CN107074816A - A kind of Hete rocyclic derivatives and preparation method thereof and in purposes pharmaceutically - Google Patents

Abstract

A compound represented by general formula (I) or its stereoisomers, hydrates, metabolites, solvates, pharmaceutically acceptable salts, co-crystals or prodrugs, as well as preparation methods and preparation methods for treating gas The application in the drug of tract obstructive disease, wherein the compound of general formula (I) is Wherein, the definition of each substituent is consistent with that in the description.

Description

A kind of heterocyclic derivative, its preparation method and its application in medicine technical field

The present invention relates to a heterocyclic derivative and its preparation method and application in medicine, in particular to a novel heterocyclic derivative with muscarinic receptor antagonism and/or β ₂ -adrenergic receptor agonistic activity compound or its stereoisomer, hydrate, solvate, metabolite, pharmaceutically acceptable salt, co-crystal or prodrug, its pharmaceutical composition and its application in medicine.

Background technique

Bronchodilators play an important role in the treatment of respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma. Bronchodilators widely used in clinical practice include muscarinic receptor antagonists and β ₂ -adrenergic agonists.

Muscarinic receptor antagonists exert their bronchodilation effects by reducing vagal cholinergic levels in airway smooth muscle. Inhaled muscarinic receptor antagonists currently in use include ipratropium bromide, oxitropium bromide, glycopyrronium bromide, tiotropium bromide, aclidinium bromide, and umeclidinium bromide. Among them, ipratropium bromide and oxitropium bromide are short-acting drugs, which need to be administered multiple times a day, which brings inconvenience to patients and may cause poor compliance due to frequent administration, thereby having the risk of insufficient treatment. Aclidinium, given twice daily, may cause serious adverse reactions, including paradoxical bronchospasm, new or worsening narrow-angle glaucoma, new or worsening urinary retention, and should not be used in patients younger than 18 years of age . Even if some muscarinic receptor antagonists are administered by inhalation, some drugs will enter the circulatory system, resulting in systemic side effects such as dry mouth, gastrointestinal symptoms, urinary retention and urinary tract infection. Such drugs include glycopyrronium bromide and tiotropium bromide.

Therefore, it is necessary to develop novel muscarinic receptor antagonistic drugs, especially novel muscarinic receptor antagonistic drugs with high potency, long acting time and reduced systemic side effects administered by inhalation. Provide patients with more clinical medication options.

β ₂ -Adrenergic agonists cause bronchodilation by stimulating adrenergic receptors in airway smooth muscle, reversing the response of bronchoconstrictors to various mediators such as acetylcholine. Currently used β ₂ -adrenergic agonists include albuterol, salmeterol, arformoterol, formoterol, vilanterol and indacaterol. In addition to improving lung function, these drugs can also improve patients' quality of life and reduce disease progression. As more clinical studies have found that the combined use of muscarinic receptor antagonists and β ₂ -adrenergic agonists is more effective than using one of the therapeutic agents alone, the current clinical use of muscarinic receptor antagonists and β ₂ -adrenergic agonists to prepare compound preparations for the treatment of asthma and moderate to severe COPD, such compound preparations mainly include Anoro Ellipta (umeclidinium/vilanterol), Ultibro Breezhaler (glycopyrrolate) ammonium/indacaterol) and ipratropium bromide/salbutamol, etc. Compound preparations have better therapeutic effects than single preparations, but have higher requirements for preparation preparation.

Therefore, people also hope to develop drugs with dual effects of muscarinic receptor antagonism and β ₂ -adrenergic agonism. This bifunctional drug has the pharmaceutical advantages of the combination of the two components, and has a single molecule pharmacokinetics at the same time. . These compounds, administered as single therapeutic agents, provide bronchodilation by two distinct and possibly synergistic modes of action. In addition, compounds with dual muscarinic receptor antagonistic and β ₂ -adrenergic agonistic (MABA) actions can also be combined with corticosteroid (ICS) anti-inflammatory drugs to form two therapeutic agents (MABA/ICS) to provide triple therapy. Therapeutic effect of action (Expert Opin. Investig. Drugs (2014) 23(4): 453-456).

Therefore, it is necessary to develop novel active drugs with muscarinic receptor antagonism and/or β ₂ -adrenergic agonism, so as to provide more effective single therapeutic dose or compound preparation, and provide patients with more clinical drug options.

Contents of the invention

The present invention provides a compound represented by general formula (I) or its stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug,

in:

a is selected from 0, 1, 2, 3, 4 or 5;

b is selected from 0, 1, 2, 3 or 4;

Each R ¹ is independently selected from F, Cl, Br, I, CF ₃ , C _1-4 alkyl, cyano, -OR ^1a , -C(O)OR ^1b , -SR ^1c , -S(O )R ^1d , -S(O) ₂ R ^1e or -NR ^1f R ^1g ;

Each R ² is independently selected from F, Cl, Br, I, CF ₃ , C _1-4 alkyl, cyano, -OR ^1a , -C(O)OR ^1b , -SR ^1c , -S(O )R ^1d , -S(O) ₂ R ^1e or -NR ^1f R ^1g ;

R ^1a , R ^1b , R ^1c , R ^1d , R ^1e , R ^1f and R ^1g are each independently selected from H or C _1-4 alkyl;

Alternatively, R ^1f , R ^1g and the nitrogen atom connected to them form a 3-membered, 4-membered, 5-membered or 6-membered heterocycle, and the heterocycle contains 1 to 3 heteroatoms selected from N, O or S ;

W is -O- or -N(W ^a )-;

W ^a is selected from H or C _1-4 alkyl;

c is selected from 0, 1, 2, 3 or 4;

Each R ³ is independently selected from F, Cl, Br, I, CF ₃ , OH, cyano, C _1-4 alkyl or C _1-4 alkoxy;

R ⁴ is selected from C _1-6 alkylene, C _2-6 alkenylene or C _2-6 alkynylene, the alkylene, alkenylene or alkynylene is optionally further replaced by 0, 1, 2 , 3, 4 or 5 selected from F, Cl, Br, I, OH, cyano, C _1-4 alkyl, C _1-4 alkoxy, phenyl or phenyl-C _1-4 alkylene replaced by substituents;

X is selected from -C(O)- or -OC(O)-;

d is selected from 0, 1, 2 or 3;

R ⁵ is selected from F, Cl, Br, I, OH, NH ₂ , carboxyl, cyano, nitro, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 Alkoxy, -OC _3-6 cycloalkyl, C _1-4 alkylthio, -S(O)-C _1-4 alkyl, -S(O) ₂ -C _1-4 alkyl, -C (O)-C _1-4 alkyl, -C(O)OC _1-4 alkyl, -OC(O)-C _1-4 alkyl or -C(O)NH ₂ , the alkyl, alkane Oxygen, cycloalkyl, alkenyl, alkynyl, NH ₂ and -C(O)NH ₂ are optionally further 0, 1, 2, 3 or 4 selected from F, Cl, Br, I, CF ₃ , Substituents of C _1-4 alkyl, C _1-4 alkoxy or -C(O)-C _1-4 alkyl;

Y is selected from -CY ^a Y ^b -, -NY ^a -, -O-, -S-, -S(O)- or -S(O) ₂ -;

Y ^a and Y ^b are each independently selected from H or C _1-4 alkyl; or Y ^a and Y ^b form a 3-membered, 4-membered, 5-membered or 6-membered carbon ring together with the carbon atoms to which they are attached;

n is 0, 1 or 2;

e is selected from 0, 1, 2, 3 or 4;

Each R is independently selected from F, ^Cl , Br, I, C=O, cyano, C _1-4 alkyl or C _1-4 alkoxy, and the alkyl or alkoxy is optionally further Substituted by 0, 1, 2, 3 or 4 substituents selected from F, Cl, Br, I, CH ₂ F, CHF ₂ , CF ₃ or cyano;

Alternatively, two R ⁶ may form a 3-membered, 4-membered, 5-membered or 6-membered carbocycle together with the atoms to which they are attached, and the carbocycle is optionally further surrounded by 0, 1, 2, 3, 4 or 5 Substituents selected from F, Cl, Br, I, cyano, OH, C _1-4 alkyl or C _1-4 alkoxy;

R ⁷ is selected from C _1-6 alkylene, and the alkylene is optionally further substituted by 0, 1, 2, 3, 4 or 5 substituents selected from R ^7a ;

R ^7a is selected from F, Cl, Br, I, cyano, OH, C _1-4 alkyl, C _1-4 alkoxy, phenyl or phenyl-C _1-4 alkylene;

Alternatively, two R ^7a may form a 3 to 6-membered carbocycle together with the atoms to which they are attached, and the carbocycle is optionally further replaced by 0, 1, 2, 3, 4 or 5 members selected from F, Cl, Br , I, cyano, OH, C _1-4 alkyl or C _1-4 alkoxy substituents;

R ⁸ and R ⁹ are each independently selected from H or C _1-4 alkyl;

表示β-肾上腺素受体结合基团。

Indicates β-adrenergic receptor binding group.

In a preferred embodiment of the present invention, a compound represented by general formula (I) or its stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug, wherein:

表示β-肾上腺素受体结合基团；

Indicates β-adrenergic receptor binding group;

R¹⁰、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、R¹⁶、R¹⁷或R¹⁸各自独立的选自H、F、Cl、Br、I、CF₃、OH、-CH₂OH、氰基、羧基、C_1-4烷基、C_1-4烷氧基、-C(O)C_1-4烷基、-C(O)OC_1-4烷基、-NHC(O)H、-NHS(O)₂-C_1-4烷基、-NHS(O)₂-NH₂或-NHS(O)₂-NHC_1-4烷基，Q选自-CR^q1＝CR^q2-、-CR^q1R^q2CR^q3R^q4-、-O-、-S-或-CR^q1R^q2O-，所述R^q1、R^q2、R^q3或R^q4各自独立的选自选自H、F、Cl、Br、I或C_1-4烷基；B preferred

R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ or R ¹⁸ are each independently selected from H, F, Cl, Br, I, CF ₃ , OH, -CH ₂ OH , cyano, carboxyl, C _1-4 alkyl, C _1-4 alkoxy, -C(O)C _1-4 alkyl, -C(O)OC _1-4 alkyl, -NHC(O) H, -NHS(O) ₂ -C _1-4 alkyl, -NHS(O) ₂ -NH ₂ or -NHS(O) ₂ -NHC _1-4 alkyl, Q is selected from -CR ^q1 = CR ^q2 - , -CR ^q1 R ^q2 CR ^q3 R ^q4 -, -O-, -S- or -CR ^q1 R ^q2 O-, said R ^q1 , R ^q2 , R ^q3 or R ^q4 are each independently selected from H, F, Cl, Br, I or C _1-4 alkyl;

其中Q选自-CH＝CH-、-CH₂CH₂-、-O-、-S-或-CH₂O-；B is more preferred

Wherein Q is selected from -CH=CH-, -CH ₂ CH ₂ -, -O-, -S- or -CH ₂ O-;

B is further preferred

Q选自-CH＝CH-、-CH₂CH₂-、-O-、-S-或-CH₂O-；B is further preferred

Q is selected from -CH=CH-, -CH ₂ CH ₂ -, -O-, -S- or -CH ₂ O-;

a is selected from 0, 1, 2, 3, 4 or 5;

b is selected from 0, 1, 2, 3 or 4;

Each R ¹ is independently selected from F, Cl, Br, I, CF ₃ , C _1-4 alkyl, cyano, -OR ^1a , -C(O)OR ^1b , -SR ^1c , -S(O )R ^1d , -S(O) ₂ R ^1e or -NR ^1f R ^1g ;

Each R ² is independently selected from F, Cl, Br, I, CF ₃ , C _1-4 alkyl, cyano, -OR ^1a , -C(O)OR ^1b , -SR ^1c , -S(O )R ^1d , -S(O) ₂ R ^1e or -NR ^1f R ^1g ;

R ^1a , R ^1b , R ^1c , R ^1d , R ^1e , R ^1f and R ^1g are each independently selected from H or C _1-4 alkyl;

Alternatively, R ^1f , R ^1g and the nitrogen atom connected to them form a 3-membered, 4-membered, 5-membered or 6-membered heterocycle, and the heterocycle contains 1 to 3 heteroatoms selected from N, O or S ;

W is -O- or -N(W ^a )-;

W ^a is selected from H or C _1-4 alkyl;

c is selected from 0, 1, 2, 3 or 4;

Each R ³ is independently selected from F, Cl, Br, I, CF ₃ , OH, cyano, C _1-4 alkyl or C _1-4 alkoxy;

R ⁴ is selected from C _1-6 alkylene, C _2-6 alkenylene or C _2-6 alkynylene, the alkylene, alkenylene or alkynylene is optionally further replaced by 0, 1, 2 , 3, 4 or 5 selected from F, Cl, Br, I, OH, cyano, C _1-4 alkyl, C _1-4 alkoxy, phenyl or phenyl-C _1-4 alkylene replaced by substituents;

X is selected from -C(O)- or -OC(O)-;

d is selected from 0, 1, 2 or 3;

R ⁵ is selected from F, Cl, Br, I, OH, NH ₂ , carboxyl, cyano, nitro, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 Alkoxy, -OC _3-6 cycloalkyl, C _1-4 alkylthio, -S(O)-C _1-4 alkyl, -S(O) ₂ -C _1-4 alkyl, -C (O)-C _1-4 alkyl, -C(O)OC _1-4 alkyl, -OC(O)-C _1-4 alkyl or -C(O)NH ₂ , the alkyl, alkane Oxygen, cycloalkyl, alkenyl, alkynyl, NH ₂ and -C(O)NH ₂ are optionally further 0, 1, 2, 3 or 4 selected from F, Cl, Br, I, CF ₃ , Substituents of C _1-4 alkyl, C _1-4 alkoxy or -C(O)-C _1-4 alkyl;

Y is selected from -CY ^a Y ^b -, -NY ^a -, -O-, -S-, -S(O)- or -S(O) ₂ -;

Y ^a and Y ^b are each independently selected from H or C _1-4 alkyl; or Y ^a and Y ^b form a 3-membered, 4-membered, 5-membered or 6-membered carbon ring together with the carbon atoms to which they are attached;

n is 0, 1 or 2;

e is selected from 0, 1, 2, 3 or 4;

R is selected from F, ^Cl , Br, I, C=O, cyano, C _1-4 alkyl or C _1-4 alkoxy, and the alkyl or alkoxy is optionally further replaced by 0, 1, 2, 3 or 4 substituents selected from F, Cl, Br, I, CH ₂ F, CHF ₂ , CF ₃ or cyano;

Alternatively, two R ⁶ may form a 3-membered, 4-membered, 5-membered or 6-membered carbocycle together with the atoms to which they are attached, and the carbocycle is optionally further surrounded by 0, 1, 2, 3, 4 or 5 Substituents selected from F, Cl, Br, I, cyano, OH, C _1-4 alkyl or C _1-4 alkoxy;

R ⁷ is selected from C _1-6 alkylene, and the alkylene is optionally further substituted by 0, 1, 2, 3, 4 or 5 substituents selected from R ^7a ;

R ^7a is selected from F, Cl, Br, I, cyano, OH, C _1-4 alkyl, C _1-4 alkoxy, phenyl or phenyl-C _1-4 alkylene;

Alternatively, two R ^7a may form a 3 to 6-membered carbocycle together with the atoms to which they are attached, and the carbocycle is optionally further replaced by 0, 1, 2, 3, 4 or 5 members selected from F, Cl, Br , I, cyano, OH, C _1-4 alkyl or C _1-4 alkoxy substituents;

R ⁸ and R ⁹ are each independently selected from H or C _1-4 alkyl.

In a preferred embodiment of the present invention, a compound represented by general formula (I) or its stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug, wherein:

R¹⁰、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、R¹⁶、R¹⁷或R¹⁸各自独立的选自H、F、Cl、Br、I、CF₃、OH、-CH₂OH、氰基、羧基、C_1-4烷基、C_1-4烷氧基、-C(O)C_1-4烷基、-C(O)OC_1-4烷基、-NHC(O)H、-NHS(O)₂-C_1-4烷基、-NHS(O)₂-NH₂或-NHS(O)₂-NHC_1-4烷基，Q选自-CR^q1＝CR^q2-、-CR^q1R^q2CR^q3R^q4-、-O-、-S-或-CR^q1R^q2O-，所述R^q1、R^q2、R^q3或R^q4各自独立的选自选自H、F、Cl、Br、I或C_1-4烷基；B from

R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ or R ¹⁸ are each independently selected from H, F, Cl, Br, I, CF ₃ , OH, -CH ₂ OH , cyano, carboxyl, C _1-4 alkyl, C _1-4 alkoxy, -C(O)C _1-4 alkyl, -C(O)OC _1-4 alkyl, -NHC(O) H, -NHS(O) ₂ -C _1-4 alkyl, -NHS(O) ₂ -NH ₂ or -NHS(O) ₂ -NHC _1-4 alkyl, Q is selected from -CR ^q1 = CR ^q2 - , -CR ^q1 R ^q2 CR ^q3 R ^q4 -, -O-, -S- or -CR ^q1 R ^q2 O-, said R ^q1 , R ^q2 , R ^q3 or R ^q4 are each independently selected from H, F, Cl, Br, I or C _1-4 alkyl;

Q选自-CH＝CH-、-CH₂CH₂-、-O-、-S-或-CH₂O-；B preferred

Q is selected from -CH=CH-, -CH ₂ CH ₂ -, -O-, -S- or -CH ₂ O-;

B is further preferred

a is selected from 0, 1, 2, 3, 4 or 5; preferably 0, 1 or 2;

b is selected from 0, 1, 2, 3 or 4; preferably 0, 1 or 2;

Each R ¹ is independently selected from F, Cl, Br, I, CF ₃ , cyano, hydroxyl, C _1-4 alkyl, C _1-4 alkoxy or C _1-4 alkylthio; preferably F , Cl, Br, I, CF ₃ , cyano, hydroxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio or ethylthio; more preferably F, Cl, Br, hydroxy, methyl, ethyl, methoxy or ethoxy;

R ² are each independently selected from F, Cl, Br, I, CF ₃ , cyano, hydroxyl, C _1-4 alkyl, C _1-4 alkoxy or C _1-4 alkylthio; preferably F , Cl, Br, I, CF ₃ , cyano, hydroxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio or ethylthio; more preferably F, Cl, Br, hydroxy, methyl, ethyl, methoxy or ethoxy;

W is -O- or -N(W ^a )-;

W is selected from H or C _1-4 alkyl ^; preferably H, methyl, ethyl or isopropyl;

c is selected from 0, 1, 2, 3 or 4; preferably 0, 1 or 2;

R ³ are each independently selected from F, Cl, Br, I, CF ₃ , OH, cyano, C _1-4 alkyl or C _1-4 alkoxy; preferably F, Cl, Br, I, CF _3. OH, cyano, methyl, ethyl, methoxy or ethoxy; more preferably F, methyl or ethyl;

R ⁴ is selected from C _1-6 alkylene, C _2-6 alkenylene or C _2-6 alkynylene; preferred C _1-6 alkylene; more preferably methylene, ethylene, propylene Or butylene, said alkylene, alkenylene, alkynylene, methylene, ethylene, propylene or butylene is optionally further selected from 0, 1, 2, 3, 4 or 5 Substituents of F, Cl, Br, I, OH, cyano, C _1-4 alkyl, C _1-4 alkoxy, phenyl or phenyl-C _1-4 alkylene;

X is selected from -C(O)- or -OC(O)-;

d is selected from 0, 1, 2 or 3;

Each R ⁵ is independently selected from F, Cl, Br, I, OH, NH ₂ , carboxyl, cyano, nitro, C _1-4 alkyl, C _2-4 alkynyl, C _1-4 alkoxy base, -OC _3-6 cycloalkyl, C _1-4 alkylthio, -S(O)-C _1-4 alkyl, -S(O) ₂ -C _1-4 alkyl, -C(O )-C _1-4 alkyl or -C(O)OC _1-4 alkyl, said alkyl, alkoxy, cycloalkyl and NH ₂ are optionally further replaced by 0 to 4 selected from F, Cl, Substituents of Br, I, CF ₃ , C _1-4 alkyl, C _1-4 alkoxy or -C(O)-C _1-4 alkyl are substituted for said alkyl, alkoxy, cycloalkane Group, alkynyl and NH ₂ are optionally further replaced by 0 to 4 selected from F, Cl, Br, I, CF ₃ , C _1-4 alkyl, C _1-4 alkoxy or -C(O)-C _1-4 alkyl substituents; R ⁵ is preferably F, Cl, Br, CH ₂ F, CHF ₂ , NH ₂ , cyano, nitro, OCH ₂ F, OCHF ₂ , OCF ₃ , methyl, ethyl radical, isopropyl, methoxy, ethoxy, methylthio, cyclopropyloxy, ethynyl, propynyl, -S(O) ₂ CH ₃ , -C(O)CH ₃ , -C (O)OCH ₃ or -C(O)OCH ₂ CH ₃ ; R ⁵ is more preferably F, Cl, Br, cyano, methyl, ethyl, propyl, isopropyl, CHF ₂ , CF ₃ , methoxy ethoxy, -OCHF ₂ , -OCF ₃ , cyclopropyloxy, ethynyl or propynyl;

Y is selected from -CY ^a Y ^b -, -NY ^a -, -O-, -S-, -S(O)- or -S(O) ₂ -; preferably -CY ^a Y ^b -, -N-, -O- or -S-;

Y ^a and Y ^b are each independently selected from H or C _1-4 alkyl; preferably H, methyl or ethyl; or Y ^a and Y ^b together form a 3-membered, 4-membered, 5-membered One- or six-membered carbocycles; preferably three- or four-membered carbocycles;

n is 0, 1 or 2;

e is selected from 0, 1, 2, 3 or 4;

R ⁶ are each independently selected from F, Cl, Br, I, C=O, cyano, C _1-4 alkyl or C _1-4 alkoxy; preferably F, Cl, Br, I, C= O, cyano, methyl, ethyl, methoxy or ethoxy, the alkyl, alkoxy, methyl, ethyl, methoxy or ethoxy are optionally further replaced by 0, 1, 2 , 3 or 4 substituents selected from F, Cl, Br, I, CH ₂ F, CHF ₂ , CF ₃ or cyano;

Alternatively, two R ⁶ may form a 3-membered, 4-membered, 5-membered or 6-membered carbocycle together with the atoms to which they are attached, and the carbocycle is optionally further surrounded by 0, 1, 2, 3, 4 or 5 Substituents selected from F, Cl, Br, I, cyano, OH, C _1-4 alkyl or C _1-4 alkoxy;

R ⁷ is selected from C _1-6 alkylene; preferably C _1-4 alkylene; more preferably methylene, ethylene, propylene or butylene, said alkylene, methylene, ethylene A group, a propylene group or a butylene group is optionally further substituted by 0, 1, 2, 3, 4 or 5 substituents selected from R ^7a ;

R ^7a is selected from F, Cl, Br, I, cyano, OH, C _1-4 alkyl, C _1-4 alkoxy, phenyl or phenyl-C _1-4 alkylene; preferably F, Cl , Br, I, cyano, OH, C _1-4 alkyl, C _1-4 alkoxy or phenyl; more preferably F, Cl, Br, cyano, OH, methyl, ethyl, methoxy , ethoxy or phenyl;

Alternatively, two R ^7a may together with the atoms to which they are attached form a 3, 4, 5 or 6 membered carbocycle which is optionally further represented by 0, 1, 2, 3, 4 or 5 members selected from F , Cl, Br, I, cyano, OH, C _1-4 alkyl or C _1-4 alkoxy substituents;

R ⁸ and R ⁹ are each independently selected from H or C _1-4 alkyl; preferably H, methyl or ethyl.

