 Hz, 1H), 5.45 (d, J = 1.6 Hz, 2H), 5.12 (s, 1H), 4.66 (t, J = 6.0 Hz, 1H), 3.63–3.50 (m, 2H), 2.04 (s, 3H), 2.02 (s, 3H), 1.42 (s, 3H).

[0209] Compound 5-P2:

[0210] MS m / z (ESI): 546.05 [[M+1]] + . Chiral HPLC: retention time = 15.36 min, UV = 220 nm. 1 H NMR (400 MHz, DMSO-d 6)δ8.68(s,1H),8.58(d,J=2.4Hz,1H),8.13–8.01(m,1H),7.77–7.63(m,2H),7.59–7.48(m,2H),7.25(t,J=7.6Hz,1H),5.45(d,J=1.6Hz,2H),5.12(s,1H),4.67(t,J=6.0Hz,1H),3.64–3.52(m,2H),2.04(s,3H),2.02(s,3H),1.42(s,3H).

[0211] Example 2 (Compounds 6-1, 6-P1 and 6-P2)

[0212]

[0213] Step 1: Synthesis of Compound 6a

[0214] At -15 °C, lithium diisopropylamide (37.1 mL, 74.22 mmol, 2 M) was slowly added dropwise to a solution of Compound 2a (9.5 g, 49.48 mmol) in anhydrous tetrahydrofuran (100 mL). After the reaction mixture was stirred at -15 °C for 1 hour, N-methoxy-N-methylacetamide (7.6 g, 74.22 mmol) was added dropwise. After the addition was complete, the reaction mixture was stirred at -15 °C for 1 hour. After the reaction was completed, the reaction was quenched by slowly adding saturated ammonium chloride solution (50 mL) to the reaction solution under an ice bath. The mixture was diluted with water (100 mL), extracted with ethyl acetate (200 mL × 2), and the combined organic phases were washed with saturated brine (200 mL × 1), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to obtain Compound 6a (3.8 g). 1 H NMR(400MHz,DMSO-d 6 )δ7.96-7.90(m,1H),7.26(td,J=9.2,1.6Hz,1H),2.58(t,J=1.6Hz,3H).

[0215] Step 2: Synthesis of Compound 6b

[0216] At 0 °C, a solution of potassium tert-butoxide (1.9 g, 16.92 mmol) in tetrahydrofuran (5 mL) was added to a solution of methyltriphenylphosphonium bromide (6.0 g, 16.92 mmol) in anhydrous tetrahydrofuran (30 mL). After the mixture was stirred at 0 °C for 1 hour, a solution of compound 6a (3.3 g, 14.10 mmol) in tetrahydrofuran (5 mL) was added dropwise. After the addition, the reaction mixture was slowly warmed to room temperature and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was quenched by dropwise addition of saturated ammonium chloride solution (20 mL), diluted with water (30 mL), extracted with ethyl acetate (100 mL × 1), and the combined organic phases were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether) to give compound 6b (2.4 g). 1 H NMR(400MHz,DMSO-d 6 )δ7.76-7.66(m,1H),7.14(td,J=9.1,1.7Hz,1H),5.67–5.38(m,1H),5.13(s,1H),2.03(s,3H).

[0217] Step 3: Synthesis of compound 6c

[0218] AD-mix-β (14 g) was added to a mixture of compound 6b (1.4 g, 6.03 mmol) in tert-butanol and water (28 mL / 28 mL). The reaction mixture was stirred at room temperature for 24 hours. After completion of the reaction, the reaction solution was quenched by addition of saturated aqueous sodium sulfite solution (30 mL), diluted with water (30 mL), extracted with ethyl acetate (60 mL × 2), and the combined organic phases were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 0 - 10 / 1) to give compound 6c (560 mg). 1 H NMR(400MHz,DMSO-d 6 )δ7.66-7.60(m,1H),7.03-6.97(m,1H),5.25(s,1H),4.89(t,J=6.1Hz,1H),3.61(dd,J=10.7,5.9Hz,1H),3.53(dd,J=10.7,6.3Hz,1H),1.54(t,J=2.7Hz,3H).

