A prodrug compound, and a method of preparing and using the same

Abstract

The present application provides a prodrug compound and a preparation method and use thereof, in particular, the present application provides a compound as shown in formula (I), and a preparation method and use thereof as a prodrug for preparing external preparations.

Description

Technical Field

[0001] This invention relates to the field of small molecule pharmaceuticals. Specifically, this invention provides a class of prodrug compounds as kinase inhibitors, their pharmaceutically acceptable salts, hydrates or solvates, and pharmaceutical compositions (preferably topical formulations) containing the above components. Background Technology

[0002] The JAK-STAT signaling pathway is a cytokine-stimulated signal transduction pathway discovered in recent years. JAKs play an important role in cytokine signal transduction, and downstream substrates of the JAK kinase family include signal transducers and activators of transcription proteins (STATs). JAK proteins are important members of this pathway, and abnormally increased JAK activity often leads to disease. Many diseases are related to abnormal cellular responses in the JAK-STAT signaling pathway, including autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, 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, with a prevalence of 0.5%-1.0%. Because the pathogenesis of RA is not fully understood, its pathological process is difficult to control, resulting in a high rate of disability and severely impacting patients' physical and mental health, thus reducing their quality of life. Currently, the main drugs used to treat RA include nonsteroidal anti-inflammatory drugs (NSAIDs), disease-modifying antirheumatic drugs (DMARDs), and antibody drugs. For a long time, DMARDs have 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 history. This drug is widely used due to its efficacy, tolerability, and safety, but it also has adverse reactions including nausea, vomiting, stomach upset, and hepatotoxicity. In contrast, newly developed antibody drugs have shown better efficacy and safety profiles for moderate to severe RA. However, because they target specific cytokines, the population that can benefit from them is significantly limited. At the same time, the cost of treatment and the method of administration by injection also limit the promotion of these drugs.

[0004] Over the past 20 years, RA treatment has made significant progress, and patients' conditions can now be effectively controlled with existing treatments. Nevertheless, RA patients still suffer from disease relapse, unsatisfactory treatment effectiveness, poor long-term tolerability, and various adverse reactions. More importantly, the quality of life of RA patients, including the function of organs such as joints, has not been truly improved with current treatments. Therefore, there remains a significant unmet clinical need in this area to restore patients' normal function.

[0005] Studies have shown that the core therapeutic role in rheumatoid arthritis (RA) is played by monocytes / macrophages and lymphocytes infiltrating the synovial tissue and cells of RA, which produce a large number of cytokines through autocrine mechanisms. These cytokines interact and activate the JAK / STAT signaling pathway (Janus kinase / signal transducer and activators of transcription signaling pathway) through different pathways. By specifically inhibiting the JAK / STAT signaling pathway, the cascade amplification effect of the above-mentioned cytokines can be blocked, thereby improving the symptoms of the damaged joints in RA patients. Therefore, the JAK / STAT signaling pathway has become a potential target for the treatment of RA.

[0006] Because JAK kinases participate in various important physiological processes in the body, broad inhibition of different subtypes may produce adverse reactions. Tofacitinib, used in patients with moderate to severe RA who have an inadequate response to or are intolerant to methotrexate (MTX), has been observed to have certain adverse reactions in clinical trials, including infection, tuberculosis, tumors, anemia, liver damage, and increased cholesterol. Tofacitinib has significant inhibitory activity against JAK1, JAK2, and JAK3 subtypes. Since JAK2 activity is related to erythrocyte differentiation and lipid metabolism, some of the aforementioned adverse reactions are believed to be related to the non-selective inhibitory characteristics of this drug. Therefore, the search for selective JAK1 and / or JAK3 inhibitors will become a new direction in RA drug research. Currently, JAK inhibitors have been proven to be used for the treatment of hematologic disorders, tumors, rheumatoid arthritis, and psoriasis. However, the number of JAK inhibitor compositions available for topical administration remains very limited. Summary of the Invention

[0007] In a first aspect, the present invention provides a prodrug molecule of a pharmaceutical compound G', and a pharmaceutically acceptable salt, hydrate, or solvate thereof, characterized in that the hydrophobicity coefficient CLogP of the drug molecule G' is <4; and the prodrug molecule has the structure shown in formula (I):

[0008]

[0009] Wherein, G is a partial structural fragment formed by the loss of H atoms in the drug molecule G', which is formed by any N, O, or S atom within the molecule interacting with... Connected;

[0010] The R mentioned 1 and R 2Each is independently selected from the following group: H, D, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, or R. 1 and R 2 It forms a C3-C8 carbon ring or heterocycle with the carbon atoms attached to it;

[0011] L is selected from the following group: unsubstituted, substituted or unsubstituted C1-C6 alkylene groups, substituted or unsubstituted C1-C6 heteroalkylene groups;

[0012] R 3 Selected from the following group: substituted or unsubstituted C1-C20 alkyl groups (straight-chain or branched), substituted or unsubstituted C3-C20 cycloalkyl groups, substituted or unsubstituted C1-C20 heteroalkyl groups, substituted or unsubstituted 3-20 membered heterocyclic groups, substituted or unsubstituted C6-C14 aryl groups, or R 3 and R 1 or R 2 These are linked together to form a substituted or unsubstituted 5-20 member lactone ring or heterolactone ring; wherein, the heterolactone ring refers to a lactone ring whose ring skeleton includes 1-3 heteroatoms selected from the group consisting of N, O, or S(O). p ;

[0013] Wherein, the heteroalkyl group refers to one or more carbon atoms in the carbon chain being replaced by heteroatoms selected from the group consisting of: N, O, or S(O). p ;

[0014] The heterocyclic group comprises 1-3 heteroatoms selected from the group consisting of N, O, or S(O). p ;

[0015] p is selected from 0, 1, or 2;

[0016] Unless otherwise specified, “substitution” means being substituted by one or more (e.g., 2, 3, 4, etc.) substituents selected from the group consisting of: deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyl, C3-C8 heterocyclic, oxo, -CN, hydroxyl, amino, carboxyl, amide, sulfonamide, sulfone, unsubstituted or substituted by one or more substituents selected from the group consisting of: C6-C10 aryl, halogenated C6-C10 aryl, 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S, and O, halogenated 5-10 membered heterocyclic having 1-3 heteroatoms selected from N, S, and O; and the substituents are selected from the group consisting of: halogen, C1-C6 alkyl, C1-C6 alkoxy, =O.

[0017] In another preferred embodiment, the drug molecule G' is selected from the group consisting of JAK inhibitors, MEK inhibitors, and BTK inhibitors.

[0018] In another preferred embodiment, the JAK inhibitor is selected from the group consisting of: INCB-52793, ATI-502, Deuterium-modified ruxolitinib analog, ATI-501, R-348, NS-018, Jaktinib, KL-130008, DTRMHS-07, WXSH-0150, TQ05105, WXFL10203614, or molecules selected from the group consisting of or pharmaceutically acceptable salts, hydrates, or solvates thereof:

[0019]

[0020] In another preferred embodiment, the MEK inhibitor is a molecule selected from the group consisting of, or a pharmaceutically acceptable salt, hydrate, or solvate thereof:

[0021]

[0022] In another preferred embodiment, the BTK inhibitor is a molecule selected from the group consisting of, or a pharmaceutically acceptable salt, hydrate, or solvate thereof:

[0023]

[0024] In another preferred embodiment, the drug molecule G' comprises structure A, where A is an optionally substituted 5-20 membered heteroaryl group or an optionally substituted 5-20 membered heterocyclic group, the heteroaryl group or heterocyclic group comprising one or more heteroatoms selected from N, S, and O, and

[0025] G' connects with one of the heteroatoms in A. Connected.

[0026] In another preferred embodiment, the CLogP of G' is less than 3.

[0027] In another preferred embodiment, the CLogP of G' is less than 2.

[0028] In another preferred embodiment, the molecular weight of G' is less than 900 Da.

[0029] In another preferred embodiment, the molecular weight of G' is less than 700 Da.

[0030] In another preferred embodiment, the molecular weight of G' is less than 500 Da.

[0031] In another preferred embodiment, the molecular weight of G' is not less than 900 Da.

[0032] In another preferred embodiment, the G' is connected to the N atom. Connected.

[0033] In another preferred embodiment, the G' is connected to the S atom. Connected.

[0034] In another preferred embodiment, the G' is connected to the O atom.

[0035] In another preferred embodiment, the structure A is a 5-20 member heteroaryl group.

[0036] In another preferred embodiment, the R 1 and R 2 Each is independently an H, D, or C1-C6 alkyl group, L is selected from alkylene groups with or without C1-C6 alkylene groups, and R is... 3 Selected from the group consisting of: C1-C20 alkyl groups, C3-C20 cycloalkyl groups, and C6-C14 aryl groups; wherein the alkyl, alkylene, cycloalkyl, or aryl group may optionally be substituted by a substituent selected from the group consisting of: halogens and C1-C4 alkyl groups.

[0037] In another preferred embodiment, the R 1 and R 2 Each is independently H, L is selected from none, and the R is... 3 Selected from the group consisting of C1-C20 alkyl groups; wherein the alkyl group may optionally be substituted with substituents selected from the group consisting of halogens and C1-C4 alkyl groups.

[0038] In another preferred embodiment, R 3 C is an optional replacement 1-20 Alkyl or substituted phenyl groups.

[0039] In another preferred embodiment, R 3 C is an optional replacement 1-12 alkyl.

[0040] In another preferred embodiment, R 3 C is an optional replacement 10-15 alkyl.