In a preferred embodiment of the present invention, a compound represented by general formula (I) or its stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug, wherein:

Q选自-CH＝CH-、-CH₂CH₂-、-O-、-S-或-CH₂O-；B from

Q is selected from -CH=CH-, -CH ₂ CH ₂ -, -O-, -S- or -CH ₂ O-;

B preferred

a is selected from 0, 1, 2, 3, 4 or 5; preferably 0, 1 or 2;

b is selected from 0, 1, 2, 3 or 4; preferably 0, 1 or 2;

Each R1 is independently selected from ^F , Cl, Br, I, _CF3 , cyano, hydroxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio or Ethylthio; preferably F, Cl, Br, hydroxy, methyl, ethyl, methoxy or ethoxy;

R ² are each independently selected from F, Cl, Br, I, CF ₃ , cyano, hydroxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio or Ethylthio; preferably F, Cl, Br, hydroxy, methyl, ethyl, methoxy or ethoxy;

W is -O- or -N(W ^a )-;

W is selected from H or C _1-4 alkyl ^; preferably H, methyl, ethyl or isopropyl;

c is selected from 0, 1, 2, 3 or 4; preferably 0, 1 or 2;

R ³ are each independently selected from F, Cl, Br, I, CF ₃ , OH, cyano, methyl, ethyl, methoxy or ethoxy; preferably F, methyl or ethyl;

R is selected from C _1-6 alkylene ^; preferably methylene, ethylene, propylene or butylene, said alkylene, alkenylene, alkynylene, methylene, ethylene, Propylene or butylene is optionally further replaced by 0, 1, 2, 3, 4 or 5 selected from F, Cl, Br, I, OH, cyano, C _1-4 alkyl, C _1-4 alkoxy Substituent group, phenyl or phenyl-C _1-4 alkylene; R ⁴ is preferably methylene, ethylene, propylene, -C(CH ₃ ) ₂ CH ₂ -, -CH ₂ C(CH ₃ ) ₂ -, -CH(CH ₃ )CH ₂ - or -CH ₂ CH(CH ₃ )-;

X is selected from -C(O)- or -OC(O)-;

d is selected from 0, 1, 2 or 3;

Each R ⁵ is independently selected from F, Cl, Br, CH ₂ F, CHF ₂ , NH ₂ , cyano, nitro, OCH ₂ F, OCHF ₂ , OCF ₃ , methyl, ethyl, isopropyl , methoxy, ethoxy, methylthio, cyclopropyloxy, ethynyl, propynyl, -S(O) ₂ CH ₃ , -C(O)CH ₃ , -C(O)OCH ₃ or -C(O)OCH ₂ CH ₃ ; preferably F, Cl, Br, cyano, methyl, ethyl, propyl, isopropyl, CHF ₂ , CF ₃ , methoxy, ethoxy, -OCHF _2. -OCF ₃ , cyclopropyloxy, ethynyl or propynyl;

Y is selected from -CY ^a Y ^b -, -N-, -O-, -S-, -S(O)- or -S(O) ₂ -; preferably -CY ^a Y ^b -, -N-, - O- or -S-;

Y ^a and Y ^b are each independently selected from H or C _1-4 alkyl; preferably H, methyl or ethyl; or Y ^a and Y ^b together form a 3-membered, 4-membered, 5-membered One- or six-membered carbocycles; preferably three- or four-membered carbocycles;

n is 0, 1 or 2;

e is selected from 0, 1, 2, 3 or 4; preferably 0, 1 or 2;

Each R is independently selected from F, ^Cl , Br, I, C═O, cyano, methyl, ethyl, methoxy or ethoxy;

Alternatively, two R ⁶ may form a 3-membered, 4-membered, 5-membered or 6-membered carbocycle together with the atoms to which they are attached, and the carbocycle is optionally further surrounded by 0, 1, 2, 3, 4 or 5 Substituents selected from F, Cl, Br, I, cyano, OH, C _1-4 alkyl or C _1-4 alkoxy;

所述亚甲基、亚乙基、亚丙基、亚丁基或

任选进一步被0、1、2、3、4或5个选自F、Cl、Br、I、氰基、OH、甲基、乙基、甲氧基或乙氧基的取代基所取代；R is selected from C _1-4 alkylene ^; preferably methylene, ethylene, propylene, butylene or

The methylene, ethylene, propylene, butylene or

Optionally further substituted by 0, 1, 2, 3, 4 or 5 substituents selected from F, Cl, Br, I, cyano, OH, methyl, ethyl, methoxy or ethoxy;

R ^7a is selected from F, Cl, Br, I, cyano, OH, C _1-4 alkyl, C _1-4 alkoxy, phenyl or phenyl-C _1-4 alkylene; preferably F, Cl , Br, I, cyano, OH, C _1-4 alkyl, C _1-4 alkoxy or phenyl; more preferably F, Cl, Br, cyano, OH, methyl, ethyl, methoxy , ethoxy or phenyl;

R ⁷ is preferably methylene, ethylene, propylene, -C(CH ₃ ) ₂ CH ₂ -, -CH ₂ C(CH ₃ ) ₂ -, -CH(CH ₃ )CH ₂ -, -CH ₂ CH(CH ₃ )-or

R ⁸ and R ⁹ are each independently selected from H or C _1-4 alkyl; preferably H, methyl or ethyl.

The preferred version of the present invention, a compound represented by general formula (I) or its stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug, wherein the compound is selected from Compound shown in general formula (II):

W is -O- or -N(W ^a )-;

W is selected from H or C _1-4 alkyl ^; preferably H, methyl, ethyl, propyl or isopropyl;

c is selected from 0, 1, 2, 3 or 4; preferably 0 or 1;

Each R ³ is independently selected from F, Cl, Br, I, CF ₃ , OH, cyano, C _1-4 alkyl or C _1-4 alkoxy; preferably F, methyl, ethyl, propyl radical, methoxy or ethoxy;

R ⁴ is selected from C _1-6 alkylene; preferably C _1-4 alkylene, the alkylene is optionally further replaced by 0, 1, 2, 3, 4 or 5 selected from F, Cl, Br, Substituents of I, OH, cyano, C _1-4 alkyl or C _1-4 alkoxy;

X is selected from -C(O)- or -OC(O)-;

d is selected from 0, 1, 2 or 3; preferably 0 or 1;

R ⁵ is selected from F, Cl, Br, I, OH, NH ₂ , carboxyl, cyano, nitro, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 Alkoxy, -OC _3-6 cycloalkyl, C _1-4 alkylthio, -S(O)-C _1-4 alkyl, -S(O) ₂ -C _1-4 alkyl, -C (O)-C _1-4 alkyl, -C(O)OC _1-4 alkyl, -OC(O)-C _1-4 alkyl or -C(O)NH ₂ ; preferably F, Cl, Br , I, OH, NH ₂ , carboxyl, cyano, nitro, C _1-4 alkyl, C _1-4 alkoxy, -OC _3-6 cycloalkyl, C _1-4 alkylthio, -S (O)-C _1-4 alkyl, -S(O) ₂ -C _1-4 alkyl, -C(O)-C _1-4 alkyl or -C(O)OC _1-4 alkyl, The alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl, NH ₂ and -C(O)NH ₂ are optionally further selected from F, Cl, Br by 0, 1, 2, 3 or 4 , I, CF ₃ , C _1-4 alkyl, C _1-4 alkoxy or -C(O)-C _1-4 alkyl substituents;

Y is selected from -CY ^a Y ^b -, -NY ^a -, -O-, -S-, -S(O)- or -S(O) ₂ -; preferably -CY ^a Y ^b -, -N-, -O- or -S-;

Y ^a and Y ^b are each independently selected from H or C _1-4 alkyl; preferably H, methyl, ethyl or propyl; or Y ^a and Y ^b can form a 3-membered, 4-, 5-, or 6-membered carbon rings;

e is selected from 0, 1, 2, 3 or 4; preferably 0, 1 or 2; more preferably 0;

R is selected from F, ^Cl , Br, C=O, cyano, C _1-4 alkyl or C _1-4 alkoxy; preferably F, Cl, C=O, cyano, methyl, ethyl, Methoxy or ethoxy;

Alternatively, two R ⁶ may form, together with the atoms to which they are attached, a 3-, 4-, 5-, or 6-membered carbocycle; preferably 3- or 4-membered, said carbocycle being optionally further selected from 0 to 5 Substituted from F, Cl, Br, I, cyano, OH, C _1-4 alkyl or C _1-4 alkoxy; preferably F, Cl, OH, cyano, methyl, ethyl, Methoxy or ethoxy;

n is 0, 1 or 2;

R ⁷ is selected from C _1-6 alkylene; preferably C _1-4 alkylene, which is optionally further substituted by 0, 1, 2, 3, 4 or 5 substituents selected from R ^7a replace;

R ^7a is selected from F, Cl, Br, I, cyano, OH, C _1-4 alkyl, C _1-4 alkoxy or phenyl; preferably F, Cl, Br, I, cyano, OH, C _1-4 alkyl or C _1-4 alkoxy; more preferably F, Cl, Br, I, cyano, OH, methyl, ethyl, methoxy or ethoxy;

Alternatively, two R ^7a may form together with the atoms to which they are attached a 3-, 4-, 5- or 6-membered carbocycle; preferably a 3- or 4-membered carbocycle, optionally further surrounded by 0, 1 , 2, 3, 4 or 5 substituents selected from F, Cl, Br, I, cyano, OH, C _1-4 alkyl or C _1-4 alkoxy;

R ⁸ and R ⁹ are each independently selected from H or C _1-4 alkyl; preferably H, methyl or ethyl;

B from

Q is selected from -CH= _CH- , _-CH2CH2- , -O-, -S- or _-CH2O- .

The preferred version of the present invention, a compound represented by general formula (I) or its stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug, wherein the compound is selected from The compound shown in general formula (II),

W is -O- or -N(W ^a )-;

W is selected from H, methyl or ethyl ^;

c is 0;

R is selected from methylene, ethylene or propylene, and said methylene, ethylene or propylene is optionally further selected from 0, 1, 2, 3, ⁴ or 5 selected from F, Substituents of Cl, Br, I, cyano, OH, methyl, ethyl, methoxy or ethoxy;

X is selected from -C(O)- or -OC(O)-;

d is selected from 0, 1, 2 or 3;

R ⁵ is selected from F, Cl, Br, CH ₂ F, CHF ₂ , NH ₂ , cyano, nitro, OCH ₂ F, OCHF ₂ , OCF ₃ , methyl, ethyl, methoxy, ethoxy, Methylthio, -S(O) ₂ CH ₃ , -C(O)CH ₃ , -C(O)OCH ₃ or -C(O)OCH ₂ CH ₃ ; preferably F, Cl, Br, CH ₂ F, CHF ₂ , cyano, nitro, OCH ₂ F, OCHF ₂ , OCF ₃ , methyl, ethyl, methoxy or ethoxy; more preferably F, Cl, Br, methyl, ethyl, methoxy or ethoxy;

Y is selected from -CY ^a Y ^b -, -NY ^a -, -O-, -S-, -S(O)- or -S(O) ₂ -; preferably -CY ^a Y ^b -, -NY ^a - , -O- or -S-;

Y ^a , Y ^b are each independently selected from H, methyl or ethyl; or Y ^a , Y ^b can form a 3-membered, 4-membered, 5-membered or 6-membered carbon ring together with the carbon atoms connected to them; preferably 3 1-membered or 4-membered carbocycle;

e is 0, 1 or 2;

R is selected from F, ^Cl , Br, C=O, cyano, methyl, ethyl, methoxy or ethoxy;

n is 0, 1 or 2;

任选进一步被0、1、2、3、4或5个选自F、Cl、Br、I、氰基、OH、甲基、乙基、甲氧基或乙氧基的取代基所取代；R ^is selected from methylene, ethylene, propylene or The methylene, ethylene, propylene or

Optionally further substituted by 0, 1, 2, 3, 4 or 5 substituents selected from F, Cl, Br, I, cyano, OH, methyl, ethyl, methoxy or ethoxy;

R ⁸ and R ⁹ are each independently selected from H, methyl or ethyl; preferably H or methyl;

B from

In a preferred embodiment of the present invention, a compound represented by general formula (I) or general formula (II) or its stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug , wherein the compound is selected from one of the following structures:

The present invention relates to providing the compound described in general formula (I) or (II) or its stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug, wherein said Salt selected from hydrochloride, hydrobromide, sulfate, phosphate, acetate, trifluoroacetate, maleate, hydroxymaleate, glutarate, fumarate, tartaric acid Salt, succinate, benzenesulfonate, p-toluenesulfonate, benzoate, salicylate, phenylacetate, cinnamate, lactate, malonate, pivalate , malate, mandelate, oxalate, gallate, gluconate, laurate, palmitate, pectate, picrate, citrate, methanesulfonate, hexasulfonate , saccharin (o-benzoylsulfonimide) or their combination; preferably hydrochloride, sulfate, trifluoroacetate, fumarate, tartrate, succinate, oxalate, methanesulfonate acid, sweetener, or a combination thereof.

The present invention also relates to providing a pharmaceutical composition, which contains a therapeutically effective dose of the compound of any one of the general formula (I) or (II) or its stereoisomer, hydrate, metabolite , solvate, pharmaceutically acceptable salt, co-crystal or prodrug, and pharmaceutically acceptable carrier, diluent, adjuvant, vehicle or vehicle; the composition can further include one or A variety of other therapeutic agents; preferably, wherein the other therapeutic agents are selected from one or more of PDE4 inhibitors, muscarinic receptor antagonists, corticosteroids and β-adrenergic receptor agonists.

The present invention also relates to providing the compound described in general formula (I) or (II) or its stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug, used in the preparation Application in medicine for treating airway obstructive disease; preferably, application in preparation of medicine for treating asthma, chronic obstructive pulmonary disease or bronchitis.

The present invention also relates to providing a method for treating airway obstructive diseases, said method comprising administering any one of the compounds described in the present invention or its stereoisomers, hydrates, metabolites, solvates, pharmaceutically acceptable Acceptable salts, co-crystals or prodrugs, or pharmaceutical compositions of the present invention.

The present invention also relates to providing a method for treating asthma, chronic obstructive pulmonary disease or bronchitis, said method comprising administering any one of the compounds of the present invention or its stereoisomers, hydrates, metabolites, solvents compounds, pharmaceutically acceptable salts, co-crystals or prodrugs, or pharmaceutical compositions of the present invention.

Unless stated to the contrary, the terms used in the specification and claims have the following meanings.

The carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur, Nitrogen or halogen is optionally further replaced by one or more of their corresponding isotopes, wherein isotopes of carbon include ¹² C, ¹³ C, and ¹⁴ C, and isotopes of hydrogen include protium (H), deuterium (D, also known as heavy hydrogen ), tritium (T, also known as tritium), the isotopes of oxygen include ¹⁶ O, ¹⁷ O and ¹⁸ O, the isotopes of sulfur include ³² S, ³³ S, ³⁴ S and ³⁶ S, and the isotopes of nitrogen include ¹⁴ N and ¹⁵ N, the isotope of fluorine is ¹⁹ F, the isotope of chlorine includes ³⁵ Cl and ³⁷ Cl, and the isotope of bromine includes ⁷⁹ Br and ⁸¹ Br.

"Alkyl" refers to straight chain and branched monovalent saturated hydrocarbon groups, the main chain includes 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, more preferably 1 Straight and branched chain groups of up to 4 carbon atoms, most preferably 1 to 2 carbon atoms, examples of alkyl groups include but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, iso Butyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, n-hexyl, n-heptyl group, n-octyl group, n-nonyl group, n-decyl group, etc.; said alkyl group can optionally be further replaced by 0 to 5 members selected from F, Cl, Br, I, =O, -CH ₂ F, -CHF ₂ , -CF ₃ , hydroxyl, -SR ¹⁸ , nitro, cyano, isocyano, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, C _2-8 alkenyl, C _2-8 Alkynyl, -(CH ₂ ) _q -C(=O)-R ¹⁹ , -(CH ₂ ) _q -C(=O)-OR ¹⁹ , -(CH ₂ ) _q -C(=O)-NR ¹⁹ Substituents of R ^19a , -(CH ₂ ) _q -S(=O) _m -R ¹⁸ , -OC(=O)-OR ¹⁸ or -NR ¹⁸ R ^18a , wherein R ¹⁹ and R ^19a are independently selected from From H, hydroxyl, amino, carboxyl, C _1-8 alkyl, C _1-8 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, 3 to 10-membered carbocyclyl, 4 to 10-membered Heterocyclyl, 3 to 10 membered carbocyclyloxy or 4 to 10 membered heterocyclyloxy, q is selected from 0, 1, 2, 3, 4 or 5, m is selected from 0, 1 or 2; R ¹⁹ and R ^19a are each independently selected from H, unsubstituted C _1-6 alkyl. The alkyl group, R ¹⁸ and R ^18a appearing herein are as defined above.

"Alkylene" refers to straight-chain and branched divalent saturated hydrocarbon groups, including -(CH ₂ ) _v - (v is an integer from 1 to 10), examples of alkylene include but not limited to methylene, methylene Ethyl, propylene, butylene, etc.; said alkylene can be optionally further replaced by 0 to 5 members selected from F, Cl, Br, I, =O, -CH ₂ F, -CHF ₂ , -CF _3. Hydroxy, -SR ¹⁸ , nitro, cyano, isocyano, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, C _2-8 alkenyl, C _2-8 alkynyl , -(CH ₂ ) _q -C(=O)-R ¹⁹ , -(CH ₂ ) _q -C(=O)-OR ¹⁹ , -(CH ₂ ) _q -C(=O)-NR ¹⁹ R ^19a , -(CH ₂ ) _q -S(=O) _m -R ¹⁸ , -OC(=O)-OR ¹⁸ or -NR ¹⁸ R ^18a are substituted by substituents, wherein R ¹⁹ and R ^19a are each independently selected from H , hydroxyl, amino, carboxyl, C _1-8 alkyl, C _1-8 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, 3 to 10 membered carbocyclyl, 4 to 10 membered heterocycle Base, 3 to 10 membered carbocyclyloxy group or 4 to 10 membered heterocyclyloxy group, q is selected from 0, 1, 2, 3, 4 or 5, m is selected from 0, 1 or 2; R ¹⁹ and R ^19a are each independently selected from H, unsubstituted C _1-6 alkyl. The alkylene group appearing herein is as defined above.

"Alkoxy" means a monovalent group of O-alkyl, wherein alkyl is as defined herein, and examples of alkylene include, but are not limited to, methoxy, ethoxy, 1-propoxy, 2 -propoxy, 1-butoxy, 2-methyl-1-propoxy, 2-butoxy, 2-methyl-2-propoxy, 1-pentyloxy, 2-pentyloxy , 3-pentyloxy, 2-methyl-2-butoxy, 3-methyl-2-butoxy, 3-methyl-1-butoxy and 2-methyl-1-butoxy, etc.

"Alkenyl" refers to straight and branched monovalent unsaturated hydrocarbon radicals having at least 1, usually 1, 2 or 3 carbon-carbon double bonds, the main chain comprising 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms in the backbone, alkenyl examples include but are not limited to vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl , 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2- Methyl-1-butenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-Methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octene Base, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1, 4-pentadiene and 1,4-hexadiene, etc.; the alkylene group can optionally be further selected from 0 to 5 members selected from F, Cl, Br, I, =O, -CH ₂ F, -CHF _2. -CF ₃ , hydroxyl, -SR ¹⁸ , nitro, cyano, isocyano, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, C _2-8 alkenyl, C _{2 -8} alkynyl, -(CH ₂ ) _q -C(=O)-R ¹⁹ , -(CH ₂ ) _q -C(=O)-OR ¹⁹ , -(CH ₂ ) _q -C(=O)- Substituents of NR ¹⁹ R ^19a , -(CH ₂ ) _q -S(=O) _m -R ¹⁸ , -OC(=O)-OR ¹⁸ or -NR ¹⁸ R ^18a , wherein R ¹⁹ and R ^19a are each independently selected from H, hydroxyl, amino, carboxyl, C _1-8 alkyl, C _1-8 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, 3 to 10 membered carbocyclyl, 4 to 10-membered heterocyclyl, 3-10-membered carbocyclyloxy or 4-10-membered heterocyclyloxy, q is selected from 0, 1, 2, 3, 4 or 5, m is selected from 0, 1 or 2; R ¹⁹ and R ^19a are each independently selected from H, unsubstituted C _1-6 alkyl. As used herein, alkenyl is as defined above.

"Alkynyl" means a straight and branched monovalent unsaturated hydrocarbon group having at least 1, usually 1, 2 or 3 carbon-carbon triple bonds, the main chain comprising 2 to 10 carbon atoms, more preferably 2 up to 6 carbon atoms, more preferably 2 to 4 carbon atoms in the backbone, alkynyl examples include but are not limited to ethynyl, 1-propynyl, 2-propynyl, butynyl, 2-but Alkynyl, 3-butynyl, 1-methyl-2-propynyl, 4-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-hexynyl, 3 -hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl and 4-decynyl etc.; is further selected from 0 to 5 selected from F, Cl, Br, I, =O, -CH ₂ F, -CHF ₂ , -CF ₃ , hydroxyl, -SR ¹⁸ , nitro, cyano, isocyano, alkane radical, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, C _2-8 alkenyl, C _2-8 alkynyl, -(CH ₂ ) _q -C(=O)-R ¹⁹ , -( CH ₂ ) _q -C(=O)-OR ¹⁹ , -(CH ₂ ) _q -C(=O)-NR ¹⁹ R ^19a , -(CH ₂ ) _q -S(=O) _m -R ¹⁸ , - OC(=O)-OR ¹⁸ or -NR ¹⁸ R ^18a is substituted by a substituent, wherein R ¹⁹ and R ^19a are each independently selected from H, hydroxyl, amino, carboxyl, C _1-8 alkyl, C _1-8 alkane Oxygen, C _2-8 alkenyl, C _2-8 alkynyl, 3 to 10 membered carbocyclyl, 4 to 10 membered heterocyclyl, 3 to 10 membered carbocyclyloxy or 4 to 10 membered heterocyclyl Oxygen, q is selected from 0, 1, 2, 3, 4 or 5, m is selected from 0, 1 or 2; R ¹⁹ and R ^19a are each independently selected from H, unsubstituted C _1-6 alkyl. As used herein, alkynyl is as defined above.

所述的碳环基可以任选进一步被0至5个选自F、Cl、Br、I、 ＝O、-CH₂F、-CHF₂、-CF₃、羟基、-SR¹⁸、硝基、氰基、异氰基、烷基、羟基烷基、烷氧基、碳环基、杂环基、C_2-8烯基、C_2-8炔基、-(CH₂)_q-C(＝O)-R¹⁹、-(CH₂)_q-C(＝O)-O-R¹⁹、-(CH₂)_q-C(＝O)-NR¹⁹R^19a、-(CH₂)_q-S(＝O)_m-R¹⁸、-O-C(＝O)-O-R¹⁸或者-NR¹⁸R^18a的取代基所取代，其中R¹⁹和R^19a各自独立选自H、羟基、氨基、羧基、C_1-8烷基、C_1-8烷氧基、C_2-8烯基、C_2-8炔基、3至10元碳环基、4至10元杂环基、3至10元碳环基氧基或者4至10元杂环基氧基，q选自0、1、2、3、4或者5，m选自0、1或者2；R¹⁹和R^19a各自独立选自H、未被取代的C_1-6的烷基。本文中出现的碳环，其定义如上所述。"Carbocycle" refers to a saturated or unsaturated 3- to 10-membered monocyclic ring or a 4- to 12-membered bicyclic ring system. Cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and

The carbocyclyl can optionally be further replaced by 0 to 5 members selected from F, Cl, Br, I, =O, -CH ₂ F, -CHF ₂ , -CF ₃ , hydroxyl, -SR ¹⁸ , nitro, Cyano, isocyano, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, C _2-8 alkenyl, C _2-8 alkynyl, -(CH ₂ ) _q -C(= O)-R ¹⁹ , -(CH ₂ ) _q -C(=O)-OR ¹⁹ , -(CH ₂ ) _q -C(=O)-NR ¹⁹ R ^19a , -(CH ₂ ) _q -S(= O) _m -R ¹⁸ , -OC(=O)-OR ¹⁸ or -NR ¹⁸ R ^18a is substituted by a substituent, wherein R ¹⁹ and R ^19a are each independently selected from H, hydroxyl, amino, carboxyl, C _1-8 Alkyl, C _1-8 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, 3 to 10 membered carbocyclyl, 4 to 10 membered heterocyclyl, 3 to 10 membered carbocyclyloxy Or 4 to 10 membered heterocyclyloxy groups, q is selected from 0, 1, 2, 3, 4 or 5, m is selected from 0, 1 or 2; R ¹⁹ and R ^19a are each independently selected from H, unsubstituted C _1-6 alkyl. Carbocycles appearing herein are as defined above.

