CN117567460A

CN117567460A - Prodrug compound and preparation method and application thereof

Info

Publication number: CN117567460A
Application number: CN202210946367.7A
Authority: CN
Inventors: 李傲; P·K·贾达夫; 陈以乐; 曹国庆
Original assignee: Minghui Pharmaceutical Shanghai Co ltd; Minghui Pharmaceutical Hangzhou Co ltd
Current assignee: Minghui Pharmaceutical Shanghai Co ltd; Minghui Pharmaceutical Hangzhou Co ltd
Priority date: 2022-08-08
Filing date: 2022-08-08
Publication date: 2024-02-20
Also published as: WO2024032569A1

Abstract

The invention provides a prodrug compound and a preparation method and application thereof, in particular to a compound shown as a formula (I), a preparation method thereof and application of the compound as a prodrug in preparing an external preparation.

Description

Prodrug compound and preparation method and application thereof

Technical Field

The invention relates to the field of small molecules of medicaments, in particular to prodrug molecules serving as medicinal compounds, pharmaceutically acceptable salts, hydrates or solvates thereof, and a medicinal composition (preferably an external preparation) containing the components.

Background

JAK-STAT signaling pathway is a cytokine-stimulated signaling pathway discovered in recent years, JAK plays an important role in cytokine signaling, and downstream substrates of the JAK kinase family include the signaling agents and activators of transcription proteins (STATs). JAK protein is an important member of this pathway, and abnormal increases in its activity often lead to the development of diseases, many of which are associated with abnormal cellular responses to JAK-STAT signaling pathways, including autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, alzheimer's disease.

Rheumatoid arthritis (rheumatoid arthritis, RA) is a clinically common chronic autoimmune disease, mainly manifested by joint swelling, pain, stiffness, deformity, severely impaired function, etc., with a prevalence of 0.5% -1.0% in the population. Because the pathogenesis of RA is not clear, the pathological process is difficult to control, the disability rate is high, the physical and mental health of patients is seriously damaged, and the life quality of the patients is reduced. Currently, drugs used to treat RA are mainly nonsteroidal anti-inflammatory drugs (NSAIDs), disease modifying antirheumatic drugs (DMARDs), and antibodies. For a long time, the first line drug for treating RA was DMARDs, and in 1988, the 1 st DMARD drug Methotrexate (MTX) was FDA approved for treating RA, MTX being an important milestone in the history of RA treatment. The medicine is widely used because of the advantages of effectiveness, tolerance, safety and the like, but has adverse reactions including nausea, vomiting, stomach discomfort, hepatotoxicity and the like. In contrast, newly developed antibody drugs have better efficacy and safety indexes for moderately severe RA, but the beneficial population is obviously limited due to targeting specific cytokines, and the promotion of the drugs is limited by treatment cost and administration in an injection mode.

In the course of development over the past 20 years, RA treatment has progressed to a great extent and patient conditions have been effectively controlled by existing methods of treatment. Nonetheless, RA patients suffer from problems of recurrent disease, unsatisfactory therapeutic efficacy, poor long-term tolerability, and some adverse reactions. More importantly, the quality of life of RA patients, including the function of organs such as joints, is not truly improved by existing therapeutic approaches, and thus there is still a great unmet clinical need in this field to focus on restoring normal functioning of patients.

Research shows that the core disease treatment function in RA is that mononuclear cells/macrophages, lymphocytes and the like infiltrated in RA synovial tissues and cells produce a large amount of cytokines in an autocrine mode, the cytokines interact, JAK/STAT signal paths (Janus kinase/Signal transducer and activators of transcription signaling pathway) are activated through different paths, and the cascade amplification function of the cytokines can be blocked through specific inhibition of the JAK/STAT signal paths, so that the damaged joint symptoms of RA patients are improved, and therefore, the JAK/STAT signal paths become potential targets for treating RA.

Because JAK kinase participates in various important physiological processes in vivo, adverse reactions are possibly generated on the extensive inhibition of different subtypes, and Tofacitinib is used for moderately severe RA patients with insufficient or intolerance MTX reaction, and clinical experiments observe that the JAK kinase accompanies certain adverse reactions, including infection, tuberculosis, tumor, anemia, liver injury, cholesterol increase and the like. Tofacitinib has remarkable inhibitory activity on all of JAK1, JAK2 and JAK3 subtypes, and the adverse reaction of the part is considered to be related to the nonselective inhibitory characteristics of the drug because the JAK2 activity is related to erythrocyte differentiation and lipid metabolism. Thus, the search for selective JAK1 and/or JAK3 inhibitors would be a new direction for RA drug research.

JAK inhibitors have been shown to be useful in the treatment of hematological disorders, tumors, rheumatoid arthritis, atopic dermatitis, psoriasis, and the like. However, JAK inhibitor compositions available for topical administration in the art remain very limited.

Disclosure of Invention

It is an object of the present invention to provide a JAK inhibitor composition for topical administration.

In a first aspect, the present invention provides a prodrug molecule of a pharmaceutical compound G', and pharmaceutically acceptable salts, hydrates or solvates thereof, characterized in that the prodrug molecule has a structure as shown in the following formula (I):

wherein, G is a part of structural fragment formed by the loss of H atom of the drug molecule G', which is formed by any O atom or S atom and any S atom in the moleculeAre connected;

l is selected from the group consisting of: an unsubstituted, substituted or unsubstituted C1-C6 alkylene group, a substituted or unsubstituted C1-C6 heteroalkylene group;

R ¹ selected from the group consisting of: substituted or unsubstituted C1-C20 alkyl (straight or branched), substituted or unsubstituted C3-C20 cycloalkyl, substituted or unsubstituted C1-C20 heteroalkyl, substituted or unsubstituted 3-20 membered heterocyclyl, substituted or unsubstituted C6-C14 aryl;

wherein, the heteroalkylene and heteroalkyl refer to one or more carbon atoms on a carbon chain replaced by a heteroatom selected from the group consisting of: NH, O or S (O) _p (wherein a hydrogen atom on NH may be substituted);

the heterocyclic group comprises 1-3 hetero atoms selected from the following groups as a ring skeleton: NH, O or S (O) _p (wherein a hydrogen atom on NH may be substituted);

p is selected from 0, 1 or 2;

unless otherwise specified, "substituted" means substituted with one or more (e.g., 2, 3, 4, etc.) substituents selected from the group consisting of: 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, hydroxy, amino, carboxyl, amide, sulfonamide, sulfone group, a group selected from the group consisting of unsubstituted or substituted with one or more substituents: C6-C10 aryl, halogenated C6-C10 aryl, 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O, halogenated 5-10 membered heterocyclyl having 1-3 heteroatoms selected from N, S and O; and the substituents are selected from the group consisting of: halogen, C1-C6 alkyl, C1-C6 alkoxy, =o.

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

In another preferred embodiment, the JAK inhibitor is a molecule selected from the group consisting of:

In another preferred embodiment, the MEK inhibitor is a molecule selected from the group consisting of:

in another preferred embodiment, the BTK inhibitor is a molecule selected from the group consisting of:

in another preferred embodiment, the JAK inhibitor is a molecule of the formula:

wherein:

x is selected from the group consisting of: n or CR, wherein R is selected from the group consisting of: hydrogen, deuterium, halogen, CN, hydroxy, CF ₃ ，N(R _o ) ₂ Substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4Alkoxy, substituted or unsubstituted C3-C6 cycloalkyl;

y is S or CH;

a is selected from the group consisting of: bond, c=o, -SO ₂ -，-(C＝O)NR _o -; wherein R is _o Is H or C1-C4 alkyl;

R ¹¹ 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 ¹² Selected from: hydrogen, deuterium, C1-C4 alkyl, C3-C6 cycloalkyl, halogen and cyano, wherein the alkyl or cycloalkyl may be substituted with one or more fluorine atoms;

R ¹³ selected from: hydrogen, deuterium and amino;

R ¹⁴ is thatWherein:

selected from the group consisting of: a substituted or unsubstituted C6-C10 monocyclic or bicyclic aryl, a substituted or unsubstituted 5-12 membered monocyclic or bicyclic heteroaryl;

rc is a group selected from the group consisting of: halogen, CN, hydroxy, 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 An amino group, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C6 alkoxy group, a substituted or unsubstituted C3-C6 cycloalkyl group, a substituted or unsubstituted 5-to 12-membered heterocyclic group, orRing B is a substituted or unsubstituted 3-6 membered carbocyclic ring; r is R ²⁴ Selected from: H. d, halogen, CN, C1-C4 alkyl, C1-C4 haloalkyl;

each R is ¹⁷ 、R ¹⁸ And R is ¹⁹ Each 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 is ¹⁷ And R is ¹⁸ And the atoms to which they are attached form the corresponding 3-8 membered carbocyclic or heterocyclic ring;