[0041] In another preferred embodiment, R 3 It is a straight-chain alkyl group.

[0042] In another preferred embodiment, R 3 It is a branched alkyl group.

[0043] In another preferred embodiment, the G group is selected from the group consisting of:

[0044]

[0045]

[0046]

[0047]

[0048]

[0049]

[0050]

[0051] In another preferred embodiment, the G group is selected from the group consisting of:

[0052]

[0053] In another preferred embodiment, the compound of formula (I) has the structure shown in formula (IIB), (IIC), or (IID):

[0054]

[0055] in,

[0056] Z, T, U, V, and W are each independently N or CR. 4 ;

[0057] Y is N or CR 5 ;

[0058] Among them, R 4 and R 5 Each is independently selected from the following groups: H, halogens, -CN, -C(O)NH2,

[0059] M is selected from the following group: None, C(O), C(O)O, S(O), S(O)2, NR 8 5-7 heteroaryl, or 5-7 heteroaryl (CHR) 8 )-;

[0060] Ring B is selected from the group consisting of 5-7-membered heteroaryl, 4-10-membered heterocyclic, C4-C10 cycloalkyl, or 4-10-membered heterocyclic substituted with heterocyclic (wherein, the heteroaryl, cycloalkyl or heterocyclic includes monocyclic, fused, spirocyclic or bridged ring).

[0061] R 8 Selected from the following group: H, C1-C4 alkyl, C2-C6 cyanoalkyl;

[0062] R 6Selected from the following groups: C1-C4 alkyl, C2-C6 cyanoalkyl, -C(O)CH2CN, -C(O)CH=CH2, -C(O)NHR 7 -NHS(O)2R 7 -NHC(R) 8 )2C(O)NHR 7 -C(O)NHR 7 ;

[0063] R 7 The group is selected from the following: -OH, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, 5-7 heteroaryl, C2-C6 cyanoalkyl; wherein the heteroaryl group may be substituted by one or more substituents selected from the following: -OH, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy.

[0064] s is selected from 0 or 1.

[0065] In another preferred embodiment, The structure is selected from the following group:

[0066]

[0067] In another preferred embodiment, the R 4 or R 5 Each person independently selects from the following groups:

[0068] In another preferred embodiment, the described The structure is selected from the following group:

[0069] In another preferred embodiment, the compound of formula (I) has the structure shown in the following formula:

[0070]

[0071] in,

[0072] Y can be N, CH, or CC(O)NH2.

[0073] In another preferred embodiment, the compound of formula (I) has the structure shown in formula (IIA):

[0074]

[0075] in,

[0076] Y is either N or CC(O)NH2;

[0077] R 4Selected from the following group:

[0078] In another preferred embodiment, the compound of formula (I) has the structure shown in formula (II):

[0079]

[0080] In another preferred embodiment, the compound of formula (I) has the structure shown in the following formula:

[0081]

[0082]

[0083] In another preferred embodiment, the compound of formula (I) has a structure selected from the group consisting of:

[0084]

[0085]

[0086]

[0087]

[0088]

[0089] In another preferred embodiment, the pharmaceutically acceptable salt is a hydrochloride salt.

[0090] A second aspect of the present invention provides a method for preparing a compound as described in the first aspect of the present invention, wherein the drug molecule G' can be prepared by combining N and O atoms in the molecule with... Connected:

[0091] (1) Option 1:

[0092]

[0093] In the above reaction formula, A'-NH is equivalent to G', and A'-N is equivalent to G. Chloroalkyl esters react with G' under basic conditions, causing the N atom to be attached to the prodrug group of this invention.

[0094] (2) Option 2:

[0095]

[0096] In the above reaction formula, A'-NH is equivalent to G', and A'-N is equivalent to G. A two-step process is used: first, chloroalkyl carbonate 1 reacts with G' to obtain intermediate 2, which is then condensed with 3, allowing the N atom to be attached to the prodrug group of this invention.

[0097] (3) Option 3:

[0098]

[0099] In the above reaction formula, A'-OH is equivalent to G', and A'-O is equivalent to G. Under alkaline or acidic conditions, A'-OH condenses with carbonyl compound 4 to obtain intermediate 5, which then condenses with acid 3 or acid anhydride 6, causing the O atom to be attached to the prodrug group of the present invention.

[0100] In another preferred embodiment, the method for compound (IIA) is characterized by comprising the steps of:

[0101]

[0102] In an inert solvent, the compound of formula 2e is reacted with R. 3 The C(O)X reaction yields 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 The definitions of the remaining groups are as described above.

[0103] In another preferred embodiment, it includes the steps of:

[0104] (1) Option 1:

[0105]

[0106] In an inert solvent, the free base of styrofoam is reacted with R. 3 C(O)CR 1 R 2 The Cl reaction yields compound (II);

[0107] or

[0108] (2) Option 2:

[0109]

[0110] In an inert solvent, the compound of formula 2e' is reacted with R. 3 The C(O)X reaction yields compound (II); wherein X is OH or an activating group (preferably a halogen or OC(O)R). 3 The definitions of the remaining groups are as described in the first aspect of this invention.

[0111] In another preferred embodiment, the method further includes the step of:

[0112]

[0113] The reaction of 1c with 1d yields compound 1e.

[0114] In another preferred embodiment, the method further includes the step of:

[0115]

[0116] Compound 1a was reacted with chloromethyl chloroformate to give compound 1c.

[0117] A third aspect of the present invention provides an intermediate as shown in formula 2e:

[0118]

[0119] Wherein, Y is N or CC(O)NH2; the definitions of the other groups are as described above.

[0120] In another preferred embodiment, the compound of formula 2e has the structure shown in formula 1e:

[0121]

[0122] A fourth aspect of the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound described in the first aspect of the present invention, and a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0123] In another preferred embodiment, the pharmaceutical composition is a topical preparation.

[0124] In another preferred embodiment, the pharmaceutical composition further comprises a skin penetration enhancer (such as surfactant, dimethyl sulfoxide, decyl methyl sulfoxide, azone enhancer, alcohol enhancer, volatile oil, amino acid, phospholipid, oleic acid).

[0125] In another preferred embodiment, after transdermal administration of the pharmaceutical composition, the compound of formula I is metabolized in vivo to form tofacitinib.

[0126] In another preferred embodiment, the pharmaceutical composition is used to treat or prevent diseases related to the activity or expression level of JAK kinase; preferably, the diseases are selected from the group consisting of: cancer, myeloproliferative disorders, inflammation, immune diseases, organ transplantation, viral diseases, cardiovascular or metabolic diseases, human or animal autoimmune diseases, rheumatoid arthritis, skin diseases, multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, myasthenia gravis, and psoriasis.

[0127] A fifth aspect of the invention provides the use of a compound as described in the first aspect of the invention, or a pharmaceutically acceptable salt or hydrate thereof, for the preparation of a pharmaceutical composition for treating or preventing diseases related to the activity or expression level of JAK kinase.

[0128] In another preferred embodiment, the disease is selected from the group consisting of: cancer, myeloproliferative disorders, inflammation, immune diseases, organ transplantation, viral diseases, cardiovascular or metabolic diseases, human or animal autoimmune diseases, rheumatoid arthritis, skin diseases, multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, myasthenia gravis, and psoriasis.

[0129] A sixth aspect of the present invention provides a topical preparation comprising:

[0130] The compound described in the first aspect of this invention;

[0131] Optional skin penetration enhancer, preferably, the skin penetration enhancer is selected from the group consisting of: surfactants, dimethyl sulfoxide and their analogues, azone compounds, pyrrolidone derivatives, alcohol compounds, ether compounds, fatty acid compounds and fatty acid ester compounds, or combinations thereof;

[0132] Optional support layer.

[0133] In another preferred embodiment, the drug exists in a single phase or multiple phases, in a solution or suspension.

[0134] In another preferred embodiment, the formulation is administered in the form of a solution, suspension, gel, emulsion, ointment, foam, etc.

[0135] In another preferred embodiment, the support layer is a membrane polymer or a backbone polymer.

[0136] In another preferred embodiment, the support layer is selected from the group consisting of pressure-sensitive adhesive materials, backing materials, anti-stick materials, and pharmacy materials.

[0137] In another preferred embodiment, the topical preparation further includes a peeling layer.

[0138] In another preferred embodiment, the formulation is a transmembrane delivery formulation.

[0139] In another preferred embodiment, the formulation is a sustained-release formulation.

[0140] In another aspect, the present invention provides a method for improving the membrane permeability of a drug molecule G', the method comprising the steps of:

[0141] The drug molecule G' is modified to introduce a fragment into the molecule. Forming CLogP>4 Simultaneously, the CLogP of the prodrug molecule (I) formed by the modification is increased by at least 1 unit compared with the CLogP of the drug molecule G'.

[0142] In another preferred embodiment, the CLogP of the modified prodrug molecule (I) is increased by at least 2 units compared to the CLogP of the drug molecule G'.

[0143] In another preferred embodiment, the CLogP of the modified prodrug molecule (I) is increased by at least 3 units compared to the CLogP of the drug molecule G'.

[0144] In another preferred embodiment, a fragment is added to the modified drug molecule G'. And formed Methods, including drug molecule G' and Couplet.

[0145] In another preferred embodiment, the prodrug molecule The Pe value of Skin-Pampa is 2-100 times higher than that of the unmodified drug molecule G'.

[0146] In another preferred embodiment, the prodrug molecule The Pe value of Skin-Pampa is 4-20 times higher than that of the unmodified drug molecule G'.

