Prodrug compounds, their preparation and use

Abstract

The present invention provides a prodrug compound, its preparation method, and use thereof, specifically, a compound represented by formula (I), its preparation method, and use thereof for preparing an external preparation as a prodrug. [Formula 1] TIFF2024506090000115.tif41170

Description

Detailed Description of the Invention

[0001] [Technical field] The present invention relates to the field of small drug molecules, and specifically, the present invention provides prodrug compounds as kinase inhibitors, and pharmaceutically acceptable salts, hydrates, or solvates thereof, as well as pharmaceutical compositions (preferably topical formulations) containing the above components.

[0002] [Background technology] The JAK-STAT signaling pathway is a recently discovered cytokine-stimulated signaling pathway. JAKs play an important role in cytokine signaling, and downstream substrates of the JAK kinase family include signal transducers and activators of transcription (STAT) proteins. JAK proteins are important members of this pathway, and abnormally elevated activity often leads to the development of diseases. Many diseases are associated with abnormal cellular responses of the JAK-STAT signaling pathway, including autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergic reactions and asthma, and Alzheimer's disease.

[0003] Rheumatoid arthritis (RA) is a common chronic autoimmune disease characterized by joint swelling, pain, stiffness, deformity, and severe functional impairment. Its human incidence rate is 0.5%–1.0%. Because the pathogenesis of RA remains unclear, its pathological process is difficult to control, resulting in a high disability rate, severely damaging patients' physical and mental health, and reducing their quality of life. Currently, medications used to treat RA primarily include nonsteroidal anti-inflammatory drugs (NSAIDs), disease-modifying antirheumatic drugs (DMARDs), and antibody-based drugs. DMARDs have long been the first-line treatment for RA. In 1988, the first DMARD, methotrexate (MTX), was approved by the FDA for the treatment of RA, marking a significant milestone in RA treatment. While these drugs are widely used due to their efficacy, tolerability, and safety, they also have side effects such as nausea, vomiting, gastric discomfort, and hepatotoxicity. On the other hand, recently developed antibody-based drugs have good therapeutic effects and safety indicators for moderate to severe RA, but because they target specific cytokines, the number of people who can benefit is clearly limited. In addition, the treatment costs and the injection-based drug administration method also limit the widespread use of these drugs.

[0004] Over the past 20 years, RA treatment has made considerable progress, and existing treatments have been able to effectively control patients' symptoms. Nevertheless, RA patients still suffer from problems such as disease recurrence, less than ideal treatment efficacy, poor long-term tolerance, and adverse reactions. More importantly, the quality of life of RA patients, including organ function such as joints, has not been truly improved by current treatments, so focusing on restoring patients' normal functions remains a huge unmet clinical need in this field.

[0005] Research has shown that the core role in the development of RA is played by the autocrine production of large amounts of cytokines by monocytes / macrophages and lymphocytes that infiltrate into RA synovial tissue and cells, and these cytokines interact with each other and activate the JAK / STAT signaling pathway (Janus kinase / Signal transducer and activators of transcription signaling pathway) through different pathways. Specific inhibition of the JAK / STAT signaling pathway can block the cascade amplification of the above cytokines, thereby improving the damaged joint symptoms of RA patients. Therefore, the JAK / STAT signaling pathway is a potential target for RA treatment.

[0006] Because JAK kinases are involved in various important physiological processes in the body, broad inhibition of various subtypes may produce adverse reactions. Tofacitinib has been used in patients with moderate to severe RA who are intolerant or lack a sufficient response to MTX. Clinical trials have shown that certain adverse reactions, including infection, tuberculosis, tumors, anemia, liver damage, and elevated cholesterol, are associated with this treatment. Tofacitinib exhibits significant inhibitory activity against all JAK1, JAK2, and JAK3 subtypes. Since JAK2 activity is involved in erythrocyte differentiation and lipid metabolism, some of these side effects may be related to the drug's nonselective inhibition. Therefore, the search for selective inhibitors of JAK1 and / or JAK3 represents a new direction in RA drug research. Currently, JAK inhibitors have been demonstrated to be useful as treatments for blood disorders, tumors, rheumatoid arthritis, and psoriasis. However, JAK inhibitor compositions available for topical administration are still very limited in this field.

[0007] [Summary of the Invention] In a first aspect of the present invention, there is provided a prodrug molecule of a pharmaceutical compound G', and pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein the drug molecule G' has a hydrophobicity coefficient CLogP of less than 4, and the prodrug molecule has a structure represented by formula (I):

[0008] [ka]

[0009] In the formula, G is a partial structural fragment formed by losing an H atom from the drug molecule G′, and is linked via any N, O, or S atom in the molecule.

[0010] [ka] is connected to

[0011] R 1 , and R 2 are each independently selected from the group consisting of H, D, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C6 heteroalkyl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted 3- to 8-membered heterocyclyl group, or R 1 and R 2 form a C3-C8 carbocyclic or heterocyclic ring together with the carbon atoms connected thereto, L is selected from the group consisting of none, a substituted or unsubstituted C1-C6 alkylene group, and a substituted or unsubstituted C1-C6 heteroalkylene group; R 3 is selected from the group consisting of a substituted or unsubstituted C1-C20 alkyl group (straight or branched chain), a substituted or unsubstituted C3-C20 cycloalkyl group, a substituted or unsubstituted C1-C20 heteroalkyl group, a substituted or unsubstituted 3-20 membered heterocyclyl group, a substituted or unsubstituted C6-C14 aryl group, or R 3 and R 1 or R 2are linked to form a substituted or unsubstituted 5- to 20-membered lactone ring or heterolactone ring, wherein the heterolactone ring has N, O, or S(O) in the ring skeleton of the lactone ring. p and containing 1 to 3 heteroatoms selected from the group consisting of: Here, the heteroalkyl group refers to a group in which one or more carbon atoms on the carbon chain are N, O, or S(O). p and is replaced by a heteroatom selected from the group consisting of The heterocyclyl group may be N, O, or S(O) p and containing 1 to 3 heteroatoms selected from the group consisting of: p is selected from 0, 1, or 2; Unless otherwise specified, the term "substituted" means a deuterium atom, a halogen, a C1-C6 alkyl group, a haloC1-C6 alkyl group, a C1-C6 alkoxy group, a haloC1-C6 alkoxy group, a C3-C8 cycloalkyl group, a haloC3-C8 cycloalkyl group, a C3-C8 heterocyclyl group, an oxo group, -CN, a hydroxyl group, an amino group, a carboxyl group, an amide, a sulfonamide, a sulfonyl group, an unsubstituted or substituted C6-C10 aryl group, a haloC6-C10 aryl group, a 5-10 membered heteroaryl group having 1-3 heteroatoms selected from N, S, and O. halo 5-10 membered heterocyclyl group (group) having 1-3 heteroatoms selected from N, S, and O; and the substituents are selected from the group consisting of halogen, C1-C6 alkyl group, C1-C6 alkoxy group, and ═O.

[0012] In another preferred example, the drug molecule G' is selected from the group consisting of a JAK inhibitor, a MEK inhibitor, and a BTK inhibitor. In another preferred example, the JAK inhibitor is selected from the group consisting of INCB-52793, ATI-502, a deuterium-modified ruxolitinib analog, ATI-501, R-348, NS-018, Jaktinib, KL-130008, DTRMHS-07, WXSH-0150, TQ05105, WXFL10203614, or a molecule selected from the group consisting of the following, a pharmaceutically acceptable salt, hydrate, or solvate thereof:

[0013] [ka]

[0014] In another preferred example, the MEK inhibitor is a molecule selected from the group consisting of the following, or a pharmaceutically acceptable salt, hydrate, or solvate thereof:

[0015] [ka]

[0016] In another preferred example, the BTK inhibitor is a molecule selected from the group consisting of:

[0017] [ka] TIFF0007759063000006.tif33170

[0018] In another preferred example, the drug molecule G' comprises the structure A, wherein A is an optionally substituted 5- to 20-membered heteroaryl group or an optionally substituted 5- to 20-membered heterocyclyl group, wherein the heteroaryl or heterocyclyl group contains one or more heteroatoms selected from N, S, and O; G' is connected via one heteroatom in A

[0019] [ka] is linked to.

[0020] In another preferred example, the CLogP of G' is less than 3. In another preferred example, the CLogP of G' is less than 2. In another preferred example, the molecular weight of G' is less than 900 Da.

[0021] In another preferred example, the molecular weight of G' is less than 700 Da. In another preferred example, the molecular weight of G' is less than 500 Da. In another preferred example, the molecular weight of G' is 900 Da or more.

[0022] In another preferred example, G' is

[0023] [ka] is linked to.

[0024] In another preferred example, the G' is

[0025] [ka] is linked to.

[0026] In another preferred example, G' is

[0027] [ka] is linked to.

[0028] In another preferred example, the structure A is a 5- to 20-membered heteroaryl group. In another preferred embodiment, the R 1 , and R 2 are each independently H, D, or a C1-C6 alkyl group, L is selected from nothing or a C1-C6 alkylene group, and 3 is selected from the group consisting of a C1 to C20 alkyl group, a C3 to C20 cycloalkyl group, and a C6 to C14 aryl group, wherein the alkyl group, alkylene group, cycloalkyl group, or aryl group may be optionally substituted with a substituent selected from the group consisting of halogen and a C1 to C4 alkyl group.

[0029] In another preferred embodiment, the R 1 , and R 2 are each independently H, L is selected from nothing, and 3 is selected from the group consisting of C1 to C20 alkyl groups, wherein said alkyl groups may be optionally substituted with a substituent selected from the group consisting of halogen, C1 to C4 alkyl groups.

[0030] In another preferred embodiment, R 3 is an optionally substituted C 1~20 It is an alkyl group or a substituted phenyl group. In another preferred embodiment, R 3 is an optionally substituted C 1~12 It is an alkyl group.

[0031] In another preferred embodiment, R 3 is an optionally substituted C 10~15 It is an alkyl group. In another preferred embodiment, R 3 is a straight chain alkyl group. In another preferred embodiment, R 3 is a branched alkyl group.

[0032] In another preferred embodiment, the G group is selected from the group consisting of:

[0033] [ka] TIFF0007759063000012.tif153170TIFF0007759063000013.tif174170TIFF0007759063000014.tif194169TIFF0007759063000015.tif16517 0TIFF0007759063000016.tif138169TIFF0007759063000017.tif239169TIFF0007759063000018.tif243169TIFF0007759063000019.tif65169

[0034] In another preferred embodiment, the G group is selected from the group consisting of:

[0035] [ka]

[0036] In another preferred example, the compound of formula (I) has a structure represented by formula (IIB), (IIC), or (IID):

[0037] [ka]

[0038] During the ceremony, Z, T, U, V, and W are each independently N or CR. 4 and Y is N or CR 5 and where R 4 , and R 5 are each independently H, halogen, -CN, -C(O)NH2,

[0039] [ka] is selected from the group consisting of

[0040] M is none, C(O), C(O)O, S(O), S(O)2, NR 8 , a 5- to 7-membered heteroaryl group, or a 5- to 7-membered heteroaryl group (CHR 8 )-, Ring B is selected from the group consisting of a 5- to 7-membered heteroaryl group, a 4- to 10-membered heterocyclyl group, a C4-C10 cycloalkyl group, or a 4- to 10-membered heterocyclyl group substituted with a 4- to 10-membered heterocyclyl group, wherein the heteroaryl group, cycloalkyl group, or heterocyclyl group includes a monocyclic ring, a fused ring, a spiro ring, or a bridged ring; R 8 is selected from the group consisting of H, a C1-C4 alkyl group, and a C2-C6 cyanoalkyl group; R 6 represents C1-C4 alkyl groups, C2-C6 cyanoalkyl groups, -C(O)CH2CN, -C(O)CH=CH2, and -C(O)NHR 7 , -NHS(O)2R 7 , -NHC(R 8 )2C(O)NHR 7 , -C(O)NHR 7 is selected from the group consisting of R 7 is selected from the group consisting of -OH, halogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a 5- to 7-membered heteroaryl group, and a C2-C6 cyanoalkyl group, wherein the heteroaryl group may be substituted with one or more substituents selected from the group consisting of -OH, halogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group, and a C1-C6 alkoxy group.