R ²³ selected from the group consisting of: H. d, halogen, CN, hydroxy, 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 selected from bond, NH, N (C1-C4 alkyl) or (CR) ₂ ) _t ；Y ¹ Is (CR) ₂ ) _s The method comprises the steps of carrying out a first treatment on the surface of 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, carboxy, a group selected from the group consisting of unsubstituted or substituted with one or more substituents: C6-C10 aryl, halogenated C6-C10 aryl, 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O, halogenated 5-10 membered heterocyclyl having 1-3 heteroatoms selected from N, S and O; and the substituents are selected from the group consisting of: halogen, C1-C6 alkoxy; t and s are independently selected from 0,1 or 2;

and when X ¹ Selected from (CH) ₂ ) _t When s and t are not 0 at the same time;

n and q are each 0,1 or 2;

m is 0,1,2,3 or 4 respectively; when m >1, each Rc is independent of each other;

the term "substituted" means, unless otherwise specified, selected from the group consisting ofOne or more (e.g., 2,3, 4, etc.) substituents: 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, carboxy, -COOH, - (CO) NH ₂ Or two substituents on the same atom together with the atom form a C3-C6 cycloalkyl group; and a group selected from the group consisting of: C6-C10 aryl, halogenated C6-C10 aryl, 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O, halogenated 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O, - (CO) NH (C1-C6 alkyl) or- (CO) N (C1-C6 alkyl) ₂ The method comprises the steps of carrying out a first treatment on the surface of the The substituents are selected from the group consisting of: halogen, C1-C6 alkoxy;

unless otherwise specified, by heteroaryl or heterocyclyl is meant that the ring atom of the group contains 1, 2 or 3 heteroatoms selected from N, O and S;

and the molecule has at least one OH group or SH group.

wherein:

x is selected from the group consisting of: n or CR, wherein R is selected from the group consisting of: hydrogen, deuterium, halogen, CN, hydroxy, 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 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-C6 cycloalkylA substituted or unsubstituted C3-C6 heterocyclyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted 5-12 membered heteroaryl group, a substituted or unsubstituted aryl group (C1-C6 alkyl group), a substituted or unsubstituted 5-12 membered heteroaryl group (C1-C6 alkyl group) and a substituted or unsubstituted heterocycle (C1-C6 alkyl group);

R ¹³ selected from: hydrogen, deuterium and amino;

R ¹⁴ is thatWherein:

rc is a group selected from the group consisting of: halogen, CN, hydroxy, 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 A mono-or di-substituted amino group, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C6 alkoxy group, a substituted or unsubstituted C3-C6 cycloalkyl group, a substituted or unsubstituted 5-to 12-membered heterocyclic group;

R ¹⁵ selected from: h, C1-C4 alkyl;

R ¹⁶ selected from: h, C1-C4 alkyl;

Each R is ¹⁷ 、R ¹⁸ And R is ¹⁹ Each 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 is ¹⁷ And R is ¹⁸ And the atoms to which they are attached form the corresponding 3-to 8-membered carbocyclic or heterocyclic ring；

n and q are each 0,1 or 2;

unless otherwise specified, "substituted" means substituted with one or more (e.g., 2,3, 4, etc.) substituents selected from the group consisting of: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyl, oxo, -CN, hydroxy, amino, carboxy, -COOH, - (CO) NH ₂ Or two substituents on the same atom together with the atom form a C3-C6 cycloalkyl group; and a group selected from the group consisting of: C6-C10 aryl, halogenated C6-C10 aryl, 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O, halogenated 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O, - (CO) NH (C1-C6 alkyl) or- (CO) N (C1-C6 alkyl) ₂ The method comprises the steps of carrying out a first treatment on the surface of the The substituents are selected from the group consisting of: halogen, C1-C6 alkoxy;

and the molecule has at least one OH group or SH group.

wherein,

ring a is a substituted or unsubstituted 5-6 membered aromatic or heteroaromatic ring;

ring B is a substituted or unsubstituted 3-6 membered carbocyclic ring;

R ²¹ 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-C4Substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted having 1 to 3 members selected from N, S (O) _p And 5-10 membered heteroaryl of heteroatoms of O, substituted or unsubstituted 4-10 membered heterocyclyl having 1-3 heteroatoms selected from N, S and O;

R ²² and R is ²⁴ Each independently selected from the group consisting of: H. d, halogen, CN, CHF ₂ 、CF ₃ ；

X ¹ 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, halogenated C3-C8 cycloalkyl, oxo, -CN, hydroxy, amino, carboxy, a group selected from the group consisting of unsubstituted or substituted with one or more substituents: C6-C10 aryl, halogenated C6-C10 aryl, 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O, halogenated 5-10 membered heterocyclyl having 1-3 heteroatoms selected from N, S and O; and the substituents are selected from the group consisting of: halogen, C1-C6 alkoxy;

t and s are independently selected from 0, 1 or 2;

unless otherwise specified, "substituted" means substituted with one or more (e.g., 2, 3, 4, etc.) substituents selected from the group consisting of: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyl, oxo, -CN, hydroxy, amino, carboxy, a group selected from the group consisting of unsubstituted or substituted with one or more substituents: C6-C10 aryl, halogenated C6-C10 aryl, 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O, halogenated 5-10 membered heterocyclyl having 1-3 heteroatoms selected from N, S and O; and the substituents are selected from the group consisting of: halogen, C1-C6 alkoxy;

And the molecule has at least one OH group or SH group.

In another preferred embodiment, the G group has a structure represented by the formula:

wherein each group is as defined above;

R ¹⁵ and R is ¹⁶ 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 A substituted or unsubstituted C1-C6 alkylene group, a substituted or unsubstituted C3-C6 cycloalkylene group, a substituted or unsubstituted 5-12 membered heterocyclylene group; r is R ¹⁷ Selected from the group consisting of: a bond, a substituted or unsubstituted C1-C6 alkylene group, a substituted or unsubstituted C3-C6 cycloalkylene group, a substituted or unsubstituted 5-12 membered heterocyclylene group.

In another preferred embodiment, X is N.

In another preferred embodiment, a is selected from the group consisting of: c=o or- (c=o) NR _o -, wherein R is _o Is H or C1-C4 alkyl.

In another preferred embodiment, R ¹¹ 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 unsubstituted5-12 membered heteroaryl (C1-C6 alkyl) and substituted or unsubstituted heterocycle (C1-C6 alkyl).

In another preferred embodiment, R ¹² Selected from hydrogen, halogen and cyano; r is R ¹³ Is hydrogen.

In another preferred embodiment, rd is a group selected from the group consisting of: (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 A substituted or unsubstituted C1-C6 alkylene group, a substituted or unsubstituted C3-C6 cycloalkylene group, a substituted or unsubstituted 5-12 membered heterocyclylene group.

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

in another preferred embodiment, X is NH or (CH ₂ ) _m 。

In another preferred embodiment, the a ring is a substituted or unsubstituted group selected from the group consisting of:

in another preferred embodiment, R ₂₁ Selected from the group consisting of: substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C1-C4 alkoxy, substitutedOr unsubstituted C1-C4 alkylamino.

In another preferred embodiment, the G group has a structure selected from the group consisting of:

wherein the B ring is a substituted or unsubstituted 3-4 membered carbocyclic ring.

In another preferred embodiment, R ₂ Selected from hydrogen, halogen and CN.

in another preferred embodiment, L is selected from the group consisting of: an unsubstituted, substituted or unsubstituted C1-C6 alkylene group, a substituted or unsubstituted C1-C6 heteroalkylene group;

R ¹ Selected from the group consisting of: substituted or unsubstituted C1-C20 alkyl (straight or branched), substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C1-C20 heteroalkyl, substituted or unsubstituted 3-20 membered heterocyclyl, substituted or unsubstituted phenyl;

and R is as described ¹ Having one or more substituents selected from the group consisting of: C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyl.

In another preferred embodiment, saidHas a structure selected from the group consisting of:

/>

in another preferred embodiment, the compound of formula (I) has the structure shown below:

/>

in another preferred embodiment, the drug molecule G' has a hydrophobicity coefficient CLogP <4.

In a second aspect of the invention there is provided a process for the preparation of a compound according to the first aspect of the invention, the process comprising the steps of:

reacting the compound II-1 with an acyl chloride compound II-2 in an inert solvent to obtain a compound II;

wherein each group is as defined in the first aspect of the invention.

In a third aspect, the present invention provides a compound according to the second aspect of the present invention, or a pharmaceutically acceptable salt or hydrate thereof, for use in the manufacture of a pharmaceutical composition for the treatment or prophylaxis of a disease associated with the activity or expression of JAK kinase.

In a fourth aspect of the present invention, there is provided a preparation for external administration, comprising:

the compound of the first aspect of the invention;

optionally a skin penetration enhancer, preferably selected from the group consisting of: surfactants, dimethyl sulfoxide and analogues thereof, azones, pyrrolidone derivatives, alcohols, ethers, fatty acids and fatty acid esters, or combinations thereof;

an optional support layer;

preferably, the drug is present in a single or multiple phases, solutions or suspensions; the preparation is administered in the form of solution, suspension, gel, emulsion, paste or foam.