[0147] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Detailed Implementation

[0148] Through long-term and in-depth research, the inventors have developed a compound as shown in formula (I). This compound consists of a hydrophilic drug molecule end and a hydrophobic end, thus exhibiting excellent transdermal properties. After topical administration, it can be metabolized in vivo to form the original drug molecule, thereby completing the drug delivery process. Based on the above findings, the inventors have completed this invention.

[0149] definition

[0150] As used herein, the term "alkyl" includes straight-chain or branched alkyl groups. For example, C1-C6 alkyl refers to straight-chain or branched alkyl groups having 1-6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, etc., and "C1-C20 alkyl" has a similar meaning. The term "alkylene" refers to an alkyl group that has lost one hydrogen atom; for example, C1-C6 alkylene refers to straight-chain or branched alkylene groups having 1-6 carbon atoms. The term "heteroalkyl" refers to an alkyl group in which one or more carbon atoms in the carbon chain are substituted by heteroatoms selected from the group consisting of O, S, NH, C(O), or C(NH), and the term "heteroalkylene" has a similar meaning.

[0151] As used herein, the term "C3-C8 cycloalkyl" refers to a cycloalkyl group having 3-8 carbon atoms. It can be monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or similar groups. It can also be bicyclic, such as bridged, fused, or spirocyclic forms. "C3-C20 cycloalkyl" has a similar definition.

[0152] As used herein, the term "C6-C14 aryl" refers to an aryl group having 6-14 carbon atoms, such as phenyl or naphthyl groups.

[0153] As used herein, the term "5-10 membered heteroaryl group having 1-3 heteroatoms selected from the group consisting of N, S, and O" refers to a cyclic aromatic group having 5-10 atoms, of which 1-3 atoms are heteroatoms selected from the group consisting of N, S, and O. It can be monocyclic or fused-ring. Specific examples include pyridinyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrroleyl, pyrazolyl, imidazoleyl, (1,2,3)-triazolyl and (1,2,4)-triazolyl, tetrazolyl, furanyl, thiopheneyl, isoxazolyl, thiazolyl, oxazolyl, etc.

[0154] As used herein, the term "3-20 membered heterocyclic group" refers to a saturated or partially saturated cyclic group having 3-20 ring atoms, wherein 1-3 of these atoms are heteroatoms selected from the group consisting of N, S, and O, preferably a 3-10 membered heterocyclic group, or a 4-7 membered heterocyclic group, or a 9-15 membered heterocyclic group. It can be monocyclic or bicyclic, such as a bridged ring or a spirocyclic ring. Specific examples include oxobutane, azabutane, tetrahydro-2H-pyranyl, piperidinyl, tetrahydrofuranyl, morpholinyl, and pyrrolidinyl, etc. "3-8 membered heterocyclic group" has a similar definition.

[0155] Unless otherwise specified as "substituted or unsubstituted", the groups described in this invention may be substituted by substituents selected from the group consisting of: halogen, nitrile, nitro, hydroxyl, amino, C1-C6 alkyl-amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, halo-C1-C6 alkyl, halo-C2-C6 alkenyl, halo-C2-C6 alkoxy, allyl, benzyl, C6-C12 aryl, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 alkoxy-carbonyl, phenoxycarbonyl, C2-C6 alkynyl-carbonyl, C2-C6 alkenyl-carbonyl, C3-C6 cycloalkyl-carbonyl, C1-C6 alkyl-sulfonyl, etc.

[0156] As used herein, "halogen" or "halogen atom" refers to F, Cl, Br, and I. More preferably, the halogen or halogen atom is selected from F, Cl, and Br. "Halogenated" means substituted by an atom selected from F, Cl, Br, and I.

[0157] Unless otherwise specified, the structural formulas described in this invention are intended to include all isomers (such as enantiomers, diastereomers, and geometric isomers (or conformational isomers)): for example, R and S configurations containing an asymmetric center, (Z) and (E) isomers with double bonds, etc. Therefore, any single stereochemical isomer of the compounds of this invention, or a mixture of its enantiomers, diastereomers, or geometric isomers (or conformational isomers), is within the scope of this invention.

[0158] As used herein, the term "hydrate" refers to a complex formed by the coordination of the compound of the present invention with water.

[0159] The compounds of this application can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining specific embodiments with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of this application.

[0160] The solvents used in this application are commercially available. The abbreviations used in this application are as follows: aq represents aqueous solution; HATU represents O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate; EDCI represents N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA represents 3-chloroperoxybenzoic acid; eq represents equivalent; CDI represents carbonyl diimidazole; DCM represents dichloromethane; PE represents petroleum ether; DIAD represents diisopropyl azodicarboxylate; DMF represents N,N-dimethyl... Formamide; DMSO represents dimethyl sulfoxide; EtOAc represents ethyl acetate; EtOH represents ethanol; MeOH represents methanol; Cbz represents benzyloxycarbonyl, an amino protecting group; Boc represents tert-butyloxycarbonyl, an amino protecting group; HOAc represents acetic acid; NaCNBH3 represents sodium cyanoborohydride; rt represents room temperature; THF represents tetrahydrofuran; TFA represents trifluoroacetic acid; DIPEA represents diisopropylethylamine; Boc2O represents di-tert-butyldicarbonate; LDA represents lithium diisopropylamino.

[0161] Compounds artificially or Software naming conventions are used; commercially available compounds use supplier catalog names.

[0162] Prodrug compounds suitable for topical administration

[0163] This invention provides a prodrug molecule of a pharmaceutical compound, and its pharmaceutically acceptable salt, hydrate, or solvate, characterized in that the prodrug molecule is metabolized in vivo after administration to form a drug molecule G'; and the hydrophobicity coefficient of the drug molecule G' is CLogP < 3; and the prodrug molecule has the structure shown in formula (I):

[0164]

[0165] Wherein, G is a partial structural fragment formed by the loss of functional groups or H atoms in the drug molecule G', which is formed by any N, O, or S atom within the molecule interacting with... Connected.

[0166] In this invention, the form is as follows The lipophilic groups can effectively increase the transdermal efficiency of the compound, thereby enabling the preparation of a new compound that can be metabolized into the prototype compound molecule through topical administration. The drug molecule G' suitable for this prodrug molecule can have any structure, and in a preferred embodiment, the hydrophobicity coefficient CLogP of the drug molecule is <3.

[0167] Because these drug molecules possess both lipophilic and hydrophilic ends, they exhibit excellent membrane permeability, particularly improving transdermal delivery. Preferably, the drug molecules are those used for skin diseases, such as JAK inhibitors, MEK inhibitors, and BTK inhibitors.

[0168] The R mentioned 1 and R 2 Each is independently selected from the following group: H, D, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, or R. 1 and R 2 It forms a C3-C8 carbon ring or heterocycle with the carbon atoms attached to it;

[0169] L is selected from the following group: unsubstituted, substituted or unsubstituted C1-C6 alkylene groups, substituted or unsubstituted C1-C6 heteroalkylene groups;

[0170] R 3 Selected from the following group: substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C3-C20 cycloalkyl, substituted or unsubstituted C1-C20 heteroalkyl, substituted or unsubstituted 3-20 membered heterocyclic, substituted or unsubstituted C6-C14 aryl, or R 3 and R 1 or R 2These are linked together to form a substituted or unsubstituted 5-20 member lactone ring or heterolactone ring; wherein, the heterolactone ring refers to a lactone ring whose ring skeleton includes 1-3 heteroatoms selected from the group consisting of N, O, or S(O). p ;

[0171] p is selected from the following group: 0, 1, or 2;

[0172] Wherein, the heteroalkyl group refers to one or more carbon atoms in the carbon chain being substituted by heteroatoms selected from the group consisting of N, O, or S(O). p ;

[0173] The heterocyclic group comprises 1-3 heteroatoms selected from the group consisting of N, O, or S(O). p ;

[0174] Unless otherwise specified, “substitution” means being substituted by one or more (e.g., 2, 3, 4, etc.) substituents selected from the group consisting of: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyl, C3-C8 heterocyclic, oxo, -CN, hydroxyl, amino, carboxyl, amide, sulfonamide, sulfone, unsubstituted or substituted by one or more substituents selected from the group consisting of: C6-C10 aryl, halogenated C6-C10 aryl, 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S, and O, halogenated 5-10 membered heterocyclic having 1-3 heteroatoms selected from N, S, and O; and the substituents are selected from the group consisting of: halogen, C1-C6 alkyl, C1-C6 alkoxy, =O.

[0175] Pharmaceutical Compositions and Administration

[0176] Since the compounds of the present invention can be metabolized in vivo to form therapeutic active ingredients after topical administration, the compounds of the present invention and their various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used to prevent and / or treat (stabilize, alleviate or cure) various autoimmune and inflammatory-related diseases, including cancer, myeloproliferative disorders, inflammation, immune diseases, organ transplantation, viral diseases, cardiovascular diseases or metabolic diseases.

[0177] The pharmaceutical compositions of the present invention comprise the compound of the present invention within a safe and effective range and a pharmaceutically acceptable excipient or carrier. "Safe and effective range" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably, 1-200 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0178] "Pharmaceutically acceptable carriers" refer to one or more compatible solid or liquid fillers or gelling substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with and with the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as... Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0179] The prodrug compounds of the present invention can be readily formulated into pharmaceutical compositions comprising one or more of the compounds of the present invention and a pharmaceutical carrier. See Remington: The Science and Practice of Pharmacy, 19th edition (Easton, Pennsylvania, Mack Publishing Co., 1995), which discloses typical carriers and common methods for preparing pharmaceutical compositions, which can be used as described or modified to produce pharmaceutical preparations containing the compounds of the present invention. As previously mentioned, the compounds of the present invention can also be administered in the form of pharmaceutical salts, etc.