[0041] s is selected from 0 or 1. In another preferred example,

[0042] [ka] teeth,

[0043] [ka] is a structure selected from the group consisting of:

[0044] In another preferred embodiment, the R 4 or R 5 are, respectively, independently,

[0045] [ka] Selected from the group consisting of:

[0046] In another preferred embodiment,

[0047] [ka] teeth,

[0048] [ka] is a structure selected from the group consisting of:

[0049] In another preferred embodiment, the compound of formula (I) has the structure shown in the following formula:

[0050] [ka]

[0051] During the ceremony, Y is N, CH or CC(O)NH2. In another preferred example, the compound of formula (I) has a structure represented by formula (IIA):

[0052] [ka]

[0053] During the ceremony, Y is N or CC(O)NH2; R4 teeth,

[0054] [ka] is selected from the group consisting of:

[0055] In another preferred example, the compound of formula (I) has a structure represented by the following formula (II):

[0056] [ka]

[0057] In another preferred example, the compound of formula (I) has the structure shown in the following formula:

[0058] [ka] TIFF0007759063000033.tif230170TIFF0007759063000034.tif45170

[0059] In another preferred example, the compound of formula (I) has a structure selected from the group consisting of:

[0060] [ka] TIFF0007759063000036.tif247169TIFF0007759063000037.tif254169TIFF00077590630 00038.tif122169TIFF0007759063000039.tif230170TIFF0007759063000040.tif169170

[0061] In another preferred example, the pharmaceutically acceptable salt is a hydrochloride salt. The second aspect of the present invention provides a method for producing the compound according to the first aspect of the present invention, wherein the drug molecule G' is prepared by converting N and O atoms in the molecule according to the following scheme:

[0062] [ka] may be linked to

[0063] (1) Scheme 1

[0064] [ka]

[0065] In the above reaction scheme, A'-NH corresponds to G' and A'-N corresponds to G. A chloroalkyl ester is reacted with G' under alkaline conditions to link the N atom to a prodrug group of the present invention. (2) Scheme 2

[0066] [ka]

[0067] In the above reaction scheme, A'-NH corresponds to G' and A'-N corresponds to G. In a two-step process, chloroalkyl carbonate 1 is first reacted with G' to give intermediate 2, which is then condensed with 3 to link the N atom to the prodrug group of the present invention.

[0068] (3) Scheme 3

[0069] [ka]

[0070] In the above reaction scheme, A'-OH corresponds to G' and A'-O corresponds to G. A'-OH is condensed with carbonyl compound 4 under alkaline or acidic conditions to give intermediate 5, which is then condensed with acid 3 or acid anhydride 6 to link the O atom to the prodrug group of the present invention.

[0071] In another preferred embodiment, the method for producing compound (IIA) comprises the steps of:

[0072] [ka]

[0073] In an inert solvent, a compound of formula 2e is reacted with R 3 -L- C(O)X to obtain a compound of formula (IIA), wherein Y is N or CC(O)NH2, and X is OH or an activating group (preferably a halogen or OC(O)R 3 ) and the remaining groups are as defined above.

[0074] Another preferred example includes the following steps: (1) Scheme 1

[0075] [ka]

[0076] In an inert solvent, the free base of tofacitinib of formula R 3 -L- C(O) O CR 1 R 2 Cl to give a compound of formula (II), or (2) Scheme 2

[0077] [ka]

[0078] In an inert solvent, compound of formula 2e′ is reacted with R 3 -L- C(O) O X to obtain a compound of formula (II), wherein X is OH or an activating group (preferably a halogen or OC(O)R 3 ) and the remaining groups are defined as described in the first aspect of the present invention.

[0079] In another preferred embodiment, the method further comprises reacting 1c with 1d to give compound 1e.

[0080] [ka]

[0081] In another preferred example, the method further comprises reacting compound 1a with chloromethyl chloroformate to obtain compound 1c.

[0082] [ka]

[0083] A third aspect of the present invention provides an intermediate of formula 2e:

[0084] [ka]

[0085] In the formula, Y is N or CC(O)NH2, and the remaining groups are defined as above. In another preferred embodiment, the compound of formula 2e has the structure shown in formula 1e:

[0086] [ka]

[0087] A fourth aspect of the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to the first aspect of the present invention, and a pharmaceutically acceptable salt, hydrate or solvate thereof. In another preferred embodiment, the pharmaceutical composition is an external preparation.

[0088] In another preferred embodiment, the pharmaceutical composition further comprises a skin penetration enhancer (e.g., a surfactant, dimethyl sulfoxide, decyl methyl sulfoxide, an azone-based enhancer, an alcohol-based enhancer, a volatile oil, an amino acid, a phospholipid, or an oleic acid).

[0089] In another preferred example, when the pharmaceutical composition is administered transdermally, the compound of formula I is metabolized in vivo to tofacitinib. In another preferred embodiment, the pharmaceutical composition is used to treat or prevent a disease associated with the activity or expression level of JAK kinase, and preferably the disease is selected from the group consisting of cancer, myeloproliferative disorders, inflammation, immune disorders, organ transplantation, viral diseases, cardiovascular or metabolic diseases, autoimmune diseases in humans or animals, rheumatoid arthritis, skin diseases, multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, myasthenia gravis, and psoriasis.

[0090] A fifth aspect of the present invention provides a use of a compound according to the first aspect of the present invention, or a pharmaceutically acceptable salt or hydrate thereof, for the manufacture of a pharmaceutical composition for treating or preventing a disease associated with the activity or expression level of a JAK kinase.

[0091] In another preferred embodiment, the disease is selected from the group consisting of cancer, myeloproliferative disorders, inflammation, immune disorders, organ transplantation, viral diseases, cardiovascular or metabolic diseases, autoimmune diseases in humans or animals, rheumatoid arthritis, skin diseases, multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, myasthenia gravis, psoriasis.

[0092] A sixth aspect of the present invention provides a topical formulation comprising: a compound according to the first aspect of the present invention; an optional skin penetration enhancer; and an optional support layer; Preferably, the optional skin penetration enhancer is selected from the group consisting of surfactants, dimethyl sulfoxide and its analogs, azone compounds, α-pyridoin derivatives, alcohol compounds, ether compounds, fatty acid compounds and fatty acid ester compounds, or combinations thereof.

[0093] In another preferred embodiment, the drug is present as a single or multi-phase solution or suspension. In another preferred embodiment, the formulation is administered in the form of a solution, suspension, gel, emulsion, plaster, foam, or the like.

[0094] In another preferred embodiment, the support layer is a membrane polymer or a backbone polymer. In another preferred embodiment, the support layer is selected from the group consisting of a pressure sensitive adhesive material, a backing material, an anti-stick material, and a drug preservative material.

[0095] In another preferred embodiment, the topical preparation further comprises a release layer. In another preferred embodiment, the formulation is a membrane-permeable administration formulation. In another preferred embodiment, the formulation is a sustained release formulation.

[0096] Another aspect of the present invention is a method for increasing membrane permeability of a drug molecule G', comprising the steps of: By modifying the drug molecule G', a single stage is formed in the molecule.

[0097] [ka] is introduced, and CLogP exceeds 4.

[0098] [ka] wherein the CLogP of the prodrug molecule (I) formed by modification is improved by at least 1 unit compared to the CLogP of the drug molecule G'.

[0099] In another preferred example, the CLogP of the prodrug molecule (I) formed by modification is improved by at least 2 units over the CLogP of the drug molecule G'. In another preferred example, the CLogP of the prodrug molecule (I) formed by modification is improved by at least 3 units over the CLogP of the drug molecule G'.

[0100] In another preferred embodiment, the modified drug molecule G' is

[0101] [ka] Add

[0102] [ka] The method for forming the drug molecule G'

[0103] [ka] The method includes the step of coupling the

[0104] In another preferred embodiment, the prodrug molecule

[0105] [ka] The Pe value of Skin-Pampa is improved by 2 to 100 times compared with the G' of the unmodified drug molecule.

[0106] In another preferred embodiment, the prodrug molecule

[0107] [ka] The Pe value of Skin-Pampa is improved by 4 to 20 times compared with the G' of the unmodified drug molecule.

[0108] It should be noted that within the scope of the present invention, the above-described constituent elements of the present invention and the constituent elements specifically explained below (for example, in the Examples) may be combined with each other to obtain new or preferred technical embodiments, which will not be repeated here due to space limitations. DETAILED DESCRIPTION OF THE INVENTION

[0109] After a long period of research, the inventors have developed a compound represented by formula (I). Because the compound has a hydrophilic drug molecule end and a hydrophobic end, it has good transdermal properties and, after topical administration, is metabolized in vivo to form a prototype drug molecule, which can then be administered. Based on the above findings, the inventors have completed the present invention.

[0110] definition As used herein, the term "alkyl group" includes straight or branched chain alkyl groups. For example, C 1~ The term "C6 alkyl group" refers to a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or t-butyl, and the term "C1-C20 alkyl group" has a similar meaning. The term "alkylene group" refers to an alkyl group that has lost one hydrogen atom, for example, a C1-C6 alkylene group refers to a linear or branched alkylene group having 1 to 6 carbon atoms. The term "heteroalkyl group" refers to an alkyl group in which one or more carbon atoms on the carbon chain are replaced with a heteroatom selected from the group consisting of O, S, NH, C(O), or C(NH), and the term "heteroalkyl group" has a similar meaning.

[0111] As used herein, the term "C3-C8 cycloalkyl group" refers to a cycloalkyl group having from 3 to 8 carbon atoms. It may be a monocyclic group such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, or similar groups. It may also be a bicyclic group, e.g., a bridged ring, a fused ring, or a spirocyclic ring, and "C3-C20 cycloalkyl group" has an analogous definition.

[0112] As used herein, the term "C6-C14 aryl group" refers to an aryl group having 6 to 14 carbon atoms, such as a phenyl group, naphthyl group, and the like. As used herein, the term "5- to 10-membered heteroaryl group having 1 to 3 heteroatoms selected from the group consisting of N, S, and O" refers to a cyclic aromatic group having 5 to 10 atoms, 1 to 3 of which are heteroatoms selected from the group consisting of N, S, and O. This may be a monocyclic or fused ring system. Specific examples include a pyridyl group, a pyridazinyl group, a pyrimidyl group, a pyrazinyl group, a triazinyl group, a pyrrolyl group, a pyrazolyl group, an imidazolyl group, a (1,2,3)-triazolyl group, a (1,2,4)-triazolyl group, a tetrazolyl group, a furyl group, a thienyl group, an isoxazolyl group, a thiazolyl group, an oxazolyl group, and the like.

[0113] As used herein, the term "3- to 20-membered heterocyclyl group" refers to a saturated or partially saturated cyclic group having 3 to 20 ring atoms, of which 1 to 3 atoms are selected from the group consisting of N, S, and O, preferably a 3- to 10-membered heterocyclyl group, a 4- to 7-membered heterocyclyl group, or a 9- to 15-membered heterocyclyl group. This may be a monocyclic ring or a bicyclic ring such as a bridged ring or a spirocyclic ring. Specific examples include oxetane, azetidine, tetrahydro-2H-pyranyl, piperidinyl, tetrahydrofuryl, morpholinyl, and pyrrolidinyl. A "3- to 8-membered heterocyclyl group" has a similar definition.

[0114] Unless otherwise specified as "substituted or unsubstituted," the above groups of the present invention may be substituted with a substituent selected from the group consisting of halogen, nitrile group, nitro group, hydroxyl group, amino group, C1-C6 alkyl-amine group, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C1-C6 alkoxy group, halo-C1-C6 alkyl group, halo-C2-C6 alkenyl group, halo-C2-C6 alkynyl group, halo-C1-C6 alkoxy group, allyl group, benzyl group, C6-C12 aryl group, C1-C6 alkoxy-C1-C6 alkyl group, C1-C6 alkoxy-carbonyl group, phenoxycarbonyl group, C2-C6 alkynyl-carbonyl group, C2-C6 alkenyl-carbonyl group, C3-C6 cycloalkyl-carbonyl group, C1-C6 alkyl-sulfonyl and the like.

[0115] As used herein, "halogen" or "halogen atom" means F, Cl, Br, and I. More preferably, the halogen or halogen atom is selected from F, Cl, and Br. "Halo" means substituted with an atom selected from F, Cl, Br, and I.

[0116] Unless otherwise specified, the structural formulae depicted in the present invention are intended to include all isomeric (e.g., astereomeric, diastereomeric, and geometric (or conformational)) forms, such as the R, S configurations containing asymmetric centers, (Z), (E) isomers of double bonds, etc. Thus, single stereochemical isomers of the compounds of the present invention or mixtures of their enantiomers, diastereomers, or geometric (or conformational) isomers are all within the scope of the present invention.