[0219] Step 4: Synthesis of compound 6d

[0220] 1,1'-Bis(diphenylphosphino)ferrocene-palladium(II) dichloride (123 mg, 0.17 mmol) was added to a solution of compound 6c (450 mg, 1.69 mmol), bis(pinacolato)diboron (1.3 g, 5.07 mmol) and potassium acetate (332 mg, 3.38 mmol) in 1,4-dioxane (10 mL). The reaction mixture was stirred at 90 °C for 16 h. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1 - 1 / 2) to obtain compound 6d (1.2 g, crude product, theoretical 660 mg).

[0221] Step 5: Synthesis of compound 6e

[0222] Tetrakis(triphenylphosphine)palladium (242 mg, 0.21 mmol) was added to a mixed solution of compound 6d (660 mg, 2.10 mmol), 2,4-dichloro-5-methylpyridine (408 mg, 2.52 mmol) and sodium carbonate (445 mg, 4.20 mmol) in 1,4-dioxane and water (10 mL / 2 mL). The reaction mixture was stirred at 90 °C for 3 h. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1 - 2 / 1) to obtain compound 6e (800 mg, crude product, containing triphenylphosphine oxide). MS m / z (ESI): 314.00 [M+H] + 。

[0223] Step 6: Synthesis of compound 6f

[0224] 1,1'-Bis(diphenylphosphino)ferrocene-palladium(II) dichloride (139 mg, 0.19 mmol) was added to a solution of compound 6e (600 mg, crude product), bis(pinacolato)diboron (1.46 g, 5.75 mmol) and potassium acetate (376 mg, 3.83 mmol) in 1,4-dioxane (10 mL). The reaction mixture was stirred at 120 °C for 6 h. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was roughly purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1 - 1:1 ~ dichloromethane / methanol = 1 / 0 - 10 / 1) to obtain compound 6f (290 mg, crude product).

[0225] Step 7: Synthesis of compound 6-1, 6-P1 and 6-P2

[0226] Tetrakis(triphenylphosphine)palladium (64 mg, 0.05 mmol) was added to a mixed solution of compound A2 (200 mg, 0.55 mmol), compound 6f (290 mg, crude product), and sodium carbonate (152 mg, 1.08 mmol) in 1,4-dioxane and water (5 mL / 1 mL). The reaction mixture was stirred at 90 °C for 4 h. After completion of the reaction, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 0 - 10 / 1) to obtain crude compound 6-1. Crude compound 6-1 was purified by preparative high performance liquid chromatography (preparation conditions: preparative column: YMC Triart C18 12 nm 10u, 30 * 250 mm; flow rate: 40 mL / min; column temperature: room temperature; mobile phase: A: water (0.1% ammonia water) B: preparative acetonitrile) to obtain compound 6-1 (44.5 mg). Compound 6-1 (40 mg) was resolved and purified by chiral preparative chromatography (preparative column: YMC CHIRALART cellulose-SC, 30 * 250 mm, flow rate: 30 mL / min, column temperature: room temperature, injection volume: 1 ml, mobile phase: A: n-hexane, B: ethanol) to obtain compound 6-P1 (2.9 mg) and compound 6-P2 (5.6 mg).

[0227] Compound 6-P1

[0228] MS m / z (ESI): 564.1 [M+1] + . Chiral HPLC: retention time = 14.74 min, UV = 220 nm. 1 1H NMR (400 MHz, DMSO-d 6 ) δ 8.71 (s, 1H), 8.60 (d, J = 2.3 Hz, 1H), 8.24–8.01 (m, 1H), 7.87–7.69 (m, 1H), 7.54 (d, J = 3.6 Hz, 2H), 7.18–7.03 (m, 1H), 5.47 (s, 2H), 5.12 (s, 1H), 4.85 (t, J = 5.8 Hz, 1H), 3.62 (dt, J = 16.2, 10.8 Hz, 2H), 2.05 (d, J = 7.5 Hz, 6H), 1.58 (s, 3H).

