CN107074816A

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

Info

Publication number: CN107074816A
Application number: CN201680003424.0A
Authority: CN
Inventors: 魏用刚; 邱关鹏; 郑苏欣; 雷柏林; 王松; 叶飞; 刘建余
Original assignee: Sichuan Haisco Pharmaceutical Co Ltd
Current assignee: Sichuan Haisco Pharmaceutical Co Ltd
Priority date: 2015-03-27
Filing date: 2016-03-25
Publication date: 2017-08-18
Anticipated expiration: 2036-03-25
Also published as: WO2016155573A1; CN107074816B

Abstract

Compound or its stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug shown in a kind of logical formula (I), and preparation method and the application in being used to treat airway obstructive disease medicine being prepared, its formula of (I) compound is

Description

Heterocyclic derivative, preparation method and medical application thereof

Technical Field

The invention relates to a heterocyclic derivative, a preparation method and application thereof in medicine, in particular to a compound with the function of inhibiting tumor cell proliferationMuscarinic receptor antagonism and/or beta₂-new heterocyclic derivatives with adrenergic receptor agonistic activity or stereoisomers, hydrates, solvates, metabolites, pharmaceutically acceptable salts, co-crystals or prodrugs thereof, pharmaceutical compositions thereof and their use in medicine.

Background

Bronchodilators play an important role in the treatment of respiratory diseases such as Chronic Obstructive Pulmonary Disease (COPD), asthma and the like. Bronchodilators widely used in the clinic include muscarinic receptor antagonists and beta₂-adrenergic agonists.

Muscarinic receptor antagonists exert their effect on bronchodilation by lowering vagal cholinergic levels of airway smooth muscle. Currently used inhaled muscarinic receptor antagonists 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, and require multiple administrations per day, which brings inconvenience to patients and may cause poor compliance due to frequent administrations, thereby risking inadequate treatment. Addisomidine administered twice daily may cause severe adverse effects including paradoxical bronchospasm, new narrow angle glaucoma or exacerbation, new urinary retention or exacerbation, and is not suitable for patients under 18 years of age. Even when administered by inhalation, some muscarinic receptor antagonists enter the circulatory system, resulting in systemic side effects such as dry mouth, gastrointestinal symptoms, urinary retention, urinary tract infection, and the like. Such as glycopyrrolate and tiotropium bromide.

Therefore, there is a need to develop novel muscarinic receptor antagonistic active drugs, particularly novel muscarinic receptor antagonistic active drugs which are administered by inhalation and have high potency, long action time and reduced systemic side effects. Provides more clinical medication options for patients.

β₂Adrenergic agonists reverse bronchoconstrictor responses to various mediators, such as acetylcholine, by stimulating adrenergic receptors on airway smooth muscle. Beta is currently used₂-adrenergic agonists including salbutamolSalmeterol, arformoterol, formoterol, vilanterol and indacaterol. These drugs, in addition to improving lung function, may also improve the quality of life and reduce the exacerbation of the disease. With the discovery of more clinical studies, the combined use of muscarinic receptor antagonists and beta was demonstrated₂Adrenergic agonists are more effective than either therapeutic agent alone, and muscarinic receptor antagonists and β are now clinically used₂Adrenergic agonists are prepared into compound preparations for treating asthma and severe COPD, and the compound preparations mainly comprise Anoro Ellipta (umeclidinium bromide/vilanterol), Ultibro Breezhaler (glycopyrronium bromide/indacaterol), ipratropium bromide/salbutamol and the like. The compound preparation has better treatment effect than the single preparation, but has higher requirements on preparation.

Therefore, it is also desired to develop a compound having muscarinic receptor antagonism and beta₂-an adrenergic agonist dual action drug having the pharmaceutical advantages of both component combinations while possessing a single molecular pharmacokinetics. These compounds are administered as a single therapeutic agent and provide bronchodilatory action from two distinct and possibly synergistic modes of action. In addition, have muscarinic receptor antagonism and beta₂Adrenergic agonist dual action (MABA) compounds may also be combined with corticosteroid (ICS) anti-inflammatory agents drugs to form two therapeutic agents (MABA/ICS) to provide triple action therapeutic effects (Expert opin investig. drugs (2014)23(4): 453-.

Therefore, there is a need to develop novel compounds having muscarinic receptor antagonism and/or β₂-an adrenergic agonist active agent to provide a more effective monotherapeutic dose or combination formulation, providing more clinical medication options for the patient.

Disclosure of Invention

The invention provides 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 3-, 4-, 5-or 6-membered 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, 1,2,3,4 or 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;

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

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

R⁵is selected 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, 1,2,3 or 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-, 4-, 5-or 6-membered carbocyclic ring;

n is 0, 1 or 2;

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

R⁶each independently selected from F, Cl, Br, I, C ═ O, cyano, C_1-4Alkyl or C_1-4Alkoxy, said alkyl or alkoxy being optionally further substituted by 0, 1,2,3 or 4 groups 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-, 4-, 5-or 6-membered carbocyclic ring, optionally further substituted by 0, 1,2,3,4 or 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 by 0, 1,2,3,4 or 5 groups selected from R^7aSubstituted with the substituent(s);

R^7aselected from F, Cl, Br, I, cyano, OH, C_1-4Alkyl radical, C_1-4Alkoxy, phenylOr 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, 1,2,3,4 or 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 beta-adrenoceptor binding group.

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

represents a beta-adrenoceptor binding group;

b is preferably

R¹⁰、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、R¹⁶、R¹⁷Or R¹⁸Each independently selected from H, F, Cl, Br, I, CF₃、OH、-CH₂OH, cyano, carboxyl, C_1-4Alkyl radical, C_1-4Alkoxy, -C (O) C_1-4Alkyl, -C (O) OC_1-4Alkyl, -NHC (O) H, -NHS (O)₂-C_1-4Alkyl, -NHS (O)₂-NH₂or-NHS (O)₂-NHC_1-4Alkyl, Q is selected from-CR^q1＝CR^q2-、-CR^q1R^q2CR^q3R^q4-, -O-, -S-or-CR^q1R^q2O-, said R^q1、R^q2、R^q3Or R^q4Each independently selected from H, F, Cl, Br, I or C_1-4An alkyl group;

b is more preferably

Wherein Q is selected from-CH ═ CH-, -CH₂CH₂-, -O-, -S-or-CH₂O-；

B is further preferably

B is further preferably

Q is selected from-CH ═ CH-, -CH₂CH₂-, -O-, -S-or-CH₂O-；

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

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

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;

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, 1,2,3 or 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-；

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, 1,2,3 or 4 groups selected from F, Cl, Br, I, CH₂F、CHF₂、CF₃Or a cyano group;

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

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

b is selected from

b is preferably

Q is selected from-CH ═ CH-, -CH₂CH₂-, -O-, -S-or-CH₂O-；

B is further preferably

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;

R¹each independently selected from F, Cl, Br, I, CF₃Cyano, hydroxy, C_1-4Alkyl radical, C_1-4Alkoxy or C_1-4An alkylthio group; preferably F, Cl, Br, I, CF₃Cyano, hydroxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio or ethylthio; more preferably F, Cl, Br, hydroxy, methyl, ethyl, methoxy or ethoxy;

R²each independently selected from F, Cl, Br, I, CF₃Cyano, hydroxy, C_1-4Alkyl radical, C_1-4Alkoxy or C_1-4An alkylthio group; preferably F, Cl, Br, I, CF₃Cyano, hydroxy, 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^aIs selected from H or C_1-4An alkyl group; preferably H, methyl, ethyl or isopropyl;

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

R³each independently selected from F, Cl, Br, I, CF₃OH, cyano, C_1-4Alkyl or C_1-4An alkoxy group; preferably F, Cl, Br, I, CF₃OH, cyano, methyl, ethyl, methoxy or ethoxy; more preferably F, methyl or ethyl;

R⁴is selected from C_1-6Alkylene radical, C_2-6Alkenylene or C_2-6An alkynylene group; preferably C_1-6An alkylene group; more preferably methylene, ethylene, propylene or butylene, optionally further substituted by 0, 1,2,3,4 or 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;

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

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

R⁵each independently selected 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; r⁵Preferably 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；R⁵More preferably F, Cl, Br, cyano, methyl, ethyl, propyl, isopropyl, CHF₂、CF₃Methoxy, ethoxy, -OCHF₂、-OCF₃Cyclopropyloxy, ethynyl or propynyl;

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

Y^a、Y^beach independently selected from H or C_1-4An alkyl group; preferably H, methyl or ethyl; or Y^a、Y^bTogether with the carbon atom to which they are attached form a 3-, 4-, 5-or 6-membered carbocyclic ring; preferably a 3-or 4-membered carbocyclic ring;

n is 0, 1 or 2;

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

R⁶each independently selected from F, Cl, Br, I, C ═ O, cyano, C_1-4Alkyl or C_1-4An alkoxy group; preferably F, Cl, Br, I, C ═ O, cyano, methyl, ethyl, methoxy or ethoxy, said alkyl, alkoxy, methyl, ethyl, methoxy or ethoxy optionally being further substituted by 0, 1,2,3 or 4 substituents selected from F, Cl, Br, I, CH₂F、CHF₂、CF₃Or a cyano group;

R⁷is selected from C_1-6An alkylene group; preferably C_1-4An alkylene group; more preferably methylene, ethylene, propylene or butylene, said alkylene, methylene, ethylene, propylene or butylene being optionally further substituted by 0, 1,2,3,4 or 5 groups 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; preferably F, Cl, Br, I, cyano, OH, C_1-4Alkyl radical, C_1-4Alkoxy or phenyl; more preferably F, Cl, Br, cyano, OH, methyl, ethyl, methoxy, ethoxy or phenyl;

alternatively, two R^7aMay form, together with the atoms to which they are attached, a 3,4, 5 or 6 membered carbocyclic ring optionally further substituted by 0, 1,2,3,4 or 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; h, methyl or ethyl is preferred.

b is selected from

Q is selected from-CH ═ CH-, -CH₂CH₂-, -O-, -S-or-CH₂O-；

B is preferably

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;

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

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

w is-O-or-N (W)^a)-；

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

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

R⁴is selected from C_1-6An alkylene group; preferably methylene, ethylene, propylene or butylene, optionally further substituted by 0, 1,2,3,4 or 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; r⁴Preferably methylene, ethylene, propylene, -C (CH)₃)₂CH₂-、-CH₂C(CH₃)₂-、-CH(CH₃)CH₂-or-CH₂CH(CH₃)-；

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

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

R⁵each independently selected 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(ii) a Preferred are F, Cl, Br, cyano, methyl, ethyl, propyl, isopropyl, and CHF₂、CF₃Methoxy, ethoxy, -OCHF₂、-OCF₃Cyclopropyloxy, ethynyl or propynyl;

y is selected from-CY^aY^b-, -N-, -O-, -S-, -S (O) -or-S (O)₂-; preference is given to-CY^aY^b-, -N-, -O-or-S-;

n is 0, 1 or 2;

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

R⁶each independently selected from F, Cl, Br, I, C ═ O, cyano, methyl, ethyl, methoxy, or ethoxy;

R⁷is selected from C_1-4An alkylene group; preferably methylene, ethylene, propylene, butylene or

The methylene, ethylene, propylene, butylene or

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

R⁷preferably methylene, ethylene, propylene, -C (CH)₃)₂CH₂-、-CH₂C(CH₃)₂-、-CH(CH₃)CH₂-、-CH₂CH(CH₃) -or

In a preferred embodiment of the present invention, the compound represented by the general formula (I) or a stereoisomer, a hydrate, a metabolite, a solvate, a pharmaceutically acceptable salt, a co-crystal or a prodrug thereof, 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; preferably H, methyl, ethyl, propyl or isopropyl;

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

R³each independently selected from F, Cl, Br, I, CF₃OH, cyano, C_1-4Alkyl or C_1-4An alkoxy group; preferably F, methyl, ethyl, propyl, methoxy or ethoxy;