[0117] As used herein, the term "hydrate" refers to a complex formed when a compound of the present invention is coordinated with water. The compounds of the present application can be produced by a variety of synthetic methods familiar to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining the specific embodiments with other chemical synthetic methods, and equivalent alternatives familiar to those skilled in the art, and preferred embodiments include, but are not limited to, the embodiments of the present application.

[0118] The solvents used herein may be commercially available. The abbreviations used herein are as follows: aq: aqueous solution; HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; EDCI: N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA: 3-chloroperoxybenzoic acid; eq: equivalent; CDI: carbonyldiimidazole; DCM: dichloromethane; PE: petroleum ether; DIAD: diisopropyl azodicarboxylate; DMF: N,N-dimethylsulfoxide; EMSO: dichloromethane. Methyl sulfoxide; EtOAc: ethyl acetate; EtOH: ethanol; MeOH: methanol; Cbz: benzyloxycarbonyl, an amino protecting group; Boc: tert-butyloxycarbonyl, an amino protecting group; HOAc: acetic acid; NaCNBH3: sodium cyanoborohydride; rt: room temperature; THF: tetrahydrofuran; TFA: trifluoroacetic acid; DIPEA: diisopropylethylamine; Boc2O: di-tert-butyldicarbonate; LDA: lithium diisopropylamide.

[0119] Compounds are named artificially or by ChemDraw® software, and commercially available compounds adopt names from supplier catalogs. Prodrug compounds suitable for topical administration The present invention provides a prodrug molecule of a pharmaceutical compound, and a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the prodrug molecule is metabolized in vivo upon administration to form a drug molecule G', the drug molecule G' having a hydrophobicity coefficient CLogP of less than 3, and the prodrug molecule has a structure represented by the following formula (I):

[0120] [ka]

[0121] In the formula, G is a partial structural fragment formed by losing a functional group or an H atom from the drug molecule G', and is linked via any N, O, or S atom in the molecule.

[0122] [ka] It is characterized in that it is connected to

[0123] In the present invention,

[0124] [ka] Lipophilic groups such as can effectively improve the transdermal efficiency of compounds, thereby producing novel compounds that can be metabolized to prototype compound molecules upon topical administration. The drug molecule G' suitable for the prodrug molecule may have any structure, and in a preferred embodiment, the hydrophobicity coefficient CLogP of the drug molecule is less than 3.

[0125] Such drug molecules have excellent membrane permeability due to their lipophilic and hydrophilic ends, which improves the transdermal permeability of the drug molecules, particularly during transdermal administration. In preferred cases, the drug molecules are drug molecules for skin diseases, such as JAK inhibitors, MEK inhibitors, and BTK inhibitors.

[0126] R 1 , and R 2 are each independently selected from the group consisting of H, D, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C6 heteroalkyl group, a substituted or unsubstituted C3-C8 cycloalkyl group, and a substituted or unsubstituted 3- to 8-membered heterocyclyl group, or R 1 and R 2 form a C3-C8 carbocyclic or heterocyclic ring together with the carbon atoms connected thereto, L is selected from the group consisting of none, a substituted or unsubstituted C1-C6 alkylene group, and a substituted or unsubstituted C1-C6 heteroalkylene group; R 3 is selected from the group consisting of a substituted or unsubstituted C1 to C20 alkyl group, a substituted or unsubstituted C3 to C20 cycloalkyl group, a substituted or unsubstituted C1 to C20 heteroalkyl group, a substituted or unsubstituted 3 to 20 membered heterocyclyl group, and a substituted or unsubstituted C6 to C14 aryl group, or R 3 and R 1 or R 2 are linked to form a substituted or unsubstituted 5- to 20-membered lactone ring or heterolactone ring, wherein the heterolactone ring has no N, O, or S(O) in the ring skeleton of the lactone ring. p and having 1 to 3 heteroatoms selected from the group consisting of: p is selected from the group consisting of 0, 1, or 2; Here, the heteroalkyl group refers to a group in which one or more carbon atoms on the carbon chain are N, O, or S(O). p means substituted with a heteroatom selected from the group consisting of The heterocyclyl group may be N, O, or S(O) p and containing 1 to 3 heteroatoms selected from the group consisting of: Unless otherwise specified, the term "substituted" as used herein includes halogen, C1-C6 alkyl group, haloC1-C6 alkyl group, C1-C6 alkoxy group, haloC1-C6 alkoxy group, C3-C8 cycloalkyl group, haloC3-C8 cycloalkyl group, C3-C8 heterocyclyl group, oxo group, -CN, hydroxy group, amino group, carboxy group, amido, sulfonamido, sulfonyl group, unsubstituted or substituted with one or more substituents, C6-C10 aryl group, haloC6-C aryl groups, 5-10 membered heteroaryl groups having 1-3 heteroatoms selected from N, S, and O, and halo 5-10 membered heterocyclyl groups having 1-3 heteroatoms selected from N, S, and O, and the substituents are selected from the group consisting of halogen, C1-C6 alkyl groups, C1-C6 alkoxy groups, and =O.

[0127] Pharmaceutical compositions and methods of administration The compounds of the present invention can be metabolized in vivo after topical administration to form therapeutically active ingredients, and therefore the compounds of the present invention and their various crystalline forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, as well as pharmaceutical compositions containing the compounds of the present invention as a major active ingredient, are useful for the prevention and / or treatment (stabilization, alleviation or cure) of various autoimmune and inflammation-related diseases, including cancer, myeloproliferative disorders, inflammation, immune disorders, organ transplants, viral diseases, cardiovascular diseases or metabolic disorders, etc.

[0128] The pharmaceutical composition of the present invention contains a compound of the present invention in a safe and effective amount and a pharmaceutically acceptable excipient or carrier. Here, "safe and effective amount" refers to an amount of the compound sufficient to clearly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1 to 2000 mg, more preferably 1 to 200 mg, of the compound of the present invention per agent. Preferably, the "agent" is one capsule or tablet.

[0129] "Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid fillers or gel-like substances that must be of sufficient purity and sufficiently low toxicity to be suitable for human use. "Compatibility" means that the components in the composition are miscible with the compound of the present invention and with each other without significantly reducing the efficacy of the compound. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate, etc.), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyhydric alcohols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., Twen®, etc.), wetting agents (e.g., sodium dodecyl sulfate, etc.), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0130] The prodrug compounds of the present invention can be easily prepared into pharmaceutical compositions containing one or more compounds of the present invention and a pharmaceutical carrier.Remington: The Science and Practice of Pharmacy, 19th Edition (Easton, PA, Mack Publishing Co., 1995), which discloses typical carriers and general methods for preparing pharmaceutical compositions, can be referenced, and the methods can be used or modified as described to produce medicaments containing the compounds of the present invention.As mentioned above, the compounds of the present invention can also be administered in the form of pharmaceutical salts, etc.

[0131] The compounds of the present invention may be administered orally, parenterally, topically, rectally, nasally, buccally, or vaginally in the form of pharmaceutical formulations containing common non-toxic pharmaceutical carriers, adjuvants, and vehicles, or via implanted reservoirs. Preferably, the compounds of the present invention may be administered via the skin or mucosal tissue in a common topical administration system, in which the drug is contained in a multilayer structure that is immobilized on the skin and functions as an administration device. In such a configuration, the pharmaceutical composition is contained in a layer beneath an upper backing layer, i.e., a "reservoir" layer. The multilayer structure may contain a single reservoir or multiple reservoirs. In one example, the reservoir comprises a polymeric matrix of a pharmaceutical adhesive material that serves to secure the system to the skin during administration. Suitable skin adhesive materials include, but are not limited to, polyethylene, polysiloxane, polyisobutylene, polyacrylate, polyurethane, and the like. Alternatively, the drug-containing reservoir and the skin-pressure adhesive can be present as separate, distinct layers, with the adhesive underlying the reservoir, which may be a polymeric matrix as described above, a liquid or hydrogel reservoir, or other form.

[0132] Of these multiple layers, the backing layer, which is the top surface of the device, functions as the main component of the multi-layer structure and provides considerable flexibility to the device. The material selected for use as the backing material should be substantially impermeable to the active substance and other substances present. The backing preferably comprises a sheet or film of a flexible, elastic material. Examples of polymers suitable for use as the backing layer include polyethylene, polypropylene, polyester, etc.

[0133] The multilayer structure includes a release layer during storage and before use. Before use, this layer is removed from the device, exposing the bottom surface or drug reservoir or another pressure-sensitive adhesive layer, allowing the system to be secured to the skin. The release layer should be made of a material that is impermeable to the drug / excipients.

[0134] The topical administration device can be manufactured by common techniques known to those skilled in the art, such as by pouring a fluid mixture of adhesive, drug, and excipients onto a backing layer, followed by lamination of a release layer. Similarly, an adhesive mixture can be poured onto a release layer, followed by lamination of a backing layer. Alternatively, a drug substance can be made without drug or excipients and then filled with a drug / excipient mixture by dipping.

[0135] The multi-layered topical administration system of the present invention may further comprise a skin penetration enhancer. That is, the inherent permeability of skin to certain drugs may be too low to allow therapeutic levels of the drug to penetrate significant areas of intact skin, and therefore a skin penetration enhancer must be administered along with these drugs. Suitable enhancers are known in the art, including, for example, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), N,N-dimethylacetamide (DMA), decylmethyl sulfoxide (C10MSO), C2-C6 alkanediols, and 1-substituted azepan-2-ones, alcohols, and the like.

[0136] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable therapeutic agents. The pharmaceutical compositions of the invention, when administered in combination, may further comprise one or more (two, three, four or more) other pharmaceutically acceptable therapeutic agents, which may be used simultaneously, separately or sequentially with the compounds of the invention for the prevention and / or treatment of cytokine and / or interferon-mediated diseases.

[0137] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is administered to a mammal (e.g., human) in need of treatment, and the dosage at the time of administration is a dosage considered to be pharmaceutically effective, and the daily dosage for a human weighing 60 kg is usually 1 to 2000 mg, preferably 1 to 500 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0138] The present invention will be further described below with reference to specific examples. It should be understood that these examples are only used to illustrate the present invention and are not used to limit the scope of the present invention. Experimental methods for which specific conditions are not described in the following examples generally follow standard conditions or conditions suggested by manufacturers. Unless otherwise specified, percentages and parts are by weight.

[0139] Example Example 1

[0140] [ka]

[0141] Step 1 Under nitrogen protection and at 0°C, chloromethyl chloroformate (4.90 g, 38.00 mmol) was added to a 50 mL dichloromethane solution of compound 1a (4.00 g, 34.13 mmol) and pyridine (5.40 g, 68.26 mmol). After the dropwise addition was completed, the reaction mixture was allowed to warm to room temperature and the reaction was continued for 4 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain crude product 1c (12.00 g).

[0142] Step 2 Under nitrogen protection, crude 1c (12.00 g, 34.13 mmol), compound 1d (5.00 g, 16.01 mmol), and potassium carbonate (6.60 g, 47.75 mmol) in 50 mL of N,N-dimethylformamide were reacted overnight at 60 °C. After completion of the reaction, the mixture was cooled and purified directly by reverse-phase column chromatography (acetonitrile:water = 0-100%) to give 1e (3.00 g). Yield: 55%.

[0143] MS-ESI calculated value [M+H] + 343, actual value 343. Step 3 Under nitrogen protection and at 0°C, octanoyl chloride (750 mg, 4.61 mmol) was added to a 30 mL dichloromethane solution of compound 1e (1.10 g, 3.21 mmol) and triethylamine (650 mg, 6.42 mmol). After the addition was complete, the reaction was continued for 0.5 h. After the reaction was complete, the reaction solution was diluted with dichloromethane (30 mL) and washed with water (50 mL × 1). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (acetonitrile:water = 0-100%) to obtain 1f (600 mg) in a 40% yield.

[0144] MS-ESI calculated value [M+H] + 469, actual value 469. Step 4 Under nitrogen protection, a solution of compound 1f (600 mg, 1.28 mmol) in 30 mL of ethyl acetate was slowly added dropwise with 5 M ethyl chloroacetate chloride solution (0.30 mL, 1.50 mmol). After the addition was complete, the mixture was stirred for another 1 hour, then the temperature was maintained below 20°C and concentrated under reduced pressure to give a solid. The solid was dissolved in a solution of acetonitrile (10 mL) and water (100 mL) and lyophilized to give 1 (620 mg). Yield: 96%.