In a fifth aspect of the present invention, there is provided a method of improving the membrane permeability of a drug molecule G', the method comprising the steps of:

modification of drug molecule G' to introduce fragments into the moleculeFormation of CLogP > 4While the CLogP of the prodrug molecule (I) formed by modification is increased by at least 1 unit over the CLogP of the drug molecule G'.

In another preferred embodiment, the prodrug moleculeThe Pe value of Skin-Pampa is improved by 2-100 times compared with the drug molecule G' before modification.

It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein.

Detailed Description

The present inventors have made intensive studies for a long time to develop a compound represented by the formula (I). The compound is composed of a hydrophilic drug molecular end and a hydrophobic end, so that the compound has good transdermal property, and can be metabolized into a proto-drug molecule in vivo after external administration, thereby completing the administration process. Based on the above findings, the inventors have completed the present invention.

Definition of the definition

As used herein, the term "alkyl" includes straight or branched chain alkyl groups. For example C ₁ -C ₆ Alkyl means a straight or branched chain alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, etc., and "C1-C20 alkyl" has similar meaning. The term "alkylene" refers to an alkyl group that loses one hydrogen atom, e.g., a C1-C6 alkylene group represents a straight or branched chain alkylene group having 1 to 6 carbon atoms. The term "heteroalkyl" refers to an alkyl group in which one or more carbon atoms in the carbon chain are replaced with a heteroatom selected from the group consisting of: o, S, NH, C (O) or C (NH), the term "heteroalkylene" has a similar meaning.

As used herein, the term "C3-C8 cycloalkyl" refers to cycloalkyl groups having 3-8 carbon atoms. It may be a single ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or the like. Also in bicyclic form, for example bridged, fused or spiro form, "C3-C20 cycloalkyl" having similar definition.

As used herein, the term "C6-C14 aryl" refers to an aryl group having 6 to 14 carbon atoms, for example, phenyl or naphthyl and the like.

As used herein, the term "5-10 membered heteroaryl having 1-3 heteroatoms selected from the following groups N, S and O" refers to a cyclic aromatic group having 5-10 atoms and wherein 1-3 atoms are heteroatoms selected from the following groups N, S and O. It may be a single ring or may be in the form of 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, and the like.

As used herein, the term "3-20 membered heterocyclyl" refers to a saturated or partially saturated cyclic group having 3-20 ring atoms, and wherein 1-3 atoms are heteroatoms selected from the following groups N, S and O, preferably a 3-10 membered heterocyclyl, or a 4-7 membered heterocyclyl or a 9-15 membered heterocyclyl. It may be a single ring or may be in the form of a double ring, for example in the form of a bridged or spiro ring. Specific examples may be oxetane, azetidine, tetrahydro-2H-pyranyl, piperidinyl, tetrahydrofuranyl, morpholinyl, pyrrolidinyl and the like. "3-8 membered heterocyclyl" has similar definition.

Unless otherwise indicated as "substituted or unsubstituted", the radicals according to the invention may be substituted by substituents selected from the group consisting of: halogen, nitrile, nitro, hydroxy, amino, C1-C6 alkyl-amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, haloC 1-C6 alkyl, haloC 2-C6 alkenyl, haloC 2-C6 alkynyl, haloC 1-C6 alkoxy, allyl, benzyl, C6-C12 aryl, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 alkoxy-carbonyl, phenoxycarbonyl, C2-C6 alkynyl-carbonyl, C2-C6 alkenyl-carbonyl, C3-C6 cycloalkyl-carbonyl, C1-C6 alkyl-sulfonyl, and the like.

As used herein, "halogen" or "halogen atom" refers to F, cl, br, and I. More preferably, the halogen or halogen atom is selected from F, cl and Br. "halogenated" means substituted with an atom selected from F, cl, br, and I.

Unless otherwise specified, the structural formulae described herein are intended to include all isomeric forms (e.g., enantiomers, diastereomers and geometric isomers (or conformational isomers)): for example R, S configuration containing asymmetric centers, the (Z), (E) isomers of double bonds, etc. Thus, individual stereochemical isomers of the compounds of the invention or mixtures of enantiomers, diastereomers or geometric isomers (or conformational isomers) thereof are all within the scope of the invention.

As used herein, the term "hydrate" refers to a complex of a compound of the present invention coordinated to water.

The compounds of the present application may 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 the specific embodiments with other chemical synthetic methods, and equivalent alternatives well known to those skilled in the art, preferred embodiments including but not limited to the examples of the present application.

The solvents used in the present application are commercially available. Abbreviations used in this application are as follows: aq represents an aqueous solution; HATU represents O- (7-azabenzotriazol-1-yl) -N, N' -tetramethyluronium hexafluorophosphate; EDCI stands for N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride; m-CPBA represents 3-chloroperoxybenzoic acid; eq represents equivalent, equivalent; CDI represents carbonyldiimidazole; DCM represents dichloromethane; PE represents petroleum ether; DIAD stands for diisopropyl azodicarboxylate; DMF represents N, N-dimethylformamide; DMSO represents dimethylsulfoxide; etOAc represents ethyl acetate; etOH stands for ethanol; meOH represents methanol; cbz represents a benzyloxycarbonyl group, an amino protecting group; boc represents tert-butyloxycarbonyl, an amino protecting group; HOAc stands for acetic acid; naCNBH ₃ Represents sodium cyanoborohydride; r.t. stands for room temperature; THF represents tetrahydrofuran; TFA represents trifluoroacetic acid; DIPEA stands for diisopropylethylamine; boc ₂ O represents di-tert-butyl dicarbonate; LDA represents lithium diisopropylamide.

The compounds being obtained by artificial or artificial meansSoftware naming, commercial compounds are referred to by vendor catalog names.

Prodrug compounds suitable for topical administration

In the present invention, there is provided 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 vivo after administration to form a drug molecule G'; and the hydrophobic coefficient CLogP <4 of said drug molecule G'; and the prodrug molecule has a structure shown in the following formula (I):

wherein, G is a part of structural fragment formed by the loss of H atom of the drug molecule G', which is formed by any O atom or S atom and any S atom in the moleculeAre connected.

In the invention, take the form ofThe lipophilic group of (c) is effective to increase the transdermal efficiency of the compound, and will be prepared as a novel compound which can be metabolized to the original compound molecule by topical administration. The drug molecule G' suitable for use in the prodrug molecule may be of any structure and in a preferred embodiment, the drug molecule has a hydrophobic coefficient CLogP <4。

Since such drug molecules have a lipophilic end and a hydrophilic drug molecule end, they can have very good permeabilities, especially improving the permeabilities of the drug molecules during dermal administration. Preferably, the drug molecule is a drug molecule for dermatological disorders, such as JAK inhibitors, MEK inhibitors, BTK inhibitors, and the like.

Pharmaceutical compositions and methods of administration

Since the compounds of the present invention are capable of being metabolized in vivo to form therapeutically active ingredients after external administration, the compounds of the present invention and various crystalline forms thereof, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates thereof, and pharmaceutical compositions containing the compounds of the present invention as main active ingredients are useful for preventing and/or treating (stabilizing, alleviating or curing) cancer, myeloproliferative diseases, inflammation, immune diseases, organ transplantation, viral diseases, cardiovascular diseases or metabolic diseases, and various autoimmune and inflammation-related diseases.

The pharmaceutical compositions of the present invention comprise a safe and effective amount of a compound of the present invention within a pharmaceutically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical compositions contain 1-2000mg of the compound of the invention per dose, more preferably 1-200mg of the compound of the invention per dose. Preferably, the "one dose" is a capsule or tablet.

"pharmaceutically acceptable carrier" means: one or more compatible solid or liquid filler or gel materials which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. "compatible" as used herein means that the components of the composition are capable of blending with and between the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, and the like), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, and the like), polyols (e.g., propylene glycol, glycerol, mannitol, sorbitol, and the like), emulsifiers (e.g. ) Wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizing agents, antioxidants, preservatives, pyrogen-free water and the like. />

The prodrug compounds of the invention may conveniently be formulated into pharmaceutical compositions comprising one or more compounds of the invention and a pharmaceutically acceptable carrier. See Remington: the Science and Practice of Pharmacy, 19 (Easton, mack Publishing Co., pa., 1995), discloses typical carriers and methods of preparing pharmaceutical compositions which may be used or modified as described to prepare medicaments containing the compounds of the invention. As previously mentioned, the compounds of the present invention may also be administered in the form of pharmaceutically acceptable salts and the like.

The compounds of the present invention may be administered in the form of pharmaceutical agents containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and excipients, orally, parenterally, topically, rectally, nasally, bucally, vaginally, or via an implanted reservoir. Preferably, the compounds of the present invention can be administered through the skin or mucosal tissue using conventional topical administration systems, wherein the agent is contained in a multi-layered structure that is immobilized on the skin and functions as an administration device. In such a configuration, the pharmaceutical composition is contained in a layer below the upper backing layer, the "reservoir" layer. The multi-layered structure may contain a single reservoir or may contain multiple reservoirs. In one example, the reservoir contains a polymeric matrix of a pharmaceutically acceptable pressure-sensitive adhesive substance that acts to secure the system to the skin during administration. Suitable skin-engaging adhesive materials include, but are not limited to, polyethylene, polysiloxanes, polyisobutylene, polyacrylates, polyurethanes, and the like. Alternatively, the drug-containing reservoir and the skin-pressure-sensitive adhesive may be present as separate and distinct layers, in which case the adhesive underlies the reservoir, which may be a polymeric matrix as described above, a liquid or hydrogel reservoir, or other forms.