"Heterocyclic ring" refers to a saturated or unsaturated non-aromatic ring. The non-aromatic ring can be a 3-10-membered monocyclic ring or a 4-12-membered bicyclic ring, and contains 1 to 4 heteroatoms selected from N, O or S , preferably a 4- to 8-membered heterocyclic group, and the selectively substituted N and S in the ring of the heterocyclic group can be oxidized into various oxidation states. The heterocyclic group can be connected to a heteroatom or a carbon atom, and the heterocyclic group can be connected to a bridged ring or a spiro ring. Non-limiting examples include oxirane, epoxypropyl, aziridyl, oxyheterocyclic Butyl, azetidinyl, thietanyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, azepanyl , oxepyl, thiepinyl, oxazepinyl, thiazepinyl, piperidinyl, homopiperidinyl, furyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl , piperazinyl, homopiperazinyl, piperidinyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, 1,3-dithiol, dihydrofuranyl, dihydropyranyl base, dithiapentyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzene Imidazolyl, benzopyridyl, pyrrolopyridyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-Dioxopentyl, pyrazolinyl, dithianyl, dithianyl, dihydrothienyl, pyrazolidinylimidazolinyl and imidazolidinyl. The heterocyclic group may optionally be further replaced by 0 to 5 members selected from F, Cl, Br, I, =O, -CH ₂ F, -CHF ₂ , -CF ₃ , hydroxyl, -SR ¹⁸ , nitro, Cyano, isocyano, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, C _2-8 alkenyl, C _2-8 alkynyl, -(CH ₂ ) _q -C(= O)-R ¹⁹ , -(CH ₂ ) _q -C(=O)-OR ¹⁹ , -(CH ₂ ) _q -C(=O)-NR ¹⁹ R ^19a , -(CH ₂ ) _q -S(= O) _m -R ¹⁸ , -OC(=O)-OR ¹⁸ or -NR ¹⁸ R ^18a is substituted by a substituent, wherein R ¹⁹ and R ^19a are each independently selected from H, hydroxyl, amino, carboxyl, C _1-8 Alkyl, C _1-8 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, 3 to 10 membered carbocyclyl, 4 to 10 membered heterocyclyl, 3 to 10 membered carbocyclyloxy Or 4 to 10 membered heterocyclyloxy groups, q is selected from 0, 1, 2, 3, 4 or 5, m is selected from 0, 1 or 2; R ¹⁹ and R ^19a are each independently selected from H, unsubstituted C _1-6 alkyl. As used herein, the heterocyclic group is as defined above.

B选自

R¹⁰、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、R¹⁶、R¹⁷或R¹⁸各自独立的选自H、F、Cl、Br、I、CF₃、OH、-CH₂OH、氰基、羧基、C_1-4烷基、C_1-4烷氧基、-C(O)C_1-4烷基、-C(O)OC_1-4烷基、-NHC(O)H、NHS(O)₂-C_1-4烷基、NHS(O)₂-NH₂或NHS(O)₂-NHC_1-4烷基，Q选自-CR^q1＝CR^q2-、-CR^q1R^q2CR^q3R^q4-、O、S或-CR^q1R^q2O-，所述R^q1、R^q2、R^q3或R^q4各自独立的选自选自H、F、Cl、Br、I或C_1-4烷基。"β-adrenergic receptor binding group" refers to a group capable of binding to a β-adrenergic receptor; see for example the review article "β-adrenergic receptors in Comprehensive Medicinal Chemistry, 1990, BEMain, p187 (Pergamon Press) ". The aforementioned groups are also described, for example, in WO/2005092841 , US/20050215542 , WO/2005070872 , WO/2006023460 , WO/2006051373 , WO/2006087315 and WO/2006032627 . Non-limiting examples include

B from

R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ or R ¹⁸ are each independently selected from H, F, Cl, Br, I, CF ₃ , OH, -CH ₂ OH , cyano, carboxyl, C _1-4 alkyl, C _1-4 alkoxy, -C(O)C _1-4 alkyl, -C(O)OC _1-4 alkyl, -NHC(O) H, NHS(O) ₂ -C _1-4 alkyl, NHS(O) ₂ -NH ₂ or NHS(O) ₂ -NHC _1-4 alkyl, Q is selected from -CR ^q1 =CR ^q2 -, -CR ^q1 R ^q2 CR ^q3 R ^q4 -, O, S or -CR ^q1 R ^q2 O-, said R ^q1 , R ^q2 , R ^q3 or R ^q4 are each independently selected from H, F, Cl, Br, I or C _1-4 alkyl.

"Optional" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs or does not occur. For example: "Alkyl optionally substituted by F" means that the alkyl group may but not necessarily be substituted by F, and the description includes the case where the alkyl group is substituted by F and the case where the alkyl group is not substituted by F.

"Pharmaceutically acceptable salts" or "pharmaceutically acceptable salts thereof" refer to those that maintain the biological effectiveness and properties of free acids or free bases, and said free acids are mixed with non-toxic inorganic bases or organic bases. , or those salts obtained by reacting the free acids with non-toxic inorganic acids or organic acids, including alkali metal salts, such as sodium salts, potassium salts, lithium salts, etc.; alkaline earth metal salts, such as calcium salts, magnesium salts, etc. ; other metal salts, such as iron salts, copper salts, cobalt salts, etc.; organic alkali salts, such as ammonium salts, triethylamine salts, pyridine salts, picoline salts, 2,6-lutidine salts, ethanolamine salts, Diethanolamine salt, triethanolamine salt, cyclohexylamine salt, ethylenediamine salt, guanidine salt, isopropylamine salt, trimethylamine salt, tripropylamine salt, triethanolamine salt, diethanolamine salt, ethanolamine salt, Dimethylethanolamine salt, dicyclohexylamine salt, caffeine salt, procaine salt, choline salt, betaine salt, benzamine salt, glucosamine salt, N-methylglucamine salt, theobromine salt , tromethamine salt, purine salt, piperazine salt, morpholine salt, piperidine salt, N-ethylpiperidine salt, tetramethylamine salt, dibenzylamine salt and phenylglycine alkyl ester salt, etc. ;Halogen salts, such as hydrofluoride, hydrochloride, hydroiodide, hydrobromide, etc.; Inorganic acid salts, such as hydrochloride, nitrate, sulfate, perchlorate, phosphate, etc. ; Lower alkane sulfonates, such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, etc.; arylsulfonates, such as benzenesulfonate, p-toluenesulfonate, etc.; organic acid salts, such as Acetate, Benzoate, Fumarate, Formate, Trifluoroacetate, Furoate, Gluconate, Saccharinate, Glutamate, Glycolate, Isethionate Salt, lactate, maleate, malate, mandelate, mucate, pamoate, pantothenate, stearate, succinate, sulfamate, tartrate, propionate Dialate, 2-hydroxypropionate, citrate, salicylate, oxalate, glycolate, glucuronate, galacturonate, citrate, lysine, Arginate, aspartate, cinnamate, etc.

"Pharmaceutical composition" means a mixture of one or more compounds of the present invention or a physiologically/pharmaceutically acceptable salt thereof and other components, wherein the other components include physiologically/pharmaceutically acceptable carriers and excipients .

"Carrier" refers to a carrier or diluent that does not cause significant irritation to the organism and does not abrogate the biological activity and properties of the administered compound.

"Excipient" refers to an inert substance added to a pharmaceutical composition to further depend on the administration of the compound. excipients Examples include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and different types of starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricating Agents, binders, disintegrants, etc.

"Prodrug" refers to a compound that can be converted under physiological conditions or by solvolysis to a biologically active compound of the invention. The prodrugs of the present invention are prepared by modifying functional groups in the compounds of the present invention, which modifications can be removed by routine manipulation or in vivo to yield the parent compound.

"Co-crystal" or "co-crystal" refers to the crystal formed by the combination of active pharmaceutical ingredient (API) and cocrystal former (CCF) under the action of hydrogen bond or other non-covalent bonds, The pure states of API and CCF are solid at room temperature, and there is a fixed stoichiometric ratio between the components. A co-crystal is a multi-component crystal, including both a binary co-crystal formed between two neutral solids and a multi-element co-crystal formed between a neutral solid and a salt or solvate. The "co-crystal formers" include, but are not limited to, various pharmaceutically acceptable acids, bases, non-ionic compounds, water, amino acids, alcohols or other solvents, non-limiting examples of which include alanine (Ala), valine amino acid (Val), leucine (Leu), isoleucine (Ile), proline (Pro), phenylalanine (Phe), tryptophan (Trp), methionine (Met), glycine ( Gly), Serine (Ser), Threonine (Thr), Cysteine (Cys), Tyrosine (Tyr), Asparagine (Asn), Glutamine (Gln), Lysine (Lys) , arginine (Arg), histidine (His), aspartic acid (Asp), glutamic acid (Glu), pyroglutamic acid, sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, hydrochloric acid, formic acid, acetic acid , propionic acid, benzenesulfonic acid, benzoic acid, phenylacetic acid, salicylic acid, alginic acid, anthranilic acid, camphoric acid, citric acid, ethylenesulfonic acid, formic acid, fumaric acid, furoic acid, gluconic acid, glucuronic acid Acid, glutamic acid, glycolic acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, mucic acid, pamoic acid, pantothenic acid, stearic acid, succinic acid, sulfanilic acid, tartaric acid, p-toluene Sulfonic acid, malonic acid, 2-hydroxypropionic acid, oxalic acid, glycolic acid, glucuronic acid, galacturonic acid, citric acid, lysine, arginine, aspartic acid, cinnamic acid, p-toluenesulfonate acid, methanesulfonic acid, ethanesulfonic acid or trifluoromethanesulfonic acid, ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, triethanolamine, di Methylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, caffeine, procaine, choline, betaine, benzamine, ethylenediamine, glucosamine, formazan Glucosamine, Theobromine, Tromethamine, Purine, Piperazine, Piperidine, N-Ethylpiperidine, Methanol, Ethanol, Butynediol, 1,2-Propanediol, (R)1,2- Propylene glycol, (S)1,2-propanediol, or 1-methyl-1,2-ethanediol.

"Stereoisomer" refers to isomers produced by different arrangements of atoms in a molecule in space, including cis-trans isomers, enantiomers and conformational isomers.

"Effective dose" means the amount of a compound that elicits a physiological or medical response in a tissue, system, or subject that is sought, including, when administered in a subject, sufficient to prevent one or more of the disorders or conditions being treated. The amount of compound that causes or alleviates a symptom to some extent.

"Solvate" refers to a compound of the present invention or a salt thereof, which also includes stoichiometric or non-stoichiometric solvents bound by intermolecular non-covalent forces. When the solvent is water, it is a hydrate.

detailed description

The technical solutions of the present invention will be described in detail below in conjunction with the drawings and embodiments, but the scope of protection of the present invention includes but is not limited thereto.

Compound structures were determined by nuclear magnetic resonance (NMR) or/and mass spectroscopy (MS). NMR shifts (δ) are given in units of 10 ^-6 (ppm). The determination of NMR is to use (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic instrument, and measuring solvent is deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD ), and the internal standard was tetramethylsilane (TMS).

For MS measurement (Agilent 6120B (ESI) and Agilent 6120B (APCI)).

For the measurement of HPLC, an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100×4.6mm) was used.

The thin-layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin-layer chromatography (TLC) is 0.15mm-0.20mm, and the specification of thin-layer chromatography separation and purification products is 0.4mm. ~0.5mm.

Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

The known starting materials of the present invention can be adopted or synthesized according to methods known in the art, or can be purchased from Titan Technology, Anaiji Chemical, Shanghai Demo, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Bailingwei Technology Waiting for the company.

The nitrogen atmosphere means that the reaction bottle is connected to a nitrogen balloon with a volume of about 1 L.

The hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

The hydrogenation reaction is usually vacuumized and filled with hydrogen, and the operation is repeated 3 times.

There is no special description in the examples, and the reaction is carried out under a nitrogen atmosphere.

Unless otherwise specified in the examples, the solution refers to an aqueous solution.

No special instructions in the examples, the temperature of the reaction is room temperature.

No special instructions in the embodiments, M is moles per liter.

Room temperature is the most suitable reaction temperature, which is 20°C to 30°C.

CHO: It is formyl.

TBS: refers to tert-butyldimethylsilyl.

Boc: refers to tert-butyloxycarbonyl.

TFA: trifluoroacetic acid.

Intermediate 1: 6-Methoxy-1-propyl-2-enoyl-indoline-5-carbaldehyde

6-methoxy-1-prop-2-enoyl-indoline-5-carbaldehyde

The first step: 6-methoxyindoline (1b)

6-methoxyindoline

6-Methoxyindole (1a) (5.0g, 33.97mmol) was dissolved in acetic acid (50mL), under nitrogen protection, sodium cyanoborohydride (5.34g, 84.94mmol) was added to the reaction solution, at 25°C React for 2 hours. Water (80 mL) was added to the reaction solution, cooled to 0°C, and sodium hydroxide was carefully added to adjust the pH to 12-13. Ethyl acetate (80 mL) was added, the layers were extracted, the aqueous phase was extracted with ethyl acetate (30 mL×2), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether (v/v)=0:1～1:4) to obtain the title compound 6 - Methoxyindoline (1b), yellow oil (4.4 g, 87% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.00 (dd, 1H), 6.28–6.24 (m, 2H), 3.76 (s, 4H), 3.56 (t, 2H), 2.97 (t, 2H).

LCMS m/z = 150.1 [M+1].

The second step: 5-bromo-6-methoxyindoline (1c)

5-bromo-6-methoxyindoline

Dissolve 6-methoxyindoline (1b) (22g, 147.46mmol) in ethyl acetate (200mL), add 1,3-dibromo-5,5-dimethylhydantoin at 0°C (CAS: 77-48-5) (21.08g, 73.73mmol), react at 0°C for 2 hours. Add 15% potassium carbonate solution (250mL) to the reaction solution, stir well, extract and separate layers, dry the organic phase over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is separated and purified by silica gel column chromatography (ethyl acetate: Petroleum ether (v/v)=0:1～1:9), the title compound 5-bromo-6-methoxyindoline (1c) was obtained as a purple liquid (16g, yield 47.57%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.19 (t, 1H), 6.26 (s, 1H), 3.80 (s, 3H), 3.56 (t, 2H), 2.95 (t, 2H).

LCMS m/z = 228.1 [M+1].

The third step: tert-butyl 5-bromo-6-methoxyindoline-1-aminocarboxylate (1d)

tert-butyl 5-bromo-6-methoxyindoline-1-carboxylate

Dissolve 5-bromo-6-methoxyindoline (1c) (16g, 70.15mmol) in tetrahydrofuran (70mL), add di-tert-butyl dicarbonate (22.97g, 105.22mmol) and 4-dimethyl Aminopyridine (1.71g, 14.03mol), react at room temperature for 2 hours. Water (50 mL) and ethyl acetate (50 mL) were added to the reaction liquid, and the layers were separated by extraction. The aqueous phase was washed with ethyl acetate (30 mL), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate:petroleum ether (v/v)=0:1～1:19) to obtain the title compound 5 - tert-butyl bromo-6-methoxyindoline-1-aminocarboxylate (1d), purple-white solid (17 g, yield 74%).

¹ H NMR (400MHz, CDCl ₃ )δ7.70–7.50(m,1H),7.25(s,1H),3.97(t,2H),3.89(s,3H),3.01(t,2H),1.56( s, 9H).

LCMS m/z = 350.0 [M+23].

The fourth step: tert-butyl 5-formyl-6-methoxyindoline-1-aminocarboxylate (1e)

tert-butyl 5-formyl-6-methoxyindoline-1-carboxylate

Dissolve tert-butyl 5-bromo-6-methoxyindoline-1-aminocarboxylate (1d) (17g, 51.80mmol) in tetrahydrofuran (300mL), protect under nitrogen, and add 2.5M n- Butyl lithium in n-hexane solution (22.8 mL, 56.98 mmol) was kept at this temperature for 30 minutes. N,N-Dimethylformamide (18.93 g, 259 mmol) was added at -78°C, and the reaction was gradually raised to room temperature for 1 hour. Water (200 mL) and ethyl acetate (100 mL) were added to the reaction solution, and the layers were extracted. The aqueous phase was extracted once with ethyl acetate (100 mL), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether (v/v)=0:1～1:4) to obtain the title compound 5 - tert-butyl formyl-6-methoxyindoline-1-aminocarboxylate (1e), yellow solid (8.6 g, 60% yield).

¹ H NMR (400MHz, CDCl ₃ )δ10.29(s,1H),7.56(d,2H),4.02(t,2H),3.93(s,3H),3.03(t,2H),1.58(s, 9H).

LCMS m/z = 278.1 [M+Na].

The fifth step: 6-methoxyindoline-5-carbaldehyde (1f)

6-methoxyindoline-5-carbaldehyde

tert-butyl 5-formyl-6-methoxyindoline-1-aminocarboxylate (1e) (8.6g, 31mmol) was dissolved in dichloromethane (50mL), trifluoroacetic acid (18g, 160mmol), reacted at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, ammonia water was added to adjust the pH to 9, water (100 mL) and dichloromethane (100 mL) were added for extraction. The aqueous phase was extracted once with dichloromethane (50 mL), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (ethyl acetate:petroleum ether (v/v)=1:9～4:1) to obtain the title compound 6-methoxyindoline-5-carbaldehyde (1f), Yellow solid (2.7 g, 49% yield).

¹ H NMR (400MHz, CDCl ₃ )δ10.13(s,1H),7.55(s,1H),6.08(s,1H),4.44(s,1H),3.83(s,3H),3.68(t, 2H), 2.99(t,2H).

LCMS m/z = 178.1 [M+1].

The sixth step: 6-methoxy-1-propyl-2-enoyl-indoline-5-carbaldehyde (intermediate 1)

6-methoxy-1-prop-2-enoyl-indoline-5-carbaldehyde

6-Methoxyindoline-5-carbaldehyde (1f) (0.100g, 0.564mmol) was dissolved in ethyl acetate (10mL), triethylamine (0.428g, 4.23mmol) was added, and nitrogen protection was carried out. Acrylic acid (0.102 g, 1.41 mmol) was added dropwise. After rising to 40°C, 1-propylphosphoric anhydride (0.449g, 1.41mmol) was added dropwise, and reacted at 40°C for 4 hours. Ethyl acetate (20 mL) was added to the reaction solution, washed successively with 2M hydrochloric acid solution (20 mL) and 3% sodium hydroxide solution (20 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 6 -Methoxy-1-propyl-2-enoyl-indoline-5-carbaldehyde (Intermediate 1), yellow solid (0.08 g, 61% yield).

¹ H NMR (400MHz, CDCl ₃ )δ10.33(s,1H),8.06(s,1H),7.65(s,1H),6.58(t,2H),5.88(dd,1H),4.23(t, 2H), 3.95(s, 3H), 3.17(t, 2H).

LCMS m/z = 232.1 [M+1].

Intermediate 2: 7-[(1R)-2-Amino-1-[tert-butyl(dimethyl)silyl]oxyethyl]-4-[tert-butyl(dimethyl)silyl]oxy yl-3H-1,3-benzothiazol-2-one (intermediate 2)

7-[(1R)-2-amino-1-[tert-butyl(dimethyl)silyl]oxy-ethyl]-4-[tert-butyl(dimethyl)silyl]oxy-3H-1,3-benzothiazol-2- one

The first step: 7-[(1R)-2-azido-1-[tert-butyl(dimethyl)silyl]oxyethyl]-4-[tert-butyl(dimethyl)silyl ]Oxy-3H-1,3-benzothiazol-2-one (2b)

7-[(1R)-2-azido-1-[tert-butyl(dimethyl)silyl]oxy-ethyl]-4-[tert-butyl(dimethyl)silyl]oxy-3H-1,3-benzothiazol-2- one

7-[(1R)-2-azido-1-hydroxy-ethyl]-4-hydroxy-3H-1,3-benzothiazol-2-one (2a) (prepared with reference to WO2009098448A1) (0.56g .2.2mmol) was dissolved in N,N-dimethylformamide (20mL), then imidazole (0.6g, 8.9mmol) was added, tert-butyldimethylsilyl chloride (1.3g, 8.9mmol) was added in batches, A catalytic amount of 4-dimethylaminopyridine was then added, and the temperature was raised to 40° C. and stirred for 7 hours. The reaction solution was poured into water (100 mL), extracted with ethyl acetate (100 mL×1), the organic phase was washed with saturated aqueous sodium chloride solution (100 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v)=0/1～5/95) to obtain the title compound 7-[(1R)-2-azido-1-[tert- Butyl(dimethyl)silyl]oxyethyl]-4-[tert-butyl(dimethyl)silyl]oxy-3H-1,3-benzothiazol-2-one (2b), White solid (0.85 g, 80% yield).

¹ H NMR (400MHz, CDCl ₃ )δ8.25(s,1H),6.92(d,1H),6.71(d,1H),4.78(dd,1H),3.41(dd,1H),3.25(dd, 1H), 1.05-0.98(m, 9H), 0.92-0.88(m, 9H), 0.28(t, 6H), 0.12(d, 3H), -0.04(d, 3H).

The second step: 7-[(1R)-2-amino-1-[tert-butyl(dimethyl)silyl]oxyethyl]-4-[tert-butyl(dimethyl)silyl]oxygen yl-3H-1,3-benzothiazol-2-one (intermediate 2)

7-[(1R)-2-amino-1-[tert-butyl(dimethyl)silyl]oxy-ethyl]-4-[tert-butyl(dimethyl)silyl]oxy-3H-1,3-benzothiazol-2- one

7-[(1R)-2-azido-1-[tert-butyl(dimethyl)silyl]oxyethyl]-4-[tert-butyl(dimethyl)silyl]oxy -3H-1,3-benzothiazol-2-one (2b) (0.85g, 1.8mmol) was dissolved in ethyl acetate (20mL), and 10% (w/w) palladium carbon (0.085g) was added, Stir overnight under a hydrogen balloon at atmospheric pressure. The reaction solution was filtered with diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain the title compound 7-[(1R)-2-amino -1-[tert-butyl(dimethyl)silyl]oxyethyl]-4-[tert-butyl(dimethyl)silyl]oxy-3H-1,3-benzothiazole-2- Ketone (Intermediate 2), pale black solid (0.7 g, 90% yield).

1H NMR (400MHz, CDCl3) δ6.89(d,1H),6.68(t,1H),4.64(dd,1H),2.88(ddd,2H),1.04-0.96(m,9H),0.95-0.87( m,9H),0.33-0.23(m,6H),0.12-0.06(m,3H),-0.04--0.11(m,3H).

Example 1: [1-[3-[5-[[[(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1H-quinolin-5-yl)ethyl]amino] Methyl]-6-methoxy-indoline-1-yl]-3-oxo-propyl]-4-piperidine]N-(2-phenylphenyl)carbamate (compound 1 )

[1-[3-[5-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-6-methoxy- indolin-1-yl]-3-oxo-propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate

The first step: [1-[3-(5-formyl-6-methoxy-indoline-1-yl)-3-oxo-propyl]-4 piperidinyl]N-(2- Phenylphenyl) carbamate (1B)

[1-[3-(5-formyl-6-methoxy-indolin-1-yl)-3-oxo-propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate

6-Methoxy-1-propyl-2-enoyl-indole-5-carbaldehyde (Intermediate 1) (0.608 g, 2.63 mmol) was dissolved in 2-methyltetrahydrofuran (10 mL) and piperidine was added -4-yl[1,1′-biphenyl]-2-ylcarbamate (1A) (0.600g, 2.02mmol) was added to acetic acid (0.243g, 4.05mmol), and microwave reaction was carried out at 100°C for 1 hour. The reaction solution was concentrated, dichloromethane (20 mL) and saturated sodium bicarbonate solution (20 mL) were added, and the layers were separated for extraction. The aqueous phase was extracted with dichloromethane (20mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate:petroleum ether (v/v )=1:1～1:0, methanol:dichloromethane (v/v)=3:97), to obtain the title compound [1-[3-(5-formyl-6-methoxy-indoline -1-yl)-3-oxo-propyl]-4piperidinyl]N-(2-phenylphenyl)carbamate (1B), yellow solid (0.72 g, 67.4% yield).

