WO2024032569A1 - 一种前药化合物及其制备方法和用途 - Google Patents

一种前药化合物及其制备方法和用途 Download PDF

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WO2024032569A1
WO2024032569A1 PCT/CN2023/111594 CN2023111594W WO2024032569A1 WO 2024032569 A1 WO2024032569 A1 WO 2024032569A1 CN 2023111594 W CN2023111594 W CN 2023111594W WO 2024032569 A1 WO2024032569 A1 WO 2024032569A1
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French (fr)
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李傲
贾达夫普拉巴卡尔·孔达基
陈以乐
曹国庆
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明慧医药（杭州）有限公司
明慧医药（上海）有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
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    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Definitions

  • the present invention relates to the field of pharmaceutical small molecules. Specifically, the present invention provides a class of prodrug molecules as pharmaceutical compounds, their pharmaceutically acceptable salts, hydrates or solvates, as well as pharmaceutical combinations containing the above components. products (preferably external preparations).
  • JAK-STAT signaling pathway is a signal transduction pathway stimulated by cytokines discovered in recent years. JAK plays an important role in cytokine signaling.
  • the downstream substrates of the JAK kinase family include signal transducers of transcription proteins and Activator (STAT).
  • STAT signal transducers of transcription proteins and Activator
  • JAK protein is an important member of this pathway, and abnormal increase in its activity often leads to the occurrence of diseases.
  • Many diseases are related to abnormal cellular responses of the JAK-STAT signaling pathway. These diseases include autoimmune diseases, inflammatory diseases, bone diseases, and metabolic diseases. , neurological and neurodegenerative diseases, cancer, cardiovascular disease, allergies and asthma, Alzheimer's disease.
  • RA Rheumatoid arthritis
  • NSAIDs nonsteroidal anti-inflammatory drugs
  • DMARDs disease-modifying antirheumatic drugs
  • antibody drugs For a long time, the first-line drugs for the treatment of RA have been DMARDs.
  • MTX methotrexate
  • RA treatment has made great progress, and patients' conditions can be effectively controlled with existing treatments. Despite this, RA patients still suffer from disease recurrence, suboptimal treatment effectiveness, poor long-term tolerance, and some adverse reactions. More importantly, the quality of life of RA patients, including joint and other organ functions, has not been truly improved by existing treatments. Therefore, there is still a huge unmet clinical need in this field that focuses on restoring patients' normal functions. .
  • cytokines infiltrating in RA synovial tissue and cells produce a large number of cytokines in an autocrine manner. These cytokines interact with each other through different The pathway activates the JAK/STAT signaling pathway (Janus kinase/Signal transducer and activators of transcription signaling pathway). By specifically inhibiting the JAK/STAT signaling pathway, the cascade amplification effect of the above cytokines can be blocked, thereby improving the damaged joints of RA patients. symptoms, therefore, the JAK/STAT signaling pathway becomes a potential target for the treatment of RA.
  • JAK/STAT signaling pathway By specifically inhibiting the JAK/STAT signaling pathway, the cascade amplification effect of the above cytokines can be blocked, thereby improving the damaged joints of RA patients. symptoms, therefore, the JAK/STAT signaling pathway becomes a potential target for the treatment of RA.
  • Tofacitinib is used in patients with moderate to severe RA who have insufficient response or intolerance to MTX. Clinical trials have observed that it is accompanied by certain adverse reactions, 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 red blood cell differentiation and lipid metabolism processes, some of the above adverse reactions are believed to be related to the non-selective inhibitory characteristics of the drug. Therefore, finding selective JAK1 and/or JAK3 inhibitors will become a new direction in RA drug research.
  • JAK inhibitors have been proven to be useful in the treatment of hematological diseases, tumors, rheumatoid arthritis, atopic dermatitis and psoriasis. Due to the side effects of systemic exposure of JAK inhibitors, their use and clinical efficacy are greatly limited. Topical administration can reduce systemic exposure and associated systemic exposure side effects. However, the JAK inhibitors and/or compositions thereof that can be used for topical administration in the art are still very limited.
  • BTK Bruton's tyrosine kinase
  • BTK inhibitors can inhibit the proliferation of B lymphoma cells, destroy the adhesion of tumor cells, and promote the apoptosis of tumor cells, making BTK a compelling drug target in B cell-related cancers.
  • B-cell lymphomas and leukemias such as non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia (CLL) and relapsed or refractory mantle cell lymphoma (mantle cell) lymphoma, MCL), etc.
  • BTK inhibitors can also inhibit the production of B-cell autoantibodies and cytokines.
  • BTK inhibitors can also be used to treat autoimmune-related diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), allergic diseases (such as esophagitis, eosoniphilic esophagitis) )wait.
  • RA rheumatoid arthritis
  • SLE systemic lupus erythematosus
  • allergic diseases such as esophagitis, eosoniphilic esophagitis
  • BTK inhibitors Due to the important role BTK plays in multiple signaling pathways, the development of BTK inhibitors has attracted the attention of many biopharmaceutical companies. However, its cardiac and hepatotoxicity greatly limits its clinical use and clinical efficacy. Topical use of BTK Compounds can reduce systemic and blood exposure and their associated side effects. However, BTK inhibitors and/or compositions thereof suitable for topical administration are still very limited in the art.
  • the MAPK (mitogen-activated protein kinase, MAPK) signal transduction pathway consists of multiple parallel three-cascade signaling pathways.
  • MAPKK mitogen-activated protein kinase kinase, MKK
  • MEK has the function of phosphorylating the serine/threonine and tyrosine residues of the substrate.
  • T202/185 and Y204/187 T: threonine, Y: tyrosine
  • T202/185 and Y204/187 T: threonine, Y: tyrosine
  • T threonine
  • Y tyrosine
  • ERK1/2 then regulates the phosphorylation levels of various transcription factors or other related proteins. function, thereby affecting various physiological functions.
  • This signaling pathway can be activated by stimulation of extracellular growth factors or by oncogenic mutations in pathway kinase components.
  • abnormally activated RAS-ERK signals have been detected in several tumor cells. Abnormal activation of this pathway can lead to the expression of a large number of genes related to tumor cell differentiation, proliferation, migration, and blood vessel growth.
  • MEK inhibitors have shown great application prospects in the treatment of tumors and other diseases.
  • the side effects of systemic exposure of MEK inhibitors have greatly limited their use and clinical efficacy.
  • Topical administration may reduce systemic exposure and its associated systemic exposure side effects.
  • the MEK inhibitors and/or compositions thereof available for topical administration in the art are still very limited.
  • An object of the present invention is to provide a prodrug molecule for external administration, in particular a JAK inhibitor, a BTK inhibitor or a MEK inhibitor.
  • Another object of the present invention is to provide a prodrug modification method to improve the external administration of drug molecules, especially transdermal administration.
  • the first aspect of the present invention provides a prodrug molecule of pharmaceutical compound G', and a pharmaceutically acceptable salt, hydrate or solvate thereof, characterized in that the prodrug molecule has the following formula The structure shown in (I):
  • the G is a partial structural fragment formed by the loss of H atoms of the drug molecule G', which is combined with any O atom or S atom in the molecule.
  • Connected preferably, the G is a partial structural fragment formed by losing the H atom of OH or SH in the drug molecule G', which is connected to the drug molecule G' through an O atom or an S atom. connected;
  • L is selected from the following group: none, substituted or unsubstituted C1-C6 alkylene, substituted or unsubstituted C1-C6 heteroalkylene;
  • R 1 is selected from the following group: H, substituted or unsubstituted C1-C20 alkyl (linear or branched), substituted or unsubstituted C3-C20 cycloalkyl, substituted or unsubstituted C1-C20 Heteroalkyl group, substituted or unsubstituted 3-20 membered heterocyclyl group, substituted or unsubstituted C6-C14 aryl group;
  • p is selected from 0, 1 or 2;
  • substituted means substituted by one or more (for example, 2, 3, 4, etc.) substituents selected from the following group: deuterium atom, halogen, C1-C6 alkyl, Halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyl, C3-C8 heterocyclyl, 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 with 1-3 heteroatoms selected from N, S and O, halogenated 5- with 1-3 heteroatoms selected from N, S and O 10-membered hetero
  • the drug molecule G' is selected from the following group: JAK inhibitors, MEK inhibitors, BTK inhibitors, or the drug molecule G' is selected from the following group:
  • the JAK inhibitor is a molecule selected from the following group or a pharmaceutically acceptable salt, hydrate or solvate thereof:
  • the MEK inhibitor is a molecule selected from the following group, or a pharmaceutically acceptable salt, hydrate or solvate thereof:
  • the BTK inhibitor is a molecule selected from the following group, or a pharmaceutically acceptable salt, hydrate or solvate thereof:
  • the JAK inhibitor is a molecule represented by the following formula, or a pharmaceutically acceptable salt, hydrate or solvate thereof:
  • X is selected from the group: N or CR, where R is selected from the group: hydrogen, deuterium, halogen, CN, hydroxyl, CF 3 , N(R o ) 2 , substituted or unsubstituted C1-C4 alkyl, substituted or Unsubstituted C1-C4 alkoxy, substituted or unsubstituted C3-C6 cycloalkyl;
  • Y is S or CH
  • R 11 is independently selected from: hydrogen, deuterium, CN, N(R o ) 2 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3- C8 cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted 6- 10-membered aryl (C1-C6 alkyl), substituted or unsubstituted 5-12-membered heteroaryl (C1-C6 alkyl) and substituted or unsubstituted 4-10-membered heterocycle (C1-C6 alkyl) ;
  • R o is H or C1-C4 alkyl
  • R 12 is selected from: hydrogen, deuterium, C1-C4 alkyl, C3-C6 cycloalkyl, halogen and cyano, wherein the alkyl or cycloalkyl may be substituted by one or more fluorine atoms;
  • R 13 is selected from: hydrogen, deuterium and amino
  • R 14 is in:
  • Rc is a group selected from the following group: halogen, CN, hydroxyl, amino, -COOH, -(CO)NR 17 R 18 , -(SO 2 )NR 17 R 18 , -SO 2 R 17 , -NR 17 COR 18 , -NR 17 SO 2 R 18 , -(CR 17 R 18 )-R 19 , mono- or disubstituted amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, Substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 5-12 membered heterocyclyl, or Ring B is a substituted or unsubstituted 3-6 membered carbocyclic ring; R 24 is selected from: H, D, halogen, CN, C1-C4 alkyl, C1-C4 haloalkyl;
  • Each R 17 , R 18 and R 19 are independently selected from: hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C6 cycloalkyl, substituted Or unsubstituted 5-12 membered heterocyclyl; or R 17 and R 18 and the atoms connected to them form the corresponding 3-8 membered carbocyclic ring or heterocyclic ring;
  • R 23 is selected from the following group: H, D, halogen, CN, hydroxyl, amino, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy, COOH, CO(C1-C4 alkyl) , CONH 2 , CONH(C1-C4 alkyl), CON(C1-C4 alkyl) 2 , NH(C1-C4 alkyl), N(C1-C4 alkyl) 2 , NH(CO)(C1-C4 Alkyl), O(CO)(C1-C4 alkyl);
  • X 1 is selected from bond, NH, N(C1-C4 alkyl) or (CR 2 ) t ; Y 1 is (CR 2 ) s ; the R is selected from the following group: H, halogen, C1-C6 alkyl , Halogenated C1-C6 alkyl, C1-C6 alkoxy, Halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, Halogenated C3-C8 cycloalkyl, oxo, -CN, Hydroxy, amino, carboxyl, unsubstituted or substituted by one or more substituents selected from the following group: C6-C10 aryl, halogenated C6-C10 aryl, having 1-3 selected from N, A 5-10-membered heteroaryl group with heteroatoms of S and O, a halogenated 5-10-membered heterocyclyl group with 1-3 heteroatoms selected from N, S and O; and the substituent
  • n 0, 1 or 2;
  • n 0, 1, 2, 3 or 4 respectively; when m>1, each Rc is independent of each other;
  • substituted means substituted by one or more (for example, 2, 3, 4, etc.) substituents selected from the following group: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyl, oxo, -CN, hydroxyl, amino, Carboxyl, -COOH, -(CO)NH 2 , or two substituents located on the same atom together with the atom form a C3-C6 cycloalkyl group; and unsubstituted or one or more substituents selected from the following group Substituted groups selected from the group consisting of: C6-C10 aryl, halogenated C6-C10 aryl, 5-10 membered heteroaryl with 1-3 heteroatoms selected from N, S
  • heteroaryl or heterocyclyl group means that the ring atoms of the group contain 1, 2 or 3 heteroatoms selected from N, O and S;
  • the molecule has at least one OH group or SH group.
  • the JAK inhibitor is a molecule represented by the following formula, or a pharmaceutically acceptable salt, hydrate or solvate thereof:
  • X is selected from the group: N or CR, where R is selected from the group: hydrogen, deuterium, halogen, CN, hydroxyl, CF 3 , N(R o ) 2 , substituted or unsubstituted C1-C4 alkyl, substituted or Unsubstituted C1-C4 alkoxy, substituted or unsubstituted C3-C6 cycloalkyl;
  • R 11 is independently selected from: hydrogen, deuterium, CN, N(R o ) 2 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted Substituted C1-C6 alkoxy group, substituted or unsubstituted C3-C6 cycloalkyl group, substituted or unsubstituted C3-C6 heterocyclyl group, substituted or unsubstituted aryl group, substituted or unsubstituted 5-12-membered Heteroaryl, substituted or unsubstituted aryl (C1-C6 alkyl), substituted or unsubstituted 5-12 membered heteroaryl (C1-C6 alkyl) and substituted or unsubstituted heterocycle (C1-C6 alkyl);
  • R o is H or C1-C4 alkyl
  • R 12 is selected from: hydrogen, deuterium, C1-C4 alkyl, C3-C6 cycloalkyl, halogen and cyano, wherein the alkyl or cycloalkyl may be substituted by one or more fluorine atoms;
  • R 13 is selected from: hydrogen, deuterium and amino
  • R 14 is in:
  • Rc is a group selected from the following group: halogen, CN, hydroxyl, amino, -COOH, -(CO)NR 17 R 18 , -(SO 2 )NR 17 R 18 , -SO 2 R 17 , -NR 17 COR 18 , -NR 17 SO 2 R 18 , -(CR 17 R 18 )-R 19 , mono- or disubstituted amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, Substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 5-12 membered heterocyclyl;
  • R 15 is selected from: H, C1-C4 alkyl
  • R 16 is selected from: H, C1-C4 alkyl
  • Each R 17 , R 18 and R 19 are independently selected from: hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C6 cycloalkyl, substituted Or unsubstituted 5-12 membered heterocyclyl; or R 17 and R 18 and the atoms connected to them form the corresponding 3-8 membered carbocyclic ring or heterocyclic ring;
  • n 0, 1 or 2;
  • n 0, 1, 2, 3 or 4 respectively; when m>1, each Rc is independent of each other;
  • substituted means substituted by one or more (for example, 2, 3, 4, etc.) substituents selected from the following group: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyl, oxo, -CN, hydroxyl, amino, Carboxyl, -COOH, -(CO)NH 2 , or two substituents located on the same atom together with the atom form a C3-C6 cycloalkyl group; and unsubstituted or one or more substituents selected from the following group Substituted groups selected from the group consisting of: C6-C10 aryl, halogenated C6-C10 aryl, 5-10 membered heteroaryl with 1-3 heteroatoms selected from N, S
  • heteroaryl or heterocyclyl group means that the ring atoms of the group contain 1, 2 or 3 heteroatoms selected from N, O and S;
  • the molecule has at least one OH group or SH group.
  • the JAK inhibitor is a molecule represented by the following formula, or a pharmaceutically acceptable salt, hydrate or solvate thereof:
  • Ring A is a substituted or unsubstituted 5-6 membered aromatic ring or heteroaromatic ring
  • Ring B is a substituted or unsubstituted 3-6 membered carbocyclic ring
  • R 21 is selected from the group consisting of substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted C1-C4 alkylamino, substituted or unsubstituted 6-10 membered aryl group, substituted or unsubstituted 5-10 membered heteroatom with 1-3 heteroatoms selected from N, S(O) p and O Aryl, substituted or unsubstituted 4-10 membered heterocyclic group with 1-3 heteroatoms selected from N, S and O;
  • R 22 and R 24 are each independently selected from the following group: H, D, halogen, CN, CHF 2 , CF 3 ;
  • R 23 is selected from the following group: H, D, halogen, CN, hydroxyl, amino, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy, COOH, CO(C1-C4 alkyl) , CONH 2 , CONH(C1-C4 alkyl), CON(C1-C4 alkyl) 2 , NH(C1-C4 alkyl), N(C1-C4 alkyl) 2 , NH(CO)(C1-C4 Alkyl), O(CO)(C1-C4 alkyl);
  • X 1 is selected from bond, NH, N(C1-C4 alkyl) or (CR 2 ) t ;
  • Y 1 is (CR 2 ) s ;
  • R is selected from the following group: H, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl Base, halogenated C3-C8 cycloalkyl, oxo, -CN, hydroxyl, amino, carboxyl, unsubstituted or substituted by one or more substituents selected from the group consisting of: C6-C10 aryl, Halogenated C6-C10 aryl group, 5-10 membered heteroaryl group with 1-3 heteroatoms selected from N, S and O, halogenated C6-C10 aryl group with 1-3 heteroatoms selected from N, S and O atomic 5-10 membered heterocyclyl; and the substituent is selected from the following group: halogen, C1-C6 alkoxy;
  • t and s are independently selected from 0, 1 or 2;
  • substituted means substituted by one or more (for example, 2, 3, 4, etc.) substituents selected from the following group: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyl, oxo, -CN, hydroxyl, amino, Carboxy, a group selected from the group consisting of unsubstituted or substituted by one or more substituents: C6-C10 aryl, halogenated C6-C10 aryl, having 1-3 selected from N, S and O 5-10-membered heteroaryl with heteroatom, halogenated 5-10-membered heterocyclyl with 1-3 heteroatoms selected from N, S and O; and the substituent is selected from the following group: halogen , C1-C6 alkyl, halogenated C1
  • the molecule has at least one OH group or SH group.
  • the G group has the structure shown in the following formula:
  • each group is defined as described above;
  • R 15 and R 16 are each independently selected from: H, C1-C4 alkyl; and Rd is selected from the group consisting of: chemical bond, -CO, -(CO)N(R 18 )R 17 -, -(SO 2 )N (R 18 )R 17 -, -SO 2 R 17 , -NR 18 COR 17 , -NR 18 SO 2 R 17 , -(CR 19 R 18 )-R 17 , substituted or unsubstituted C1-C6 alkylene group, Substituted or unsubstituted C3-C6 cycloalkylene, substituted or unsubstituted 5-12 membered heterocyclylene; R 17 is selected from the following group: chemical bond, substituted or unsubstituted C1-C6 alkylene, substituted or unsubstituted C3 -C6 cycloalkylene, substituted or unsubstituted 5-12 membered heterocyclylene.
  • X is N.
  • R 11 is independently selected from CN, N(R o ) 2 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted aryl (C1- C6 alkyl), substituted or unsubstituted 5-12 membered heteroaryl (C1-C6 alkyl) and substituted or unsubstituted heterocycle (C1-C6 alkyl); preferably, R 11 is selected from unsubstituted C3-C6 cycloalkyl, or C3-C6 cycloalkyl substituted by 1-3 fluorine atoms or deuterium
  • R 12 is selected from hydrogen, halogen and cyano;
  • R 13 is hydrogen; preferably, Ar is pyrazolyl, more preferably, Ar is group.
  • Rd is a group selected from the following group: (CO)N(R 18 )R 17 -, -(SO 2 )N(R 18 )R 17 -, -SO 2 R 17 , - NR 18 COR 17 , -NR 18 SO 2 R 17 , -(CR 19 R 18 )-R 17 , substituted or unsubstituted C1-C6 alkylene, substituted or unsubstituted C3-C6 cycloalkylene, substituted or unsubstituted Substituted 5-12 membered heterocyclylene.
  • the G group is selected from the following group:
  • the G group has the structure shown in the following formula:
  • the X 1 is NH or (CH 2 ) m .
  • the A ring is a substituted or unsubstituted group selected from the following group:
  • R 21 is selected from the following group: substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C1-C4 alkoxy group, substituted or unsubstituted C1-C4 alkylamino.
  • the G group has a structure selected from the following group:
  • ring B is a substituted or unsubstituted 3-4 membered carbocyclic ring.
  • R 22 is selected from hydrogen, halogen and CN.
  • the G group has a structure selected from the following group:
  • L is selected from the following group: none, substituted or unsubstituted C1-C6 alkylene, substituted or unsubstituted C1-C6 heteroalkylene;