[0229] Compound 6-P2

[0230] MS m / z (ESI): 564.1 [M+1] + . Chiral HPLC: retention time = 22.42 min, UV = 220 nm. 1 1H NMR (400 MHz, DMSO-d 6)δ8.70(s,1H),8.60(d,J=2.3Hz,1H),8.15–8.03(m,1H),7.78(dd,J=14.6,8.4Hz,1H),7.54(d,J=4.9Hz,2H),7.19–7.05(m,1H),5.47(s,2H),5.13(s,1H),4.86(s,1H),3.62(q,J=10.7Hz,2H),2.05(d,J=6.7Hz,6H),1.58(s,3H).

[0231] Example 3 (Compounds 11, 11-P1 and 11-P2)

[0232]

[0233] First step: Synthesis of compound 11b

[0234] At 0 °C, sodium hydride (2.10 g, 52.6 mmol) was added in three portions to a solution of compound 11a (4.50 g, 21.0 mmol) and 1,2-dibromoethane (5.10 g, 27.3 mmol) in tetrahydrofuran (45 mL). The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was quenched by dropwise addition of isopropanol (6 mL), diluted with water (40 mL), extracted with ethyl acetate (40 mL × 2), the combined organic phases were washed with saturated brine (40 mL × 1), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1 - 10 / 1) to obtain compound 11b (4.8 g). MS m / z (ESI): 241.95 [M+1] + .

[0235] Second step: Synthesis of compound 11c

[0236] Compound 11b (4.80 g, 20.0 mmol) was dissolved in ethanol (80 mL), and concentrated sulfuric acid (12 mL) was added under ice bath conditions. The reaction mixture was stirred at 90 °C for 48 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, the residue was added to ice water (50 mL), extracted with ethyl acetate (50 mL × 2), the combined organic phases were washed with saturated sodium chloride aqueous solution (50 mL × 1), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1 - 10 / 1) to obtain compound 11c (4.4 g). MS m / z (ESI): 286.95 [M+1] + .

[0237] Third step: Synthesis of compound 11d

[0238] At -75 °C, DIBAL-H (20 mL, 20.2 mmol, 1 M) was added dropwise to a solution of compound 11c (2.90 g, 10.1 mmol) in dichloromethane (30 mL). The reaction mixture was stirred at -75 °C for 2 h. After completion of the reaction, the reaction solution was quenched with water (6 mL), then anhydrous sodium sulfate was added and stirred for 5 min. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 - 5 / 1) to give compound 11d (2.4 g). MS m / z (ESI): 228.05 [M - 17] + 。

[0239] Step 4: Synthesis of compound 11e

[0240] 1,1'-Bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (326 mg, 0.45 mmol) was added to a solution of compound 11d (1.10 g, 4.5 mmol), pinacol borate (3.42 g, 13.5 mmol), and potassium acetate (880 mg, 8.9 mmol) in 1,4-dioxane (20 mL). The reaction mixture was stirred at 90 °C for 3 h. After completion of the reaction, the reaction solution was directly concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1 - 5 / 1) to give compound 11e (2 g, crude product). MS m / z (ESI): 275.10 [M - 17] + 。

[0241] Step 5: Synthesis of compound 11f

[0242] Tetrakis(triphenylphosphine)palladium (0.71 g, 0.62 mmol) was added to a mixed solution of 2,4-dichloro-5-methylpyridine (1 g, 6.17 mmol), compound 11e (3.61 g, crude product), and sodium carbonate (1.31 g, 12.34 mmol) in 1,4-dioxane and water (20 mL / 4 mL). The reaction mixture was stirred at 80 °C for 3.5 h. After completion of the reaction, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1 - 3 / 1) to give compound 11f (3 g), MS m / z (ESI): 291.95 [M + H] + 。