[0145] 1H NMR(400 MHz, DMSO-d6) δ 8.29-8.26 (m, 1H), 7.40-7.40 (m, 1H), 6.77 (brs, 1H), 6.15-6.14 (m, 2H), 4.77 (brs, 1H), 4.16-3.94 (m, 3H), 3.88-3.65 (m, 2H), 3.42-3.41 (m, 1H), 3.29 (s, 3H), 2.41-2.33 (m, 1H), 2.29 (t, J = 7.6 Hz, 2H), 1.89-1.74 (m, 1H), 1.62-1.56 (m, 1H), 1.51-1.44 (m, 3H), 1.24-1.16 (m, 8H), 1.04-1.01 (m, 3H), 0.83-0.80 (m, 3H). MS-ESI calculated value [M+H] + 469, actual value 469.

[0146] Example 2

[0147] [ka]

[0148] Step 1 Compound 2 (500 mg) was obtained by a two-step reaction using compound 1e according to the synthesis method of Example 1. Two-step yield: 39%.

[0149] 1 H NMR(400 MHz, DMSO-d6) δ 8.40-8.36 (m, 1H), 7.53 (brs, 1H), 6.87 (brs, 1H),6.20-6.18 (m, 2H), 4.67 (brs, 1H), 4.19-3.73 (m, 5H), 3.43-3.41 (m, 1H), 3.33 (s, 3H), 2.56-2.51 (m, 1H), 2.41-2.40 (m, 1H), 1.88-1.76 (m, 1H), 1.61-1.58 (m, 1H), 1.12-1.10 (m, 9H). MS-ESI calculated value [M+H] +413, measured value 413.

[0150] Example 3

[0151] [ka]

[0152] Compound 3 (500 mg) was obtained by a two-step reaction using compound 1e according to the synthesis method of Example 1. Two-step yield: 37%. 1 H NMR(400 MHz, DMSO-d6) δ 8.38-8.34 (m, 1H), 7.50 (brs, 1H), 6.85(brs, 1H), 6.19-6.17 (m, 2H), 4.68(brs, 1H), 4.19-3.74 (m, 4H), 3.43-3.32 (m, 5H), 2.42-2.39 (m, 1H), 2.29 (t, J= 7.6 Hz, 2H), 1.89-1.78 (m, 1H), 1.57-1.46 (m, 3H), 1.24-1.16 (m, 4H), 1.07-1.02 (m, 3H), 0.82-0.78 (m, 3H). MS-ESI calculated value [M+H] + 441, actual value 441.

[0153] Example 4

[0154] [ka]

[0155] Compound 4 (4.47 g) was obtained by a two-step reaction using compound 1e according to the synthesis method of Example 1. Two-step yield: 64%. 1H NMR(400 MHz, DMSO-d6) δ 8.38-8.34 (m, 1H), 7.52-7.50 (m, 1H), 6.86-6.85 (m, 1H), 6.20-6.18 (m, 2H), 4.69 (brs, 1H), 4.19-3.74 (m, 5H), 3.43-3.41 (m, 1H), 3.33 (s, 3H), 2.44-2.41 (m, 1H), 2.28 (t, J = 7.6 Hz, 1H), 1.91-1.80 (m, 1H), 1.62-1.57 (m, 1H), 1.46-1.44 (m, 2H), 1.20-1.02 (m, 12H), 0.84-0.80 (m, 3H), 0.76-0.72 (m, 3H). MS-ESI calculated value [M+H] + 497, actual value 497.

[0156] Example 5

[0157] [ka]

[0158] Compound 5 (815 mg) was obtained by a two-step reaction using compound 1e according to the synthesis method of Example 1. Two-step yield: 42%. 1 H NMR(400 MHz, DMSO-d6) δ 8.27-8.26 (m, 1H), 7.40-7.39 (m, 1H), 6.76-6.75 (m, 1H), 6.15-6.14 (m, 2H), 4.77 (brs, 1H), 4.17-3.70 (m, 5H), 3.43-3.20 (m, 5H), 2.41-2.33 (m, 1H), 2.28 (t, J = 7.6 Hz, 2H), 1.89-1.74 (m, 1H), 1.59-1.45 (m, 3H), 1.28-1.17 (m, 16H), 1.04-1.01 (m, 3H), 0.87-0.83 (m, 3H). MS-ESI calculated value [M+H] + 525, actual value 525.

[0159] Example 6

[0160] [ka]

[0161] Compound 6 (510 mg) was obtained by a two-step reaction using compound 1e according to the synthesis method of Example 1. Two-step yield: 35%. 1 H NMR(400 MHz, DMSO-d6) δ 8.30-8.27 (m, 1H), 7.42-7.41 (m, 1H), 6.78-6.77 (m, 1H), 6.16-6.15(m, 2H), 4.73(brs, 1H), 4.17-3.70 (m, 5H), 3.42-3.40 (m, 1H), 3.29 (s, 3H), 2.40-2.38 (m, 1H), 2.28 (t, J = 7.6 Hz, 2H), 1.89-1.76 (m, 1H), 1.62-1.45 (m, 3H), 1.27-1.17 (m, 24H), 1.05-1.01 (m, 3H), 0.87-0.83 (m, 3H). MS-ESI calculated value [M+H] + 581, actual value 581.

[0162] Example 7

[0163] [ka]

[0164] Compound 7 (350 mg) was obtained by a two-step reaction using compound 1e according to the synthesis method of Example 1. Two-step yield: 33%. 1H NMR(400 MHz, DMSO-d6) δ 8.37-8.37 (m, 1H), 7.52-7.49 (m, 1H), 6.85 (brs, 1H), 6.19-6.17 (m, 2H), 4.70 (brs, 1H), 4.18-3.71 (m, 5H), 3.42-3.40 (m, 1H), 3.32 (s, 3H), 2.42-2.37 (m, 1H), 2.29 (t, J = 7.6 Hz, 2H), 1.90-1.86 (m, 1H), 1.62-1.46 (m, 3H), 1.24-1.17 (m, 10H), 1.07-1.02 (m, 3H), 0.83-0.82 (m, 3H). MS-ESI calculated value [M+H] + 483, measured value 483.

[0165] Example 8

[0166]

change

[0167] According to the synthetic method of Example 1, compound 1e was obtained by using the compound 8 (350 mg) in the 2-stage reaction of the compound. Stage 2 yield: 36%. 1 H NMR(400 MHz, DMSO-d6) δ 8.38-8.34 (m, 1H), 7.52-7.50 (m, 1H), 6.85 (brs, 1H), 6.18-6.17 (m, 2H), 4.69 (brs, 1H), 4.18-3.68 (m, 5H), 3.42-3.40 (m, 1H), 3.32 (s, 3H), 2.42-2.37 (m, 1H), 2.29 (t, J = 7.2 Hz, 2H), 1.92-1.83(m, 1H), 1.62-1.46 (m, 3H), 1.24-1.18 (m, 12H), 1.07-0.98 (m, 3H), 0.86-0.83 (m, 3H). MS-ESI calculated value [M+H] + 497, measured value 497.

[0168] Example 9

[0169] [ka]

[0170] Step 1 Under nitrogen protection, compound 9a (5.00 g, 32.89 mmol) was added to N,N-dimethylformamide (30 mL), cooled to 0 °C, and 60% sodium hydride (1.58 g, 36.18 mmol) was added. The mixture was allowed to react at 0 °C for 0.5 hours, after which 2-(trimethylsilyl)ethoxymethyl chloride (6.00 g, 36.18 mmol) was added. The mixture was allowed to warm to room temperature and react for 1 hour. Water (100 mL) and ethyl acetate (100 mL x 3) were added for extraction. The combined organic phases were washed with saturated brine (100 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (ethyl acetate:petroleum ether = 0 to 100%) to obtain compound 9b (5.10 g). Yield: 55%.

[0171] 1 H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 7.39 (d, J = 3.6 Hz, 1H), 6.66 (d, J = 3.6 Hz, 1H), 5.64 (s, 2H), 3.52 (t, J = 8.4 Hz, 2H), 0.90 (t, J = 8.4 Hz, 2H), -0.06 (s, 9H). MS-ESI calculated value [M+H] + 284, actual value 284.

[0172] Step 2 Compound 9b (2.00 g, 7.07 mmol) was added to dichloromethane (10 mL), trifluoroacetic acid (8.80 g, 70.67 mmol) was added, and the mixture was allowed to react at room temperature for 16 hours. Water (50 mL) and dichloromethane (50 mL × 3) were added for extraction, and the organic phases were combined, washed with saturated brine (50 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 9c (1.20 g). Yield: 92%.

[0173] 1 H NMR (400 MHz, DMSO-d6) δ 8.67 (s, 1H), 7.79 (d, J = 3.6 Hz, 1H), 6.68 (d, J = 3.6 Hz, 1H), 5.63 (s, 2H). MS-ESI calculated value [M+H] + 184, measured value 184.

[0174] Step 3 Compound 9c (2.00 g, 7.07 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.50 g, 13.11 mmol), and 4-dimethylaminopyridine (1.60 g, 13.11 mmol) were added to dichloromethane (30 mL) and reacted at room temperature for 0.5 hours. 4-Ethyloctanoic acid (1.19 g, 13.11 mmol) was added and reacted at room temperature for 16 hours. Water (100 mL) and ethyl acetate (100 mL × 3) were added for extraction. The combined organic phases were washed with saturated brine (100 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (ethyl acetate:petroleum ether = 0-100%) to give compound 9d (1.21 g). Yield: 55%.

[0175] 1H NMR (400 MHz, CDCl3) δ 8.70 (s, 1H), 7.49 (d, J = 3.6 Hz, 1H), 6.63 (d, J = 3.6 Hz, 1H), 6.22 (s, 2H), 2.34-2.27 (m, 2H), 1.59-1.50 (m, 2H), 1.25-1.13 (m, 9H), 0.85 (t, J = 5.4 Hz, 3H), 0.78 (t, J = 7.2 Hz, 3H). Step 4 Compound 9e (0.27 g, 0.98 mmol), N,N-diisopropylethylamine (0.25 g, 1.96 mmol), and compound 9d (0.33 g, 1.08 mmol) were added to dimethyl sulfoxide (5 mL) and reacted at 100 °C for 16 hours. Extraction was performed with water (50 mL) and ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (50 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (ethyl acetate:petroleum ether = 0-100%) to obtain compound 9f (0.35 g). Yield: 66%.

[0176] 1 H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 7.41-7.30 (m, 5H), 7.13 (d, J = 3.6 Hz, 1H), 6.38 (d, J = 3.6 Hz, 1H), 6.14 (s, 2H), 5.23-5.10 (m, 2H), 4.58-4.45 (m, 2H), 2.79-2.67 (m, 1H), 2.30 (t, J = 8.0 Hz, 2H), 2.00-1.83 (m, 4H), 1.66 (d, J = 10.8 Hz, 2H), 1.58-1.53 ​​(m, 2H), 1.27-1.17 (m, 12H), 0.85 (t, J = 6.8 Hz, 3H), 0.79 (t, J = 7.2 Hz, 3H). Step 5 Compound 9f (0.35 g, 0.64 mmol) was added to tetrahydrofuran (5 mL), 10% wet palladium on carbon (0.15 g) was added, and the mixture was purged with a hydrogen balloon three times and reacted at room temperature for 2 hours. The mixture was filtered through diatomaceous earth, and the filtrate was collected and concentrated under reduced pressure to give compound 9h (0.26 g). Yield: 97%.

[0177] 1 H NMR (400 MHz, CDCl3) δ 8.38 (s, 1H), 7.14 (d, J = 3.6 Hz, 1H), 6.44 (d, J = 3.6 Hz, 1H), 6.14 (s, 2H), 6.12 (s, 1H), 4.39 (s, 1H), 3.18-2.93 (m, 2H), 2.76-2.66 (m, 1H), 2.33-2.23 (m, 2H), 2.10-1.99 (m, 2H), 1.66-1.45 (m, 6H), 1.26-1.16 (m, 9H), 1.10 (d, J = 6.0, 3H), 0.85 (t, J = 6.8 Hz, 3H), 0.79 (t, J = 7.2 Hz, 3H). MS-ESI calculated value [M+H] + 416, measured value 416.