[0180] The compounds of the present invention can be in the form of pharmaceutical preparations containing commonly used nontoxic pharmaceutical carriers, excipients, and excipients, administered orally, parenterally, topically, rectally, nasally, sublingually, vaginally, or via an implanted reservoir. Preferably, the compounds of the present invention can be administered via skin or mucous membrane tissue using commonly used topical delivery systems, wherein the pharmaceutical preparation is contained in a multilayer structure fixed to the skin, functioning as a delivery device. In such a structure, the pharmaceutical composition is contained in a layer below 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 polymer matrix of a pharmaceutically adhesive bonding material, which serves to fix the system to the skin during administration. Suitable skin-adhesive bonding materials include, but are not limited to, polyethylene, polysiloxane, polyisobutylene, polyacrylate, polyurethane, etc. Alternatively, the drug-containing reservoir and the skin-pressing adhesive can exist as separate and distinct layers, in which case the adhesive is beneath the reservoir, which can be the aforementioned polymer matrix, a liquid or hydrogel reservoir, or other forms.

[0181] In these multilayer structures, the backing layer, serving as the upper surface of the device, acts as a key structural element, providing the device with considerable flexibility. The selected backing material should be substantially impermeable to active substances and any other substances present; the backing is preferably made of a soft, elastic sheet or film. Examples of suitable polymers for backing layers include polyethylene, polypropylene, and polyester.

[0182] The multi-layered structure includes a release liner during storage and before use. This liner is removed from the device immediately before use, exposing its underside, the drug reservoir, or a separate press-fit adhesive layer, allowing the system to be secured to the skin. The release liner should be made of a material that is impermeable to the drug / excipient.

[0183] External drug delivery devices can be fabricated using techniques commonly known in the art, such as casting a fluid mixture of adhesive, drug, and excipients onto a backing layer and then laminating a release layer. Similarly, an adhesive mixture can be cast onto a release layer and then laminated with a backing layer. Alternatively, a drug reservoir can be fabricated without the drug or excipients and then filled with a drug / excipient mixture by immersion.

[0184] Multilayered topical drug delivery systems may also contain skin penetration enhancers. That is, because the inherent permeability of the skin to certain drugs may be too low to allow therapeutic levels of the drug to pass through a considerable amount of unbroken skin, skin penetration enhancers need to be applied together with these drugs. Suitable enhancers are well known in the art and include, for example, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), N,N-dimethylacetamide (DMA), decylmethyl sulfoxide (C10MSO), C2-C6 alkyldiols, and 1-substituted azaheptan-2-ones and alcohols.

[0185] The compounds of this invention can be administered alone or in combination with other pharmaceutically acceptable therapeutic agents.

[0186] When administered in combination, the pharmaceutical composition further comprises one or more (two, three, four, or more) other pharmaceutically acceptable therapeutic agents. One or more (two, three, four, or more) of these other pharmaceutically acceptable therapeutic agents may be used simultaneously, separately, or sequentially with the compounds of the present invention for the prevention and / or treatment of cytokine and / or interferon-mediated diseases.

[0187] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to the mammal (such as a human) requiring treatment. The dosage administered is the pharmaceutically considered effective dose. For a person weighing 60 kg, the daily dose is typically 1–2000 mg, preferably 1–500 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the scope of the skill of a skilled physician.

[0188] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.

[0189] Example

[0190] Example 1

[0191]

[0192]

[0193] first step

[0194] Under nitrogen protection and at 0°C, methyl chloroformate (4.90 g, 38.00 mmol) was added to 50 mL of a dichloromethane solution containing compound 1a (4.00 g, 34.13 mmol) and pyridine (5.40 g, 68.26 mmol). After the addition was complete, the reaction solution was allowed to rise naturally to room temperature and the reaction continued for 4 hours. Upon completion of the reaction, the solution was concentrated under reduced pressure to obtain crude product 1c (12.00 g).

[0195] Step 2

[0196] Under nitrogen protection, 50 mL of N,N-dimethylformamide solution containing crude compound 1c (12.00 g, 34.13 mmol), compound 1d (5.00 g, 16.01 mmol), and potassium carbonate (6.60 g, 47.75 mmol) was reacted overnight at 60 °C. After the reaction was completed and cooled, the reaction solution was directly purified by reversed-phase column chromatography (acetonitrile:water = 0-100%) to give 1e (3.00 g), yield: 55%.

[0197] MS-ESI calculated value [M+H] + 343, measured value 343.

[0198] Step 3

[0199] Under nitrogen protection and at 0°C, octanoyl chloride (750 mg, 4.61 mmol) was added to a 30 mL solution of compound 1e (1.10 g, 3.21 mmol) and triethylamine (650 mg, 6.42 mmol) in dichloromethane. After the addition was complete, the reaction was continued for 0.5 hours. After the reaction was complete, the reaction solution was diluted with dichloromethane (30 mL), washed with water (50 mL x 1), 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), yield: 40%.

[0200] MS-ESI calculated value [M+H] + 469, measured value 469.

[0201] Step 4

[0202] Under nitrogen protection, ethyl hydrochloride solution (5M, 0.30 mL, 1.50 mmol) was slowly added dropwise to a 30 mL ethyl acetate solution of compound 1f (600 mg, 1.28 mmol). After the addition was complete, stirring was continued for 1 hour, and then the mixture was concentrated under reduced pressure while maintaining a temperature below 20 °C to obtain a solid. The solid was dissolved in a solution of acetonitrile (10 mL) and water (100 mL) and lyophilized to obtain 1 (620 mg), yield: 96%.

[0203] 1 H NMR(400MHz,DMSO-d6)δ8.29-8.26(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=7.6Hz,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).

[0204] MS-ESI calculated value [M+H] + 469, measured value 469.

[0205] Example 2

[0206]

[0207] first step

[0208] Compound 2 (500 mg) was synthesized from compound 1e via a two-step reaction, with a two-step yield of 39%.

[0209] 1 H NMR(400MHz,DMSO-d6)δ8.40-8.36(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).

[0210] MS-ESI calculated value [M+H] + 413, measured value 413.

[0211] Example 3

[0212]

[0213] Compound 3 (500 mg) was synthesized from compound 1e via a two-step reaction, with a two-step yield of 37%.

[0214] 1 H NMR(400MHz, DMSO-d6)δ8.38-8.34(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=7.6Hz,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).

[0215] MS-ESI calculated value [M+H] + 441, measured value 441.

[0216] Example 4

[0217]

[0218] Compound 4 (4.47 g) was synthesized from compound 1e via a two-step reaction, with a two-step yield of 64%.

[0219] 1 H NMR(400MHz,DMSO-d6)δ8.38-8.34(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=7.6Hz,1H),1.91-1.80(m,1H),1.62-1.57(m,1 H),1.46-1.44(m,2H),1.20-1.02(m,12H),0.84-0.80(m,3H),0.76-0.72(m,3H).

[0220] MS-ESI calculated value [M+H] + 497, measured value 497.

[0221] Example 5

[0222]

[0223] Compound 5 (815 mg) was synthesized from compound 1e via a two-step reaction according to the method described in Example 1, with a two-step yield of 42%.

[0224] 1 H NMR(400MHz,DMSO-d6)δ8.27-8.26(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=7.6Hz,2H),1.89-1.74(m,1H),1.5 9-1.45(m,3H),1.28-1.17(m,16H),1.04-1.01(m,3H),0.87-0.83(m,3H).

[0225] MS-ESI calculated value [M+H] + 525, measured value 525.

[0226] Example 6

[0227]

[0228] Compound 6 (510 mg) was synthesized from compound 1e via a two-step reaction, with a two-step yield of 35%.

[0229] 1 H NMR(400MHz,DMSO-d6)δ8.30-8.27(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=7.6Hz,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).

[0230] MS-ESI calculated value [M+H] + 581, measured value 581.

[0231] Example 7

[0232]

[0233]

[0234] Compound 7 (350 mg) was synthesized from compound 1e via a two-step reaction, with a two-step yield of 33%.

[0235] 1 H NMR(400MHz,DMSO-d6)δ8.37-8.37(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=7.6Hz,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).

[0236] MS-ESI calculated value [M+H] + 483, measured value 483.

[0237] Example 8

[0238]

[0239] Compound 8 (350 mg) was synthesized from compound 1e via a two-step reaction, with a two-step yield of 36%.

[0240] 1 H NMR(400MHz,DMSO-d6)δ8.38-8.34(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=7.2Hz,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).

[0241] MS-ESI calculated value [M+H] + 497, measured value 497.

[0242] Example 9

[0243]

[0244] first step

[0245] 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 reaction was carried out at 0 °C for 0.5 h, followed by the addition of 2-(trimethylsilyl)ethoxymethyl chloride (6.00 g, 36.18 mmol), and the mixture was allowed to rise naturally to room temperature for 1 h. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, 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 give compound 9b (5.10 g), yield: 55%.

[0246] 1 H NMR (400MHz, CDCl3) δ8.66(s,1H),7.39(d,J=3.6Hz,1H),6.66(d,J=3.6Hz,1 H),5.64(s,2H),3.52(t,J=8.4Hz,2H),0.90(t,J=8.4Hz,2H),-0.06(s,9H).

[0247] MS-ESI calculated value [M+H]+ 284, measured value 284.