In these multiple layers, the backing layer, which is the upper surface of the device, acts as the primary structural element of the multiple layer structure, providing the device with a number of flexibilities. The material selected for use as the backing material should be substantially impermeable to the active material and any other materials present; the backing is preferably made of a soft, resilient material sheet or film. Examples of polymers suitable for use as the backing layer include polyethylene, polypropylene, polyester, and the like.

The multilayer structure includes a release layer during storage and prior to use. Just prior to use, the layer is removed from the device, exposing its bottom surface or drug reservoir or a separate layer of pressure-sensitive adhesive, allowing the system to be secured to the skin. The release layer should be made of a material that is impermeable to the drug/excipient.

The topical drug delivery device may be made using conventional techniques known in the art, for example, by casting a fluid mixture of adhesive, drug and excipient onto a backing layer, and then laminating the release layer. Similarly, the adhesive mixture may be cast onto the release layer and then the backing layer laminated. Alternatively, the drug reservoir may be made without the drug or excipient and then filled with the drug/excipient mixture by soaking.

The multi-layered topical delivery system may also contain a skin penetration enhancer. That is, because the inherent permeability of the skin to certain drugs may be too small to allow therapeutic levels of the drugs to penetrate the reasonably large, unbroken skin, it is desirable to administer skin penetration enhancers with these drugs. Suitable accelerators are well known in the art and include, for example, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), N-Dimethylacetamide (DMA), decyl methyl sulfoxide (C10 MSO), C2-C6 alkanediols and 1-substituted azepan-2-ones, alcohols, and the like.

The compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable therapeutic agents.

When administered in combination, the pharmaceutical composition also includes a pharmaceutical composition in combination with 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 may be used simultaneously, separately or sequentially with the compounds of the invention for the prevention and/or treatment of cytokine and/or interferon mediated diseases.

When a pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is applied to a mammal (e.g., a human) in need of treatment, wherein the dose at the time of administration is a pharmaceutically effective dose, and the daily dose is usually 1 to 2000mg, preferably 1 to 500mg, for a human having a body weight of 60 kg. Of course, the particular dosage should also take into account factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled practitioner.

The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise indicated.

Example 1

First step

Compound 1a (6.00 g,53.10 mmol) was dissolved in N, N-dimethylformamide (50 mL) under nitrogen, 60% sodium hydride (2.50 g,63.72 mmol) was added in portions under ice-bath, methyl bromoacetate (6.00 mL,63.72 mmol) was added after 30 minutes of reaction, and the reaction was continued under ice-bath for 2 hours. The reaction was quenched with water (200 mL) in ice bath, extracted with ethyl acetate (200 mL x 2), the organic phase was successively dried over saturated brine (200 mL x 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a residue, which was purified by column chromatography (ethyl acetate: petroleum ether=0-100%) to give compound 1b (8.80 g), yield: 89%.

MS-ESI calculated [ M+H ]] ⁺ 186, found 186.

Second step

1b (8.80 g,45.57 mmol) was dissolved in methanol (80 mL), 10% wet palladium on carbon (800 mg) was added, hydrogen (15 psi) was replaced, and the reaction was carried out at room temperature overnight. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to give 1c (6.20 g), yield: 84%.

MS-ESI calculated [ M+H ]] ⁺ 156, found 156.

Third step

Compound 1d (50.00 g,0.11 mol), N, O-dimethylhydroxylamine hydrochloride (12.60 g,0.13 mol) and triethylamine (32.70 g,0.13 mol) were dissolved in methylene chloride (500 mL) under nitrogen, and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (24.80 g,0.13 mol) and 1-hydroxybenzotriazole (17.50 g,0.13 mol) were added to the reaction mixture to react overnight at room temperature. The reaction mixture was diluted with water (400 mL), dichloromethane (200 mL x 2) was extracted, the organic phase was washed with saturated brine (300 mL x 1) in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a residue, and the residue was purified by column chromatography (ethyl acetate: petroleum ether=0-100%) to give compound 1e (52.10 g), yield: 95%.

MS-ESI calculated [ M+H ]] ⁺ 507, found 507.

Fourth step

Compound 1e (20.00 g,39.53 mmol) was dissolved in ultra-dry tetrahydrofuran (200 mL) under nitrogen, cooled to-78deg.C, lithium aluminum hydride (1.80 g,47.43 mmol) was added in portions, and the reaction was continued for 2 hours. The reaction was quenched by the addition of 0.5M dilute hydrochloric acid (50 mL) at-78deg.C, extracted with ethyl acetate (100 mL. Times.2), and the organic phase was washed with saturated brine (100 mL. Times.1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude 1f (19.50 g).

Fifth step

The crude 1f (19.50 g,39.53 mmol) and 2, 2-dimethoxyethylamine (13.7 g,130.58 mmol) were dissolved in anhydrous methanol (200 mL) under nitrogen and cooled to 0deg.C after 30 min, sodium cyanoborohydride (3.20 g,47.44 mmol) was added in portions and the reaction was allowed to warm to room temperature overnight. The reaction solution was concentrated under reduced pressure to give a residue, which was purified by column chromatography (ethyl acetate: petroleum ether=0-100%) to give 1g (9.20 g) of a compound, yield: 43%.

MS-ESI calculated [ M+H ]] ⁺ 537, found 537.

¹ H NMR(400MHz,CDCl ₃ )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).

Sixth step

1g (9.20 g,16.17 mmol), triethylamine (4.80 mL,34.32 mmol) and 2, 4-dichloropyrimidine (3.10 g,20.60 mmol) were dissolved in ethanol (100 mL) and warmed to 70℃for overnight reaction. The reaction was cooled to room temperature naturally, the reaction mixture was concentrated under reduced pressure to give a residue, and the residue was purified by column chromatography (ethyl acetate: petroleum ether=0-100%) to give compound 1h (7.10 g), yield: 64%.

MS-ESI calculated [ M+H ]] ⁺ 649, found 649.

Seventh step

1h (3.00 g,4.63 mmol) and 1c (861 mg,5.56 mmol) were dissolved in isopropanol (20 mL) and heated to 130℃for 1 hour. The reaction solution was cooled to room temperature, concentrated under reduced pressure to give a residue, and the residue was purified by reverse phase column chromatography (acetonitrile: water=0-100%) to give compound 1i (3.10 g), yield: 86%.

MS-ESI calculated [ M+H ]] ⁺ 768, found 768.

Eighth step

Compound 1i (3.10 g,4.04 mmol) was dissolved in a mixed solvent of trifluoroacetic acid (30 mL) and water (10 mL), and the temperature was raised to 60℃for reaction for 1 hour. The reaction solution was cooled to room temperature, concentrated under reduced pressure to give a residue, and the residue was purified by reverse phase column chromatography (acetonitrile: water=0-100%) to give 1j (1.30 g), yield: 86%.

MS-ESI calculated [ M+H ]] ⁺ 362, measured 362.

Ninth step

Compound 1j (400 mg,1.11 mmol), (1S) -2, 2-difluorocyclopropane-1-carboxylic acid (162 mg,1.33 mmol) and triethylamine (4478 mg,4.44 mmol) were dissolved in N, N-dimethylformamide (3 mL), and 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (264 mg,1.67 mmol) was added to the reaction system and reacted at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC to give compound 1k (18 mg), yield: 43%.

MS-ESI calculated [ M+H ]] ⁺ 466, actual measurement 466.

Tenth step

1k (570 mg,1.23 mmol) was dissolved in a mixed solvent of tetrahydrofuran (2 mL) and ethanol (5 mL) under nitrogen protection, cooled to 0 ℃, and 2M lithium borohydride tetrahydrofuran solution (3.10 mL,6.13 mmol) was added dropwise, and the mixture was allowed to react at room temperature for 2 hours. The reaction was quenched with saturated ammonium chloride (1 mL), concentrated under reduced pressure, and the residue was purified by reverse phase column chromatography (acetonitrile: water=0-100%) and preparative HPLC to give compound 1l (80 mg), yield: 15%.

MS-ESI calculated [ M+H ]] ⁺ 438, found 438.

¹ H NMR(400MHz,DMSO-d ₆ )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).

Eleventh step

1l (300 mg,0.69 mmol), 4-ethyl octanoic acid (154 mg,0.89 mmol) and 4-dimethylaminopyridine (109 mg,0.89 mmol) were dissolved in 10mL of methylene chloride, and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (170 mg,0.89 mmol) was added thereto, and the reaction was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the crude product was purified by high performance liquid chromatography and lyophilized to give compound 1 (331 mg), yield: 91%.