[0243] Step 6: Synthesis of compound 11g

[0244] A solution of compound 11f (3 g, 10.28 mmol), bis(pinacolato)diboron (3.92 g, 15.42 mmol), potassium acetate (2.02 g, 20.56 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.84 g, 1.03 mmol) in 1,4-dioxane (40 mL) was added to a glass sealed tube (120 mL), and the reaction mixture was heated to 120 °C and stirred overnight. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1 - 1 / 2) to obtain compound 11g (2.52 g), MS m / z (ESI): 302.00 [M+H] + 。

[0245] Step 7: Synthesis of compounds 11, 11-P1 and 11-P2

[0246] Tetrakis(triphenylphosphine)palladium (110.93 mg, 0.096 mmol) was added to a mixed solution of compound A2 (350 mg, 0.96 mmol), compound 11g (433.61 mg, 1.44 mmol) and potassium carbonate (265.36 mg, 1.92 mmol) in 1,4-dioxane and water (5 mL / 1 mL), and the reaction mixture was stirred at 90 °C overnight. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1 - 0 / 1) to obtain the crude compound 11. The crude product was purified by preparative high performance liquid chromatography (column: YMC Triart C18 50*250 mm, mobile phase: A: 0.1% ammonia water - water; B: acetonitrile; flow rate: 70 mL / min) to obtain compound 11 (195 mg), and a total of 223 mg was obtained by combining small test batches. Compound 11 (223 mg) was resolved by chiral preparative chromatography (preparative column: YMCCHIRALART cellulose-SC, 30*250 mm; flow rate: 30 mL / min; column temperature: room temperature; mobile phase: A: n-hexane; B: ethanol) to obtain compound 11-P1 (87 mg) and compound 11-P2 (89.2 mg).

[0247] Compound 11-P1:

[0248] MS m / z (ESI): 542.1 [M+1] + 。Chiral HPLC: retention time = 8.167 min, UV = 220 nm. 1 H NMR(400

[0249] MHz, DMSO-d 6)δ8.71(s,1H),8.60(d,J=2.3Hz,1H),8.10(td,J=9.8,2.3Hz,1H),7.78(td,J=

[0250] 7.6,1.6Hz,1H),7.61(d,J=1.4Hz,1H),7.55(s,1H),7.47–7.35(m,1H),7.23(t,J=7.6Hz,1H),5.48(d,J=1.1Hz,2H),4.69(s,1H),3.47(s,2H),2.06(d,J=5.2Hz,6H),0.85(t,J=4.9Hz,2H),0.73(t,J=4.9Hz,2H).

[0251] Compound 11-P2:

[0252] MS m / z(ESI):542.1[M+1] + . Chiral HPLC: retention time = 14.412 min, UV = 220 nm. 1 H NMR(400MHz, DMSO-d 6 )δ8.71(s,1H),8.60(d,J=2.3Hz,1H),8.10(td,J=9.9,2.3Hz,1H),7.78(td,J=7.6,1.7Hz,1H),7.61(d,J=1.5Hz,1H),7.55(s,1H),7.39(td,J=7.4,1.7Hz,1H),7.23(t,J=7.6Hz,1H),5.48(d,J=1.3Hz,2H),4.69(s,1H),3.47(s,2H),2.06(d,J=5.2Hz,6H),0.85(t,J=4.9Hz,2H),0.73(t,J=5.0Hz,2H).

[0253] Example 4 (Compounds 12, 12-P1 and 12-P2)

[0254]

[0255] First step: Synthesis of Compound 12b

[0256] Tetrakis(triphenylphosphine)palladium (23.9 mg, 0.021 mmol) was added to a mixed solution of 2,4-dichloro-5-methylpyridine (335 mg, 2.07 mmol), compound 12a (913 mg, 3.10 mmol) and sodium carbonate (439 mg, 4.14 mmol) in 1,4-dioxane and water (20 mL / 4 mL). The reaction mixture was stirred at 80 °C for 2 h. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 - 1 / 5) to obtain compound 12b (1.0 g), MS m / z (ESI): 294.0 [M+H] + .