R⁴is selected from C_1-6An alkylene group; preferably C_1-4Alkylene optionally further substituted by 0, 1,2,3,4 or 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) -;

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

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) NH₂(ii) a Preferred are 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, alkenyl, alkynyl, NH₂and-C (O) NH₂Optionally further substituted by 0, 1,2,3 or 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^a、Y^beach independently selected from H or C_1-4An alkyl group; preferably H, methyl, ethyl or propyl; or Y^a、Y^bMay be taken together with the carbon atom to which they are attached to form aA 3-, 4-, 5-or 6-membered carbocyclic ring;

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

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

alternatively, two R⁶May form together with the atoms to which they are attached a 3-, 4-, 5-or 6-membered carbocyclic ring; preferably 3 or 4, said carbocyclic ring being 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; preferably F, Cl, OH, cyano, methyl, ethyl, methoxy or ethoxy;

n is 0, 1 or 2;

R⁷is selected from C_1-6An alkylene group; preferably C_1-4Alkylene optionally further substituted by 0, 1,2,3,4 or 5 groups 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; preferably F, Cl, Br, I, cyano, OH, C_1-4Alkyl or C_1-4An alkoxy group; more preferably F, Cl, Br, I, cyano, OH, methyl, ethyl, methoxy or ethoxy;

alternatively, two R^7aMay form together with the atoms to which they are attached a 3-, 4-, 5-or 6-membered carbocyclic ring; preferably 3-or 4-membered carbocycle, optionally further substituted by 0, 1,2,3,4 or 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; preferably H, methyl or ethyl;

b is selected from

Q is selected from-CH ═ CH-, -CH₂CH₂-, -O-, -S-or-CH₂O-。

In a preferable embodiment of the invention, the compound shown in the general formula (I) or a stereoisomer, a hydrate, a metabolite, a solvate, a pharmaceutically acceptable salt, a eutectic crystal or a prodrug thereof is selected from compounds shown in the general formula (II),

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, 1,2,3,4 or 5 substituents selected from F, 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;

R⁵selected from F, Cl, Br, CH₂F、CHF₂、NH₂Cyano, nitro, OCH₂F、OCHF₂、OCF₃Methyl, ethyl, methoxy, ethoxy, methylthio, -S (O)₂CH₃、-C(O)CH₃、-C(O)OCH₃or-C (O) OCH₂CH₃(ii) a Preferably F, Cl, Br, CH₂F、CHF₂Cyano, nitro, OCH₂F、OCHF₂、OCF₃Methyl, ethyl, methoxy or ethoxy; more preferably 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-; preference is given to-CY^aY^b-、-NY^a-, -O-or-S-;

Y^a、Y^beach independently selected from H, methyl or ethyl; or Y^a、Y^bMay form a 3-, 4-, 5-or 6-membered carbocyclic ring together with the carbon atoms to which they are attached; preferably a 3-or 4-membered carbocyclic ring;

e is 0, 1 or 2;

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

n is 0, 1 or 2;

R⁷selected from methylene and ethylenePropylene orThe methylene, ethylene, propylene or

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

b is selected from

In a preferred embodiment of the present invention, the compound represented by formula (I) or formula (II) 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:

the present invention relates to the provision of a compound according to formula (I) or (II) 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, saccharin (phthalimide) or a combination thereof; preferably hydrochloride, sulfate, trifluoroacetate, fumarate, tartrate, succinate, oxalate, methanesulphonic acid, saccharine or combinations thereof.

The invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of the general formulae (I) or (II) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, in combination with a pharmaceutically acceptable carrier, diluent, adjuvant, vehicle or excipient; the composition may further comprise one or more other therapeutic agents; preferably, 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.

The invention also relates to application of the compound shown in the general formula (I) or (II) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic crystal or prodrug thereof in preparing medicaments for treating the airway obstruction diseases; preferably, for use in the manufacture of a medicament for the treatment of asthma, chronic obstructive pulmonary disease or bronchitis.

The present invention also relates to a method for treating an obstructive airways disease which comprises administering a compound according to any one of the present invention or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, or a pharmaceutical composition according to the present invention.

The present invention also relates to a method of treating asthma, chronic obstructive pulmonary disease or bronchitis, which comprises administering a compound according to any one of the present invention or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, or a pharmaceutical composition according to the invention.

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

Carbon, hydrogen, oxygen, sulfur, nitrogen or halogen referred to in the groups and compounds of the invention all include isotopes thereof, and carbon, hydrogen, oxygen, sulfur, nitrogen or halogen referred to in the groups and compounds of the invention are optionally further replaced by one or more of their corresponding isotopes, wherein isotopes of carbon include isotopes of carbon¹²C、¹³C and¹⁴c, isotopes of hydrogen including protium (H), deuterium (D, also known as deuterium), tritium (T, also known as deuterium), and isotopes of oxygen including¹⁶O、¹⁷O and¹⁸isotopes of O, sulfur including³²S、³³S、³⁴S and³⁶isotopes of S, nitrogen include¹⁴N and¹⁵isotopes of N, F¹⁹Isotopes of F, chlorine including³⁵Cl and³⁷cl, isotopes of bromine including⁷⁹Br and⁸¹Br。

"alkyl" means a straight and branched chain monovalent saturated hydrocarbon group, the backbone comprising 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms, further preferably 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms, straight and branched chain groups, most preferably 1 to 2 carbon atoms, examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like; said alkyl may optionally be further substituted by 0 to 5 substituents selected from F, Cl, Br, I, ═ O, -CH₂F、-CHF₂、-CF₃Hydroxy, -SR¹⁸Nitro, cyano, isocyano, alkyl, hydroxyalkylAlkoxy, carbocyclyl, heterocyclyl, C_2-8Alkenyl radical, C_2-8Alkynyl, - (CH)₂)_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-R¹⁸or-NR¹⁸R^18aWherein R is substituted by a substituent of (1)¹⁹And R^19aEach independently selected from H, hydroxy, amino, carboxyl and C_1-8Alkyl radical, C_1-8Alkoxy radical, C_2-8Alkenyl radical, C_2-8Alkynyl, 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; r¹⁹And R^19aEach independently selected from H, unsubstituted C_1-6Alkyl group of (1). Alkyl, R, as appearing herein¹⁸And R^18aAs defined above.

"alkylene" refers to a straight and branched chain divalent saturated hydrocarbon radical, including- (CH)₂)_v- (v is an integer of 1 to 10), examples of alkylene include, but are not limited to, methylene, ethylene, propylene, butylene, and the like; said alkylene group may optionally be further substituted by 0 to 5 groups selected from F, Cl, Br, I, ═ O, -CH₂F、-CHF₂、-CF₃Hydroxy, -SR¹⁸Nitro, cyano, isocyano, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, C_2-8Alkenyl radical, C_2-8Alkynyl, - (CH)₂)_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-R¹⁸or-NR¹⁸R^18aWherein R is substituted by a substituent of (1)¹⁹And R^19aEach independently selected from H, hydroxy, amino, carboxyl and C_1-8Alkyl radical, C_1-8Alkoxy radical, C_2-8Alkenyl radical, C_2-8Alkynyl, 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; r¹⁹And R^19aEach independently selected from H, unsubstituted C_1-6Alkyl group of (1). Alkylene, as used herein, is defined as above.

"alkoxy" refers to a monovalent radical of an O-alkyl group, where alkyl is as defined herein, and alkylene examples 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-1-butoxy, and 2-methyl-1-butoxy, and the like.

"alkenyl" means a straight and branched chain monovalent unsaturated hydrocarbon group having at least 1, and usually 1,2 or 3 carbon double bonds, and the main chain includes 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and even more preferably 2 to 4 carbon atoms in the main chain, examples of alkenyl 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-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 2-hexenyl, and the like, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1, 3-butadiene, 1, 3-pentadiene, 1, 4-hexadiene, and the like; said alkylene group may optionally be further substituted by 0 to 5 groups selected from F, Cl, Br, I, ═ O, -CH₂F、-CHF₂、-CF₃Hydroxy, -SR¹⁸Nitro, cyano, isocyano, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, C_2-8Alkenyl radical, C_2-8Alkynyl, - (CH)₂)_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-R¹⁸or-NR¹⁸R^18aWherein R is substituted by a substituent of (1)¹⁹And R^19aEach independently selected from H, hydroxy, amino, carboxyl and C_1-8Alkyl radical, C_1-8Alkoxy radical, C_2-8Alkenyl radical, C_2-8Alkynyl, 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; r¹⁹And R^19aEach independently selected from H, unsubstituted C_1-6Alkyl group of (1). Alkenyl as used herein, is defined as above.

"alkynyl" refers to straight and branched chain monovalent unsaturated hydrocarbon radicals having at least 1, and typically 1,2 or 3 carbon-carbon triple bonds, and the backbone includes 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and even more preferably 2 to 4 carbon atoms in the backbone, with examples of alkynyl including, but not limited to, ethynyl, 1-propynyl, 2-propynyl, butynyl, 2-butynyl, 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, and the like; said alkylene group may optionally be further substituted by 0 to 5 groups selected from F, Cl, Br, I, ═ O, -CH₂F、-CHF₂、-CF₃Hydroxy, -SR¹⁸Nitro, cyano, isocyano, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, C_2-8Alkenyl radical, C_2-8Alkynyl, - (CH)₂)_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-R¹⁸or-NR¹⁸R^18aWherein R is substituted by a substituent of (1)¹⁹And R^19aEach independently selected from H, hydroxy, amino, carboxyl and C_1-8Alkyl radical, C_1-8Alkoxy radical, C_2-8Alkenyl radical, C_2-8Alkynyl, 3-to 10-membered carbocyclyl, 4-to 10-membered heterocyclyl, 3-to 10-membered carbocyclyloxy, or 4-to 10-memberedHeterocyclyloxy, q is selected from 0, 1,2,3,4 or 5, m is selected from 0, 1 or 2; r¹⁹And R^19aEach independently selected from H, unsubstituted C_1-6Alkyl group of (1). Alkynyl, as found herein, is defined as above.

"carbocycle" refers to a 3 to 10 membered monocyclic or 4 to 12 membered bicyclic ring system which is saturated or unsaturated, the carbocycle may have a bridged or spiro ring attached, non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and cyclodecyl

The carbocyclyl may optionally be further substituted with 0 to 5 substituents selected from F, Cl, Br, I, ═ O, -CH₂F、-CHF₂、-CF₃Hydroxy, -SR¹⁸Nitro, cyano, isocyano, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, C_2-8Alkenyl radical, C_2-8Alkynyl, - (CH)₂)_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-R¹⁸or-NR¹⁸R^18aWherein R is substituted by a substituent of (1)¹⁹And R^19aEach independently selected from H, hydroxy, amino, carboxyl and C_1-8Alkyl radical, C_1-8Alkoxy radical, C_2-8Alkenyl radical, C_2-8Alkynyl, 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; r¹⁹And R^19aEach independently selected from H, unsubstituted C_1-6Alkyl group of (1). Carbocycle as used herein is defined as above.

"heterocyclic" means a saturated or unsaturated non-aromatic ring which may be a 3 to 10 membered monocyclic ringOr 4 to 12 membered bicyclic and containing 1 to 4 heteroatoms selected from N, O or S, preferably a 4 to 8 membered heterocyclyl, the optionally substituted N, S of which may be oxidized to various oxidation states. The heterocyclic group may be attached at a heteroatom or carbon atom to which the heterocyclic group may be attached, and the heterocyclic group may be attached to a bridged or spiro ring, non-limiting examples of which include epoxyethyl, epoxypropyl, aziridinyl, oxetanyl, azetidinyl, thietanyl, 1, 3-dioxolanyl, 1, 4-dioxolanyl, 1, 3-dioxanyl, azepinyl, oxepinyl, thiepinyl, oxazepinyl, thiazepinyl, piperidinyl, homopiperidinyl, furyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, piperazinyl, homopiperazinyl, piperidinyl, perinyl, morpholinyl, thiomorpholinyl, thiadiazolyl, 1, 3-dithiayl, dihydrofuranyl, dihydropyranyl, dithiapentyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, Tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1, 3-dioxolyl, pyrazolinyl, dithianyl, dithienyl, dihydrothienyl, pyrazolylimidazolinyl, and imidazolidinyl. Said heterocyclyl may optionally be further substituted by 0 to 5 substituents selected from F, Cl, Br, I, ═ O, -CH₂F、-CHF₂、-CF₃Hydroxy, -SR¹⁸Nitro, cyano, isocyano, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, C_2-8Alkenyl radical, C_2-8Alkynyl, - (CH)₂)_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-R¹⁸or-NR¹⁸R^18aWherein R is substituted by a substituent of (1)¹⁹And R^19aEach independently selected from H, hydroxy, amino, carboxyl and C_1-8Alkyl radical, C_1-8Alkoxy radical, C_2-8Alkenyl radical, C_2-8Alkynyl, 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; r¹⁹And R^19aEach independently selected from H, unsubstituted C_1-6Alkyl group of (1). Heterocyclyl, as used herein, is defined as above.