MS-ESI calculated [ M+H ]] ⁺ 591, found 591.

¹ H NMR(400MHz,DMSO-d ₆ )：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).

Example 2

First step

Compound 1l (200 mg,0.48 mmol), isobutyric acid (42 mg,0.48 mmol), 4-dimethylaminopyridine (111 mg,0.91 mmol) and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (144 mg,0.73 mmol) were successively added to a reaction flask, reacted at room temperature for 4 hours, and the reaction solution was purified by column chromatography (ethyl acetate: methanol: dichloromethane) and lyophilized to give compound 2 (153 mg), yield: 66%.

MS-ESI calculated [ M+H ]] ⁺ 508, found 508.

¹ H NMR(400MHz,DMSO-d ₆ )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).

Example 3

/>

First step

1l (200 mg,0.48 mmol) of 1-hexanoic acid (55 mg,0.48 mmol), 4-dimethylaminopyridine (111 mg,0.91 mmol) and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (140 mg,0.73 mmol) were successively added to a reaction flask, reacted at room temperature for 4 hours, and after completion of the detection reaction, the reaction solution was purified by column chromatography (ethyl acetate: methanol: dichloromethane) and lyophilized to give compound 3 (188 mg), yield: 77%.

MS-ESI calculated [ M+H ]] ⁺ 536, found 536.

¹ H NMR(400MHz,DMSO-d ₆ )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)

Example 4

First step

1l (200 mg,0.48 mmol) of 1-octanoic acid (68 mg,0.48 mmol), 4-dimethylaminopyridine (111 mg,0.91 mmol) and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (140 mg,0.73 mmol) were successively added to a reaction flask, reacted at room temperature for 4 hours, and after completion of the detection reaction, the reaction solution was purified by column chromatography (ethyl acetate: methanol: dichloromethane) and lyophilized to give compound 4 (198 mg), yield: 76%.

MS-ESI calculated [ M+H ]] ⁺ 564, the actual measurement 564.

¹ H NMR(400MHz,DMSO-d ₆ )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).

Example 5

First step

1l (200 mg,0.48 mmol) of 1-nonanoic acid (75 mg,0.48 mmol), 4-dimethylaminopyridine (111 mg,0.91 mmol) and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (140 mg,0.73 mmol) were successively added to a reaction flask, reacted at room temperature for 4 hours, and after completion of the detection reaction, the reaction solution was purified by column chromatography (ethyl acetate: methanol: dichloromethane) and lyophilized to give compound 5 (214 mg), yield: 80%.

MS-ESI calculated [ M+H ]] ⁺ 578, observed 578.

¹ H NMR(400MHz,DMSO-d ₆ )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).

Example 6

First step

1l (200 mg,0.48 mmol) of the compound, 1-decanoic acid (78 mg,0.48 mmol), 4-dimethylaminopyridine (111 mg,0.91 mmol) and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (140 mg,0.73 mmol) were successively added to a reaction flask, reacted at room temperature for 4 hours, and after completion of the detection reaction, the reaction solution was purified by column chromatography (ethyl acetate: methanol: dichloromethane) and lyophilized to give compound 6 (226 mg), yield: 83%.

MS-ESI calculated [ M+H ]] ⁺ 592, found 592.

¹ H NMR(400MHz,DMSO-d ₆ )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).

Example 7

First step

1l (200 mg,0.48 mmol) of the compound, 92mg,0.48 mmol) of dodecanoic acid, 111mg,0.91mmol of 4-dimethylaminopyridine and 140mg,0.73mmol of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride were successively added to a reaction flask, reacted at room temperature for 4 hours, and after completion of the detection reaction, the reaction solution was purified by column chromatography (ethyl acetate: methanol: dichloromethane) and lyophilized to give compound 7 (220 mg), yield: 79%.

MS-ESI calculated [ M+H ]] ⁺ 620, measured 620.

¹ H NMR(400MHz,DMSO-d ₆ )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).

Example 8

First step

1l (200 mg,0.48 mmol) of compound, hexadecanoic acid (112 mg,0.48 mmol), 4-dimethylaminopyridine (111 mg,0.91 mmol) and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (140 mg,0.73 mmol) were successively added to a reaction flask, reacted at room temperature for 4 hours, and after completion of the detection reaction, the reaction solution was purified by column chromatography (ethyl acetate: methanol: dichloromethane) and lyophilized to give compound 8 (196 mg), yield: 63%.

MS-ESI calculated [ M+H ]] ⁺ 676, found 676.

¹ H NMR(400MHz,DMSO-d ₆ )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).

Example 9

First step

1l (200 mg,0.48 mmol), 9a (90 mg,0.48 mmol), 4-dimethylaminopyridine (111 mg,0.91 mmol) and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (140 mg,0.73 mmol) were successively added to a reaction flask, reacted at room temperature for 4 hours, and after completion of the detection reaction, the reaction solution was purified by column chromatography (ethyl acetate: methanol: dichloromethane) and lyophilized to give compound 9 (127 mg), yield: 44%.

MS-ESI calculated [ M+H ]] ⁺ 626, found 626.

¹ H NMR(400MHz,DMSO-d ₆ )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).

Example 10

First step

Compound 10a (2.51 g,11.83 mmol) was added, methanol (45 mL), triethylamine (2.39 g,23.66 mmol) was added, stirred at room temperature for 10 minutes, 2, 4-dichloropyrimidine (1.94 g,13.01 mmol) was added, the reaction was carried out for 2 hours, methylene chloride (100 mL) was added, the organic phase was washed with saturated ammonium chloride solution (100 mL. Times.3), dried over anhydrous sodium sulfate, and the solvent was removed by concentration under reduced pressure to give compound 10b (4.12 g), yield: 100%.

MS-ESI calculated [ M+H ]] ⁺ 325, the actual measurement 325.

Second step

Compound 10b (4.12 g,11.83 mmol) was added, methanol (50 mL) was added, 4M hydrochloric acid/1, 4-dioxane solution (24 mL,94.46 mmol) was added and stirred at room temperature for 60 minutes, 2, 4-dichloropyrimidine (1.94 g,13.01 mmol) was added, the reaction was carried out for 2 hours, the solvent was concentrated under reduced pressure, water (50 mL) was added for dilution, the aqueous phase was washed with methylene chloride (50 mL. Times.3), the pH of the aqueous phase was adjusted to between 9 and 10 with saturated sodium carbonate solution, the aqueous phase was extracted with methylene chloride (50 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed by concentration under reduced pressure to give compound 10c (2.74 g), yield: 100%.

MS-ESI calculated [ M+H ] ] ⁺ 225, measured 225.

Third step

Compound 10c (2.02 g,9.0 mmol) was added, ethyl acetate (50 mL), (1S) -2, 2-difluorocyclopropane-1-carboxylic acid (1.00 g,8.19 mmol) was added, N-diisopropylethylamine (2.5 mL,14.4 mmol) was added, 50% ethyl acetate solution of 1-propylphosphoric anhydride (7.16 g,11.25 mmol) was added, stirring was stopped at room temperature for 90 minutes, the reaction solution was washed with saturated ammonium chloride (50 mL. Times.3), the organic phase was washed with saturated sodium chloride solution (50 mL. Times.1), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed by concentration under reduced pressure, and the residue was purified by column chromatography (ethyl acetate: petroleum ether=0-100%) to give compound 10d (2.65 g), yield: 89%.

MS-ESI calculated [ M+H ]] ⁺ 329, found 329.

Fourth step

Compound 10d (1.51 g,4.59 mmol) was added, ethylene glycol diethyl ether (10 mL) was added, 10e (0.70 g,5.51 mmol) was added, the temperature was raised to 115 ℃ and stirred at 115 ℃ for 50 minutes, the reaction was stopped, the solvent was removed by concentration under reduced pressure, saturated sodium carbonate solution (100 mL) was added, dichloromethane (100 mL) was added, the liquid was separated, the organic phase was washed with saturated sodium chloride solution (50 mL x 3), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed by concentration under reduced pressure, and the residue was purified by column chromatography (methanol: dichloromethane=0 to 100%) to give compound 10f (2.00 g), yield: 100%.

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

¹ H NMR(400MHz,DMSO-d ₆ )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).

Fifth step

Compound 10f (250 mg,0.60 mmol), 4-ethyl octanoic acid (102 mg,0.60 mmol), 4-dimethylaminopyridine (145 mg,1.19 mmol) and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (184 mg,0.96 mmol) were successively added to a reaction flask, reacted at room temperature for 4 hours, after the completion of the detection reaction, the reaction solution was purified by column chromatography (ethyl acetate: methanol: dichloromethane) and lyophilized to give compound 10 (236 mg), yield: 69%.

MS-ESI calculated [ M+H ]] ⁺ 574, the actual measurement 574.

¹ H NMR(400MHz,DMSO-d ₆ )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).