[0257] Step 2: Synthesis of compound 12c

[0258] Compound 12b (1.0 g, 3.40 mmol), bis(pinacolato)diboron (1.73 g, 6.8 mmol), potassium acetate (667 mg, 6.80 mmol), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (278 mg, 0.34 mmol) were mixed in 1,4-dioxane (12 mL). The mixture was purged with nitrogen three times and then sealed and stirred at 120 °C for 12 h under nitrogen protection. After completion of the reaction, the insoluble matter was removed by filtration through diatomaceous earth, and the solvent was removed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 0 - 1 / 20) to obtain compound 12c (0.54 g). MS m / z (ESI): 304.05 [M+1] +

[0259] Step 3: Synthesis of compounds 12, 12-P1 and 12-P2

[0260] Compound A2 (230 mg, 0.63 mmol), compound 12c (0.50 g, 1.64 mmol), sodium carbonate (134 mg, 1.26 mmol) and tetrakis(triphenylphosphine)palladium (109 mg, 0.095 mmol) were mixed in 1,4-dioxane (6 mL) and water (1.2 mL). The mixture was purged with nitrogen three times and then stirred at 100 °C for 12 hours under nitrogen protection in a sealed tube. After completion of the reaction, the insoluble substances were removed by filtration through diatomaceous earth. The filtrate was concentrated under reduced pressure to remove the solvent. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 10 - 0 / 1) to obtain a crude product, which was further purified by preparative high performance liquid chromatography (preparative column: YMC Triart C18, 30 * 250 mm; flow rate: 40 mL / min; column temperature: room temperature; mobile phase: A: water (0.1% ammonia - water), B: preparative acetonitrile) to obtain compound 12 (0.13 g). Compound 12 (0.13 g) was resolved by chiral preparative chromatography (preparative column: YMC CHIRALART Amylose-C NEO, 30 * 250 mm; flow rate: 30 mL / min; column temperature: room temperature; mobile phase: A: n-hexane, B: isopropanol) to obtain compound 12-P1 (42.1 mg) and compound 12-P2 (45.3 mg).

[0261] Compound 12-P1: MS m / z (ESI): 544.25 [M + 1] + . Chiral HPLC: retention time = 7.629 min, UV = 220 nm. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.71 (s, 1H), 8.60 (d, J = 2.0 Hz, 1H), 8.09 (td, J = 9.6, 2.0 Hz, 1H), 7.71 (t, J = 7.6 Hz, 1H), 7.58–7.54 (m, 2H), 7.41 (t, J = 7.2 Hz, 1H), 7.24 (t, J = 7.6 Hz, 1H), 5.48 (s, 2H), 4.75 (s, 1H), 3.59 (s, 2H), 2.06 (d, J = 4.8 Hz, 6H), 1.31 (s, 6H).

[0262] Compound 12-P2: MS m / z (ESI): 544.25 [M + 1] + . Chiral HPLC: retention time = 14.886 min, UV = 220 nm. 1 H NMR (400 MHz, DMSO-d 6)δ8.71(s,1H),8.60(d,J=2.0Hz,1H),8.13–8.06(m,1H),7.71(t,J=7.6Hz,1H),7.56(d,J=8.0Hz,2H),7.41(t,J=7.2Hz,1H),7.24(t,J=7.8Hz,1H),5.47(s,2H),4.75(s,1H),3.59(s,2H),2.06(d,J=4.8Hz,6H),1.31(s,6H).