  • R 1 is selected from the following group: substituted or unsubstituted C1-C20 alkyl (linear or branched), substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C1-C20 hetero Alkyl group, substituted or unsubstituted 3-20 membered heterocyclyl group, substituted or unsubstituted phenyl group;
  • R 1 has one or more substituents selected from the following group: C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyl .
  • L is selected from the following group: none, substituted or unsubstituted C1-C4 alkylene;
  • R 1 is selected from the following group: substituted or unsubstituted C2-C20 alkyl group (linear or branched);
  • R 1 has one or more substituents selected from the following group: C1-C6 alkyl.
  • the prodrug molecule has a structure represented by the following formula (I):
  • the G is a partial structural fragment formed by losing one or more H atoms of the drug molecule G', which is formed by combining any O atom or S atom in the molecule with connected.
  • the drug molecule G' is selected from the following group: JAK inhibitors, MEK inhibitors, BTK inhibitors, or the drug molecule G' is selected from the following group:
  • the G is selected from the following group:
  • the compound of formula (I) has the structure shown in the following formula:
  • the hydrophobicity coefficient CLogP of the drug molecule G' is ⁇ 4.
  • a second aspect of the present invention provides a method for preparing the compound according to the first aspect of the present invention, the method comprising the steps:
  • the compound of formula I has the structure shown in formula II below, and the method includes the steps:
  • the third aspect of the present invention provides the use of a compound as described in the second aspect of the present invention, or a pharmaceutically acceptable salt or hydrate thereof, which is characterized in that it is used for the preparation of a compound selected from the following for treatment or prevention:
  • the disease is selected from the following group: inflammation, autoimmune disease, neuroinflammation, arthritis, rheumatoid arthritis, spinal osteoarthritis, systemic Lupus erythematosus, lupus nephritis, gouty arthritis, pain, fever, pulmonary sarcoidosis, silicosis, cardiovascular disease, atherosclerosis, nodular myocarditis, myocarditis and cardiac reperfusion injury, cardiomyopathy, stroke, ischemia , reperfusion injury, cerebral edema, traumatic brain injury, neurodegenerative diseases, liver disease, inflammatory bowel disease, Crohn's disease, ulcerative colitis, nephritis, retinitis, retinopathy, macular degeneration, glaucoma, diabetes mellitus (type 1 ) and type 2), diabetic neuropathy, viral and bacterial infections, myalgia, endotoxic shock, toxic shock syndrome,
  • the disease is selected from the following group: bladder cancer, brain tumor, breast cancer, uterine cancer, colorectal cancer, esophageal cancer, liver cancer, follicular cancer Lymphoma, melanoma, hematological malignancies, myeloma, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, and lymphoid malignancies of B-cell origin, B-cell proliferative disorders: diffuse B-cell lymphoma , follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma/tile Eldenström's macroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B-cell lymphoma, intranodal marginal zone B-cell
  • the disease is selected from the following group: chronic pain, non-small cell lung cancer, chronic myelogenous leukemia (CML), metastatic biliary tract cancer, ovarian cancer, peritoneal cancer cancer.
  • CML chronic myelogenous leukemia
  • the fourth aspect of the present invention provides an external dosage preparation, which is characterized in that it includes:
  • the skin penetration enhancer is selected from the following group: surfactants, dimethyl sulfoxide and its analogs, azone compounds, pyrrolidone derivatives, alcohol compounds, Ether compounds, fatty acid compounds and fatty acid ester compounds, or combinations thereof;
  • the drug exists in a single phase or multiple phases, a solution or a suspension; the preparation is administered in the form of a solution, suspension, gel, emulsion, ointment or foam.
  • a fifth aspect of the present invention provides a method for improving the membrane permeability of drug molecule G', which method includes the steps:
  • the prodrug molecule The Pe value of Skin-Pampa is 2-100 times higher than the G' of the drug molecule before modification.
  • Figure 1 shows the changes in skin thickness of mice in each administration group during the test period in Test Example 2 (*P ⁇ 0.05, **P ⁇ 0.01, ***P ⁇ 0.001);
  • Figure 2 is a graph showing changes in PASI scores of mice in each administration group during the test period in Test Example 2 (*P ⁇ 0.05, **P ⁇ 0.01, ***P ⁇ 0.001);
  • Figure 3 shows the increase in skin thickness of mice in each administration group during the test period in Test Example 3 (**P ⁇ 0.01).
  • the compound is composed of a hydrophilic drug molecule end and a hydrophobic end, so it can have good transdermal performance. After external administration, it can be metabolized in the body to form a prototype drug molecule, thereby completing the drug administration process. Based on the above findings, the inventor completed the present invention.
  • alkyl includes straight or branched chain alkyl groups.
  • C 1 -C 6 alkyl represents a straight-chain or branched alkyl group with 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl etc.
  • C1-C20 alkyl has a similar meaning.
  • alkylene refers to an alkyl group that has lost one hydrogen atom.
  • C1-C6 alkylene represents a straight or branched chain alkylene group having 1 to 6 carbon atoms.
  • heteroalkyl refers to an alkyl group in which one or more carbon atoms in the carbon chain are substituted with a heteroatom selected from the group consisting of O, S, NH, C(O) or C(NH).
  • heteroatom selected from the group consisting of O, S, NH, C(O) or C(NH).
  • Alkyl has a similar meaning.
  • C3-C8 cycloalkyl refers to a cycloalkyl group having 3 to 8 carbon atoms (eg, 3, 4, 5, 6, 7, 8). It may be a monocyclic ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or similar groups. It can also be in the form of a bicyclic ring, such as a bridged ring, a paracyclic ring or a spirocyclic ring. "C3-C20 cycloalkyl” has a similar definition.
  • C6-C14 aryl refers to an aryl group having 6 to 14 carbon atoms (eg, 6, 7, 8, 9, 10, 11, 12, 13, 14), for example, phenyl or Naphthyl and other similar groups.
  • the term "5-10 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S, and O” means having 5-10 ring atoms (e.g., 5, 6, 7, 8, 9, 10) and in which 1-3 atoms are heteroatoms selected from the following group of N, S and O. It can be a single ring or a fused ring.
  • Specific examples may be pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)-triazolyl and (1,2, 4)-Triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, etc.
  • 3-20 membered heterocyclyl refers to a group having 3-20 ring atoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 , 16, 17, 18, 19 or 20), and 1-3 atoms are saturated or partially saturated cyclic groups selected from the heteroatoms of the following group of N, S and O, preferably 3-10 membered heteroatoms Cyclic group, or 4-7 membered heterocyclic group or 9-15 membered heterocyclic group. It can be a single ring or a double ring, such as a bridged ring or a spiro ring.
  • the groups described in the present invention can be substituted with substituents selected from the following group: halogen, nitrile group, nitro group, hydroxyl group, amino group , C1-C6 alkyl-amino group, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C1-C6 alkoxy group, halogenated C1-C6 alkyl group, halogenated C2-C6 alkenyl group , Halogenated C2-C6 alkynyl, Halogenated C1-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-carbony
  • 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. "Halosubstituted” means substituted with atoms selected from the group consisting of F, Cl, Br, and I.
  • the structural formulas described in the present invention are intended to include all isomeric forms (such as enantiomers, diastereomers and geometric isomers (or conformational isomers)): for example, containing asymmetric The R and S configurations of the center, the (Z) and (E) isomers of the double bond, etc. Therefore, individual stereochemical isomers of the compounds of the present invention or mixtures of their enantiomers, diastereomers or geometric isomers (or conformational isomers) are within the scope of the present invention.
  • hydrate refers to a complex of a compound of the invention coordinated with water.
  • the compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining specific embodiments with other chemical synthesis methods, and those skilled in the art. Well-known equivalents and preferred embodiments include but are not limited to the embodiments of the present application.
  • aq represents aqueous solution
  • HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate
  • EDCI represents N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride
  • m-CPBA 3-chloroperoxybenzoic acid
  • eq represents equivalent, equivalent
  • CDI represents Carbonyldiimidazole
  • DCM represents dichloromethane
  • PE represents petroleum ether
  • DIAD represents diisopropyl azodicarboxylate
  • DMF represents N,N-dimethylformamide
  • DMSO represents dimethyl sulfoxide
  • EtOAc represents ethyl acetate Ester
  • EtOH represents ethanol
  • MeOH represents methanol
  • Cbz represents benzyloxycarbonyl
  • the present invention provides a prodrug molecule of a pharmaceutical compound, and a pharmaceutically acceptable salt, hydrate or solvate thereof, characterized in that the prodrug molecule is metabolized in the body to form a drug molecule after administration G'; and the hydrophobicity coefficient CLogP of the drug molecule G' is ⁇ 4; and the prodrug molecule has the structure shown in the following formula (I):
  • the G is a partial structural fragment formed by the loss of H atoms of the drug molecule G', which is combined with any O atom or S atom in the molecule. connected.
  • the lipophilic group can effectively increase the transdermal efficiency of the compound, thereby preparing new compounds that can be metabolized into the prototype compound molecules through topical administration.
  • the drug molecule G' suitable for the prodrug molecule can be of any structure.
  • the drug molecule has a hydrophobicity coefficient CLogP ⁇ 4.
  • the drug molecule is a drug molecule used for skin diseases, such as JAK inhibitors, MEK inhibitors, BTK inhibitors, etc.
  • compositions and methods of administration are provided.
  • the compound of the present invention can be metabolized in the body to form therapeutically active ingredients after external administration
  • the compound of the present invention The compound and its various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compound of the present invention as the main active ingredient can be used for prevention and/or treatment (stabilization, alleviation) or cure) various autoimmune and inflammation-related diseases including cancer, myeloproliferative diseases, inflammation, immune diseases, organ transplantation, viral diseases, cardiovascular diseases or metabolic diseases, as well as hematological tumors, lymphomas, solid tumors and other malignant tumors.
  • the pharmaceutical composition of the present invention contains a compound of the present invention and a pharmaceutically acceptable excipient or carrier within a safe and effective amount.
  • the “safe and effective dose” refers to the amount of compound that is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 1-2000 mg of the compound of the present invention/dose, more preferably, it contains 1-200 mg of the compound of the present invention/dose.
  • the "dose" is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to one or more compatible solid or liquid filler or gel substances that are suitable for human use and must be of sufficient purity and low enough toxicity. "Compatibility” here means that the components of the composition can be blended with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds.
  • Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, 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 Tween ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
  • the prodrug compounds of the invention are conveniently formulated into pharmaceutical compositions containing one or more compounds of the invention and a pharmaceutically acceptable carrier. See Remington: The Science and Practice of Pharmacy, 19th ed. (Easton, Pa., Mack Publishing Co., 1995), which discloses typical carriers and common methods of preparing pharmaceutical compositions, which may be used as described or by Improve it to prepare a pharmaceutical containing the compound of the present invention. As mentioned above, the compounds of the present invention can also be administered in the form of pharmaceutically acceptable salts and the like.
  • the compounds of the present invention may be in the form of pharmaceutical preparations containing commonly used non-toxic pharmaceutical carriers, auxiliaries and excipients, and may be administered orally, parenterally, externally, rectal, nasally or bucally. Administration, vaginally, or via an implanted reservoir.
  • the compounds of the present invention can be administered through the skin or mucosal tissue using commonly used external drug delivery systems, in which the pharmaceutical agent is contained in a multilayer structure that is fixed on the skin and functions as a drug delivery device.
  • the pharmaceutical composition is contained in a layer, the "reservoir" layer, beneath the upper backing layer.
  • the multilayer structure may contain a single receptacle or multiple receptacles.
  • the reservoir contains a polymeric matrix of a pharmaceutically acceptable pressure-fit adhesive material that serves to secure the system to the skin during administration.
  • suitable skin pressure adhesive materials include, but are not limited to, polyethylene, polysiloxane, polyisobutylene, polyacrylate, polyurethane, and the like.
  • the drug-containing reservoir and the skin-compression adhesive may be present as separate and distinct layers, in which case the adhesive is beneath the reservoir, which may be the polymeric matrix described above, or This may be a liquid or hydrogel reservoir, or other forms.
  • the backing layer which is the upper surface of the device, serves as the main structural element of the multilayer structure, providing much of the flexibility to the device.
  • the substance selected for use as the backing material should be substantially impermeable to the active substance and any other substances present; the backing is preferably made from a soft elastic material sheet or film.
  • polymers suitable for use as the backing layer include polyethylene, polypropylene, polyester, and the like.
  • the multi-layer construction includes peel layers. Immediately before use, this layer is removed from the device, exposing the underside or drug reservoir or a separate layer of press-fit adhesive that allows the system to be secured to the skin.
  • the release layer should be made of material that is impermeable to the drug/excipient.
  • Topical delivery devices can be made using common techniques known in the art, for example, casting a fluid mixture of adhesive, drug, and excipient onto a backing layer and then laminating a release layer. Similarly, the adhesive mixture can be cast on the release layer and then the backing layer can be laminated. Alternatively, drug reservoirs can be made without drug or excipients and then filled with the drug/excipient mixture by soaking.
  • Multilayered topical delivery systems may also contain skin penetration enhancers. That is, because the inherent permeability of the skin to certain drugs may be too small to allow therapeutic levels of the drug to penetrate a substantial amount of unbroken skin, a skin penetration enhancer may need to be administered with these drugs.
  • Suitable accelerators are well known in the art and include, for example, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), N,N-dimethylacetamide (DMA), decylmethyl sulfoxide (C10MSO) ), C2-C6 alkanediols and 1-substituted azepan-2-ones, alcohols, etc.
  • the compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable therapeutic agents.
  • the pharmaceutical composition When administered in combination, the pharmaceutical composition also includes one or more (2, 3, 4, or more) other pharmaceutically acceptable therapeutic agents.
  • One or more (2, 3, 4, or more) of the other pharmaceutically acceptable therapeutic agents can be used for prevention and/or treatment simultaneously, separately, or sequentially with the compound of the present invention. Cytokine and/or interferon mediated diseases.
  • a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, and the dosage when administered is a pharmaceutically effective dosage.
  • a mammal such as a human
  • the daily dose is usually 1 to 2000 mg, preferably 1 to 500 mg.
  • 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 skill of a skilled physician.
  • compound 1d 50.00g, 0.11mol
  • N,O-dimethylhydroxylamine hydrochloride (12.60g, 0.13mol) and triethylamine (32.70g, 0.13mol) were dissolved in dichloromethane. (500mL), add 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (24.80g, 0.13mol) and 1-hydroxybenzotriazole (17.50g, 0.13mol) ), the reaction solution was allowed to react at room temperature overnight. The reaction solution was diluted with water (400mL), extracted with dichloromethane (200mL x 2), and the organic phase was diluted with saturated brine (300mL x 2).
  • Dissolve 12b (1.00g, 5.00mmol) in tetrahydrofuran (20mL), add lithium aluminum hydride (380mg, 10.00mmol) to the reaction system in batches under ice bath and nitrogen protection, and react at room temperature for 2 hours.
  • Water (1 mL) was slowly added dropwise to quench the reaction, and then 15% sodium hydroxide aqueous solution (1 mL) and water (3 mL) were slowly added dropwise to the reaction system, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude product 12c ( 0.86g) and used directly for the next reaction.
  • Test example 1 Skin-Pampa experiment
  • Test Example 2 Psoriasis mouse model drug efficacy evaluation experiment
  • a psoriasis mouse model induced by imiquimod (IMQ) was used to study the therapeutic effect of Example 1 on psoriasis-like symptoms.
  • Female BALB/c mice with depilated back hair were divided into 5 groups according to skin thickness using a stratified randomization method, namely the solvent control group (normal control), the model control group, and the three groups of low, medium and high in Example 1. Dosage groups (concentrations of dosage preparations are 3mg/mL, 10mg/mL and 30mg/mL respectively). Except for the solvent control group, the other mice were Apply imiquimod cream to the hair removal area on the back once a day for 7 consecutive days, and the solvent control group applies Vaseline every day.
  • Example 1 The compound treatment group of Example 1 applied the dosage preparation twice a day, with an interval of about 8 hours between the two times, for 7 consecutive days; the solvent control group and the model control group were given the same volume of solvent control; only one dose was administered in the morning on the 7th day. .
  • the animals were weighed, dorsal skin thickness measured, dorsal affected areas photographed, and PASI scores were performed daily.
  • mice were euthanized, and the skin from the modeling area was collected, fixed with 10% neutral formaldehyde, embedded in paraffin, and sectioned for HE staining. The thickness of the epidermis and dermis was measured, and pathological scoring was performed. The test results are shown in Table 1. Compared with the solvent control group, the skin of the mice in the model control group showed obvious pathological changes, mainly including thickening of the epidermis and dermis, epidermal hyperkeratosis, a small amount of small focal necrosis, and neutrophil infiltration in the dermis.
  • Example 1 After local administration, compared with the model control group, various lesions in each treatment group were reduced, and there was a certain dose-effect relationship.
  • Example 1 the skin thickness, PASI score and pathological evaluation results of mice in each administration group of Example 1 all show that topical administration of Example 1 has a good therapeutic effect on psoriasis-like changes induced by imiquimod. And it has a certain degree of dose dependence. It is suggested that the topical administration of the compound of this application has a good therapeutic effect on the IMQ-induced psoriasis model.
  • the compound treatment group was smeared with the drug preparation twice a day, with an interval of about 8 hours between the two times, for 7 consecutive days; the normal control group and the model control group were given the same volume of solvent control; only one dose was administered in the morning on the 7th day.
  • the animals were weighed, dorsal skin thickness measured, dorsal affected areas photographed, and PASI scores were performed daily.