[0248] Step 2

[0249] Compound 9b (2.00 g, 7.07 mmol) was added to dichloromethane (10 mL), followed by trifluoroacetic acid (8.80 g, 70.67 mmol). The reaction was carried out at room temperature for 16 hours. Water (50 mL) was added, followed by extraction with dichloromethane (50 mL x 3). The organic phases were combined, washed with saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 9c (1.20 g), yield: 92%.

[0250] 1 H NMR (400MHz, DMSO-d6) δ8.67(s,1H),7.79(d,J=3.6Hz,1H),6.68(d,J=3.6Hz,1H),5.63(s,2H).

[0251] MS-ESI calculated value [M+H] + 184, measured value 184.

[0252] Step 3

[0253] 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 sequentially added to dichloromethane (30 mL) and reacted at room temperature for 0.5 h. Then, 4-ethyloctanoic acid (1.19 g, 13.11 mmol) was added, and the reaction was continued at room temperature for 16 h. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, 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 give compound 9d (1.21 g), yield: 55%.

[0254] 1 H NMR (400MHz, CDCl3) δ8.70(s,1H),7.49(d,J=3.6Hz,1H),6.63(d,J=3.6Hz,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=5.4Hz,3H),0.78(t,J=7.2Hz,3H).

[0255] Step 4

[0256] 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 sequentially added to dimethyl sulfoxide (5 mL) and reacted at 100 °C for 16 hours. Water (50 mL) was added, followed by extraction with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (50 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 give compound 9f (0.35 g), yield: 66%.

[0257] 1 H NMR (400MHz, CDCl3) δ8.35 (s, 1H), 7.41-7.30 (m, 5H), 7.13 (d, J = 3.6Hz, 1H), 6.3 8(d,J=3.6Hz,1H),6.14(s,2H),5.23-5.10(m,2H),4.58-4.45(m,2H),2.79-2.6 7(m,1H),2.30(t,J=8.0Hz,2H),2.00-1.83(m,4H),1.66(d,J=10.8Hz,2H),1.58 -1.53(m,2H),1.27-1.17(m,12H),0.85(t,J=6.8Hz,3H),0.79(t,J=7.2Hz,3H).

[0258] Step 5

[0259] Compound 9f (0.35 g, 0.64 mmol) was added to tetrahydrofuran (5 mL), followed by the addition of 10% wetted palladium on carbon (0.15 g). The mixture was purged three times with a hydrogen balloon 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%.

[0260] 1 H NMR(400MHz, CDCl3)δ8.38(s,1H),7.14(d,J=3.6Hz,1H),6.44(d,J=3.6Hz ,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),1.26-1.1 6(m,9H),1.10(d,J=6.0,3H),0.85(t,J=6.8Hz,3H),0.79(t,J=7.2Hz,3H).

[0261] MS-ESI calculated value [M+H] + 416, measured value 416.

[0262] Step 6

[0263] Compound 9 (0.22 g, 0.52 mmol) was added to tetrahydrofuran (10 mL), followed by 0.52 N sodium bicarbonate aqueous solution (5 mL). The mixture was cooled to 0 °C, and acryloyl chloride (0.06 g, 0.62 mmol) was added dropwise. The mixture was allowed to return to room temperature naturally for 2 hours. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (50 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 give compound 9 (0.21 g), yield: 87%.

[0264] 1 H NMR (500MHz, DMSO-d6) δ8.20 (s, 1H), 7.36 (d, J = 7.5Hz, 1H), 7.23 (d, J = 4.0Hz, 1H), 6.75 (dd, J = 16. 5,10.5Hz,1H),6.66(d,J=4.0Hz,1H),6.11(s,2H),6.07(dd,J=16.5,2.5Hz,1H),5.65(dd,J=10.5 ,2.5Hz,1H),4.86-4.15(m,2H),4.11-4.02(m,1H),2.97-2.60(m,1H),2.27(t,J=7.5Hz,2H),1.89 -1.65(m,4H),1.49-1.43(m,2H),1.22-1.13(m,12H),0.83(t,J=7.0Hz,3H),0.75(t,J=7.5Hz,3H).

[0265] MS-ESI calculated value [M+H] + 470, measured value 470.

[0266] Example 10

[0267]

[0268] first step

[0269] Compound 10a (48 mg, 0.16 mmol) and N,N-diisopropylethylamine (30 mg, 0.24 mmol) were added sequentially to dichloromethane (3 mL), stirred at room temperature for 5 minutes, and then 2-(trimethylsilyl)ethoxymethyl chloride (39 mg, 0.24 mmol) was added. The reaction was carried out at room temperature for 3 hours. The residue was concentrated under reduced pressure and purified by column chromatography (ethyl acetate: petroleum ether = 0-100%) to give compound 10b (62 mg), yield: 91%.

[0270] 1 H NMR (500MHz, DMSO-d6) δ8.82(d,J=0.8Hz,1H),8.75(s,1H),8.39(s,1H),7.77(d,J=3.5Hz,1H),7.09(d,J=3.5Hz,1H),5.63(s,2H),4.54 (td,J=9.5,4.0Hz,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=8.5Hz,2H),-0.10(s,9H).

[0271] MS-ESI calculated value [M+H] + 437, measured value 437.

[0272] Step 2

[0273] Compound 10b (58 mg, 0.13 mmol) was added to dichloromethane (2 mL), followed by trifluoroacetic acid (379 mg, 3.33 mmol). The reaction was carried out at room temperature for 6 hours. Saturated sodium bicarbonate aqueous solution (20 mL) was added, followed by extraction with dichloromethane (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 10c (48 mg), yield: 99%.

[0274] Step 3

[0275] 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 sequentially added to dichloromethane (3 mL), and the reaction was carried out at room temperature for 0.5 h. Then, 4-ethyloctanoic acid (37 mg, 0.21 mmol) was added, and the reaction was carried out at room temperature for 2 h. The residue was concentrated under reduced pressure and purified by column chromatography (ethyl acetate: petroleum ether = 0-100%) to give compound 10 (37 mg), yield: 71%.

[0276] 1H NMR (400MHz, CDCl3) δ8.89(s,1H),8.34(s,1H),8.30(s,1H),7.49(d,J=3.6Hz,1H ),6.77(d,J=3.6Hz,1H),6.25(s,2H),4.27(td,J=9.4,3.2Hz,1H),3.18-3.07(m,1 H),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=7.0Hz,3H),0.78(t,J=7.2Hz,3H).

[0277] MS-ESI calculated value [M+H] + 491, measured value 491.

[0278] Example 11

[0279]

[0280] first step

[0281] Under nitrogen protection, compound 11a (0.99 g, 4.40 mmol) was added to methanol (10 mL), cooled to 0 °C, and sodium borohydride (0.20 g, 5.29 mmol) was added. The mixture was allowed to return to room temperature naturally for 1 hour. A saturated aqueous sodium chloride solution (50 mL) was added, followed by extraction with dichloromethane (50 mL x 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%.

[0282] 1 H NMR (400MHz, CDCl3) δ4.30 (p, J = 6.4Hz, 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).

[0283] Step 2

[0284] Under nitrogen protection, compound 11b (0.80 g, 3.52 mmol) was added to dichloromethane (3 mL), followed by N,N-diisopropylethylamine (0.91 g, 7.05 mmol) and methanesulfonic anhydride (1.23 g, 7.05 mmol). The reaction was carried out at room temperature for 3 hours. Water (25 mL) was added, and the mixture was extracted with ethyl acetate (25 mL x 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution (50 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 11c (0.90 g), yield: 84%.

[0285] 1 H NMR (400MHz, CDCl3) δ5.11 (p, J = 6.0Hz, 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).

[0286] Step 3

[0287] In a Schlenk tube, compound 11c (0.90 g, 2.95 mmol) was added to 10 mL of 30% methylamine methanol solution and reacted at 80 °C under sealed conditions for 7 hours. After cooling to room temperature, water (100 mL) was added, followed by extraction with ethyl acetate (100 mL x 3). The organic phases were combined, washed with 50 mL x 1 saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (dichloromethane:methanol = 0-100%) to give compound 11d (0.68 g), yield: 86%.

[0288] 1 H NMR (400MHz, CDCl3) δ3.53-3.48(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).

[0289] Step 4

[0290] In a microwave-safe tube, compounds 11d (0.68 g, 2.01 mmol), 9d (0.54 g, 2.01 mmol), and N,N-diisopropylethylamine (0.52 g, 4.03 mmol) were sequentially added to N-methylpyrrolidone (8 mL), and the mixture was microwaved at 150 °C for 3 hours. Water (50 mL) was added, followed by extraction with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution (50 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 give compound 11e (0.65 g), yield: 60%.

[0291] 1 H NMR (400MHz, CDCl3) δ8.36(s,1H),7.13(d,J=4.0Hz,1H),6.52(d,J=4.0Hz,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=6.8Hz,3H),0.79(t,J=7.2Hz,3H).

[0292] MS-ESI calculated value [M+1] + 542, measured value 542.

[0293] Step 5

[0294] Compound 11e (0.65 g, 1.20 mmol) was added to dichloromethane (20 mL), followed by trifluoroacetic acid (2.74 g, 24.03 mmol). The reaction was carried out at room temperature for 3 hours. The mixture was concentrated under reduced pressure to give compound 11f (0.80 g), yield: 99%.

[0295] MS-ESI calculated value [M+H] + 442, measured value 442.

[0296] Step 6

[0297] 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 sequentially added to tetrahydrofuran (10 mL). The mixture was reacted at 70 °C for 5 h. Water (50 mL) was added, followed by extraction with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution (50 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 give compound 11 (0.56 g), yield: 79%.