¹ H NMR (400MHz, CDCl ₃ ) δ10.32(s, 1H), 8.08(d, 1H), 7.97(s, 1H), 7.64(s, 1H), 7.50(t, 2H), 7.45–7.39( m,1H),7.39–7.33(m,3H),7.23(dd,1H),7.14(td,1H),6.61(s,1H),4.82(s,1H),4.13(t,2H),3.92 (s,3H), 3.15(t,2H), 2.97(s,2H), 2.80(s,4H), 2.54(s,2H), 2.13–1.98(m,2H), 1.82(s,2H).

LCMS m/z = 528.1 [M+1].

The second step: [1-[3-[5-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxyl-2-oxo-1H -quinolin-5-yl)ethyl]amino]methyl]-6-methoxy-indoline-1-yl]-3-oxo-propyl]-4-piperidine]N-(2 -Phenylphenyl)carbamate (1C)

[1-[3-[5-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl] amino]methyl]-6-methoxy-indolin-1-yl]-3-oxo-propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate

[1-[3-(5-Formyl-6-methoxy-indoline-1-yl)-3-oxo-propyl]-4 piperidinyl]N-(2-phenylbenzene Base) carbamate (1B) (0.670g, 1.27mmol) was dissolved in a mixed solution of dichloromethane (10mL) and methanol (10mL), and 5-[(1R)-2-amino-1-[tert Butyl(dimethyl)silyl]oxy-ethyl]-8-hydroxy-1H-quinolin-2-one (1D) (0.425g, 1.27mmol), react at room temperature for 1 hour. Then sodium triacetoxyborohydride (0.811g, 3.81mmol) was added and reacted at room temperature for 3 hours. Dichloromethane (20 mL) and saturated sodium bicarbonate solution (20 mL) were added to the reaction solution, and the layers were extracted and separated. The aqueous phase was extracted with dichloromethane (20mL×1), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate:petroleum ether (v/v )=1:1～1:0, methanol:dichloromethane (v/v)=1:99～1:19), the title compound [1-[3-[5-[[[(2R)-2 -[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-6-methoxy yl-indolin-1-yl]-3-oxo-propyl]-4-piperidine]N-(2-phenylphenyl)carbamate (1C), yellow solid (0.62g, yield rate 57.7%).

¹ H NMR(400MHz,DMSO-d6)δ10.27(s,1H),8.61(s,1H),8.18(d,1H),7.79(s,1H),7.45–7.24(m,10H),6.99 (d,2H),6.90(d,1H),6.47(d,1H),5.12(dd,1H),4.52–4.38(m,1H),4.08(dd,2H),3.72–3.54(m,5H ),2.99(t,2H),2.69–2.53(m,8H),2.18(t,2H),1.71(s,2H),1.46(dd,2H),0.84(d,9H),0.03(d, 3H), -0.12–-0.25 (m, 3H).

LCMS m/z = 423.8 [M/2+1].

The third step: [1-[3-[5-[[[(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1H-quinolin-5-yl)ethyl]amino] Methyl]-6-methoxy-indoline-1-yl]-3-oxo-propyl]-4-piperidine]N-(2-phenylphenyl)carbamate (compound 1 )

[1-[3-[5-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-6-methoxy- indolin-1-yl]-3-oxo-propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate

[1-[3-[5-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxyl-2-oxo-1H-quinoline -5-yl)ethyl]amino]methyl]-6-methoxy-indoline-1-yl]-3-oxo-propyl]-4-piperidine]N-(2-phenyl Phenyl)carbamate (1C) (0.620g, 0.733mmol) was dissolved in dichloromethane (8mL), triethylamine trihydrofluoride (1.18g, 7.33mmol) was added, and reacted at room temperature for 24 hours. Water (20 mL) and dichloromethane (20 mL) were added to the reaction solution, and 3% sodium hydroxide solution was added to adjust the pH to about 12, and the layers were extracted. The aqueous phase was extracted with dichloromethane (20 mL×2), and the organic phases were combined. The organic phase was washed successively with saturated brine (20mL×1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate:petroleum ether (v/v)=1 :1～1:0, methanol:dichloromethane (v/v)=3:97～1:9), the title compound [1-[3-[5-[[[(2R)-2-hydroxyl- 2-(8-Hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-6-methoxy-indoline-1-yl]-3-oxo- Propyl]-4-piperidine]N-(2-phenylphenyl)carbamate (compound 1), yellow solid (0.26 g, 48.5% yield).

¹ H NMR (400MHz, CD ₃ OD) δ8.18(d,1H),7.80(s,1H),7.55(d,1H),7.47–7.19(m,8H),7.12(d,1H),7.04 –6.89(m,2H),6.53(d,1H),5.22–5.10(m,1H),4.70–4.57(m,1H),4.13(t,2H),3.79(d,2H),3.73(d ,3H), 3.08(t,2H), 2.95–2.84(m,2H), 2.84–2.64(m,6H), 2.42(d,2H), 1.88(d,2H), 1.65(d,2H).

LCMS m/z = 366.7 [M/2+1].

Example 2: [1-[3-[5-[[[(2R)-2-hydroxyl-2-[4-hydroxyl-3-(methanesulfonamido)phenyl]ethyl]amino]methyl ]-6-methoxy-indoline-1-yl]-3-oxo-propyl]-4-piperidine]N-(2-phenylphenyl)carbamate (compound 2)

[1-[3-[5-[[[(2R)-2-hydroxy-2-[4-hydroxy-3-(methanesulfonamido)phenyl]ethyl]amino]methyl]-6-methoxy-indolin-1-yl ]-3-oxo-propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate

The first step: [1-[3-[5-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-[4-hydroxyl-3-(methanesulfonic acid Amino)phenyl]ethyl]amino]methyl]-6-methoxy-indoline-1-yl]-3-oxo-propyl]-4-piperidine]N-(2-benzene phenyl) carbamate (2A)

[1-[3-[5-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-[4-hydroxy-3-(methanesulfonamido)phenyl]ethyl]amino]methyl]- 6-methoxy-indolin-1-yl]-3-oxo-propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate

[1-[3-(5-Formyl-6-methoxy-indoline-1-yl)-3-oxo-propyl]-4 piperidinyl]N-(2-phenylbenzene Base) carbamate (1B) (0.500g, 0.948mmol) was dissolved in dichloromethane (10mL) and methanol (10mL), and N-[5-[(1R)-2-amino-1-[tert Butyl(dimethyl)silyl]oxy-ethyl]-2-hydroxy-phenyl]methanesulfonic acid amide (2B) (0.342g, 0.948mmol) was reacted at room temperature for 1 hour. Add sodium triacetoxyborohydride (0.605g, 2.84mmol) and react at room temperature for 3 hours. Dichloromethane (20 mL) and saturated sodium bicarbonate solution (20 mL) were added to the reaction solution, and the layers were extracted and separated. The aqueous phase was extracted with dichloromethane (20mL×1), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate:petroleum ether (v/v) =1:1～1:0, methanol:dichloromethane (v/v)=1:99～1:19), to obtain the title compound [1-[3-[5-[[[(2R)-2- [tert-butyl(dimethyl)silyl]oxy-2-[4-hydroxy-3-(methanesulfonamido)phenyl]ethyl]amino]methyl]-6-methoxy-ind Indolin-1-yl]-3-oxo-propyl]-4-piperidine]N-(2-phenylphenyl)carbamate (2A), yellow solid (0.53 g, 64.1% yield ).

¹ H NMR(400MHz,DMSO-d6)δ8.77(s,1H),7.98(s,1H),7.64–7.40(m,9H),7.33(d,1H),7.20(s,1H),7.11 (dd,1H),6.97(d,1H),4.83(dd,1H),4.68–4.54(m,1H),4.26(t,2H),3.86(s,3H),3.77(dd,2H), 3.46(s,1H),3.18(t,2H),3.08–3.02(m,3H),2.76(dd,7H),2.33(dd,2H),1.87(s,2H),1.60(d,2H) ,0.99(s,9H),0.16(d,3H),0.01(d,3H).

LCMS m/z = 436.7 [M/2+1].

The second step: [1-[3-[5-[[[(2R)-2-hydroxyl-2-[4-hydroxyl-3-(methanesulfonic acid amido)phenyl]ethyl]amino]methyl ]-6-methoxy-indoline-1-yl]-3-oxo-propyl]-4-piperidine]N-(2-phenylphenyl)carbamate (compound 2)

[1-[3-[5-[[[(2R)-2-hydroxy-2-[4-hydroxy-3-(methanesulfonamido)phenyl]ethyl]amino]methyl]-6-methoxy-indolin-1-yl ]-3-oxo-propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate

[1-[3-[5-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-[4-hydroxyl-3-(methanesulfonic acid amido) Phenyl]ethyl]amino]methyl]-6-methoxy-indolin-1-yl]-3-oxo-propyl]-4-piperidine]N-(2-phenylphenyl ) Carbamate (2A) (0.530g, 0.608mmol) was dissolved in dichloromethane (8mL), triethylamine trihydrofluoride (0.980g, 6.08mmol) was added, and reacted at room temperature for 24 hours. Water (20 mL) and dichloromethane (20 mL) were added to the reaction solution, and 3% sodium hydroxide solution was added to adjust the pH to about 12, and the layers were extracted. The aqueous phase was extracted with dichloromethane (20 mL×2), and the organic phases were combined. The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate: petroleum ether (v/v)=1:1～1:0, methanol: dichloromethane (v/v)=3:97～1:9), to obtain the title compound [1-[3-[5-[[[ (2R)-2-Hydroxy-2-[4-hydroxy-3-(methanesulfonamido)phenyl]ethyl]amino]methyl]-6-methoxy-indoline-1-yl] -3-oxo-propyl]-4-piperidine]N-(2-phenylphenyl)carbamate (compound 2), yellow solid (0.20 g, yield 43.4%).

¹ H NMR (400MHz, CD ₃ OD) δ7.90(s,1H),7.55(d,1H),7.45–7.21(m,9H),7.08(s,1H),7.02(dd,1H),6.85 (d,1H),4.69(dd,1H),4.65–4.56(m,1H),4.14(t,2H),3.82(d,2H),3.78(s,3H),3.12(t,2H), 2.94–2.87(m,3H), 2.86–2.62(m,8H), 2.37(t,2H), 1.92–1.79(m,2H), 1.70–1.56(m,2H).

LCMS m/z = 379.6 [M/2+1].

Example 3: 2-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidinyl]ethyl 5-[[[(2R)-2-hydroxyl-2-(8 -Hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-6-methoxy-indoline-1-carboxylate (compound 3)

2-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]ethyl 5-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl )ethyl]amino]methyl]-6-methoxy-indoline-1-carboxylate

The first step: 2-bromoethyl 5-formyl-6-methoxy-indoline-1-carboxylate (3B)

2-bromoethyl 5-formyl-6-methoxy-indoline-1-carboxylate

Bromoethanol (1.4g, 11.29mmol) was dissolved in dichloromethane (20mL), triethylamine (1.8g, 14.11mmol) was added, nitrogen was replaced three times, and triphosgene (1.34g, 4.51mmol) was added dropwise at 0°C Dichloromethane solution (10 mL) was gradually raised to room temperature and reacted for 1 hour to obtain reaction solution 1. Dissolve 6-methoxyindoline-5-carbaldehyde (3A) (1.00g, 5.64mmol) in tetrahydrofuran (20mL), add triethylamine (1.8g, 14.11mmol), and add the reaction solution dropwise at 0°C 1. Gradually raise to room temperature and react for 1 hour. The reaction solution was concentrated, added with water (30 mL) and dichloromethane (30 mL), and extracted. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (ethyl acetate:petroleum ether (v/v)=1:9～3:7) to obtain the title compound 2-bromoethyl 5-formyl-6-methoxy-indole Indoline-1-carboxylate (3B), pink solid (1.5 g, 81% yield).

¹ H NMR (400MHz, CDCl ₃ ) δ10.31(s,1H),7.62(d,2H),4.55(s,2H),4.15–4.08(m,2H),3.94(s,3H),3.62( s,2H), 3.09(t,2H).

LCMS m/z = 328.0 [M+1].

The second step: 2-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidinyl]ethyl 5-formyl-6-methoxy-indoline-1- Carboxylate (3C)

2-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]ethyl 5-formyl-6-methoxy-indoline-1-carboxylate

2-Bromoethyl 5-formyl-6-methoxy-indoline-1-carboxylate (3B) (1.5 g, 4.6 mmol) was dissolved in acetonitrile (20 mL) and tetrahydrofuran (10 mL), and added Piperidin-4-yl[1,1'-biphenyl]-2-ylcarbamate (1A) (1.4g, 4.6mmol) and triethylamine (1.8g, 18mmol) were reacted at 80°C for 8 hours. Ethyl acetate (30 mL) and water (30 mL) were added to the reaction solution for extraction. The aqueous phase was extracted with ethyl acetate (20 mL×1), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate:petroleum ether (v/v)=3:7～7:3) to obtain the title compound 2 -[4-[(2-Phenylphenyl)carbamoyloxy]-1-piperidinyl]ethyl 5-formyl-6-methoxy-indoline-1-carboxylate (3C ), a yellow solid (1.4 g, 56% yield).

¹ H NMR (400MHz, CDCl ₃ )δ10.30(s,1H),8.09(d,1H),7.62(s,2H),7.52–7.44(m,2H),7.44–7.32(m,4H), 7.22(dd,1H),7.16-7.09(m,1H),6.58(s,1H),4.78–4.69(m,1H),4.35(s,2H),4.06(t,2H),3.92(s, 3H), 3.07(t,2H), 2.83–2.66(m,4H), 2.36(s,2H), 1.93(s,2H), 1.69(d,2H).

LCMS m/z = 544.1 [M+1].

The third step: 2-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidinyl]ethyl 5-[[[(2R)-2-[tert-butyl(di Methyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-6-methoxy-indoline-1 -Carboxylate (3D)

2-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]ethyl 5-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2- oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-6-methoxy-indoline-1-carboxylate

2-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidinyl]ethyl 5-formyl-6-methoxyl-indole-1-carboxylate ( 3C) (0.700g, 1.29mmol) was dissolved in dichloromethane (10mL) and methanol (10mL), and (R)-5-(2-amino-1-((tert-butyldimethylsilyl)oxy )ethyl)-8-hydroxyquinolin-2(1H)-one (1D) (0.431g, 1.29mmol), react at room temperature for 1 hour. Add sodium triacetoxyborohydride (0.823g, 3.86mmol) and react at room temperature for 3 hours. Dichloromethane (20 mL) was added to the reaction solution, and saturated aqueous sodium bicarbonate solution (20 mL) was added for extraction. The aqueous phase was extracted with dichloromethane (20mL×1), and the combined organic phases were washed with anhydrous Dry over sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue was separated and purified by silica gel column chromatography (ethyl acetate:petroleum ether (v/v)=1:1～1:0, methanol:dichloromethane (v/v)=1:99～1:19) to obtain The title compound 2-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidinyl]ethyl 5-[[[(2R)-2-[tert-butyl(dimethyl )silyl]oxy-2-(8-hydroxyl-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-6-methoxy-indoline-1-carboxyl Ester (3D), brown solid (0.74 g, 66.7% yield).

¹ H NMR (400MHz, CD ₃ OD) δ8.20(d,1H),7.55(s,1H),7.42–7.20(m,9H),7.14(d,1H),7.02–6.89(m,2H) ,6.55(d,1H),5.31(s,1H),4.64(s,1H),4.37(s,2H),4.01(t,2H),3.89(s,2H),3.73(s,3H), 3.12-3.03(m,2H),2.98(t,2H),2.90–2.71(m,4H),2.52(s,2H),1.88(s,2H),1.68(s,2H),0.86(d, 9H), 0.16–0.01(m,3H), -0.16(d,3H).

LCMS m/z = 431.7 [M/2+1].

The fourth step: 2-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidinyl]ethyl 5-[[[(2R)-2-hydroxyl-2-(8 -Hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-6-methoxy-indoline-1-carboxylate (compound 3)

2-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]ethyl 5-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl )ethyl]amino]methyl]-6-methoxy-indoline-1-carboxylate

2-[4-[(2-Phenylphenyl)carbamoyloxy]-1-piperidinyl]ethyl 5-[[[(2R)-2-[tert-butyl(dimethyl) Silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-6-methoxy-indoline-1-carboxylic acid Ester (3D) (0.740g, 0.858mmol) was dissolved in dichloromethane (8mL), triethylamine trihydrofluoride (1.38g, 8.58mmol) was added, and reacted at room temperature for 24 hours. Water (20 mL) and dichloromethane (20 mL) were added to the reaction solution, and 3% sodium hydroxide solution was added to adjust the pH to about 12, and extracted. The aqueous phase was extracted with dichloromethane (20 mL×2), and the organic phases were combined, washed successively with saturated aqueous sodium chloride (20 mL×1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (ethyl acetate:petroleum ether (v/v)=1:1～1:0, methanol:dichloromethane (v/v)=3:97～1:9) to obtain The title compound 2-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidinyl]ethyl 5-[[[(2R)-2-hydroxyl-2-(8-hydroxyl -2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-6-methoxy-indoline-1-carboxylate (compound 3), yellow solid (0.10g, Yield 15.6%).

¹ H NMR (400MHz, CD ₃ OD) δ8.22(d,1H),7.57(d,1H),7.52–7.30(m,7H),7.30–7.23(m,2H),7.16(d,1H) ,7.03–6.92(m,2H),6.57(d,1H),5.19(dd,1H),4.67–4.55(m,1H),4.36(s,2H),4.04(t,2H),3.80(d ,2H),3.76(s,3H),3.04(t,2H),2.92(t,2H),2.77(s,4H),2.44(s,2H),1.87(s,2H),1.66(s, 2H).

LCMS m/z = 374.6 [M/2+1].

Example 4: [1-[3-[6-[[[(2R)-2-hydroxyl-(8-hydroxyl-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl ]-7-methoxy-3,4-dihydro-2H-quinolin-1-yl]-3-oxo-propyl]-4-piperidinyl]N-(2-phenylphenyl) Carbamate bistrifluoroacetate (Chem. compound 4)

[1-[3-[6-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-7-methoxy- 3,4-dihydro-2H-quinolin-1-yl]-3-oxo-propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate; 2,2,2-trifluoroacetic acid

The first step: 7-methoxy-1,2,3,4-tetrahydroquinoline (4B)

7-methoxy-1,2,3,4-tetrahydroquinoline

Dissolve 7-methoxy-3,4-dihydro-1H-quinolin-2-one (4A) (1.0g, 5.64mmol) in tetrahydrofuran (15mL), under nitrogen protection, add lithium aluminum tetrahydrogen at 0°C (0.428g, 11.3mmol), react at room temperature for 3 hours. After cooling to 0°C, water (2 mL) was carefully added to quench the reaction. Add ethyl acetate (20mL), filter with diatomaceous earth, dry the filtrate with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the title compound 7-methoxy-1,2,3,4-tetrahydroquinoline ( 4B), yellow liquid (0.58 g, 63% yield).

¹ H NMR (400MHz, CDCl ₃ ) δ6.83(d,1H),6.19(dd,1H),6.02(d,1H),3.71(s,4H),3.29–3.19(m,2H),2.68( t,2H), 1.97–1.81(m,2H).

LCMS m/z = 164.1 [M+1].

The second step: 6-bromo-7-methoxy-1,2,3,4-tetrahydroquinoline (4C)

6-bromo-7-methoxy-1,2,3,4-tetrahydroquinoline

Dissolve 7-methoxy-1,2,3,4-tetrahydroquinoline (4B) (0.100g, 0.613mmol) in ethyl acetate (10mL), add 1,3-dibromo -5,5-Dimethylhydantoin (0.088g, 0.306mmol), react at 0°C for 2 hours. A 15% potassium carbonate solution (20 mL) was added to the reaction solution, followed by thorough stirring. Ethyl acetate (20 mL) was added for extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (ethyl acetate:petroleum ether (v/v)=0:1～1:9) to obtain The title compound 6-bromo-7-methoxy-1,2,3,4-tetrahydroquinoline (4C), purple liquid (0.105 g, yield 70.8%).

¹ H NMR (400MHz, CDCl ₃ ) δ7.06(s,1H),6.05(s,1H),3.79(s,3H),3.30–3.22(m,2H),2.66(t,2H),1.89( dd,2H).

LCMS m/z = 242.9 [M+1].

The third step: 7-methoxy-1,2,3,4-tetrahydroquinoline-6-carbaldehyde (4D)

7-methoxy-1,2,3,4-tetrahydroquinoline-6-carbaldehyde

Dissolve 6-bromo-7-methoxy-1,2,3,4-tetrahydroquinoline (4C) (0.500g, 2.07mmol) in tetrahydrofuran (15mL), protect under nitrogen, and add 2M iso A tetrahydrofuran solution of propylmagnesium chloride (1.15 mL, 2.27 mmol) was heated to 0°C for 1 hour. Add 2.5M n-butyllithium n-hexane solution (4 mL, 10.3 mmol) at -25°C and react at -10°C for 30 minutes. N,N-Dimethylformamide (0.755 g, 10.3 mmol) was added at -10°C, and the reaction was gradually raised to room temperature for 0.5 hours. The reaction solution was poured into a solution of citric acid (1 g) in water (20 mL), ethyl acetate (20 mL) was added, and extracted. The aqueous phase was extracted with ethyl acetate (10 mL×1), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (ethyl acetate:petroleum ether (v/v)=0:1～1:4) to obtain the title compound 7-methoxy-1,2,3,4-tetrahydroquinone Phenyl-6-carbaldehyde (4D), yellow solid (0.270 g, 68.4% yield).

¹ H NMR (400MHz, CDCl ₃ ) δ10.10(s,1H),7.45(s,1H),5.88(s,1H),4.64(s,1H),3.80(s,3H),3.39–3.30( m,2H), 2.69(t,2H), 1.96–1.85(m,2H).

LCMS m/z = 192.1 [M+1].

The fourth step: 7-methoxy-1-propyl-2-enoyl-3,4-dihydro-2H-quinoline-6-carbaldehyde (4E)

7-methoxy-1-prop-2-enoyl-3,4-dihydro-2H-quinoline-6-carbaldehyde

Dissolve 7-methoxy-1,2,3,4-tetrahydroquinoline-6-carbaldehyde (4D) (1.5g, 7.84mmol) in ethyl acetate (30mL), add triethylamine (5.95g ,58.8mmol), nitrogen protection. Acrylic acid (1.41 g, 19.6 mmol) was added dropwise. After rising to 40°C, 1-propylphosphoric anhydride (6.24g, 19.6mmol) was added dropwise, and reacted at 80°C for 4 hours. Ethyl acetate (20mL) and water (20mL) were added to the reaction solution, extracted, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate:petroleum ether (v /v)=0:1～3:7), to obtain the title compound 7-methoxy-1-propyl-2-enoyl-3,4-dihydro-2H-quinoline-6-carbaldehyde (4E) , a yellow solid (1.1 g, 57% yield).

¹ H NMR (400MHz, CDCl ₃ )δ10.37(s,1H),7.63(s,1H),6.84(s,1H),6.61(dd,1H),6.47(dd,1H),5.76(dd, 1H), 3.89–3.81(m,5H), 2.72(q,2H), 2.02–1.93(m,2H).

LCMS m/z = 246.2 [M+1].

The fifth step: [1-[3-(6-formyl-7-methoxy-3,4-dihydro-2H-quinolin-1-yl)-3-oxo-propyl]4-piper Pyridyl]N-(2-phenylphenyl) carbamate (4F)

[1-[3-(6-formyl-7-methoxy-3,4-dihydro-2H-quinolin-1-yl)-3-oxo-propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate

7-Methoxy-1-propyl-2-enoyl-3,4-dihydro-2H-quinoline-6-carbaldehyde (4E) (1.1 g, 4.48 mmol) was dissolved in 2-methyltetrahydrofuran ( 10mL), add piperidin-4-yl[1,1'-biphenyl]-2-ylcarbamate (1A) (1.33g, 4.48mmol), add triethylamine (0.908g, 8.97mmol) , 100 ° C microwave reaction for 1 hour. The reaction solution was concentrated, added dichloromethane (20 mL) and saturated aqueous sodium bicarbonate (20 mL), and extracted. The aqueous phase was extracted with dichloromethane (20 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (ethyl acetate:petroleum ether (v/v)=1:1～1:0, methanol:dichloromethane (v/v)=3:97) to obtain the title compound [1 -[3-(6-formyl-7-methoxy-3,4-dihydro-2H-quinolin-1-yl)-3-oxo-propyl]4-piperidinyl]N-( 2-Phenylphenyl)carbamate (4F), yellow solid (1.6 g, 66% yield).