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Abstract

本发明提供了一种前药化合物及其制备方法和用途，具体地，本发明提供了一种如式(I)所示的化合物，及其制备方法和作为前药用于制备外用制剂的用途。

Description

一种前药化合物及其制备方法和用途 技术领域
本发明涉及药物小分子领域，具体地，本发明提供了一类作为药用化合物的前药分子，及其药学上可接受的盐，水合物或溶剂合物，以及含有上述组分的药物组合物(优选为外用制剂)。
背景技术
JAK-STAT信号通路是近年来发现的一条由细胞因子刺激的信号转导通路，JAK在细胞因子信号传导中起着重要的作用，JAK激酶家族的下游底物包括转录蛋白的信号转导剂和激活剂(STAT)。JAK蛋白是该通路中重要成员，而其活性的异常提高往往导致疾病的发生，很多疾病都与JAK-STAT信号通路异常细胞反应有关，这些疾病包括自身免疫病、炎性病、骨病、代谢病、神经和神经变性病、癌症、心血管病、变态反应和哮喘、阿尔兹海默氏病。
类风湿性关节炎(rheumatoid arthritis,RA)是一种临床常见的慢性自身免疫性疾病，主要表现为关节肿胀、疼痛、僵硬、畸形和功能严重受损等，人群发病率为0.5％-1.0％。由于RA的发病机制尚未明确，因此其病理过程难以控制，致残率高，严重损害患者身心健康，降低患者生存质量。目前用于治疗RA的药物主要有非甾体抗炎药(NSAID)、改善病情抗风湿药(DMARD)、以及抗体类药物。长期以来，治疗RA的一线药物为DMARDs，1988年，第1个DMARD药物甲氨蝶呤(MTX)获FDA批准治疗RA，MTX是RA治疗史上的一个重要里程碑。该药物因其有效性、耐受性、安全性等优势而被广泛应用，但其具有包括恶心、呕吐、胃部不适、肝毒性等不良反应。相比之下，新近发展的抗体类药物对于中重度RA具有较好的疗效和安全性指标，但是因其靶向特定的细胞因子，获益人群受到明显限制，同时治疗费用和注射方式给药也限制了这类药物的推广。
在过去20年的发展历程中，RA治疗已经取得长足进步，患者病情经现有治疗方法已经可以有效控制。尽管如此，RA患者仍经受疾病复发、治疗有效性不理想、长期耐受性差及一些不良反应等问题。更为重要的是，RA患者的生活质量包括关节等器官功能在现有治疗手段并没有得到真正的改善，因此，着眼于恢复患者的正常机能在这一领域仍存在巨大的未满足的临床需求。
研究表明，在RA中起核心治病作用的是RA滑膜组织及细胞中浸润的单核/巨噬细胞、淋巴细胞等通过自分泌的方式产生大量细胞因子，这些细胞因子相互作用，通过不同途径激活JAK/STAT信号通路(Janus kinase/Signal transducer and activators of transcription signaling pathway)，通过特异性抑制JAK/STAT信号通路，可阻断上述细胞因子的级联放大作用，从而改善RA患者受损关节症状，因此，JAK/STAT信号通路成为治疗RA的潜在靶点。
由于JAK激酶参与体内各种重要的生理过程，对不同亚型的广泛抑制有可能产生 不良反应，Tofacitinib用于MTX反应不足或不耐受的中重度RA患者，临床试验观察其伴随一定的不良反应，包括感染、结核、肿瘤、贫血、肝损伤及胆固醇增加等。Tofacitinib对JAK1，JAK2，JAK3亚型均有显著的抑制活性，由于JAK2活性与红细胞分化以及脂代谢过程相关，上述部分不良反应被认为与该药物的非选择性抑制特点相关。因此，寻找选择性JAK1和/或JAK3抑制剂将成为RA药物研究的新方向。
目前JAK抑制剂已经被证实可以用于血液系统疾病、肿瘤、类风湿性关节炎、特异性皮炎及银屑病等治疗药物。由于JAK抑制剂的系统暴露的副作用，极大的限制了其使用以及临床疗效。外用的局部给药可以降低其系统暴露量以及其相关的系统暴露副作用。然而，本领域可以用于外用给药的JAK抑制剂和/或其组合物仍然非常有限。
Bruton酪氨酸激酶(BTK)是Tec酪氨酸激酶家族中的重要一员，存在于浆细胞，包括B细胞、肥大细胞和巨噬细胞中，在B细胞受体(BCR)介导的信号通路中起了决定性的作用。当BTK被上游的Src家族激酶激活后，可以磷酸化下游的磷脂酶C(PLC)，从而激活PI3和DAG信号通路。这一信号通路可以促进细胞的增殖、粘附和存活，在B细胞淋巴瘤的发展过程中起重要的作用。
BTK抑制剂通过抑制BTK的活性，可以抑制B淋巴瘤细胞的增殖，破坏瘤细胞的粘附，促进瘤细胞的凋亡，使BTK在与B细胞有关的癌症中成为令人注目的药物靶点，尤其对B细胞淋巴瘤和白血病，比如非霍奇金淋巴瘤(non-Hodgkin’s lvmphoma,NHL)慢性淋巴细胞白血病(chronic lymphocytic leukemia,CLL)和复发性或难治性套细胞淋巴瘤(mantle cell lymphoma,MCL)等。
BTK抑制剂除了可以抗B细胞淋巴瘤和白血病，还可以抑制B细胞自身抗体和细胞因子的产生。BTK抑制剂也可以用于治疗和自身免疫相关的疾病，比如类风湿性关节炎(rheumatoid arthritis,RA)、系统性红狼疮(systemic upus erythematosus,SLE)、过敏性疾病(例如食道炎、eosoniphilic esophagitis)等。
由于BTK在多个信号通路中所起的重要作用，BTK抑制剂的开发吸引了众多生物制药公司的关注，但是由于其心脏和肝毒性极大的限制了其临床使用和临床疗效，局部外用BTK化合物可以降低系统、血液的暴露量以及其相关的副作用。然而，本领域适合外用给药的BTK抑制剂和/或其组合物仍然非常有限。
MAPK(mitogen-activated protein kinase,MAPK)信号转导通路由多条平行的三级联信号通路组成。MAPKK(mitogen-activated protein kinase kinase,MKK)位于通路的第二级，MEK作为MAPKK家族中的重要成员,具有磷酸化底物的丝氨酸/苏氨酸和酪氨酸残基的功能，通过磷酸化靶蛋白ERK1/2的T202/185和Y204/187(T:苏氨酸，Y:酪氨酸)使得ERK1/2活化，ERK1/2再通过调节多种转录因子的磷酸化水平或其他相关蛋白作用，进而影响多种生理功能。
细胞外生长因子的刺激下或通路激酶组分的致癌突变均可激活该信号通路。目前，已在数种肿瘤细胞内检测到异常活化的RAS-ERK信号。该通路的异常活化可导致大量与肿瘤细胞分化、增殖、迁移和血管生长相关基因的表达。MEK抑制剂展现了其在肿瘤等疾病治疗中的极大的应用前景，但是由于MEK抑制剂的系统暴露的副作用，极大的限制了其使用以及临床疗效。外用的局部给药可以降低其系统暴露量 以及其相关的系统暴露副作用。然而，本领域可以用于外用给药的MEK抑制剂和/或其组合物仍然非常有限。
发明内容
本发明的一个目的是提供一种用于外用给药的前药分子，特别是JAK抑制剂、BTK抑制剂或MEK抑制剂。
本发明的另一个目的是提供一种改善药物分子外用给药，尤其是透皮给药的前药修饰方法。
本发明的第一方面，提供了一种药用化合物G'的前药分子，及其药学上可接受的盐，水合物或溶剂合物，其特征在于，所述的前药分子具有如下式(I)所示的结构：
其中，所述的G为药物分子G'失去H原子形成的部分结构片段，其通过分子内任意O原子或S原子与相连(较佳地，所述的G为药物分子G'中的OH或SH失去H原子形成的部分结构片段，其通过O原子或S原子与相连)；
L选自下组：无、取代或未取代的C1-C6的亚烷基、取代或未取代的C1-C6的亚杂烷基；
R1选自下组：H、取代或未取代的C1-C20的烷基(直链或支链的)、取代或未取代的C3-C20的环烷基、取代或未取代的C1-C20的杂烷基、取代或未取代的3-20元的杂环基、取代或未取代的C6-C14的芳基；
其中，所述的亚杂烷基、杂烷基指碳链上的一个或多个碳原子被选自下组的杂原子替代：NH、O、S(O)p或C＝O(其中NH上的氢原子可以被取代)；
所述的杂环基包括1-3个选自下组的杂原子作为环骨架：NH、O、S(O)p或C＝O(其中NH上的氢原子可以被取代)；
p选自0、1或2；
除非特别说明，所述的“取代”是指被选自下组的一个或多个(例如2个、3个、4个等)取代基所取代：氘原子、卤素、C1-C6烷基、卤代的C1-C6烷基、C1-C6烷氧基、卤代的C1-C6烷氧基、C3-C8环烷基、卤代的C3-C8环烷基、C3-C8杂环基、氧代、-CN、羟基、氨基、羧基、酰胺、磺酰胺、砜基、未取代或被一个或多个取代基取代的选自下组的基团：C6-C10芳基、卤代的C6-C10芳基、具有1-3个选自N、S和O的杂原子的5-10元杂芳基、卤代的具有1-3个选自N、S和O的杂原子的5-10元杂环基；且所述的取代基选自下组：卤素、C1-C6烷基、C1-C6烷氧基、＝O。
在另一优选例中，所述的药物分子G'选自下组：JAK抑制剂、MEK抑制剂、BTK抑制剂，或所述的药物分子G'选自下组：
在另一优选例中，所述的JAK抑制剂为选自下组的分子或其药学上可接受的盐，水合物或溶剂合物：
在另一优选例中，所述的MEK抑制剂为选自下组的分子，或其药学上可接受的盐，水合物或溶剂合物：

在另一优选例中，所述的BTK抑制剂为选自下组的分子，或其药学上可接受的盐，水合物或溶剂合物：
在另一优选例中，所述的JAK抑制剂为如下式所示的分子，或其药学上可接受的盐，水合物或溶剂合物：
其中：
X选自下组：N或CR，其中R选自下组：氢，氘，卤素，CN，羟基，CF3，N(Ro)2，取代或未取代的C1-C4烷基，取代或未取代的C1-C4烷氧基，取代或未取代的C3-C6环烷基；
Y为S或CH；
A选自下组：键，C＝O，-SO2-，-(C＝O)NRo-；
R11独立地选自：氢，氘，CN，N(Ro)2，取代或未取代的C1-C4烷基，取代或未取代的C1-C6烷氧基，取代或未取代的C3-C8环烷基，取代或未取代的4-10元杂环基，取代或未取代的6-10元芳基，取代或未取代的5-12元杂芳基，取代或未取代的6-10元芳基(C1-C6烷基)，取代或未取代的5-12元杂芳基(C1-C6烷基)和取代或未取代的4-10元杂环(C1-C6烷基)；
Ro为H或C1-C4烷基；
R12选自：氢，氘，C1-C4烷基，C3-C6环烷基，卤素和氰基，其中所述烷基或环烷基可以被一个或多个氟原子取代；
R13选自：氢，氘和氨基；
R14为其中：
选自下组：取代或未取代的C6-C10单环或双环芳基，取代或未取代的5-12元单环或双环杂芳基；
Rc为选自下组的基团：卤素，CN，羟基，氨基，-COOH，-(CO)NR17R18，-(SO2)NR17R18，-SO2R17，-NR17COR18，-NR17SO2R18、-(CR17R18)-R19，单取代或双取代的氨基，取代或未取代C1-C6烷基，取代或未取代C1-C6烷氧基，取代或未取代C3-C6环烷基，取代或未取代5-12元杂环基，或环B为取代或未取代的3-6元碳环；R24选自：H、D、卤素、CN、C1-C4烷基、C1-C4卤代烷基；
各个R17、R18和R19分别独立的选自：氢，取代或未取代C1-C6烷基，取代或未取代C1-C6烷氧基，取代或未取代C3-C6环烷基，取代或未取代5-12元杂环基；或R17和R18和与其相连的原子形成相应的3-8元碳环或杂环；
R23选自下组：H、D、卤素、CN、羟基、氨基、取代或未取代C1-C4烷基、取代或未取代C1-C4烷氧基、COOH、CO(C1-C4烷基)、CONH2、CONH(C1-C4烷基)、CON(C1-C4烷基)2、NH(C1-C4烷基)、N(C1-C4烷基)2、NH(CO)(C1-C4烷基)、O(CO)(C1-C4烷基)；
X1选自键、NH、N(C1-C4烷基)或(CR2)t；Y1为(CR2)s；所述的R选自下组：H、卤素、C1-C6烷基、卤代的C1-C6烷基、C1-C6烷氧基、卤代的C1-C6烷氧基、C3-C8环烷基、卤代的C3-C8环烷基、氧代、-CN、羟基、氨基、羧基、未取代或被一个或多个取代基取代的选自下组的基团：C6-C10芳基、卤代的C6-C10芳基、具有1-3个选自N、S和O的杂原子的5-10元杂芳基、卤代的具有1-3个选自N、S和O的杂原子的5-10元杂环基；且所述的取代基选自下组：卤素、C1-C6烷氧基；t、s分别独立的选自0、1或2；
且当X1选自(CH2)t时，s和t不同时为0；
n为0，1或2；
m分别为0，1，2，3或4；当m>1时，各Rc相互独立；
除非特别说明，所述的“取代”是指被选自下组的一个或多个(例如2个、3个、4个等)取代基所取代：卤素、C1-C6烷基、卤代的C1-C6烷基、C1-C6烷氧基、卤代的C1-C6烷氧基、C3-C8环烷基、卤代的C3-C8环烷基、氧代、-CN、羟基、氨基、羧基、-COOH，-(CO)NH2、或位于同一原子上的两个取代基与该原子共同形成C3-C6环烷基；以及未取代或被一个或多个选自下组的取代基取代的选自下组的基团：C6-C10芳基、卤代的C6-C10芳基、具有1-3个选自N、S和O的杂原子的5-10元杂芳基、卤代的具有1-3个选自N、S和O的杂原子的5-10元杂芳基、-(CO)NH(C1-C6烷基)或-(CO)N(C1-C6烷基)2；所述的取代基选自下组：卤素、C1-C6烷氧基；
除非特别说明，所述的杂芳基或杂环基是指基团的环原子中包含1、2或3个选自N，O和S的杂原子；
且所述的分子中至少有一个OH基团或者SH基团。
在另一优选例中，所述的JAK抑制剂为如下式所示的分子，或其药学上可接受的盐，水合物或溶剂合物：
其中：
X选自下组：N或CR，其中R选自下组：氢，氘，卤素，CN，羟基，CF3，N(Ro)2，取代或未取代的C1-C4烷基，取代或未取代的C1-C4烷氧基，取代或未取代的C3-C6环烷基；
A选自下组：键，C＝O，-SO2-，-(C＝O)NRo-；
R11独立地选自：氢，氘，CN，N(Ro)2，取代或未取代的C1-C4烷基，取代或未取 代的C1-C6烷氧基，取代或未取代的C3-C6环烷基，取代或未取代的C3-C6杂环基，取代或未取代的芳基，取代或未取代的5-12元杂芳基，取代或未取代的芳基(C1-C6烷基)，取代或未取代的5-12元杂芳基(C1-C6烷基)和取代或未取代的杂环(C1-C6烷基)；
Ro为H或C1-C4烷基；
R12选自：氢，氘，C1-C4烷基，C3-C6环烷基，卤素和氰基，其中所述烷基或环烷基可以被一个或多个氟原子取代；
R13选自：氢，氘和氨基；
R14为其中：
选自下组：取代或未取代的C6-C10单环或双环芳基，取代或未取代的5-12元单环或双环杂芳基；
Rc为选自下组的基团：卤素，CN，羟基，氨基，-COOH，-(CO)NR17R18，-(SO2)NR17R18，-SO2R17，-NR17COR18，-NR17SO2R18、-(CR17R18)-R19，单取代或双取代的氨基，取代或未取代C1-C6烷基，取代或未取代C1-C6烷氧基，取代或未取代C3-C6环烷基，取代或未取代5-12元杂环基；
R15选自：H，C1-C4烷基；
R16选自：H，C1-C4烷基；
各个R17、R18和R19分别独立的选自：氢，取代或未取代C1-C6烷基，取代或未取代C1-C6烷氧基，取代或未取代C3-C6环烷基，取代或未取代5-12元杂环基；或R17和R18和与其相连的原子形成相应的3-8元碳环或杂环；
n为0，1或2；
m分别为0，1，2，3或4；当m>1时，各Rc相互独立；
除非特别说明，所述的“取代”是指被选自下组的一个或多个(例如2个、3个、4个等)取代基所取代：卤素、C1-C6烷基、卤代的C1-C6烷基、C1-C6烷氧基、卤代的C1-C6烷氧基、C3-C8环烷基、卤代的C3-C8环烷基、氧代、-CN、羟基、氨基、羧基、-COOH，-(CO)NH2、或位于同一原子上的两个取代基与该原子共同形成C3-C6环烷基；以及未取代或被一个或多个选自下组的取代基取代的选自下组的基团：C6-C10芳基、卤代的C6-C10芳基、具有1-3个选自N、S和O的杂原子的5-10元杂芳基、卤代的具有1-3个选自N、S和O的杂原子的5-10元杂芳基、-(CO)NH(C1-C6烷基)或-(CO)N(C1-C6烷基)2；所述的取代基选自下组：卤素、C1-C6烷氧基；
除非特别说明，所述的杂芳基或杂环基是指基团的环原子中包含1、2或3个选自N，O和S的杂原子；
且所述的分子中至少有一个OH基团或者SH基团。
在另一优选例中，所述的JAK抑制剂为如下式所示的分子，或其药学上可接受的盐，水合物或溶剂合物：
其中，
环A为取代或未取代的5-6元芳香环或杂芳环；
环B为取代或未取代的3-6元碳环；
R21选自下组：取代或未取代的C1-C4的烷基、取代或未取代的C3-C8的环烷基、取代或未取代的C1-C4的烷氧基、取代或未取代的C1-C4的烷基氨基、取代或未取代的6-10元芳基、取代或未取代的具有1-3个选自N、S(O)p和O的杂原子的5-10元杂芳基、取代或未取代的具有1-3个选自N、S和O的杂原子的4-10元杂环基；
R22和R24各自独立地选自下组：H、D、卤素、CN、CHF2、CF3；
R23选自下组：H、D、卤素、CN、羟基、氨基、取代或未取代C1-C4烷基、取代或未取代C1-C4烷氧基、COOH、CO(C1-C4烷基)、CONH2、CONH(C1-C4烷基)、CON(C1-C4烷基)2、NH(C1-C4烷基)、N(C1-C4烷基)2、NH(CO)(C1-C4烷基)、O(CO)(C1-C4烷基)；
X1选自键、NH、N(C1-C4烷基)或(CR2)t；
Y1为(CR2)s；
所述的R选自下组：H、卤素、C1-C6烷基、卤代的C1-C6烷基、C1-C6烷氧基、卤代的C1-C6烷氧基、C3-C8环烷基、卤代的C3-C8环烷基、氧代、-CN、羟基、氨基、羧基、未取代或被一个或多个取代基取代的选自下组的基团：C6-C10芳基、卤代的C6-C10芳基、具有1-3个选自N、S和O的杂原子的5-10元杂芳基、卤代的具有1-3个选自N、S和O的杂原子的5-10元杂环基；且所述的取代基选自下组：卤素、C1-C6烷氧基；
t、s分别独立的选自0、1或2；
且当X1选自(CH2)t时，s和t不同时为0；
除非特别说明，所述的“取代”是指被选自下组的一个或多个(例如2个、3个、4个等)取代基所取代：卤素、C1-C6烷基、卤代的C1-C6烷基、C1-C6烷氧基、卤代的C1-C6烷氧基、C3-C8环烷基、卤代的C3-C8环烷基、氧代、-CN、羟基、氨基、羧基、未取代或被一个或多个取代基取代的选自下组的基团：C6-C10芳基、卤代的C6-C10芳基、具有1-3个选自N、S和O的杂原子的5-10元杂芳基、卤代的具有1-3个选自N、S和O的杂原子的5-10元杂环基；且所述的取代基选自下组：卤素、C1-C6烷氧基；
且所述的分子中至少有一个OH基团或者SH基团。
在另一优选例中，所述的G基团具有如下式所示的结构：
其中，各个基团定义如上文中所述；
R15和R16各自独立地选自：H，C1-C4烷基；且Rd选自下组：化学键，-CO，-(CO)N(R18)R17-，-(SO2)N(R18)R17-，-SO2R17，-NR18COR17，-NR18SO2R17、-(CR19R18)-R17，取代或未取代C1-C6亚烷基，取代或未取代C3-C6亚环烷基，取代或未取代5-12元亚杂环基；R17选自下组：化学键、取代或未取代C1-C6亚烷基，取代或未取代C3-C6亚环烷基，取代或未取代5-12元亚杂环基。
在另一优选例中，X为N。
在另一优选例中，A选自下组：C＝O或-(C＝O)NRo-，其中Ro为H或C1-C4烷基。
在另一优选例中，R11独立地选自CN，N(Ro)2，取代或未取代的C1-C4烷基，取代或未取代的C1-C6烷氧基，取代或未取代的C3-C6环烷基，取代或未取代的C3-C6杂环基，取代或未取代的芳基，取代或未取代的5-12元杂芳基，取代或未取代的芳基(C1-C6烷基)，取代或未取代的5-12元杂芳基(C1-C6烷基)和取代或未取代的杂环(C1-C6烷基)；较佳地，R11选自未取代的C3-C6环烷基，或被1-3氟原子或者氘原子取代的C3-C6环烷基。
在另一优选例中，R12选自氢、卤素和氰基；R13为氢；较佳地，Ar为吡唑基，更佳地，Ar为基团。
在另一优选例中，Rd为选自下组的基团：(CO)N(R18)R17-，-(SO2)N(R18)R17-，-SO2R17，-NR18COR17，-NR18SO2R17、-(CR19R18)-R17，取代或未取代C1-C6亚烷基，取代或未取代C3-C6亚环烷基，取代或未取代5-12元亚杂环基。
在另一优选例中，所述的G基团选自下组：
在另一优选例中，所述的G基团具有如下式所示的结构：
在另一优选例中，所述的X1为NH或(CH2)m。
在另一优选例中，所述的A环为取代或未取代的选自下组的基团：
在另一优选例中，R21选自下组：取代或未取代的C1-C4的烷基、取代或未取代的C3-C8的环烷基、取代或未取代的C1-C4的烷氧基、取代或未取代的C1-C4的烷基氨基。
在另一优选例中，所述的G基团具有选自下组的结构：
其中，B环为取代或未取代的3-4元碳环。
在另一优选例中，R22选自氢、卤素和CN。
在另一优选例中，所述的G基团具有选自下组的结构：
在另一优选例中，L选自下组：无、取代或未取代的C1-C6的亚烷基、取代或未取代的C1-C6的亚杂烷基；
R1选自下组：取代或未取代的C1-C20的烷基(直链或支链的)、取代或未取代的C3-C10的环烷基、取代或未取代的C1-C20的杂烷基、取代或未取代的3-20元的杂环基、取代或未取代的苯基；
且所述的R1具有一个或多个选自下组的取代基：C1-C6烷基、卤代的C1-C6烷基、C3-C8环烷基、卤代的C3-C8环烷基。
在另一优选例中，L选自下组：无、取代或未取代的C1-C4的亚烷基；
R1选自下组：取代或未取代的C2-C20的烷基(直链或支链的)；
且所述的R1具有一个或多个选自下组的取代基：C1-C6烷基。
在另一优选例中，所述的具有选自下组的结构：
在另一优选例中，所述的前药分子具有如下式(I)所示的结构：
其中，所述的G为药物分子G'失去一个或多个H原子形成的部分结构片段，其通过分子内任意O原子或S原子与相连。
在另一优选例中，所述的药物分子G'选自下组：JAK抑制剂、MEK抑制剂、BTK抑制剂，或所述的药物分子G'选自下组：
在另一优选例中，所述的G选自下组：