"beta-adrenergic receptor binding group" refers to a group capable of binding to a beta-adrenergic receptor; see, for example, the review article "beta-acquired receivers in Comprehensive medical Chemistry, 1990, B.E. Main, p187(Pergamon Press)". See also, for example, WO/2005092841, US/20050215542, WO/2005070872, WO/2006023460, WO/2006051373, WO/2006087315 and WO/2006032627. Non-limiting examples include

B is selected from

R¹⁰、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、R¹⁶、R¹⁷Or R¹⁸Each independently selected from H, F, Cl, Br, I, CF₃、OH、-CH₂OH, cyano, carboxyl, C_1-4Alkyl radical, C_1-4Alkoxy, -C (O) C_1-4Alkyl, -C (O) OC_1-4Alkyl, -NHC (O) H, NHS (O)₂-C_1-4Alkyl, NHS (O)₂-NH₂Or NHS (O)₂-NHC_1-4Alkyl, Q is selected from-CR^q1＝CR^q2-、-CR^q1R^q2CR^q3R^q4-, O, S or-CR^q1R^q2O-, said R^q1、R^q2、R^q3Or R^q4Each independently selected from H, F, Cl, Br, I or C_1-4An alkyl group.

"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. Such as: "alkyl optionally substituted with F" means that the alkyl group may, but need not, be substituted with F, and the description includes the case where the alkyl group is substituted with F and the case where the alkyl group is not substituted with F.

"pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" means that the biological effectiveness and properties of the free acid or free base are maintained and the free acid is obtained by reaction with a non-toxic inorganic or organic base or a salt of the free acid obtained by reaction with a non-toxic inorganic or organic acid, including alkali metal salts such as sodium, potassium, lithium, and the like; alkaline earth metal salts such as calcium salts, magnesium salts, and the like; other metal salts such as iron salts, copper salts, cobalt salts, etc.; organic base salts such as ammonium salts, triethylamine salts, pyridine salts, picoline salts, 2, 6-lutidine salts, ethanolamine salts, diethanolamine salts, triethanolamine salts, cyclohexylamine salts, ethylenediamine salts, guanidine salts, isopropylamine salts, trimethylamine salts, tripropylamine salts, triethanolamine salts, diethanolamine salts, ethanolamine salts, dimethylethanolamine salts, dicyclohexylamine salts, caffeine salts, procaine salts, choline salts, betaine salts, benzamidine penicillin salts, glucamine salts, N-methylglucamine salts, theobromine salts, tromethamine salts, purine salts, piperazine salts, morpholine salts, piperidine salts, N-ethylpiperidine salts, tetramethylamine salts, dibenzylamine salts, phenylglycine alkyl ester salts and the like; hydrohalic acid salts such as hydrofluoride, hydrochloride, hydroiodide, hydrobromide and the like; inorganic acid salts such as hydrochloride, nitrate, sulfate, perchlorate, phosphate and the like; lower alkanesulfonates such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate and the like; arylsulfonates such as benzenesulfonate, p-toluenesulfonate and the like; organic acid salts such as acetate, benzoate, fumarate, formate, trifluoroacetate, furoate, gluconate, saccharin (saccharate), glutamate, glycolate, isethionate, lactate, maleate, malate, mandelate, mucate, pamoate, pantothenate, stearate, succinate, sulfamate, tartrate, malonate, 2-hydroxypropionate, citrate, salicylate, oxalate, glycolate, glucuronate, galacturonate, citrate, lysine, arginine, aspartate, cinnamate, and the like.

"pharmaceutical composition" means a mixture of one or more compounds of the present invention or physiologically/pharmaceutically acceptable salts thereof with other ingredients, wherein the other ingredients comprise physiologically/pharmaceutically acceptable carriers and excipients.

"carrier" refers to a carrier or diluent that does not cause significant irritation to an 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. Examples of excipients 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, lubricants, binders, disintegrating agents, and the like.

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

"cocrystals" or "cocrystals" refers to crystals of an Active Pharmaceutical Ingredient (API) and a cocrystal former (CCF) that are bound together by hydrogen bonding or other non-covalent bonds, wherein the API and CCF are both solid in pure form at room temperature and a fixed stoichiometric ratio exists between the components. A co-crystal is a multi-component crystal that contains both a binary co-crystal formed between two neutral solids and a multicomponent co-crystal formed between a neutral solid and a salt or solvate. The "co-crystal former" includes, but is 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 (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 (gin), 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, benzoic acid, propionic acid, benzenesulfonic acid, benzoic acid, salicylic acid, and other solvents, Camphoric acid, citric acid, ethenesulfonic acid, formic acid, fumaric acid, furoic acid, gluconic acid, glucuronic 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-toluenesulfonic acid, malonic acid, 2-hydroxypropionic acid, oxalic acid, glycolic acid, glucuronic acid, galacturonic acid, citric acid, lysine, arginine, aspartic acid, cinnamic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid or trifluoromethanesulfonic acid, ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, caffeine, procaine, choline, and mixtures thereof, Betaine, phentermine, ethylenediamine, glucosamine, methylglucamine, theobromine, tromethamine, purine, piperazine, piperidine, N-ethylpiperidine, methanol, ethanol, butynediol, 1, 2-propanediol, (R)1, 2-propanediol, (S)1, 2-propanediol, or 1-methyl-1, 2-ethanediol.

"stereoisomers" refers to isomers resulting from the different arrangement of atoms in a molecule, including cis, trans isomers, enantiomers and conformational isomers.

An "effective dose" refers to an amount of a compound that elicits a physiological or medical response in a tissue, system, or subject that is sought, including an amount of the compound that, when administered to a subject, is sufficient to prevent the onset of, or alleviate to some extent, one or more symptoms of the condition or disorder being treated.

"solvates" refers to compounds of the invention or salts thereof, which also include stoichiometric or non-stoichiometric amounts of 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 are described in detail below with reference to the drawings and the embodiments, but the scope of the present invention includes but is not limited thereto.

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or (and) Mass Spectrometry (MS). NMR shift (. delta.) of 10^-6The units in (ppm) are given. NMR was measured using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic spectrometers in deuterated dimethyl sulfoxide (DMSO-d)₆) Deuterated chloroform (CDCl)₃) Deuterated methanol (CD)₃OD), internal standard Tetramethylsilane (TMS).

MS was measured by Agilent 6120B (ESI) and Agilent 6120B (APCI).

HPLC was carried out using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18100X 4.6 mm).

The thin layer chromatography silica gel plate adopts HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of the silica gel plate used by Thin Layer Chromatography (TLC) is 0.15 mm-0.20 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.

The column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.

Known starting materials of the present invention can be synthesized by or according to methods known in the art, or can be purchased from companies such as Tatan technology, Annaiji chemistry, Shanghai Demer, Chengdong chemical, Shaoshan far chemical technology, and Bailingwei technology.

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

The hydrogen atmosphere refers to a reaction flask connected with a hydrogen balloon with a volume of about 1L.

The hydrogenation reaction was usually evacuated and charged with hydrogen and repeated 3 times.

In the examples, the reaction was carried out under a nitrogen atmosphere without specific mention.

In the examples, the solution means an aqueous solution unless otherwise specified.

In the examples, the reaction temperature is room temperature, unless otherwise specified.

In the examples, M is mole per liter, unless otherwise specified.

The room temperature is the most suitable reaction temperature and is 20-30 ℃.

CHO: refers to a formyl group.

TBS: refers to tert-butyl dimethyl silicon base.

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 is as follows: 6-methoxyindoline (1b)

6-methoxyindoline

6-methoxyindole (1a) (5.0g,33.97mmol) was dissolved in acetic acid (50mL), and sodium cyanoborohydride (5.34g,84.94mmol) was added to the reaction mixture under nitrogen and reacted at 25 ℃ for 2 hours. Water (80mL) is added to the reaction solution, the reaction solution is cooled to 0 ℃, and sodium hydroxide is carefully added to adjust the pH value to 12-13. Ethyl acetate (80mL) was added, the layers were extracted, the aqueous phase was extracted with ethyl acetate (30 mL. times.2), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, and 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 to 1:4) to give the title compound 6-methoxyindoline (1b) as a yellow oil (4.4g, yield 87%).

¹H NMR(400MHz,CDCl₃)δ7.00(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 is that: 5-bromo-6-methoxyindoline (1c)

5-bromo-6-methoxyindoline

6-Methoxyindoline (1b) (22g,147.46mmol) was dissolved in ethyl acetate (200mL), and 1, 3-dibromo-5, 5-dimethylhydantoin (CAS:77-48-5) (21.08g,73.73mmol) was added at 0 ℃ to react for 2 hours at 0 ℃. To the reaction solution was added 15% potassium carbonate solution (250mL), the mixture was sufficiently stirred, and then the layers were separated by extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether (v/v) ═ 0:1 to 1:9) to obtain the title compound 5-bromo-6-methoxyindoline (1c) as a purple liquid (16g, yield 47.57%).

¹H NMR(400MHz,CDCl₃)δ7.19(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: 5-bromo-6-methoxyindoline-1-carbamic acid tert-butyl ester (1d)

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

5-bromo-6-methoxyindoline (1c) (16g,70.15mmol) was dissolved in tetrahydrofuran (70mL), and di-tert-butyl dicarbonate (22.97g,105.22mmol) and 4-dimethylaminopyridine (1.71g,14.03mol) were added and reacted at room temperature for 2 hours. To the reaction mixture were added water (50mL) and ethyl acetate (50mL), and the layers were extracted. The aqueous phase was extracted with ethyl acetate (30mL) and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, and 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 to 1:19) to give the title compound, tert-butyl 5-bromo-6-methoxyindoline-1-aminocarboxylate (1d), as a violet white solid (17g, yield 74%).

¹H NMR(400MHz,CDCl₃)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: 5-formyl-6-methoxyindoline-1-carbamic acid tert-butyl ester (1e)

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

Tert-butyl 5-bromo-6-methoxyindolin-1-aminocarboxylate (1d) (17g,51.80mmol) was dissolved in tetrahydrofuran (300mL) under nitrogen and 2.5M n-butyllithium in n-hexane (22.8mL,56.98mmol) was added at-78 ℃ and the reaction was maintained at this temperature for 30 minutes. N, N-dimethylformamide (18.93g,259mmol) was added at-78 ℃ and the reaction was gradually warmed to room temperature for 1 hour. To the reaction mixture were added water (200mL) and ethyl acetate (100mL), and the layers were separated by extraction. The aqueous phase was extracted once with ethyl acetate (100mL) and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, and 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 to 1:4) to give the title compound, tert-butyl 5-formyl-6-methoxyindoline-1-aminocarboxylate (1e), as a yellow solid (8.6g, yield 60%).

¹H NMR(400MHz,CDCl₃)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), and trifluoroacetic acid (18g,160mmol) was added to react at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and then ammonia water was added to adjust the pH to 9, followed by addition of water (100mL) and methylene chloride (100mL) and extraction. The aqueous phase was extracted once with dichloromethane (50mL) 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 purified by silica gel column chromatography (ethyl acetate: petroleum ether (v/v) ═ 1:9 to 4:1) to give the title compound 6-methoxyindoline-5-carbaldehyde (1f) as a yellow solid (2.7g, yield 49%).