[0178] Step 6 Compound 9h (0.22 g, 0.52 mmol) was added to tetrahydrofuran (10 mL), 0.52 N aqueous sodium bicarbonate solution (5 mL) was added, and the mixture was cooled to 0 °C. Acryloyl chloride (0.06 g, 0.62 mmol) was added dropwise, and the mixture was allowed to warm to room temperature and react for 2 hours. Water (50 mL) and ethyl acetate (50 mL × 3) were added for extraction. The combined organic phases were washed with saturated brine (50 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (ethyl acetate:petroleum ether = 0-100%) to obtain compound 9 (0.21 g). Yield: 87%.

[0179] 1H NMR (500 MHz, DMSO-d6) δ 8.20 (s, 1H), 7.36 (d, J = 7.5 Hz, 1H), 7.23 (d, J = 4.0 Hz, 1H), 6.75 (dd, J = 16.5, 10.5 Hz, 1H), 6.66 (d, J = 4.0 Hz, 1H), 6.11 (s, 2H), 6.07 (dd, J = 16.5, 2.5 Hz, 1H), 5.65 (dd, J = 10.5, 2.5 Hz, 1H), 4.86-4.15 (m, 2H), 4.11-4.02 (m, 1H), 2.97-2.60 (m, 1H), 2.27 (t, J = 7.5 Hz, 2H), 1.89-1.65 (m, 4H), 1.49-1.43 (m, 2H), 1.22-1.13 (m, 12H), 0.83 (t, J = 7.0 Hz, 3H), 0.75 (t, J = 7.5 Hz, 3H). MS-ESI calculated value [M+H] + 470, actual value 470.

[0180] Example 10

[0181] [ka]

[0182] Step 1 Compound 10a (48 mg, 0.16 mmol) and N,N-diisopropylethylamine (30 mg, 0.24 mmol) were added to dichloromethane (3 mL) and stirred at room temperature for 5 minutes. 2-(trimethylsilyl)ethoxymethyl chloride (39 mg, 0.24 mmol) was added and the mixture was allowed to react at room temperature for 3 hours. The mixture was concentrated under reduced pressure to give a residue, which was purified by column chromatography (ethyl acetate:petroleum ether = 0-100%) to give compound 10b (62 mg). Yield: 91%.

[0183] 1H NMR (500 MHz, DMSO-d6) δ 8.82 (d, J = 0.8 Hz, 1H), 8.75 (s, 1H), 8.39 (s, 1H), 7.77 (d, J = 3.5 Hz, 1H), 7.09 (d, J = 3.5 Hz, 1H), 5.63 (s, 2H), 4.54 (td, J = 9.5, 4.0 Hz, 1H), 3.57-3.48 (m, 2H), 3.30-3.16 (m, 2H), 2.45-2.35 (m, 1H), 1.85-1.22 (m, 8H), 0.83 (t, J = 8.5 Hz, 2H), -0.10 (s, 9H). MS-ESI calculated value [M+H] + 437, actual value 437.

[0184] Step 2 Compound 10b (58 mg, 0.13 mmol) was added to dichloromethane (2 mL), trifluoroacetic acid (379 mg, 3.33 mmol) was added, and the mixture was allowed to react at room temperature for 6 hours. Saturated aqueous sodium bicarbonate solution (20 mL) and dichloromethane (20 mL × 3) were added for extraction, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 10c (48 mg). Yield: 99%.

[0185] Step 3 Compound 10c (36 mg, 0.11 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (41 mg, 0.21 mmol), and 4-dimethylaminopyridine (26 mg, 0.21 mmol) were added to dichloromethane (3 mL) and reacted at room temperature for 0.5 hours. 4-Ethyloctanoic acid (37 mg, 0.21 mmol) was added and reacted at room temperature for 2 hours. The mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (ethyl acetate:petroleum ether = 0-100%) to obtain compound 10 (37 mg). Yield: 71%.

[0186] 1H NMR (400 MHz, CDCl3) δ 8.89 (s, 1H), 8.34 (s, 1H), 8.30 (s, 1H), 7.49 (d, J = 3.6 Hz, 1H), 6.77 (d, J = 3.6 Hz, 1H), 6.25 (s, 2H), 4.27 (td, J = 9.4, 3.2Hz, 1H), 3.18-3.07 (m, 1H), 3.00-2.90 (m, 1H), 2.64-2.55 (m, 1H), 2.34-2.29 (m, 2H), 2.05-1.92 (m, 2H), 1.73-1.54 (m, 8H), 1.22-1.16 (m, 9H), 0.84 (t, J = 7.0 Hz, 3H), 0.78 (t, J = 7.2 Hz, 3H). MS-ESI calculated value [M+H] + 491, actual value 491.

[0187] Example 11

[0188] [ka]

[0189] Step 1 Under nitrogen protection, compound 11a (0.99 g, 4.40 mmol) was added to methanol (10 mL), cooled to 0 °C, sodium borohydride (0.20 g, 5.29 mmol) was added, and the mixture was allowed to warm to room temperature and react for 1 hour. Saturated aqueous sodium chloride solution (50 mL) was added, and the mixture was extracted with dichloromethane (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 11b (1.01 g). Yield: 99%.

[0190] 1H NMR (400 MHz, CDCl3) δ 4.30 (p, J = 6.4 Hz, 1H), 3.54-3.45 (m, 2H), 3.38-3.30 (m, 2H), 2.62-2.57 (m, 2H), 2.24-2.10 (m, 2H), 1.53-1.48 (m, 2H), 1.45 (s, 9H). Step 2 Under nitrogen protection, compound 11b (0.80 g, 3.52 mmol) was added to dichloromethane (3 mL), N,N-diisopropylethylamine (0.91 g, 7.05 mmol), and methanesulfonic anhydride (1.23 g, 7.05 mmol) were added sequentially, and the mixture was allowed to react at room temperature for 3 hours. Water (25 mL) and ethyl acetate (25 mL × 3) were added and extracted. The combined organic phases were washed with saturated aqueous sodium chloride solution (50 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (ethyl acetate:petroleum ether = 0-100%) to obtain compound 11c (0.90 g). Yield: 84%.

[0191] 1 H NMR (400 MHz, CDCl3) δ 5.11 (p, J = 6.0 Hz, 1H), 3.54 (s, 1H), 3.36 (s, 1H), 3.05-2.96 (m, 3H), 2.68-2.66 (m, 2H), 2.36-2.29 (m, 2H), 2.06-1.95 (m, 2H), 1.89-1.82 (m, 2H), 1.25 (s, 9H). Step 3 In a Schlenk tube, compound 11c (0.90 g, 2.95 mmol) was added to a 30% methylamine methanol solution (10 mL) and reacted at 80 ° C for 7 hours under sealed conditions. After cooling to room temperature, water (100 mL) and ethyl acetate (100 mL × 3) were added for extraction. The organic phases were combined, washed with saturated aqueous sodium chloride solution (50 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (dichloromethane:methanol = 0-100%) to obtain compound 11d (0.68 g). Yield: 86%.

[0192] 1 H NMR (400 MHz, CDCl3) δ 3.53-3.48 (m, 2H), 3.15-3.12 (m, 2H), 2.95-2.87 (m, 2H), 2.76 (s, 2H), 2.66 (s, 3H), 2.18-2.11 (m, 2H), 2.00-1.95 (m, 2H), 1.44 (s, 9H). Step 4 In a microwave tube, compound 11d (0.68 g, 2.01 mmol), compound 9d (0.54 g, 2.01 mmol), and N,N-diisopropylethylamine (0.52 g, 4.03 mmol) were added sequentially to N-methylpyrrolidone (8 mL) and reacted in a microwave at 150 °C for 3 hours. Water (50 mL) and ethyl acetate (50 mL × 3) were added for extraction, and the combined organic phases were washed with saturated aqueous sodium chloride (50 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (ethyl acetate:petroleum ether = 0-100%) to obtain compound 11e (0.65 g). Yield: 60%.

[0193] 1 H NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 7.13 (d, J = 4.0 Hz, 1H), 6.52 (d, J = 4.0 Hz, 1H), 6.15 (s, 2H), 5.57-5.47 (m, 1H), 3.61 (s, 2H), 3.32-3.10 (m, 5H), 2.83 (s, 2H), 2.32-2.25 (m, 2H), 2.05-1.93 (m, 2H), 1.92-1.83 (m, 2H), 1.57-1.52 (m, 2H), 1.48 (s, 9H), 1.25-1.16 (m, 9H), 0.85 (t, J = 6.8 Hz, 3H), 0.79 (t, J = 7.2 Hz, 3H). MS-ESI calculated value [M+1] + 542, actual value 542.

[0194] Step 5 Compound 11e (0.65 g, 1.20 mmol) was added to dichloromethane (20 mL), and trifluoroacetic acid (2.74 g, 24.03 mmol) was added. The mixture was allowed to react at room temperature for 3 hours. The mixture was concentrated under reduced pressure to give compound 11f (0.80 g). Yield: 99%.

[0195] MS-ESI calculated value [M+H] + 442, actual value 442. Step 6 Compound 11f (0.80 g, 1.2 mmol), triethylamine (0.97 g, 9.60 mmol), and phenyl (3-methoxy-1,2,4-thiadiazol-5-yl) carbamate (0.33 g, 1.32 mmol) were added to tetrahydrofuran (10 mL) in order, and the mixture was reacted at 70 ° C for 5 hours. Water (50 mL) and ethyl acetate (50 mL × 3) were added and extracted. The organic phases were combined, washed with saturated aqueous sodium chloride solution (50 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (ethyl acetate: petroleum ether = 0-100%) to obtain compound 11 (0.56 g). Yield: 79%.

[0196] 1 H NMR (400 MHz, DMSO-d6) δ 11.58 (s, 1H), 8.17 (s, 1H), 7.23 (d, J = 4.0 Hz, 1H), 6.64 (d, J = 4.0 Hz, 1H), 6.09 (s, 2H), 5.44 (p, J = 9.0 Hz, 1H), 3.90 (s, 3H), 3.74-3.61 (m, 2H), 3.44-3.35 (m, 2H), 3.15 (s, 3H), 2.90 (s, 2H), 2.25 (t, J = 7.6 Hz, 2H), 2.05-1.97 (m, 2H), 1.82-1.73 (m, 2H), 1.48-1.37 (m, 2H), 1.20-1.07 (m, 9H), 0.80 (t, J = 7.2 Hz, 3H), 0.73 (t, J = 7.2 Hz, 3H). MS-ESI calculated value [M+H] + 599, actual value 599.

[0197] Example 12

[0198] [ka]

[0199] Step 1 Under nitrogen protection, compound 12a (195 mg, 0.83 mmol), N,N-diisopropylethylamine (215 mg, 1.67 mmol), and compound 9d (337 mg, 1.00 mmol) were added to dimethyl sulfoxide (6 mL) and reacted at 100 °C for 7 hours. Extraction was performed with water (50 mL) and ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated aqueous sodium chloride (50 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (ethyl acetate:petroleum ether = 0-100%) to obtain compound 12b (420 mg). Yield: 94%.

[0200] 1 H NMR (400 MHz, DMSO-d6) δ 8.19 (s, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.41-7.31 (m, 5H), 7.30 (d, J = 4.0 Hz, 1H), 6.75 (d, J = 4.0 Hz, 1H), 6.11 (s, 2H), 5.02 (s, 2H), 4.96-4.85 (m, 1H), 3.88-3.77 (m, 1H), 3.25 (s, 3H), 2.57-2.51 (m, 2H), 2.29-2.18 (m, 4H), 1.47-1.39 (m, 2H), 1.34-0.91 (m, 9H), 0.80 (t, J = 7.0 Hz, 3H), 0.73 (t, J = 7.0 Hz, 3H). MS-ESI calculated value [M+H] + 536, actual value 536.

[0201] Step 2 Compound 12b (0.42 g, 0.79 mmol) was added to tetrahydrofuran (12 mL), 10% wet palladium on carbon (0.20 g) was added, and the mixture was purged with a hydrogen balloon three times and stirred at room temperature for 1.5 hours. The mixture was filtered through diatomaceous earth, and the filtrate was collected and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (ethyl acetate:petroleum ether = 0-100%) to give compound 12c (0.30 g). Yield: 95%.