在另一优选例中，所述的式(I)化合物具有如下式所示的结构：






在另一优选例中，所述的药物分子G'的疏水系数CLogP<4。
本发明的第二方面，提供了一种制备如本发明第一方面所述的化合物的方法，所述的方法包括步骤：
在惰性溶剂中，用药物分子G’与酰氯化合物II-2或羧酸化合物II-3反应，得到式I化合物；
在另一优选例中，所述的式I化合物具有如下式II所示的结构，且所述方法包括步骤：
在惰性溶剂中，用式II-1与酰氯化合物II-2或羧酸化合物II-3反应，得到式II化合物；
其中，各基团的定义如本发明第一方面中所述。
本发明的第三方面，提供了一种如本发明第二方面所述的化合物，或其药学上可接受的盐或水合物的用途，其特征在于，用于制备治疗或预防与选自下组的激酶的活性或表达量相关的疾病的药物组合物：JAK、BTK，和MEK。
在另一优选例中，当所述的激酶为JAK时，所述的疾病选自下组：炎症，自身免疫性疾病，神经炎症，关节炎，类风湿性关节炎，脊椎骨关节炎，系统性红斑狼疮，狼疮肾炎，痛风性关节炎，疼痛，发烧，肺结节病，矽肺，心血管疾病，动脉粥样硬化，结节性心肌炎，心肌炎和心脏再灌注损伤，心肌病，中风，缺血，再灌注损伤，脑水肿，脑外伤，神经退行性疾病，肝病，炎性肠病，克罗恩病，溃疡性结肠炎，肾炎，视网膜炎，视网膜病，黄斑变性，青光眼，糖尿病(1型)和2型)，糖尿病性神经病，病毒和细菌感染，肌痛，内毒素性休克，中毒性休克综合征，自身免疫性疾病，骨质疏松症，多发性硬化症，子宫内膜异位症，月经来潮，阴道炎，念珠菌病，癌症，纤维化，肥胖症，肌肉营养不良，多发性肌炎，皮肌炎，自身免疫性肝炎，原发性胆汁性肝硬化，原发性硬化性胆管炎，白癜风，脱发，阿尔茨海默氏病，皮肤潮红，湿疹，牛皮癣，特应性皮炎和晒伤。
在另一优选例中，当所述的激酶为BTK时，所述的疾病选自下组：膀胱癌，脑肿瘤，乳腺癌，子宫癌，结肠直肠癌，食道癌，肝脏癌症，滤泡性淋巴瘤，黑色素瘤，恶性血液病，骨髓瘤，卵巢癌，非小细胞肺癌，前列腺癌，小细胞肺癌，和B-细胞来源的淋巴恶性肿瘤，B细胞增殖性病症：弥漫性B细胞淋巴瘤、滤泡性淋巴瘤、慢性淋巴细胞淋巴瘤、慢性淋巴细胞白血病、B细胞幼淋巴细胞白血病、淋巴质浆细胞淋巴瘤/瓦 尔登斯特伦氏巨球蛋白血症、脾脏边缘带淋巴瘤、浆细胞性骨髓瘤、浆细胞瘤、结外边缘带B细胞淋巴瘤、结内边缘带B细胞淋巴瘤、外套细胞淋巴瘤、纵隔(胸腺)大B细胞淋巴瘤、血管内大B细胞淋巴瘤、原发性渗出性淋巴瘤、伯基特氏淋巴瘤/白血病或淋巴瘤样肉芽肿病；较佳地，所述的疾病或病症选自自身免疫疾病和炎性疾病包括类风湿关节炎、银屑病关节炎、骨性关节炎和幼年型关节炎；所述肝炎包括自身免疫性肝炎；所述膀胱炎包括间质性膀胱炎；所述过敏反应包括过敏症、I型超敏反应、过敏性鼻炎；所述支气管炎包括细支气管炎；所述肠炎包括结肠炎、直肠炎；所述皮炎包括特异性皮炎、硬皮病、银屑病；所述脊髓炎包括急性播散性脑脊髓炎；所述胃炎包括胃肠炎；所述肾炎包括肾盂肾炎；所述鼻炎包括鼻窦炎。
在另一优选例中，当所述的激酶为MEK时，所述的疾病选自下组：慢性疼痛、非小细胞肺癌、慢性髓性白血病(CML)、转移性胆道癌、卵巢癌、腹膜癌。
本发明的第四方面，提供了一种外用给药制剂，其特征在于，包括：
本发明第一方面所述的化合物；
任选的皮肤渗透促进剂，优选地，所述的皮肤渗透促进剂选自下组：表面活性剂、二甲亚砜及其类似物、氮酮类化合物、吡咯酮衍生物、醇类化合物、醚类化合物、脂肪酸类化合物及脂肪酸酯类化合物，或其组合；
任选的支撑层；
较佳地，药物以单一相或者多相，溶液或者混悬存在；制剂以溶液、混悬剂、凝胶剂、乳剂、膏剂或泡沫剂形式给药。
本发明的第五方面，提供了一种提高药物分子G’透膜性的方法，所述方法包括步骤：
将药物分子G’进行修饰，从而在分子中引入片段形成CLogP＞4的同时修饰形成的前药分子(I)的CLogP比药物分子G’的CLogP提高至少1个单位。
在另一优选例中，前药分子的Skin-Pampa的Pe值比修饰前的药物分子G’提高2-100倍。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1为测试例2中试验期间各给药组小鼠皮肤厚度变化图(*P<0.05，**P<0.01，***P<0.001)；
图2为测试例2中试验期间各给药组小鼠PASI评分变化图(*P<0.05，**P<0.01，***P<0.001)；
图3为测试例3中试验期间各给药组小鼠皮肤厚度增加量(**P<0.01)。
具体实施方式
本发明人经过长期而深入的研究，开发了一种如式(I)所示的化合物。所述的化合物由亲水性药物分子端和疏水性末端组成，因此可以具有良好的透皮性能，在外用给药后可以于体内被代谢形成原型药物分子，从而完成给药过程。基于上述发现，发明人完成了本发明。
定义
如本文所用，术语“烷基”包括直链或支链的烷基。例如C1-C6烷基表示具有1-6个碳原子的直链或支链的烷基，例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基等，“C1-C20烷基”具有类似的含义。术语“亚烷基”指失去一个氢原子的烷基，例如C1-C6亚烷基表示具有1-6个碳原子的直链或支链的亚烷基。术语“杂烷基”指碳链上的一个或多个碳原子被选自下组的杂原子取代的烷基：O、S、NH、C(O)或C(NH)，术语“亚杂烷基”具有类似的含义。
如本文所用，术语“C3-C8环烷基”指具有3-8个碳原子(例如3、4、5、6、7、8)的环烷基。其可以是单环，例如环丙基、环丁基、环戊基、环己基、或类似基团。也可以是双环形式，例如桥环、并环或螺环形式，“C3-C20的环烷基”具有类似的定义。
如本文所用，术语“C6-C14芳基”是指具有6-14个碳原子(例如6、7、8、9、10、11、12、13、14)的芳基，例如，苯基或萘基等类似基团。
如本文所用，术语“具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基”指具有5-10个环原子(例如5、6、7、8、9、10)的且其中1-3个原子为选自下组N、S和O的杂原子的环状芳香基团。其可以是单环，也可以是稠环形式。具体的实例可以为吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基、吡咯基、吡唑基、咪唑基、(1,2,3)-三唑基以及(1,2,4)-三唑基、四唑基、呋喃基、噻吩基、异恶唑基、噻唑基、恶唑基等。
如本文所用，术语“3-20元杂环基”是指具有3-20个环原子(例如3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20)，且其中1-3个原子为选自下组N、S和O的杂原子的饱和或部分饱和的环状基团，优选为3-10元杂环基，或4-7元杂环基或9-15元杂环基。其可以是单环，也可以是双环形式，例如桥环或螺环形式。具体的实例可以为氧杂环丁烷、氮杂环丁烷、四氢-2H-吡喃基、哌啶基、四氢呋喃基、吗啉基和吡咯烷基等。“3-8元杂环基”具有类似的定义。
本发明所述的基团除非特别说明是“取代的或未取代的”，否则本发明的基团均可被选自下组的取代基所取代：卤素、腈基、硝基、羟基、氨基、C1-C6烷基-胺基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、卤代C1-C6烷基、卤代C2-C6烯基、卤代C2-C6炔基、卤代C1-C6烷氧基、烯丙基、苄基、C6-C12芳基、C1-C6烷氧基-C1-C6烷基、C1-C6烷氧基-羰基、苯氧羰基、C2-C6炔基-羰基、C2-C6烯基-羰基、C3-C6环烷基-羰基、C1-C6烷基-磺酰基等。
如本文所用，“卤素”或“卤原子”指F、Cl、Br、和I。更佳地，卤素或卤原子选自F、Cl和Br。“卤代的”是指被选自F、Cl、Br、和I的原子所取代。
除非特别说明，本发明所描述的结构式意在包括所有的同分异构形式(如对映异构，非对映异构和几何异构体(或构象异构体))：例如含有不对称中心的R、S构型，双键的(Z)、(E)异构体等。因此，本发明化合物的单个立体化学异构体或其对映异构体、非对映异构体或几何异构体(或构象异构体)的混合物都属于本发明的范围。
如本文所用，术语“水合物”是指本发明化合物与水进行配位形成的配合物。
本申请的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、具体实施方式与其他化学合成方法的结合所形成的实施方式、以及本领域技术人员所熟知的等同替换方式，优选的实施方式包括但不限于本申请的实施例。
本申请所使用的溶剂可以经市售获得。本申请采用的缩略词如：aq代表水溶液；HATU代表O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲六氟磷酸盐；EDCI代表N-(3-二甲基氨基丙基)-N’-乙基碳二亚胺盐酸盐；m-CPBA代表3-氯过氧苯甲酸；eq代表当量、等量；CDI代表羰基二咪唑；DCM代表二氯甲烷；PE代表石油醚；DIAD代表偶氮二羧酸二异丙酯；DMF代表N,N-二甲基甲酰胺；DMSO代表二甲亚砜；EtOAc代表乙酸乙酯；EtOH代表乙醇；MeOH代表甲醇；Cbz代表苄氧羰基，一种氨基保护基；Boc代表叔丁基氧羰基，一种氨基保护基；HOAc代表乙酸；NaCNBH3代表氰基硼氢化钠；r.t.代表室温；THF代表四氢呋喃；TFA代表三氟乙酸；DIPEA代表二异丙基乙基胺；Boc2O代表二-叔丁基二碳酸酯；LDA代表二异丙基氨基锂。
化合物经人工或者软件命名，市售化合物采用供应商目录名称。
适用于外用给药的前药化合物
本发明中，提供了一种药用化合物的前药分子，及其药学上可接受的盐，水合物或溶剂合物，其特征在于，所述前药分子在施用后于体内代谢形成药物分子G'；且所述的药物分子G'的疏水系数CLogP<4；且所述的前药分子具有如下式(I)所示的结构：
其中，所述的G为药物分子G'失去H原子形成的部分结构片段，其通过分子内任意O原子或S原子与相连。
本发明中，形如的亲脂性基团可以有效增加化合物的透皮效率，从而将制备成可以通过外用给药从而代谢成原型化合物分子的新化合物。适用于该前药分子的药物分子G'可以是任意结构，在优选的实施方式下，该药物分子的疏水系数CLogP<4。
由于此类药物分子具有亲脂性端和亲水性的药物分子端，因此可以具有非常好的透膜性，尤其是改善了在皮肤给药过程中药物分子的透皮性。优选的情况下，药物分子是用于皮肤类疾病的药物分子，例如JAK抑制剂，MEK抑制剂，BTK抑制剂等。
药物组合物和施用方法
由于本发明化合物在外用给药后能够在体内代谢形成治疗活性成分，因此本发明化 合物及其各种晶型，药学上可接受的无机或有机盐，水合物或溶剂合物，以及含有本发明化合物为主要活性成分的药物组合物可用于预防和/或治疗(稳定、减轻或治愈)癌症、骨髓增殖性疾病、炎症、免疫性疾病、器官移植、病毒性疾病、心血管疾病或代谢性疾病等在内的多种自身免疫及炎症相关疾病以及血液瘤、淋巴瘤、实体瘤等恶性肿瘤。
本发明的药物组合物包含安全有效量范围内的本发明化合物及药学上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有1-200mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明的前药化合物可方便地配制成包含一种或多种本发明化合物和药用载体的药学组合物。参见Remington：The Science and Practice of Pharmacy第19版(宾夕法尼亚州Easton，Mack Publishing Co.，1995)，该书公开了典型的载体和制备药学组合物的常用方法，所述方法可按叙述使用或经改良，制成含有本发明化合物的药剂。如前所述，本发明的化合物还可以药用盐等形式施用。
本发明的化合物可以含有常用的非毒性药用载体、辅剂和赋形剂的药剂的形式，经口给药、肠胃外给药、外用给药、直肠给药、经鼻给药、口含给药、阴道给药或通过植入的贮器给药。优选地，本发明的化合物可用常用的外用给药系统通过皮肤或粘膜组织进行给药，其中，药剂含于多层结构中，所述多层结构固定在皮肤上，起给药装置的作用。在这样的结构中，药物组合物含于上部的背衬层之下的一层亦即“贮器”层中。多层结构可含有单个贮器，也可含有多个贮器。在一个实例中，贮器包含药用压合式粘合物质的高分子基质，所述粘合物质起着在给药过程中将系统固定于皮肤的作用。合适的皮肤压合式粘合物质包括但不限于聚乙烯、聚硅氧烷、聚异丁烯、聚丙烯酸酯、聚氨酯等。或者，含有药物的贮器和皮肤压合式粘合剂可作为分开的和不同的层存在，在这种情况下，粘合剂在贮器之下，而贮器可以是上述高分子基质，也可以是液体或水凝胶贮器，或者是其他形式。
在这些多层中，作为装置上表面的背衬层起着多层结构的主要结构元素的作用，为装置提供了许多柔韧性。所选的用作背衬材料的物质应基本上不会被活性物质和存在的其他任何物质透过；背衬最好由柔软的弹性材料片或膜制成。适合用作背衬层的聚合物的例子包括聚乙烯、聚丙烯、聚酯等。
在贮存过程中和使用之前，多层结构包括剥离层。在临用之前，将该层从装置上除去，将其底面或药物贮器或单独的压合式粘合剂层露出，使系统可固定在皮肤上。剥离层应由不会被药物/赋形剂透过的材料制成。
外用给药装置可用本领域已知的常用技术制作，例如，在背衬层上浇注粘合剂、药物和赋形剂的流体混合物，然后层压剥离层。类似地，可将粘合剂混合物浇注在剥离层上，然后层压背衬层。或者，可在没有药物或赋形剂的情况下制作药物贮器，然后通过浸泡装入药物/赋形剂混合物。
多层的外用给药系统还可含有皮肤渗透促进剂。即，由于皮肤对某些药物的固有的渗透性可能太小，无法使治疗水平的药物透过相当大小的未破皮肤，需要将皮肤渗透促进剂与这些药物一起施用。合适的促进剂是本领域周知的，例如包括二甲亚砜(DMSO)、二甲基甲酰胺(DMF)、N，N-二甲基乙酰胺(DMA)、癸基甲基亚砜(C10MSO)、C2-C6链烷二醇和1-取代的氮杂环庚-2-酮、醇等。
本发明化合物可以单独给药，或者与其他药学上可接受的治疗剂联合给药。
联合给药时，所述药物组合物还包括与一种或多种(2种，3种，4种，或更多种)其他药学上可接受的治疗剂。该其他药学上可接受的治疗剂中的一种或多种(2种，3种，4种，或更多种)可与本发明的化合物同时、分开或顺序地用于预防和/或治疗细胞因子和/或干扰素介导的疾病。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选1～500mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
实施例1