¹H NMR(400MHz,CDCl₃)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]。

And a 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), and triethylamine (0.428g,4.23mmol) was added under nitrogen. Acrylic acid (0.102g,1.41mmol) was added dropwise. After the temperature was raised to 40 ℃, 1-propylphosphoric anhydride (0.449g,1.41mmol) was added dropwise thereto, and the reaction was carried out at 40 ℃ for 4 hours. Ethyl acetate (20mL) was added to the reaction mixture, which was washed with 2M hydrochloric acid solution (20mL) and 3% sodium hydroxide solution (20mL) in this order, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 6-methoxy-1-propyl-2-enoyl-indoline-5-carbaldehyde (intermediate 1) as a yellow solid (0.08g, yield 61%).

¹H NMR(400MHz,CDCl₃)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-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 is as follows: 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 WO2009098448A 1) (0.56g.2.2mmol) was dissolved in N, N-dimethylformamide (20mL), followed by addition of imidazole (0.6g, 8.9mmol), addition of tert-butyldimethylchlorosilane (1.3g, 8.9mmol) in portions, addition of a catalytic amount of 4-dimethylaminopyridine, raising the temperature to 40 ℃ and stirring for 7 hours. The reaction mixture was poured into water (100mL), extracted with ethyl acetate (100mL × 1), the organic phase was washed with a saturated aqueous solution of sodium chloride (100mL × 2), dried over anhydrous sodium sulfate, filtered, and 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 to 5/95) to give 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) as a white solid (0.85g, yield 80%).

¹H NMR(400MHz,CDCl₃)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 is that: 7- [ (1R) -2-amino-1- [ tert-butyl (dimethyl) silyl ] oxyethyl ] -4- [ tert-butyl (dimethyl) silyl ] oxy-3H-1, 3-benzothiazol-2-one (intermediate 2)

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), 10% (w/w) palladium on carbon (0.085g) was added, and the mixture was stirred under a hydrogen balloon at normal pressure overnight. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give the title compound 7- [ (1R) -2-amino-1- [ tert-butyl (dimethyl) silyl ] oxyethyl ] -4- [ tert-butyl (dimethyl) silyl ] oxy-3H-1, 3-benzothiazol-2-one (intermediate 2) as a pale black solid (0.7g, 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-hydroxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] methyl ] -6-methoxy-indolin-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 is as follows: [1- [3- (5-formyl-6-methoxy-indolin-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) (0.608g,2.63mmol) was dissolved in 2-methyltetrahydrofuran (10mL), piperidin-4-yl [1, 1' -biphenyl ] -2-ylcarbamate (1A) (0.600g,2.02mmol) was added, acetic acid (0.243g,4.05mmol) was added, and microwave reaction was performed at 100 ℃ for 1 hour. The reaction mixture was concentrated, and methylene chloride (20mL) and a saturated sodium bicarbonate solution (20mL) were added to the mixture, followed by extraction and separation. The aqueous phase was extracted with dichloromethane (20mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether (v/v) ═ 1:1 to 1:0, methanol: dichloromethane (v/v) ═ 3:97) to give the title compound [1- [3- (5-formyl-6-methoxy-indolin-1-yl) -3-oxo-propyl ] -4-piperidinyl ] N- (2-phenylphenyl) carbamate (1B) as a yellow solid (0.72g, yield 67.4%).

¹H NMR(400MHz,CDCl₃)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 is that: [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-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-indolin-1-yl) -3-oxo-propyl ] -4-piperidinyl ] N- (2-phenylphenyl) 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) was added and reacted at room temperature for 1 hour. Then, sodium triacetoxyborohydride (0.811g,3.81mmol) was added thereto, and the reaction was carried out at room temperature for 3 hours. Dichloromethane (20mL) and saturated sodium bicarbonate solution (20mL) were added to the reaction mixture, and the layers were extracted. The aqueous phase was extracted with dichloromethane (20mL × 1), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether (v/v) ═ 1:1 to 1:0, methanol: dichloromethane (v/v) ═ 1:99 to 1:19) to give 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-indolin-1-yl ] -3-oxo-propyl ] -4-piperidine ] N- (2-phenylphenyl) carbamate (1C), yellow solid (0.62g, 57.7% yield).

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

[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-piperidine ] N- (2-phenylphenyl) carbamate (1C) (0.620g,0.733mmol) was dissolved in dichloromethane (8mL), triethylamine trihydrofluoride salt (1.18g,7.33mmol) was added and the reaction was carried out at room temperature for 24 hours. Water (20mL) and methylene chloride (20mL) were added to the reaction mixture, and 3% sodium hydroxide solution was added to adjust the pH to about 12, followed by extraction and separation. The aqueous phase was extracted with dichloromethane (20 mL. times.2) and the organic phases were combined. The organic phase was washed with saturated brine (20mL × 1) in this order, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether (v/v) ═ 1:1 to 1:0, methanol: dichloromethane (v/v) ═ 3:97 to 1:9) 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-indolin-1-yl ] -3-oxo-propyl ] -4-piperidine ] N- (2-phenylphenyl) carbamate (compound 1), yellow solid (0.26g, 48.5% yield).

¹H NMR(400MHz,CD₃OD)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-hydroxy-2- [ 4-hydroxy-3- (methanesulfonamido) phenyl ] ethyl ] amino ] methyl ] -6-methoxy-indolin-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 is as follows: [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-piperidine ] N- (2-phenylphenyl) 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-indolin-1-yl) -3-oxo-propyl ] -4-piperidinyl ] N- (2-phenylphenyl) carbamate (1B) (0.500g,0.948mmol) was dissolved in methylene chloride (10mL) and methanol (10mL), and N- [5- [ (1R) -2-amino-1- [ tert-butyl (dimethyl) silyl ] oxy-ethyl ] -2-hydroxy-phenyl ] methanesulfonamide (2B) (0.342g,0.948mmol) was added and reacted at room temperature for 1 hour. Sodium triacetoxyborohydride (0.605g,2.84mmol) was added and the reaction was allowed to proceed at room temperature for 3 hours. Dichloromethane (20mL) and saturated sodium bicarbonate solution (20mL) were added to the reaction mixture, and the layers were extracted. 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 purified by silica gel column chromatography (ethyl acetate: petroleum ether (v/v) ═ 1:1 to 1:0, methanol: dichloromethane (v/v) ═ 1:99 to 1:19) to give the title compound [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-piperidine ] N- (2-phenylphenyl) carbamate (2A), yellow solid (0.53g, 64.1% yield).

¹H 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 is that: [1- [3- [5- [ [ [ (2R) -2-hydroxy-2- [ 4-hydroxy-3- (methanesulfonamido) phenyl ] ethyl ] amino ] methyl ] -6-methoxy-indolin-1-yl ] -3-oxo-propyl ] -4-piperidine ] N- (2-phenylphenyl) carbamate (Compound 2)

[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-piperidine ] N- (2-phenylphenyl) carbamate (2A) (0.530g,0.608mmol) was dissolved in dichloromethane (8mL), triethylamine trihydrofluoride salt (0.980g,6.08mmol) was added, and the reaction was carried out at room temperature for 24 hours. Water (20mL) and methylene chloride (20mL) were added to the reaction mixture, and 3% sodium hydroxide solution was added to adjust the pH to about 12, followed by extraction and separation. The aqueous phase was extracted with dichloromethane (20 mL. times.2) and the organic phases were combined. The organic phase was washed with saturated brine (20mL), 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) ═ 1:1 to 1:0, methanol: dichloromethane (v/v) ═ 3:97 to 1:9) to give the title compound [1- [3- [5- [ [ [ (2R) -2-hydroxy-2- [ 4-hydroxy-3- (methanesulfonamido) phenyl ] ethyl ] amino ] methyl ] -6-methoxy-indolin-1-yl ] -3-oxo-propyl ] -4-piperidine ] N- (2-phenylphenyl) carbamate (compound 2), a yellow solid (0.20g, yield 43.4%).

¹H NMR(400MHz,CD₃OD)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-hydroxy-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 is as follows: 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 gas was substituted three times, a solution of triphosgene (1.34g,4.51mmol) in dichloromethane (10mL) was added dropwise at 0 ℃ and the reaction was gradually warmed to room temperature for 1 hour to obtain reaction solution 1. 6-Methoxyindoline-5-carbaldehyde (3A) (1.00g,5.64mmol) was dissolved in tetrahydrofuran (20mL), triethylamine (1.8g,14.11mmol) was added thereto, and the reaction mixture 1 was added dropwise at 0 ℃ and gradually warmed to room temperature for 1 hour. The reaction mixture was concentrated, and water (30mL) and methylene chloride (30mL) were added to conduct extraction. The organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether (v/v) ═ 1:9 to 3:7) to give the title compound 2-bromoethyl 5-formyl-6-methoxy-indoline-1-carboxylate (3B) as a pink solid (1.5g, yield 81%).

¹H NMR(400MHz,CDCl₃)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 is that: 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) (1.5g,4.6mmol) was dissolved in acetonitrile (20mL) and tetrahydrofuran (10mL), and piperidin-4-yl [1, 1' -biphenyl ] -2-ylcarbamate (1A) (1.4g,4.6mmol) and triethylamine (1.8g,18mmol) were added and reacted at 80 ℃ for 8 hours. Ethyl acetate (30mL) and water (30mL) were added to the reaction mixture, and the mixture was extracted. The aqueous phase was extracted with ethyl acetate (20 mL. times.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 purified by silica gel column chromatography (ethyl acetate: petroleum ether (v/v) ═ 3:7 to 7:3) to give the title compound 2- [4- [ (2-phenylphenyl) carbamoyloxy ] -1-piperidinyl ] ethyl 5-formyl-6-methoxy-indoline-1-carboxylate (3C) as a yellow solid (1.4g, 56% yield).

¹H NMR(400MHz,CDCl₃)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 (dimethyl) 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-methoxy-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) was added and reacted at room temperature for 1 hour. Sodium triacetoxyborohydride (0.823g,3.86mmol) was added and the reaction was allowed to proceed at room temperature for 3 hours. Methylene chloride (20mL) was added to the reaction mixture, and a saturated aqueous solution of sodium hydrogencarbonate (20mL) was added to the reaction mixture to conduct extraction. The aqueous phase was extracted with dichloromethane (20mL × 1), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether (v/v) ═ 1:1 to 1:0, methanol: dichloromethane (v/v) ═ 1:99 to 1:19) to give the title compound 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-carboxylate (3D) as a brown solid (0.74g, 66.7% yield).

¹H NMR(400MHz,CD₃OD)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-hydroxy-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-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-carboxylate (3D) (0.740g,0.858mmol) was dissolved in dichloromethane (8mL), triethylamine trihydrofluoride salt (1.38g,8.58mmol) was added and the reaction was carried out at room temperature for 24 hours. Water (20mL) and methylene chloride (20mL) were added to the reaction mixture, and a 3% sodium hydroxide solution was added to adjust the pH to about 12, followed by extraction. The aqueous phase was extracted with dichloromethane (20 mL. times.2), the organic phases were combined, washed successively with saturated aqueous sodium chloride (20 mL. times.1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether (v/v) ═ 1:1 to 1:0, methanol: dichloromethane (v/v) ═ 3:97 to 1:9) to give the title compound 2- [4- [ (2-phenylphenyl) carbamoyloxy ] -1-piperidinyl ] ethyl 5- [ [ [ (2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] methyl ] -6-methoxy-indoline-1-carboxylate (compound 3) as a yellow solid (0.10g, yield 15.6%).