[0298] 1 H NMR (400MHz, DMSO-d6) δ11.58(s,1H),8.17(s,1H),7.23(d,J=4.0Hz,1H),6.64(d,J=4.0 Hz,1H),6.09(s,2H),5.44(p,J=9.0Hz,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=7.6Hz,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=7.2Hz,3H),0.73(t,J=7.2Hz,3H).

[0299] MS-ESI calculated value [M+H] + 599, measured value 599.

[0300] Example 12

[0301]

[0302]

[0303] first step

[0304] 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 sequentially added to dimethyl sulfoxide (6 mL), and reacted at 100 °C for 7 hours. Water (50 mL) was added, followed by extraction with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution (50 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 give compound 12b (420 mg), yield: 94%.

[0305] 1 H NMR (400MHz, DMSO-d6) δ8.19 (s, 1H), 7.63 (d, J = 8.0Hz, 1H), 7.41-7.31 (m, 5H), 7 .30(d,J=4.0Hz,1H),6.75(d,J=4.0Hz,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=7.0Hz,3H),0.73(t,J=7.0Hz,3H).

[0306] MS-ESI calculated value [M+H] + 536, measured value 536.

[0307] Step 2

[0308] Compound 12b (0.42 g, 0.79 mmol) was added to tetrahydrofuran (12 mL), followed by the addition of 10% wetted palladium on carbon (0.20 g). The mixture was purged three times with hydrogen balloons 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 obtain the residue. The residue was purified by column chromatography (ethyl acetate: petroleum ether = 0-100%) to give compound 12c (0.30 g), yield: 95%.

[0309] 1H NMR (400MHz, DMSO-d6) δ8.17(s,1H),7.29(d,J=4.0Hz,1H),6.71(d,J=4.0Hz,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=7.6Hz,2H),2.03-1.93(m,2H),1.46-1.40 (m,2H),1.19-1.06(m,9H),0.80(t,J=7.0Hz,3H),0.73(t,J=7.2Hz,3H).

[0310] MS-ESI calculated value [M+H] + 402, measured value 402.

[0311] Step 3

[0312] Under nitrogen protection, compound 12c (298 mg, 0.74 mmol) was added to dichloromethane (10 mL), the mixture was cooled to 0 °C, triethylamine (150 mg, 14.9 mmol) was added, followed by dropwise addition of propylsulfonyl chloride (127 mg, 0.89 mmol). The mixture was allowed to return to room temperature naturally for 2 hours. The residue was concentrated under reduced pressure and purified by column chromatography (ethyl acetate: petroleum ether = 0-100%) to give compound 12 (260 mg), yield: 69%.

[0313] 1 H NMR (500MHz, DMSO-d6) δ8.19(s,1H),7.50(d,J=9.0Hz,1H),7.31(d,J=4.0Hz,1H),6.76( d,J=4.0Hz,1H),6.11(s,2H),4.88(p,J=9.5Hz,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=7.5Hz,3H),0.80(t,J=7.0Hz,3H),0.73(t,J=7.5Hz,3H).

[0314] MS-ESI calculated value [M+H] + 508, measured value 508.

[0315] Example 13

[0316]

[0317] first step

[0318] 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 reacted at room temperature for 2 hours, then cooled to 0 °C, and 1.3 mL of 28% ammonia solution was added dropwise. The mixture was allowed to return to room temperature naturally for 1 hour. Dichloromethane (50 mL) was added, the mixture was filtered, washed with water (50 mL), and the filter cake was collected and dried under vacuum to give compound 13b (0.77 g), yield: 90%.

[0319] 1 H NMR (400MHz, DMSO-d6) δ12.10(s,1H),8.29(s,1H),7.89(s,1H),7.64(d,J=3.6Hz,1H),7.62(s,1H),6.56(d,J=3.6Hz,1H).

[0320] MS-ESI calculated value [M+H] + 196, measured value 196.

[0321] Step 2

[0322] 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), followed by dropwise addition of 2-(trimethylsilyl)ethoxymethyl chloride (0.92 g, 5.52 mmol). The reaction was carried out at room temperature for 1 hour. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution (50 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 give compound 13c (1.12 g), yield: 93%.

[0323] 1 H NMR(500MHz,DMSO-d6)δ8.35(s,1H),7.96(s,1H),7.83(d,J=3.6Hz,1H),7.70(s,1H),6.66 (d,J=3.6Hz,1H),5.64(s,2H),3.51(t,J=6.4Hz,2H),0.82(t,J=6.4Hz,2H),-0.09(s,9H).

[0324] MS-ESI calculated value [M+H] +326, measured value 326.

[0325] Step 3

[0326] Compound 13c (1.12 g, 3.45 mmol) was added to dichloromethane (20 mL), followed by trifluoroacetic acid (7.86 g, 68.92 mmol). The reaction was carried out at room temperature for 20 hours. The mixture was concentrated under reduced pressure to give compound 13d (1.80 g), in 95% yield.

[0327] 1 H NMR (400MHz, DMSO-d6) δ8.35(s,1H),7.94(s,1H),7.75(d,J=3.6Hz,1H),7.67(s,1H),6.62(d,J=3.6Hz,1H),5.63(s,2H).

[0328] MS-ESI calculated value [M+H] + 226, measured value 226.

[0329] Step 4

[0330] 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 sequentially added to dichloromethane (30 mL), and the mixture was stirred at room temperature for 10 minutes. Then, 13d (1.60 g, 2.80 mmol) was added, and the mixture was reacted at room temperature for 2 hours. The residue was concentrated under reduced pressure and purified by column chromatography (ethyl acetate: petroleum ether = 0-100%) to give compound 13e (750 mg), yield: 75%.

[0331] 1 H NMR (400MHz, DMSO-d6) δ8.38(s,1H),7.96(s,1H),7.79(d,J=3.6Hz,1H),7.73-7.69(m,1H),6.68(d,J=3.6Hz,1H),6. 25(s,2H),2.27(t,J=7.6Hz,2H),1.47-1.39(m,2H),1.25-1.10(m,9H),0.81(t,J=7.0Hz,3H),0.72(t,J=7.2Hz,3H).

[0332] MS-ESI calculated value [M+H] + 380, measured value 380.

[0333] Step 5

[0334] In a microwave-safe tube, 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 sequentially added to N-methylpyrrolidone (15 mL), and the mixture was microwaved at 150 °C for 1 hour. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution (200 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 give compound 13 (0.35 g), yield: 47%.

[0335] 1 H NMR (400MHz, DMSO-d6) δ10.11(d,J=8.0Hz,1H),8.43(s,1H),7.88(s,1H),7.29(d,J=3.6H z,1H),7.12(s,1H),6.49(d,J=3.6Hz,1H),6.20-6.05(m,2H),4.50(s,1H),4.10(d,J=8.0 Hz,1H),2.25(t,J=7.6Hz,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=7.0Hz,3H),0.72(t,J=7.2Hz,3H).

[0336] MS-ESI calculated value [M+H] + 511, measured value 511.

[0337] Example 14

[0338]

[0339]

[0340] first step

[0341] 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 in a single batch. The reaction was carried out at 0 °C for 0.5 h. 2-(trimethylsilyl)ethoxymethyl chloride (1.01 g, 6.06 mmol) was added dropwise, and the mixture was allowed to rise naturally to room temperature for 3 h. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, 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 give compound 14b (1.60 g), yield: 96%.

[0342] 1 H NMR (400MHz, DMSO-d6) δ8.45(s,1H),8.15(d,J=3.6Hz,1H),6.74(d,J=3.6Hz,1H),5.62(s,2H),3.55–3.45(m,2H),0.82–0.78(m,2H),-0.11(s,9H).

[0343] Step 2

[0344] 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(diphenylphosphine)-9,9-dimethyloxanthracene (0.53 g, 0.91 mmol), and palladium acetate (0.10 g, 0.46 mmol) were sequentially added to dioxane (30 mL), and the reaction was carried out at 115 °C for 3 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was collected and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (ethyl acetate: petroleum ether = 0-100%) to give compound 14c (0.90 g), yield: 58%.

[0345] 1 H NMR (400MHz, DMSO-d6) δ10.17(s,1H),8.74(s,1H),7.97(d,J=3.6Hz,1H),6.56(d,J=3.6Hz,1H),5.59(s,2 H), 4.16 (q, J = 6.4Hz, 2H), 3.50 (t, J = 8.0Hz, 2H), 1.25 (t, J = 7.2Hz, 3H), 0.81 (d, J = 8.0, 2H), -0.11 (s, 9H).

[0346] Step 3

[0347] Under nitrogen protection, compound 14c (900 mg, 2.68 mmol) was added to N,N-dimethylacetamide (10 mL), cooled to 0 °C, and lithium tert-butoxide (214 mg, 2.68 mmol) was added. The reaction was carried out at 0 °C for 30 minutes, then cooled to -10 °C, and a solution of (3R,4S)-3-(2-bromoacetyl)-4-ethylpyrrolidine-1-carboxylic acid benzyl ester (948 mg, 2.68 mmol) dissolved in N,N-dimethylacetamide (5 mL) was added dropwise. The reaction was carried out at -10 °C for 30 minutes. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, 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 give compound 14d (1.20 g), yield: 75%.

[0348] 1 H NMR(400MHz,DMSO-d6)δ8.61(s,1H),7.99(dd,J=6.4,3.6Hz,1H),7.36–7.29(m,5H ),6.52(dd,J=30.4,3.6Hz,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=8.0Hz,2H),-0.11(s,9H).