第一步
在氮气保护下，将化合物1a(6.00g，53.10mmol)溶解在N,N-二甲基甲酰胺(50mL)中，在冰浴下分批加入60％的氢化钠(2.50g，63.72mmol)，反应30分钟后加入溴乙酸甲酯(6.00mL，63.72mmol)，在冰浴下继续反应2小时。冰浴下，反应体系加水(200mL)淬灭，乙酸乙酯(200mL x 2)萃取，有机相依次经饱和食盐水(200mL x 1)，无水硫酸钠干燥，过滤，减压浓缩得到残余物，残余物经柱层析(乙酸乙酯：石油醚＝0-100％)纯化得到化合物1b(8.80g)，收率：89％。
MS-ESI计算值[M+H]+186，实测值186。
第二步
将1b(8.80g，45.57mmol)溶解于甲醇(80mL)中，加入10％湿钯碳(800mg)，置换氢气(15psi)，室温反应过夜。反应液经硅藻土过滤，滤液减压浓缩得到1c(6.20g)，收率：84％。
MS-ESI计算值[M+H]+156，实测值156。
第三步
在氮气保护下，将化合物1d(50.00g，0.11mol)、N,O-二甲基羟胺盐酸盐(12.60g，0.13mol)和三乙胺(32.70g，0.13mol)溶于二氯甲烷(500mL)中，加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(24.80g，0.13mol)和1-羟基苯并三唑(17.50g，0.13mol)，反应液在室温下反应过夜。反应液中加入水(400mL)稀释，二氯甲烷(200mL x 2)萃取，有机相依次用饱和食盐水(300mL x  1)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到残余物，残余物经柱层析(乙酸乙酯：石油醚＝0-100％)纯化得到化合物1e(52.10g)，收率：95％。
MS-ESI计算值[M+H]+507，实测值507。
第四步
在氮气保护下，将化合物1e(20.00g，39.53mmol)溶解在超干四氢呋喃(200mL)中，冷却至-78℃分批加入氢化铝锂(1.80g,47.43mmol)，继续反应2小时。维持-78℃加入0.5M稀盐酸(50mL)淬灭反应，乙酸乙酯(100mL x 2)萃取，有机相经饱和食盐水(100mL x 1)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到粗品1f(19.50g)。
第五步
在氮气保护下，将粗品1f(19.50g，39.53mmol)和2,2-二甲氧基乙胺(13.7g，130.58mmol)溶解在无水甲醇(200mL)中，反应30分钟后冷却至0℃，分批加入氰基硼氢化钠(3.20g，47.44mmol)，自然恢复至室温反应过夜。反应液减压浓缩得到残余物，残余物经柱层析(乙酸乙酯：石油醚＝0-100％)纯化得到化合物1g(9.20g)，收率：43％。
MS-ESI计算值[M+H]+537，实测值537。
1H NMR(400MHz,CDCl3)δ7.41-7.39(m,6H),7.30-7.26(m,6H),7.22-7.18(m,3H),4.74-4.66(brs,1H),4.36(t,J＝5.6Hz，1H),3.67-3.62(m,1H),3.34(s,6H),2.67-2.61(m,3H),2.55-2.41(m,1H),2.24-2.04(m,2H),1.42(s,9H).
第六步
将1g(9.20g，16.17mmol)，三乙胺(4.80mL，34.32mmol)和2,4-二氯嘧啶(3.10g，20.60mmol)溶解在乙醇(100mL)中，升温至70℃反应过夜。反应自然冷却至室温，反应液减压浓缩得到残余物，残余物经柱层析(乙酸乙酯：石油醚＝0-100％)纯化得到化合物1h(7.10g)，收率：64％。
MS-ESI计算值[M+H]+649，实测值649。
第七步
将1h(3.00g，4.63mmol)和1c(861mg，5.56mmol)溶解在异丙醇(20mL)中，升温至130℃反应1小时。反应液冷却至室温，减压浓缩得到残余物，残余物经反相柱层析(乙腈：水＝0-100％)纯化得到化合物1i(3.10g)，收率：86％。
MS-ESI计算值[M+H]+768，实测值768。
第八步
将化合物1i(3.10g，4.04mmol)溶解在三氟乙酸(30mL)和水(10mL)混合溶剂中，升温至60℃反应1小时。反应液冷却至室温，减压浓缩得到残余物，残余物经反相柱层析(乙腈：水＝0-100％)纯化得到1j(1.30g)，收率：86％。
MS-ESI计算值[M+H]+362，实测值362。
第九步
将化合物1j(400mg，1.11mmol)，(1S)-2,2-二氟环丙烷-1-羧酸(162mg，1.33mmol)和三乙胺(448mg，4.44mmol)溶于N,N-二甲基甲酰胺(3mL)中，向反应体系中加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(634mg，1.67mmol)，室温反应30分钟。反应液减压浓缩得到残余物，残余物经制备HPLC纯化得到化合物1k(18mg)，收率：43％。
MS-ESI计算值[M+H]+466，实测值466。
第十步
在氮气保护下，将1k(570mg，1.23mmol)溶解在四氢呋喃(2mL)和乙醇(5mL)混合溶剂中，降温至0℃下，逐滴加入2M硼氢化锂四氢呋喃溶液(3.10mL，6.13mmol)，自然升至室温反应2小时。反应使用饱和氯化铵(1mL)淬灭， 减压浓缩，残余物依次经反相柱层析(乙腈：水＝0-100％)和制备HPLC纯化得到化合物1l(80mg)，收率：15％。
MS-ESI计算值[M+H]+438，实测值438。
1H NMR(400MHz,DMSO-d6)δ8.90(s,1H),8.14(s,1H),7.94(d,J＝6.0Hz,1H),7.81(s,1H),7.45(s,1H),6.15-5.93(m,2H),5.21-5.09(m,1H),4.89-4.77(m,1H),4.46-4.22(m,1H),4.08(t,J＝5.2Hz,2H),3.70(t,J＝5.2Hz,2H),3.19-3.16(m,2H),3.02-2.85(m,3H),2.02-1.98(m,2H).
第十一步
将1l(300mg,0.69mmol)、4-乙基辛酸(154mg,0.89mmol)和4-二甲氨基吡啶(109mg,0.89mmol)溶于10mL二氯甲烷中,加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(170mg,0.89mmol)，反应室温搅拌30分钟。反应液减压浓缩，粗产品经高效液相色谱纯化，冻干得到化合物1(331mg)，收率：91％。
MS-ESI计算值[M+H]+591，实测值591。
1H NMR(400MHz,DMSO-d6)：7.99-7.88(m,2H),7.75-7.64(m,1H),6.71-6.50(m,1H),6.16-5.90(m,1H),5.03-4.70(m,1H),4.57-4.38(m,5H),4.19-4.10(m,1H),3.49-3.33(m,2H),2.97-2.50(m,2H),2.22(t,J＝7.6Hz，2H),2.01-1.99(m,2H),1.44-1.34(m,2H),1.28-1.14(m,10H),0.82(t,J＝6.8Hz，2H),0.75(t,J＝6.8Hz，2H).
实施例2
第一步
依次将化合物1l(200mg，0.48mmol)，异丁酸(42mg，0.48mmol)，4-二甲氨基吡啶(111mg，0.91mmol)以及1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(144mg，0.73mmol)加入反应瓶中，在室温反应4小时，反应液经柱层析(乙酸乙酯：甲醇：二氯甲烷)纯化、冻干得到化合物2(153mg)，收率：66％。
MS-ESI计算值[M+H]+508，实测值508。
1H NMR(400MHz,DMSO-d6)δ8.94(s,1H),7.94(d,J＝6.0Hz,1H),7.81(s,1H),7.48(s,1H),6.26–5.86(m,2H),5.36–4.96(m,1H),4.53–4.07(d,J＝3.7Hz,5H),3.40–2.86(m,6H),2.61–2.28(m,1H),2.12–1.69(m,2H),1.03(d,J＝7.0Hz,6H).
实施例3
第一步
依次将化合物1l(200mg，0.48mmol)，1-己酸(55mg，0.48mmol)，4-二甲氨基吡啶(111mg，0.91mmol)以及1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(140mg，0.73mmol)加入反应瓶中，在室温反应4小时，待检测反应完全后，反应液经柱层析(乙酸乙酯：甲醇：二氯甲烷)纯化、冻干得到化合物3(188mg)，收率：77％。
MS-ESI计算值[M+H]+536，实测值536。
1H NMR(400MHz,DMSO-d6)δ8.92(s,1H),7.94(d,J＝6.0Hz,1H),7.81(s,1H),7.48(s,1H),6.25–5.86(m,2H),5.28–5.04(m,1H),4.62–3.82(m,5H),3.40–2.87(m,6H),2.23(t,J＝7.4Hz,2H),2.09–1.86(m,2H),1.46(p,J＝7.4Hz,2H),1.18(q,J＝8.2,7.4Hz,4H),0.79(t,J＝6.8Hz,3H)
实施例4
第一步
依次将化合物1l(200mg，0.48mmol)，1-辛酸(68mg，0.48mmol)，4-二甲氨基吡啶(111mg，0.91mmol)以及1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(140mg，0.73mmol)加入反应瓶中，在室温反应4小时，待检测反应完全后， 反应液经柱层析(乙酸乙酯：甲醇：二氯甲烷)纯化、冻干得到化合物4(198mg)，收率：76％。
MS-ESI计算值[M+H]+564，实测值564。
1H NMR(400MHz,DMSO-d6)δ8.94(s,1H),7.96(d,J＝6.0Hz,1H),7.83(s,1H),7.50(s,1H),6.31–5.70(m,2H),5.27–5.09(m,1H),4.56–4.16(m,4H),3.44–2.90(m,6H),2.25(t,J＝7.4Hz,2H),2.11–1.91(m,2H),1.54–1.41(m,2H),1.31–1.12(m,9H),0.83(t,J＝6.8Hz,3H).
实施例5
第一步
依次将化合物1l(200mg，0.48mmol)，1-壬酸(75mg，0.48mmol)，4-二甲氨基吡啶(111mg，0.91mmol)以及1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(140mg，0.73mmol)加入反应瓶中，在室温反应4小时，待检测反应完全后，反应液经柱层析(乙酸乙酯：甲醇：二氯甲烷)纯化、冻干得到化合物5(214mg)，收率：80％。
MS-ESI计算值[M+H]+578，实测值578。
1H NMR(400MHz,DMSO-d6)δ8.94(s,1H),7.96(d,J＝6.0Hz,1H),7.82(s,1H),7.49(s,1H),6.40–5.87(m,2H),5.34–5.10(m,1H),4.65–4.02(m,5H),3.43–2.85(m,6H),2.25(t,J＝7.4Hz,2H),2.08–1.89(m,2H),1.56–1.40(m,2H),1.30–1.10(m,10H),0.84(t,J＝6.8Hz,3H).
实施例6