¹ H NMR (400MHz, CDCl ₃ )δ10.36(s,1H),8.08(d,1H),7.60(s,1H),7.52–7.44(m,2H),7.44-7.39(m,1H), 7.39–7.31(m,3H),7.26–7.19(m,2H),7.16–7.08(m,1H),6.59(s,1H),4.80–4.65(m,1H),3.89(d,3H), 3.80–3.70(m,2H), 2.83–2.62(m,8H), 2.29(s,2H), 2.00–1.88(m,4H), 1.75–1.56(m,2H).

LCMS m/z = 542.1 [M+1].

The sixth step: [1-[3-[6-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxyl-2-oxo-1H -quinolin-5-yl)ethyl]amino]methyl]-7-methoxy-3,4-dihydro-2H-quinolin-1-yl]-3-oxo-propyl]-4 -piperidinyl]N-(2-phenylphenyl)carbamate (4G)

[1-[3-[6-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl] amino]methyl]-7-methoxy-3,4-dihydro-2H-quinolin-1-yl]-3-oxo-propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate

[1-[3-(6-formyl-7-methoxy-3,4-dihydro-2H-quinolin-1-yl)-3-oxo-propyl]4-piperidinyl] N-(2-phenylphenyl) Carbamate (4F) (0.700g, 1.29mmol) was dissolved in dichloromethane (10mL) and methanol (10mL), and (R)-5-(2-amino-1-((tert-butyldimethyl (Silyl)oxy)ethyl)-8-hydroxyquinolin-2(1H)-one (1D) (0.432g, 1.29mmol), react at room temperature for 1 hour. Add sodium triacetoxyborohydride (0.826g, 3.88mmol) and react at room temperature for 3 hours. Dichloromethane (20 mL) and saturated aqueous sodium bicarbonate (20 mL) were added to the reaction solution for extraction. The aqueous phase was extracted with dichloromethane (20 mL×1), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (ethyl acetate:petroleum ether (v/v)=1:1～1:0, methanol:dichloromethane (v/v)=1:99～1:19) to obtain The title compound [1-[3-[6-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinone Lin-5-yl)ethyl]amino]methyl]-7-methoxy-3,4-dihydro-2H-quinolin-1-yl]-3-oxo-propyl]-4-piper Pyridyl]N-(2-phenylphenyl)carbamate (4G), yellow oil (1.1 g, 100% yield).

LCMS m/z = 430.8 [M/2+1].

The seventh step: [1-[3-[6-[[[(2R)-2-hydroxyl-(8-hydroxyl-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl ]-7-methoxy-3,4-dihydro-2H-quinolin-1-yl]-3-oxo-propyl]-4-piperidinyl]N-(2-phenylphenyl) Carbamate bistrifluoroacetate (compound 4)

[1-[3-[6-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-7-methoxy- 3,4-dihydro-2H-quinolin-1-yl]-3-oxo-propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate; 2,2,2-trifluoroacetic acid

[1-[3-[6-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxyl-2-oxo-1H-quinoline -5-yl)ethyl]amino]methyl]-7-methoxy-3,4-dihydro-2H-quinolin-1-yl]-3-oxo-propyl]-4-piperidine Base] N-(2-phenylphenyl) carbamate (4G) (1.1g, 1.3mmol) was dissolved in dichloromethane (8mL), triethylamine trihydrofluoride (2.1g, 13mmol) was added ), react at room temperature for 24 hours. Water (20 mL) and dichloromethane (20 mL) were added to the reaction solution, and 3% sodium hydroxide solution was added to adjust the pH to about 12, and extracted. The aqueous phase was extracted with dichloromethane (20 mL×2), and the organic phases were combined, washed successively with saturated aqueous sodium chloride solution (20 mL×1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was prepared by acid method to give the title compound [1-[3-[6-[[[(2R)-2-hydroxy-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl] Amino]methyl]-7-methoxy-3,4-dihydro-2H-quinolin-1-yl]-3-oxo-propyl]-4-piperidinyl]N-(2-benzene phenyl) carbamate ditrifluoroacetate (compound 4), white solid (0.200 g, yield 21%).

¹ H NMR (400MHz, CD ₃ OD) δ8.03(s,1H),7.47(s,1H),7.40–7.12(m,10H),7.03(s,1H),6.95(d,1H),6.50 (d,1H),5.33(dd,1H),4.82(s,1H),4.17(s,2H),3.74(d,3H),3.69(t,2H),3.64–3.43(m,2H), 3.39 (s, 2H), 3.19–2.96 (m, 6H), 2.63 (t, 2H), 2.14–1.65 (m, 6H).

LCMS m/z = 373.7 [M/2+1].

Example 5: [1-[3-[5-[[[(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1H-quinolin-5-yl)ethyl]amino] Methyl]-6-methoxy-indoline-1-yl]-3-oxo-propyl]-4-piperidinyl]N-[2-(3-chloro-4-hydroxy-phenyl ) phenyl] carbamate (compound 5)

[1-[3-[5-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-6-methoxy- indolin-1-yl]-3-oxo-propyl]-4-piperidyl]N-[2-(3-chloro-4-hydroxy-phenyl)phenyl]carbamate

The first step: 2-(4-benzyloxy-3-chloro-phenyl)aniline (5C)

2-(4-benzyloxy-3-chloro-phenyl)aniline

Dissolve o-iodoaniline (5B) (4.0 g, 18 mmol) in ethylene glycol dimethyl ether (5 mL) and water (5 mL), add (4-benzyloxy-3-chloro-phenyl) boronic acid (5A) (4.8g, 18mmol) and potassium carbonate (10g, 73mmol), tetrakistriphenylphosphine palladium (1.1g, 0.91mmol) was added under nitrogen protection, and microwave reaction was carried out at 120°C for 1 hour. Ethyl acetate (50 mL) and water (50 mL) were added to the reaction solution for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v)=0:1～1:9) to obtain the title compound 2 -(4-Benzyloxy-3-chloro-phenyl)aniline (5C), yellow solid (4.5 g, 80% yield).

¹ H NMR (400MHz, CDCl ₃ ) δ7.51–7.45(m,3H),7.43–7.36(m,2H),7.36–7.29(m,1H),7.26(dd,1H),7.16-7.10(m ,1H), 7.07(dd,1H), 7.02(d,1H), 6.80(m,1H), 6.74(dd,1H), 5.19(s,2H), 3.76(s,2H).

LCMS m/z = 310.1 [M+1].

The second step: tert-butyl 4-[[2-(4-benzyloxy-3-chloro-phenyl)phenyl]carbamoyloxy]piperidine-1-carboxylate (5E)

tert-butyl 4-[[2-(4-benzyloxy-3-chloro-phenyl)phenyl]carbamoyloxy]piperidine-1-carboxylate

Dissolve 2-(4-benzyloxy-3-chloro-phenyl)aniline (5C) (2.3g, 7.4mmol) in toluene (50mL), add triphosgene (0.88g, 3.0mmol), and react at 125°C 4 hours. Add tetrahydrofuran (100mL) after concentration, add tert-butyl 4-hydroxy-piperidine-1-carboxylate (5D) (1.5g, 7.4mmol), add triethylamine (2.3g, 22mmol), and react at 70°C for 2 Hour. The reaction solution was concentrated, and the residue was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v)=0:1～1:9) to obtain the title compound 4-[[2-(4-benzyloxy- tert-butyl 3-chloro-phenyl)phenyl]carbamoyloxy]piperidine-1-carboxylate (5E), yellow oil (3.5 g, 88% yield).

LCMS m/z = 559.2 [M+23].

The third step: 4-piperidinyl N-[2-(4-benzyloxy-3-chloro-phenyl)phenyl]carbamate (5F)

4-piperidyl N-[2-(4-benzyloxy-3-chloro-phenyl)phenyl]carbamate

4-[[2-(4-Benzyloxy-3-chloro-phenyl)phenyl]carbamoyloxy]piperidine-1-carboxylic acid tert-butyl ester (5E) (3.5g, 6.5mmol) Dissolve in dichloromethane (10 mL), add trifluoroacetic acid (10 mL), and react at room temperature for 2 hours. The reaction solution was concentrated, adjusted to pH 8 to 9 with ammonia water, added dichloromethane (50 mL), and extracted. The aqueous phase was extracted with dichloromethane (20 mL×1), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (methanol/dichloromethane (v/v)=1:99～1:19) to obtain the title compound 4-piperidinyl N-[2-(4-benzyloxy-3 -Chloro-phenyl)phenyl]carbamate (5F), white solid (1.2 g, 42% yield).

¹ H NMR (400MHz, CDCl ₃ )δ8.01(d,1H),7.50(d,2H),7.46–7.30(m,5H),7.23–7.03(m,4H),6.54(s,1H), 5.23(s,2H),4.94–4.87(m,1H),4.34(s,1H),3.22–3.06(m,2H),2.98–2.85(m,2H),2.15–1.97(m,2H), 1.90-1.70(m,2H).

LCMS m/z = 437.1 [M+1].

The fourth step: 4-piperidinyl N-[2-(3-chloro-4-hydroxy-phenyl)phenyl]carbamate (5G)

4-piperidyl N-[2-(3-chloro-4-hydroxy-phenyl)phenyl]carbamate

4-Piperidinyl N-[2-(4-benzyloxy-3-chloro-phenyl)phenyl]carbamate (5F) (0.860 g, 1.97 mmol) was dissolved in methanol (20 mL), Add o-dichlorobenzene (1.45 g, 9.84 mmol), add 10% (w/w) palladium carbon (0.3 g), replace hydrogen, and react at room temperature under hydrogen atmosphere for 4 hours. The reaction solution was concentrated, and the residue was separated and purified by silica gel column chromatography (methanol/dichloromethane (v/v)=1:99～1:9) to obtain the title compound 4-piperidinyl N-[2-(3-chloro -4-Hydroxy-phenyl)phenyl]carbamate (5G), pale yellow solid (0.700g, 103% yield).

¹ H NMR (400MHz,DMSO-d6)δ10.32(s,1H),8.84(s,1H),7.37–7.24(m,5H),7.14(dd,1H),7.04(d,1H),4.81 –4.68 (m, 1H), 3.17 (s, 1H), 3.05 (s, 4H), 1.93 (s, 2H), 1.70 (d, 2H).

LCMS m/z = 347.0 [M+1].

The fifth step: [1-[3-(5-formyl-6-methoxy-indoline-1-yl)-3-oxo-propyl]-4-piperidinyl]N-[2 -(3-Chloro-4-hydroxy-phenyl)phenyl]carbamate (5H)

[1-[3-(5-formyl-6-methoxy-indolin-1-yl)-3-oxo-propyl]-4-piperidyl]N-[2-(3-chloro-4-hydroxy-phenyl)phenyl ]carbamate

Dissolve 6-methoxy-1-propyl-2-enoyl-indoline-5-carbaldehyde (Intermediate 1) (0.520 g, 2.25 mmol) in 2-methyltetrahydrofuran (10 mL), add 4 -Piperidinyl N-[2-(3-chloro-4-hydroxy-phenyl)phenyl]carbamate (5G) (0.780g, 2.25mmol), added triethylamine (0.455g, 4.50mmol) , 100 ° C microwave reaction for 1 hour. The reaction solution was concentrated, and the residue was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v)=1:1～1:0, methanol/dichloromethane (v/v)=3:97) to obtain The title compound [1-[3-(5-formyl-6-methoxy-indoline-1-yl)-3-oxo-propyl]-4-piperidinyl]N-[2-( 3-Chloro-4-hydroxy-phenyl)phenyl]carbamate (5H), yellow solid (1.25 g, 96.1% yield).

¹ H NMR (400MHz, CDCl ₃ )δ10.32(s,1H),8.02(d,1H),7.95(s,1H),7.64(s,1H),7.38–7.29(m,2H),7.19– 7.08(m,4H),6.53(s,1H),4.84(s,1H),4.14(dd,2H),3.91(s,3H),3.16(d,2H),3.01(s,2H),2.89 (d,4H), 2.60(s,2H), 2.10(s,2H), 1.88(s,2H).

LCMS m/z = 578.1 [M+1].

The sixth step: [1-[3-[5-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxyl-2-oxo-1H- Quinolin-5-yl)ethyl]amino]methyl]-6-methoxy-indoline-1-yl]-3-oxo-propyl]-4-piperidinyl]N-[2 -(3-Chloro-4-hydroxy-phenyl)phenyl]carbamate (5I)

[1-[3-[5-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl] amino]methyl]-6-methoxy-indolin-1-yl]-3-oxo-propyl]-4-piperidyl]N-[2-(3-chloro-4-hydroxy-phenyl)phenyl]carbamate

[1-[3-(5-Formyl-6-methoxy-indoline-1-yl)-3-oxo-propyl]-4-piperidinyl]N-[2-(3 -Chloro-4-hydroxy-phenyl)phenyl]carbamate (5H) (0.500g, 0.865mmol) was dissolved in dichloromethane (10mL) and methanol (10mL), and (R)-5-( 2-Amino-1-((tert-butyldimethylsilyl)oxy)ethyl)-8-hydroxyquinolin-2(1H)-one (1D) (0.318g, 0.951mmol), react at room temperature for 1 hour . Add sodium triacetoxyborohydride (0.553 g, 2.59 mmol) and react at room temperature for 3 hours. Dichloromethane (20 mL) was added to the reaction solution, and saturated aqueous sodium bicarbonate solution (20 mL) was added for extraction. The aqueous phase was extracted with dichloromethane (20 mL×1), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v)=1:1～1:0, methanol/dichloromethane (v/v)=1:99～1:19) to obtain The title compound [1-[3-[5-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinoline -5-yl)ethyl]amino]methyl]-6-methoxy-indoline-1-yl]-3-oxo-propyl]-4-piperidinyl]N-[2-( 3-Chloro-4-hydroxy-phenyl)phenyl]carbamate (5I), yellow solid (0.42 g, 54% yield).

¹ H NMR (400MHz, CD ₃ OD) δ8.15(d,1H),7.68(s,1H),7.39(d,1H),7.28–7.14(m,5H),7.07(dd,1H),6.99 (d,1H),6.93–6.80(m,3H),6.43(d,1H),5.05(t,1H),4.61(d,1H),4.08(t,2H),3.64–3.54(m,5H ),3.09–2.94(m,2H),2.88–2.81(m,2H),2.78–2.63(m,6H),2.50(s,2H),1.84(s,2H),1.65(s,2H), 0.84–0.75(m,9H),-0.00(s,3H),-0.25(d,3H).

LCMS m/z = 448.8 [M/2+1].

The seventh step: [1-[3-[5-[[[(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1H-quinolin-5-yl)ethyl]amino] Methyl]-6-methoxy-indoline-1-yl]-3-oxo-propyl]-4-piperidinyl]N-[2-(3-chloro-4-hydroxy-phenyl ) phenyl] carbamate (compound 5)

[1-[3-[5-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-6-methoxy- indolin-1-yl]-3-oxo-propyl]-4-piperidyl]N-[2-(3-chloro-4-hydroxy-phenyl)phenyl]carbamate

[1-[3-[5-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxyl-2-oxo-1H-quinoline- 5-yl)ethyl]amino]methyl]-6-methoxy-indoline-1-yl]-3-oxo-propyl]-4-piperidinyl]N-[2-(3 -Chloro-4-hydroxy-phenyl)phenyl]carbamate (5I) (0.420g, 0.468mmol) was dissolved in tetrahydrofuran (5mL), triethylamine trihydrofluoride (0.755g, 4.68mmol) was added ), react at room temperature for 24 hours. Add 10% methanol/dichloromethane (v/v=1/10, 50mL) solution to the reaction solution, add saturated aqueous sodium bicarbonate solution to adjust the pH to about 8, and extract. The aqueous phase was extracted with 10% methanol/dichloromethane (v/v=1/10, 50 mL×2), and the organic phases were combined. The organic phase was washed with saturated aqueous sodium chloride (20 mL×1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was slurried twice with dichloromethane (30 mL) to give the title compound [1-[3-[5-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H- Quinolin-5-yl)ethyl]amino]methyl]-6-methoxy-indoline-1-yl]-3-oxo-propyl]-4-piperidinyl]N-[2 -(3-Chloro-4-hydroxy-phenyl)phenyl]carbamate (compound 5), yellow solid (0.150 g, 40.9% yield).

¹ H NMR (400MHz, CD ₃ OD) δ8.18(d,1H),7.86(s,1H),7.48(d,1H),7.37–7.31(m,2H),7.28(dd,2H),7.21 (d,1H),7.16(dd,1H),7.09(s,1H),7.00(dd,2H),6.58(d,1H),5.33–5.24(m,1H),4.70(s,1H), 4.19(t,2H),4.00(s,2H),3.79(s,3H),3.13(dd,2H),3.09–3.02(m,2H),2.92(t,2H),2.86–2.73(m, 4H), 2.57(s,2H), 1.93(s,2H), 1.75(s,2H).

LCMS m/z = 391.8 [M/2+1].

Example 6: [1-[3-[5-[[[(2R)-2-hydroxyl-2-(4-hydroxyl-2-oxo-3H-1,3-benzothiazol-7-yl) Ethyl]amino]methyl]-6-methoxy-indoline-1-yl]-3-oxo-propyl]-4-piperidinyl]N-[2-(3-chloro-4 -Hydroxy-phenyl)phenyl]carbamate ditrifluoroacetate (compound 6)

[1-[3-[5-[[[(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethyl]amino]methyl]- 6-methoxy-indolin-1-yl]-3-oxo-propyl]-4-piperidyl]N-[2-(3-chloro-4-hydroxy-phenyl)phenyl]carbamate

[1-[3-(5-Formyl-6-methoxy-indoline-1-yl)-3-oxo-propyl]-4-piperidinyl]N-[2-(3 -Chloro-4-hydroxy-phenyl)phenyl]carbamate (5H) (0.420g, 0.727mmol) was dissolved in dichloromethane (10mL) and methanol (10mL) and added 7-[(1R)-2-amino-1-hydroxy-ethyl]-4-hydroxy-3H-1,3-benzothiazol-2-one (6A, refer to Bioorganic & Medicinal Chemistry Letters, 21(15), 4612 -4616; prepared in 2011) (0.181g, 0.799mmol), react at room temperature for 1 hour. Add sodium triacetoxyborohydride (0.464g, 2.18mmol) and react at room temperature for 24 hours. The reaction solution was added methanol/dichloromethane (v/v=1/10, 50mL) solution, and saturated aqueous sodium bicarbonate solution (30mL) was added for extraction. The aqueous phase was extracted with methanol/dichloromethane (v/v=1/10, 50 mL×1), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was sent to acid preparation to obtain the title compound [1-[3-[5-[[[(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-3H-1,3-benzene Andthiazol-7-yl)ethyl]amino]methyl]-6-methoxy-indoline-1-yl]-3-oxo-propyl]-4-piperidinyl]N-[2 -(3-Chloro-4-hydroxy-phenyl)phenyl]carbamate ditrifluoroacetate (compound 6), white solid (0.060 g, 10% yield).

¹ H NMR(400MHz,DMSO-d6)δ7.24(d,1H),6.68(s,1H),6.54(d,4H),6.40(d,2H),6.19(d,2H),5.95(dd ,1H),4.18(dd,2H),3.51–3.34(m,4H),3.09(s,3H),2.95–2.66(m,4H),2.45-2.33(m,4H),2.32-2.20(m ,4H), 1.51–1.00(m,4H).

LCMS m/z = 394.7 [M/2+1].

Example 7: [1-[3-[5-[[[(2R)-2-hydroxyl-2-(5-hydroxyl-3-oxo-4H-1,4-benzoxazin-8-yl ) ethyl] amino] methyl] -6-methoxy-indoline-1-yl] -3-oxo-propyl] -4-piperidinyl] N-(2-phenylphenyl) Carbamate bistrifluoroacetate (Compound 7)

[1-[3-[5-[[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino]methyl]- 6-methoxy-indolin-1-yl]-3-oxo-propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate; 2,2,2-trifluoroacetic acid

[1-[3-(5-formyl-6-methoxy-indoline-1-yl)-3-oxo-propyl]-4-piperidinyl]N-(2-phenyl Phenyl)carbamate (1B) (0.400g, 0.758mmol) was dissolved in tetrahydrofuran (2mL) and methanol (10mL), and 8-[(1R)-2-amino-1-hydroxyl-ethyl]- 5-Hydroxy-4H-1,4-benzoxan-3-one (7A, prepared by referring to WO2009098448A1) (0.170g, 0.758mmol), added anhydrous zinc chloride (0.413g, 3.03mmol), and reacted at 55°C 1 hour. Add sodium cyanoborohydride (0.143g, 2.27mmol) and react at 55°C for 2 hours. Dichloromethane (50 mL) was added to the reaction solution, and saturated aqueous sodium bicarbonate solution (50 mL) was added for extraction. The aqueous phase was extracted with methanol/dichloromethane (v/v=1/10, 30 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Use dichloromethane (30mL) to make a slurry, and the solid is separated and purified by liquid phase preparative column (liquid phase preparation conditions: C18 reverse phase preparative column, mobile phase is deionized water (A) containing 0.05% TFA, acetonitrile (B), etc. Degree elution B: A=25%, elution time 20 minutes), obtain title compound [1-[3-[5-[[[(2R)-2-hydroxyl-2-(5-hydroxyl-3-oxo Substitute-4H-1,4-benzoxazin-8-yl) Ethyl]amino]methyl]-6-methoxy-indolin-1-yl]-3-oxo-propyl]-4-piperidinyl]N-(2-phenylphenyl)amino Formate ditrifluoroacetate (compound 7), white solid (0.020 g, yield 3.6%).

¹ H NMR (400MHz, CD ₃ OD) δ7.99(s,1H),7.57(s,1H),7.50-7.28(m,8H),7.19(s,1H),7.04(d,1H),6.59 (d,1H),5.14(dd,1H),4.93(s,1H),4.40(dd,2H),4.28-4.09(m,4H),3.83(s,3H),3.77–3.49(m,4H ), 3.24–2.99(m,8H), 2.25-1.70(m,4H).

^19F NMR (376 MHz, CD ₃ OD) δ-75.45.

LCMS m/z = 368.6 [M/2+1].

Example 8: [1-[3-[5-[[[(2R)-2-hydroxyl-2-[4-hydroxyl-3-(hydroxymethyl)phenyl]ethyl]amino]methyl]- 6-Methoxy-indolin-1-yl]-3-oxo-propyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate ditrifluoroacetate (Compound 8)

[1-[3-[5-[[[(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl]amino]methyl]-6-methoxy-indolin-1-yl ]-3-oxo-propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate; 2,2,2-trifluoroacetic acid

The first step: (1R)-2-amino-1-(2,2-dimethyl-4H-1,3-benzodioxan-6-yl)ethanol (8B)

(1R)-2-amino-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol

(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxan-6-yl)oxazolidin-2-one (8A) (2.0g, 8.0mmol) Dissolve in ethanol (10mL) and water (10mL), add sodium hydroxide (0.64g, 16mmol), and react under reflux at 90°C for 2 hours. Dichloromethane (30 mL) and water (30 mL) were added to the reaction solution for extraction. The aqueous phase was extracted with dichloromethane (30mL×1), the organic phases were combined, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (1R)-2-amino-1-(2,2 -Dimethyl-4H-1,3-benzodioxan-6-yl)ethanol (8B), yellow solid (1.6 g, 89% yield).

¹ H NMR (400MHz, CDCl ₃ )δ7.11(dd,1H),6.99(d,1H),6.79(d,1H),4.82(d,2H),4.53(dd,1H),2.94(dd, 1H), 2.77(dd,1H), 2.04(s,3H), 1.53(d,6H).