Example 11

First step

Compound 10f (250 mg,0.60 mmol), decanoic acid (102 mg,0.60 mmol), 4-dimethylaminopyridine (145 mg,1.19 mmol) and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (184 mg,0.96 mmol) were successively added to a reaction flask, reacted at room temperature for 4 hours, and after the completion of the detection reaction, the reaction solution was purified by column chromatography (ethyl acetate: methanol: dichloromethane) and lyophilized to give compound 11 (300 mg), yield: 88%.

MS-ESI calculated [ M+H ]] ⁺ 574, the actual measurement 574.

¹ H NMR(400MHz,DMSO-d ₆ )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).

Example 12

First step

Compound 12a (1.16 g,0.01 mol) was dissolved in methylene chloride (10 mL), 3, 4-dihydro-2H-pyran (0.84 g,0.01 mol) was added to the system under nitrogen protection, and pyridine p-toluenesulfonate (241 mg,1.00 mmol) was reacted at room temperature overnight. The reaction system was concentrated under reduced pressure to give a residue, which was purified by column chromatography (ethyl acetate: petroleum ether=0-100%) to give compound 12b (1.00 g), yield: 50%.

Second step

12b (1.00 g,5.00 mmol) was dissolved in tetrahydrofuran (20 mL), lithium aluminum hydride (380 mg,10.00 mmol) was added to the reaction system in portions under the protection of ice bath and nitrogen, the reaction was quenched by slowly dropping water (1 mL) into the reaction system, then 15% aqueous sodium hydroxide solution (1 mL) and water (3 mL) were slowly dropped into the reaction system in sequence, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude 12c (0.86 g) which was directly used for the next reaction.

Third step

After dissolving crude 12c (0.86 g,5.00 mmol) in tetrahydrofuran (10 mL), and adding 4-nitropyrazole (560 mg,5.00 mmol) and triphenylphosphine (2.60 g,10.00 mmol) under ice bath and nitrogen protection, the reaction mixture was added dropwise diisopropyl azodicarboxylate (2.00 g,10.00 mmol), and the reaction mixture was concentrated under reduced pressure at room temperature to give a residue, which was purified by column layer (ethyl acetate: petroleum ether=0-100%) to give compound 12d (1.20 g), yield: 89%.

MS-ESI calculated [ M+Na ]] ⁺ 290, measured 290.

Fourth step

Compound 12d (1.76 g,6.60 mmol) was dissolved in methanol (50 mL), and a saturated ammonium chloride solution (20 mL) and iron powder (1.85 g,33.00 mmol) were added sequentially thereto. The reaction was stirred at 90℃for 1 hour. After the reaction system was cooled to room temperature, it was diluted with water (200 mL) and ethyl acetate (100 mL) and separated, and the organic phase was washed with saturated brine (50 ml×1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane=0-100%) to give compound 12e (950 mg), yield: 60%.

MS-ESI calculated [ M+H ]] ⁺ 238, measured 238.

¹ H NMR(400MHz,CDCl ₃ )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).

Fifth step

To a solution of 10d (324 mg,1.00 mmol), 12e (237 mg,1.00 mmol), dibenzylideneacetone dipalladium (45 mg,0.05 mmol) and 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (59 mg,0.10 mmol) in toluene (10 mL) under nitrogen was added cesium carbonate (750 mg,2.00 mmol). The reaction was stirred at 120℃overnight. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (ethyl acetate: petroleum ether=0-100%) to give 12f (95 mg), yield: 18%.

MS-ESI calculated [ M+H ]] ⁺ 526, found 526.

Sixth step

To a solution of 12f (90 mg,0.17 mmol) in methanol (2 mL) was added hydrogen chloride/ethyl acetate solution (4M, 2 mL). The reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated to obtain 12g (90 mg) of crude product, which was directly used in the next reaction.

MS-ESI calculated [ M+H ]] ⁺ 342, the actual measurement 342.

Seventh step

12g (90 mg,0.17 mmol) of crude (1S) -2, 2-difluorocyclopropane-1-carboxylic acid (23 mg,0.18 mmol) and N, N-diisopropylethylamine (88 mg,0.68 mmol) were dissolved in N, N-dimethylformamide (1 mL). To this was added 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (84 mg,0.22 mmol). The reaction was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was quenched with water (40 mL), diluted with ethyl acetate (40 mL), and separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by preparative high performance liquid chromatography to give 12h (32 mg), yield: two steps 43%.

MS-ESI calculated [ M+H ]] ⁺ 446, found 446.

¹ H NMR(400MHz,DMSO-d ₆ )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).

Eighth step

Raw materials 12h (170 mg,0.38 mmol), 4-ethyl octanoic acid (69 mg,0.40 mmol) and 4-dimethylaminopyridine (23 mg,0.57 mmol) were dissolved in 10mL of dichloromethane, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (110 mg,0.57 mmol) was added and the reaction was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the crude product was purified by preparative high performance liquid chromatography to give 12i (150 mg) as a white solid product, yield: 66%.

MS-ESI calculated [ M+H ]] ⁺ 600, measured 600.

¹ H NMR(400MHz,CDCl ₃ )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).

Ninth step

12i (150 mg,0.25 mmol) was added to methanol (5 mL), and an ethyl acetate solution (0.1 mL, 5M) of hydrochloric acid was added to the reaction mixture, followed by stirring at room temperature for 30 minutes. The solvent was removed by concentration under reduced pressure, and the residue was prepared by dissolution in acetonitrile and then freeze-dried to give compound 12 (120 mg), yield: 76%.

MS-ESI calculated [ M+H ]] ⁺ 600, measured 600.

¹ H NMR(400MHz,DMSO-d ₆ )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).

Example 13

First step

60% sodium hydride (142 mg,3.54 mmol) was added to a solution of 1a (200 mg,1.77 mmol) in N, N-dimethylformamide (3 mL) under nitrogen atmosphere in an ice bath, after 30 minutes of reaction, 13a (460 mg,1.77 mmol) was added to the system, and the reaction was carried out overnight at room temperature, and the reaction solution was purified by reverse phase column chromatography (acetonitrile: water=0-100%) to give compound 13b (240 mg), yield: 64%.

MS-ESI calculated [ M+H ]] ⁺ 212, measured 212.

¹ H NMR(400MHz,CDCl ₃ )δ8.28(s,1H),8.08(s,1H),3.73(s,3H),1.93-1.90(m,2H),1.73-1.70(m,2H).

Second step

10% wet palladium on carbon (10 mg) was added to a solution of 13b (130 mg,0.62 mmol) in methanol (3 mL) under nitrogen, the reaction system was reacted at room temperature for 3 hours, and after the reaction system was filtered through celite, and concentrated under reduced pressure to give crude 13c (110 mg).

MS-ESI calculated [ M+H ]] ⁺ 182, measured 182.

Third step

10d (196 mg,0.61 mmol) was added to a solution of crude 13c (110 mg,0.61 mmol) in n-butanol (5 mL), reacted at 130℃for 2 hours, the reaction solution cooled to room temperature, concentrated under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane=0-100%) to give compound 13d (280 mg), yield: 98%.

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

Fourth step

1M lithium borohydride in tetrahydrofuran (1.00 mL,1.00 mmol) was added to a solution of compound 13d (50 mg,0.11 mmol) in methanol (2 mL), reacted overnight at room temperature, concentrated under reduced pressure to give a residue, which was purified by reverse phase column chromatography (acetonitrile: water=0-100%) to give the title compound 13e (23 mg), yield: 47%.

MS-ESI calculated [ M+H ]] ⁺ 442, actual measurement 442.

Fifth step

13e (23 mg,0.05 mmol) was dissolved in 4M ethyl acetate hydrochloride (2 mL), reacted at room temperature for 1 hour, and concentrated under reduced pressure to give crude 13f (17 mg).

Sixth step

2- (7-Benzotriazol-N, N, N ', N' -tetramethylurea hexafluorophosphate (27 mg,0.07 mmol) was added to a solution of compound 13f (17 mg,0.05 mmol), (1S) -2, 2-difluorocyclopropane-1-carboxylic acid (6 mg,0.05 mmol) and triethylamine (10 mg,0.10 mmol) in N, N-dimethylformamide (2 mL), and reacted overnight at room temperature. Concentration under reduced pressure gave a residue, which was purified by reverse phase column chromatography (acetonitrile: water=0-100%) to give 13g (3 mg) of compound, yield: 13%.

MS-ESI calculated [ M+H ]] ⁺ 446, found 446.

¹ H NMR(400MHz,CDCl ₃ )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).

Seventh step

13g (160 mg,0.39 mmol), 4-ethyl octanoic acid (69 mg,0.40 mmol) and 4-dimethylaminopyridine (52 mg,0.43 mmol) were dissolved in 5mL dichloromethane, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (82 mg,0.43 mmol) was added and the reaction stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the crude product was purified directly by high performance liquid chromatography to give compound 13h (140 mg), yield: 65%.

Eighth step

13h (140 mg,0.23 mmol) was added to an ethyl acetate solution (2 mL), and an ethyl acetate solution of hydrochloric acid (0.15 mL, 4M) was added to the reaction mixture, followed by stirring at room temperature for 30 minutes. The solvent was removed by concentration under reduced pressure, and the residue was freeze-dried to give the desired product 13 (108 mg) as a white solid, yield: 74%.