[0349] MS-ESI calculated value [M+H] + 610, measured value 610.

[0350] Step 4

[0351] 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 sequentially added to acetonitrile (20 mL), and the reaction was carried out at 75 °C for 2 hours. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, 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 give compound 14e (0.61 g), yield: 65%.

[0352] 1H NMR (400MHz, DMSO-d6) δ8.66(s,1H),7.67(d,J=3.6Hz,1H),7.61(d,J=4.8Hz,1H) ,7.41–7.31(m,5H),7.09(t,J=4.0Hz,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=8.0Hz,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).

[0353] MS-ESI calculated value [M+H] + 520, measured value 520.

[0354] Step 5

[0355] Compound 14e (560 mg, 1.08 mmol) was added to dichloromethane (20 mL), followed by trifluoroacetic acid (4 mL). The reaction was carried out at room temperature for 20 hours. The mixture was concentrated under reduced pressure to give compound 14f (660 mg), yield: 99%.

[0356] MS-ESI calculated value [M+H] + 420, measured value 420.

[0357] Step 6

[0358] 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 sequentially added to dichloromethane (20 mL), stirred at room temperature for 10 minutes, and then 14f (660 mg, 1.08 mmol) was added. The reaction was carried out at room temperature for 2 hours. The residue was concentrated under reduced pressure and purified by column chromatography (ethyl acetate: petroleum ether = 0-100%) to give 14 g (502 mg) of the compound, yield: 81%.

[0359] 1H NMR(400MHz, DMSO-d6)δ8.69(s,1H),7.65–7.62(m,2H),7.42–7.31(m,5H),7.13(t,J= 4.0Hz,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=7.6Hz,2H),1.42(q,J=6.8Hz,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).

[0360] MS-ESI calculated value [M+H] + 574, measured value 574.

[0361] Step 7

[0362] 14 g (502 mg, 0.88 mmol) of compound was added to tetrahydrofuran (20 mL), followed by the addition of 10% wet Pd / C (500 mg). The mixture was purged three times with a hydrogen balloon 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 obtain the residue. The residue was purified by column chromatography (ethyl acetate: petroleum ether = 0-100%) to give compound 14 h (213 mg), yield: 55%.

[0363] 1 H NMR (400MHz, DMSO-d6) δ8.72 (s, 1H), 7.87 (s, 1H), 7.68 (d, J = 3.6Hz, 1H), 7.14 (d,J=3.6Hz,1H),6.31(s,2H),4.37(q,J=7.6Hz,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=7.6Hz,2H),1.45(q,J=6.4Hz,2H),1.16 –1.00(m,9H),0.96–0.85(m,2H),0.77(q,J=7.2Hz,3H),0.70(q,J=7.2Hz,3H),0.62(t,J=7.2Hz,3H).

[0364] MS-ESI calculated value [M+H] + 440, measured value 440.

[0365] Step 8

[0366] Under nitrogen protection, N,N-carbazide (116 mg, 0.70 mmol), triethylamine (70 mg, 0.70 mmol), and trifluoroethylamine (58 mg, 0.58 mmol) were sequentially added to dichloromethane (3 mL), and the reaction was carried out at room temperature for 30 minutes. Then, a solution of compound 14h (170 mg, 0.39 mmol) dissolved in dichloromethane (2 mL) was added dropwise, and the reaction was carried out at room temperature for 3 hours. The residue was concentrated under reduced pressure and purified by column chromatography (ethyl acetate: petroleum ether = 0-100%) to give compound 14 (182 mg), yield: 83%.

[0367] 1 H NMR (400MHz, DMSO-d6) δ8.69(s,1H),7.63(d,J=3.6Hz,1H),7.53(s,1H),7.15(d,J=3.6Hz,1H),6.97(t,J=6.4Hz,1H),6.29(s,2H),4.34(q,J=6.4Hz ,1H),3.88–3.66(m,5H),3.28–3.24(m,1H),2.58–2.54(m,1H),2.29(t,J= 7.6Hz, 2H), 1.43 (q, J = 6.4Hz, 2H), 1.14–1.03 (m, 9H), 0.86–0.61 (m, 11H).

[0368] MS-ESI calculated value [M+H] + 565, measured value 565.

[0369] Example 15

[0370]

[0371] first step

[0372] Under nitrogen protection, compound 15a (0.45 g, 2.15 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (1.23 g, 3.23 mmol), N,N-diisopropylethylamine (0.82 g, 6.45 mmol), and 4-oxopiperidone hydrochloride (0.44 g, 3.23 mmol) were sequentially added to N,N-dimethylacetamide (5 mL), and the reaction was carried out at room temperature for 1 hour. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (50 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 give compound 15b (0.60 g), yield: 96%.

[0373] 1 H NMR (400MHz, DMSO-d6) δ8.71(d,J=4.8Hz,1H),8.01(t,J=4.8Hz,1H),3.94(s,2H),3.58(t,J=6.4Hz,2H),2.55–2.52(m,2H),2.38–2.36(m,2H).

[0374] MS-ESI calculated value [M+H] + 291, measured value 291.

[0375] Step 2

[0376] Under nitrogen protection, compound 15c (1.00 g, 3.17 mmol) and tert-butyl 3-(cyanomethylene)azabutane-1-carboxylic acid (0.74 g, 3.80 mmol) were sequentially added to acetonitrile (20 mL), followed by dropwise addition of 1,8-diazabicyclo[5.4.0]undec-7-ene (0.58 g, 3.80 mmol). The reaction was carried out at room temperature for 3 hours. The residue was concentrated under reduced pressure and purified by column chromatography (ethyl acetate: petroleum ether = 0-100%) to give compound 15d (1.38 g), yield: 86%.

[0377] 1 H NMR (400MHz, DMSO-d6) δ8.93(s,1H),8.78(s,1H),8.47(s,1H),7.80(d,J=4.0Hz,1H),7.20(d,J=3.6Hz,1H),5.64(s,2H),4.51 (d,J=9.6Hz,2H),4.22(d,J=9.6Hz,2H),3.67(s,2H),3.53(t,J=7.6Hz,2H),1.41(s,9H),0.82(d,J=8.0Hz,2H),-0.11(s,9H).

[0378] MS-ESI calculated value [M+H] + 510, measured value 510.

[0379] Step 3

[0380] Compound 15d (1.38 g, 2.71 mmol) was dissolved in a solution of dioxane (4.02 M, 20 mL) of hydrogen chloride and reacted at room temperature for 1 hour. The solution was concentrated under reduced pressure to give compound 15e (1.30 g), yield: 99%.

[0381] 1H NMR (400MHz, DMSO-d6) δ10.06(s,1H),9.83(s,1H),9.32(s,1H),8.95(s,1H),8.75(s,1H),8.03(d,J=4.0Hz,1H),7.44(d,J=4.0Hz ,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=7.6Hz,2H),0.84(t,J=8.0Hz,2H),-0.09(s,9H).

[0382] MS-ESI calculated value [M+H] + 410, measured value 410.

[0383] Step 4

[0384] 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 sequentially added to dichloromethane (5 mL) and reacted at room temperature for 5 minutes. Sodium triacetoxyborohydride (83 mg, 0.39 mmol) was then added, and the reaction was continued at room temperature for 1 hour. The mixture was extracted with saturated sodium bicarbonate aqueous solution (25 mL) and ethyl acetate (25 mL x 3). The organic phases were combined, washed with saturated brine (25 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 give compound 15f (100 mg), yield: 56%.

[0385] 1 H NMR(400MHz,DMSO-d6)δ8.85(s,1H),8.77(s,1H),8.67(d,J=4.8Hz,1H),8.44(s,1H) ,7.91(t,J=4.8Hz,1H),7.80(d,J=3.6Hz,1H),7.18(d,J=3.6Hz,1H),5.64(s,2H),4.1 2–4.07(m,1H),3.76(d,J=8.0Hz,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=8.0Hz,2H),-0.11(s,9H).

[0386] MS-ESI calculated value [M+H] + 684, measured value 684.

[0387] Step 5

[0388] Compound 15f (95 mg, 0.14 mmol) was added to dichloromethane (5 mL), followed by trifluoroacetic acid (1 mL), and the reaction was carried out at room temperature for 24 hours. The mixture was concentrated under reduced pressure to give compound 15 g (115 mg), yield: 99%.

[0389] MS-ESI calculated value [M+H] + 584, measured value 584.

[0390] Step 6

[0391] 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 sequentially added to dichloromethane (5 mL), stirred at room temperature for 10 minutes, and then 15 g (660 mg, 1.08 mmol) was added, and the reaction was carried out at room temperature for 1 hour. The residue was concentrated under reduced pressure and purified by column chromatography (ethyl acetate: petroleum ether = 0-100%) to give compound 15 (65 mg), yield: 73%.

[0392] 1 H NMR (400MHz, DMSO-d6) δ8.86(s,1H),8.80(s,1H),8.67(d,J=4.4Hz,1H),8.45(s,1H),7.91(t,J=4.8Hz,1H), 7.75(d,J=3.6Hz,1H),7.20(d,J=3.6Hz,1H),6.24(s,2H),4.10–4.07(m,1H),3.75(d,J=8.0Hz,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=7.6Hz,1H) ,1.80–1.58(m,2H),1.44(q,J=4.8Hz,2H),1.23–1.09(m,11H),0.77(t,J=7.0Hz,3H),0.70(t,J=7.2Hz,3H).

[0393] MS-ESI calculated value [M+H] + 738, measured value 738.