第一步
依次将化合物1l(200mg，0.48mmol)，1-癸酸(78mg，0.48mmol)，4-二甲氨基吡啶(111mg，0.91mmol)以及1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(140mg，0.73mmol)加入反应瓶中，在室温反应4小时，待检测反应完全后，反应液经柱层析(乙酸乙酯：甲醇：二氯甲烷)纯化、冻干得到化合物6(226mg)，收率：83％。
MS-ESI计算值[M+H]+592，实测值592。
1H NMR(400MHz,DMSO-d6)δ8.92(s,1H),7.94(d,J＝6.0Hz,1H),7.80(s,1H),7.48(s,1H),6.27–5.77(m,2H),5.34–5.02(m,1H),4.52–4.00(m,5H),3.39–2.81(m,6H),2.23(t,J＝7.4Hz,2H),2.06–1.86(m,2H),1.51–1.41(m,2H),1.29–1.11(m,12H),0.83(t,J＝6.8Hz,3H).
实施例7
第一步
依次将化合物1l(200mg，0.48mmol)，十二酸(92mg，0.48mmol)，4-二甲氨基吡啶(111mg，0.91mmol)以及1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(140mg，0.73mmol)加入反应瓶中，在室温反应4小时，待检测反应完全后，反应液经柱层析(乙酸乙酯：甲醇：二氯甲烷)纯化、冻干得到化合物7(220mg)，收率：79％。
MS-ESI计算值[M+H]+620，实测值620。
1H NMR(400MHz,DMSO-d6)δ8.92(s,1H),7.94(d,J＝5.9Hz,1H),7.80(s,1H),7.48(s,1H),6.28–5.82(m,2H),5.27–5.07(m,1H),4.59–4.05(m,5H),3.43–2.81(m,6H),2.23(t,J＝7.4Hz,2H),2.08–1.84(m,2H),1.52–1.38(m,2H),1.31–1.11(m,16H),0.84(t,J＝6.8Hz,3H).
实施例8
第一步
依次将化合物1l(200mg，0.48mmol)，十六酸(112mg，0.48mmol)，4-二甲氨基吡啶(111mg，0.91mmol)以及1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(140mg，0.73mmol)加入反应瓶中，在室温反应4小时，待检测反应完全后，反应液经柱层析(乙酸乙酯：甲醇：二氯甲烷)纯化、冻干得到化合物8(196mg)，收率：63％。
MS-ESI计算值[M+H]+676，实测值676。
1H NMR(400MHz,DMSO-d6)δ8.93(s,1H),7.93(d,J＝5.9Hz,1H),7.80(s,1H),7.47(s,1H),6.25–5.70(m,2H),5.25–5.08(m,1H),4.45–4.13(m,5H),3.41–2.82(m,6H),2.23(t,J＝7.4Hz,2H),2.08–1.89(m,2H),1.51–1.37(m,2H),1.33–1.07(m,24H),0.84(t,J＝6.8Hz,3H).
实施例9
第一步
依次将化合物1l(200mg，0.48mmol)，9a(90mg，0.48mmol)，4-二甲氨基吡啶(111mg，0.91mmol)以及1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(140mg，0.73mmol)加入反应瓶中，在室温反应4小时，待检测反应完全后，反应液经柱层析(乙酸乙酯：甲醇：二氯甲烷)纯化、冻干得到化合物9(127mg)，收率：44％。
MS-ESI计算值[M+H]+626，实测值626。
1H NMR(400MHz,DMSO-d6)δ8.94(s,1H),7.96(d,J＝6.0Hz,1H),7.76(s,1H),7.49(s,1H),7.06(d,J＝7.8Hz,2H),6.99(d,J＝7.6Hz,2H),6.25–5.79(m,2H),5.27–5.07(m,1H),4.44–4.13(m,5H),3.68(q,J＝7.2Hz,1H),3.41–2.78(m,6H),2.31(d,J＝7.2Hz,2H),2.08–1.89(m,2H),1.72(dt,J＝13.8,7.0Hz,1H),1.33(dd,J＝7.2,1.6Hz,3H),0.79(d,J＝6.8Hz,6H).
实施例10
第一步
加入化合物10a(2.51g，11.83mmol)，加入甲醇(45mL)，三乙胺(2.39
g，23.66mmol)，在室温搅拌10分钟，加入2,4-二氯嘧啶(1.94g，13.01mmol)，反应2小时，减压浓缩除去溶剂，加入二氯甲烷(100mL)，有机相经饱和氯化铵溶液(100mL x 3)洗涤，无水硫酸钠干燥，减压浓缩除去溶剂得到化合物10b(4.12g)，收率：100％。
MS-ESI计算值[M+H]+325，实测值325。
第二步
加入化合物10b(4.12g，11.83mmol)，加入甲醇(50mL)，加入4M盐酸/1,4-二氧六环溶液(24mL，94.46mmol)在室温搅拌60分钟，加入2,4-二氯嘧啶(1.94g，13.01mmol)，反应2小时，减压浓缩除去溶剂，加入水(50mL)稀释，水相经二氯甲烷(50mL x 3)洗涤，水相经饱和碳酸钠溶液调节pH到9-10之间，水相经二氯甲烷(50mL x 3)萃取，合并有机相，有机相经无水硫酸钠干燥，减压浓缩除去溶剂得到化合物10c(2.74g)，收率：100％。
MS-ESI计算值[M+H]+225，实测值225。
第三步
加入化合物10c(2.02g，9.0mmol)，加入乙酸乙酯(50mL)，加入(1S)-2,2-二氟环丙烷-1-羧酸(1.00g，8.19mmol)，加入N,N-二异丙基乙胺(2.5mL，14.4mmol)，加入50％的1-丙基磷酸酐乙酸乙酯溶液(7.16g，11.25mmol)，在室温搅拌90分钟，停止反应，反应液经饱和氯化铵(50mL x 3)洗涤，有机相经饱和氯化钠溶液(50mL x 1)洗涤，有机相经无水硫酸钠干燥，减压浓缩除去溶剂，残余物经柱层析(乙酸乙酯：石油醚＝0-100％)纯化得到化合物10d(2.65g)，收率： 89％。
MS-ESI计算值[M+H]+329，实测值329。
第四步
加入化合物10d(1.51g，4.59mmol)，加入乙二醇乙醚(10mL)，加入10e(0.70g，5.51mmol)，升温到115℃，在115℃搅拌50分钟，停止反应，减压浓缩除去溶剂，加入饱和碳酸钠溶液(100mL)，加入二氯甲烷(100mL)，分液，有机相经饱和氯化钠溶液(50mL x 3)洗涤，有机相经无水硫酸钠干燥，减压浓缩除去溶剂，残余物经柱层析(甲醇：二氯甲烷＝0-100％)纯化得到化合物10f(2.00g)，收率：100％。
MS-ESI计算值[M+H]+420，实测值420。
1H NMR(400MHz,DMSO-d6)δ8.89(s,1H),7.93(d,J＝6.0Hz,1H),7.81(s,1H),7.45(d,J＝3.2Hz,1H),6.11(dd,J＝10.8,6.0Hz,1H),5.00–4.79(m,1H),4.74–4.49(m,2H),4.13(brs,1H),4.08(t,J＝5.6Hz,3H),3.70(q,J＝5.6Hz,2H),3.28–2.78(m,3H),2.15–1.52(m,6H).
第五步
依次将化合物10f(250mg，0.60mmol)，4-乙基辛酸(102mg，0.60mmol)，4-二甲氨基吡啶(145mg，1.19mmol)以及1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(184mg，0.96mmol)加入反应瓶中，在室温反应4小时，待检测反应完全后，反应液经柱层析(乙酸乙酯：甲醇：二氯甲烷)纯化、冻干得到化合物10(236mg)，收率：69％。
MS-ESI计算值[M+H]+574，实测值574。
1H NMR(400MHz,DMSO-d6)δ8.91(s,1H),7.93(d,J＝6.0Hz,1H),7.80(s,1H),7.47(d,J＝5.2Hz,1H),6.37–5.90(m,1H),4.79–4.41(m,2H),4.44–3.80(m,6H),3.28–2.81(m,3H),2.21(td,J＝7.6,3.6Hz,2H),,2.11–1.61(m,6H),1.56–1.37(m,2H),1.26–1.03(m,11H),0.90–0.70(m,7H).
实施例11
第一步
依次将化合物10f(250mg，0.60mmol)，癸酸(102mg，0.60mmol)，4-二甲氨基吡啶(145mg，1.19mmol)以及1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(184mg，0.96mmol)加入反应瓶中，在室温反应4小时，待检测反应完全后，反应液经柱层析(乙酸乙酯：甲醇：二氯甲烷)纯化、冻干得到化合物11(300mg)，收率：88％。
MS-ESI计算值[M+H]+574，实测值574。
1H NMR(400MHz,DMSO-d6)δ8.91(s,1H),7.93(d,J＝6.0Hz,1H),7.80(s,1H),7.47(d,J＝5.2Hz,1H),6.37–5.90(m,1H),4.79–4.41(m,2H),4.44–3.80(m,6H),3.28–2.81(m,3H),2.22(td,J＝7.6,3.6Hz,2H),2.03–1.64(m,6H),1.43(d,J＝7.6Hz,2H),1.28–1.07(m,12H),0.82(td,J＝6.8,2.8Hz,3H).
实施例12
第一步
将化合物12a(1.16g，0.01mol)溶于二氯甲烷(10mL)中，在氮气保护下，向体系中加入3,4-二氢-2H-吡喃(0.84g，0.01mol)，吡啶对甲苯磺酸盐(241mg，1.00mmol)，室温反应过夜。反应体系减压浓缩得到残余物，残余物经柱层析(乙酸乙酯：石油醚＝0-100％)纯化得到化合物12b(1.00g)，收率：50％。
第二步
将12b(1.00g，5.00mmol)溶解于四氢呋喃(20mL)，在冰浴、氮气保护下，向反应体系中分批加入氢化铝锂(380mg，10.00mmol)，室温反应2小时，向反应体系中缓慢滴加水(1mL)淬灭反应，然后依次向反应体系中缓慢滴加15％氢氧化钠水溶液(1mL)和水(3mL)，无水硫酸镁干燥，过滤，滤液减压浓缩得到粗品12c(0.86g)，直接用于下一步反应。
第三步
将粗品12c(0.86g，5.00mmol)溶解于四氢呋喃(10mL)中，在冰浴和氮气保护下依次加入4-硝基吡唑(565mg，5.00mmol)，三苯基膦(2.60g，10.00mmol)后，向反应体系中滴加偶氮二甲酸二异丙酯(2.00g，10.00mmol)后，室温反应过夜，反应液减压浓缩得到残余物，残余物经柱层(乙酸乙酯：石油醚＝0-100％)纯化得到化合物12d(1.20g)，收率：89％。
MS-ESI计算值[M+Na]+290，实测值290。
第四步
将化合物12d(1.76g，6.60mmol)溶于甲醇(50mL)向其中依次加入饱和氯 化铵溶液(20mL)和铁粉(1.85g，33.00mmol)。反应在90℃搅拌1小时。反应体系冷却至室温后，用水(200mL)和乙酸乙酯(100mL)稀释并分液，有机相用饱和食盐水(50mL x 1)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到残余物，残余物经柱层析(甲醇：二氯甲烷＝0-100％)纯化得到化合物12e(950mg)，收率：60％。
MS-ESI计算值[M+H]+238，实测值238。
1H NMR(400MHz,CDCl3)δ7.28(s,1H),7.15(s,1H),4.68-4.67(m,1H),4.55-4.51(m,1H),3.96-3.93(m,1H),3.85-3.84(m,1H),3.50-3.47(m,1H),2.85(brs,2H),1.63-1.58(m,2H),1.51-1.44(m,4H),1.16-1.11(m,1H),0.90-0.86(m,1H),0.79-0.66(m,2H).
第五步
在氮气保护下，向10d(324mg，1.00mmol)，12e(237mg，1.00mmol)，三二亚苄基丙酮二钯(45mg，0.05mmol)和4,5-双二苯基膦-9,9-二甲基氧杂蒽(59mg，0.10mmol)的甲苯(10mL)溶液中加入碳酸铯(752mg，2.00mmol)。反应液在120℃下搅拌过夜。反应液过滤，滤液减压浓缩得到残余物。残留物经柱层析(乙酸乙酯：石油醚＝0-100％)纯化得到12f(95mg)，收率：18％。
MS-ESI计算值[M+H]+526，实测值526。
第六步
向12f(90mg，0.17mmol)的甲醇溶液(2mL)中加入氯化氢/乙酸乙酯溶液(4M，2mL)。反应在室温下搅拌1小时。反应液浓缩得到粗品12g(90mg)，直接用于下一步反应。
MS-ESI计算值[M+H]+342，实测值342。
第七步
将粗品12g(90mg，0.17mmol)和(1S)-2,2-二氟环丙烷-1-羧酸(23mg，0.18mmol)和N，N-二异丙基乙胺(88mg，0.68mmol)混溶于N，N-二甲基甲酰胺(1mL)中。向其中加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(84mg，0.22mmol)。反应在室温下搅拌1小时。反应结束后，向反应体系中加水(40mL)淬灭反应，用乙酸乙酯(40mL)稀释，分液。有机相用无水硫酸钠干燥，过滤，减压浓缩得到残余物，残余物经制备高效液相色谱纯化得到12h(32mg)，收率：两步43％。
MS-ESI计算值[M+H]+446，实测值446。
1H NMR(400MHz,DMSO-d6)δ8.91(brs,1H),7.90-7.94(m，2H),7.38-7.44(m,1H),6.12-6.08(m,1H),5.49(s,1H),4.68-4.57(m,2H),4.11-4.09(m,4H),3.22-3.14(m,1.5H),2.94-2.91(m,1.5H),2.03-1.94(m,6H),0.64(s,4H).
第八步
将原料12h(170mg,0.38mmol)、4-乙基辛酸(69mg,0.40mmol)和4-二甲氨基吡啶(23mg,0.57mmol)溶于10mL二氯甲烷中，加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(110mg,0.57mmol)，反应室温搅拌过夜。反应液减压浓缩，粗产品经制备高效液相色谱纯化得到白色固体产物12i(150mg)，收率：66％。
MS-ESI计算值[M+H]+600，实测值600。
1H NMR(400MHz,CDCl3)δ7.99(m,1H),7.73(s,1H),7.57(s,1H),6.64(s,1H),4.89-4.80(m,1H),4.44(s,3H),4.26(s,1H),3.94(s,1H),3.17(m,2H),2.56(m,1H),2.22-2.18(m,3H),2.11-1.61(m,5H),1.56(m,2H),1.24-1.19(m,9H),0.97-0.78(m,10H).
第九步
将12i(150mg,0.25mmol)加入到甲醇(5mL)中，向反应液中加入盐酸的乙 酸乙酯溶液(0.1mL,5M)，在室温条件下搅拌30分钟。减压浓缩除去溶剂，残余物经乙腈溶解制备后冷冻干燥，得到化合物12(120mg)，收率：76％。
MS-ESI计算值[M+H]+600，实测值600。
1H NMR(400MHz,DMSO-d6)δ10.21(brs,1H),7.96(m,2H),7.54(m,1H),6.60(m,1H),4.75-4.41(m,5H),3.75(m,1H),3.25-3.23(m,2H),2.12-1.75(m,7H),1.54-0.82(m,23H).
实施例13
第一步
在氮气保护、冰浴下将60％的氢化钠(142mg，3.54mmol)加入到1a(200mg，1.77mmol)的N,N-二甲基甲酰胺(3mL)溶液中，反应30分钟后，向体系中加入13a(460mg，1.77mmol)，在室温条件下反应过夜，反应液经反相柱层析(乙腈：水＝0-100％)纯化得到化合物13b(240mg)，收率：64％。
MS-ESI计算值[M+H]+212，实测值212。
1H NMR(400MHz,CDCl3)δ8.28(s,1H),8.08(s,1H),3.73(s,3H),1.93-1.90(m,2H),1.73-1.70(m,2H).
第二步
在氮气保护下，将10％湿钯碳(10mg)加入到13b(130mg，0.62mmol)的甲醇(3mL)溶液中，反应体系在室温条件下反应3小时后，体系经硅藻土过滤，减压浓缩得到粗品13c(110mg)。
MS-ESI计算值[M+H]+182，实测值182。
第三步
将10d(196mg，0.61mmol)加入粗品13c(110mg，0.61mmol)的正丁醇溶液(5mL)中，130℃反应2小时，反应液冷却至室温，减压浓缩得到残余物，残余物经柱层析(甲醇：二氯甲烷＝0-100％)纯化得到化合物13d(280mg)，收率：98％。
MS-ESI计算值[M+H]+470，实测值470。
第四步
将1M的硼氢化锂四氢呋喃溶液(1.00mL，1.00mmol)加入化合物13d(50mg，0.11mmol)的甲醇(2mL)溶液中，室温反应过夜，减压浓缩得到残余物，残余物经反相柱层析(乙腈：水＝0-100％)纯化得到目化合物13e(23mg)，收率：47％。
MS-ESI计算值[M+H]+442，实测值442。
第五步
将13e(23mg，0.05mmol)溶解在4M盐酸乙酸乙酯溶液(2mL)中，室温反应1小时，减压浓缩得到粗品13f(17mg)。
第六步
将2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐(27mg,0.07mmol)加入化合物13f(17mg，0.05mmol)，(1S)-2,2-二氟环丙烷-1-羧酸(6mg，0.05mmol)和三乙胺(10mg,0.10mmol)的N,N-二甲基甲酰胺溶液(2mL)中，室温反应过夜。减压浓缩得到残余物，残余物经反相柱层析(乙腈：水＝0-100％)纯化得到化合物13g(3mg)，收率：13％。
MS-ESI计算值[M+H]+446，实测值446。
1H NMR(400MHz,CDCl3)δ7.98-7.93(m,1H),7.77(s,1H),7.58-7.54(s,1H),6.54(s,1H),5.96-5.90(m,1H),4.90-4.76(m,1H),4.43(s,1H),4.26-3.92(m,2H),3.77(s,2H),3.22-3.08(m,2H),2.50-1.60(m,8H),1.29(t,J＝6.0Hz,2H),1.10(t,J＝6.0Hz,2H).
第七步
将13g(160mg,0.39mmol)、4-乙基辛酸(69mg,0.40mmol)和4-二甲氨基吡啶(52mg,0.43mmol)溶于5mL二氯甲烷中,加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(82mg,0.43mmol)，反应室温搅拌30分钟。反应液减压浓缩，粗产品直接使用高效液相色谱纯化得到化合物13h(140mg)，收率：65％。
第八步
将13h(140mg,0.23mmol)加入到乙酸乙酯溶液(2mL)中，向反应液中加入盐酸的乙酸乙酯溶液(0.15mL,4M),在室温条件下搅拌30分钟。减压浓缩除去溶剂,残余物经冷冻干燥，得到白色固体目标产物13(108mg)，收率：74％。
MS-ESI计算值[M+H]+600，实测值600。
1H NMR(400MHz,DMSO-d6)δ10.45(brs,1H),8.05-7.85(m,2H),7.62(s,1H),6.63-6.52(m,1H),4.78-4.60(m,2H),4.58-4.44(m,1H),4.31(s,2H),4.05(s,1H),3.32-3.05(m,2H),2.29-2.21(m,2H),2.08-1.92(m,4H),1.78-1.58(m,2H),1.52-1.36(m,2H),1.33-1.12(m,14H),0.85-0.68(m,6H).
实施例14

第一步
将13g(200mg,0.45mmol)和三乙胺(0.2mL,0.90mmol)加入到二氯甲烷溶液(3mL)中，向反应体系中加入辛酰氯(88mg,0.54mmol),在室温条件下搅拌1小时后，液质监测反应完全。向体系中加入水(2mL)淬灭反应，减压浓缩除去溶剂，残余物经反相柱纯化，得到产物14a(190mg)，收率：74％。
MS-ESI计算值[M+H]+572，实测值572。
第二步
将14a(190mg,0.33mmol)入到乙酸乙酯溶液(2mL)，向反应液中加入盐酸的乙酸乙酯溶液(0.1mL,4M),在室温条件下搅拌30分钟。减压浓缩除去溶剂,残余物经冷冻干燥，得到产物14(145mg)，收率：73％。
MS-ESI计算值[M+H]+572，实测值572。
1H NMR(400MHz,DMSO-d6)δ10.40(brs,1H),8.02-7.26(m,2H),7.69-7.56(m,1H),6.63-6.52(m,1H),4.63-4.49(m,2H),4.37-4.30(m,1H),4.18-4.05(m,2H),4.03-3.96(m,1H),3.24-2.95(m,2H),2.29-2.10(m,2H),2.10-1.77(m,4H),1.59-1.48(m,2H),1.23-1.11(m,14H),0.83-0.79(m,3H).
实施例15
第一步
将13g(200mg,0.45mmol)和三乙胺(0.15mL,0.90mmol)加入到二氯甲烷溶液(3mL)中，向反应体系中加入辛酰氯(111mg,0.54mmol),在室温条件下搅拌1小时后，液质监测反应完全。向体系中加入水(2mL)淬灭反应，减压浓缩除去溶剂,残余物经反相柱纯化，得到产物15a(160mg)，收率：58％。
MS-ESI计算值[M+H]+614，实测值614。
第二步
将15a(160mg,0.26mmol)加入到乙酸乙酯溶液(5mL)中，向反应液中加入盐酸的乙酸乙酯溶液(0.1mL,4M),在室温条件下搅拌30分钟。减压浓缩除去溶剂,残余物经冷冻干燥，得到产物15(129mg)，收率：76％。
MS-ESI计算值[M+H]+614，实测值614。
1H NMR(400MHz,DMSO-d6)δ10.45(brs,1H),7.99-7.89(m,2H),7.61(s,1H), 6.68-6.65(m,1H),4.78-4.40(m,3H),4.37-4.30(m,2H),4.23-3.87(m,1H),3.33-3.05(m,3H),2.22-2.21(m,2H),2.06-1.79(m,4H),1.76-1.57(m,2H),1.27-1.17(m,18H),0.85-0.82(m,3H).
实施例16
第一步
将13g(150mg,0.34mmol)和三乙胺(68mg,0.68mmol)加入到二氯甲烷溶液(3mL)，向反应体系中加入己酰氯(6mg,0.34mmol)在室温条件下搅拌1小时后，液质监测反应完全。向体系中加入水(2mL)淬灭反应，有机相旋干经反相柱纯化得到产物16a(130mg)，收率：70％。
MS-ESI计算值[M+H]+544，实测值544。
第二步
将16a(168mg,0.31mmol)加入到乙酸乙酯溶液(2mL)中，向反应液中加入盐酸的乙酸乙酯溶液(0.1mL,4M),在室温条件下搅拌30分钟。减压浓缩干除去溶剂，残余物经冷冻干燥得到白色固体产物16(149mg)，收率：83％。
MS-ESI计算值[M+H]+544，实测值544。
1H NMR(400MHz,DMSO-d6)δ10.50(brs,1H),8.05-7.85(m,2H),7.62(s,1H),6.63-6.52(m,1H),4.78-4.45(m,3H),4.31(s,2H),4.05(s,1H),3.32-3.05(m,3H),2.29-2.21(m,2H),2.08-1.92(m,4H),1.78-1.58(m,2H),1.52-1.36(m,2H),1.33-1.12(m,8H),0.85-0.68(m,3H).
实施例17
第一步
将13g(200mg,0.45mmol)和三乙胺(136mg,1.35mmol)加入到二氯甲烷溶液(5mL)中，向反应体系中加入壬酰氯(87mg,0.49mmol),在室温条件下搅拌1小时后，液质监测反应完全。向体系中加入水(2mL)淬灭反应，减压浓缩除去溶剂，残余物经反相柱纯化得到产物17a(190mg)，收率：72％。
MS-ESI计算值[M+H]+586，实测值586。
第二步
将17a(168mg,0.31mmol)加入到乙酸乙酯溶液(2mL)中，向反应液中加入盐酸的乙酸乙酯溶液(0.1mL,4M),在室温条件下搅拌30分钟。减压浓缩除去溶剂，残余物经冷冻干燥得到产物17(164mg)，收率：83％。
MS-ESI计算值[M+H]+586，实测值586。
1H NMR(400MHz,DMSO-d6)δ10.50(brs,1H),8.05-7.85(m,2H),7.62(s,1H),6.63-6.52(m,1H),4.78-4.45(m,3H),4.31(s,2H),4.05(s,1H),3.32-3.05(m,3H),2.29-2.21(m,2H),2.08-1.92(m,4H),1.78-1.58(m,2H),1.52-1.36(m,2H),1.33-1.12(m,14H),0.85-0.68(m,3H).
实施例18
第一步
将13g(200mg,0.45mmol)和三乙胺(136mg,1.35mmol)加入到二氯甲烷溶液(5mL)中，向反应体系中加入癸酰氯(93mg,0.49mmol),在室温条件下搅拌1小时后，液质监测反应完全。向体系中加入水(2mL)淬灭反应，有机相旋干，残余物经反相柱纯化得到产物18a(225mg)，收率：83％。
MS-ESI计算值[M+H]+600，实测值600。
第二步
将18a(225mg,0.37mmol)加入到乙酸乙酯溶液(2mL)中，向反应液中加入盐酸的乙酸乙酯溶液(0.1mL,4M),在室温条件下搅拌30分钟。减压浓缩除去溶剂，残余物经冷冻干燥得到产物18(135mg)，收率：57％。
MS-ESI计算值[M+H]+600，实测值600。
1H NMR(400MHz,DMSO-d6)δ10.50(brs,1H),8.05-7.85(m,2H),7.62(s,1H),6.63-6.52(m,1H),4.78-4.45(m,3H),4.31(s,2H),4.05(s,1H),3.32-3.05(m,3H),2.29-2.21(m,2H),2.08-1.92(m,4H),1.78-1.58(m,2H),1.52-1.36(m,2H),1.33-1.12(m,16H),0.85-0.68(m,3H).
实施例19
第一步
将13g(200mg,0.45mmol)和三乙胺(136mg,1.35mmol)加入到二氯甲烷溶液(5mL)中，向反应体系中加入十二烷酰氯(107mg,0.49mmol),在室温条件下搅拌1小时后，液质监测反应完全。向体系中加入水(2mL)淬灭反应，减压浓缩除去溶剂，残余物经反相柱纯化得到产物19a(140mg)，收率：50％。
MS-ESI计算值[M+H]+628，实测值628。
第二步
将19a(140mg,0.22mmol)加入到乙酸乙酯溶液(2mL)中，向反应液中加入盐酸的乙酸乙酯溶液(0.1mL,4M),在室温条件下搅拌30分钟。减压浓缩除去溶剂，残余物经冷冻干燥得到产物19(129mg)，收率：88％。
MS-ESI计算值[M+H]+628，实测值628。
1H NMR(400MHz,DMSO-d6)δ10.50(brs,1H),8.05-7.85(m,2H),7.62(s,1H),6.63-6.52(m,1H),4.78-4.45(m,3H),4.31(s,2H),4.05(s,1H),3.32-3.05(m,3H),2.29-2.21(m,2H),2.08-1.92(m,4H),1.78-1.58(m,2H),1.52-1.36(m,2H),1.33-1.12(m,20H),0.85-0.68(m,3H).
实施例20
第一步
将氯化亚砜(69mg,0.58mmol)逐滴加入到9a(97mg,0.47mmol)的二氯甲烷溶液(2mL)中，在室温条件下搅拌1小时后将其加入到13g(200mg,0.45mmol)和三乙胺(136mg,1.35mmol)的二氯甲烷溶液(2mL)中，混合体系在室温条件 下搅拌1小时后，液质监测反应完全。向体系中加入水(2mL)淬灭反应，减压浓缩除去溶剂，残余物经反相柱纯化得到产物20a(119mg)，收率：42％。
MS-ESI计算值[M+H]+634，实测值634。
第二步
将20a(115mg,0.18mmol)加入到乙酸乙酯溶液(2mL)中，向反应液中加入盐酸的乙酸乙酯溶液(0.1mL,4M),在室温条件下搅拌30分钟。减压浓缩除去溶剂，残余物经冷冻干燥得到产物20(103mg)，收率：85％。
MS-ESI计算值[M+H]+634，实测值634。
1H NMR(400MHz,DMSO-d6)δ10.24(brs,1H),8.00(s,1H),7.60(s,2H),7.10-7.00(m,4H),6.57(s,1H),4.78-4.45(m,2H),4.32-4.06(m,4H),3.72(s,1H),3.32-3.05(m,3H),2.29-2.21(m,2H),2.08-1.92(m,4H),1.78-1.58(m,2H),1.52-1.36(m,1H),1.33-1.12(m,7H),0.82-0.76(m,6H).
实施例21
第一步
依次将化合物21a(250mg，0.56mmol)，4-乙基辛酸(115mg，0.67mmol)，N,N,N′,N′-四甲基-O-(7-氮杂苯并三唑-1-基)六氟磷酸脲(380mg，1.00mmol)以及N,N-二异丙基乙胺(180mg，1.39mmol)加入到四氢呋喃(5mL)中，混合体系室温反应过夜。反应液经硅胶柱层析(甲醇：二氯甲烷＝0-100％)纯化得到产物21(248mg)，收率：74％。
MS-ESI计算值[M+H]+604，实测值604。
1H NMR(400MHz,DMSO-d6)δ8.73(s,1H),7.59(d,J＝8.0Hz,2H),7.14(td,J＝8.4,2.0Hz,1H),7.02(d,J＝8.8Hz,2H),6.69(ddd,J＝8.4,6.8,1.6Hz,1H),5.30–5.11(m,1H),4.15(s,1H),3.87(s,3H),2.27–2.07(m,4H),1.98–1.80(m,4H),1.71–1.55(m,2H),1.55–1.38(m,2H),1.29–1.03(m,11H),0.92–0.58(m,6H).
实施例22