¹H NMR(400MHz,CD₃OD)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-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-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

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

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

7-methoxy-3, 4-dihydro-1H-quinolin-2-one (4A) (1.0g,5.64mmol) was dissolved in tetrahydrofuran (15mL) and reacted at 0 ℃ for 3 hours at room temperature under nitrogen protection with lithium aluminum hydride (0.428g,11.3 mmol). The reaction was cooled to 0 ℃ and quenched by careful addition of water (2 mL). Ethyl acetate (20mL) was added, the mixture was filtered through celite, the filtrate was dried over anhydrous sodium sulfate, the filtrate was filtered, and the filtrate was concentrated under reduced pressure to give the title compound 7-methoxy-1, 2,3, 4-tetrahydroquinoline (4B) as a yellow liquid (0.58g, 63% yield).

¹H NMR(400MHz,CDCl₃)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 is that: 6-bromo-7-methoxy-1, 2,3, 4-tetrahydroquinoline (4C)

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

7-methoxy-1, 2,3, 4-tetrahydroquinoline (4B) (0.100g,0.613mmol) was dissolved in ethyl acetate (10mL), and 1, 3-dibromo-5, 5-dimethylhydantoin (0.088g,0.306mmol) was added at 0 ℃ to react at 0 ℃ for 2 hours. To the reaction solution was added 15% potassium carbonate solution (20mL) and the mixture was stirred well. Ethyl acetate (20mL) was added, extraction was performed, the organic phase was dried over anhydrous sodium sulfate, filtration was performed, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether (v/v) ═ 0:1 to 1:9) to give the title compound 6-bromo-7-methoxy-1, 2,3, 4-tetrahydroquinoline (4C) as a purple liquid (0.105g, yield 70.8%).

¹H NMR(400MHz,CDCl₃)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

6-bromo-7-methoxy-1, 2,3, 4-tetrahydroquinoline (4C) (0.500g,2.07mmol) was dissolved in tetrahydrofuran (15mL) and, under nitrogen, a 2M solution of isopropyl magnesium chloride in tetrahydrofuran (1.15mL,2.27mmol) was added at-10 deg.C and the reaction was allowed to warm to 0 deg.C for 1 hour. 2.5M n-butyllithium in n-hexane (4mL,10.3mmol) was added at-25 ℃ and the reaction was carried out at-10 ℃ for 30 minutes. N, N-dimethylformamide (0.755g,10.3mmol) was added at-10 ℃ and the reaction was gradually warmed to room temperature for 0.5 hour. The reaction mixture was poured into a solution of citric acid (1g) in water (20mL), and ethyl acetate (20mL) was added to conduct extraction. The aqueous phase was extracted with ethyl acetate (10 mL. times.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 purified by silica gel column chromatography (ethyl acetate: petroleum ether (v/v) ═ 0:1 to 1:4) to give the title compound 7-methoxy-1, 2,3, 4-tetrahydroquinoline-6-carbaldehyde (4D) as a yellow solid (0.270g, yield 68.4%).

¹H NMR(400MHz,CDCl₃)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

7-methoxy-1, 2,3, 4-tetrahydroquinoline-6-carbaldehyde (4D) (1.5g,7.84mmol) was dissolved in ethyl acetate (30mL), and triethylamine (5.95g,58.8mmol) was added under nitrogen. Acrylic acid (1.41g,19.6mmol) was added dropwise. After the temperature was raised to 40 ℃ and 1-propylphosphoric anhydride (6.24g,19.6mmol) was added dropwise, the reaction was carried out at 80 ℃ for 4 hours. The reaction mixture was added with ethyl acetate (20mL) and water (20mL), extracted, 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 to 3:7) to give the title compound 7-methoxy-1-propyl-2-enoyl-3, 4-dihydro-2H-quinoline-6-carbaldehyde (4E) as a yellow solid (1.1g, yield 57%).

¹H NMR(400MHz,CDCl₃)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-piperidinyl ] 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) (1.1g,4.48mmol) was dissolved in 2-methyltetrahydrofuran (10mL), piperidin-4-yl [1, 1' -biphenyl ] -2-ylcarbamate (1A) (1.33g,4.48mmol) was added, triethylamine (0.908g,8.97mmol) was added, and the mixture was reacted with microwave at 100 ℃ for 1 hour. The reaction mixture was concentrated, and methylene chloride (20mL) and a saturated aqueous solution of sodium hydrogencarbonate (20mL) were added to conduct extraction. The aqueous phase was extracted with dichloromethane (20mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether (v/v) ═ 1:1 to 1:0, methanol: dichloromethane (v/v) ═ 3:97) to give 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) as a yellow solid (1.6g, 66% yield).

¹H NMR(400MHz,CDCl₃)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]。

And a sixth step: [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-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-butyldimethylsilyl) oxy) ethyl) -8-hydroxyquinolin-2 (1H) -one (1D) (0.432g,1.29mmol) was added and reacted at room temperature for 1 hour. Sodium triacetoxyborohydride (0.826g,3.88mmol) was added thereto, and the mixture was reacted at room temperature for 3 hours. The reaction mixture was extracted with dichloromethane (20mL) and saturated aqueous sodium bicarbonate (20 mL). The aqueous phase was extracted with dichloromethane (20 mL. times.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 residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether (v/v) ═ 1:1 to 1:0, methanol: dichloromethane (v/v) ═ 1:99 to 1:19) to give the title compound [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-piperidinyl ] N- (2-phenylphenyl) carbamate (4G) as a yellow oil (1.1G, yield 100%).

LCMS m/z＝430.8[M/2+1]。

The seventh step: [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-phenylphenyl) carbamate bistrifluoroacetate (Compound 4)

[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-piperidinyl ] N- (2-phenylphenyl) carbamate (4G) (1.1G,1.3mmol) was dissolved in dichloromethane (8mL), triethylamine trihydrofluoride salt (2.1G,13mmol) was added, and the reaction was carried out at room temperature for 24 hours. Water (20mL) and methylene chloride (20mL) were added to the reaction mixture, and a 3% sodium hydroxide solution was added to adjust the pH to about 12, followed by extraction. The aqueous phase was extracted with dichloromethane (20 mL. times.2), the organic phases were combined, washed successively with saturated aqueous sodium chloride (20 mL. times.1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was prepared acid-wise 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-phenylphenyl) carbamate bistrifluoroacetate salt (Compound 4) as a white solid (0.200g, 21% yield).

¹H NMR(400MHz,CD₃OD)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-hydroxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] methyl ] -6-methoxy-indolin-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 is as follows: 2- (4-benzyloxy-3-chloro-phenyl) aniline (5C)

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

O-iodoaniline (5B) (4.0g,18mmol) was dissolved in ethylene glycol dimethyl ether (5mL) and water (5mL), and (4.8g,18mmol) of (4-benzyloxy-3-chloro-phenyl) boronic acid (5A) and potassium carbonate (10g,73mmol) were added, and tetrakistriphenylphosphine palladium (1.1g,0.91mmol) was added under nitrogen protection, and microwave reaction was carried out at 120 ℃ for 1 hour. Ethyl acetate (50mL) and water (50mL) were added to the reaction mixture, and the mixture was extracted. 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 to 1:9) to give the title compound 2- (4-benzyloxy-3-chloro-phenyl) aniline (5C) as a yellow solid (4.5g, yield 80%).

¹H NMR(400MHz,CDCl₃)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 is that: 4- [ [2- (4-benzyloxy-3-chloro-phenyl) phenyl ] carbamoyloxy ] piperidine-1-carboxylic acid tert-butyl ester (5E)

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

2- (4-benzyloxy-3-chloro-phenyl) aniline (5C) (2.3g,7.4mmol) was dissolved in toluene (50mL), and triphosgene (0.88g,3.0mmol) was added and reacted at 125 ℃ for 4 hours. After concentration, tetrahydrofuran (100mL) was added, tert-butyl 4-hydroxy-piperidine-1-carboxylate (5D) (1.5g,7.4mmol) was added, triethylamine (2.3g,22mmol) was added, and the reaction was carried out at 70 ℃ for 2 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) ═ 0:1 to 1:9) to give the title compound, tert-butyl 4- [ [2- (4-benzyloxy-3-chloro-phenyl) phenyl ] carbamoyloxy ] piperidine-1-carboxylate (5E), as a yellow oil (3.5g, yield 88%).

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

Tert-butyl 4- [ [2- (4-benzyloxy-3-chloro-phenyl) phenyl ] carbamoyloxy ] piperidine-1-carboxylate (5E) (3.5g,6.5mmol) was dissolved in dichloromethane (10mL), and trifluoroacetic acid (10mL) was added to react at room temperature for 2 hours. The reaction mixture was concentrated, adjusted to pH 8 to 9 with aqueous ammonia, and extracted with dichloromethane (50 mL). The aqueous phase was extracted with dichloromethane (20 mL. times.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 purified by silica gel column chromatography (methanol/dichloromethane (v/v) ═ 1:99 to 1:19) to give the title compound 4-piperidyl N- [2- (4-benzyloxy-3-chloro-phenyl) phenyl ] carbamate (5F) as a white solid (1.2g, yield 42%).

¹H NMR(400MHz,CDCl₃)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) (0.860g,1.97mmol) was dissolved in methanol (20mL), and o-dichlorobenzene (1.45g,9.84mmol) was added thereto, followed by addition of 10% (w/w) palladium on carbon (0.3g) and replacement of hydrogen gas, followed by reaction at room temperature under a hydrogen atmosphere for 4 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (methanol/dichloromethane (v/v) ═ 1:99 to 1:9) to give the title compound, 4-piperidyl N- [2- (3-chloro-4-hydroxy-phenyl) phenyl ] carbamate (5G), as a pale yellow solid (0.700G, yield 103%).

¹H 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-indolin-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

6-methoxy-1-propyl-2-enoyl-indoline-5-carbaldehyde (intermediate 1) (0.520G,2.25mmol) was dissolved in 2-methyltetrahydrofuran (10mL), 4-piperidyl N- [2- (3-chloro-4-hydroxy-phenyl) phenyl ] carbamate (5G) (0.780G,2.25mmol) was added, triethylamine (0.455G,4.50mmol) was added, and microwave reaction was carried out at 100 ℃ for 1 hour. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) ═ 1:1 to 1:0, methanol/dichloromethane (v/v) ═ 3:97) to give the title compound [1- [3- (5-formyl-6-methoxy-indolin-1-yl) -3-oxo-propyl ] -4-piperidinyl ] N- [2- (3-chloro-4-hydroxy-phenyl) phenyl ] carbamate (5H) as a yellow solid (1.25g, 96.1% yield).

¹H NMR(400MHz,CDCl₃)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]。

And a sixth step: [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-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-indolin-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) was added and reacted at room temperature for 1 hour. Sodium triacetoxyborohydride (0.553g,2.59mmol) was added and the reaction was allowed to proceed at room temperature for 3 hours. Methylene chloride (20mL) was added to the reaction mixture, and a saturated aqueous solution of sodium hydrogencarbonate (20mL) was added to the reaction mixture to conduct extraction. The aqueous phase was extracted with dichloromethane (20 mL. times.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 residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) ═ 1:1 to 1:0, methanol/dichloromethane (v/v) ═ 1:99 to 1:19) to give 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-indolin-1-yl ] -3-oxo-propyl ] -4-piperidinyl ] N- [2- (3-chloro-4-hydroxy-phenyl) phenyl ] carbamate (5I), yellow solid (0.42g, 54% yield).

¹H NMR(400MHz,CD₃OD)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-hydroxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] methyl ] -6-methoxy-indolin-1-yl ] -3-oxo-propyl ] -4-piperidinyl ] N- [2- (3-chloro-4-hydroxy-phenyl) phenyl ] carbamate (Compound 5)

[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-piperidinyl ] N- [2- (3-chloro-4-hydroxy-phenyl) phenyl ] carbamate (5I) (0.420g,0.468mmol) was dissolved in tetrahydrofuran (5mL), triethylamine trihydrofluoride salt (0.755g,4.68mmol) was added, and the reaction was carried out at room temperature for 24 hours. To the reaction mixture was added a 10% methanol/dichloromethane (v/v. 1/10,50mL) solution, and a saturated aqueous sodium bicarbonate solution was added to adjust the pH to about 8, followed by extraction. The aqueous phase was extracted with 10% methanol/dichloromethane (v/v ═ 1/10,50mL × 2) and the organic phases were combined. The organic phase was washed with a saturated aqueous solution of sodium chloride (20 mL. times.1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was slurried twice with dichloromethane (30mL) 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-indolin-1-yl ] -3-oxo-propyl ] -4-piperidinyl ] N- [2- (3-chloro-4-hydroxy-phenyl) phenyl ] carbamate (compound 5) as a yellow solid (0.150g, 40.9% yield).