The second step: [1-[3-[5-[[[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxan-6-yl)-2 -Hydroxy-ethyl]amino]methyl]-6-methoxy-indol-1-yl]-3-oxo-propyl]-4-piperidinyl]N-(2-phenylphenyl ) carbamate (8C)

[1-[3-[5-[[[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxy-ethyl]amino]methyl]-6 -methoxy-indolin-1-yl]-3-oxo-propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate

[1-[3-(5-formyl-6-methoxy-indoline-1-yl)-3-oxo-propyl]-4-piperidinyl]N-(2-phenyl Phenyl)carbamate (1B) (0.400g, 0.758mmol) was dissolved in tetrahydrofuran (2mL) and methanol (10mL), and (1R)-2-amino-1-(2,2-dimethyl- 4H-1,3-benzodioxan-6-yl)ethanol (8B) (0.203g, 0.910mmol), was added with anhydrous zinc chloride (0.413g, 3.03mmol), and reacted at 55°C for 1 hour. Add sodium cyanoborohydride (0.143g, 2.27mmol) and react at 55°C for 2 hours. Dichloromethane (30 mL) was added to the reaction solution, and water (30 mL) was added for extraction. The aqueous phase was extracted with dichloromethane (30 mL×1), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (methanol/dichloromethane (v/v)=1:99～3:47) to obtain the title compound [1-[3-[5-[[[(2R)-2- (2,2-Dimethyl-4H-1,3-benzodioxan-6-yl)-2-hydroxy-ethyl]amino]methyl]-6-methoxy-indoline- 1-yl]-3-oxo-propyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate (8C), pale yellow solid (0.320 g, 57.4% yield) .

LCMS m/z = 368.4 [M/2+1].

The third step: [1-[3-[5-[[[(2R)-2-hydroxyl-2-[4-hydroxyl-3-(hydroxymethyl)phenyl]ethyl]amino]methyl]- 6-Methoxy-indolin-1-yl]-3-oxo-propyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate ditrifluoroacetate (Compound 8)

[1-[3-[5-[[[(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl]amino]methyl]-6-methoxy-indolin-1-yl ]-3-oxo-propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate; 2,2,2-trifluoroacetic acid

[1-[3-[5-[[[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxan-6-yl)-2-hydroxy- Ethyl]amino]methyl]-6-methoxy-indol-1-yl]-3-oxo-propyl]-4-piperidinyl]N-(2-phenylphenyl)aminomethyl Ester (8C) (0.220g, 0.299mmol) was dissolved in dichloromethane (15mL), added trifluoroacetic acid (0.0683g, 0.599mmol), and reacted at room temperature for 2 hours. The reaction solution was added with saturated aqueous sodium bicarbonate solution (15 mL) and extracted. The aqueous phase was extracted with dichloromethane (20 mL×1), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by liquid phase preparation column (liquid phase preparation condition: C18 Reversed-phase preparative column, mobile phase is deionized water (A) containing 0.05% TFA, acetonitrile (B), isocratic elution B:A=25%, elution time 20 minutes), to obtain the title compound [1- [3-[5-[[[(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl]amino]methyl]-6-methoxy-ind Indolin-1-yl]-3-oxo-propyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate ditrifluoroacetate (compound 8), white solid (0.040 g, 19% yield).

¹ H NMR (400MHz, CD ₃ OD) δ8.04(s,1H),7.57(d,1H),7.49–7.28(m,9H),7.26(s,1H),7.15(dd,1H),6.80 (d,1H),4.91(dd,2H),4.65(s,2H),4.25(s,2H),4.20(t,2H),3.91(s,3H),3.75–3.45(m,4H), 3.25–3.00(m,8H), 2.25-1.75(m,4H).

^19F NMR (376 MHz, CD ₃ OD) δ-75.35.

LCMS m/z = 348.3 [M/2+1].

Example 9: [1-[3-[6-[[[(2R)-2-hydroxyl-2-(5-hydroxyl-3-oxo-4H-1,4-benzoxazin-8-yl ) ethyl] amino] methyl] -7-methoxy-3,4-dihydro-2H-quinolin-1-yl] -3-oxo-propyl] -4-piperidinyl] N- (2-Phenylphenyl)carbamate ditrifluoroacetate (compound 9)

[1-[3-[6-[[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino]methyl]- 7-methoxy-3,4-dihydro-2H-quinolin-1-yl]-3-oxo-propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate; 2,2,2-trifluoroacetic acid

[1-[3-(6-formyl-7-methoxy-3,4-dihydro-2H-quinolin-1-yl)-3-oxo-propyl]-4-piperidinyl ]N-(2-Phenylphenyl)carbamate (4F) (0.300g, 0.554mmol) was dissolved in methanol (15mL), and 8-[(1R)-2-amino-1-hydroxyl-ethyl Base]-5-hydroxyl-4H-1,4-benzoxazin-3-one (7A) (0.124g, 0.554mmol), adding anhydrous zinc chloride (0.302g, 2.22mmol), 55 ° C reaction 1 Hour. Add sodium cyanoborohydride (0.104 g, 1.66 mmol) and react at 55°C for 2 hours. Dichloromethane (50 mL) and saturated aqueous sodium bicarbonate (50 mL) were added to the reaction solution for extraction. The aqueous phase was extracted with methanol/dichloromethane (v/v=1/10, 30 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by liquid phase preparative column (liquid phase preparation condition: C18 reverse phase preparative column, mobile phase was deionized water (A) containing 0.05% TFA, acetonitrile (B), isocratic elution B:A=25 %, elution time 20 minutes), the title compound [1-[3-[6-[[[(2R)-2-hydroxyl-2-(5-hydroxyl-3-oxo-4H-1,4- Benzoxazin-8-yl)ethyl]amino]methyl]-7-methoxy-3,4-dihydro-2H-quinolin-1-yl]-3-oxo-propyl]- 4-piperidinyl]N-(2-phenylphenyl)carbamate ditrifluoroacetate (compound 9), white solid (0.350 g, yield 64.6%).

¹ H NMR (400MHz, CD ₃ OD) δ7.57(s,1H),7.50-7.25(m,9H),7.14(s,1H),7.05(d,1H),6.60(d,1H),5.16 (d,1H),4.93(s,1H),4.50-4.30(m,2H),4.29–4.18(m,2H),3.91-3.75(m,5H),3.75–3.43(m,4H),3.25 –2.93 (m, 6H), 2.76 (t, 2H), 2.25 – 1.73 (m, 6H).

^19F NMR (376 MHz, CD ₃ OD) δ-75.37.

LCMS m/z = 375.8 [M/2+1].

Example 10: [1-[3-[5-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino] Methyl]-6-methoxy-indol-1-yl]-3-oxo-propyl]-4-piperidinyl]N-[2-(4-hydroxyphenyl)phenyl]aminomethyl Ester ditrifluoroacetate (Compound 10)

[1-[3-[5-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-6-methoxy- indolin-1-yl]-3-oxo-propyl]-4-piperidyl]N-[2-(4-hydroxyphenyl)phenyl]carbamate; 2,2,2-trifluoroacetic acid

The first step: 4-piperidinyl N-[2-(4-hydroxyphenyl)phenyl]carbamate (10A)

4-piperidyl N-[2-(4-hydroxyphenyl)phenyl]carbamate

4-piperidinyl N-[2-(3-chloro-4-hydroxy-phenyl)phenyl]carbamate (5G) (0.600g, 1.73mmol) was dissolved in methanol (10mL), and 10 % palladium on carbon (2.0 g), replace the hydrogen, and react at room temperature under a hydrogen atmosphere for 24 hours. The reaction solution was filtered with diatomaceous earth, the filtrate was concentrated, and the residue was separated and purified by silica gel column chromatography (methanol/dichloromethane (v/v)=1:99～1:9) to obtain the title compound 4-piperidinyl N- [2-(4-Hydroxyphenyl)phenyl]carbamate (10A), yellow oil (0.47 g, 87% yield).

¹ H NMR (400MHz, DMSO-d6) δ9.58(s,1H),9.24(s,1H),9.14(s,1H),8.65(s,1H),7.36(t,1H),7.32–7.27 (m,1H), 7.18(d,2H), 6.83(d,2H), 4.74(s,1H), 3.02(s,4H), 1.94(s,2H), 1.72(s,2H).

LCMS m/z = 313.1 [M+1].

The second step: [1-[3-(5-formyl-6-methoxy-indol-1-yl)-3-oxo-propyl]-4-piperidinyl]N-[2- (4-Hydroxyphenyl)phenyl]carbamate (10B)

[1-[3-(5-formyl-6-methoxy-indolin-1-yl)-3-oxo-propyl]-4-piperidyl]N-[2-(4-hydroxyphenyl)phenyl]carbamate

Dissolve 6-methoxy-1-propyl-2-enoyl-indole-5-carbaldehyde (Intermediate 1) (0.348g, 1.50mmol) in 2-methyltetrahydrofuran (10mL), add 4- Piperidinyl N-[2-(4-hydroxyphenyl)phenyl]carbamate (10A) (0.470g, 1.50mmol), added triethylamine (0.304g, 3.01mmol), microwave reaction at 100℃ for 1h . The reaction solution was concentrated, and the residue was separated and purified by silica gel column chromatography (ethyl acetate:petroleum ether (v/v)=1:1～1:0) to obtain the title compound [1-[3-(5-formyl-6 -Methoxy-indol-1-yl)-3-oxo-propyl]-4-piperidinyl]N-[2-(4-hydroxyphenyl)phenyl]carbamate (10B) , a yellow solid (0.580 g, 70.9% yield).

¹ H NMR (400MHz, CDCl ₃ )δ10.31(s,1H),8.02(d,1H),7.93(s,1H),7.63(s,1H),7.36–7.29(m,1H),7.20– 7.08(m,4H),6.99(d,2H),6.65(s,1H),4.85(s,1H),4.14(t,2H),3.90(s,3H),3.17–3.11(m,4H) , 2.96(d,4H), 2.72(s,2H), 2.14(s,2H), 1.92(s,2H).

LCMS m/z = 544.3 [M+1].

The third step: [1-[3-[5-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxyl-2-oxo-1H- Quinolin-5-yl)ethyl]amino]methyl]-6-methoxy-indol-1-yl]-3-oxo-propyl]-4-piperidinyl]N-[2- (4-Hydroxyphenyl)phenyl]carbamate (10C)

[1-[3-[5-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl] amino]methyl]-6-methoxy-indolin-1-yl]-3-oxo-propyl]-4-piperidyl]N-[2-(4-hydroxyphenyl)phenyl]carbamate

[1-[3-(5-Formyl-6-methoxy-indol-1-yl)-3-oxo-propyl]-4-piperidinyl]N-[2-(4- Hydroxyphenyl)phenyl]carbamate (10B) (0.250g, 0.460mmol) was dissolved in methanol (10mL), and (R)-5-(2-amino-1-((tert-butyldimethyl Silylyl)oxy)ethyl)-8-hydroxyquinolin-2(1H)-one (1D) (0.318g, 0.951mmol), add anhydrous zinc chloride (0.251g, 1.84mmol), and react at 55°C 1 hour. Add sodium cyanoborohydride (0.0867g, 1.38mmol) and react at 55°C for 2 hours. Dichloromethane (30 mL) was added to the reaction solution, and water (30 mL) was added for extraction. The aqueous phase was extracted with dichloromethane (30 mL×1), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The reaction solution was added dichloromethane (20mL), and Saturated aqueous sodium bicarbonate solution (20 mL), extracted. The aqueous phase was extracted with dichloromethane (20 mL×1), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v)=1:1～1:0, methanol/dichloromethane (v/v)=1:99～1:9) to obtain The title compound [1-[3-[5-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinoline -5-yl)ethyl]amino]methyl]-6-methoxy-indol-1-yl]-3-oxo-propyl]-4-piperidinyl]N-[2-(4 -Hydroxyphenyl)phenyl]carbamate (10C), yellow oil (0.20 g, 50.4% yield).

LCMS m/z = 431.9 [M/2+1].

The fourth step: [1-[3-[5-[[[(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1H-quinolin-5-yl)ethyl]amino] Methyl]-6-methoxy-indol-1-yl]-3-oxo-propyl]-4-piperidinyl]N-[2-(4-hydroxyphenyl)phenyl]aminomethyl Ester ditrifluoroacetate (Compound 10)

[1-[3-[5-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-6-methoxy- indolin-1-yl]-3-oxo-propyl]-4-piperidyl]N-[2-(4-hydroxyphenyl)phenyl]carbamate; 2,2,2-trifluoroacetic acid

[1-[3-[5-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxyl-2-oxo-1H-quinoline- 5-yl)ethyl]amino]methyl]-6-methoxy-indol-1-yl]-3-oxo-propyl]-4-piperidinyl]N-[2-(4- Hydroxyphenyl)phenyl]carbamate (10C) (0.200g, 0.232mmol) was dissolved in tetrahydrofuran (5mL), triethylamine trihydrofluoride (0.374g, 2.32mmol) was added, and reacted at room temperature for 24 hours . Dichloromethane (50 mL) was added to the reaction solution, and saturated aqueous sodium bicarbonate solution was added to adjust the pH to about 8, followed by extraction. The aqueous phase was extracted with dichloromethane (50 mL×2), and the organic phases were combined. The organic phase was washed with saturated aqueous sodium chloride (20 mL×1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by liquid phase preparative column (liquid phase preparation condition: C18 reverse phase preparative column, mobile phase was deionized water (A) containing 0.05% TFA, acetonitrile (B), isocratic elution B:A=25 %, elution time 20 minutes), the title compound [1-[3-[5-[[[(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1H-quinoline-5 -yl)ethyl]amino]methyl]-6-methoxy-indol-1-yl]-3-oxo-propyl]-4-piperidinyl]N-[2-(4-hydroxy Phenyl)phenyl]carbamate ditrifluoroacetate (compound 10), white solid (0.060 g, yield 27%).

¹ H NMR (400MHz, CD ₃ OD) δ7.97(d,1H),7.81(s,1H),7.57(s,1H),7.39–7.17(m,6H),7.06(d,2H),6.93 -6.79(m,2H),6.53(d,1H),5.41(dd,1H),4.96(s,1H),4.26–4.06(m,4H),3.77(s,3H),3.70-3.45(m ,4H), 3.30–2.98(m,8H), 2.35-1.85(m,4H).

LCMS m/z = 374.8 [M/2+1].

Example 11: 1-[3-[5-[[[(2R)-2-hydroxyl-2-(4-hydroxyl-2-oxo-3H-1,3-benzothiazol-7-yl)ethyl base] amino] methyl Base]-6-methoxyindolin-1-yl]-3-oxo-propyl]-4-piperidinyl]-N-(2-phenylphenyl)carbamate (compound 11)

[1-[3-[5-[[[(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethyl]amino]methyl]- 6-methoxy-indolin-1-yl]-3-oxo-propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate

1-[3-(5-Formyl-6-methoxyindolin-1-yl)-3-oxo-propyl]-4-piperidinyl]-N-(2-phenylphenyl ) carbamic acid (1B) (0.35g, 0.66mmol) and 7-[(1R)-2-amino-1-hydroxyl-ethyl]-4-hydroxyl-3H--1,3-benzothiazole-2- Ketone (6A) (0.57g, 2.5mmol) was dissolved in a mixed solvent of dichloromethane (5mL) and methanol (5mL), stirred at room temperature for 30 minutes, and sodium triacetoxyborohydride (0.42g, 2.0mmol) was added, React at room temperature for 2 hours. Dichloromethane (10 mL) was added, washed with saturated sodium bicarbonate solution (20 mL×2) and saturated brine (20 mL×1), the organic phase was successively dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/dichloromethane (v/v)=1:100～1:20) to obtain the title compound 1-[3-[5-[[[(2R)-2-hydroxyl -2-(4-Hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethyl]amino]methyl]-6-methoxyindolin-1-yl] -3-Oxo-propyl]-4-piperidinyl]-N-(2-phenylphenyl)carbamate (compound 11), pale yellow solid (0.14 g, yield 28.6%).

¹ H NMR (400MHz, CD ₃ OD) δ7.82(s,1H),7.57(d,1H),7.47–7.24(m,8H),7.00(s,1H),6.88(d,1H),6.71 (d,1H),4.74-4.71(m,1H),4.69–4.59(m,1H),4.17(t,2H),3.78–3.64(m,5H),3.13(t,2H),2.88–2.67 (m,8H), 2.41(t,2H), 1.87(s,2H), 1.67(s,2H).

LCMS m/z = 739.1 [M+1].

Example 12: [[1-[4-[5-[[[(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1H-quinolin-5-yl)ethyl]amino ]methyl]-6-methoxyindolin-1-yl]-4-oxobutyl]-4-piperidinyl]-N-(2-phenylphenyl)carbamate ( Compound 12)

[1-[4-[5-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-6-methoxy- indolin-1-yl]-4-oxo-butyl]-4-piperidyl]N-(2-phenylphenyl)carbamate

The first step: 1-(4-bromobutyl)-6-methoxyindoline-5-carbaldehyde (12A)

1-(4-bromobutanoyl)-6-methoxy-indoline-5-carbaldehyde

Dissolve tetrabromobutyric acid (2g, 10mmol) in anhydrous dichloromethane (20mL), cool to 0°C, add dropwise oxalyl chloride (3g, 30mmol), stir at low temperature for 30 minutes, concentrate, add dichloromethane (10mL ) to obtain reaction solution 1; 6-methoxyindoline-5-formaldehyde (1f) (0.8g, 5mmol) and triethylamine (1g, 10mmol) were added in dichloromethane (20mL), cooled to 0 ℃, drop the reaction solution 1, and react at low temperature for 0.5 hours. Dichloromethane (50mL) and water (50mL) were added to the reaction solution, separated and extracted, the organic phase was washed with saturated sodium chloride solution (50mL×1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v)=0:1～1:2) to obtain the title compound 1-(4-bromobutyl)-6-methoxydi Indoline-5-carbaldehyde (12A), light red solid (0.8 g, 50% yield).

¹ HNMR (400MHz, CDCl ₃ )δ10.32(d,1H),8.00(s,1H),7.65(s,1H),3.93(d,3H),3.59(t,2H),3.16(dd,2H ), 2.67(dd,2H), 2.51(m,4H).

LCMS m/z = 326.0 [M+1].

The second step: [1-[4-(5-formyl-6-methoxyindolin-1-yl)-4-oxobutyl]-4-piperidinyl]N-(2- Phenylphenyl) carbamate (12B)

[1-[4-(5-formyl-6-methoxy-indolin-1-yl)-4-oxo-butyl]-4-piperidyl]N-(2-phenylphenyl)carbamate

1-(4-bromobutyl)-6-methoxyindoline-5-carbaldehyde (12A) (0.8g, 2mmol) and 4-piperidinyl-N-(2-phenylphenyl) Carbamate (1A) (0.7g, 2mmol) was dissolved in acetonitrile/tetrahydrofuran (v/v) = 2/1 mixed solvent (15mL), then triethylamine (0.5g, 5mmol), tetrabutyl Ammonium iodide (0.2 g, 0.2 mmol), stirred in a microwave reactor for 7 hours. Concentrate, add ethyl acetate (50 mL) to the residue to dissolve, wash with water (50 mL×1) and saturated sodium chloride solution (50 mL×1) successively, dry the organic phase over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue was separated and purified by silica gel column chromatography (methanol/dichloromethane (v/v)=0:1~5:95) to obtain the title compound [1-[4-(5-formyl-6-methoxy Indolin-1-yl)-4-oxobutyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate (12B), pale yellow (0.11g, yield 8%).

LCMS m/z = 542.1 [M+1].

The third step: [1-[4-[5-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxyl-2-oxo-1H -quinolin-5-yl)ethyl]amino]methyl]-6-methoxyindolin-1-yl]-4-oxobutyl]-4-piperidinyl]N-(2 -Phenylphenyl) carbamate (12C)

[1-[4-[5-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl] amino]methyl]-6-methoxy-indolin-1-yl]-4-oxo-butyl]-4-piperidyl]N-(2-phenylphenyl)carbamate

[1-[4-(5-formyl-6-methoxyindolin-1-yl)-4-oxobutyl]-4-piperidinyl]-N-(2-phenyl Phenyl)carbamate (12B) (0.11g, 0.20mmol) and 5-[(1R)-2-amino-1-[tert-butyl(dimethyl)silyl]oxyethyl]-8 -Hydroxy-1H-quinolin-2-one (1D) (0.10g, 0.30mmol) was dissolved in a mixed solvent (10mL) of methanol/dichloromethane (v/v=1/1), stirred at room temperature for 1 hour Sodium triacetoxyborohydride (0.25 g, 1.2 mmol) was added and the reaction was continued for 2 hours. Dichloromethane (50mL) and water (50mL) were added to the reaction solution, layered extraction, the organic phase was washed with saturated sodium chloride solution (50mL×1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title Compound [1-[4-[5-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinoline -5-yl)ethyl]amino]methyl]-6-methoxyindolin-1-yl]-4-oxobutyl]-4-piperidinyl]N-(2-phenyl Phenyl) carbamate (12C), pale oil (0.11 g, 63% yield).

LCMS m/z = 430.8 [1/2M+1].

The fourth step: [[1-[4-[5-[[[(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1H-quinolin-5-yl)ethyl]amino ]methyl]-6-methoxyindolin-1-yl]-4-oxobutyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate (compound 12)

[1-[4-[5-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-6-methoxy- indolin-1-yl]-4-oxo-butyl]-4-piperidyl]N-(2-phenylphenyl)carbamate

[1-[4-[5-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxyl-2-oxo-1H-quinoline -5-yl)ethyl]amino]methyl]-6-methoxyindolin-1-yl]-4-oxobutyl]-4-piperidinyl]-N-(2-benzene phenyl) carbamate (12C) (0.11g, 0.13mmol) was dissolved in dichloromethane (10mL), triethylamine trihydrofluoride (0.21g, 1.3mmol) was added, room temperature was reacted overnight, and the reaction The solution was adjusted with saturated sodium bicarbonate, extracted with 8% methanol/dichloromethane (v/v) (50mL×1), washed with saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate Concentrate under reduced pressure. The residue was separated and purified by silica gel column chromatography (methanol/dichloromethane (v/v)=0:1～1:9) to obtain the title compound [[1-[4-[5-[[[(2R)- 2-Hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-6-methoxyindolin-1-yl]-4 -Oxobutyl]-4-piperidinyl]-N-(2-phenyl Phenyl) carbamate (compound 12), pale yellow solid (0.02 g, yield 20%).

¹ HNMR(400MHz,DMSO-d6)δ8.61(m,1H),8.14(m,1H),7.85(m,1H),7.39(m,8H),7.06(m,2H),6.93(m, 1H),6.49(m,1H),5.05(s,1H),4.46(s,1H),4.11(t,2H),3.72(s,3H),3.66(s,2H),3.46(dd,2H ),3.05(d,2H),2.70(m,2H),2.61(s,2H),2.46(d,2H),2.33(t,2H),2.13(d,2H),1.74(d,4H) .

LCMS m/z = 373.8 [1/2M+1].

Example 13: 2-[4-[(2-Phenylphenyl)carbamoyloxy]-1-piperidinyl]ethyl 5-[[[(2R)-2-hydroxyl-2-(5 -Hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino]methyl]-6-methoxyindoline-1-carboxylate (compound 13 )

2-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]ethyl5-[[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin- 8-yl)ethyl]amino]methyl]-6-methoxy-indoline-1-carboxylate

The first step: 2-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidinyl]ethyl 5-[[[(2R)-2-[tert-butyl(di Methyl)silyl]oxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino]methyl]-6-methoxy Indoline-1-carboxylate (13B)

2-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]ethyl5-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(5-hydroxy-3-oxo -4H-1,4-benzoxazin-8-yl)ethyl]amino]methyl]-6-methoxy-indoline-1-carboxylate

2-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidinyl]ethyl 5-formyl-6-methoxyl-indole-1-carboxylate ( 3C) (0.200 g, 0.368 mmol) was dissolved in anhydrous methanol (6 mL), dichloromethane (3 mL) was added, 8-[(1R)-2-amino-1-[tert-butyl(dimethyl) Silyl]oxyethyl]-5-hydroxy-4H-1,4-benzoxazin-3-one (13A) (0.125g, 0.368mmol), after stirring at room temperature for 1 hour, triacetoxyboron was added After adding sodium hydride (0.234g, 1.10mmol), react at room temperature for 2 hours. Dichloromethane (30 mL) was added, washed with saturated aqueous sodium bicarbonate (10 mL×3), and then washed with saturated aqueous sodium chloride (10 mL×1), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue Separation and purification with silica gel column chromatography (dichloromethane: Methanol (v/v)=1:0～19:1), the title compound 2-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidinyl]ethyl 5- [[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazine-8- yl)ethyl]amino]methyl]-6-methoxyindoline-1-carboxylate (13B), pale yellow solid (0.19 g, 60% yield).