[0394] Example 16

[0395]

[0396] first step

[0397] 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 sequentially added to isopropanol (30 mL), and the reaction was carried out at 100 °C for 8 hours. After returning to room temperature, the mixture was concentrated under reduced pressure to obtain the residue, which was purified by column chromatography (methanol:dichloromethane = 0-100%) to give compound 16b (1.50 g), yield: 79%.

[0398] 1 H NMR (400MHz, DMSO-d6) δ12.51(s,1H),7.98(s,1H),7.94(d,J=6.0Hz,1H),6.60(d,J= 6.0Hz,1H),2.03–1.93(m,1H),1.89–1.80(m,1H),1.44(s,3H),0.82(t,J=7.4Hz,3H).

[0399] MS-ESI calculated value [M+H] + 230, measured value 230.

[0400] Step 2

[0401] 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 sequentially added to N,N-dimethylformamide (30 mL). The mixture was cooled to 0 °C, and 50% propylphosphonic anhydride (50% w / w, ethyl acetate solution, 4.20 g, 6.55 mmol) was added dropwise. The mixture was allowed to return to room temperature naturally for 17 hours. Water (100 mL) was added, followed by extraction with ethyl acetate (100 mL x 3). The organic phases were combined, 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 give compound 16c (0.50 g), yield: 37%.

[0402] 1 H NMR(400MHz, DMSO-d6)δ8.23(s,1H),7.95(d,J=4.8Hz,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=7.6Hz,3H).

[0403] MS-ESI calculated value [M+H] + 311, measured value 311.

[0404] Step 3

[0405] Under nitrogen protection, compound 16d (1.00 g, 5.07 mmol) and N,N-diisopropylethylamine (0.98 g, 7.61 mmol) were added sequentially to dichloromethane (20 mL), followed by dropwise addition of 2-(trimethylsilyl)ethoxymethyl chloride (1.26 g, 7.61 mmol). The reaction was carried out at room temperature for 3 hours. The residue was concentrated under reduced pressure and purified by column chromatography (ethyl acetate: petroleum ether = 0-100%) to give compound 16e (1.30 g), yield: 77%.

[0406] 1 H NMR(400MHz,DMSO-d6)δ8.36(dd,J=4.8,1.6Hz,1H),7.92(s,1H),7.89(dd,J=8.0,1.6Hz,1H),7.2 6(dd,J=8.0,4.8Hz,1H),5.62(s,2H),3.50(t,J=8.0Hz,2H),0.80(t,J=8.0Hz,2H),-0.12(s,9H).

[0407] MS-ESI calculated value [M+H] + 327, measured value 327.

[0408] Step 4

[0409] Under nitrogen protection, compound 16e (1.05 g, 3.22 mmol), bis-pinacol borate (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 sequentially added to dioxane (20 mL), and the reaction was carried out at 100 °C for 2 hours. After returning to room temperature, the mixture was filtered through diatomaceous earth, and the filtrate was collected and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (ethyl acetate: petroleum ether = 0-100%) to give compound 16f (0.80 g), yield: 67%.

[0410] 1H NMR (400MHz, DMSO-d6) δ8.29(dd,J=4.8,1.6Hz,1H),8.11(dd,J=8.0,1.6Hz,1H),7.98(s,1H),7.20(dd,J =8.0,4.8Hz,1H),5.63(s,2H),3.51(t,J=8.0Hz,2H),1.31(s,12H),0.80(t,J=8.0Hz,2H),-0.11(s,9H).

[0411] MS-ESI calculated value [M+H] + 375, measured value 375.

[0412] Step 5

[0413] 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 sequentially added to a mixed solution of dioxane (20 mL) and water (4 mL). The reaction was carried out at 100 °C for 2 hours. After returning to room temperature, the mixture was filtered through diatomaceous earth, and the filtrate was collected and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (ethyl acetate: petroleum ether = 0-100%) to give compound 16 g (230 mg), yield: 24%.

[0414] 1 H NMR (400MHz, DMSO-d6) δ8.75(d,J=8.0Hz,1H),8.31–8.30(m,2H),8.19(s,1H),8.14(d,J=5.6Hz,1H),7.36(s,1H),7.22(dd,J=8.0,4.8Hz,1H),6.44 (s,1H),5.68(s,2H),3.87–3.66(m,2H),3.53(t,J=8.0Hz,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).

[0415] MS-ESI calculated value [M+H] + 523, measured value 523.

[0416] Step 6

[0417] 16 g (220 mg, 0.42 mmol) of compound was added to 20 mL of dichloromethane, followed by 4 mL of trifluoroacetic acid. The reaction was carried out at room temperature for 16 hours. The mixture was concentrated under reduced pressure to give compound 16h (290 mg), yield: 99%.

[0418] MS-ESI calculated value [M+H] + 423, measured value 423.

[0419] Step 7

[0420] 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 sequentially added to dichloromethane (15 mL), stirred at room temperature for 10 min, and then added for 16 h (290 mg, 0.45 mmol), reacting at room temperature for 2 h. The residue was concentrated under reduced pressure and purified by column chromatography (ethyl acetate: petroleum ether = 0-100%) to give compound 16 (139 mg), yield: 53%.

[0421] 1 H NMR(400MHz,DMSO-d6)δ8.76(d,J=8.0Hz,1H),8.33(dd,J=4.8,1.6Hz,1H),8.30(s,1H ),8.23(s,1H),8.14(d,J=5.6Hz,1H),7.42(s,1H),7.26(dd,J=8.0,4.8Hz,1H),6.46(s ,1H),6.28(s,2H),3.91–3.67(m,2H),2.27(t,J=7.6Hz,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=7.2Hz,3H).

[0422] MS-ESI calculated value [M+H] + 577, measured value 577.

[0423] Example 17 Skin-Pampa Analysis Method

[0424] 1. Hydrate the Skin-Pampa membrane overnight with a hydration solution.

[0425] 2. Dissolve each API in DMSO to prepare 0.5 mL of a 20 mM stock solution. Add 50 μL of the stock solution to the corresponding 5 mL supply solution and mix thoroughly.

[0426] 3. Add 200 μL of supply solution to the receiving well and 200 μL of sample to the supply well. Each sample is placed in 12 parallel wells for incubation.

[0427] 4. After incubation for 7 hours, take 100 μL of sample from each feed well and 100 μL of sample from each receiver well, dilute each with 200 μL of 50% acetonitrile, vortex mix and centrifuge, and take 200 μL of supernatant for HPLC content detection.

[0428] 5. Calculate the Skin-Pampa parameter using the following formula.

[0429]

[0430]

[0431] Pe – Effective permeability coefficient

[0432] V A – Receiver orifice volume (ml);

[0433] V D – Supply orifice volume (ml);

[0434] A – Membrane area (cm²) 2 );

[0435] t – incubation time (s);

[0436] t LAG – Membrane equilibrium time (s);

[0437] C D (t) – Concentration supplied to the orifice at time t;

[0438] C A (t) – Concentration at the receiving orifice at time t;

[0439] C D (0) – Initial concentration at the supply orifice.

[0440] Table 6. Summary of Skin-Pampa Test Results

[0441]

[0442] Conclusion: The compounds synthesized in this invention exhibit excellent transdermal properties in rat transdermal experiments and are suitable for the preparation of topical formulations.

[0443] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A prodrug molecule of a pharmaceutical compound G' or a pharmaceutically acceptable salt thereof, characterized in that, The hydrophobicity coefficient of the drug molecule G' is CLogP < 4; and the prodrug molecule has the structure shown in formula (I): Wherein, G is a partial structural fragment formed by the loss of H atoms in the drug molecule G', which is formed by any N atom within the molecule interacting with... Connected; The G group is selected from the following group: The R mentioned 1 and R 2 Each is independently selected from the following group: H, D, substituted or unsubstituted C1-C6 alkyl groups; L is selected from the following group: unsubstituted, substituted or unsubstituted C1-C6 alkylene groups; R 3 Selected from the group consisting of substituted or unsubstituted C5-C20 alkyl groups; Unless otherwise specified, "substitution" means being replaced by one or more substituents selected from the group consisting of: deuterium atom, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, and C3-C8 cycloalkyl.

2. The prodrug molecule or its pharmaceutically acceptable salt as described in claim 1, characterized in that, The compound of formula (I) has the structure shown in the following formula:

3. A prodrug molecule as described in claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, The compound of formula (I) has a structure selected from the group consisting of:

4. A prodrug molecule as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The compound of formula (I) has a structure selected from the group consisting of:

5. A method for preparing the prodrug molecule of claim 1, characterized in that, Including the following steps: In an inert solvent, the compound of formula 2e is reacted with R. 3 The -LC(O)X reaction yields compound (I); X is OH or an activating group; the definitions of the remaining groups are as described in claim 1.

6. A pharmaceutical composition, characterized in that, It contains a pharmaceutically acceptable carrier and a prodrug molecule or a pharmaceutically acceptable salt thereof as described in any one of claims 1-4.

7. Use of a prodrug molecule or a pharmaceutically acceptable salt thereof according to any one of claims 1-4, characterized in that, This is used to prepare pharmaceutical compositions for the treatment or prevention of diseases related to the activity or expression level of JAK kinase.

8. A topical medication, characterized in that, include: The prodrug molecule according to any one of claims 1-4; Optional skin penetration enhancers; Optional support layer.

9. A topical medication formulation according to claim 8, characterized in that, Drugs exist in a single phase or multiple phases, in solution or suspension; formulations are administered in the form of solutions, suspensions, gels, emulsions, ointments or foams.

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