[0263] Biological Evaluation

[0264] Test Example 1. Determination of in vitro activity of p38 MAPK / MK2

[0265] The inhibitory effect of the compound on p38 MAPK / MK2 was detected using the Z-LYTE kinase detection kit (Thermo, PV3177). The test compound was dissolved in DMSO to a 10 mM stock solution and stored at -20 °C for later use. The initial concentration of the compound was 10 μM, 1% DMSO, and it was serially diluted 5-fold, with 8 concentrations and duplicate wells; 50 mM HEPES pH 7.5, 10 mM MgCl 2 , 0.01% Brij-35, 1 mM EGTA were used as the reaction buffer to prepare a 2x active p38a / inactive MK2 / Ser / Thr 4 mixture. Finally, a 10 μL reaction system was carried out in a 384-well plate (Corning, 4514), containing 500 ng / mL inactive MK2 (abcam, 79910), 8 ng / mL active p38a (Carna, 04-152), 2 μM Ser / Thr 4; after reacting at 20 °C for 1 hour, 2048-fold diluted Development Reagent A was added to each well, incubated at room temperature for 1 hour, and then 5 μL of the termination buffer solution was added to terminate the reaction. The enzyme-linked immunosorbent assay (ELISA) was detected (Ex. 400 nm, Em. 445 nm; Ex. 400 nm, Em. 520 nm). The concentration-effect curve was fitted using GraphPad Prism 8 software, and the compound concentration with 50% inhibitory effect, that is, IC 50 . The results are shown in Table 1.

[0266] Table 1

[0267]

[0268] As can be seen from Table 1, the compounds of the present disclosure have good inhibitory activity against p38 MAPK / MK2.

[0269] Test Example 2. In vitro Activity Assay of TNF-α in Human PBMC Cell Supernatant

[0270] Experimental protocol for the inhibitory effect of the compound on TNF-α in human PBMC cell supernatant was detected using an Elisa detection kit (Beyotime, PI518). The test compound was dissolved in DMSO to a 10 mM stock solution and stored at -20 °C for later use. The starting concentration of the compound was 2 μM, diluted 5-fold in a serial dilution, with 6 concentrations. The cells were plated in duplicate wells, and the Elisa detection was performed in single wells. The final concentration of DMSO was 0.4%. Also, according to the actual situation of compound screening, the starting concentration of the compound, the dilution factor, the number of gradient concentrations, and the number of duplicate wells can be changed.

[0271] Fresh human peripheral blood mononuclear cells (PBMCs) (Saile Biotech) were plated in a 96-well plate (Corning, 3599) at a density of 2*10^5 cells per well, with each well containing 100 μL of RPMI-1640 (Gibco#A1049101) + 10% FBS (Gibco, 10099141C), and incubated at 37 °C in 5% CO 2 overnight. The test compound was added to the 96-well culture plate at a volume of 25 μL per well. After 1 h, 5 μL of LPS was added to make the final concentration 100 ng / mL. The negative control wells did not add LPS or the compound, and the positive control wells did not add the compound. Incubate at 37 °C in 5% CO 2 After continued incubation for 24 h, the cell culture supernatant was collected by centrifugation at 500 rcf for 8 min. The operation was carried out according to the operation manual in the Elisaa kit to detect the concentration of TNF-α. The concentration-effect curve was fitted using GraphPad Prism 8 software, and the compound concentration with 50% inhibitory effect, i.e., IC 50 .

[0272] The above has given an exemplary description of the implementation manner of the technical solution of the present disclosure. It should be understood that the protection scope of the present disclosure is not limited to the above implementation manner. Any modifications, equivalent replacements, improvements, etc. made by those skilled in the art within the spirit and principle of the present disclosure shall be included within the protection scope of the claims of this application.