¹ HNMR (400MHz, CDCl ₃ )δ8.09(d,1H),7.57(s,1H),7.50-7.46(m,2H),7.44–7.33(m,4H),7.21(dd,1H),7.15 –7.10(m,1H),7.06–7.03(s,1H),6.77(d,1H),6.59(s,1H),6.17(d,1H),5.16-5.10(m,1H),4.78-4.70 (m,1H),4.52-4.38(m,2H),4.36-4.28(m,2H),4.06–3.89(m,3H),3.83(s,3H),3.13–2.90(m,4H),2.84 -2.68(m,4H),2.44-2.34(m,2H),1.96-1.92(m,2H),1.76-1.66(m,2H),0.85(s,9H),0.00(s,3H),- 0.10(s,3H).

LCMS m/z = 433.7 [M/2+1].

The second step: 2-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidinyl]ethyl 5-[[[(2R)-2-hydroxyl-2-(5 -Hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino]methyl]-6-methoxyindoline-1-carboxylate (compound 13 )

2-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]ethyl5-[[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin- 8-yl)ethyl]amino]methyl]-6-methoxy-indoline-1-carboxylate

2-[4-[(2-Phenylphenyl)carbamoyloxy]-1-piperidinyl]ethyl 5-[[[(2R)-2-[tert-butyl(dimethyl) Silyl]oxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino]methyl]-6-methoxydihydro Indole-1-carboxylate (13B) (0.19g, 0.22mmol) was dissolved in dichloromethane (3mL), added triethylamine trihydrofluoride (0.71g, 4.4mmol), and heated to React at 30°C for 6 hours. Add dichloromethane (20mL), adjust the pH to 9 with saturated aqueous sodium bicarbonate solution, separate the layers, extract the aqueous layer with dichloromethane (20mL×3), combine the organic layers, wash with saturated aqueous sodium chloride solution (10mL×1 ), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=1:0～93:7) to obtain the title compound 2-[ 4-[(2-phenylphenyl)carbamoyloxy]-1-piperidinyl]ethyl 5-[[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo -4H-1,4-Benzoxazin-8-yl)ethyl]amino]methyl]-6-methoxyindoline-1-carboxylate (compound 13), pale yellow solid (0.078 g, yield 47%).

¹ HNMR (400MHz, CD ₃ OD) δ7.44(d,2H),7.34–7.19(m,7H),7.19–7.12(m,2H),6.93(s,1H),6.79(d,1H), 6.41(d,1H),4.95-4.91(m,1H),4.56–4.47(m,1H),4.34(s,2H),4.28-4.20(m,2H),3.94(t,2H),3.76– 3.62(m,5H),2.95(t,2H),2.78–2.70(m,2H),2.70–2.60(m,5H),2.32-2.28(m,2H),1.80-1.72(s,3H), 1.58-1.50(s,4H).

LCMS m/z = 376.7 [M/2+1].

Example 14: [1-[3-[6-[[[(2R)-2-hydroxyl-(4-hydroxyl-2-oxo-3H-1,3-benzothiazol-7-yl)ethyl ]amino]methyl]-7-methoxy-3,4-dihydro-2H-quinolin-1-yl]-3-oxo-propyl]-4-piperidinyl]N-(2- Phenylphenyl) carbamate ditri Fluoroacetate (Compound 14)

[1-[3-[6-[[[(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethyl]amino]methyl]- 7-methoxy-3,4-dihydro-2H-quinolin-1-yl]-3-oxo-propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate; 2,2,2-trifluoroacetic acid

The first step: [1-[3-[6-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-[4-[tert-butyl(dimethyl )silyl]oxy-2-oxo-3H-1,3-benzothiazol-7-yl]ethyl]amino]methyl]-7-methoxy-3,4-dihydro-2H- Quinolin-1-yl]-3-oxo-propyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate (14A)

[1-[3-[6-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-[4-[tert-butyl(dimethyl)silyl]oxy-2-oxo-3H -1,3-benzothiazol-7-yl]ethyl]amino]methyl]-7-methoxy-3,4-dihydro-2H-quinolin-1-yl]-3-oxo-propyl]-4-piperidyl]N- (2-phenylphenyl)carbamate

[1-[3-(6-formyl-7-methoxy-3,4-dihydro-2H-quinolin-1-yl)-3-oxo-propyl]-4-piperidinyl ]N-(2-phenylphenyl)carbamate (4F) (0.550g, 1.02mmol) was dissolved in methanol (10mL), and 7-[(1R)-2-amino-1-[tert-butyl yl(dimethyl)silyl]oxyethyl]-4-[tert-butyl(dimethyl)silyl]oxy-3H-1,3-benzothiazol-2-one (intermediate 2) (0.600g, 1.32mmol), add anhydrous zinc chloride (0.554g, 4.06mmol), and react at 55°C for 1 hour. Add sodium cyanoborohydride (0.191g, 3.05mmol) and react at 55°C for 2 hours. Dichloromethane (50mL) and water (20mL) were added to the reaction solution for extraction, the aqueous phase was extracted with dichloromethane (30mL×1), the organic phases were combined, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The title compound [1-[3-[6-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-[4-[tert-butyl(dimethyl) Silyl]oxy-2-oxo-3H-1,3-benzothiazol-7-yl]ethyl]amino]methyl]-7-methoxy-3,4-dihydro-2H-quinol Lin-1-yl]-3-oxo-propyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate (14A), yellow solid (1.0 g, yield 100% ).

LCMS m/z = 490.9 [M/2+1].

The second step: [1-[3-[6-[[[(2R)-2-hydroxyl-(4-hydroxyl-2-oxo-3H-1,3-benzothiazol-7-yl)ethyl ]amino]methyl]-7-methoxy-3,4-dihydro-2H-quinolin-1-yl]-3-oxo-propyl]-4-piperidinyl]N-(2- Phenylphenyl) carbamate ditrifluoroacetate (compound 14)

[1-[3-[6-[[[(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethyl]amino]methyl]- 7-methoxy-3,4-dihydro-2H-quinolin-1-yl]-3-oxo-propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate; 2,2,2-trifluoroacetic acid

[1-[3-[6-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-[4-[tert-butyl(dimethyl)silyl ]oxy-2-oxo-3H-1,3-benzothiazol-7-yl]ethyl]amino]methyl]-7-methoxy-3,4-dihydro-2H-quinoline- 1-yl]-3-oxo-propyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate (14A) (1.0 g, 1.0 mmol) was dissolved in tetrahydrofuran (5 mL) , added triethylamine trihydrofluoride (1.6 g, 10 mmol), and reacted at room temperature for 24 hours. Add dichloromethane (20mL) to the reaction solution, add saturated sodium bicarbonate solution to adjust the pH to about 8, extract, extract the aqueous phase with dichloromethane (20mL×2), combine the organic phase, and use saturated brine (20mL×2) for the organic phase 1) Washing, drying over anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, separation and purification of the residue by liquid phase preparative column (liquid phase preparation conditions: C18 reverse phase preparative column, mobile phase is deionized water containing 0.05% TFA (A ), acetonitrile (B), isocratic elution B:A=25%, elution time 20 minutes), to obtain the title compound [1-[3-[6-[[[(2R)-2-hydroxyl-(4 -Hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethyl]amino]methyl]-7-methoxy-3,4-dihydro-2H-quinoline-1 -yl]-3-oxo-propyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate ditrifluoroacetate (compound 14), white solid (0.100 g, Yield 10%).

1H NMR (400MHz, CD ₃ OD) δ7.57(s,1H),7.49–7.27(m,9H),7.20(s,1H),7.00(d,1H),6.78(d,1H),5.02– 4.88(m,2H),4.28(dd,2H),3.91(s,3H),3.87–3.73(m,2H),3.72-3.44(s,4H),3.17(s,4H),3.11–3.04( m,2H), 2.77(t,2H), 2.25–1.73(m,6H).

19F NMR (376 MHz, CD ₃ OD) δ-76.93.

LCMS m/z = 376.7 [M/2+1].

Example 15: [1-[3-[7-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino] Methyl]-6-methoxy-2,3-dihydro-1,4-benzoxazin-4-yl]-3-oxo-propyl]-4-piperidinyl]N-(2 -Phenylphenyl)carbamate ditrifluoroacetate (compound 15)

[1-[3-[7-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-6-methoxy- 2,3-dihydro-1,4-benzoxazin-4-yl]-3-oxo-propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate; 2,2,2-trifluoroacetic acid

The first step: 6-methoxy-4H-1,4-benzoxazin-3-one (15B)

6-methoxy-4H-1,4-benzoxazin-3-one

2-Amino-4-methoxy-phenol (15A) (8.5g, 61.1mmol) was dissolved in acetonitrile (100mL), chloroacetyl chloride (8.28g, 73.3mmol) was added at 0°C, and then potassium carbonate (22g , 159mmol), heated and refluxed and stirred for 3 hours. Add ethyl acetate (200mL) and water (150mL) to the reaction solution for extraction, extract the aqueous phase with ethyl acetate (100mL×1), combine the organic phases, and use saturated brine (200mL×2) for the organic phase, anhydrous sodium sulfate Dry, filter, and concentrate the filtrate under reduced pressure to obtain the title compound 6-methoxy-4H-1,4-benzoxazin-3-one (15B) as a brown solid (9.8 g, yield 90%).

11H NMR (400MHz, CDCl3) δ8.86(s,1H),6.89(d,1H),6.51(dd,1H),6.41(d,1H),4.56(s,2H),3.76(s,3H) .

LCMS m/z = 180.2 [M+1].

The second step: 6-methoxy-3,4-dihydro-2H-1,4-benzoxazine (15C)

6-methoxy-3,4-dihydro-2H-1,4-benzoxazine

6-Methoxy-4H-1,4-benzoxazin-3-one (15B) (9.8g, 55mmol) was dissolved in tetrahydrofuran (100mL), under nitrogen protection, lithium aluminum tetrahydrogen (1.1 g, 71 mmol), reacted at 60°C for 3 hours. Cool to 0°C, and carefully add water to quench the reaction. Add ethyl acetate (200mL), filter with diatomaceous earth, dry the filtrate over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the title compound 6-methoxy-3,4-dihydro-2H-1,4- Benzoxazine (15C), brown oil (6.0 g, 66% yield).

¹ H NMR (400MHz, CDCl ₃ )δ6.68(d,1H),6.21(dd,1H),6.16(d,1H),4.18(dd,2H),3.71(s,3H),3.39(dd, 2H).

LCMS m/z = 166.2 [M+1].

The third step: 7-bromo-6-methoxy-3,4-dihydro-2H-1,4-benzoxazine (15D)

7-bromo-6-methoxy-3,4-dihydro-2H-1,4-benzoxazine

Dissolve 6-methoxy-3,4-dihydro-2H-1,4-benzoxazine (15C) (5.5g, 33mmol) in ethyl acetate (50mL), add 1, 3-Dibromo-5,5-dimethylhydantoin (4.88g, 17mmol), react at 0°C for 2 hours. A 15% potassium carbonate solution (100 mL) was added to the reaction solution, followed by thorough stirring. Add ethyl acetate (50mL), extract, dry the organic phase over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and separate and purify the residue by silica gel column chromatography (ethyl acetate:petroleum ether (v/v)=0:1～ 1:9), the title compound 7-bromo-6-methoxy-3,4-dihydro-2H-1,4-benzoxazine (15D) was obtained as a brown oil (1.6 g, 20% yield) .

LCMS m/z = 244.1 [M+1].

The fourth step: 6-methoxy-3,4-dihydro-2H-1,4-benzoxazine-7-carbaldehyde (15E)

6-methoxy-3,4-dihydro-2H-1,4-benzoxazine-7-carbaldehyde

7-bromo-6-methoxy-3,4-dihydro-2H-1,4-benzoxazine (15D) (1.6g, 6.6mmol) was dissolved in tetrahydrofuran (30mL), under nitrogen protection,- 2M tetrahydrofuran solution of isopropylmagnesium chloride (3.6 mL, 7.2 mmol) was added at 10°C, and the temperature was raised to 0°C for 1 hour. Add 2.5M n-butyl lithium in n-hexane solution (13 mL, 33 mmol) at -25°C and react at -10°C for 30 minutes. N,N-Dimethylformamide (4.8 g, 66 mmol) was added at -10°C, and the reaction was gradually raised to room temperature for 0.5 hours. Take 5g of citric acid (5.0g) and add water (50mL), pour the reaction solution into it, add ethyl acetate (50mL) for extraction, extract the aqueous phase with ethyl acetate (50mL×1), combine the organic phases, and use Dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and separate and purify the residue by silica gel column chromatography (ethyl acetate:petroleum ether (v/v)=0:1～1:4), the title compound 6-methoxy-3,4-dihydro-2H-1,4-benzoxazine-7 - Formaldehyde (15E), yellow solid (0.420 g, 35% yield).

¹ H NMR (400MHz, CDCl3) δ10.13(s,1H),7.25(s,1H),6.06(s,1H),4.20-4.12(m,2H),3.80(s,3H),3.55–3.37 (m,2H).

LCMS m/z = 194.1 [M+1].

The fifth step: 6-methoxy-4-prop-2-enoyl-3,4-dihydro-2H-1,4-benzoxazine-7-carbaldehyde (15F)

6-methoxy-4-prop-2-enoyl-2,3-dihydro-1,4-benzoxazine-7-carbaldehyde

Dissolve 6-methoxy-3,4-dihydro-2H-1,4-benzoxazine-7-carbaldehyde (15E) (0.42 g, 2.2 mmol) in ethyl acetate (30 mL), add tris Ethylamine (1.6g, 16mmol), nitrogen protection. Acrylic acid (0.39, 5.4 mmol) was added dropwise. After rising to 40°C, 1-propylphosphoric anhydride (1.7, 5.4mmol) was added dropwise, and reacted at 80°C for 4 hours. Ethyl acetate (20 mL) and water (20 mL) were added to the reaction solution for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 6-methoxy-4-prop-2-enoyl-3,4-dihydro-2H-1,4-benzoxa Oxazine-7-carbaldehyde (15F), yellow solid (0.54 g, 100% yield).

¹ H NMR (400MHz, CDCl3) δ10.34(s,1H),7.39(s,1H),7.08(s,1H),6.74(dd,1H),6.52(dd,1H),5.88(dd,1H ), 4.35–4.21(m,2H), 4.04–3.93(m,2H), 3.85(s,3H).

LCMS m/z = 248.1 [M+1].

The sixth step: [1-[3-(7-formyl-6-methoxy-2,3-dihydro-1,4-benzoxazin-4-yl)-3-oxo-propyl ]4-piperidinyl]N-(2-phenylphenyl)carbamate (15G)

[1-[3-(7-formyl-6-methoxy-2,3-dihydro-1,4-benzoxazin-4-yl)-3-oxo-propyl]-4-piperidyl]N-(2-phenylphenyl) carbamate

6-Methoxy-4-prop-2-enoyl-3,4-dihydro-2H-1,4-benzoxazine-7-carbaldehyde (15F) (0.540 g, 2.18 mmol) was dissolved in 2 -Methyltetrahydrofuran (10mL), add piperidin-4-yl[1,1'-biphenyl]-2-ylcarbamate (1A) (0.647g, 2.18mmol), add triethylamine (0.442 g, 4.37mmol), microwave reaction at 100°C for 1 hour. The reaction solution was concentrated, and the residue was separated and purified by silica gel column chromatography (ethyl acetate:petroleum ether (v/v)=1:1～1:0, methanol:dichloromethane (v/v)=3:97) to obtain The title compound [1-[3-(7-formyl-6-methoxy-2,3-dihydro-1,4-benzoxazin-4-yl)-3-oxo-propyl]4 -piperidinyl]N-(2-phenyl Phenyl)carbamate (15G), yellow solid (0.570g, 48% yield).

¹ H NMR (400MHz, CDCl ₃ )δ10.34(s,1H),8.08(d,1H),7.52–7.33(m,8H),7.22(dd,1H),7.16-7.10(m,1H), 6.59(s,1H),4.76(s,1H),4.31–4.21(m,2H),3.91(dd,2H),3.88(s,3H),2.87(s,4H),2.74(s,2H) ,2.40(s,2H),1.97(s,2H),1.73(s,2H).

LCMS m/z = 544.3 [M+1].

The seventh step: [1-[3-[7-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxyl-2-oxo-1H -quinolin-5-yl)ethyl]amino]methyl]-6-methoxy-2,3-dihydro-1,4-benzoxazin-4-yl]-3-oxo-propane Base]-4-piperidinyl]N-(2-phenylphenyl)carbamate (15H)

[1-[3-[7-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl] amino]methyl]-6-methoxy-2,3-dihydro-1,4-benzoxazin-4-yl]-3-oxo-propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate

[1-[3-(7-Formyl-6-methoxy-2,3-dihydro-1,4-benzoxazin-4-yl)-3-oxo-propyl]4- Piperidinyl]N-(2-phenylphenyl)carbamate (15G) (0.300g, 0.552mmol) was dissolved in methanol (10mL), and (R)-5-(2-amino-1- ((tert-butyldimethylsilyl)oxy)ethyl)-8-hydroxyquinolin-2(1H)-one (1D) (0.222g, 0.662mmol), adding anhydrous zinc chloride (0.301g, 2.21 mmol), react at 55°C for 1 hour. Add sodium cyanoborohydride (0.104 g, 1.66 mmol) and react at 55°C for 2 hours. Dichloromethane (30 mL) and saturated aqueous sodium bicarbonate (20 mL) were added to the reaction solution for extraction. The aqueous phase was extracted with dichloromethane (30mL×1), the organic phases were combined, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound [1-[3-[7-[[[(2R )-2-[tert-butyl(dimethyl)silyl]oxyl-2-(8-hydroxyl-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-6 -Methoxy-2,3-dihydro-1,4-benzoxazin-4-yl]-3-oxo-propyl]-4-piperidinyl]N-(2-phenylphenyl ) carbamate (15H), yellow solid (0.450 g, 94.6% yield).

LCMS m/z = 431.8 [M/2+1].

The eighth step: [1-[3-[7-[[[(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1H-quinolin-5-yl)ethyl]amino] Methyl]-6-methoxy-2,3-dihydro-1,4-benzoxazin-4-yl]-3-oxo-propyl]-4-piperidinyl]N-(2 -Phenylphenyl)carbamate ditrifluoroacetate (Compound 15)

[1-[3-[7-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-6-methoxy- 2,3-dihydro-1,4-benzoxazin-4-yl]-3-oxo-propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate2,2,2-trifluoroacetic acid

[1-[3-[7-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxyl-2-oxo-1H-quinoline -5-yl)ethyl]amino]methyl]-6-methoxy-2,3-dihydro-1,4-benzoxazin-4-yl]-3-oxo-propyl]- 4-piperidinyl]N-(2-phenylphenyl)carbamate (15H) (0.450g, 0.522mmol) was dissolved in tetrahydrofuran (5mL), and triethylamine trihydrofluoride (0.841g , 5.22mmol), react at room temperature for 24 hours. Add methanol/dichloromethane (v/v=1/10, 50mL) solution to the reaction solution, add saturated sodium bicarbonate solution to adjust the pH to about 8, and extract. The aqueous phase was extracted with methanol/dichloromethane (v/v=1/10, 20mL×2), the organic phases were combined, washed with saturated brine (20mL×1), dried over anhydrous sodium sulfate, filtered, and the filtrate was Concentrate under pressure. Residue liquid phase preparative column separation and purification (liquid phase preparation conditions: C18 reverse phase preparative column, mobile phase is deionized water (A) containing 0.05% TFA, acetonitrile (B), isocratic elution B:A=25% , elution time 20 minutes), the title compound [1-[3-[7-[[[(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1H-quinoline-5- Base) ethyl] amino] methyl] -6-methoxy-2,3-dihydro-1,4-benzoxazin-4-yl]-3-oxo-propyl]-4-piper Pyridyl]N-(2-phenylphenyl)carbamate ditrifluoroacetate (compound 15), white solid (0.120 g, yield 23.6%).

¹ H NMR (400MHz, CD ₃ OD) δ8.07(s,2H),7.55(s,1H),7.48–7.22(m,9H),7.03(d,1H),6.88(s,1H),6.58 (d,1H),5.40(dd,1H),4.91(s,1H),4.34–4.09(m,4H),3.91(s,2H),3.77(s,3H),3.72-3.45(m4H) ,3.28–3.04(m,6H),2.25-1.70(m,4H).

¹⁹ F NMR (376MHz, CD ₃ OD) δ-75.44.

LCMS m/z = 374.8 [M/2+1].

Example 16: [1-[3-[5-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino] Methyl]-6-methoxyindolin-1-yl]-3-oxo-propyl]-4-methyl-4-piperidinyl]N-(2-phenylphenyl)amino Formate (compound 16)

[1-[3-[5-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-6-methoxy- indolin-1-yl]-3-oxo-propyl]-4-methyl-4-piperidyl]N-(2-phenylphenyl)carbamate

The first step: tert-butyl 4-hydroxy-4-methyl-piperidine-1-carboxylate (16B)

tert-butyl 4-hydroxy-4-methyl-piperidine-1-carboxylate

Dissolve N-tert-butoxycarbonyl-4-piperidone (16A) (4g, 20mmol) in anhydrous tetrahydrofuran (20mL), cool to 0°C, add dropwise 1.0M tetrahydrofuran solution of methylmagnesium bromide (40mL ), raised to room temperature and reacted for 2 hours, cooled to 0°C, then slowly added saturated ammonium chloride solution, added ethyl acetate (200mL) and water (200mL), extracted, and the organic phase was extracted with saturated sodium chloride solution (200mL ×1) washed, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 4-hydroxyl-4-methyl-piperidine-1 carboxylic acid tert-butyl ester (16B), light oil (4.0g, yield rate of 92.5%).

¹ H NMR (400 MHz, CDCl ₃ ) 3.87 (t, 2H), 3.71 (dd, 2H), 3.21 (m, 4H), 1.53 (m, 3H), 1.49 (s, 9H).

LCMS m/z = 238.1 [M+23].

The second step: tert-butyl 4-methyl-4-[(2-phenylphenyl)carbamoyloxy]piperidine-1-carboxylate (16C)

tert-butyl 4-methyl-4-[(2-phenylphenyl)carbamoyloxy]piperidine-1-carboxylate

Dissolve o-aniline (3.4g, 20mmol) and triphosgene (3.0g, 10mmol) in anhydrous toluene (50mL), heat up to 110°C for 3 hours, concentrate, then add tetrahydrofuran (50mL), and 4-hydroxy - tert-butyl 4-methyl-piperidine-1-carboxylate (16B) (3.5g, 16mmol) and triethylamine (4.0g, 40mmol), heated to reflux for 3 hours. The reaction solution was cooled to room temperature, ethyl acetate (100 mL) and sodium chloride solution (120 mL) were added, the layers were extracted, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 4-methyl- tert-butyl 4-[(2-phenylphenyl)carbamoyloxy]piperidine-1-carboxylate (16C), yellow oil (6.6 g, yield 100%).

LCMS m/z = 433.3 [M+23].