¹H NMR(400MHz,CD₃OD)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-hydroxy-2- (4-hydroxy-2-oxo-3H-1, 3-benzothiazol-7-yl) ethyl ] amino ] methyl ] -6-methoxy-indolin-1-yl ] -3-oxo-propyl ] -4-piperidinyl ] N- [2- (3-chloro-4-hydroxy-phenyl) phenyl ] carbamate bistrifluoroacetate salt (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-indolin-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 7- [ (1R) -2-amino-1-hydroxy-ethyl ] -4-hydroxy-3H-1, 3-benzothiazol-2-one (6A, prepared by reference to Bioorganic & Medicinal Chemistry Letters,21(15), 4612-one 4616; 2011) (0.181g,0.799mmol) was added and reacted at room temperature for 1 hour. Sodium triacetoxyborohydride (0.464g,2.18mmol) was added and reacted at room temperature for 24 hours. A methanol/dichloromethane (v/v-1/10, 50mL) solution was added to the reaction solution, and a saturated aqueous sodium bicarbonate solution (30mL) was added thereto and extracted. The aqueous phase was extracted with methanol/dichloromethane (v/v ═ 1/10,50mL × 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 residue was prepared by acid route to give the title compound [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-piperidinyl ] N- [2- (3-chloro-4-hydroxy-phenyl) phenyl ] carbamate bistrifluoroacetate salt (compound 6) as a white solid (0.060g, 10% yield).

¹H 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-hydroxy-2- (5-hydroxy-3-oxo-4H-1, 4-benzoxazin-8-yl) ethyl ] amino ] methyl ] -6-methoxy-indolin-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-trifluoroaceticacid

[1- [3- (5-formyl-6-methoxy-indolin-1-yl) -3-oxo-propyl ] -4-piperidinyl ] N- (2-phenylphenyl) carbamate (1B) (0.400g,0.758mmol) was dissolved in tetrahydrofuran (2mL) and methanol (10mL), 8- [ (1R) -2-amino-1-hydroxy-ethyl ] -5-hydroxy-4H-1, 4-benzooxan-3-one (7A, prepared in reference WO2009098448A 1) (0.170g,0.758mmol) was added, anhydrous zinc chloride (0.413g,3.03mmol) was added, and the reaction was carried out at 55 ℃ for 1 hour. Sodium cyanoborohydride (0.143g,2.27mmol) was added and reacted at 55 ℃ for 2 hours. Dichloromethane (50mL) was added to the reaction solution, and a saturated aqueous solution of sodium hydrogencarbonate (50mL) was added to the reaction solution to conduct extraction. The aqueous phase was extracted with methanol/dichloromethane (v/v ═ 1/10,30mL × 3), the organic phases were combined, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Slurried with dichloromethane (30mL), the solid was isolated and purified using a liquid preparative column (liquid preparative conditions: C18 reverse phase preparative column with mobile phase of 0.05% TFA in deionized water (a), acetonitrile (B), isocratic elution of B: a ═ 25%, elution time 20 minutes) to give the title compound [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-piperidinyl ] N- (2-phenylphenyl) carbamate bistrifluoroacetate salt (compound 7), white solid (0.020g, 3.6% yield).

¹H NMR(400MHz,CD₃OD)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(376MHz,CD₃OD)δ-75.45。

LCMS m/z＝368.6[M/2+1]。

Example 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-piperidinyl ] N- (2-phenylphenyl) carbamate bistrifluoroacetate salt (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 is as follows: (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) was dissolved in ethanol (10mL) and water (10mL), and sodium hydroxide (0.64g,16mmol) was added and the reaction was refluxed at 90 ℃ for 2 hours. Methylene chloride (30mL) and water (30mL) were added to the reaction mixture, followed by 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 give the title compound (1R) -2-amino-1- (2, 2-dimethyl-4H-1, 3-benzodioxan-6-yl) ethanol (8B) as a yellow solid (1.6g, 89% yield).

¹H NMR(400MHz,CDCl₃)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 is that: [1- [3- [5- [ [ [ (2R) -2- (2, 2-dimethyl-4H-1, 3-benzodioxol-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-indolin-1-yl) -3-oxo-propyl ] -4-piperidinyl ] N- (2-phenylphenyl) 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, followed by addition of anhydrous zinc chloride (0.413g,3.03mmol) and reaction at 55 ℃ for 1 hour. Sodium cyanoborohydride (0.143g,2.27mmol) was added and reacted at 55 ℃ for 2 hours. Methylene chloride (30mL) and water (30mL) were added to the reaction mixture, followed by 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 residue was purified by silica gel column chromatography (methanol/dichloromethane (v/v) ═ 1:99 to 3:47) to give the title compound [1- [3- [5- [ [ [ (2R) -2- (2, 2-dimethyl-4H-1, 3-benzodioxol-6-yl) -2-hydroxy-ethyl ] amino ] methyl ] -6-methoxy-indolin-1-yl ] -3-oxo-propyl ] -4-piperidinyl ] N- (2-phenylphenyl) carbamate (8C) as a pale yellow solid (0.320g, yield 57.4%).

LCMS m/z＝368.4[M/2+1]。

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

[1- [3- [5- [ [ [ (2R) -2- (2, 2-dimethyl-4H-1, 3-benzodioxol-6-yl) -2-hydroxy-ethyl ] amino ] methyl ] -6-methoxy-indol-1-yl ] -3-oxo-propyl ] -4-piperidinyl ] N- (2-phenylphenyl) carbamate (8C) (0.220g,0.299mmol) was dissolved in dichloromethane (15mL), and trifluoroacetic acid (0.0683g,0.599mmol) was added and reacted at room temperature for 2 hours. The reaction mixture was extracted with saturated aqueous sodium bicarbonate (15 mL). The aqueous phase was extracted with dichloromethane (20 mL. times.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 residue was separated and purified by a liquid phase preparative column (liquid phase preparative conditions: C18 reverse phase preparative column, mobile phase of deionized water (a) containing 0.05% TFA, acetonitrile (B), isocratic elution B: a ═ 25%, elution time 20 minutes) to give the title compound [1- [3- [5- [ [ [ (2R) -2-hydroxy-2- [ 4-hydroxy-3- (hydroxymethyl) phenyl ] ethyl ] amino ] methyl ] -6-methoxy-indolin-1-yl ] -3-oxo-propyl ] -4-piperidinyl ] N- (2-phenylphenyl) carbamate bistrifluoroacetate salt (compound 8) as a white solid (0.040g, yield 19%).

¹H NMR(400MHz,CD₃OD)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(376MHz,CD₃OD)δ-75.35。

LCMS m/z＝348.3[M/2+1]。

Example 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-piperidinyl ] N- (2-phenylphenyl) carbamate bistrifluoroacetate salt (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), 8- [ (1R) -2-amino-1-hydroxy-ethyl ] -5-hydroxy-4H-1, 4-benzoxazin-3-one (7A) (0.124g,0.554mmol) was added, anhydrous zinc chloride (0.302g,2.22mmol) was added, and the reaction was carried out at 55 ℃ for 1 hour. Sodium cyanoborohydride (0.104g,1.66mmol) was added and reacted at 55 ℃ for 2 hours. The reaction mixture was extracted with dichloromethane (50mL) and saturated aqueous sodium bicarbonate (50 mL). The aqueous phase was extracted with methanol/dichloromethane (v/v ═ 1/10,30mL × 3), 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 a liquid phase preparative column (liquid phase preparative conditions: C18 reverse phase preparative column with mobile phase of deionized water (a) containing 0.05% TFA, acetonitrile (B), isocratic elution B: a ═ 25%, elution time 20 minutes) to give the title compound [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-piperidinyl ] N- (2-phenylphenyl) carbamate bistrifluoroacetate salt (compound 9), white solid (0.350g, 64.6% yield).

¹H NMR(400MHz,CD₃OD)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(376MHz,CD₃OD)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 ] carbamate bistrifluoroacetate salt (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 is as follows: 4-piperidinyl N- [2- (4-hydroxyphenyl) phenyl ] carbamate (10A)

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

4-piperidyl N- [2- (3-chloro-4-hydroxy-phenyl) phenyl ] carbamate (5G) (0.600G,1.73mmol) was dissolved in methanol (10mL), and 10% palladium on carbon (2.0G) was added to replace hydrogen, followed by reaction at room temperature for 24 hours under a hydrogen atmosphere. The reaction mixture was filtered with celite, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (methanol/dichloromethane (v/v) ═ 1:99 to 1:9) to give the title compound, 4-piperidyl N- [2- (4-hydroxyphenyl) phenyl ] carbamate (10A), as a yellow oil (0.47g, yield 87%).

¹H 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 is that: [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

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

¹H NMR(400MHz,CDCl₃)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-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 ] 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-butyldimethylsilyl) oxy) ethyl) -8-hydroxyquinolin-2 (1H) -one (1D) (0.318g,0.951mmol) was added, anhydrous zinc chloride (0.251g,1.84mmol) was added, and the reaction was carried out at 55 ℃ for 1 hour. Sodium cyanoborohydride (0.0867g,1.38mmol) was added and reacted at 55 ℃ for 2 hours. Methylene chloride (30mL) and water (30mL) were added to the reaction mixture, followed by 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. Methylene chloride (20mL) was added to the reaction mixture, and a saturated aqueous solution of sodium hydrogencarbonate (20mL) was added to the reaction mixture to conduct extraction. The aqueous phase was extracted with dichloromethane (20 mL. times.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 residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) ═ 1:1 to 1:0, methanol/dichloromethane (v/v) ═ 1:99 to 1:9) to give 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-indol-1-yl ] -3-oxo-propyl ] -4-piperidinyl ] N- [2- (4-hydroxyphenyl) phenyl ] carbamate (10C) as a yellow oil (0.20g, 50.4% yield).

LCMS m/z＝431.9[M/2+1]。

The fourth step: [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 ] carbamate bistrifluoroacetate salt (Compound 10)

[1- [3- [5- [ [ [ (2R) -2- [ tert-butyl (dimethyl) silyl ] oxy-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 ] carbamate (10C) (0.200g,0.232mmol) was dissolved in tetrahydrofuran (5mL), triethylamine trihydrofluoride salt (0.374g,2.32mmol) was added, and the reaction was carried out at room temperature for 24 hours. Dichloromethane (50mL) was added to the reaction mixture, and a 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. times.2) and the organic phases were combined. The organic phase was washed with a saturated aqueous solution of sodium chloride (20 mL. times.1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by a liquid preparative column (liquid preparative conditions: C18 reverse phase preparative column, mobile phase of deionized water (a) containing 0.05% TFA, acetonitrile (B), isocratic elution B: a ═ 25%, elution time 20 minutes) 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-indol-1-yl ] -3-oxo-propyl ] -4-piperidinyl ] N- [2- (4-hydroxyphenyl) phenyl ] carbamate bistrifluoroacetate salt (compound 10), white solid (0.060g, yield 27%).

¹H NMR(400MHz,CD₃OD)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-hydroxy-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)

[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-hydroxy-ethyl ] -4-hydroxy-3H- -1, 3-benzothiazol-2-one (6A) (0.57g,2.5mmol) were dissolved in a mixed solvent of dichloromethane (5mL) and methanol (5mL), stirred at room temperature for 30 minutes, sodium triacetoxyborohydride (0.42g, 2.0mmol) was added, and reacted at room temperature for 2 hours. Dichloromethane (10mL) was added, and the mixture was washed with a saturated sodium bicarbonate solution (20 mL. times.2), a saturated brine (20 mL. times.1), the organic phase was 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 to 1:20) to give the title compound 1- [3- [5- [ [ [ (2R) -2-hydroxy-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) as a light yellow solid (0.14g, yield 28.6%).