[0202] 1 H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 1H), 7.29 (d, J = 4.0 Hz, 1H), 6.71 (d, J = 4.0 Hz, 1H), 6.11 (s, 2H), 4.83-4.73 (m, 1H), 3.26 (s, 3H), 3.14-3.05 (m, 1H), 2.47-2.41 (m, 2H), 2.26 (t, J = 7.6 Hz, 2H), 2.03-1.93 (m, 2H), 1.46-1.40 (m, 2H), 1.19-1.06 (m, 9H), 0.80 (t, J = 7.0 Hz, 3H), 0.73 (t, J = 7.2 Hz, 3H). MS-ESI calculated value [M+H] + 402, actual value 402.

[0203] Step 3 Under nitrogen protection, compound 12c (298 mg, 0.74 mmol) was added to dichloromethane (10 mL), cooled to 0 °C, triethylamine (150 mg, 14.9 mmol) was added, and propylsulfonyl chloride (127 mg, 0.89 mmol) was added dropwise. The mixture was allowed to warm to room temperature and react for 2 hours. The mixture was concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (ethyl acetate:petroleum ether = 0-100%) to obtain compound 12 (260 mg). Yield: 69%.

[0204] 1H NMR (500 MHz, DMSO-d6) δ 8.19 (s, 1H), 7.50 (d, J = 9.0 Hz, 1H), 7.31 (d, J = 4.0 Hz, 1H), 6.76 (d, J = 4.0 Hz, 1H), 6.11 (s, 2H), 4.88 (p, J = 9.5 Hz, 1H), 3.62-3.53 (m, 1H), 3.25 (s, 3H), 2.96-2.89 (m, 2H), 2.62-2.56 (m, 2H), 2.28-2.18 (m, 4H), 1.73-1.62 (m, 2H), 1.46-1.39 (m, 2H), 1.24-1.05 (m, 9H), 0.97 (t, J = 7.5 Hz, 3H), 0.80 (t, J = 7.0 Hz, 3H), 0.73 (t, J = 7.5 Hz, 3H). MS-ESI calculated value [M+H] + 508, measured value 508.

[0205] Example 13

[0206] [ka]

[0207] Step 1 Under nitrogen protection, compound 13a (0.85 g, 4.34 mmol) and N,N'-carbonyldiimidazole (1.05 g, 6.51 mmol) were added sequentially to N,N-dimethylformamide (8 mL). The mixture was allowed to react at room temperature for 2 hours, cooled to 0°C, and 28% aqueous ammonia (1.3 mL) was added dropwise. The mixture was allowed to warm to room temperature and react for 1 hour. Dichloromethane (50 mL) was added, filtered, and washed with water (50 mL). The filter cake was collected and dried under vacuum to give compound 13b (0.77 g). Yield: 90%.

[0208] 1H NMR (400 MHz, DMSO-d6) δ 12.10 (s, 1H), 8.29 (s, 1H), 7.89 (s, 1H), 7.64 (d, J = 3.6 Hz, 1H), 7.62 (s, 1H), 6.56 (d, J = 3.6 Hz, 1H). MS-ESI calculated value [M+H] + 196, actual value 196.

[0209] Step 2 Under nitrogen protection, compound 13b (0.72 g, 3.68 mmol) and N,N-diisopropylethylamine (0.71 g, 5.52 mmol) were added sequentially to N,N-dimethylformamide (10 mL), and 2-(trimethylsilyl)ethoxymethyl chloride (0.92 g, 5.52 mmol) was added dropwise. The mixture was allowed to react at room temperature for 1 hour. Water (50 mL) and ethyl acetate (50 mL × 3) were added for extraction. The combined organic phases were washed with saturated aqueous sodium chloride (50 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (ethyl acetate:petroleum ether = 0-100%) to give compound 13c (1.12 g). Yield: 93%.

[0210] 1 H NMR (500 MHz, DMSO-d6) δ 8.35 (s, 1H), 7.96 (s, 1H), 7.83 (d, J = 3.6 Hz, 1H), 7.70 (s, 1H), 6.66 (d, J = 3.6 Hz, 1H), 5.64 (s, 2H), 3.51 (t, J = 6.4 Hz, 2H), 0.82 (t, J = 6.4 Hz, 2H), -0.09 (s, 9H). MS-ESI calculated value [M+H] + 326, actual value 326.

[0211] Step 3 Compound 13c (1.12 g, 3.45 mmol) was added to dichloromethane (20 mL), and trifluoroacetic acid (7.86 g, 68.92 mmol) was added. The mixture was allowed to react at room temperature for 20 hours. The mixture was concentrated under reduced pressure to give compound 13d (1.80 g). Yield: 95%.

[0212] 1 H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 7.94 (s, 1H), 7.75 (d, J = 3.6 Hz, 1H), 7.67 (s, 1H), 6.62 (d, J = 3.6 Hz, 1H), 5.63 (s, 2H). MS-ESI calculated value [M+H] + 226, actual value 226.

[0213] Step 4 4-Ethyloctanoic acid (0.97 g, 5.60 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.08 g, 5.60 mmol), and 4-dimethylaminopyridine (1.70 mg, 14.00 mmol) were added to dichloromethane (30 mL) and stirred at room temperature for 10 minutes. 13d (1.60 g, 2.80 mmol) was added and the mixture was allowed to react at room temperature for 2 hours. The mixture was concentrated under reduced pressure to give the residue, which was purified by column chromatography (ethyl acetate:petroleum ether = 0-100%) to give compound 13e (750 mg). Yield: 75%.

[0214] 1 H NMR (400 MHz, DMSO-d6) δ 8.38 (s, 1H), 7.96 (s, 1H), 7.79 (d, J = 3.6 Hz, 1H), 7.73-7.69 (m, 1H), 6.68 (d, J = 3.6 Hz, 1H), 6.25 (s, 2H), 2.27 (t, J = 7.6 Hz, 2H), 1.47-1.39 (m, 2H), 1.25-1.10 (m, 9H), 0.81 (t, J = 7.0 Hz, 3H), 0.72 (t, J = 7.2 Hz, 3H). MS-ESI calculated value [M+H]+ 380, actual value 380.

[0215] Step 5 Compound 13e (0.55 g, 1.45 mmol), trans-4-amino-1-adamantanol (0.48 g, 2.90 mmol), and N,N-diisopropylethylamine (0.37 g, 2.90 mmol) were added to N-methylpyrrolidone (15 mL) in a microwave tube and reacted at 150 °C for 1 hour. Extraction was performed with water (100 mL) and ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated aqueous sodium chloride (200 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (ethyl acetate:petroleum ether = 0-100%) to obtain compound 13 (0.35 g). Yield: 47%.

[0216] 1 H NMR (400 MHz, DMSO-d6) δ 10.11 (d, J = 8.0 Hz, 1H), 8.43 (s, 1H), 7.88 (s, 1H), 7.29 (d, J = 3.6 Hz, 1H), 7.12 (s, 1H), 6.49 (d, J = 3.6 Hz, 1H), 6.20-6.05 (m, 2H), 4.50 (s, 1H), 4.10 (d, J = 8.0 Hz, 1H), 2.25 (t, J = 7.6 Hz, 2H), 2.13 (s, 2H), 2.04 (s, 1H), 1.88-1.78 (m, 4H), 1.70-1.63 (m, 4H), 1.46-1.36 (m, 4H), 1.24-1.09 (m, 9H), 0.81 (t, J = 7.0 Hz, 3H), 0.72 (t, J = 7.2 Hz, 3H). MS-ESI calculated value [M+H] + 511, measured value 511.

[0217] Example 14

[0218] [ka]

[0219] Step 1 Under nitrogen protection, compound 14a (1.00 g, 5.05 mmol) was added to N,N-dimethylformamide (10 mL), cooled to 0 °C, and 60% sodium hydride (224 mg, 6.06 mmol) was added all at once. The mixture was then allowed to react at 0 °C for 0.5 hours. 2-(Trimethylsilyl)ethoxymethyl chloride (1.01 g, 6.06 mmol) was added dropwise, and the mixture was allowed to warm to room temperature and react for 3 hours. Extraction was performed with water (100 mL) and ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine (100 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (ethyl acetate:petroleum ether = 0-100%) to obtain compound 14b (1.60 g). Yield: 96%.

[0220] 1 H NMR (400 MHz, DMSO-d6) δ 8.45 (s, 1H), 8.15 (d, J = 3.6 Hz, 1H), 6.74 (d, J = 3.6 Hz, 1H), 5.62 (s, 2H), 3.55 - 3.45 (m, 2H), 0.82 - 0.78 (m, 2H), -0.11 (s, 9H). Step 2 Under nitrogen protection, compound 14b (1.50 g, 4.57 mmol), ethyl carbamate (0.81 g, 9.15 mmol), potassium carbonate (1.89 g, 13.71 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.53 g, 0.91 mmol), and palladium acetate (0.10 g, 0.46 mmol) were added sequentially to dioxane (30 mL) and reacted at 115 °C for 3 h. The mixture was cooled to room temperature, filtered, and the filtrate was collected and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (ethyl acetate:petroleum ether = 0-100%) to give compound 14c (0.90 g). Yield: 58%.

[0221] 1H NMR (400 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.74 (s, 1H), 7.97 (d, J = 3.6 Hz, 1H), 6.56 (d, J = 3.6 Hz, 1H), 5.59 (s, 2H), 4.16 (q, J = 6.4 Hz, 2H), 3.50 (t, J = 8.0 Hz, 2H), 1.25 (t, J = 7.2 Hz, 3H), 0.81 (d, J = 8.0, 2H), -0.11 (s, 9H). Step 3 Under nitrogen protection, compound 14c (900 mg, 2.68 mmol) was added to N,N-dimethylacetamide (10 mL), the temperature was lowered to 0°C, lithium t-butoxide (214 mg, 2.68 mmol) was added, and the mixture was reacted at 0°C for 30 minutes. The temperature was lowered to -10°C, and a solution of benzyl (3R,4S)-3-(2-bromoacetyl)-4-ethylpyrrolidine-1-carboxylate (948 mg, 2.68 mmol) dissolved in N,N-dimethylacetamide (5 mL) was added dropwise, and the mixture was reacted at -10°C for 30 minutes. The mixture was extracted with water (100 mL) and ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated brine (100 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (ethyl acetate:petroleum ether = 0-100%) to obtain compound 14d (1.20 g). Yield: 75%.

[0222] 1H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 1H), 7.99 (dd, J = 6.4, 3.6 Hz, 1H), 7.36 - 7.29 (m, 5H), 6.52 (dd, J = 30.4, 3.6 Hz, 1H), 5.61 (s, 2H), 5.06 - 5.05 (m, 2H), 4.84 (s, 2H), 4.18 - 4.12 (m, 2H), 3.59 - 3.42 (m, 6H), 3.20 - 3.16 (m, 1H), 2.46 - 2.38 (m, 1H), 1.47 - 1.39 (m, 1H), 1.20 - 1.15 (m, 3H), 0.91 - 0.85 (m, 4H), 0.81 (t, J = 8.0 Hz, 2H), -0.11 (s, 9H). MS-ESI calculated value [M+H] + 610, actual measured value 610.

[0223] Step 4 Under nitrogen protection, compound 14c (1.10 g, 1.81 mmol), trifluoroacetic anhydride (1.89 g, 9.03 mmol), and pyridine (0.43 g, 5.43 mmol) were added to acetonitrile (20 mL) sequentially and reacted at 75 °C for 2 hours. Water (100 mL) and ethyl acetate (100 mL × 3) were added for extraction, and the combined organic phases were washed with saturated brine (100 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (ethyl acetate:petroleum ether = 0-100%) to obtain compound 14e (0.61 g). Yield: 65%.

[0224] 1H NMR (400 MHz, DMSO-d6) δ 8.66 (s, 1H), 7.67 (d, J = 3.6 Hz, 1H), 7.61 (d, J = 4.8 Hz, 1H), 7.41 - 7.31 (m, 5H), 7.09 (t, J = 4.0 Hz, 1H), 5.67 (s, 2H), 5.18 - 5.09 (m, 2H), 4.41 - 4.33 (m, 1H), 3.93 - 3.710 (m, 3H), 3.55 (t, J = 8.0 Hz, 2H), 3.31 - 3.22 (m, 1H), 2.58 - 2.53 (m, 1H), 1.08 - 0.99 (m, 1H), 0.89 - 0.78 (m, 3H), 0.61 - 0.57 (m, 3H), -0.13 (s, 9H). MS-ESI calculated value [M+H] + 520, actual measured value 520.