Claims

1. A compound as represented by formula (I) or a pharmaceutically acceptable salt thereof, in: R 1 Selected from R 1a and R 1b The same or different, and each independently selected from H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl and 3- to 8-membered cycloalkyl; or R 1a and R 1b Together with the carbon atoms to which they are attached, they form a 3- to 8-membered cycloalkyl or a 3- to 8-membered heterocyclic group, wherein the 3- to 8-membered cycloalkyl or the 3- to 8-membered heterocyclic group is optionally selected from halogen or C 1-6 One or more substituents in the alkyl group are substituted; R 1c and R 1d are the same or different and are each independently selected from H, D, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl and 3- to 8-membered cycloalkyl; or R 1c and R 1d Together with the carbon atoms to which they are attached, they form a 3- to 8-membered cycloalkyl or a 3- to 8-membered heterocyclic group, wherein the 3- to 8-membered cycloalkyl or the 3- to 8-membered heterocyclic group is optionally selected from halogen or C 1-6 One or more substituents in the alkyl group are substituted; Each R 2 are the same or different and are each independently selected from H, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl and 3- to 8-membered cycloalkyl; R 3a and R 3b are the same or different and are each independently selected from H, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl and 3- to 8-membered cycloalkyl; R 4 Selected from H, halogen, C 1-6 Alkyl and C 1-6 Haloalkyl; R 5 Selected from H, halogen, C 1-6 Alkyl and C 1-6 Haloalkyl; R 6 and R 7 are the same or different and are each independently selected from H, D, halogen and C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted with one or more substituents selected from halogen, cyano, hydroxyl and amino; Each R 8 are the same or different and are each independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, cyano, hydroxy, amino, nitro and 3- to 8-membered cycloalkyl; q is selected from 0, 1, 2, 3 and 4; t is selected from 0, 1, 2, 3 and 4.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is a compound represented by formula (I-1) or formula (I-2) or a pharmaceutically acceptable salt thereof, in: R 1 , R 2 , R 3a , R 3b , R 4 , R 5 , R 6 , R 7 , R 8 , q and t are as defined in claim 1.

3. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from R 1a and R 1b are the same or different and are each independently selected from H or methyl; or R 1a and R 1b Together with the carbon to which it is attached, it forms a 3- to 6-membered cycloalkyl group; R 1c and R 1d are the same or different and are each independently selected from H or methyl; or R 1c and R 1d Together with the carbon to which it is attached, it forms a 3- to 6-membered cycloalkyl group.

4. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from 5. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein R 2 is H or halogen; preferably, R 2 It is H or F.

6. The compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, wherein R 3a Selected from halogen or C 1-6 Alkyl; and / or, R 3b Selected from H or halogen.

7. A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein R 4 is halogen; preferably, R 4 For Cl.

8. A compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, wherein R 5 C 1-6 Alkyl; preferably, R 5 It is methyl.

9. A compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 are the same or different and are each independently H or D.

10. The compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, wherein each R 8 are the same or different and are each independently selected from H, halogen, C 1-6 Alkyl and C 1-6 Preferably, R 8 It is a halogen.

11. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein the compound is selected from any one of the following compounds, 12. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein the compound is selected from any one of the following compounds, 13. A method for preparing the compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, comprising the following steps: The compound of formula (IA) undergoes a coupling reaction with the compound of formula (IB) in the presence of a catalyst to obtain a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, in: X is halogen; preferably Br; R w -B(OH)2 or R 1 , R 2 , R 3a , R 3b , R 4 , R 5 , R 6 , R 7 , R 8 , q and t are as defined in claims 1-12.

14. A pharmaceutical composition comprising at least one therapeutically effective amount of a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

15. Use of the compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 14, in the preparation of a medicament for use as a p38 kinase inhibitor; Preferably, the invention relates to a use of the invention in the preparation of a drug for preventing and / or treating a p38 kinase-mediated disease; more preferably, the p38 kinase-mediated disease is a disease associated with the p38 MAPK / MK2 pathway.

16. Use of a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 14, in the preparation of a medicament for preventing and / or treating autoimmune diseases, inflammatory diseases, cardiovascular diseases, central nervous system diseases and cancer; preferably, use of a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 14, in the preparation of a medicament for preventing and / or treating arthritis, psoriasis, systemic lupus erythematosus, diabetes, leukemia, lymphoma, atherosclerosis and Alzheimer's disease.

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