MS-ESI calculated [ M+H ]] ⁺ 600, measured 600.

¹ H NMR(400MHz,DMSO-d ₆ )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).

Example 14

First step

13g (200 mg,0.45 mmol) and triethylamine (0.2 mL,0.90 mmol) were added to a dichloromethane solution (3 mL), octanoyl chloride (88 mg,0.54 mmol) was added to the reaction system, and after stirring at room temperature for 1 hour, the liquid was monitored to be complete. The reaction was quenched by addition of water (2 mL), concentrated under reduced pressure to remove the solvent, and the residue was purified by reverse phase column to give product 14a (190 mg), yield: 74%.

MS-ESI calculated [ M+H ]] ⁺ 572, measured value 572.

Second step

14a (190 mg,0.33 mmol) was added to an ethyl acetate solution (2 mL), and an ethyl acetate solution (0.1 mL, 4M) of hydrochloric acid was added to the reaction mixture, followed by stirring at room temperature for 30 minutes. The solvent was removed by concentration under reduced pressure, and the residue was freeze-dried to give product 14 (145 mg), yield: 73%.

MS-ESI calculated [ M+H ]] ⁺ 572, measured value 572.

¹ H NMR(400MHz,DMSO-d ₆ )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).

Example 15

First step

13g (200 mg,0.45 mmol) and triethylamine (0.15 mL,0.90 mmol) were added to a dichloromethane solution (3 mL), octanoyl chloride (111 mg,0.54 mmol) was added to the reaction system, and after stirring at room temperature for 1 hour, the liquid was monitored to be complete. The reaction was quenched by addition of water (2 mL), concentrated under reduced pressure to remove the solvent, and the residue was purified by reverse phase column to give product 15a (160 mg), yield: 58%.

MS-ESI calculated [ M+H ]] ⁺ 614, found 614.

Second step

15a (160 mg,0.26 mmol) was added to an ethyl acetate solution (5 mL), and an ethyl acetate solution (0.1 mL, 4M) of hydrochloric acid was added to the reaction solution, followed by stirring at room temperature for 30 minutes. The solvent was removed by concentration under reduced pressure, and the residue was freeze-dried to give product 15 (129 mg), yield: 76%.

MS-ESI calculated [ M+H ]] ⁺ 614, found 614.

¹ H NMR(400MHz,DMSO-d ₆ )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).

Example 16

First step

13g (150 mg,0.34 mmol) and triethylamine (68 mg,0.68 mmol) were added to a dichloromethane solution (3 mL), and after hexanoyl chloride (6 mg,0.34 mmol) was added to the reaction system and stirred at room temperature for 1 hour, the liquid was monitored to be complete. The reaction was quenched by addition of water (2 mL) and the organic phase was dried by spin-drying and purified on reverse phase column to give product 16a (130 mg), yield: 70%.

MS-ESI calculated [ M+H ]] ⁺ 544, the actual measurement 544.

Second step

16a (168 mg,0.31 mmol) was added to an ethyl acetate solution (2 mL), and an ethyl acetate solution (0.1 mL, 4M) of hydrochloric acid was added to the reaction solution, followed by stirring at room temperature for 30 minutes. The solvent was removed by concentration under reduced pressure, and the residue was freeze-dried to give product 16 (149 mg) as a white solid, yield: 83%.

MS-ESI calculated [ M+H ]] ⁺ 544, the actual measurement 544.

¹ H NMR(400MHz,DMSO-d ₆ )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).

Example 17

First step

13g (200 mg,0.45 mmol) and triethylamine (136 mg,1.35 mmol) were added to a dichloromethane solution (5 mL), and nonanoyl chloride (87 mg,0.49 mmol) was added to the reaction system, and after stirring at room temperature for 1 hour, the liquid was monitored to be complete. The reaction was quenched by addition of water (2 mL), concentrated under reduced pressure to remove the solvent, and the residue was purified by reverse phase column to give product 17a (190 mg), yield: 72%.

MS-ESI calculated [ M+H ]] ⁺ 586, measured 586.

Second step

17a (168 mg,0.31 mmol) was added to an ethyl acetate solution (2 mL), and an ethyl acetate solution (0.1 mL, 4M) of hydrochloric acid was added to the reaction solution, followed by stirring at room temperature for 30 minutes. The solvent was removed by concentration under reduced pressure, and the residue was freeze-dried to give product 17 (164 mg), yield: 83%.

MS-ESI calculated [ M+H ]] ⁺ 586, measured 586.

¹ H NMR(400MHz,DMSO-d ₆ )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).

Example 18

First step

13g (200 mg,0.45 mmol) and triethylamine (136 mg,1.35 mmol) were added to a dichloromethane solution (5 mL), decanoyl chloride (93 mg,0.49 mmol) was added to the reaction system, and after stirring at room temperature for 1 hour, the liquid was monitored to be complete. The reaction was quenched by addition of water (2 mL), the organic phase was dried by spinning, and the residue was purified by reverse phase column to give product 18a (225 mg), yield: 83%.

MS-ESI calculated [ M+H ]] ⁺ 600, measured 600.

Second step

18a (225 mg,0.37 mmol) was added to an ethyl acetate solution (2 mL), and an ethyl acetate solution (0.1 mL, 4M) of hydrochloric acid was added to the reaction mixture, followed by stirring at room temperature for 30 minutes. The solvent was removed by concentration under reduced pressure, and the residue was freeze-dried to give product 18 (135 mg), yield: 57%.

MS-ESI calculated [ M+H ]] ⁺ 600, measured 600.

¹ H NMR(400MHz,DMSO-d ₆ )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).

Example 19

First step

13g (200 mg,0.45 mmol) and triethylamine (136 mg,1.35 mmol) were added to a dichloromethane solution (5 mL), and dodecanoyl chloride (107 mg,0.49 mmol) was added to the reaction system, followed by stirring at room temperature for 1 hour, and then completion of the liquid chromatography was monitored. The reaction was quenched by addition of water (2 mL), concentrated under reduced pressure to remove the solvent, and the residue was purified by reverse phase column to give product 19a (140 mg), yield: 50%.

MS-ESI calculated [ M+H ]] ⁺ 628, found 628.

Second step

19a (140 mg,0.22 mmol) was added to an ethyl acetate solution (2 mL), and an ethyl acetate solution (0.1 mL, 4M) of hydrochloric acid was added to the reaction solution, followed by stirring at room temperature for 30 minutes. The solvent was removed by concentration under reduced pressure, and the residue was freeze-dried to give product 19 (129 mg), yield: 88%.

MS-ESI calculated [ M+H ] ] ⁺ 628, found 628.

¹ H NMR(400MHz,DMSO-d ₆ )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).

Example 20

First step

Thionyl chloride (69 mg,0.58 mmol) was added dropwise to a dichloromethane solution (2 mL) of 9a (97 mg,0.47 mmol), and after stirring at room temperature for 1 hour, it was added to a dichloromethane solution (2 mL) of 13g (200 mg,0.45 mmol) and triethylamine (136 mg,1.35 mmol), and after stirring the mixed system at room temperature for 1 hour, the liquid was monitored to be complete. The reaction was quenched by addition of water (2 mL), concentrated under reduced pressure to remove the solvent, and the residue was purified by reverse phase column to give product 20a (119 mg), yield: 42%.

MS-ESI calculated [ M+H ]] ⁺ 634, found 634.

Second step

20a (115 mg,0.18 mmol) was added to an ethyl acetate solution (2 mL), and an ethyl acetate solution (0.1 mL, 4M) of hydrochloric acid was added to the reaction solution, followed by stirring at room temperature for 30 minutes. The solvent was removed by concentration under reduced pressure, and the residue was freeze-dried to give product 20 (103 mg), yield: 85%.

MS-ESI calculated [ M+H ]] ⁺ 634, found 634.

¹ H NMR(400MHz,DMSO-d ₆ )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).

Skin-Pampa experiment

1. The Skin-Pampa membrane was hydrated overnight with an aqueous solution (hydration solution).

2. Each test compound was dissolved in DMSO to prepare about 20mM of stock solution, 0.5mL.

3. 10. Mu.L of the mother liquor was added to 0.99mL of pH7.4 buffer, and if precipitation occurred, an attempt was made to add mixed solutions of pH7.4 and ethanol in different proportions until no precipitation occurred, and the mixed solutions in these proportions were used as the feed solution and the receiving solution. .

4. 10uL of mother liquor is taken to be added into corresponding 0.99mL of feed liquor, and the mixture is uniformly mixed.

5. 200. Mu.L of a feed solution was added to the receiving wells, 200. Mu.L of samples were added to the feed wells, and each sample was incubated in parallel with 12 wells.

6. After incubation for 8 hours, 100. Mu.L of sample per well in the feed well was taken, 100. Mu.L of sample per well in the receiving well was added with 900. Mu.L of diluent (50% acetonitrile in water), vortexed, centrifuged, and HPLC content was measured.