[0225] Step 5 Compound 14e (560 mg, 1.08 mmol) was added to dichloromethane (20 mL), trifluoroacetic acid (4 mL) was added, and the mixture was allowed to react at room temperature for 20 hours. The mixture was concentrated under reduced pressure to give compound 14f (660 mg). Yield: 99%. MS-ESI calculated value [M+H] + 420, actual value 420.

[0226] Step 6 4-Ethyloctanoic acid (371 mg, 2.16 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (412 mg, 2.16 mmol), and 4-dimethylaminopyridine (695 mg, 5.40 mmol) were added to dichloromethane (20 mL) sequentially and stirred at room temperature for 10 minutes. 14f (660 mg, 1.08 mmol) was added and the mixture was allowed to react at room temperature for 2 hours. The mixture was concentrated under reduced pressure to give a residue, which was purified by column chromatography (ethyl acetate:petroleum ether = 0-100%) to give compound 14g (502 mg). Yield: 81%.

[0227] 1H NMR (400 MHz, DMSO-d6) δ 8.69 (s, 1H), 7.65 - 7.62 (m, 2H), 7.42 - 7.31 (m, 5H), 7.13 (t, J = 4.0 Hz, 1H), 6.29 (s, 2H), 5.18 - 5.08 (m, 2H), 4.39 - 4.31 (m, 1H), 3.91 - 3.71 (m, 3H), 3.33 - 3.28 (m, 1H), 2.58 - 2.53 (m, 1H), 2.29 (t, J = 7.6 Hz, 2H), 1.42 (q, J = 6.8 Hz, 2H), 1.13 - 1.08 (m, 4H), 1.06 - 1.01 (m, 5H), 0.90 - 0.81 (m, 2H), 0.76 - 0.66 (m, 6H), 0.64 - 0.58 (m, 3H). MS-ESI calculated value [M+H] + 574, actual value 574.

[0228] Step 7 Compound 14g (502 mg, 0.88 mmol) was added to tetrahydrofuran (20 mL), 10% wet Pd / C (500 mg) was added, and the mixture was purged with a hydrogen balloon three times and stirred at room temperature for 20 hours. The mixture was filtered through diatomaceous earth, and the filtrate was collected and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (ethyl acetate:petroleum ether = 0-100%) to give compound 14h (213 mg). Yield: 55%.

[0229] 1H NMR (400 MHz, DMSO-d6) δ 8.72 (s, 1H), 7.87 (s, 1H), 7.68 (d, J = 3.6 Hz, 1H), 7.14 (d, J = 3.6 Hz, 1H), 6.31 (s, 2H), 4.37 (q, J = 7.6 Hz, 1H), 3.69 - 3.65 (m, 1H), 3.55 - 3.54 (m, 2H), 3.05 - 3.00 (m, 1H), 2.62 - 2.56 (m, 1H), 2.31 (t, J = 7.6 Hz, 2H), 1.45 (q, J = 6.4 Hz, 2H), 1.16 - 1.00 (m, 9H), 0.96 - 0.85 (m, 2H), 0.77 (q, J = 7.2 Hz, 3H), 0.70 (q, J = 7.2 Hz, 3H), 0.62 (t, J = 7.2 Hz, 3H). MS-ESI calculated value [M+H] + 440, actual value 440.

[0230] Step 8 Under nitrogen protection, N,N-carbonyldiimidazole (116 mg, 0.70 mmol), triethylamine (70 mg, 0.70 mmol), and trifluoroethylamine (58 mg, 0.58 mmol) were added sequentially to dichloromethane (3 mL) and reacted at room temperature for 30 minutes. Compound 14h (170 mg, 0.39 mmol) dissolved in dichloromethane (2 mL) was added dropwise and reacted at room temperature for 3 hours. The mixture was concentrated under reduced pressure to give the residue, which was purified by column chromatography (ethyl acetate:petroleum ether = 0-100%) to give compound 14 (182 mg). Yield: 83%.

[0231] 1H NMR (400 MHz, DMSO-d6) δ 8.69 (s, 1H), 7.63 (d, J = 3.6 Hz, 1H), 7.53 (s, 1H), 7.15 (d, J = 3.6 Hz, 1H), 6.97 (t, J = 6.4 Hz, 1H), 6.29 (s, 2H), 4.34 (q, J = 6.4 Hz, 1H), 3.88 - 3.66 (m, 5H), 3.28 - 3.24 (m, 1H), 2.58 - 2.54 (m, 1H), 2.29 (t, J = 7.6 Hz, 2H), 1.43 (q, J = 6.4 Hz, 2H), 1.14 - 1.03 (m, 9H), 0.86 - 0.61 (m, 11H). MS-ESI calculated value [M+H] + 565, actual value 565.

[0232] Example 15

[0233] [ka]

[0234] Step 1 Under nitrogen protection, compound 15a (0.45 g, 2.15 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.23 g, 3.23 mmol), N,N-diisopropylethylamine (0.82 g, 6.45 mmol), and 4-oxopiperidinium chloride (0.44 g, 3.23 mmol) were added to N,N-dimethylacetamide (5 mL) and reacted at room temperature for 1 hour. Water (50 mL) and ethyl acetate (50 mL × 3) were added for extraction. The combined organic phases were washed with saturated brine (50 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (ethyl acetate:petroleum ether = 0-100%) to give compound 15b (0.60 g). Yield: 96%.

[0235] 1H NMR(400 MHz, DMSO-d6) δ 8.71(d, J=4.8 Hz, 1H), 8.01(t, J=4.8 Hz, 1H), 3.94(s, 2H), 3.58(t, J=6.4 Hz, 2H), 2.55 - 2.52(m, 2H), 2.38 - 2.36(m, 2H). MS-ESI calculated value [M+H] + 291, actual value 291.

[0236] Step 2 Under nitrogen protection, compound 15c (1.00 g, 3.17 mmol) and tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (0.74 g, 3.80 mmol) were added sequentially to acetonitrile (20 mL), and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.58 g, 3.80 mmol) was added dropwise. The mixture was allowed to react at room temperature for 3 hours. The mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (ethyl acetate:petroleum ether = 0-100%) to obtain compound 15d (1.38 g). Yield: 86%.

[0237] 1 H NMR(400 MHz, DMSO-d6) δ 8.93(s, 1H), 8.78(s, 1H), 8.47(s, 1H), 7.80(d, J=4.0 Hz, 1H), 7.20(d, J=3.6 Hz, 1H), 5.64(s, 2H), 4.51(d, J=9.6 Hz, 2H), 4.22(d, J=9.6 Hz, 2H), 3.67(s, 2H), 3.53(t, J=7.6 Hz, 2H), 1.41(s, 9H), 0.82(d, J=8.0 Hz, 2H), -0.11(s, 9H). MS-ESI calculated value [M+H] + 510, actual value 510.

[0238] Step 3 Compound 15d (1.38 g, 2.71 mmol) was dissolved in a solution of hydrogen chloride in dioxane (4.02 M, 20 mL) and reacted at room temperature for 1 hour. The mixture was concentrated under reduced pressure to give compound 15e (1.30 g). Yield: 99%.

[0239] 1 H NMR(400 MHz, DMSO-d6) δ 10.06(s, 1H), 9.83(s, 1H), 9.32(s, 1H), 8.95(s, 1H), 8.75(s, 1H), 8.03(d, J=4.0 Hz, 1H), 7.44(d, J=4.0 Hz, 1H), 5.70(s, 2H), 4.74 - 4.68(m, 2H), 4.39 - 4.37(m, 2H), 3.94(s, 2H), 3.55(t, J=7.6 Hz, 2H), 0.84(t, J=8.0 Hz, 2H), -0.09(s, 9H). MS-ESI calculated value [M+H] + 410, actual value 410.

[0240] Step 4 Under nitrogen protection, compound 15e (130 mg, 0.26 mmol), triethylamine (52 mg, 0.52 mmol), and compound 15b (113 mg, 0.39 mmol) were added to dichloromethane (5 mL) sequentially and reacted at room temperature for 5 minutes. Sodium triacetoxyborohydride (83 mg, 0.39 mmol) was added and reacted at room temperature for 1 hour. Saturated aqueous sodium bicarbonate (25 mL) and ethyl acetate (25 mL × 3) were added for extraction. The combined organic phases were washed with saturated brine (25 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (ethyl acetate:petroleum ether = 0-100%) to obtain compound 15f (100 mg). Yield: 56%.

[0241] 1H NMR(400 MHz, DMSO-d6) δ 8.85(s, 1H), 8.77(s, 1H), 8.67(d, J=4.8 Hz, 1H), 8.44(s, 1H), 7.91(t, J=4.8 Hz, 1H), 7.80(d, J=3.6 Hz, 1H), 7.18(d, J=3.6 Hz, 1H), 5.64(s, 2H), 4.12 - 4.07(m, 1H), 3.76(d, J=8.0 Hz, 2H), 3.61 - 3.51(m, 6H), 3.11 - 3.05(m, 1H), 2.59 - 2.54(m, 1H), 1.80 - 1.60(m, 2H), 1.34 - 1.23(m, 4H), 0.83(t, J=8.0 Hz, 2H), -0.11(s, 9H). MS-ESI calculated value [M+H] + 684, actual value 684.

[0242] Step 5 Compound 15f (95 mg, 0.14 mmol) was added to dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and the mixture was reacted at room temperature for 24 hours. The mixture was concentrated under reduced pressure to give compound 15g (115 mg). Yield: 99%.

[0243] MS-ESI calculated value [M+H] + 584, actual value 584. Step 6 4-Ethyloctanoic acid (46 mg, 0.27 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (52 mg, 0.27 mmol), and 4-dimethylaminopyridine (83 mg, 0.68 mmol) were added to dichloromethane (5 mL) sequentially and stirred at room temperature for 10 minutes. 15g (660 mg, 1.08 mmol) was added and the mixture was allowed to react at room temperature for 1 hour. The mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (ethyl acetate:petroleum ether = 0-100%) to obtain compound 15 (65 mg). Yield: 73%.

[0244] 1H NMR(400 MHz, DMSO-d6) δ 8.86(s, 1H), 8.80(s, 1H), 8.67(d, J=4.4 Hz, 1H), 8.45(s, 1H), 7.91(t, J=4.8 Hz, 1H), 7.75(d, J=3.6 Hz, 1H), 7.20(d, J=3.6 Hz, 1H), 6.24(s, 2H), 4.10 - 4.07(m, 1H), 3.75(d, J=8.0 Hz, 2H), 3.60 - 3.56(m, 4H), 3.44 - 3.40(m, 1H), 3.28 - 3.21(m, 1H), 3.11 - 3.05(m, 1H), 2.61 - 2.53(m, 1H), 2.29(t, J=7.6 Hz, 1H), 1.80 - 1.58(m, 2H), 1.44(q, J=4.8 Hz, 2H), 1.23 - 1.09(m, 11H), 0.77(t, J=7.0 Hz, 3H), 0.70(t, J=7.2 Hz, 3H). MS-ESI calculated value [M+H] + 738, actual value 738.

[0245] Example 16

[0246] [ka]

[0247] Step 1 Compound 16a (1.00 g, 8.55 mmol), 2,4-dichloropyrimidine (1.27 g, 8.55 mmol), and potassium carbonate (1.75 g, 12.83 mmol) were added sequentially to isopropanol (30 mL) and reacted at 100 °C for 8 hours. The mixture was returned to room temperature and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (methanol:dichloromethane = 0-100%) to obtain compound 16b (1.50 g). Yield: 79%.

[0248] 1H NMR(400 MHz, DMSO-d6) δ 12.51(s, 1H), 7.98(s, 1H), 7.94(d, J=6.0 Hz, 1H), 6.60(d, J=6.0 Hz, 1H), 2.03 - 1.93(m, 1H), 1.89 - 1.80(m, 1H), 1.44(s, 3H), 0.82(t, J=7.4 Hz, 3H). MS-ESI calculated value [M+H] + 230, actual value 230.

[0249] Step 2 Under nitrogen protection, compound 16b (1.00 g, 4.37 mmol), 2,2,2-trifluoroethylamine (0.65 g, 6.55 mmol), and N,N-diisopropylethylamine (0.84 g, 6.55 mmol) were added sequentially to N,N-dimethylformamide (30 mL). The mixture was cooled to 0 °C, and 50% propylphosphoric acid anhydride (50% w / w, ethyl acetate solution, 4.20 g, 6.55 mmol) was added dropwise. The mixture was allowed to warm to room temperature and react for 17 h. Water (100 mL) and ethyl acetate (100 mL x 3) were added for extraction. The combined organic phases were washed with saturated brine (100 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (ethyl acetate:petroleum ether = 0-100%) to give compound 16c (0.50 g). Yield: 37%.