¹H NMR(400MHz,CD₃OD)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-hydroxy-2- (8-hydroxy-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 is as follows: 1- (4-bromobutyl) -6-methoxyindoline-5-carbaldehyde (12A)

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

Tetrabromobutyric acid (2g,10mmol) is dissolved in anhydrous dichloromethane (20mL), cooled to 0 ℃, oxalyl chloride (3g,30mmol) is added dropwise, stirred at low temperature for 30 minutes, concentrated, and dichloromethane (10mL) is added to obtain reaction solution 1; 6-Methoxyindoline-5-carbaldehyde (1f) (0.8g,5mmol) and triethylamine (1g,10mmol) were added to dichloromethane (20mL), cooled to 0 deg.C, and the reaction mixture 1 was added dropwise and reacted at low temperature for 0.5 hour. 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, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) ═ 0:1 to 1:2) to give the title compound 1- (4-bromobutyl) -6-methoxyindoline-5-carbaldehyde (12A) as a pale red solid (0.8g, 50% yield).

¹HNMR(400MHz,CDCl₃)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)。

LCMSm/z＝326.0[M+1]。

The second step is that: [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) were dissolved in a mixed solvent of acetonitrile/tetrahydrofuran (v/v) ═ 2/1 (15mL), and then triethylamine (0.5g,5mmol) and tetrabutylammonium iodide (0.2g,0.2mmol) were added and stirred in a microwave reactor for 7 hours. After concentration, the residue was dissolved in ethyl acetate (50mL), washed successively with water (50 mL. times.1) and a saturated sodium chloride solution (50 mL. times.1), the organic phase was 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) ═ 0:1 to 5:95) to give the title compound [1- [4- (5-formyl-6-methoxyindolin-1-yl) -4-oxobutyl ] -4-piperidinyl ] N- (2-phenylphenyl) carbamate (12B) as a pale yellow oil (0.11g, yield 8%).

LCMSm/z＝542.1[M+1]。

The third step: [1- [4- [5- [ [ [ (2R) -2- [ tert-butyl (dimethyl) silyl ] oxy-2- (8-hydroxy-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-phenylphenyl) 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) were dissolved in a mixed solvent (10mL) of methanol/dichloromethane (v/v ═ 1/1), stirred at room temperature for 1 hour, sodium triacetoxyborohydride (0.25g,1.2mmol) 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 (50 mL. times.1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound [1- [4- [5- [ [ [ (2R) -2- [ tert-butyl (dimethyl) silyl ] oxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] methyl ] -6-methoxyindolin-1-yl ] -4-oxobutyl ] -4-piperidinyl ] N- (2-phenylphenyl) carbamate (12C) as a pale yellow oil (0.11g, 63% yield).

LCMSm/z＝430.8[1/2M+1]。

The fourth step: [ [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-phenylphenyl) carbamate (Compound 12)

[1- [4- [5- [ [ [ (2R) -2- [ tert-butyl (dimethyl) silyl ] oxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] methyl ] -6-methoxyindolin-1-yl ] -4-oxobutyl ] -4-piperidinyl ] -N- (2-phenylphenyl) carbamate (12C) (0.11g,0.13mmol) was dissolved in dichloromethane (10mL), triethylamine trihydrofluoride salt (0.21g,1.3mmol) was added, reaction was allowed to proceed overnight at room temperature, the reaction solution was made alkaline with saturated sodium bicarbonate, extracted with 8% methanol/dichloromethane (v/v) (50 mL. times.1), and washed with saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/dichloromethane (v/v) ═ 0:1 to 1:9) to give 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-phenylphenyl) carbamate (compound 12) as a pale yellow solid (0.02g, 20% yield).

¹HNMR(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)。

LCMSm/z＝373.8[1/2M+1]。

Example 13: 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)

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 is as follows: 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-methoxyindoline-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-methoxy-indole-1-carboxylate (3C) (0.200g, 0.368mmol) was dissolved in anhydrous methanol (6mL), methylene chloride (3mL) 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) was added, and after stirring at room temperature for 1 hour, sodium triacetoxyborohydride (0.234g, 1.10mmol) was added, followed by reaction at room temperature for 2 hours. Dichloromethane (30mL) was added, and the mixture was washed with a saturated aqueous sodium bicarbonate solution (10mL × 3) and then with a saturated aqueous sodium chloride solution (10mL × 1), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol (v/v) ═ 1:0 to 19:1) to give 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-benzoxazin-8-yl) ethyl ] amino ] methyl ] -6-methoxyindoline-1-carboxylate (13B), pale yellow solid (0.19g, 60% yield).

¹HNMR(400MHz,CDCl₃)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)。

LCMSm/z＝433.7[M/2+1]。

The second step is that: 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)

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-methoxyindoline-1-carboxylate (13B) (0.19g, 0.22mmol) was dissolved in dichloromethane (3mL), triethylamine trihydrofluoride salt (0.71g, 4.4mmol) was added, and after the addition, the reaction was heated to 30 ℃ for 6 hours. Dichloromethane (20mL) was added, the pH was adjusted to 9 with a saturated aqueous solution of sodium bicarbonate, the aqueous layer was separated, the aqueous layer was extracted with dichloromethane (20mL × 3), the organic layers were combined, washed with a saturated aqueous solution of sodium chloride (10mL × 1), dried over anhydrous sodium sulfate, filtered, and the residue was concentrated under reduced pressure to give a filtrate, and the residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 1:0 to 93:7) to give 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 (0.078g, 47% yield).

¹HNMR(400MHz,CD₃OD)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)。

LCMSm/z＝376.7[M/2+1]。

Example 14: [1- [3- [6- [ [ [ (2R) -2-hydroxy- (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-piperidinyl ] N- (2-phenylphenyl) carbamate bistrifluoroacetate salt (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 is as follows: [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), 7- [ (1R) -2-amino-1- [ tert-butyl (dimethyl) silyl ] oxyethyl ] -4- [ tert-butyl (dimethyl) silyl ] oxy-3H-1, 3-benzothiazol-2-one (intermediate 2) (0.600g,1.32mmol) was added, anhydrous zinc chloride (0.554g,4.06mmol) was added, and the reaction was carried out at 55 ℃ for 1 hour. Sodium cyanoborohydride (0.191g,3.05mmol) was added and reacted at 55 ℃ for 2 hours. The reaction mixture was extracted by adding methylene chloride (50mL) and water (20mL), the aqueous phase was extracted with methylene chloride (30 mL. times.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 give the title compound [1- [3- [6- [ [ [ (2R) -2- [ 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), yellow solid (1.0g, 100% yield).

LCMS m/z＝490.9[M/2+1]。

The second step is that: [1- [3- [6- [ [ [ (2R) -2-hydroxy- (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-piperidinyl ] N- (2-phenylphenyl) carbamate bistrifluoroacetate salt (Compound 14)

[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) (1.0g,1.0mmol) was dissolved in tetrahydrofuran (5mL), triethylamine trihydrofluoride (1.6g,10mmol) was added, and the reaction was carried out at room temperature for 24 hours. Dichloromethane (20mL) was added to the reaction solution, a saturated sodium bicarbonate solution was added to adjust the pH to about 8, extraction was performed, the aqueous phase was extracted with dichloromethane (20 mL. times.2), the organic phases were combined, the organic phase was washed with a saturated common salt solution (20 mL. times.1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by a liquid phase preparative column (liquid phase preparative conditions: C18 reverse phase preparative column, mobile phase was deionized water (A) containing 0.05% TFA, acetonitrile (B), isocratic elution B: A. about.25%, elution time 20 minutes) to obtain the title compound [1- [3- [6- [ [ [ (2R) -2-hydroxy- (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-piperidinyl ] N- (2-phenylphenyl) carbamate bistrifluoroacetate (Compound 14) as a white solid (0.100g, 10% yield).

1H NMR(400MHz,CD₃OD)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(376MHz,CD₃OD)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 bistrifluoroacetate salt (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 is as follows: 6-methoxy-4H-1, 4-benzoxazine-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 deg.C, followed by potassium carbonate (22g,159mmol), and stirred at reflux for 3 hours. Ethyl acetate (200mL) and water (150mL) were added to the reaction mixture, followed by extraction, extraction of the aqueous phase with ethyl acetate (100 mL. times.1), combination of the organic phases, drying of the organic phase with saturated brine (200 mL. times.2) over anhydrous sodium sulfate, filtration, and concentration of the filtrate under reduced pressure to give the title compound 6-methoxy-4H-1, 4-benzoxazin-3-one (15B) as a brown solid (9.8g, 90% yield).

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 is that: 6-methoxy-3, 4-dihydro-2H-1, 4-benzoxazine (15C)

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

6-methoxy-4H-1, 4-benzoxazine-3-one (15B) (9.8g,55mmol) was dissolved in tetrahydrofuran (100mL) and reacted at 60 ℃ for 3 hours under nitrogen protection with lithium aluminum hydride (1.1g,71mmol) added at 0 ℃. Cooled to 0 ℃ and carefully added water to quench the reaction. Ethyl acetate (200mL) was added, the mixture was filtered through celite, the filtrate was dried over anhydrous sodium sulfate, the filtrate was filtered, and the filtrate was concentrated under reduced pressure to give the title compound 6-methoxy-3, 4-dihydro-2H-1, 4-benzoxazine (15C) as a brown oil (6.0g, 66% yield).

¹H NMR(400MHz,CDCl₃)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

6-methoxy-3, 4-dihydro-2H-1, 4-benzoxazine (15C) (5.5g,33mmol) was dissolved in ethyl acetate (50mL), and 1, 3-dibromo-5, 5-dimethylhydantoin (4.88g,17mmol) was added thereto at 0 ℃ to react at 0 ℃ for 2 hours. To the reaction solution was added a 15% potassium carbonate solution (100mL) and the mixture was stirred well. Ethyl acetate (50mL) was added, extraction was performed, the organic phase was dried over anhydrous sodium sulfate, filtration was performed, 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 to 1:9) to give the title compound 7-bromo-6-methoxy-3, 4-dihydro-2H-1, 4-benzoxazine (15D) as a brown oil (1.6g, 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) and, under nitrogen, a 2M solution of isopropyl magnesium chloride in tetrahydrofuran (3.6mL,7.2mmol) was added at-10 deg.C and the temperature was raised to 0 deg.C for 1 hour. 2.5M n-butyllithium in n-hexane (13mL,33mmol) was added at-25 ℃ and the reaction was carried out at-10 ℃ for 30 minutes. N, N-dimethylformamide (4.8g,66mmol) was added at-10 ℃ and the reaction was gradually warmed to room temperature for 0.5 hour. 5g of citric acid (5.0g) was added to water (50mL), the reaction solution was poured into the flask, ethyl acetate (50mL) was added, extraction was performed, the aqueous phase was extracted with ethyl acetate (50 mL. times.1), the organic phases were combined, the organic phase was dried over anhydrous sodium sulfate, filtration was performed, 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 to 1:4) to give the title compound 6-methoxy-3, 4-dihydro-2H-1, 4-benzoxazine-7-carbaldehyde (15E) as a yellow solid (0.420g, yield 35%).

¹H 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

6-methoxy-3, 4-dihydro-2H-1, 4-benzoxazine-7-carbaldehyde (15E) (0.42g,2.2mmol) was dissolved in ethyl acetate (30mL), and triethylamine (1.6g,16mmol) was added under nitrogen. Acrylic acid (0.39,5.4mmol) was added dropwise. After the temperature was raised to 40 ℃, 1-propylphosphoric anhydride (1.7,5.4mmol) was added dropwise and reacted at 80 ℃ for 4 hours. Ethyl acetate (20mL) and water (20mL) were added to the reaction mixture, and the mixture was extracted. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 6-methoxy-4-prop-2-enoyl-3, 4-dihydro-2H-1, 4-benzoxazine-7-carbaldehyde (15F) as a yellow solid (0.54g, 100% yield).