The third step: (4-methyl-4-piperidine) N-(2-phenylphenyl) carbamate (16D)

(4-methyl-4-piperidyl)N-(2-phenylphenyl)carbamate

tert-butyl 4-methyl-4-[(2-phenylphenyl)carbamoyloxy]piperidine-1-carboxylate (16C) (6.6 g, 16 mmol) was dissolved in dichloromethane (40 mL) In, add trifluoroacetic acid (18g, 160mmol), react at room temperature for 5 hours, cool at 0°C, and use saturated carbon Sodium bicarbonate solution to adjust the pH to greater than 7, add dichloromethane (50mL) and water (50mL), extract and separate layers, wash the organic phase with saturated sodium chloride solution (50mL×1), dry over anhydrous sodium sulfate, filter, and the filtrate Concentrate under reduced pressure, and the residue is separated and purified by silica gel column chromatography (methanol/dichloromethane (v/v)=0:1～1:9) to obtain the title compound (4-methyl-4-piperidine)N-( 2-Phenylphenyl)carbamate (16D), yellow oil (0.77g, 15% yield).

¹ H NMR (400MHz, CDCl ₃ )7.97(s,1H),7.51(dd,2H),7.42(m,1H),7.36(m,3H),7.24(m,1H),7.16(td,1H) , 6.59(s,1H), 3.20(d,2H), 3.02(m,2H), 2.45(d,2H), 1.88(td,2H), 1.56(m,3H).

LCMS m/z = 311.2 [M+1].

The fourth step: [1-[3-(5-formyl-6-methoxyindolin-1-yl)-3-oxo-propyl]-4-methyl-4-piperidinyl ]N-(2-phenylphenyl) carbamate (16E)

[1-[3-(5-formyl-6-methoxy-indolin-1-yl)-3-oxo-propyl]-4-methyl-4-piperidyl]N-(2-phenylphenyl)carbamate

(4-Methyl-4-piperidine)N-(2-phenylphenyl)carbamate (16D) (0.77g, 2.5mmol) and 6-methoxy-1-propene-2-yl -Indoline-5-carbaldehyde (Intermediate 1) (0.57g, 2.5mmol) was dissolved in 2-methyltetrahydrofuran (20mL), added triethylamine (0.50g, 5.0mmol), placed in a microwave reactor , heated to 100°C for 1 hour. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol/dichloromethane (v/v)=0:1～1:9) to obtain the title compound [1-[3-(5 -Formyl-6-methoxyindolin-1-yl)-3-oxo-propyl]-4-methyl-4-piperidinyl]N-(2-phenylphenyl)amino Formate (16E), pale yellow solid (0.77 g, 57% yield).

¹ H NMR (400MHz, CDCl ₃ )δ10.32(s,1H),8.00(m,2H),7.65(s,1H),7.51(t,2H),7.39(m,4H),7.23(d, 1H),7.16(t,1H),6.54(s,1H),4.13(t,2H),3.92(s,3H),3.16(t,2H),2.87(s,6H),2.44(d,4H ), 1.85(s,2H), 1.57(s,3H).

LCMS m/z = 542.2 [M+1].

The fifth step: [1-[3-[5-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxyl-2-oxo- 1H-quinolin-5-yl)ethyl]amino]methyl]-6-methoxyindolin-1-yl]-3-oxo-propyl]-4-methyl-4-piper Pyridyl]N-(2-phenylphenyl) carbamate (16F)

[1-[3-[5-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl] amino]methyl]-6-methoxy-indolin-1-yl]-3-oxo-propyl]-4-methyl-4-piperidyl]N-(2-phenylphenyl)carbamate

[1-[3-(5-formyl-6-methoxyindolin-1-yl)-3-oxo-propyl]-4-methyl-4-piperidinyl]N- (2-Phenylphenyl)carbamate (16E) (0.25g, 0.46mmol) and (R)-5-(2-amino-1-((tert-butyldimethylsilyl)oxy)ethyl Base)-8-hydroxyquinolin-2(1H)-one (1D) (0.10g, 0.30mmol) was dissolved in methanol/dichloromethane (v/v=1:1, 10mL) solution, and reacted at room temperature for 1 hour After that, sodium triacetoxyborohydride (0.2 g, 0.9 mmol) was added, and the reaction was continued for 2 hours. Dichloromethane (50mL) and water (50mL) were added to the reaction solution, the layers were extracted, the organic phase was washed with saturated sodium chloride solution (50mL×1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue Separation and purification by silica gel column chromatography (methanol/dichloromethane (v/v)=0:1～1:9) to obtain the title compound [1-[3-[5-[[[(2R)-2-[tert Butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-6-methoxydi Indolin-1-yl]-3-oxo-propyl]-4-methyl-4-piperidinyl]N-(2-phenylphenyl)carbamate (16F), pale yellow solid ( 0.11 g, 40% yield).

LCMS m/z = 430.8 [M/2+1].

The sixth step: [1-[3-[5-[[[(2R)-2-hydroxyl-2-(8-hydroxyl-2-oxo-1H-quinolin-5-yl)ethyl]amino] Methyl]-6-methoxyindolin-1-yl]-3-oxo-propyl]-4-methyl-4-piperidinyl]N-(2-phenylphenyl)amino Formate (compound 16)

[1-[3-[5-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-6-methoxy- indolin-1-yl]-3-oxo-propyl]-4-methyl-4-piperidyl]N-(2-phenylphenyl)carbamate

[1-[3-[5-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxyl-2-oxo-1H-quinone Lin-5-yl)ethyl]amino]methyl]-6-methoxyindolin-1-yl]-3-oxo-propyl]-4-methyl-4-piperidinyl] N-(2-Phenylphenyl) carbamate (16F) (0.11g, 0.13mmol) was dissolved in tetrahydrofuran (5mL), triethylamine trihydrofluoride (0.10g, 0.65mmol) was added, room temperature React overnight. The reaction solution was filtered, and the filter cake was dissolved with 8% (v/v) methanol/dichloromethane solution (50mL), then added with saturated aqueous sodium bicarbonate solution to adjust the pH to alkaline, extracted and separated, and the organic phase was washed with saturated sodium chloride solution (50mL×1), washed with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound [1-[3-[5-[[[(2R)-2-hydroxyl-2-(8-hydroxyl- 2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-6-methoxyindolin-1-yl]-3-oxo-propyl]-4-methyl yl-4-piperidinyl]N-(2-phenylphenyl)carbamate (compound 16), pale yellow solid (0.04 g, yield 40%).

¹ H NMR (400MHz,DMSO-d6)δ7.26(d,1H),6.93(s,1H),6.47(m,10H),6.27(d,1H),6.10(m,2H),5.64(d ,1H),4.32(t,1H),3.26(t,2H),3.01(d,2H),2.85(s,3H),2.21(t,2H),2.09(d,2H),1.98(t, 2H), 1.86(m, 4H), 1.53(d, 2H), 1.30(m, 2H), 0.77(t, 2H), 0.55(d, 3H).

LCMS m/z = 373.7 [M/2+1].

biological test case

Test Example 1: Inhibitory Activity on Human Muscarinic M3 Receptor

CHO cells (PerkinElmer) stably expressing human muscarinic receptor 3 (hM3) and apo-Aequorin were cultured in 10% fetal bovine serum (FBS) (Gibico 10099-141), 400 μg/mL G418 (sigma G5013) and 250 μg /mL Zeocin (invivogen ant-zn-5p) in Ham'S F12 medium (Invitrogen 12500-062) was cultured at 37°C and 5% CO ₂ to reach 90-100% confluence. Wash and separate the cells with PBS/5mM EDTA, collect by centrifugation, resuspend the cells in phenol red-free Ham's F12 medium (Invitrogen 11039-021) containing 0.1% BSA (BOVOGEN BSAS 100) and count them, and adjust the cell concentration to 1x10 ⁶ cells/mL . Add 15ml of cell suspension to a 50mL centrifuge tube, and add Coelenterazine-h (promega S2011) to a final concentration of 5μM. Wrap it in tin foil to avoid light, and incubate at 20°C for 4 hours on a rotary shaker. Then dilute the cells with 0.1% BSA/phenol red-free Ham's F12 medium to a final concentration of 5.0×10 ⁵ cells/mL, place the cells on a rotary shaker at low speed, and incubate at room temperature for at least 1 hour. The inhibitor of the embodiment is prepared as 10mM stock solution with DMSO, 0.1%BSA/phenol red-free Ham's F12 medium gradient dilution (log(M):-7,-8,-9,-10,-11), added to 96 wells plate, 50 μL per well. Add 50 μL of cell suspension (25000 cells/well) to each well and incubate at room temperature for 15 minutes. Put the 96-well plate into a microplate reader (Perkin Elmer, Envision), add acetylcholine chloride (Sigma A6625) solution with a sampler of the microplate reader, and its concentration is 112.92nM (hM3), record luminescence for 20 seconds, use origin7. 5 Calculation and analysis of IC ₅₀ . The inhibitory activity of the compounds of the present invention on human muscarinic receptors was determined by the above experiments, and the measured IC ₅₀ values are shown in Table 1 below.

Table 1 test compound to the inhibitory activity result of human muscarinic M3 receptor

Conclusion: the compound of the present invention has significant inhibitory activity on human muscarinic M3 receptor.

Test Example 2: Agonist activity on human adrenergic β2 receptor

The agonistic activity of the compounds of the examples on human adrenergic receptors was determined by LANCE Ultra cAMP Assay.

CHO cells (PerkinElmer) stably expressing human adrenergic receptor (hβ2) were cultured in MEM- alpha medium (Invitrogen 12561-056), cultured at 37°C, 5% CO ₂ , and after reaching 90-100% fusion, use the LANCE Ultra cAMP Assay kit (PerkinElmer TRF0263) to detect the agonistic effect of the examples on cAMP. The cells were separated with PBS/5mM EDTA, collected by centrifugation, and resuspended with Stimulation Buffer (1x HBSS, 5mM HEPES, 0.5mM IBMX, 0.1% BSA, pH7.4) to adjust the cell concentration to 6x10 ⁵ cells/ml. The inhibitor of the example was prepared as a 10 mM stock solution with DMSO, diluted with Stimulation Buffer and added to a 384-well plate at 5 μl per well. Add 5 μL cell suspension (3000 cells/well) to each well, incubate at room temperature for 30 minutes, add 5 μl 4x Eu-cAMP tracer working solution to each well, then add 5 μl 4x Ulight-anti-cAMP working solution to each well, and incubate at room temperature Incubate for 1 hour. TR-FRET was detected with a microplate reader (Perkin Elmer, Envision) in a 384-well plate, and EC ₅₀ was calculated and analyzed using origin7.5. The agonistic activity of the compounds of the present invention on human adrenergic receptors is determined by the above experiments, and the measured _EC50 values are shown in Table 2:

Table 2 test compound agonistic activity results to human adrenergic β2 receptor

Conclusion: the compounds of the present invention have significant agonistic activity on β2 adrenergic receptors.

Claims (15)

1. A compound shown in a general formula (I) or a stereoisomer, a hydrate, a metabolite, a solvate, a pharmaceutically acceptable salt, a eutectic crystal or a prodrug thereof,

   

   wherein:

   a is selected from 0, 1,2,3,4 or 5;

   b is selected from 0, 1,2,3 or 4;

   R¹each independently selected from F, Cl, Br, I, CF₃、C_1-4Alkyl, cyano, -OR^1a、-C(O)OR^1b、-SR^1c、-S(O)R^1d、-S(O)₂R^1eor-NR^1fR^1g；

   R²Each independently selected from F, Cl, Br, I, CF₃、C_1-4Alkyl, cyano, -OR^1a、-C(O)OR^1b、-SR^1c、-S(O)R^1d、-S(O)₂R^1eor-NR^1fR^1g；

   R^1a、R^1b、R^1c、R^1d、R^1e、R^1fAnd R^1gEach independently selected from H or C_1-4An alkyl group;

   alternatively, R^1f、R^1gA 5-to 6-membered heterocyclic ring formed with the nitrogen atom to which it is attached, said heterocyclic ring containing 1 to 3 heteroatoms selected from N, O or S;

   w is-O-or-N (W)^a)-；

   W^aIs selected from H or C_1-4An alkyl group;

   c is selected from 0, 1,2,3 or 4;

   R³each independently selected from F, Cl, Br, I, CF₃OH, cyano, C_1-4Alkyl or C_1-4An alkoxy group;

   R⁴is selected from C_1-6Alkylene radical, C_2-6Alkenylene or C_2-6Alkynylene, said alkylene, alkenylene or alkynylene being optionally further substituted by 0 to 5 substituents selected from F, Cl, Br, I, OH, cyano, C_1-4Alkyl radical, C_1-4Alkoxy, phenyl or phenyl-C_1-4Substituted by a substituent of alkylene;

   x is selected from-C (O) -or-OC (O) -;

   d is selected from 0, 1,2 or 3;

   R⁵selected from F, Cl, Br, I, OH, NH₂Carboxy, cyano, nitro, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4Alkoxy, -OC_3-6Cycloalkyl radical, C_1-4Alkylthio, -S (O) -C_1-4Alkyl, -S (O)₂-C_1-4Alkyl, -C (O) -C_1-4Alkyl, -C (O) O-C_1-4Alkyl, -OC (O) -C_1-4Alkyl or-C (O) NH₂The alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl, NH₂and-C (O) NH₂Optionally further substituted by 0 to 4 substituents selected from F, Cl, Br, I, CF₃、C_1-4Alkyl radical, C_1-4Alkoxy or-C (O) -C_1-4Alkyl is substituted by a substituent;

   y is selected from-CY^aY^b-、-NY^a-, -O-, -S-, -S (O) -or-S (O)₂-；

   Y^a、Y^bEach independently selected from H or C_1-4An alkyl group; or Y^a、Y^bTogether with the carbon atom to which they are attached form a 3-to 6-membered carbocyclic ring;

   n is 0, 1 or 2;

   e is selected from 0, 1,2,3 or 4;

   R⁶selected from F, Cl, Br, I, C ═ O, cyano and C_1-4Alkyl or C_1-4Alkoxy, said alkyl or alkoxy being optionally further substituted by 0 to 4 substituents selected from F, Cl, Br, I, CH₂F、CHF₂、CF₃Or a cyano group;

   alternatively, two R⁶May form, together with the atoms to which they are attached, a 3 to 6 membered carbocyclic ring optionally further substituted by 0 to 5 substituents selected from F, Cl, Br, I, cyano, OH, C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

   R⁷is selected from C_1-6Alkylene optionally further substituted with 0 to 5 substituents selected from R^7aSubstituted with the substituent(s);

   R^7aselected from F, Cl, Br, I, cyano, OH, C_1-4Alkyl radical, C_1-4Alkoxy, phenyl or phenyl-C_1-4An alkylene group;

   alternatively, two R^7aMay form, together with the atoms to which they are attached, a 3 to 6 membered carbocyclic ring optionally further substituted by 0 to 5 substituents selected from F, Cl, Br, I, cyano, OH, C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

   R⁸、R⁹each independently selected from H or C_1-4An alkyl group;

   

   represents a group capable of binding to a beta-adrenergic receptor.
2. The compound of claim 1, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal, or prodrug thereof, wherein:

   b is selected from

   

   

   Wherein Q is selected from-CH ═ CH-, -CH₂CH₂-, -O-, -S-or-CH₂O-。
3. The compound of claim 2, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal, or prodrug thereof, wherein:

   a is selected from 0, 1 or 2;

   b is selected from 0, 1 or 2;

   R¹each independently selected from F, Cl, Br, I, CF₃Cyano, hydroxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio or ethylthio;

   R²each independently selected from preferably F, Cl, Br, I, CF₃Cyano, hydroxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio or ethylthio;

   c is selected from 0, 1 or 2;

   R³each independently selected from F, Cl, Br, I, CF₃OH, cyano, methyl, ethyl, methoxy or ethoxy,

   R⁴is selected from C_1-6Alkylene optionally further substituted by 0 to 5 groups selected from F, Cl, Br, I, OH, cyano, C_1-4Alkyl radical, C_1-4Alkoxy, phenyl or phenyl-C_1-4Substituted by a substituent of alkylene;

   R⁵selected from F, Cl, Br, I, OH, NH₂Carboxy, cyano, nitro, C_1-4Alkyl radical, C_2-4Alkynyl, C_1-4Alkoxy, -OC_3-6Cycloalkyl radical, C_1-4Alkylthio, -S (O) -C_1-4Alkyl, -S: (O)₂-C_1-4Alkyl, -C (O) -C_1-4Alkyl or-C (O) O-C_1-4Alkyl, said alkyl, alkoxy, cycloalkyl and NH₂Optionally further substituted by 0 to 4 substituents selected from F, Cl, Br, I, CF₃、C_1-4Alkyl radical, C_1-4Alkoxy or-C (O) -C_1-4Alkyl, alkoxy, cycloalkyl, alkynyl and NH₂Optionally further substituted by 0 to 4 substituents selected from F, Cl, Br, I, CF₃、C_1-4Alkyl radical, C_1-4Alkoxy or-C (O) -C_1-4Alkyl is substituted by a substituent;

   R⁷is selected from C_1-4Alkylene optionally further substituted with 0 to 5 substituents selected from R^7aSubstituted with the substituent(s);

   R^7aselected from F, Cl, Br, I, cyano, OH, C_1-4Alkyl radical, C_1-4Alkoxy or phenyl;

   alternatively, two R^7aMay form, together with the atoms to which they are attached, a 3 to 6 membered carbocyclic ring optionally further substituted by 0 to 5 substituents selected from F, Cl, Br, I, cyano, OH, C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy.
4. The compound according to claim 3, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof,

   b is selected from

   

   

   W is-O-or-N (W)^a)-；

   W^aSelected from H, methyl or ethyl;

   R⁴selected from methylene, ethylene, propylene or butylene, said methylene, ethylene, propylene or butyleneOptionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, cyano, OH, methyl, ethyl, methoxy or ethoxy;

   R⁵selected from F, Cl, Br, CH₂F、CHF₂、NH₂Cyano, nitro, OCH₂F、OCHF₂、OCF₃Methyl, ethyl, isopropyl, methoxy, ethoxy, methylthio, cyclopropyloxy, ethynyl, propynyl, -S (O)₂CH₃、-C(O)CH₃、-C(O)OCH₃or-C (O) OCH₂CH₃；

   Y is selected from-CY^aY^b-、-NY^a-, -O-, -S-, -S (O) -or-S (O)₂-；

   Y^a、Y^bEach independently selected from H, methyl or ethyl; or Y^a、Y^bMay each independently form a 3-to 6-membered carbocyclic ring with the carbon atom to which it is attached;

   e is 0, 1 or 2;

   R⁶selected from F, Cl, Br, C ═ O, cyano, methyl, ethyl, methoxy or ethoxy;

   R⁷selected from methylene, ethylene, propylene, butylene or

   

   The methylene, ethylene, propylene, butylene or

   

   Optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, cyano, OH, methyl, ethyl, methoxy or ethoxy;

   R⁸、R⁹each independently selected from H, methyl or ethyl.
5. The compound according to claim 2, wherein the compound is a compound selected from the group consisting of compounds represented by the general formula (II):

   

   w is-O-or-N (W)^a)-；

   W^aIs selected from H or C_1-4An alkyl group;

   R⁴is selected from C_1-4Alkylene optionally further substituted by 0 to 5 groups selected from F, Cl, Br, I, OH, cyano, C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

   x is selected from-C (O) -or-OC (O) -;

   R⁵selected from F, Cl, Br, I, OH, NH₂Carboxy, cyano, nitro, C_1-4Alkyl radical, C_1-4Alkoxy, -OC_3-6Cycloalkyl radical, C_1-4Alkylthio, -S (O) -C_1-4Alkyl, -S (O)₂-C_1-4Alkyl, -C (O) -C_1-4Alkyl or-C (O) O-C_1-4Alkyl, said alkyl, alkoxy, cycloalkyl and NH₂Optionally further substituted by 0 to 4 substituents selected from F, Cl, Br, I, CF₃、C_1-4Alkyl radical, C_1-4Alkoxy or-C (O) -C_1-4Alkyl is substituted by a substituent;

   y is selected from-CY^aY^b-、-NY^a-, -O-, -S-, -S (O) -or-S (O)₂-；

   Y^a、Y^bEach independently selected from H or C_1-4An alkyl group; or Y^a、Y^bTogether with the carbon atom to which they are attached form a 3-to 6-membered carbocyclic ring;

   R⁶selected from F, Cl, Br, C ═ O, cyano and C_1-4Alkyl or C_1-4An alkoxy group;

   alternatively, two R⁶May form, together with the atoms to which they are attached, a 3 to 6 membered carbocyclic ring optionally further substituted by 0 to 5 substituents selected from F, Cl, Br, I, cyano, OH, C_1-4Alkyl or C_1-4Substituted by substituents of alkoxy groups；

   R⁷Is selected from C_1-4Alkylene optionally further substituted with 0 to 5 substituents selected from R^7aSubstituted with the substituent(s);

   R^7aselected from F, Cl, Br, I, cyano, OH, C_1-4Alkyl radical, C_1-4Alkoxy or phenyl;

   alternatively, two R^7aMay form, together with the atoms to which they are attached, a 3 to 6 membered carbocyclic ring optionally further substituted by 0 to 5 substituents selected from F, Cl, Br, I, cyano, OH, C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

   R⁸、R⁹each independently selected from H or C_1-4An alkyl group;

   b is selected from

   

   Q is selected from-CH ═ CH-, -CH₂CH₂-, O, S or-CH₂O-。
6. The compound of claim 5, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal, or prodrug thereof, wherein:

   w is-O-or-N (W)^a)-；

   W^aSelected from H, methyl or ethyl;

   c is 0;

   R⁴selected from methylene, ethylene or propylene, said methylene, ethylene or propylene being optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, cyano, OH, methyl, ethyl, methoxy or ethoxy;

   x is selected from-C (O) -or-OC (O) -;

   R⁵selected from F, Cl, Br, methyl, ethyl, methoxy or ethoxy;

   y is selected from-CY^aY^b-、-NY^a-, -O-, -S-, -S (O) -or-S (O)₂-；

   Y^a、Y^bEach independently selected from H, methyl or ethyl; or Y^a、Y^bMay each independently form a 3-to 6-membered carbocyclic ring with the carbon atom to which it is attached;

   e is 0, 1 or 2;

   R⁶selected from F, Cl, Br, C ═ O, cyano, methyl, ethyl, methoxy or ethoxy;

   R⁷selected from methylene, ethylene, propylene or

   

   The methylene, ethylene, propylene or

   

   Optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, cyano, OH, methyl, ethyl, methoxy or ethoxy;

   R⁸、R⁹each independently selected from H, methyl or ethyl;

   b is selected from

   
7. A compound according to any one of claims 1 to 6, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein the compound is selected from one of the following structures:

   

   
8. a compound according to claims 1-7, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein the salt is selected from the group consisting of hydrochloride, hydrobromide, sulfate, phosphate, acetate, trifluoroacetate, maleate, hydroxymaleate, glutarate, fumarate, tartrate, succinate, benzenesulfonate, p-toluenesulfonate, benzoate, salicylate, phenylacetate, cinnamate, lactate, malonate, pivalate, malate, mandelate, oxalate, gallate, gluconate, laurate, palmitate, pectate, picrate, citrate, methanesulphonic acid, hexanesulphonate, saccharine or a combination thereof.
9. A compound according to claims 1 to 7, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein the salt is selected from the group consisting of hydrochloride, sulfate, trifluoroacetate, fumarate, tartrate, succinate, oxalate, methanesulphonic acid, saccharin or a combination thereof.
10. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1-9, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, and a pharmaceutically acceptable carrier, diluent, adjuvant, vehicle or excipient; the composition may further comprise one or more additional therapeutic agents.
11. The pharmaceutical composition of claim 10, wherein the additional therapeutic agent is selected from one or more of a PDE4 inhibitor, a muscarinic receptor antagonist, a corticosteroid, and a β -adrenergic receptor agonist.
12. Use of a compound according to any one of claims 1 to 9, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, in the manufacture of a medicament for the treatment of an obstructive airways disease.
13. Use of a compound according to any one of claims 1 to 9, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, in the manufacture of a medicament for use in the treatment of asthma, chronic obstructive pulmonary disease or bronchitis.
14. A method of treating an obstructive airways disease which comprises administering a compound as claimed in any one of claims 1 to 9 or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, or a pharmaceutical composition as claimed in claim 10 or claim 11.
15. A method of treating asthma, chronic obstructive pulmonary disease or bronchitis, which comprises administering a compound according to any one of claims 1 to 9, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, or a pharmaceutical composition according to claim 10 or 11.