[0250] 1 H NMR(400 MHz, DMSO-d6) δ 8.23(s, 1H), 7.95(d, J=4.8 Hz, 1H), 7.81(s, 1H), 6.61 - 6.59(m, 1H), 3.84 - 3.76(m, 2H), 1.97 - 1.89(m, 1H), 1.87 - 1.78(m, 1H), 1.42(s, 3H), 0.76(t, J=7.6 Hz, 3H). MS-ESI calculated value [M+H] + 311, measured value 311.

[0251] Step 3 Under nitrogen protection, compound 16d (1.00 g, 5.07 mmol) and N,N-diisopropylethylamine (0.98 g, 7.61 mmol) were added to dichloromethane (20 mL) in succession, and 2-(trimethylsilyl)ethoxymethyl chloride (1.26 g, 7.61 mmol) was added dropwise. The mixture was allowed to react at room temperature for 3 hours. The mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (ethyl acetate:petroleum ether = 0-100%) to obtain compound 16e (1.30 g). Yield: 77%.

[0252] 1 H NMR(400 MHz, DMSO-d6) δ 8.36(dd, J=4.8, 1.6 Hz, 1H), 7.92(s, 1H), 7.89(dd, J=8.0, 1.6 Hz, 1H), 7.26(dd, J=8.0, 4.8 Hz, 1H), 5.62(s, 2H), 3.50(t, J=8.0 Hz, 2H), 0.80(t, J=8.0 Hz, 2H), -0.12(s, 9H). MS-ESI calculated value [M+H] + 327, actual value 327.

[0253] Step 4 Under nitrogen protection, compound 16e (1.05 g, 3.22 mmol), bis(pinacolato)diboron (2.45 g, 9.66 mmol), potassium acetate (0.95 g, 9.66 mmol), and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.25 g, 0.32 mmol) were added to dioxane (20 mL) and reacted at 100 °C for 2 h. The mixture was cooled to room temperature, filtered through diatomaceous earth, and the filtrate was collected and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (ethyl acetate:petroleum ether = 0-100%) to give compound 16f (0.80 g). Yield: 67%.

[0254] 1H NMR(400 MHz, DMSO-d6) δ 8.29(dd, J=4.8, 1.6 Hz, 1H), 8.11(dd, J=8.0, 1.6 Hz, 1H), 7.98(s, 1H), 7.20(dd, J=8.0, 4.8 Hz, 1H), 5.63(s, 2H), 3.51(t, J=8.0 Hz, 2H), 1.31(s, 12H), 0.80(t, J=8.0 Hz, 2H), -0.11(s, 9H). MS-ESI calculated value [M+H] + 375, actual value 375.

[0255] Step 5 Under nitrogen protection, compound 16f (675 mg, 1.80 mmol), compound 16c (700 mg, 2.26 mmol), potassium carbonate (623 mg, 4.56 mmol), and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (177 mg, 0.23 mmol) were added sequentially to a mixture of dioxane (20 mL) and water (4 mL) and reacted at 100 °C for 2 h. The mixture was then cooled to room temperature, filtered through diatomaceous earth, and the filtrate was collected and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (ethyl acetate:petroleum ether = 0-100%) to give compound 16g (230 mg). Yield: 24%.

[0256] 1 H NMR(400 MHz, DMSO-d6) δ 8.75(d, J=8.0 Hz, 1H), 8.31 - 8.30(m, 2H), 8.19(s, 1H), 8.14(d, J=5.6 Hz, 1H), 7.36(s, 1H), 7.22(dd, J=8.0, 4.8 Hz, 1H), 6.44(s, 1H), 5.68(s, 2H), 3.87 - 3.66(m, 2H), 3.53(t, J=8.0 Hz, 2H), 2.12 - 2.02(m, 1H), 1.89 - 1.79(m, 1H), 1.49(s, 3H), 0.85 - 0.80(m, 5H), -0.11(s, 9H). MS-ESI calculated value [M+H] + 523, actual value 523.

[0257] Step 6 Compound 16g (220 mg, 0.42 mmol) was added to dichloromethane (20 mL), trifluoroacetic acid (4 mL) was added, and the mixture was reacted at room temperature for 16 hours. The mixture was concentrated under reduced pressure to give compound 16h (290 mg). Yield: 99%.

[0258] MS-ESI calculated value [M+H] + 423, actual value 423. Step 7 4-Ethyloctanoic acid (290 mg, 0.90 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (172 mg, 0.90 mmol), and 4-dimethylaminopyridine (274 mg, 2.25 mmol) were added to dichloromethane (15 mL) and stirred at room temperature for 10 minutes. 16h (290 mg, 0.45 mmol) was added and the mixture was allowed to react at room temperature for 2 hours. The mixture was concentrated under reduced pressure to give a residue, which was purified by column chromatography (ethyl acetate:petroleum ether = 0-100%) to give compound 16 (139 mg). Yield: 53%.

[0259] 1 H NMR(400 MHz, DMSO-d6) δ 8.76(d, J=8.0 Hz, 1H), 8.33(dd, J=4.8, 1.6 Hz, 1H), 8.30(s, 1H), 8.23(s, 1H), 8.14(d, J=5.6 Hz, 1H), 7.42(s, 1H), 7.26(dd, J=8.0, 4.8 Hz, 1H), 6.46(s, 1H), 6.28(s, 2H), 3.91 - 3.67(m, 2H), 2.27(t, J=7.6 Hz, 2H), 2.11 - 2.00(m, 1H), 1.89 - 1.80(m, 1H), 1.49(s, 3H), 1.13 - 1.07(m, 9H), 0.86 - 0.75(m, 8H), 0.68(t, J=7.2 Hz, 3H). MS-ESI calculated value [M+H]+ 577, actual value 577.

[0260] Example 17 Skin-Pampa Analysis Method 1. The Skin-Pampa membrane was hydrated overnight in hydration solution.

[0261] 2. Each API was dissolved in DMSO to prepare 0.5 mL of approximately 20 mM mother solution. 50 μL of the mother solution was added to the corresponding 5 mL feed solution and mixed uniformly. 3. 200 μL of feeding solution was added to the receiving wells and 200 μL of sample was added to the feeding wells, equilibrated and incubated with 12 wells per sample.

[0262] After 4.7 hours of incubation, 100 μL of sample was taken into the supply well and 100 μL of sample into the receiving well, each diluted with 200 μL of 50% acetonitrile, vortexed to mix, centrifuged, and 200 μL of the supernatant was taken to detect the content by HPLC.

[0263] 5. Skin-Pampa parameters were calculated using the following formula:

[0264]

number

[0265] Pe - effective permeability coefficient V A - Volume of receiving well (ml) V D - Volume of supply well (ml) A-Membrane area (cm 2 ) t - incubation time (s) t LAG -Membrane equilibration time (s) C D (t) - Concentration of the supply well at time t C A(t) - concentration of the receiving well at time t C D (0) - Initial concentration in the supply well.

[0266] [Table 1] JPEG0007759063000080.jpg36170

[0267] Conclusion: The compound synthesized in this invention has excellent transdermal properties in rat transdermal experiments and is suitable for the preparation of topical formulations. All documents mentioned in this application are incorporated by reference in this application to the same extent as if each document was individually incorporated by reference. Furthermore, it should be understood that, after reading the above teachings of the present invention, one skilled in the art may make various changes or modifications to the present invention, and that equivalents thereof are also within the scope defined by the claims appended hereto.

Claims

1. Pharmaceutical compound G′ or a pharmaceutically acceptable salt, hydrate, or solvate thereof, The compound has a structure represented by formula (I): 【Chemical 1】 The G group is selected from the group consisting of: 【Chemistry 2】 Alternatively, the compound of formula (I) has a structure represented by the following formula (IIB) or (IIC): 【Chemistry 3】 During the ceremony, Z, T, U, V, and W are each independently N or CR. ４ and Y is N or CR ５ and Here, R ４ and R ５ are each independently H, halogen, —CN, or —C(O)NH ２ , and 【Chemistry 4】 is selected from the group consisting of M is none, C(O), C(O)O, S(O), S(O) ２ , N.R. ８ , 5- to 7-membered heteroaryl groups, and 5- to 7-membered heteroaryl groups (CHR ８ )- is selected from the group consisting of Ring B is selected from the group consisting of a 5- to 7-membered heteroaryl group, a 4- to 10-membered heterocyclyl group, a C4-C10 cycloalkyl group, and a 4- to 10-membered heterocyclyl group substituted with a 4- to 10-membered heterocyclyl group; R ６ represents a C1-C4 alkyl group, a C2-C6 cyanoalkyl group, or —C(O)CH ２ CN, -C(O)CH=CH ２ , -NHS(O) ２ R ７ , -NHC(R ８ ) ２ C(O)NHR ７ , and —C(O)NHR ７ is selected from the group consisting of R ７ is selected from the group consisting of -OH, halogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a 5- to 7-membered heteroaryl group, and a C2-C6 cyanoalkyl group, wherein the heteroaryl group is optionally substituted with one or more substituents selected from the group consisting of -OH, halogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group, and a C1-C6 alkoxy group; R ８ is selected from the group consisting of H, a C1-C4 alkyl group, and a C2-C6 cyanoalkyl group; s is 0 or 1; R １ and R ２ are each independently selected from the group consisting of H, D, and a substituted or unsubstituted C1-C6 alkyl group; L is selected from the group consisting of nothing and a substituted or unsubstituted C1-C6 alkylene group; R ３ is selected from the group consisting of substituted or unsubstituted C5 to C20 alkyl groups; Each heterocyclyl group is selected from N, O, and S(O) ｐ and containing 1 to 3 heteroatoms selected from the group consisting of: p is selected from 0, 1, and 2; Unless otherwise specified, the compound, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, characterized in that each "substituted" means substituted with one or more substituents selected from the group consisting of a deuterium atom, a halogen, a C1-C6 alkyl group, a haloC1-C6 alkyl group, a C1-C6 alkoxy group, a haloC1-C6 alkoxy group, and a C3-C8 cycloalkyl group.

2. The G group is selected from the group consisting of:

10. The compound of claim 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof. 【Chemistry 5】

3. The compound of formula (I) has a structure represented by the following formula (IIB) or (IIC): 【Chemistry 6】 wherein each group is as defined in claim 1.

10. The compound of claim 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof. 【Request 4】 【Chemical 7】 teeth, 【Chemistry 8】 2. The compound of claim 1, wherein the compound has a structure selected from the group consisting of:

5. The compound of formula (I) has a structure represented by the following formula (IIA): 【Chemistry 9】 During the ceremony, Y is N or C—C(O)NH ２ and R ４ teeth, 【Chemistry 10】 characterized in that the compound is selected from the group consisting of 10. The compound of claim 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

6. The compound of formula (I) is characterized in that it has a structure selected from the group consisting of:

10. The compound of claim 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof. 【Chemistry 11】 【change】

7. The compound of formula (I) is characterized in that it has a structure selected from the group consisting of:

10. The compound of claim 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof. 【Chemistry 12】 【change】 【change】 【change】

8. The compound of formula (I) is characterized in that it has a structure selected from the group consisting of:

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, hydrate, or solvate thereof. 【Chemistry 13】

9. A method for producing the compound of claim 5, comprising the steps of: 【Chemistry 14】 In an inert solvent, a compound of formula 2e is reacted with R ３ -LC(O)X to obtain a compound of formula (IIA), wherein Y is N or C-C(O)NH ２ wherein X is OH or an activating group, and the remaining groups are as defined in claim 1.

10. 1. A pharmaceutical composition comprising:

9. The pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

11. 10. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt or hydrate thereof, for use in the manufacture of a pharmaceutical composition for treating or preventing a disease associated with the activity or expression level of JAK kinase.

12. A formulation for external administration, A compound according to any one of claims 1 to 8; A skin penetration enhancer; an optional support layer; The topical formulation, wherein the optional skin penetration enhancer is selected from the group consisting of surfactants, dimethyl sulfoxide and its analogs, azone compounds, α-pyridoin derivatives, alcohol compounds, ether compounds, fatty acid compounds, fatty acid ester compounds, and combinations thereof.

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