第一步
依次将化合物22a(150mg，0.35mmol)，4-乙基辛酸(91mg，0.53mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(135mg，0.70mmol)以及4-二甲氨基吡啶(43mg，0.35mmol)加入到二氯甲烷(5mL)中，混合体系室温反应过夜。反应液经硅胶柱层析(甲醇：二氯甲烷＝0-100％)纯化得到产物22(220mg)，收率：100％。
MS-ESI计算值[M+H]+581，实测值581。
1H NMR(400MHz,DMSO-d6)δ8.00(dd,J＝8.8,5.2Hz,1H),7.67(dd,J＝8.8,2.0Hz,1H),7.28(td,J＝9.2,2.0Hz,1H),5.68(t,J＝4.8Hz,1H),3.93(dt,J＝12.8,5.6Hz,1H),3.70(dt,J＝13.2,6.4Hz,1H),3.18(s,2H),2.78–2.64(m,3H),2.36–2.28(m,3H),2.23(s,3H),2.20–2.04(m,3H),2.02–1.79(m,5H),1.61–1.37(m,2H),1.35–1.04(m,13H),0.94–0.68(m,6H).
实施例23
第一步
依次将化合物23a(180mg，0.39mmol)，4-乙基辛酸(75mg，0.43mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(151mg，0.79mmol)以及4-二甲氨基吡啶(99mg，2.45mmol)加入到四氢呋喃(5mL)中，混合体系室温反应过夜。反应液经硅胶柱层析(甲醇：二氯甲烷＝0-100％)纯化得到产物23(178mg)，收率：71％。
MS-ESI计算值[M+H]+611，实测值611。
1H NMR(400MHz,DMSO-d6)δ8.50–8.37(m,1H),8.24–7.68(m,1H),7.67–7.58(m,1H),7.40–7.20(m,1H),6.51–6.35(m,1H),4.56–4.17(m,2H),4.13–4.00(m,2H),3.98–3.86(m,3H),2.41–2.12(m,2H),1.92(t,J＝8.0Hz,1H),1.57–1.37(m,3H),1.42–0.92(m,9H),0.94–0.41(m,6H).
实施例24

第一步
依次将化合物24a(247mg，1.00mmol)，4-乙基辛酸(258mg，1.50mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(383mg，2.00mmol)以及4-二甲氨基吡啶(122mg，1.00mmol)加入到二氯甲烷(5mL)中，混合体系室温反应过夜。反应液经硅胶柱层析(甲醇：二氯甲烷＝0-100％)纯化得到产物24(230mg)，收率：57％。
MS-ESI计算值[M+H]+402，实测值402。
1H NMR(400MHz,DMSO-d6)δ7.93(d,J＝6.8Hz,1H),6.16(td,J＝4.8,2.0Hz,1H),5.36(dd,J＝4.8,3.2Hz,1H),4.47(dd,J＝12.4,4.8Hz,1H),4.35(dd,J＝12.4,3.2Hz,1H),3.46(t,J＝6.0Hz,1H),3.17(dd,J＝11.6,4.8Hz,1H),2.32(t,J＝7.2Hz,2H),1.50(q,J＝7.2,6.8Hz,2H),1.33–1.06(m,9H),0.83(td,J＝6.8,1.6Hz,3H),0.81–0.76(m,3H).
实施例25
第一步
依次将化合物25a(250mg，0.59mmol)，4-乙基辛酸(201mg，1.17mmol)，N,N,N′,N′-四甲基-O-(7-氮杂苯并三唑-1-基)六氟磷酸脲(167mg，1.76mmol)以及N,N-二异丙基乙胺(302mg，2.34mmol)加入到四氢呋喃(5mL)中，混合体系室温反应过夜。反应液经硅胶柱层析(甲醇：二氯甲烷＝0-100％)纯化得到产物25(140mg)，收率：41％。
MS-ESI计算值[M+H]+582，实测值582。
1H NMR(400MHz,DMSO-d6)δ7.32–6.58(m,7H),5.23(dd,J＝6.0,3.6Hz,1H),4.18–3.99(m,2H),3.73(s,3H),3.09(s,2H),2.68(s,4H),2.60–2.53(m,6H),2.24(t,J＝7.6Hz,2H),2.11(s,6H),1.57–1.38(m,2H),1.33–1.07(m,10H),0.98–0.72(m,6H).
实施例26
第一步
依次将化合物26a(150mg，0.38mmol)，4-乙基辛酸(164mg，0.95mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(255mg，1.33mmol)以及4-二甲氨基吡啶(46mg，0.38mmol)加入到四氢呋喃(5mL)中，混合体系室温反应过夜。反应液经硅胶柱层析(甲醇：二氯甲烷＝0-100％)纯化得到产物26(168mg)，收率：77％。
MS-ESI计算值[M+H]+551，实测值551。
1H NMR(400MHz,DMSO-d6)δ8.28(s,1H),8.09(dt,J＝4.8,2.0Hz,1H),7.67(s,1H),7.36(d,J＝4.8Hz,2H),5.53(s,1H),4.78(s,1H),4.54(s,3H),4.16(d,J＝13.6Hz,1H),3.94(t,J＝6.8Hz,2H),2.87(t,J＝13.2Hz,1H),2.16(t,J＝7.6Hz,2H),2.05–1.71(m,,2H),1.67–1.48(m,5H),1.46–1.04(m,18H),0.82(t,J＝7.0Hz,3H),0.75(t,J＝6.8Hz,3H).
实施例27
第一步
依次将化合物27a(250mg，0.52mmol)，4-乙基辛酸(178mg，1.03mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(297mg，1.55mmol)以及4-二甲氨基吡啶(63mg，0.52mmol)加入到二氯甲烷(5mL)中，混合体系室温反应过夜。反应液经硅胶柱层析(甲醇：二氯甲烷＝0-100％)纯化得到产物27(270mg)，收率：82％。
MS-ESI计算值[M+H]+638，实测值638。
1H NMR(400MHz,DMSO-d6)δ8.74(d,J＝4.8Hz,2H),8.52(s,1H),7.45–7.14(m,3H),7.11–6.96(m,1H),4.57(s,2H),4.48(s,2H),4.33(br s,0.5H),4.26–4.12(m, 2H),3.95(br s,0.5H),3.79(s,3H),3.57–3.44(m,2H),2.25(t,J＝7.6Hz,2H),1.97(br s,2H),1.87(br s,2H),1.46(br s,2H),1.26–1.08(m,9H),0.92–0.65(m,6H).
实施例28
第一步
依次将化合物28a(190mg，0.36mmol)，4-乙基辛酸(69mg，0.40mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(140mg，0.73mmol)以及4-二甲氨基吡啶(45mg，0.36mmol)加入到四氢呋喃(5mL)中，混合体系室温反应过夜。反应液经硅胶柱层析(甲醇：二氯甲烷＝0-100％)纯化得到混合产物28-1，28-2，28-3(120mg)，收率：49％。
MS-ESI计算值[M+H]+677，实测值677。
1H NMR(400MHz,DMSO-d6)δ7.40–7.19(m,2H),7.05(s,1H),5.62–4.48(m,3H),4.20–3.62(m,2H),3.62–3.46(m,3H),3.17–3.03(m,1H),2.96–2.79(m,1H),2.77–2.63(m,1H),2.40–2.28(m,1H),2.23–1.99(m,2H),1.71–1.34(m,6H),1.31–0.86(m,11H),0.91–0.73(m,8H),0.72–0.53(m,1H).
实施例29
第一步
依次将化合物29a(180mg，0.41mmol)，4-乙基辛酸(141mg，0.82mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(198mg，1.03mmol)以及4-二甲氨基吡啶(50mg，0.41mmol)加入到四氢呋喃/N,N二甲基甲酰胺(5mL/1mL)的混合溶剂中，混合体系室温反应过夜。反应液经硅胶柱层析(甲醇：二氯甲烷＝0-100％)纯化得到产物29(178mg)，收率：69％。
MS-ESI计算值[M+H]+595，实测值595。
1H NMR(400MHz,DMSO-d6)δ8.68(s,1H),8.07–7.70(m,2H),5.13(s,1H),4.82 (s,2H),4.39(d,J＝10.4Hz,2H),2.33(t,J＝7.6Hz,2H),1.57–1.44(m,2H),1.28–1.14(m,9H),0.94–0.68(m,6H).
实施例30
第一步
依次将化合物30a(250mg，0.51mmol)，4-乙基辛酸(132mg，0.77mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(196mg，1.02mmol)以及4-二甲氨基吡啶(63mg，0.51mmol)加入到四氢呋喃/N,N二甲基甲酰胺(5mL/1mL)的混合溶剂中，混合体系室温反应过夜。反应液经硅胶柱层析(甲醇：二氯甲烷＝0-100％)纯化得到产物30(271mg)，收率：82％。
MS-ESI计算值[M+H]+642，实测值642。
1H NMR(400MHz,DMSO-d6)δ8.21(s,1H),7.44–7.33(m,1H),7.32–7.17(m,2H),6.05(s,1H),4.14(t,J＝5.6Hz,2H),3.68–3.47(m,4H),2.77–2.55(m,4H),2.40(s,3H),2.34–2.25(m,3H),2.23(s,3H),1.55–1.44(m,2H),1.30–1.12(m,9H),0.94–0.65(m,6H).
测试例1：Skin-Pampa实验
1.将Skin-Pampa膜用水化溶液(hydration solution)过夜进行水化。
2.将各待测化合物溶于DMSO中，配制约20mM的母液0.5mL。
3.取上述母液10μL加入到0.99mL pH7.4缓冲液中，若出现析出，则尝试加入不同比例的pH7.4与乙醇混合溶液直至不出现析出现象，将该比例的混合液作为供给液和接收液。。
4.取10uL母液至相应的0.99mL供给液中，混合均匀。
5.在接收孔中加入200μL供给液，供给孔中加入200μL样品，每个样品平行12孔，进行孵化。
6.孵化8小时后，取供给孔中样品每孔100μL，接收孔中样品每孔100μL，各加900μL的稀释剂(50％乙腈水溶液)，涡旋混合后离心，HPLC含量检测。
7.根据下公式计算Skin-Pampa参数

Pe–有效渗透系数(effective permeability coefficient)
VA–接收孔体积(ml)；
VD–供给孔体积(ml)；
A–膜面积(cm2)；
t–孵化时间(s)；
tLAG–膜平衡时间(s)；
CD(t)–在t时供给孔的浓度；
CA(t)–在t时接收孔的浓度；
CD(0)–供给孔起始的浓度.
表6.Skin-Pampa测试结果汇总

结论：本发明合成的化合物在大鼠透皮实验中具有优良的透皮特性，与药物原型
相比，前药分子可以极大的提高透皮效率，适合用于制备外用制剂。
测试例2：银屑病小鼠模型药效评价实验
采用咪喹莫特(Imiquimod,IMQ)诱导的银屑病小鼠模型，研究实施例1对类-银屑病症状的治疗作用。将背部脱毛的雌性BALB/c小鼠根据皮肤厚度、采用分层随机化法分为5组，分别为溶剂对照组(正常对照)、模型对照组，和实施例1的低、中、高三个剂量组(给药制剂浓度分别为3mg/mL、10mg/mL及30mg/mL)。除溶剂对照组外，其余小鼠每 天在背部脱毛区域涂抹咪喹莫特乳膏一次，连续7天，溶剂对照组每天涂抹凡士林。实施例1化合物处理组每天涂抹给药制剂2次，两次间隔约8小时，连续给药7天；溶剂对照组及模型对照组给予相同体积的溶剂对照；其中第7天仅上午给药一次。每天对动物进行称重、测量背部皮肤厚度、对背部患处拍照并进行PASI评分。
开始造模后，动物皮损区域逐渐出现了典型的银屑病症状，各组动物的皮肤逐渐增厚，PASI评分日益升高。与模型对照组相比，在实施例1局部给药(3mg/mL、10mg/mL和30mg/mL)治疗后，小鼠皮肤厚度均显著减小(如图1)，PASI的评分显著降低(如图2)。
试验结束后，对小鼠实施安乐死，采集造模区域皮肤，采用10％中性甲醛固定、石蜡包埋、切片后进行HE染色、测量表皮及真皮厚度，并进行病理学评分。检测结果如表1所示。与溶剂对照组相比，模型对照组小鼠皮肤出现明显病理改变，主要表现为表皮以及真皮层增厚，表皮角化过度以及少量小灶性坏死，真皮层中性粒细胞浸润。实施例1局部给药后，各治疗组与模型对照组相比，各项病变均有所减轻，并具有一定的量效关系。
表1.小鼠皮肤病理学分析结果

注：##表示与空白对照组比差异极显著(P<0.01)；**表示与模型对照组比差异极显著(P<0.01)。
综上，各实施例1给药组小鼠皮肤厚、PASI评分以及病理学评价结果均显示，实施例1局部给药对于咪喹莫特诱导的银屑病样改变具有较好的治疗作用，且具有一定程度的剂量依赖性。提示本申请化合物局部给药治疗对IMQ诱导的银屑病模型有较好的治疗效果。
测试例3：银屑病小鼠模型药效评价实验2
采用咪喹莫特(Imiquimod,IMQ)诱导的银屑病小鼠模型，研究受试化合物对类-银屑病症状的治疗作用。将背部脱毛的雌性BALB/c小鼠根据皮肤厚度、采用分层随机化法分组，分别为模型对照组和不同化合物处理组(溶剂为PEG400：无水乙醇＝7:3，给药制剂浓度30mg/mL)。除正常对照组外，其余小鼠每天在背部脱毛区域涂抹咪喹莫特乳膏一次，连续7天，正常对照组每天涂抹凡士林。化合物处理组每天涂抹给药制剂2次，两次间隔约8小时，连续给药7天；正常对照组及模型对照组给予相同体积的溶剂对照；其中第7天仅上午给药一次。每天对动物进行称重、测量背部皮肤厚度、对背部患处拍照并进行PASI评分。
开始造模后，动物皮损区域逐渐出现了典型的银屑病症状，各组动物的皮肤逐渐增厚，PASI评分日益升高。与模型组相比，在实施例12化合物及实施例13化合物局部 给药(30mg/mL)治疗后，模型小鼠皮肤厚度均显著减小(如图3)，提示本申请化合物局部给药治疗对IMQ诱导的银屑病模型有较好的治疗效果。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (37)

  1. 一种药用化合物G'的前药分子，及其药学上可接受的盐，水合物或溶剂合物，其特征在于，所述的前药分子具有如下式(I)所示的结构：
    其中，所述的G为药物分子G'失去H原子形成的部分结构片段，其通过分子内任意O原子或S原子与相连；
    L选自下组：无、取代或未取代的C1-C6的亚烷基、取代或未取代的C1-C6的亚杂烷基；
    R1选自下组：氢、取代或未取代的C1-C20的烷基(直链或支链的)、取代或未取代的C3-C20的环烷基、取代或未取代的C1-C20的杂烷基、取代或未取代的3-20元的杂环基、取代或未取代的C6-C14的芳基；
    其中，所述的亚杂烷基、杂烷基指碳链上的一个或多个碳原子被选自下组的杂原子替代：NH、O、S(O)p或C＝O(其中NH上的氢原子可以被取代)；
    所述的杂环基包括1-3个选自下组的杂原子作为环骨架：NH、O、S(O)p或C＝O(其中NH上的氢原子可以被取代)；
    p选自0、1或2；
    除非特别说明，所述的“取代”是指被选自下组的一个或多个(例如2个、3个、4个等)取代基所取代：氘原子、卤素、C1-C6烷基、卤代的C1-C6烷基、C1-C6烷氧基、卤代的C1-C6烷氧基、C3-C8环烷基、卤代的C3-C8环烷基、C3-C8杂环基、氧代、-CN、羟基、氨基、羧基、酰胺、磺酰胺、砜基、未取代或被一个或多个取代基取代的选自下组的基团：C6-C10芳基、卤代的C6-C10芳基、具有1-3个选自N、S和O的杂原子的5-10元杂芳基、卤代的具有1-3个选自N、S和O的杂原子的5-10元杂环基；且所述的取代基选自下组：卤素、C1-C6烷基、C1-C6烷氧基、＝O。
  2. 如权利要求1所述的前药分子，及其药学上可接受的盐，水合物或溶剂合物，其特征在于，所述的药物分子G'选自下组：JAK抑制剂、MEK抑制剂、BTK抑制剂，或所述的药物分子G'选自下组：
  3. 如权利要求2所述的前药分子，及其药学上可接受的盐，水合物或溶剂合物，其特征在于，所述的JAK抑制剂为选自下组的分子或其药学上可接受的盐，水合物或溶剂合物：
  4. 如权利要求2所述的前药分子，及其药学上可接受的盐，水合物或溶剂合物，其特征在于，所述的MEK抑制剂为选自下组的分子，或其药学上可接受的盐，水合物或溶剂合物：