5. Calculation of the Skin-Pampaparameters according to the following formula

Pe-effective permeability coefficient (effective permeability coefficient)

V _A -a receiving pore volume (ml);

V _D -a feed pore volume (ml);

A-Membrane area (cm) ² )；

t-incubation time(s);

t _LAG -membrane equilibration time(s);

C _D (t) -the concentration of the feed well at t;

C _A (t) -the concentration of the receiving well at t;

C _D (0) -the initial concentration of the feed holes.

TABLE 6 summary of skin-Pampas test results

Conclusion: the compound synthesized by the invention has excellent transdermal property in a rat transdermal experiment, and compared with a drug prototype, the prodrug molecule can greatly improve the transdermal efficiency, and is suitable for preparing external preparations.

All documents mentioned in this application are incorporated by reference as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the claims appended hereto.

Claims

1. A prodrug molecule of a pharmaceutical compound G', and pharmaceutically acceptable salts, hydrates or solvates thereof, characterized in that the prodrug molecule has a structure represented by the following formula (I):

p is selected from 0, 1 or 2;

2. The prodrug molecule according to claim 1, wherein the drug molecule G' is selected from the group consisting of: JAK inhibitors, MEK inhibitors, BTK inhibitors.

3. The prodrug molecule according to claims 1 to 2, wherein the JAK inhibitor is a molecule selected from the group consisting of:

4. the prodrug molecule of claims 1 to 2, wherein the MEK inhibitor is a molecule selected from the group consisting of:

5. the prodrug molecule of claims 1 to 2, wherein the BTK inhibitor is a molecule selected from the group consisting of:

6. the prodrug molecule according to any one of claims 1 to 2, wherein the JAK inhibitor is a molecule of the formula:

Wherein:

y is S or CH;

R ¹¹ 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 unsubstitutedSubstituted 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 ¹³ selected from: hydrogen, deuterium and amino;

R ¹⁴ is thatWherein:

each R is ¹⁷ 、R ¹⁸ And R is ¹⁹ Each 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 is ¹⁷ And R is ¹⁸ And atoms connected thereto form the corresponding3-8 membered carbocycle or heterocycle;

X ¹ selected from bond, NH, N (C1-C4 alkyl) or (CR) ₂ ) _t ；Y ¹ Is (CR) ₂ ) _s The method comprises the steps of carrying out a first treatment on the surface of 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, carboxy, a group selected from the group consisting of unsubstituted or substituted with one or more substituents: C6-C10 aryl, halogenated C6-C10 aryl, 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O, halogenated 5-10 membered heterocyclyl having 1-3 heteroatoms selected from N, S and O; and the substituents are selected from the group consisting of: halogen, C1-C6 alkoxy; t and s are independently selected from 0, 1 or 2;

n and q are each 0,1 or 2;

unless otherwise specified, "substituted" means substituted with one or more (e.g., 2,3, 4, etc.) substituents selected from the group consisting of: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyl, oxo, -CN, hydroxy, amino, carboxy, -COOH, - (CO) NH ₂ Or two substituents on the same atom together with the atom form a C3-C6 cycloalkyl group; and a group selected from the group consisting of: C6-C10 aryl, halogenated C6-C10 aryl, 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O, halogenated having 1-3 heteroatoms selected from N, S and O(CO) NH (C1-C6 alkyl) or- (CO) N (C1-C6 alkyl) ₂ The method comprises the steps of carrying out a first treatment on the surface of the The substituents are selected from the group consisting of: halogen, C1-C6 alkoxy;

unless otherwise specified, by heteroaryl or heterocyclyl is meant that the ring atom of the group contains 1,2 or 3 heteroatoms selected from N, O and S;

And the molecule has at least one OH group or SH group.

7. The prodrug molecule according to any one of claims 1 to 2,6, and pharmaceutically acceptable salts, hydrates or solvates thereof, wherein the JAK inhibitor is a molecule of the formula:

wherein:

R ¹¹ 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-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);

R ¹² selected from: hydrogen, deuterium, C1-C4 alkyl, C3-C6 cycloalkyl, halogen and cyano, wherein the alkyl or cycloalkyl may be substituted with one or more fluorine atoms Substitution;

R ¹³ selected from: hydrogen, deuterium and amino;

R ¹⁴ is thatWherein:

R ¹⁵ selected from: h, C1-C4 alkyl;

R ¹⁶ selected from: h, C1-C4 alkyl;

n and q are each 0,1 or 2;

unless otherwise specified, "substituted" means substituted with one or more (e.g., 2,3, 4, etc.) substituents selected from the group consisting of: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3 -C8 cycloalkyl, halogenated C3-C8 cycloalkyl, oxo, -CN, hydroxy, amino, carboxy, -COOH, - (CO) NH ₂ Or two substituents on the same atom together with the atom form a C3-C6 cycloalkyl group; and a group selected from the group consisting of: C6-C10 aryl, halogenated C6-C10 aryl, 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O, halogenated 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O, - (CO) NH (C1-C6 alkyl) or- (CO) N (C1-C6 alkyl) ₂ The method comprises the steps of carrying out a first treatment on the surface of the The substituents are selected from the group consisting of: halogen, C1-C6 alkoxy;

and the molecule has at least one OH group or SH group.

8. The prodrug molecule according to any one of claims 1 to 2 or 6, and a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the JAK inhibitor is a molecule of the formula:

wherein,

Ring B is a substituted or unsubstituted 3-6 membered carbocyclic ring;

R ²¹ 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, substituted or unsubstituted having 1 to 3 members selected from N, S (O) _p And 5-10 membered heteroaryl of heteroatoms of O, substituted or unsubstituted 4-10 membered heterocyclyl having 1-3 heteroatoms selected from N, S and O;

X ¹ selected from bond, NH, N (C1-C4 alkyl) or (CR) ₂ ) _t ；

Y ¹ Is (CR) ₂ ) _s ；

t and s are independently selected from 0, 1 or 2;

and the molecule has at least one OH group or SH group.

9. The prodrug molecule according to claim 1, 2 or 6 wherein the G group has the structure shown in the formula:

wherein each group is as defined in claim 6;

10. The prodrug molecule of claim 9, wherein X is N, and a pharmaceutically acceptable salt, hydrate or solvate thereof.

11. The prodrug molecule of claim 9 wherein a is selected from the group consisting of: c=o or- (c=o) NR _o -, wherein R is _o Is H or C1-C4 alkyl.

12. The prodrug molecule of claim 9, wherein R ¹¹ 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).

13. The prodrug molecule of claim 9, wherein R ¹² Selected from hydrogen, halogen and cyano; r is R ¹³ Is hydrogen.

14. The prodrug molecule of claim 9, wherein Rd is a group selected from the group consisting of: (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 A substituted or unsubstituted C1-C6 alkylene group, a substituted or unsubstituted C3-C6 cycloalkylene group, a substituted or unsubstituted 5-12 membered heterocyclylene group.

15. The prodrug molecule according to claim 9, and pharmaceutically acceptable salts, hydrates or solvates thereof, wherein the G group is selected from the group consisting of:

16. the prodrug molecule according to claim 1, 2 or 6 wherein the G group has the structure shown in the formula:

17. the prodrug molecule of claim 16 wherein X is NH or (CH ₂ ) _m 。

18. The prodrug molecule of claim 16 wherein the a ring is a substituted or unsubstituted group selected from the group consisting of:

19. the prodrug molecule of claim 16 wherein R ₂₁ 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.

20. The prodrug molecule of claim 16 wherein the G group has a structure selected from the group consisting of:

21. The prodrug molecule of claim 16 wherein R ₂ Selected from hydrogen, halogen and CN.

22. The prodrug molecule of claim 16 wherein the G group has a structure selected from the group consisting of:

23. the prodrug molecule of any of claims 1 to 22, wherein L is selected from the group consisting of: an unsubstituted, substituted or unsubstituted C1-C6 alkylene group, a substituted or unsubstituted C1-C6 heteroalkylene group;

24. The prodrug molecule according to any one of claims 1 to 22, wherein the pharmaceutically acceptable salt, hydrate or solvate thereofHas a structure selected from the group consisting of:

25. the prodrug molecule according to any one of claims 1 to 22, wherein the compound of formula (I) has the structure shown in the following formula:

/>

26. the prodrug molecule of claim 1, wherein the drug molecule G' has a hydrophobic coefficient CLogP <4, and a pharmaceutically acceptable salt, hydrate or solvate thereof.

27. A process for preparing a compound according to claim 1, comprising the steps of:

/>

wherein each group is as defined in claim 9.

28. Use of a compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt or hydrate thereof, for the preparation of a pharmaceutical composition for the treatment or prophylaxis of a disease associated with the activity or expression of JAK kinase.

29. A topical formulation for administration comprising:

a compound according to any one of claims 1 to 28;

an optional support layer;

30. A method for improving the membrane permeability of a drug molecule G', comprising the steps of:

31. The method of claim 30, wherein the prodrug moleculePe value ratio of Skin-Pampas of (C) to G, a drug molecule before modification' increase by 2-100 times. />