¹H 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]。

And a 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) (0.540g,2.18mmol) was dissolved in 2-methyltetrahydrofuran (10mL), piperidin-4-yl [1, 1' -biphenyl ] -2-ylcarbamate (1A) (0.647g,2.18mmol) was added, triethylamine (0.442g,4.37mmol) was added, and the mixture was reacted with microwave at 100 ℃ for 1 hour. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether (v/v) ═ 1:1 to 1:0, methanol: dichloromethane (v/v) ═ 3:97) to give the title compound [1- [3- (7-formyl-6-methoxy-2, 3-dihydro-1, 4-benzoxazin-4-yl) -3-oxo-propyl ] 4-piperidinyl ] N- (2-phenylphenyl) carbamate (15G) as a yellow solid (0.570G, yield 48%).

¹H NMR(400MHz,CDCl₃)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-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 (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) was added, and anhydrous zinc chloride (0.301G,2.21mmol) was added and reacted at 55 ℃ for 1 hour. Sodium cyanoborohydride (0.104g,1.66mmol) was added and reacted at 55 ℃ for 2 hours. The reaction mixture was extracted with dichloromethane (30mL) and saturated aqueous sodium bicarbonate (20 mL). The aqueous phase was extracted with dichloromethane (30 mL. times.1), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound [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-piperidinyl ] N- (2-phenylphenyl) carbamate (15H) as a yellow solid (0.450g, 94.6% yield).

LCMS m/z＝431.8[M/2+1]。

Eighth step: [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 bistrifluoroacetate salt (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-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 (15H) (0.450g,0.522mmol) was dissolved in tetrahydrofuran (5mL), triethylamine trihydrofluoride salt (0.841g,5.22mmol) was added, and the reaction was carried out at room temperature for 24 hours. A methanol/dichloromethane (v/v-1/10, 50mL) solution was added to the reaction solution, and a saturated sodium bicarbonate solution was added to adjust the pH to about 8, followed by extraction. The aqueous phase was extracted with methanol/dichloromethane (v/v ═ 1/10,20mL × 2), the organic phases were combined, the organic phase was washed with saturated brine (20mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Separation and purification of the residue by liquid phase preparative column (conditions for preparation of liquid phase: C18 reverse phase preparative column, mobile phase of deionized water (a) containing 0.05% TFA, acetonitrile (B), isocratic elution B: a ═ 25%, elution time 20 minutes) to give the title compound [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 bistrifluoroacetate salt (compound 15), white solid (0.120g, 23.6% yield).

¹H NMR(400MHz,CD₃OD)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(m 4H),3.28–3.04(m,6H),2.25-1.70(m,4H)。

¹⁹F NMR(376MHz,CD₃OD)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) carbamate (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 is as follows: 4-hydroxy-4-methyl-piperidine-1-carboxylic acid tert-butyl ester (16B)

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

N-tert-Butoxycarbonyl-4-piperidone (16A) (4g,20mmol) was dissolved in anhydrous tetrahydrofuran (20mL), cooled to 0 deg.C, 1.0M solution of methylmagnesium bromide in tetrahydrofuran (40mL) was added dropwise, allowed to react at room temperature for 2 hours, cooled to 0 deg.C, then saturated ammonium chloride solution was slowly added, ethyl acetate (200mL) and water (200mL) were added, extracted, the organic phase was washed with saturated sodium chloride solution (200 mL. times.1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound tert-butyl 4-hydroxy-4-methyl-piperidine-1-carboxylate (16B) as a pale yellow oil (4.0g, 92.5% yield).

¹H NMR(400MHz,CDCl₃)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 is that: 4-methyl-4- [ (2-phenylphenyl) carbamoyloxy ] piperidine-1-carboxylic acid tert-butyl ester (16C)

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

O-phenylamine (3.4g,20mmol) and triphosgene (3.0g,10mmol) were dissolved in anhydrous toluene (50mL), heated to 110 ℃ for reaction for 3 hours, concentrated, and then tetrahydrofuran (50mL) was added, and tert-butyl 4-hydroxy-4-methyl-piperidine-1-carboxylate (16B) (3.5g,16mmol) and triethylamine (4.0g,40mmol) were heated to reflux for reaction for 3 hours. The reaction mixture was cooled to room temperature, ethyl acetate (100mL) and sodium chloride solution (120mL) 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 give the title compound, tert-butyl 4-methyl-4- [ (2-phenylphenyl) carbamoyloxy ] piperidine-1-carboxylate (16C), as a yellow oil (6.6g, 100% yield).

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

Dissolving tert-butyl 4-methyl-4- [ (2-phenylphenyl) carbamoyloxy ] piperidine-1-carboxylate (16C) (6.6g,16mmol) in dichloromethane (40mL), adding trifluoroacetic acid (18g,160mmol), reacting at room temperature for 5 hours, cooling to 0 ℃, adjusting the pH to more than 7 with a saturated sodium bicarbonate solution, adding dichloromethane (50mL) and water (50mL), extracting and layering, washing the organic phase with a saturated sodium chloride solution (50mL × 1), drying over anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, separating and purifying the residue with silica gel column chromatography (methanol/dichloromethane (v/v) ═ 0:1 to 1:9) to obtain the title compound (4-methyl-4-piperidine) N- (2-phenylphenyl) carbamate (16D), yellow oil (0.77g, 15% yield).

¹H NMR(400MHz,CDCl₃)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-acyl-indoline-5-carbaldehyde (intermediate 1) (0.57g,2.5mmol) were dissolved in 2-methyltetrahydrofuran (20mL), triethylamine (0.50g,5.0mmol) was added, the mixture was placed in a microwave reactor, and the temperature was raised to 100 ℃ to react for 1 hour. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/dichloromethane (v/v) ═ 0:1 to 1:9) to give the title compound [1- [3- (5-formyl-6-methoxyindolin-1-yl) -3-oxo-propyl ] -4-methyl-4-piperidinyl ] N- (2-phenylphenyl) carbamate (16E) as a pale yellow solid (0.77g, yield 57%).

¹H NMR(400MHz,CDCl₃)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-hydroxy-2-oxo-1H-quinolin-5-yl) ethyl ] amino ] methyl ] -6-methoxyindolin-1-yl ] -3-oxo-propyl ] -4-methyl-4-piperidinyl ] 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) -8-hydroxyquinolin-2 (1H) -one (1D) (0.10g,0.30mmol) were dissolved in a methanol/dichloromethane (v/v ═ 1:1, 10mL) solution and reacted at room temperature for 1 hour, then sodium triacetoxyborohydride (0.2g,0.9mmol) was added and the reaction was continued for 2 hours. Dichloromethane (50mL) and water (50mL) were added to the reaction solution, the layers were separated by extraction, the organic phase was washed with a saturated sodium chloride solution (50mL × 1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/dichloromethane (v/v) ═ 0:1 to 1:9) to give 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-methoxyindolin-1-yl ] -3-oxo-propyl ] -4-methyl-4-piperidinyl ] N- (2-phenylphenyl) carbamate (16F), pale yellow solid (0.11g, 40% yield).

LCMS m/z＝430.8[M/2+1]。

And a sixth step: [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) carbamate (Compound 16)

[1- [3- [5- [ [ [ (2R) -2- [ tert-butyl (dimethyl) silyl ] oxy-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) carbamate (16F) (0.11g,0.13mmol) was dissolved in tetrahydrofuran (5mL), triethylamine trihydrofluoride salt (0.10g,0.65mmol) was added, and the reaction was allowed to proceed overnight at room temperature. The reaction solution was filtered, the filter cake was dissolved with 8% (v/v) methanol/dichloromethane solution (50mL), then saturated aqueous sodium bicarbonate solution was added to adjust the pH to basicity, the layers were extracted, the organic phase was washed with saturated sodium chloride solution (50 mL. times.1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound [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) carbamate (compound 16), pale yellow solid (0.04g, 40% yield).

¹H 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 example

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 Ham' S F12 medium (Invitrogen 12500-062) containing 10% Fetal Bovine Serum (FBS) (Gibico 10099-141), 400. mu.g/mL G418(sigma G5013) and 250. mu.g/mL Zeocin (Invitrogen ant-zn-5p) at 37 ℃ with 5% CO₂Culturing under the condition to achieve 90-100% fusion. Washing with PBS/5mM EDTA to separate cells, centrifuging, collecting, resuspending and counting the cells in 0.1% BSA (BOVOGEN BSAS 100) phenol red-free Ham's F12 medium (Invitrogen 11039-⁶cells/mL. 15mL of the cell suspension was added to a 50mL centrifuge tube and Coelenterazine-h (Promega S2011) was added to a final concentration of 5. mu.M. Wrapped with tinfoil and protected from light, and incubated for 4 hours at 20 ℃ on a rotary shaker. The cells were then diluted with 0.1% BSA/phenol red free Ham's F12 medium to a final concentration of 5.0X 10⁵cells/mL, cells were placed on a rotary shaker and spun at low speed and incubated at room temperature for at least 1 hour. Examples of the inventionInhibitors were made as 10mM stock in DMSO, gradient diluted (log (M): 7, -8, -9, -10, -11) in 0.1% BSA/phenol red free Ham's F12 medium, and added to 96-well plates at 50. mu.L per well. A further 50. mu.L of cell suspension (25000 cells/well) was added to each well and incubated for 15 minutes at room temperature. The 96-well plate was placed in a microplate reader (Perkin Elmer, Envision), a solution of acetylcholine chloride (Sigma A6625) was added at a concentration of 112.92nM (hM3) with a microplate reader applicator, luminescence was recorded for 20 seconds, and IC was calculated and analyzed using origin7.5₅₀. Inhibitory Activity of the Compounds of the invention at human muscarinic receptors the IC determined by the above assay₅₀The values are given in table 1 below.

Table 1 results of the inhibitory activity of the test compounds on human muscarinic M3 receptor

And (4) conclusion: the compound has obvious inhibition activity on human muscarinic M3 receptor.

Test example 2: agonistic activity at the human adrenergic beta 2 receptor

Agonist 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 (h.beta.2) were cultured in MEM-alpha medium (Invitrogen12561-056) containing 10% Fetal Bovine Serum (FBS) (Gibico 10099-141) and 250. mu.g/mL Zeocin (InvivGen ant-zn-5p) at 37 ℃ and 5% CO₂Culturing under the condition, and detecting the cAMP agonism of the examples by using a LANCE Ultra cAMP Assay kit (PerkinElmer TRF0263) after 90-100% fusion is achieved. The cells were detached with PBS/5mM EDTA, harvested by centrifugation, resuspended in Stimulation Buffer (1 XHBSS, 5mM HEPES,0.5mM IBMX, 0.1% BSA, pH7.4), and adjusted to 6X10 cell concentration⁵cells/ml. The inhibitors of the examples were made up in 10mM stock solution in DMSO and added to 384 well plates at 5. mu.l per well after dilution with a Ststimulation Buffer gradient. mu.L of cell suspension (3000 cells/well) was added to each well, and after incubation at room temperature for 30 minutes, 5. mu.l of 4 × Eu-cAMP concentrator working solution was added to each well, followed by 5. mu.l of 4 × Ulight-anti-cAMP working solution to each wellIncubate at room temperature for 1 hour. The TR-FRET was detected in 384 well plates using a microplate reader (Perkin Elmer, Envision) and EC was calculated and analyzed using origin7.5₅₀. The agonistic activity of the compound of the present invention on human adrenergic receptors was determined by the above experiment, and the EC was measured₅₀The values are shown in Table 2:

TABLE 2 results of agonist activity of test compounds at the human adrenergic beta 2 receptor

And (4) conclusion: the compounds of the present invention have significant agonist activity at the beta 2 adrenergic receptor.

Claims

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.
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-。
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.
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.
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-。
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
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:
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.
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.
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.
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.
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.
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.
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.
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.