  5. 如权利要求2所述的前药分子，及其药学上可接受的盐，水合物或溶剂合物，其特征在于，所述的BTK抑制剂为选自下组的分子，或其药学上可接受的盐，水合物或溶剂合物：

  6. 如权利要求2任一所述的前药分子，及其药学上可接受的盐，水合物或溶剂合物，其特征在于，所述的JAK抑制剂为如下式所示的分子，或其药学上可接受的盐，水合物或溶剂合物：
    其中：
    X选自下组：N或CR，其中R选自下组：氢，氘，卤素，CN，羟基，CF3，N(Ro)2，取代或未取代的C1-C4烷基，取代或未取代的C1-C4烷氧基，取代或未取代的C3-C6环烷基；
    Y为S或CH2；
    A选自下组：键，C＝O，-SO2-，-(C＝O)NRo-；
    R11独立地选自：氢，氘，CN，N(Ro)2，取代或未取代的C1-C4烷基，取代或未取代的C1-C6烷氧基，取代或未取代的C3-C8环烷基，取代或未取代的4-10元杂环基，取代或未取代的6-10元芳基，取代或未取代的5-12元杂芳基，取代或未取代的6-10元芳基(C1-C6烷基)，取代或未取代的5-12元杂芳基(C1-C6烷基)和取代或未取代的4-10元杂环(C1-C6烷基)；
    Ro为H或C1-C4烷基；
    R12选自：氢，氘，C1-C4烷基，C3-C6环烷基，卤素和氰基，其中所述烷基或环烷基可以被一个或多个氟原子取代；
    R13选自：氢，氘和氨基；
    R14为其中：
    选自下组：取代或未取代的C6-C10单环或双环芳基，取代或未取代的5-12 元单环或双环杂芳基；
    Rc为选自下组的基团：卤素，CN，羟基，氨基，-COOH，-(CO)NR17R18，-(SO2)NR17R18，-SO2R17，-NR17COR18，-NR17SO2R18、-(CR17R18)-R19，单取代或双取代的氨基，取代或未取代C1-C6烷基，取代或未取代C1-C6烷氧基，取代或未取代C3-C6环烷基，取代或未取代5-12元杂环基，或环B为取代或未取代的3-6元碳环；R24选自：H、D、卤素、CN、C1-C4烷基、C1-C4卤代烷基；
    各个R17、R18和R19分别独立的选自：氢，取代或未取代C1-C6烷基，取代或未取代C1-C6烷氧基，取代或未取代C3-C6环烷基，取代或未取代5-12元杂环基；或R17和R18和与其相连的原子形成相应的3-8元碳环或杂环；
    R23选自下组：H、D、卤素、CN、羟基、氨基、取代或未取代C1-C4烷基、取代或未取代C1-C4烷氧基、COOH、CO(C1-C4烷基)、CONH2、CONH(C1-C4烷基)、CON(C1-C4烷基)2、NH(C1-C4烷基)、N(C1-C4烷基)2、NH(CO)(C1-C4烷基)、O(CO)(C1-C4烷基)；
    X1选自键、NH、N(C1-C4烷基)或(CR2)t；Y1为(CR2)s；所述的R2选自下组：H、卤素、C1-C6烷基、卤代的C1-C6烷基、C1-C6烷氧基、卤代的C1-C6烷氧基、C3-C8环烷基、卤代的C3-C8环烷基、氧代、-CN、羟基、氨基、羧基、未取代或被一个或多个取代基取代的选自下组的基团：C6-C10芳基、卤代的C6-C10芳基、具有1-3个选自N、S和O的杂原子的5-10元杂芳基、卤代的具有1-3个选自N、S和O的杂原子的5-10元杂环基；且所述的取代基选自下组：卤素、C1-C6烷氧基；t、s分别独立的选自0、1或2；
    且当X1选自(CH2)t时，s和t不同时为0；
    n为0，1或2；
    m分别为0，1，2，3或4；当m>1时，各Rc相互独立；
    除非特别说明，所述的“取代”是指被选自下组的一个或多个(例如2个、3个、4个等)取代基所取代：卤素、C1-C6烷基、卤代的C1-C6烷基、C1-C6烷氧基、卤代的C1-C6烷氧基、C3-C8环烷基、卤代的C3-C8环烷基、氧代、-CN、羟基、氨基、羧基、-COOH，-(CO)NH2、或位于同一原子上的两个取代基与该原子共同形成C3-C6环烷基；以及未取代或被一个或多个选自下组的取代基取代的选自下组的基团：C6-C10芳基、卤代的C6-C10芳基、具有1-3个选自N、S和O的杂原子的5-10元杂芳基、卤代的具有1-3个选自N、S和O的杂原子的5-10元杂芳基、-(CO)NH(C1-C6烷基)或-(CO)N(C1-C6烷基)2；所述的取代基选自下组：卤素、C1-C6烷氧基；
    除非特别说明，所述的杂芳基或杂环基是指基团的环原子中包含1、2或3个选自N，O和S的杂原子；
    且所述的分子中至少有一个OH基团或者SH基团。
  7. 如权利要求2，6任一所述的前药分子，及其药学上可接受的盐，水合物或溶剂合物，其特征在于，所述的JAK抑制剂为如下式所示的分子，或其药学上可接受的盐，水合物或溶剂合物：
    其中：
    X选自下组：N或CR，其中R选自下组：氢，氘，卤素，CN，羟基，CF3，N(Ro)2，取代或未取代的C1-C4烷基，取代或未取代的C1-C4烷氧基，取代或未取代的C3-C6环烷基；
    A选自下组：键，C＝O，-SO2-，-(C＝O)NRo-；
    R11独立地选自：氢，氘，CN，N(Ro)2，取代或未取代的C1-C4烷基，取代或未取代的C1-C6烷氧基，取代或未取代的C3-C6环烷基，取代或未取代的C3-C6杂环基，取代或未取代的芳基，取代或未取代的5-12元杂芳基，取代或未取代的芳基(C1-C6烷基)，取代或未取代的5-12元杂芳基(C1-C6烷基)和取代或未取代的杂环(C1-C6烷基)；
    Ro为H或C1-C4烷基；
    R12选自：氢，氘，C1-C4烷基，C3-C6环烷基，卤素和氰基，其中所述烷基或环烷基可以被一个或多个氟原子取代；
    R13选自：氢，氘和氨基；
    R14为其中：
    选自下组：取代或未取代的C6-C10单环或双环芳基，取代或未取代的5-12元单环或双环杂芳基；
    Rc为选自下组的基团：卤素，CN，羟基，氨基，-COOH，-(CO)NR17R18，-(SO2)NR17R18，-SO2R17，-NR17COR18，-NR17SO2R18、-(CR17R18)-R19，单取代或双取代的氨基，取代或未取代C1-C6烷基，取代或未取代C1-C6烷氧基，取代或未取代C3-C6环烷基，取代或未取代5-12元杂环基；
    R15选自：H，C1-C4烷基；
    R16选自：H，C1-C4烷基；
    各个R17、R18和R19分别独立的选自：氢，取代或未取代C1-C6烷基，取代或未取代C1-C6烷氧基，取代或未取代C3-C6环烷基，取代或未取代5-12元杂环基；或R17和R18和与其相连的原子形成相应的3-8元碳环或杂环；
    n为0，1或2；
    m分别为0，1，2，3或4；当m>1时，各Rc相互独立；
    除非特别说明，所述的“取代”是指被选自下组的一个或多个(例如2个、3个、4个等)取 代基所取代：卤素、C1-C6烷基、卤代的C1-C6烷基、C1-C6烷氧基、卤代的C1-C6烷氧基、C3-C8环烷基、卤代的C3-C8环烷基、氧代、-CN、羟基、氨基、羧基、-COOH，-(CO)NH2、或位于同一原子上的两个取代基与该原子共同形成C3-C6环烷基；以及未取代或被一个或多个选自下组的取代基取代的选自下组的基团：C6-C10芳基、卤代的C6-C10芳基、具有1-3个选自N、S和O的杂原子的5-10元杂芳基、卤代的具有1-3个选自N、S和O的杂原子的5-10元杂芳基、-(CO)NH(C1-C6烷基)或-(CO)N(C1-C6烷基)2；所述的取代基选自下组：卤素、C1-C6烷氧基；
    除非特别说明，所述的杂芳基或杂环基是指基团的环原子中包含1、2或3个选自N，O和S的杂原子；
    且所述的分子中至少有一个OH基团或者SH基团。
  8. 如权利要求2或6任一所述的前药分子，及其药学上可接受的盐，水合物或溶剂合物，其特征在于，所述的JAK抑制剂为如下式所示的分子，或其药学上可接受的盐，水合物或溶剂合物：
    其中，
    环A为取代或未取代的5-6元芳香环或杂芳环；
    环B为取代或未取代的3-6元碳环；
    R21选自下组：取代或未取代的C1-C4的烷基、取代或未取代的C3-C8的环烷基、取代或未取代的C1-C4的烷氧基、取代或未取代的C1-C4的烷基氨基、取代或未取代的6-10元芳基、取代或未取代的具有1-3个选自N、S(O)p和O的杂原子的5-10元杂芳基、取代或未取代的具有1-3个选自N、S和O的杂原子的4-10元杂环基；
    R22和R24各自独立地选自下组：H、D、卤素、CN、CHF2、CF3；
    R23选自下组：H、D、卤素、CN、羟基、氨基、取代或未取代C1-C4烷基、取代或未取代C1-C4烷氧基、COOH、CO(C1-C4烷基)、CONH2、CONH(C1-C4烷基)、CON(C1-C4烷基)2、NH(C1-C4烷基)、N(C1-C4烷基)2、NH(CO)(C1-C4烷基)、O(CO)(C1-C4烷基)；
    X1选自键、NH、N(C1-C4烷基)或(CR2)t；
    Y1为(CR2)s；
    所述的R选自下组：H、卤素、C1-C6烷基、卤代的C1-C6烷基、C1-C6烷氧基、卤代的C1-C6烷氧基、C3-C8环烷基、卤代的C3-C8环烷基、氧代、-CN、羟基、氨基、羧基、未取代或被一个或多个取代基取代的选自下组的基团：C6-C10芳基、卤代的C6-C10芳基、具有1-3个选自N、S和O的杂原子的5-10元杂芳基、卤代的具有1-3个选自N、S和O的杂原子的5-10元杂环基；且所述的取代基选自下组：卤素、C1-C6烷氧基；
    t、s分别独立的选自0、1或2；
    且当X1选自(CH2)t时，s和t不同时为0；
    除非特别说明，所述的“取代”是指被选自下组的一个或多个(例如2个、3个、4个等)取代基所取代：卤素、C1-C6烷基、卤代的C1-C6烷基、C1-C6烷氧基、卤代的C1-C6烷氧基、C3-C8环烷基、卤代的C3-C8环烷基、氧代、-CN、羟基、氨基、羧基、未取代或被一个或多个取代基取代的选自下组的基团：C6-C10芳基、卤代的C6-C10芳基、具有1-3个选自N、S和O的杂原子的5-10元杂芳基、卤代的具有1-3个选自N、S和O的杂原子的5-10元杂环基；且所述的取代基选自下组：卤素、C1-C6烷氧基；
    且所述的分子中至少有一个OH基团或者SH基团。
  9. 如权利要求1、2或6所述的前药分子，及其药学上可接受的盐，水合物或溶剂合物，其特征在于，所述的G基团具有如下式所示的结构：
    其中，各个基团定义如权利要求6中所述；
    R15和R16各自独立地选自：H，C1-C4烷基；且Rd选自下组：化学键，-CO，-(CO)N(R18)R17-，-(SO2)N(R18)R17-，-SO2R17，-NR18COR17，-NR18SO2R17、-(CR19R18)-R17，取代或未取代C1-C6亚烷基，取代或未取代C3-C6亚环烷基，取代或未取代5-12元亚杂环基；R17选自下组：化学键、取代或未取代C1-C6亚烷基，取代或未取代C3-C6亚环烷基，取代或未取代5-12元亚杂环基。
  10. 如权利要求9所述的前药分子，及其药学上可接受的盐，水合物或溶剂合物，其特征在于，X为N。
  11. 如权利要求9所述的前药分子，及其药学上可接受的盐，水合物或溶剂合物，其特征在于，A选自下组：C＝O或-(C＝O)NRo-，其中Ro为H或C1-C4烷基。
  12. 如权利要求9所述的前药分子，及其药学上可接受的盐，水合物或溶剂合物，其特征在于，R11独立地选自CN，N(Ro)2，取代或未取代的C1-C4烷基，取代或未取代的C1-C6烷氧基，取代或未取代的C3-C6环烷基，取代或未取代的C3-C6杂环基，取代或未取代的芳基，取代或未取代的5-12元杂芳基，取代或未取代的芳基(C1-C6烷基)，取代或未取代的5-12元杂芳基(C1-C6烷基)和取代或未取代的杂环(C1-C6烷基)；较佳地，R11选自未取代的C3-C6环烷基，或被1-3氟原子或者氘原子取代的C3-C6环烷基。
  13. 如权利要求9所述的前药分子，及其药学上可接受的盐，水合物或溶剂合物，其特征在于，R12选自氢、卤素和氰基；R13为氢；较佳地，Ar为吡唑基，更佳地，Ar为基团。
  14. 如权利要求9所述的前药分子，及其药学上可接受的盐，水合物或溶剂合物，其特征在于，Rd为选自下组的基团：(CO)N(R18)R17-，-(SO2)N(R18)R17-，-SO2R17，- NR18COR17，-NR18SO2R17、-(CR19R18)-R17，取代或未取代C1-C6亚烷基，取代或未取代C3-C6亚环烷基，取代或未取代5-12元亚杂环基。
  15. 如权利要求9所述的前药分子，及其药学上可接受的盐，水合物或溶剂合物，所述的G基团选自下组：
  16. 如权利要求1、2或6所述的前药分子，及其药学上可接受的盐，水合物或溶剂合物，其特征在于，所述的G基团具有如下式所示的结构：
  17. 如权利要求16所述的前药分子，其特征在于，所述的X1为NH或(CH2)m。
  18. 如权利要求16所述的前药分子，其特征在于，所述的A环为取代或未取代的选自下组的基团：
  19. 如权利要求16所述的前药分子，其特征在于，R21选自下组：取代或未取代的C1-C4的烷基、取代或未取代的C3-C8的环烷基、取代或未取代的C1-C4的烷氧基、取代或未取代的C1-C4的烷基氨基。
  20. 如权利要求16所述的前药分子，其特征在于，所述的G基团具有选自下组的结构：
    其中，B环为取代或未取代的3-4元碳环。
  21. 如权利要求16所述的前药分子，其特征在于，R22选自氢、卤素和CN。
  22. 如权利要求16所述的前药分子，其特征在于，所述的G基团具有选自下组的结构：
  23. 如权利要求1-22任一所述的前药分子，及其药学上可接受的盐，水合物或溶剂合物，其特征在于，L选自下组：无、取代或未取代的C1-C6的亚烷基、取代或未取代的C1-C6的亚杂烷基；
    R1选自下组：取代或未取代的C1-C20的烷基(直链或支链的)、取代或未取代的C3-C10的环烷基、取代或未取代的C1-C20的杂烷基、取代或未取代的3-20元的杂环基、取代或未取代的苯基；
    且所述的R1具有一个或多个选自下组的取代基：C1-C6烷基、卤代的C1-C6烷基、C3-C8环烷基、卤代的C3-C8环烷基。
  24. 如权利要求1-22任一所述的前药分子，及其药学上可接受的盐，水合物或溶剂合物，其特征在于，L选自下组：无、取代或未取代的C1-C4的亚烷基；
    R1选自下组：取代或未取代的C2-C20的烷基(直链或支链的)；
    且所述的R1具有一个或多个选自下组的取代基：C1-C6烷基。
  25. 如权利要求1-22任一所述的前药分子，及其药学上可接受的盐，水合物或溶剂合 物，其特征在于，所述的具有选自下组的结构：
  26. 如权利要求1所述的前药分子，及其药学上可接受的盐，水合物或溶剂合物，其特征在于，所述的前药分子具有如下式(I)所示的结构：
    其中，所述的G为药物分子G'失去一个或多个H原子形成的部分结构片段，其通过分子内任意O原子或S原子与相连。
  27. 如权利要求26所述的前药分子，及其药学上可接受的盐，水合物或溶剂合物，其特征在于，所述的药物分子G'选自下组：JAK抑制剂、MEK抑制剂、BTK抑制剂，或所述的药物分子G'选自下组：
  28. 如权利要求26-27任一所述的前药分子，及其药学上可接受的盐，水合物或溶剂合物，其特征在于，所述的G选自下组：

  29. 如权利要求1-22，或26-27任一所述的前药分子，及其药学上可接受的盐，水合物或溶剂合物，其特征在于，所述的式(I)化合物具有如下式所示的结构：







  30. 如权利要求1-22，或26-27任一所述的前药分子，及其药学上可接受的盐，水合物或溶剂合物，其特征在于，所述的药物分子选自下组：


  31. 如权利要求1所述的前药分子，及其药学上可接受的盐，水合物或溶剂合物，其特征在于，所述的药物分子G'的疏水系数CLogP<4。
  32. 一种制备如权利要求1所述的化合物的方法，其特征在于，所述的方法包括步骤：
    在惰性溶剂中，用药物分子G’与酰氯化合物II-2或羧酸化合物II-3反应，得到式I化合物；
    其中，各基团的定义如权利要求1中所述。
  33. 如权利要求32所述的方法，其特征在于，所述的式I化合物具有如下式II所示的结构，且所述的方法包括步骤：
    在惰性溶剂中，用式II-1与酰氯化合物II-2或羧酸化合物II-3反应，得到式II化合物；
    其中，各基团的定义如权利要求9中所述。
  34. 一种权利要求1-30任一所述的化合物，或其药学上可接受的盐或水合物的用途，其特征在于，用于制备治疗或预防与JAK激酶的活性或表达量相关的疾病的药物组合物。
  35. 一种外用给药制剂，其特征在于，包括：
    权利要求1-30任一所述的化合物；
    任选的皮肤渗透促进剂，优选地，所述的皮肤渗透促进剂选自下组：表面活性剂、二甲亚砜及其类似物、氮酮类化合物、吡咯酮衍生物、醇类化合物、醚类化合物、脂肪酸类化合物及脂肪酸酯类化合物，或其组合；
    任选的支撑层；
    较佳地，药物以单一相或者多相，溶液或者混悬存在；制剂以溶液、混悬剂、凝胶剂、乳剂、膏剂或泡沫剂形式给药。
  36. 一种提高药物分子G’透膜性的方法，其特征在于，包括步骤：
    将药物分子G’进行修饰，从而在分子中引入片段形成CLogP＞4的同时修饰形成的前药分子(I)的CLogP比药物分子G’的CLogP提高至少1；
    其中，各个基团具有如权利要求1-30中任一所述的定义。
  37. 如权利要求36所述的方法，其特征在于，前药分子的Skin-Pampa的Pe值比修饰前的药物分子G’提高2-100倍。
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